Hypercalcemia

Introduction

Background

Hypercalcemia can result when too much calcium (Ca) enters the extracellular fluid (ECF) or when there is insufficient calcium excretion from the kidneys.

Calcium plays an important role in intracellular and extracellular metabolism controlling such processes as nerve conduction, muscle contraction, coagulation, electrolyte and enzyme regulation, and hormone release. Calcium metabolism, in turn, is tightly regulated by a series of hormones that affect not only the entry of calcium into the extracellular space from bone and the GI tract but also control its excretion from the kidneys.

Calcium hemostasis

Ninety-eight percent of body calcium is found in the skeleton; this is closely related to the extracellular concentration of calcium. Intracellular calcium is less than extracellular calcium by a factor of 100,000. Intracellular processes, including the activity of many enzymes, cell division, and exocytosis, are controlled by intracellular calcium. The primary mediator of the intracellular effects of calcium is the calcium-binding regulatory protein, calmodulin.

Plasma calcium is maintained despite its large movements across the gut, bone, kidney, and cells. Changes in calcium ions usually are accompanied by changes in total calcium in the ECF. In plasma, calcium exists in 3 different forms: (1) 50% as ionized or the biologically active form, (2) 45% bound to plasma proteins (mainly albumin), and (3) 5% complexed to phosphate and citrate. Because the proportion of bound calcium varies little within individuals, in the absence of severe acidosis or alkalosis, the amount of albumin is the major factor determining the amount of calcium that is bound.

Very little evidence suggests that intracellular stores of calcium contribute in any way to plasma calcium homeostasis. An exception is in the parathyroid gland, in which the intracellular concentration increases in response to changes in extracellular concentration, which in turn alters the rate of parathyroid hormone (PTH) secretion. Any decrease in extracellular calcium ion concentration leads to an increase in PTH secretion. PTH increases distal renal tubular reabsorption of calcium within minutes and stimulates osteoclast activity, with release of calcium from the skeleton within 1-2 hours. More prolonged PTH elevation stimulates 1alpha-hydroxylase activity in the proximal tubular cells, which leads to 1,25-dihydroxyvitamin D (1,25(OH)2 D3) production. All these mechanisms help to maintain the serum calcium level within normal limits.

A normal serum calcium level is 8-10 mg/dL (2-2.5 mmol/L) with some interlaboratory variation in the reference range, and hypercalcemia is defined as a serum calcium level greater than 10.5 mg/dL (>2.5 mmol/L).Hypercalcemia may be classified based on total serum and ionized calcium levels, as follows:

Mild: Total Ca 10.5-11.9 mg/dL (2.5-3 mmol/L) or Ionized Ca 5.6-8 mg/dL (1.4-2 mmol/L) Moderate: Total Ca 12-13.9 mg/dL (3-3.5 mmol/L) or Ionized Ca 5.6-8 mg/dL (2-2.5 mmol/L)

Hypercalcemic crisis: Total Ca 14-16 mg/dL (3.5-4 mmol/L) or Ionized Ca 10-12 mg/dL (2.5-3 mmol/L)

Only 1-2% of total body calcium is in the exchangeable form in circulation, and the rest forms part of the skeleton. Only one half of the exchangeable calcium is in the active ionized form with the remainder bound to albumin, globulin, and other inorganic molecules. Protein binding of calcium is influenced by pH with metabolic acidosis leading to increased ionized calcium from reduced protein binding, and alkalosis leading to reduced ionized calcium from increased protein binding. Because calcium binds to albumin and only the unbound (free or ionized) calcium is biologically active, the serum level must be adjusted for abnormal albumin levels.

For every 1-g/dL drop in serum albumin below 4 g/dL, measured serum calcium decreases by 0.8 mg/dL. Therefore, to correct for an albumin level of less than 4 g/dL, one should add 0.8 to the measured value of calcium for each 1-g/dL decrease in albumin. Without this correction, an abnormally high serum calcium level may appear to be normal.

A patient with a serum calcium level of 10.3 mg/dL but an albumin level of 3 g/dL appears to have a normal serum calcium level. However, when corrected for the low albumin, the real serum calcium value is 11.1 mg/dL (10.3 + 0.8), a more obviously abnormal level. Alternatively, serum free (ionized) calcium levels can be directly measured, negating the need for correction for albumin. Corrected calcium can be calculated using the following formula:

Corrected Ca = ([4 - plasma albumin in g/dL] X 0.8 + serum calcium)

Mild cases of hypercalcemia can be asymptomatic and are more often diagnosed incidentally from routine blood tests. Because calcium metabolism normally is tightly controlled by the body, even mild persistent elevations above normal signal disease and should be investigated.

Calcium is controlled by 2 mechanisms. These are (1) controlling or major regulatory hormones and (2) influencing hormones. Controlling or major regulatory hormones include PTH, calcitonin, and vitamin D. The image below reviews vitamin D metabolism. In the kidney, vitamin D and PTH stimulate the activity of the epithelial calcium channel and the calcium-binding protein (ie, calbindin) to increase active transcellular calcium absorption in the distal convoluted tubule. Influencing hormones include thyroid hormones, growth hormone, and adrenal and gonadal steroids.

Vitamin D metabolism.

Role of the calcium-sensing receptor

The calcium-sensing receptor (CaSR) is a G protein–coupled receptor, which allows the parathyroid chief cells, the thyroidal C cells, and the ascending limb of the loop of Henle (renal tubular epithelial cells) to respond to changes in the extracellular calcium concentration. The ability of the CaSR to sense the serum Ca++ is essential for the appropriate regulation of PTH secretion by the parathyroid glands and for the regulation of passive paracellular calcium absorption in the loop of Henle. Calcitonin secretion and renal tubular calcium reabsorption also are directly regulated by the action of Ca++ on the calcium receptor.1

The CaSR gene is located on band 3q13-q21 and encodes a 1078 amino acid protein. CaSR is expressed in many tissues. Three uncommon human disorders are due to abnormalities of the CaSR gene, (1) familial benign hypocalciuric hypercalcemia, (2) neonatal severe hyperparathyroidism, and (3) autosomal dominant hypocalcemiawith hypercalciuria.2,3 

Recent studies 

In a study of 90 patients with advanced head and neck squamous cell carcinoma (HNSCC), Alsirafy et al compared outcomes for those patients in the cohort who had hypercalcemia (46 patients) with those of patients who did not. The authors found that compared with nonhypercalcemic inpatients, inpatients with hypercalcemia had a higher rate of palliative care referrals. Moreover, during the final 3 months of patient follow-up, a greater percentage of individuals with hypercalcemia paid more than 1 visit to the emergency room and a larger proportion of hypercalcemic patients were hospitalized for at least 14 days.

The authors also determined that among the study's patients who were referred for palliative care, the median postreferral survival time for those with hypercalcemia was 43 days, while that for nonhypercalcemic patients was 128 days. Alsirafy et al concluded that if hypercalcemia in patients with HNSCC is detected and managed early, this may help to prevent hypercalcemia-associated symptoms and to reduce hospitalization time.4

Pathophysiology

Hypercalcemia affects nearly every organ system in the body, but it particularly affects the CNS and kidneys. Mild hypercalcemia may not produce any symptoms. With modest hypercalcemia, most patients begin to feel fatigued. With higher levels, patients may have anxiety, depression, personality changes, and confusion. With very high levels, somnolence, coma, and death may ensue. The CNS effects are thought to be due to the direct depressant effect of hypercalcemia.

Renal effects include nephrolithiasis from the hypercalciuria. Distal renal tubular acidosis may be observed, and the increase in urine pH and hypocitraturia also may contribute to stone disease. Nephrogenic diabetes insipidus occurs from medullary calcium deposition and inhibition of aquaporin-2, the arginine-vasopressin–regulated water channel. Renal function may decrease due to hypercalcemia-induced renal vasoconstriction or if hypercalcemia is prolonged from calcium deposition (nephrocalcinosis) and interstitial renal disease.

High calcium levels also affect the conducting system of the heart and cause cardiac arrhythmias. Calcium has a positive inotropic effect. Hypercalcemia also causes hypertension, presumably from renal dysfunction and direct vasoconstriction.

The GI manifestations of hypercalcemia include anorexia, nausea, vomiting, and constipation. Prolonged hypercalcemia tends to cause high gastrin levels, which may contribute to peptic ulcer disease and may lead to pancreatitis or the deposition of calcium in any soft tissue. This deposition of calcium is especially prevalent if phosphorous levels also are elevated, as in renal failure.

The severity of symptoms is related not only to the absolute calcium level but also to how fast the rise in serum calcium occurred. Serum calcium levels greater than approximately 15 mg/dL usually are considered to be a medical emergency and must be treated aggressively.

Frequency

United States

Hypercalcemia is relatively common and often is mild but of long duration. The incidence of hyperparathyroidism alone is approximately 1-2 cases per 1000 adults. Mild cases are often not diagnosed.

International

Screenings of large groups of patients have found prevalence rates as high as 39 cases per 1000 persons in Scandinavia. Similar screenings in South Africa showed a prevalence of 8 cases per 1000 persons. These higher incidences may reflect underdiagnosis in the United States rather than a true difference in prevalence.

Mortality/Morbidity

Morbidity and mortality from hypercalcemia depend entirely on the cause.

Hypercalcemia from hyperparathyroidism tends to be mild and prolonged. Morbidity is related to the resultant bone disease. Because this condition is underdiagnosed so often, actual morbidity is unknown. Mild hypercalcemia rarely, if ever, leads directly to death.

Hypercalcemia caused by a neoplasm tends to be much more serious. The mechanism of hypercalcemia in malignancy can be from the ectopic production of a PTH-like factor, PTH-related protein (PTHrP), or osteolytic metastases. Often, the hypercalcemia is the immediate cause of death in patients with ectopic PTHrP production. These patients rarely survive more than a few weeks or months. Osteolytic metastases tend to cause morbidity and mortality from nerve compression and other orthopedic complications. These patients may live longer but still have a poor prognosis, especially if their serum calcium levels are very high.

Morbidity and mortality associated with hypercalcemia from other causes are directly related to the underlying cause and tend to be less serious. In these patients, hypercalcemia is a reflection of their disease state and morbidity and mortality depend on control of the underlying disease.

Sex

Some studies show a higher incidence in men compared to women, but this difference tends to diminish with increasing age. One study found the highest incidence to be in women aged 60-63 years.

Age

Hypercalcemia from nearly all causes increases with advancing age, especially the 2 most common causes, malignancy and hyperparathyroidism. However, hypercalcemia may occur in persons of any age.

Clinical

History

The mnemonic "stones," "bones," "abdominal moans," and "psychic groans" describes the constellation of symptoms and signs of hypercalcemia. These may be due directly to the hypercalcemia, to increased calcium and phosphate excretion, or to skeleton changes. The history of hypercalcemia is dependent on its cause and the sensitivity of the individual to higher calcium levels. Individuals with mild prolonged hypercalcemia may have mild or no symptoms, or, they may have recurring problems such as kidney stones. Those with more sudden onset and severe hypercalcemia may experience dramatic symptoms, usually including confusion and lethargy, possibly leading quickly to death.

Central nervous system effects include the following:o Lethargy

o Weakness

o Confusion

o Coma

Renal effects include the following:

o Polyuria

o Nocturia

o Dehydration

o Renal stones

o Renal failure

Gastrointestinal effects include the following:

o Constipation

o Nausea

o Anorexia

o Pancreatitis

o Gastric ulcer

Cardiac effects include syncope from arrhythmias.

Physical

Most patients with hypercalcemia do not have any specific findings upon physical examination. Those with higher calcium levels may have findings that are more striking. Evidence of the underlying cause may be found, such as a suggestive breast mass in someone with hypercalcemia secondary to malignancy.

Nervous system findings include the following:o Confusion

o Hypotonia

o Hyporeflexia

o Paresis

o Coma

Renal findings include the following:

o Volume depletion

o Signs of renal failure

Gastrointestinal findings include the following:

o Fecal impaction (from constipation)

o Signs of pancreatitis

o Signs of malignancy (eg, enlarged liver or masses)

Cardiac findings include the following:

o Arrhythmias

o Hypotension

o Shortened QT interval

General findings may include band keratopathy, which is calcium precipitation in a horizontal band across the cornea in the palpebral aperture.

Causes

Approximately 90% of cases of hypercalcemia are caused by malignancy or hyperparathyroidism. About 20-30% of patients with cancer have hypercalcemia during the course of the disease, and its detection may signify an unfavorable prognosis. Of the cases due to malignancy, approximately 80% are due to bony metastases, while the other 20% are due to PTHrP effects. Hypercalcemia secondary to malignancy may be classified into the following 4 types, based on the mechanism involved:

Humoral hypercalcemia of malignancy (HHCM) from an increased secretion of PTHrP - Most common form, accounting for up to 80% of cases

Osteolytic hypercalcemia from osteoclastic activity and bone resorption surrounding the tumor tissue - The second most common mechanism, accounting for about 20% of cases

Secretion of active vitamin D by some lymphomas

Ectopic PTH secretion - Very rare

The remaining 10% of cases of hypercalcemia are caused by many different conditions, including vitamin D–related problems, disorders associated with rapid bone turnover, thiazides or renal failure, and in rare cases, familial causes.

Causes of hypercalcemia that are related to malignancy (lung, breast, and myeloma are the most common tumors) include the following:

o Solid tumor metastases

o Solid tumors with humoral effects

o Hematologic malignancies

Causes of hypercalcemia that are related to the parathyroid include the following:

o Primary hyperparathyroidism

Solitary adenoma

Generalized hyperplasia

Multiple endocrine neoplasia type 1 or type 2A

o Lithium-related release of PTH

o Familial cases of high PTH

Those related to vitamin D include the following:

o Vitamin D toxicity

o Granulomatous disease (especially sarcoidosis)

Those related to high bone turnover include the following:

o Hyperthyroidism

o Immobilization (especially in Paget disease)

o Thiazides

o Vitamin A intoxication

Renal failure (milk-alkali syndrome)

Other causes related to particular mechanisms are as follows:

o Increased intestinal calcium absorption

Idiopathic infantile hypercalcemia (Williams syndrome)

Vitamin D intoxication

Vitamin A intoxication

Granulomatous disorders, eg, sarcoidosis

o Decreased renal calcium excretion

Hyperparathyroidism

Familial hypocalciuric hypercalcemia

Thiazide diuretics

o Increased bone resorption

Immobilization

Hyperparathyroidism

Malignancy

o Mutations of the calcium-sensing receptor

Familial benign hypocalciuric hypercalcemia

Neonatal severe hyperparathyroidism

o Uncertain mechanism

Hypophosphatasia

Subcutaneous fat necrosis

Blue diaper syndrome

Dietary phosphate deficiency

Hyperchloremic Acidosis

Introduction

Background

This article covers the pathophysiology and causes of hyperchloremic metabolic acidoses, in particular the renal tubular acidoses (RTAs). It also addresses approaches to the diagnosis and management of these disorders.

A low plasma bicarbonate concentration represents, by definition, metabolic acidosis, which may be primary or secondary to a respiratory alkalosis. Primary metabolic acidoses can occur as a result of a marked increase in endogenous acid production (eg, lactic or keto acids), loss of bicarbonate stores through diarrhea or renal tubular wasting, or progressive accumulation of endogenous acids when excretion is impaired by renal insufficiency.

The initial differentiation of metabolic acidosis should involve a determination of the anion gap (AG). This is usually defined as AG = (Na+) - [(HCO3 - + Cl-)], in which Na+ is sodium concentration, HCO3 - is bicarbonate concentration, and Cl- is chloride concentration; all concentrations are in mmol/L. It represents the difference between unmeasured cations and anions. This difference is due to the presence of anions in the plasma that are not routinely measured.

An increased AG is associated with renal failure, ketoacidosis, lactic acidosis, and ingestion of various toxins; it can usually be easily identified by evaluating routine plasma chemistry results and from the clinical picture. A normal AG acidosis is characterized by a lowered bicarbonate concentration, which (in the presence of a normal sodium concentration) is counterbalanced by an equivalent increase in plasma chloride concentration. For this reason, it is also known as hyperchloremic metabolic acidosis.

This finding suggests that HCO3 - has been effectively replaced by Cl- and arises from one of the following conditions1,2 :

Bicarbonate loss from body fluids through the GI tract or kidneys, with subsequent chloride retention

Defective renal acidification with failure to excrete normal quantities of metabolically produced acid (The conjugate base is excreted as the sodium salt and sodium chloride is retained.)

Addition of hydrochloric acid to body fluids

Addition or generation of another acid with rapid titration of bicarbonate and rapid renal excretion of the accompanying anion and replacement by chloride

Rapid dilution of the plasma bicarbonate by saline

Pathophysiology

Gastrointestinal

Diarrhea is the most common cause of external loss of alkali resulting in metabolic acidosis. Biliary, pancreatic, and duodenal secretions are alkaline and are capable of neutralizing the acidity of gastric secretions. In normal situations, a luminal Na+/H+ exchanger in the jejunal mucosa effectively results in sodium bicarbonate (NaHCO3) reabsorption, and the 100 mL of stool excreted daily has very small amounts of bicarbonate.

The development of diarrheal states and increased stool volume (potentially several L/d) may cause a daily loss of several hundred millimoles of bicarbonate. Some of this loss may not occur as bicarbonate loss itself; instead, intestinal flora produce organic acids that titrate bicarbonate, resulting in loss of organic anions in the stool stoichiometrically equivalent to the titrated bicarbonate. Because diarrheal stools have a higher bicarbonate concentration than plasma, the net result is a metabolic acidosis with volume depletion.

Other GI conditions associated with external losses of fluids may lead to large alkali losses. These include enteric fistulas and drainage of biliary, pancreatic, and enteric secretions; ileus secondary to intestinal obstruction, in which up to several liters of alkaline fluid may accumulate within the intestinal lumen; and villous adenomas that secrete fluid with a high bicarbonate content.

Renal

The kidneys maintain acid-base balance by bicarbonate reclamation and acid excretion. Most conditions that affect the kidneys cause a proportionate simultaneous loss of glomerular and tubular function. Loss of glomerular function results in the retention of many products of metabolism, including the anions of various organic and inorganic acids and urea. Loss of tubular function prevents the kidneys from excreting hydrogen ions and thereby causes metabolic acidosis. The development of azotemia, anion retention, and acidosis is defined as uremic acidosis. The term hyperchloremic acidosis (ie, RTA) refers to a diverse group of tubular disorders, uncoupled from glomerular damage, characterized by impairment of urinary acidification without urea and anion retention. These disorders can be divided into 2 general categories, proximal (type II) and distal (types I and IV).

Proximal renal tubular acidosis (type II [bicarbonate-wasting acidosis])o The proximal tubule is the major site for reabsorption of filtered bicarbonate. In proximal

RTA (pRTA), bicarbonate reabsorption is defective. pRTA rarely occurs as an isolated defect of bicarbonate transport and is usually associated with multiple proximal tubule transport defects; therefore, urinary loss of glucose, amino acids, phosphate, uric acid, and other organic anions such as citrate can also occur (Fanconi syndrome).

o A distinctive feature of type II pRTA is that it is nonprogressing, and when the serum

bicarbonate is reduced to approximately 15 mEq/L, a new transport maximum is established and the proximal tubule is able to reabsorb all of the filtered bicarbonate. A fractional excretion of bicarbonate greater than 15% when the plasma bicarbonate is normal after bicarbonate loading is diagnostic of pRTA. In contrast, the fractional excretion of bicarbonate in low and normal bicarbonate levels is always less than 5% in

distal RTA (dRTA). Another feature of pRTA is that the urine pH can be lowered to less than 5.5 with acid loading.

o The pathogenic mechanisms responsible for the tubular defect in persons with pRTA are

not completely understood. Defective pump secretion or function, namely the proton pump ([H+adenosine triphosphatase [ATPase]),3 the Na+/H+ antiporter, and the basolateral membrane Na+/K+ATPase, impair bicarbonate reabsorption. Deficiency of carbonic anhydrase (CA) in the brush-border membrane or its inhibition also results in bicarbonate wasting. Finally, structural damage to the luminal membrane with increased bicarbonate influx or a failure of generated bicarbonate to exit is a proposed mechanism that does not currently have strong experimental backing.

Distal renal tubular acidosis

o The distal nephron, primarily the collecting duct, is the site at which urine pH reaches its

lowest values. Inadequate acid secretion and excretion produce a systemic acidosis. A metabolic acidosis occurring secondary to decreased renal acid secretion in the absence of marked decreases in the glomerular filtration rate and characterized by a normal AG is due to diseases that are usually grouped under the term dRTA. These are further classified into hypokalemic (type I) and hyperkalemic (type IV) RTA. Until the 1970s, dRTA was thought to be a single disorder caused by an inability to maintain a steep H+ gradient across the distal nephron, either as a failure to excrete H+ or as a result of increased back-diffusion of H+ through an abnormally permeable distal nephron. Structural damage to the nephron from a variety of sources has been shown to result in different pathogenic mechanisms.

o Excretion of urinary ammonium (NH4+) accounts for the largest portion of the kidneys'

response to the accumulation of metabolic acids. Patients with dRTA are unable to excrete ammonium in amounts adequate to keep pace with a normal rate of acid production. In some forms of the syndrome, maximally acidic urine can be formed, indicating the ability to establish a maximal H+gradient. However, despite the maximally acidic urine, the total amount of ammonium excretion is low. In other forms, urine pH cannot reach maximal acidity despite systemic acidemia, indicating low H+ secretion in the collecting duct.

o In the presence of systemic acidemia, a low rate of urinary ammonium secretion is

related either to decreased production of ammonia by the cells of the proximal convoluted tubule or to failure to accumulate ammonium in the distal convoluted tubule and excrete it in the urine. Decreased ammonium production is observed in hyperkalemic types of dRTA, also known as type IV RTA, because hyperkalemia causes an intracellular alkalosis with resultant impairment of ammonium generation and excretion. Acid secretion is thus reduced because of the deficiency of urinary buffers. This type of acidosis is also observed in early renal failure, due to a reduction in renal mass and decreased ammonium production in the remaining proximal tubular cells.

Hypokalemic (classic) distal renal tubular acidosis (type I): In hypokalemic dRTA, also known as classic RTA or type I RTA, the deficiency is secondary to 2 main pathophysiological mechanisms, (1) a secretory defect and (2) a permeability defect.

When a secretory defect predominates, the decreased secretion of protons fails to maximally decrease the urinary pH. A decrease in the formation of titratable acidity and in ammonium trapping and secretion results in systemic acidosis. The mechanism of the hypokalemia is unclear, but hypotheses include (1) increased leakage of K+ into the lumen, (2) volume contraction due to urinary sodium loss and resulting in aldosterone stimulation that increases potassium losses, and (3) decreased proximal K+ reabsorption due to acidemia and hypocapnia.

When a permeability defect predominates, the collecting-duct proton pump functions normally but the high intratubular concentration of H+ dissipates due to abnormal permeability of the tubular epithelium.

Hyperkalemic distal renal tubular acidosis (type IV): The pathogenesis of hyperkalemic dRTA, the most common RTA, is ascribed to 2 mechanisms, (1) a voltage defect or (2) a rate defect due to aldosterone deficiency or resistance.

The voltage-related type is more rare and is thought to be caused by inadequate negative intratubular potential at the cortical collecting duct. This, in turn, causes inadequate secretion of protons and potassium, with decreased trapping and excretion of ammonium and decreased excretion of potassium. Inadequate voltage generation may be secondary to several factors, including (1) administration of certain drugs, such as amiloride; (2) structural defects that inhibit active sodium reabsorption, such as sickle cell nephropathy; (3) severe limitation of sodium reabsorption in the distal tubule because of proximal sodium avidity, secondary to diseases such as cirrhosis; and (4) increased epithelial permeability to chloride, causing increased reabsorption and preventing the negative voltage linked to sodium reabsorption.

The more common form of hyperkalemic dRTA is due to aldosterone resistance or deficiency. Postulated mechanisms include (1) destruction of juxtaglomerular cells; (2) decreased sympathetic denervation of the juxtaglomerular apparatus; (3) decreased production of prostacyclin, causing a decrease in renin-aldosterone production; (4) primary hypoaldosteronism; and (5) secondary hypoaldosteronism from the long-term use of heparin. Aldosterone increases Na+ absorption and the negative intratubular potential. It also increases luminal membrane permeability to potassium and stimulates basolateral Na+/K+/ATPase,3 causing increased urinary potassium losses. Because aldosterone also directly stimulates the proton pump, aldosterone deficiency or resistance would be expected to cause hyperkalemia and acidosis. Another major factor in decreasing net acid excretion is the inhibition of ammoniagenesis due to hyperkalemia.

Incomplete distal renal tubular acidosis is another clinically important entity. It is considered a variant/milder form of type I RTA, in which the plasma bicarbonate concentration is normal, but there is a defect in tubular acid secretion. However, daily net acid excretion is maintained by

increased ammoniagenesis. Hypercalciuria and hypocitraturia are present, so there is a propensity to nephrolithiasis and nephrocalcinosis. Most of the cases are those of idiopathic calcium phosphate stone formers, relatives of individuals with RTA or with unexplained osteoporosis. Any idiopathic stone former should be evaluated (by NH4Cl infusion).

Miscellaneous

The administration of calcium chloride or cholestyramine (cationic resin that is given as chloride salt) may cause acidosis because of the formation of calcium carbonate or the bicarbonate salt of cholestyramine in the lumen of the intestine, which is then eliminated in the stool. Ureteral-GI connections, such as ureterosigmoidostomy for urinary diversion, also cause a potentially severe acidosis in virtually all patients.4 This acidosis results from the retention of urinary ammonium across the colonic mucosa and from the stool losses of bicarbonate. Because of this complication, ileal conduits have now largely replaced the procedure. However, hyperchloremic metabolic acidosis still occurs in approximately 10% of patients with ileal conduits, especially if obstruction is present.

The occurrence of metabolic acidosis with a normal AG is common in the late phase of diabetic ketoacidosis. This results from urinary loss of ketoanions with sodium and potassium. This external loss is equivalent to a loss of potential bicarbonate because each ketoanion, if retained and metabolized, would consume a proton and generate a new molecule of bicarbonate.

Infusion of large volumes of solutions containing sodium chloride and no alkali can cause a hyperchloremic metabolic acidosis. This is due to a dilution of the preexisting bicarbonate and to decreased renal bicarbonate reabsorption as a result of volume expansion.

In patients with a chronic respiratory alkalosis, renal acid secretion is decreased but endogenous acid production and chloride reabsorption are normal, resulting in a decreased plasma bicarbonate concentration and elevated chloride concentration. When the hypocapnia is repaired, the return of the PCO2 to normal unveils a metabolic acidosis.

Clinical

History

Metabolic acidosis, per se, has no specific symptoms and signs; however, it can produce symptoms and signs from changes in pulmonary, cardiovascular, neurologic, and musculoskeletal function. Patients may report dyspnea upon exertion or, in severe cases, at rest.

Physical

Although metabolic acidosis has no specific symptoms and signs, changes in pulmonary, cardiovascular, neurologic, and musculoskeletal function may produce signs.

General neurologico If the acidosis is marked and of acute onset, the patient may report headache, lack of

energy, nausea, and vomiting.

o Neurologic abnormalities such as mental confusion progressing to stupor, when

observed, are not usually secondary to the acidosis but are the cause of the acidosis itself.

o In general, neurologic abnormalities are less common in persons with metabolic acidosis

than in persons with respiratory acidosis.

Pulmonary

o An increase in minute ventilation of up to 4- to- 8-fold may occur in persons with

respiratory compensation.

o Tachypnea or hyperpnea (affecting the depth more than the rate of ventilation) may be

the only clue to an underlying acidotic state.

Cardiovascular

o Effects on the cardiovascular system include direct impairment of myocardial contraction

(especially at a pH <7.2), tachycardia, and increased risk of ventricular fibrillation or heart failure with pulmonary edema.

o In advanced stages, overt cardiovascular collapse may occur from impaired

catecholamine release.

Musculoskeletal

o Chronic acidemia, as is observed in RTA, can lead to a variety of skeletal problems. This

is probably due in part to the release of calcium and phosphate during bone buffering of the excess protons. Decreased tubular absorption of calcium secondary to acidemia, especially in dRTA, leads to a negative calcium balance.

o Clinical consequences include osteomalacia (leading to impaired growth in children),

osteitis fibrosa (from secondary hyperparathyroidism), rickets (in children), and osteomalacia or osteopenia (in adults).

Genitourinary

o An important complication of chronic renal tubular acidosis (mainly distal, type I) is

nephrocalcinosis and urolithiasis. A number of pathophysiological alterations contribute to stone formation.

Buffering of the chronic acid load by the bone, causing bone dissolution and promoting hypercalciuria

Diminution of renal tubular calcium reabsorption, further aggravating the hypercalciuria

Hypocitraturia because of avid citrate reabsorption by the proximal tubule

High urinary pH, causing insolubility of calcium phosphate and promoting its precipitation

o In contrast, stone disease is rare with type 2 RTA because of the difference in its

pathogenesis. Since the fall in plasma HCO3 is nonprogressive, after the renal HCO3 threshold is reached, there is complete absorption of luminal HCO3. At this point, the urine pH is acid, since urine is devoid of HCO3 and there is no defect in distal proton secretion. The daily acid load is thus excreted by the collecting duct, obviating the need for bone buffering. Also, citrate usually escapes proximal reabsorption (along with other solutes) and promotes calcium phosphate solubility.

Causes

GI bicarbonate losso Diarrhea may be caused by external pancreatic, biliary, or small bowel drainage; an ileus;

a ureterosigmoidostomy; a jejunal loop; or an ileal loop, which may result in persons with hyperchloremic metabolic acidosis.

o Drugs that increase GI bicarbonate loss include calcium chloride, magnesium sulfate,

and cholestyramine.

Proximal renal tubular acidosis

o Causes of proximal tubular bicarbonate wasting are numerous. A selective defect (eg,

isolated bicarbonate wasting) can occur as a primary disorder (with no obvious associated disease) that can be genetically transmitted or occur in transient form in infants.

o Alterations in CA activity through drugs such as acetazolamide, sulfanilamide, and

mafenide acetate produce bicarbonate wasting. Osteopetrosis with CA II deficiency and genetically transmitted and idiopathic CA deficiency also fall into the selective defect category. A generalized proximal tubule defect associated with multiple dysfunctions of the proximal tubule can also occur as a primary disorder in sporadic and genetically transmitted forms. It also occurs in association with genetically transmitted systemic diseases, including Wilson disease, cystinosis and tyrosinemia, Lowe syndrome, hereditary fructose intolerance, pyruvate carboxylase deficiency, metachromatic leukodystrophy, and methylmalonic acidemia.

o pRTA is also observed in conditions associated with chronic hypocalcemia and

secondary hyperparathyroidism, such as vitamin D deficiency or vitamin D resistance. Dysproteinemic states, such as multiple myeloma and monoclonal gammopathy, are also associated with pRTA.

o Drugs or toxins that can induce pRTA include streptozotocin, lead, mercury, arginine,

valproic acid, gentamicin, ifosfamide, and outdated tetracycline.

o Renal tubulointerstitial conditions that are associated with pRTA include renal

transplantation, Sjögren syndrome, and medullary cystic disease. Other renal causes include nephrotic syndrome and amyloidosis.

o Paroxysmal nocturnal hemoglobinuria and hyperparathyroidism can also cause pRTA.

o A summary of the causes of pRTA (type II) is as follows:

Primary - Familial or sporadic

Dysproteinemic states - Multiple myeloma (both pRTA and dRTA), amyloidosis (both pRTA and dRTA), light chain disease, cryoglobulinemia, monoclonal gammopathy

CA-related conditions - Osteopetrosis (anhydrase II deficiency), acetazolamide, mafenide

Drug or toxic nephropathy - Lead, cadmium, mercury, streptozotocin, outdated tetracycline, ifosfamide (both pRTA and dRTA)

Hereditary disorders - Cystinosis, galactosemia, Wilson disease, hereditary fructose intolerance, glycogen storage disease type I, tyrosinemia, Lowe syndrome

Interstitial renal conditions - Sjögren syndrome, medullary cystic disease (both pRTA and dRTA), Balkan nephropathy, renal transplant rejection (both pRTA and dRTA)

Miscellaneous - Paroxysmal nocturnal hemoglobinuria, malignancy, nephrotic syndrome, chronic renal vein thrombosis

Hypokalemic (classic) distal renal tubular acidosis (type I)

o Primary dRTA has been described in both sporadic and genetically transmitted forms.

Autoimmune disorders such as hypergammaglobulinemia, cryoglobulinemia, Sjögren syndrome, thyroiditis, pulmonary fibrosis, chronic active hepatitis, primary biliary cirrhosis, systemic lupus erythematosus, and vasculitis can be associated with dRTA. dRTA can be secondary to genetically transmitted systemic diseases, including Ehlers-Danlos syndrome, hereditary elliptocytosis, sickle cell disease, Marfan syndrome, CA I deficiency or alteration, medullary cystic disease, and neuroaxonal dystrophy.

o Disorders associated with nephrocalcinosis that cause hypokalemic dRTA include

primary or familial hyperparathyroidism, vitamin D intoxication, milk-alkali syndrome, hyperthyroidism, idiopathic hypercalciuria, hereditary fructose intolerance, Fabry disease, and Wilson disease.

o Drugs or toxins that can cause dRTA include amphotericin B, toluene, nonsteroidal anti-

inflammatory drugs, lithium, and cyclamate.

o Renal tubulointerstitial conditions associated with dRTA include chronic pyelonephritis,

obstructive uropathy, renal transplantation, leprosy, and hyperoxaluria.

o A summary of the causes of dRTA (type I) is as follows:

Primary - Idiopathic, isolated, sporadic

Tubulointerstitial conditions - Renal transplantation, chronic pyelonephritis, obstructive uropathy, leprosy

Genetic - Familial, Marfan syndrome, Wilson disease, Ehlers-Danlos syndrome, medullary cystic disease (dRTA and pRTA), osteopetrosis

Conditions associated with nephrocalcinosis - Hyperoxaluria, primary hypercalciuria, hyperthyroidism, primary hyperparathyroidism, vitamin D intoxication, milk-alkali syndrome, medullary sponge kidney

Autoimmune disorders - Chronic active hepatitis, primary biliary cirrhosis, Sjögren syndrome (dRTA and pRTA), systemic lupus erythematosus, autoimmune thyroiditis, pulmonary fibrosis, vasculitis

Drugs and toxicity - Amphotericin B, analgesics, lithium, toluene, ifosfamide (dRTA and pRTA)

Hypergammaglobulinemic states - Myeloma (both dRTA and pRTA), amyloidosis (dRTA and pRTA), cryoglobulinemia

Miscellaneous - Hepatic cirrhosis, AIDS (possibly)

Hyperkalemic distal renal tubular acidosis (type IV)

o Deficiency of or resistance to aldosterone is the most common cause of hyperkalemic

dRTA. Deficiency of aldosterone with glucocorticoid deficiency is associated with Addison disease, bilateral adrenalectomy, and enzymatic defects (eg, 21-hydroxylase deficiency, 3 beta-ol-dehydrogenase deficiency, desmolase deficiency). Isolated aldosterone deficiency can be secondary to states of deficient renin secretion, including diabetic nephropathy, tubulointerstitial renal disease, nonsteroidal anti-inflammatory drug use, beta-adrenergic blocker use, AIDS, and renal transplantation.

o Isolated aldosterone deficiency can also be observed secondary to heparin use; in

corticosterone methyl oxidase deficiency, a genetically transmitted disorder; and in a transient infantile form.

o Angiotensin1-converting enzyme inhibition, either endogenously or through ACE

inhibitors such as captopril, and the newer angiotensin AT1 receptor blockers can cause hyperkalemic dRTA.

o Resistance to aldosterone secretion is observed in pseudohypoaldosteronism, childhood

forms of obstructive uropathy, cyclosporine nephrotoxicity, renal transplantation, and the use of spironolactone.

o Voltage-mediated defects that cause hyperkalemic dRTA can be observed in obstructive

uropathy; sickle cell disease; and the use of lithium, triamterene, amiloride, trimethoprim, or pentamidine.

Hyperkalemia

Introduction

Background

Potassium homeostasis

Hyperkalemia is defined as a condition in which serum potassium greater than 5.3 mEq/L.

Potassium, the most abundant intracellular cation, is essential for the life of the organism. Potassium is obtained through the diet. Common potassium-rich foods include meats, beans, fruits, and potatoes. Gastrointestinal absorption is complete, resulting in daily excess intake of about 1 mEq/kg/d (60-100 mEq). This excess is excreted through the kidneys (90%) and the gut (10%). Potassium homeostasis is maintained predominantly through the regulation of renal excretion. The most important site of regulation is the distal nephron, including the distal convoluted tubule, the connecting tubule, and the cortical collecting tubule, where aldosterone receptors are present.

The regulation of potassium excretion at the cortical collecting tubule has been extensively studied. Sodium reabsorption through epithelial sodium channels (ENaC) located on the apical membrane of cortical collecting tubule cells, is driven by aldosterone and generates a tubular lumen negative electrical potential, driving the secretion of potassium at this site through specific potassium channels called the renal outer medullary K channels (ROMK). Studies have demonstrated, however that aldosterone also regulates sodium transport in the thick ascending limb of the loop of Henle, the distal convoluted tubule, and the connecting tubule.

A family of signaling molecules, the WNK (with no K [lysine]) kinases, play a critical role in the regulation of sodium and potassium transport in the distal nephron1 The WNK kinases are suspected to play a role in the pathogenesis of several forms of hypertension.2,3

Excretion is increased by the following:

Aldosterone High sodium delivery to the distal tubule (eg, diuretics)

High urine flow (eg, osmotic diuresis)

High serum potassium level

Delivery of negatively charged ions to the distal tubule (eg, bicarbonate)

Excretion is decreased by the following:

Absence of aldosterone Low sodium delivery to the distal tubule

Low urine flow

Low serum potassium level

Renal failure

Kidneys adapt to acute and chronic alterations in potassium intake. When potassium intake is chronically high, potassium excretion also is increased. In the absence of potassium intake, obligatory renal losses are 10-15 mEq/d. Thus, chronic losses occur in the absence of any ingested potassium. The kidney maintains a central role in the maintenance of potassium homeostasis, even in the setting of chronic renal failure. Renal adaptive mechanisms allow the kidneys to maintain potassium homeostasis until the glomerular filtration rate drops to less than 15-20 mL/min. Additionally, in the presence of renal failure, the proportion of potassium excreted through the gut increases.

The colon is the major site of gut regulation of potassium excretion. Therefore, potassium levels can remain relatively normal under stable conditions, even with advanced renal insufficiency. However, as renal function worsens, the kidneys may not be capable of handling an acute potassium load. An excess of only 100-200 mEq will increase the serum potassium concentration by about 1 mEq/L.4

Serum potassium level

Potassium is predominantly an intracellular cation; thus, serum potassium levels can be a very poor indicator of total body stores. Potassium moves easily across cell membranes; therefore, serum potassium levels reflect the movement of potassium between intracellular and extracellular fluid compartments as well as total-body potassium homeostasis. Several factors regulate the distribution of potassium between the intracellular and extracellular space.

Glucoregulatory hormoneso Insulin enhances potassium entry into cells.

o Glucagon impairs potassium entry into cells.

Adrenergic stimuli

o Beta-adrenergic stimuli enhance potassium entry into cells, whereas beta-blocking drugs

inhibit potassium entry into cells.

o Alpha-adrenergic stimuli impair potassium entry into cells.

pH

o Alkalosis  enhances potassium entry into cells.

o Acidosi  s causes shift of potassium from intracellular space into extracellular space.

Inorganic or mineral acid acidoses are more likely to cause a shift of potassium out of the cells than organic acidoses.

Shift from intracellular pool

o Acute increase in osmolality, such as hyperglycemia, causes potassium to exit from cells.

o Acute cell-tissue breakdown releases potassium into extracellular space.

The 2 sets of regulatory factors, those that regulate total-body homeostasis and those that regulate the distribution of potassium between intracellular and extracellular space, meld to create smooth control of potassium levels throughout the day. For example, a high-protein meal, such as a steak, may contain enough potassium to raise the serum potassium acutely to lethal levels if the potassium remained in the extracellular space. Although renal potassium excretion can increase fairly rapidly, this mechanism easily is overwhelmed by such an acute potassium load.

The acute hyperkalemic effect of an extremely potassium-rich meal is blunted substantially by the release of insulin, which causes potassium to be taken up into cells. The excessive potassium then can be excreted by the kidneys, allowing serum potassium levels to return to normal. This integrated regulatory process is manifested in the diurnal rhythm for renal potassium excretion. The highest excretion occurs at midday, approximately 18 hours after peak potassium ingestion at the evening meal.

Recent studies 

In a retrospective observational study of 27,355 patients with diabetes, Raebel et al investigated whether potassium monitoring could lower the rate of hyperkalemic adverse events in such patients after the initiation of renin-angiotensin-aldosterone system (RAAS) inhibitor therapy. (RAAS inhibitor treatment has been associated with the development of hyperkalemia.) Potassium levels were monitored in 19,391 of the study's patients, with the authors determining relative risks by comparing the incidence of serious hyperkalemia-associated adverse events in these patients (calculated in person-years) with those in unmonitored patients, during the first year of RAAS inhibitor treatment.

The investigators found the adjusted relative risk for the monitored patients to be 0.50. Monitored patients who also had chronic kidney disease had an adjusted relative risk of 0.29. According to Raebel et al, their data supported the efficacy of potassium monitoring in reducing the incidence of serious hyperkalemia-associated adverse events in patients with a combination of diabetes and chronic kidney disease who are undergoing RAAS inhibitor therapy.5

Pathophysiology

Any of the following 3 pathogenetic mechanisms can cause hyperkalemia:

Excessive intake - Excessive potassium intake alone is an uncommon cause of hyperkalemia. The mechanisms for shifting potassium intracellularly and for renal excretion allow a person with normal potassium homeostatic mechanisms to ingest virtually unlimited quantities of potassium. Even parenteral administration of as much as 60 mEq/h for several hours creates only a minimal increase in serum potassium concentration in healthy individuals. Most often, hyperkalemia is caused by a relatively high potassium intake in a patient with impaired mechanisms for the intracellular shift of potassium or for renal potassium excretion.

Decreased excretion - Decreased excretion of potassium, especially coupled with excessive intake, is the most common cause of hyperkalemia. The most common causes of decreased renal potassium excretion include renal failure, ingestion of drugs that interfere with potassium excretion (eg, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors,5,6,7,8 nonsteroidal anti-inflammatory drugs), or impaired responsiveness of the distal

tubule to aldosterone (eg, type IV renal tubular acidosis observed with diabetes mellitus, sickle cell disease, or chronic partial urinary tract obstruction).9,10

Shift from intracellular to extracellular space - This pathogenetic mechanism alone is a relatively uncommon cause of hyperkalemia but can exacerbate hyperkalemia produced by a high intake or impaired renal excretion of potassium. Clinical situations in which this mechanism is the major cause of hyperkalemia include hyperosmolality, rhabdomyolysis, tumor lysis, and succinylcholine administration, which depolarizes the cell membrane and thus permits potassium to leave the cells.11 However, more often, mild to moderate impairment of intracellular shifting of potassium occurs with insulin deficiency or acute acidosis.

Hyperkalemia may also be caused by IV administration of epsilon amino caproic acid (EACA), a synthetic amino acid. EACA has been found to cause hyperkalemia in studies conducted in dogs. The mechanism of action is presumed to be a similarity in structure of EACA to arginine and lysine. These latter amino acids enter the muscle cell in exchange for potassium, thereby leading to an increase in extracellular potassium.12,13

Regardless of the cause, hyperkalemia produces similar signs and symptoms. Because potassium overwhelmingly is an intracellular cation and various factors can regulate the actual serum potassium concentration, an individual can ingest a substantial potassium load without exhibiting frank hyperkalemia. Conversely, hyperkalemia does not always reflect a true increase in total body potassium stores.

Frequency

United States

Hyperkalemia, defined as serum potassium greater than 5.3 mEq/L, is rare in a general population of healthy individuals. However, certain groups definitely exhibit a higher incidence of hyperkalemia. In patients who are hospitalized, the incidence of hyperkalemia has ranged from 1-10%, depending on the definition of hyperkalemia. Patients at the extremes of life, either premature or elderly, are at high risk. The presence of decreased renal function, genitourinary disease, cancer, severe diabetes, or polypharmacy also predisposes patients to hyperkalemia. Generally, in patients who are hospitalized, drugs are implicated in the development of hyperkalemia in as many as 75% of cases.

Military recruits, individuals with sickle cell traits, and people who abuse drugs are at risk for hyperkalemia due to acute rhabdomyolysis. These cases disproportionately occur in males, probably reflecting the higher muscle mass of males, although an underlying hormonal predisposition cannot be excluded absolutely.

Patients with diabetes constitute a unique high-risk group. They develop defects in all aspects of potassium metabolism. The typical healthy diabetic diet often is high in potassium and low in sodium. Diabetic persons frequently have underlying renal disease and often develop hyporeninemic hypoaldosteronism (ie, decreased aldosterone secondary to suppressed renin levels), impairing renal excretion of potassium.9,10 They frequently are placed on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for treatment of diabetic nephropathy, exacerbating the defect in potassium excretion. Finally, persons with diabetes have insulin deficiency and/or resistance to insulin action, limiting their ability to shift potassium intracellularly. All of these factors combine to render people with diabetes particularly prone to hyperkalemia.5,6

One review of the incidence of hyperkalemia in people with diabetes found that, in an unselected group of diabetic persons treated in a clinic, hyperkalemia (defined as a serum potassium level >5 mEq/L) was found in 15% (270 out of 1764 patients).14 However, fewer than 4% had potassium levels that were higher than 5.4 mEq/L. Clinical risk factors significant in predicting the occurrence of hyperkalemia included renal insufficiency, duration of diabetes mellitus, age, glycosylated hemoglobin levels, and retinopathy. Interestingly, neither the serum glucose level nor the agent for diabetes treatment was significantly correlated.

Significant concern also has been raised about the potential for hyperkalemia in patients taking angiotensin-converting enzyme inhibitors, particularly because the indications for their use in high-risk populations, such as diabetic persons, are broadening rapidly. In one series, the incidence of hyperkalemia in an outpatient clinic was 11%.15 Hyperkalemia occurred in less than 6% of patients with normal renal function. Risk factors for hyperkalemia in patients using angiotensin-converting enzyme inhibitors included elevated blood urea nitrogen (BUN) and serum creatinine, severe diabetes mellitus, congestive heart failure, peripheral vascular disease, and the use of a long-acting drug.

As cardiovascular therapy has evolved, the growing population of patients with congestive heart failure also has come to constitute a high-risk group. The factors promoting the development of hyperkalemia in these patients include underlying renal insufficiency due to poor cardiac output and reduced renal blood flow, as well as the high prevalence of diabetes mellitus in patients with heart failure and the growing use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone inhibitors, such as spironolactone.9,10 Initial studies examining the risk of hyperkalemia in patients with heart failure who were treated with aldosterone inhibitors revealed only a minor increase in hyperkalemia, but later studies showed that as the treatment became more widespread, the morbidity and mortality from hyperkalemia had increased.16

International

As in the United States, the incidence of hyperkalemia in the general population has been reported in less than 5% of people. Patients who are hospitalized in countries as diverse as England, Australia, and Israel experience hyperkalemia approximately 10% of the time. Similar to those reported in the United States, risk factors include advanced age, significant prematurity, and the presence of renal failure, diabetes mellitus, and heart failure. Additionally, one series documented an increased incidence of hyperkalemia with cancer and gastrointestinal disease.17 Polypharmacy, particularly the use of potassium supplements and potassium-sparing diuretics, in patients with underlying renal insufficiency contributed to hyperkalemia in almost one half of the cases.

Mortality/Morbidity

Hyperkalemia in a patient who is hospitalized is an independent risk factor for death. In one series, 1.4% of patients who were hospitalized (406 out of 29,063 patients) developed hyperkalemia.17 

The overall mortality rate in patients with hyperkalemia was 14.3% (58 out of 406 patients), with the risk increasing as the potassium level increases.

Twenty-eight percent of patients with a serum potassium level greater than 7 mEq/L died, as opposed to 9% of those with a potassium level below 6.5 mEq/L. In 7 out of 58 deaths, the cause of death was directly attributable to hyperkalemia. Most cases resulting in death were complicated by renal failure.

Interestingly, all patients who died of hyperkalemia had normal potassium levels within the 36 hours prior to death.

Race

No racial predisposition to hyperkalemia appears to exist.

Sex

Men are significantly more prone to hyperkalemia than are women. This difference has been noted in several series and stands in contrast to the increased incidence of hypokalemia in women. The reasons for this discrepancy are unknown.

Age

Several series document the increasing tendency for hyperkalemia in patients at the extremes of life, that is, small, premature infants and elderly people, with renal insufficiency playing a significant role in both groups.

Premature infants are a high-risk group. Relative renal immaturity is likely to be a contributory factor; studies comparing small, premature infants who developed hyperkalemia to those who did not indicate that incidence is increased in infants with a lower glomerular filtration rate as estimated by endogenous creatinine clearance. In these small infants, hyperkalemia often occurs within the first 48 hours of life.

Elderly patients are another high-risk group. In several series, an age older than 60 years was an independent risk factor for the development of hyperkalemia in the hospital. Several factors contribute to the increased propensity for elderly people to become hyperkalemic. Renal function tends to deteriorate with age, even in relatively healthy individuals. The glomerular filtration rate decreases by 1 mL/min/y in people older than 30 years. Renal blood flow also decreases. Oral intake declines, resulting in decreased urine flow rates. Plasma renin activity and aldosterone levels also tend to decrease with age, reducing the ability of the distal nephron to secrete potassium.

Elderly patients are more likely to be taking medications that could interfere with potassium secretion, such as nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, and potassium-sparing diuretics. Elderly individuals who are bedridden often are placed on subcutaneous heparin, which can decrease aldosterone production.

Clinical

History

Symptoms are nonspecific and predominantly related to muscular or cardiac function. The most common complaints are weakness and fatigue. Occasionally, a patient may complain of frank muscle paralysis or shortness of breath. Patients also may complain of palpitations or chest pain.

When hyperkalemia is discovered, investigate potential pathophysiologic mechanisms.

For excessive potassium intake, query patients about the following:o Eating disorders - Very unusual diets consisting almost exclusively of high-potassium

foods, such as fruits, dried fruits, juices, and vegetables with little to no sodium

o Heart healthy diets - Very low–sodium and high-potassium diets recommended for

patients with cardiac disease, hypertension, and diabetes mellitus

o Use of potassium supplements in over-the-counter herbal supplements, salt substitutes,

or prescribed pharmacologic agents - Many patients with renal insufficiency and hypertension have heard the advice to eat a banana a day because the potassium reduces blood pressure. They may not realize that in the case of renal insufficiency and hypertension, this is potentially a life-threatening therapy.

For decreased potassium excretion, query patients about the following:

o Ingestion of medications that impair renal potassium excretion

Potassium-sparing diuretics, especially popular in the treatment of cirrhosis and congestive heart failure

Nonsteroidal anti-inflammatory drugs

Angiotensin-converting enzyme inhibitors

Angiotensin receptor blockers

Cyclosporine or tacrolimus

Antibiotics, such as pentamidine or trimethoprim/sulfamethoxazole18

EACA12

o History of renal insufficiency or renal failure

o History of diabetes mellitus, sickle cell disease or trait, or symptoms of lower urinary tract

obstruction - These diseases predispose people to type IV renal tubular acidosis, also called hyperkalemic renal tubular acidosis. Type IV renal tubular acidosis also may accompany other tubulointerstitial disorders, such as polycystic kidney disease or amyloidosis. Often, patients with type IV renal tubular acidosis have hyporeninemic hypoaldosteronism.9,10 One example is diabetes mellitus, where the relative volume overload leads to low renin.

For a shift of potassium into the extracellular space, query patients about the following:

o Recurrent episodes of flaccid paralysis

o Presence of diabetes mellitus

o Use of beta-adrenergic antagonist therapy (eg, for hypertension or angina)

o Risk factors for rhabdomyolysis, such as heat stroke, chronic alcoholism, seizures,

sudden excessive exertion (eg, in military recruits undergoing basic training), or use of medications that interfere with heat dissipation (eg, tricyclic antidepressants or anesthesia)

o Risk factors for tumor lysis syndrome, such as ongoing treatment for widespread

lymphoma, leukemia, or other large tumors

o Risk factors for hemolysis, such as blood transfusion and sickle cell disease

Other mechanisms

o Drugs, such as cyclooxygenase-2 (COX-2) inhibitors19

o Ingestion of toad venom (Bufo bufo gargarizans) in southeastern Asian countries

In Southeast Asia, toads are a common folk remedy for strengthening the heart. Bufadienolides, which are forms of cardiac glycoside that are present in toad venom, have a similar structure and biochemical activity to digitalis and cardenolides, the major plant-derived cardiac glycosides. Bufadienolides cause hyperkalemia by binding to the alpha subunit of Na+–K+ –ATPase, thus inhibiting the reuptake of potassium from the extracellular space.20

This compound has also turned up in some aphrodisiacs and Chinese medications (eg, chan su).

With regard to Western countries, at least 2 cases of poisoning by toad and eggs have been reported in the United States.21

Physical

In patients with hyperkalemia, vital signs generally are normal, except occasionally in bradycardia due to heart block or tachypnea due to respiratory muscle weakness.

Muscle weakness and flaccid paralysis

Depressed or absent deep tendon reflexes

In general, the results of the physical examination alone do not alert the physician to the diagnosis, except when severe bradycardia is present or muscle tenderness accompanies muscle weakness, suggesting rhabdomyolysis.

Causes

Listed by pathophysiologic mechanisms, causes of hyperkalemia include increased potassium intake, decreased potassium excretion, or a shift of potassium from the intracellular to the extracellular space. The most common causes are due to decreased excretion. Alone, excessive intake or an extracellular shift is distinctly uncommon. Often, several disorders are present simultaneously.

Increased intake - Alone, this is a rare cause of hyperkalemia, because the mechanisms for renal excretion and intracellular disposition are very efficient. In general, a relatively high potassium intake contributes to hyperkalemia in individuals who have impaired renal excretion and/or impaired intracellular shift.

o High-potassium, low-sodium diets

o Ingestion of potassium supplements - Ingested amounts would have to be massive to

be the sole cause of hyperkalemia, but even relatively small amounts can produce hyperkalemia in a patient with impaired renal excretion.

o High concentrations of potassium in intravenous fluid preparations, such as total

parenteral nutrition

o Dietary salt substitutes, penicillin potassium therapy

Decreased excretion - Impaired renal excretion almost always is present when a patient presents with persistent hyperkalemia. Mild degrees of renal failure generally do not result in resting hyperkalemia, due to adaptive mechanisms in the kidneys and gastrointestinal tract. However, once the glomerular filtration rate falls below 15-20 mL/min, significant hyperkalemia can occur, even in the absence of an abnormally large potassium load. The simple lack of nephron mass prevents normal potassium homeostasis. Hyperkalemia due to decreased renal excretion can occur when a patient has normal or only mildly decreased renal function as a result of other mechanisms, such as drugs or renal tubular acidosis. Two other causes of decreased excretion of potassium include reduced distal sodium delivery and reduced tubular fluid flow rate.

o Drugs

Potassium-sparing diuretics, spironolactone, triamterene, amiloride

Nonsteroidal anti-inflammatory drugs

Angiotensin-converting enzyme inhibitors

Angiotensin receptor blockers

Cyclosporine or tacrolimus

Pentamidine

Trimethoprim/sulfamethoxazole

Heparin

Ketoconazole

Metyrapone

Herbs

o Type IV renal tubular acidosis

Diabetes mellitus

Sickle cell disease or trait

Lower urinary tract obstruction

Adrenal insufficiency

Primary Addison syndrome due to autoimmune disease, tuberculosis, or infarct

Enzyme deficiencies

o Disorders of steroid metabolism and mineralocorticoid receptors22,23

21-hydroxylase deficiency in classical form and aldosterone synthase deficiency result in hyperkalemia due to low aldosterone levels.

11-beta hydroxylase deficiency, 3-beta hydroxysteroid dehydrogenase deficiency, and 17 alpha-hydroxylase/17,20-lyase deficiency are generally not characterized by the development of hyperkalemia.

Type 1 pseudohypoaldosteronism is caused by an inactivating mutation of the mineralocorticoid receptor, resulting in impaired potassium secretion due to impaired sodium reabsorption in the distal tubule.24

o Gordon syndrome, or pseudohypoaldosteronism Type II, characterized by hyperkalemia

and hypertension, is caused by mutations in either WNK1 or WNK4, protein kinases that are localized to the distal tubule and that regulate ion transport in this nephron segment. WNK4 appears to have several roles in regulating sodium, potassium, and chloride transport through transcellular and paracellular pathways.25

Shift of potassium into the extracellular space - Like increased intake, this rarely is the sole cause of hyperkalemia, because the mechanisms for renal excretion are very efficient. However, the inability to transport potassium intracellularly exacerbates hyperkalemia in individuals who have impaired renal excretion.

o Hyperkalemic periodic paralysis

o Insulin deficiency or insulin resistance (ie, type I or type II diabetes mellitus)

o Use of beta-adrenergic antagonist therapy (eg, for hypertension or angina)

o Tissue breakdown

Rhabdomyolysis

Tumor lysis syndrome

Massive hemolysis

o Drugs

Nonselective beta blockers (inhibits Na-K-ATPase pump)

Digitalis toxicity (inhibits Na-K-ATPase pump)

Succinylcholine (membrane leak)

Inhibition of the sodium pump will impair K entry into the cells and facilitate K exit from the cells.

o Hypertonicity - This may lead to hyperkalemia by 2 mechanisms: (1) loss of intracellular

water, resulting in an increased intracellular potassium concentration, favoring a gradient for potassium to move out of the cells, and (2) as water exits the cells, "solvent drag," which sweeps potassium along. The most common cause of hyperosmolality is hyperglycemia in uncontrolled diabetes mellitus. Other conditions with hypertonicity are hypernatremia and hypertonic mannitol.

o Aldosterone deficiency - This is somewhat controversial. Some evidence that long-term

aldosterone deficiency impairs cell potassium uptake exists.

Hypermagnesemia

Introduction

Hypermagnesemia is an uncommon clinical finding, and symptomatic hypermagnesemia is even less common. This disorder has a low incidence of occurrence, because the kidney is able to eliminate excess magnesium by rapidly reducing its tubular reabsorption to almost negligible amounts.

In healthy adults, plasma magnesium ranges from 1.7-2.3 mg/dL. Approximately 30% of total plasma magnesium is protein-bound and approximately 70% is filterable through artificial membranes (15% complexed, 55% free Mg2+ions). With a glomerular filtration rate (GFR) of approximately 150 L per day and an ultrafiltrable magnesium concentration of 14 mg/L, the filtered magnesium load is approximately 2,100 mg per day. Normally, only 3% of filtered magnesium appears in urine; thus, 97% is reabsorbed by the renal tubules. In contrast to sodium and calcium, only approximately 25-30% of filtered magnesium is reabsorbed in the proximal tubule. Approximately 60-65% of filtered magnesium is reabsorbed in the thick ascending loop of Henle and 5% is reabsorbed in the distal nephron.1 Relatively little is known about cellular magnesium transport mechanisms.2

The most common cause of hypermagnesemia is renal failure. Other causes include the following3,4 :

Excessive intake Lithium therapy

Hypothyroidism

Addison disease

Familial hypocalciuric hypercalcemia

Milk alkali syndrome

Depression

Renal Failure

Patients with end-stage renal disease often have mild hypermagnesemia, and the ingestion of magnesium-containing medications (eg, antacids, cathartics) can exacerbate the condition. In patients undergoing regular dialysis, the serum magnesium level directly relates to the dialysate magnesium concentration.5

In patients with acute renal failure, hypermagnesemia usually presents during the oliguric phase; the serum magnesium level returns to normal during the diuretic phase. If a patient receives exogenous magnesium during the oliguric phase, severe hypermagnesemia can result, especially if the patient is acidotic.

Other Causes

People often take magnesium-containing medications (eg, antacids, laxatives,6 rectal enemas). Hypermagnesemia can develop after treatment of drug overdoses with magnesium-containing cathartics,7 and it also occurs in patients taking magnesium-containing medications for therapeutic purposes8,9 ; however, most of these patients have normal renal function. If the patient does not ingest a large amount of magnesium but has a gastrointestinal disorder (eg, gastritis, colitis, gastric dilation), absorption may increase.10,11 In any case, monitoring serum magnesium levels in patients taking magnesium-containing medications is prudent.

Excessive tissue breakdown (sepsis, shock, large burns), especially with concurrent renal failure, can deliver a large amount of magnesium from the intracellular space, along with a massive elevation of phosphorus and potassium.4 

In the treatment of eclampsia, hypermagnesemia is induced deliberately and sometimes can be symptomatic.8,12,13 Occasionally, hypermagnesemia also can occur in the newborn infant.14 Maternal magnesium therapy can cause neurobehavioral disorders in the newborn.15 

Magnesium-containing phosphorus binders are rarely used in end-stage renal disease patients16 and can lead to elevated magnesium levels.

Lithium therapy causes hypermagnesemia by decreasing urinary excretion, although the mechanism for this is not completely clear.

Familial hypocalciuric hypercalcemia may cause modest elevations in serum magnesium.17 This autosomal dominant disorder is characterized by very low excretion of calcium and magnesium and by a normal parathyroid hormone level. Abnormalities of calcium and magnesium handling are due to mutations in the calcium-sensing receptor,18 resulting in increased magnesium reabsorption in the loop of Henle.

Hypothyroidism, adrenal insufficiency, milk-alkali syndrome3,4 and theophylline intoxication occasionally produce mild elevations of serum magnesium. 

There has been some interest in the use of magnesium in the treatment and prevention of cardiac arrhythmias and in the treatment of subarachnoid hemorrhage19,20 ; however, significant hypermagnesemia has not been reported in these settings.

Effects of Hypermagnesemia

Symptoms of hypermagnesemia usually are not apparent unless the serum magnesium level is greater than 2 mmol/L. Concomitant hypocalcemia, hyperkalemia, or uremia exaggerate the symptoms of hypermagnesemia at any given level.

Neuromuscular symptoms

These are the most common presenting problems. Hypermagnesemia causes blockage of neuromuscular transmission by preventing presynaptic acetylcholine release and by competitively inhibiting calcium influx into the presynaptic nerve channels via the voltage-dependent calcium channel.21

One of the earliest symptoms of hypermagnesemia is deep-tendon reflex attenuation. Facial paresthesias also may occur at moderate serum levels.

Muscle weakness is a more severe manifestation, occurring at levels greater than 5 mmol/L. This manifestation can result in flaccid muscle paralysis and depressed respiration and can eventually progress to apnea.

Conduction system symptoms

Hypermagnesemia depresses the conduction system of the heart and sympathetic ganglia.21 A moderate increase in serum magnesium can lead to a mild decrease in blood pressure, and a greater concentration may cause severe symptomatic hypotension. Magnesium is also cardiotoxic and, in high concentrations, can cause bradycardia. Occasionally, complete heart block and cardiac arrest may occur at levels greater than 7 mmol/L.

Hypocalcemia

Apparently, hypocalcemia results from a decrease in the secretion of parathyroid hormone (PTH) or from end-organ resistance to PTH.22 Paralytic ileus develops from smooth-muscle paralysis,10 and mothers being treated with magnesium for preterm labor suppression are at risk.23

Hypermagnesemia may interfere with blood clotting through interference with platelet adhesiveness, thrombin generation time, and clotting time.

Nonspecific symptoms

These symptoms include nausea, vomiting, and cutaneous flushing.

Medication

Prevention of hypermagnesemia is usually possible. Anticipate hypermagnesemia in patients who are receiving magnesium treatment, especially those with reduced renal function. Initially, withdraw magnesium therapy, which often is enough to correct mild to moderate hypermagnesemia.

In patients with symptomatic hypermagnesemia that is causing cardiac effects or respiratory distress, antagonize the effects by infusing calcium gluconate. Calcium antagonizes the toxic effect of magnesium, and these ions electrically oppose each other at their sites of action. This treatment usually leads to immediate symptomatic improvement.

Diuretics

Agents that promote magnesium excretion are effective in treating hypermagnesemia.

Furosemide (Lasix)

May promote excretion of magnesium. Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule.

Dosing

Interactions

Contraindications

Precautions

Adult

Suggested dosing: 20-80 mg/d PO/IV/IM; titrate up to 600 mg/d for severe edematous states

Pediatric

Suggested PO dosing: 1-2 mg/kg/dose; not to exceed 6 mg/kg/dose; do not administer more often than q6hSuggested IV/IM dosing: 1 mg/kg slowly under close supervision; not to exceed 6 mg/kg

Calcium salts

Calcium may moderate nerve and muscle performance in hypermagnesemia.

Calcium gluconate (Kalcinate)

Calcium directly antagonizes neuromuscular and cardiovascular effects of magnesium. Use for patients with symptomatic hypermagnesemia that is causing cardiac effects or respiratory distress.

Dosing

Interactions

Contraindications

Precautions

Adult

Suggested dosing: 100-300 mg elemental calcium IV diluted in 150 mL D5W over 10 min; initial rate of infusion should be 0.3-2 mg of elemental calcium/kg/h

Pediatric

Suggested dosing: 2 mg/kg of elemental calcium IV (about 20 mg/kg of calcium gluconate 10%)

Antidiabetic agents

Agents that shift magnesium ions into cells are helpful in treating hypermagnesemia.

Glucose and insulin

May help promote magnesium entry into cells. Glucose should be administered with insulin to prevent hypoglycemia. Monitor blood sugar levels frequently.

Dosing

Interactions

Contraindications

Precautions

Adult

Suggested dosing: 10 U IV and 50 mL D50W bolus or 500 mL D10W over 1 h

Pediatric

Suggested dosing: 0.5-1 g/kg IV followed by 1 U of regular insulin per 3 g glucose

Diagnosis and Summary

Hypermagnesemia usually results from a combination of excess magnesium intake and a coexisting impairment of renal function. Diagnosis is usually straightforward and involves measuring serum magnesium levels, as many cases are unsuspected.24 If a magnesium level is not immediately available, a clue to the existence of hypermagnesemia would be the disease context (preeclampsia, renal failure), the presence of magnesium-containing preparations, or a decreased anion gap.

Hypernatremia

Introduction

Background

Hypernatremia  is a common electrolyte problem and is defined as a rise in serum sodium concentration to a value exceeding 145 mmol/L.1,2

Hypernatremia  is strictly defined as a hyperosmolar condition caused by a decrease in total body water (TBW)3 relative to electrolyte content. Hypernatremia is a “water-problem,” not a problem of sodium homeostasis. (See image below)

Figure A: Normal cell. Figure B: Cell initially responds to extracellular hypertonicity

through passive osmosis of water extracellularly, resulting in cell shrinkage. Figure

C: Cell actively responds to extracellular hypertonicity and cell shrinkage in order to

limit water loss through transport of organic osmolytes across the cell membrane,

as well as through intracellular production of these osmolytes. Figure D: Rapid

correction of extracellular hypertonicity results in passive movement of water

molecules into the relatively hypertonic intracellular space, causing cellular

swelling, damage, and ultimately death.

Patients developing hypernatremia outside of the hospital are generally elderly people who are mentally and physically impaired, often with an acute infection. Patients who develop hypernatremia during the course of hospitalization have an age distribution similar to that of the general hospital population. In both patient groups, hypernatremia is caused by impaired thirst and/or restricted access to water, often exacerbated by pathologic conditions with increased fluid loss.

The development of hyperosmolality from the water loss can lead to neuronal cell shrinkage and resultant brain injury. Loss of volume can lead to circulatory problems (eg, tachycardia, hypotension). Rapid free-water replacement can cause cerebral edema.

Pathophysiology

Hypernatremia results when there is a net water loss or a hypertonic sodium gain and reflects too little water in relation to total body sodium and potassium. Hypernatremia by definition is a state of hyperosmolality, because sodium is the dominant extracellular cation and solute.4

The normal plasma osmolality (Posm) lies between 275 and 290 mOsm/kg and is primarily determined by the concentration of sodium salts. (Calculated plasma osmolality: 2(Na) mEq/L + serum glucose (mg/dL)/18 + BUN (mg/dL)/2.8). Regulation of the Posm and the plasma sodium concentration is mediated by changes in water intake and water excretion. This occurs via 2 mechanisms:

Urinary concentration (via pituitary secretion and renal effects of the antidiuretic hormone arginine vasopressin [AVP])5,6

Thirst

In the normal individual, thirst is stimulated by an increase in body fluid osmolality above a certain threshold and results in increased water ingestion, rapidly correcting the hypernatremic state.

This mechanism is so effective that even in pathologic states in which patients are unable to concentrate their urine (diabetes insipidus) and excrete excessive amounts of urine (10-15 liters per day), hypernatremia will not develop, because thirst is stimulated and body fluid osmolality is maintained at the expense of profound secondary polydipsia.

Thus, sustained hypernatremia can occur only when the thirst mechanism is impaired and water intake does not increase in response to hyperosmolality, or when water ingestion is restricted.

Urinary concentration - AVP and the kidney7 

Conservation and excretion of water by the kidney depends on the normal secretion and action of AVP and is very tightly regulated. The stimulus for AVP secretion is an activation of hypothalamic

osmoreceptors, which occurs when the plasma osmolality reaches a certain threshold (approximately 280 mOsm/kg). At plasma osmolalities below this threshold level, AVP secretion is suppressed to low or undetectable levels.

AVP is synthesized in specialized magnocellular neurons whose cell bodies are located in the supraoptic and paraventricular nuclei of the hypothalamus. The prohormone is processed and transported down the axon, which terminates in the posterior pituitary gland. From there, it is secreted as active AVP hormone into the circulation in response to an appropriate stimulus (hyperosmolality, hypovolemia).

AVP binds to the V2 receptor located on the basolateral membrane of the principal cells of the renal collection ducts. The binding to this G-protein coupled receptor initiates a signal transduction cascade, leading to phosphorylation of aquaporin-2 and its translocation and insertion into the apical (luminal) membrane, creating "water channels" that enable the absorption of free water in this otherwise water-impermeable segment of the tubular system

Thirst

Thirst is the body’s mechanism to increase water consumption in response to detected deficits in body fluid. As with AVP secretion, thirst is mediated by an increase in effective plasma osmolality of only 2-3%. Thirst is thought to be mediated by osmoreceptors located in the anteroventral hypothalamus. The osmotic thirst threshold averages approximately 288-295 mOsm/kg.

Of physiologic significance is the fact that this level lies above the osmotic threshold for AVP release and approximates the plasma osmolality at which maximal urine concentration is normally achieved. Thus, under normal physiological conditions, AVP accounts for the regulation of plasma osmolality within narrow limits and adjusts water excretion to small changes in osmolality. Only when unregulated water intake (beverages) is not enough in the presence of maximal AVP secretion to maintain plasma osmolality will the perceived desire for water (thirst) become crucial.

Significant hypovolemia stimulates AVP secretion and thirst. Blood pressure decreases of 20-30% result in AVP levels many times those required for maximal antidiuresis.

Hypernatremic states can be classified as isolated water deficits (which are generally not associated with intravascular volume changes), hypotonic fluid deficits, and hypertonic sodium gain.

Acute hypernatremia is associated with a rapid decrease in intracellular water content and brain volume caused by an osmotic shift of free water out of the cells. Within 24 hours, electrolyte uptake into the intracellular compartment results in partial restoration of brain volume. A second phase of adaptation, characterized by an increase in intracellular organic solute content (accumulation of amino acids, polyols, and methylamines), restores brain volume to normal. The accumulation of intracellular solutes bears the risk for cerebral edema during rehydration. The brain cell response to hypernatremia is critical.

Frequency

United States

The overall incidence of hospitalized patients with hypernatremia ranges from 0.3-5.5%. The incidence of patients who have hypernatremia on admission to the hospital is very low, being estimated at 0.12-1.4%. Over 60% of hypernatremia cases are hospital acquired. The prevalence

in intensive care units (ICUs) appears to be much higher. Hypernatremia is most prevalent in the geriatric population.

International

A retrospective, single-center study from Europe, which included 981 patients, found a 9% incidence of hypernatremia at the center's intensive care unit (ICU). However, it was also found that among those patients with hypernatremia, only 23% already had the condition when admitted to the ICU.8,9

A Canadian study of 8000 adult patients identified ICU-acquired hyponatremia in 11% of them and ICU-acquired hypernatremia in 26% of these patients.9 The report found that the mortality rate in patients with ICU-acquired hyponatremia or hypernatremia was greater than that of study patients with normal serum sodium levels, being 28% versus 16%, p <0.001, and 34% versus 16%, p <0.001, respectively.

Darmon et al sought to determine the prevalence of ICU-acquired hypernatremia and whether this condition can affect patient outcomes. Of 8140 patients reviewed in the retrospective study, 1245 were found to have had ICU-acquired hypernatremia (defined in the study as hypernatremia acquired 24 hours or more after ICU admission); this included 901 patients (11.1%) with mild hypernatremia, and 344 patients (4.2%) with moderate to severe hypernatremia. Comparing hospital mortality rates for the patients without hypernatremia with those for cohort members with the condition, the authors determined that the subdistribution hazard ratio for mortality from ICU-acquired hypernatremia was 2.03 for the mild form of the condition and 2.67 for moderate to severe hypernatremia.10

Mortality/Morbidity

Morbidity and mortality estimates in hypernatremic adults range from 42% to more than 70%, with the highest rates being found in the geriatric age group.

The mortality rate for chronic hypernatremia is approximately 10%, while the mortality rate for severe acute hypernatremia in the ICU setting is as high as 75%.10,11

Race

No race predilection exists for hypernatremia.

Sex

No sex predilection exists for hypernatremia.12

Age

The groups most commonly affected by hypernatremia are elderly people and children.12

Clinical

History

Patients developing hypernatremia outside of the hospital setting are generally elderly and debilitated, and often present with an intercurrent acute (febrile) illness. Hospital-acquired hypernatremia affects patients of all ages.

The history should be used to discover why the patient was unable to prevent hypernatremia with adequate oral fluid intake; eg, it should be determined whether the patient is suffering from an altered mental status or whether there are any factors causing increased fluid excretion (eg, the use of diuretic therapy, the existence of diabetes mellitus, or the occurrence of fever, diarrhea, and vomiting). The history should also cover the symptoms and causes of possible diabetes insipidus (eg, the presence of preexisting polydipsia or polyuria, a history of cerebral pathology, or medication use [lithium]).

It is important to find out if the hypernatremia developed acutely or over time, because this will guide treatment decisions.

Risk factors for hypernatremia include the following:

Advanced age Mental or physical impairment

Uncontrolled diabetes (solute diuresis)

Underlying polyuria disorders

Diuretic therapy

Residency in nursing home, inadequate nursing care

Hospitalization10,13

o Decreased baseline levels of consciousness

o Tube feeding

o Hypertonic infusions

o Osmotic diuresis

o Lactulose

o Mechanical ventilation

o Medication (eg, diuretics, sedatives)

Physical

The examination should include an accurate assessment of volume status and cognitive function. Symptoms can be related to volume deficit and/or hypertonicity and shrinkage of brain cells.

The worsening symptoms associated with hypernatremia may go unnoticed in elderly patients who have a preexisting impairment of their mental status and decreased access to water.

Table 1. Characteristics and symptoms of hypernatremia

Open table in new window

Characteristics of hypernatremia Symptoms related to the characteristics of

hypernatremia

Cognitive dysfunction and symptoms associated with neuronal cell shrinkage

Lethargy, obtundation, confusion, abnormal speech, irritability, seizures, nystagmus, myoclonic jerks

Dehydration or clinical signs of volume depletion

Orthostatic blood pressure changes, tachycardia, oliguria, dry oral mucosa, abnormal skin turgor, dry axillae,

Other clinical findings Weight loss, generalized weakness

In a prospective, case-control, multicenter study, Chassagne and colleagues looked at the symptoms associated with hypernatremia in 150 geriatric patients.14 The likelihood that patients with hypernatremia would have low blood pressure, tachycardia, dry oral mucosa, abnormal skin turgor, and a recent change in consciousness was significantly greater than that of the controls. The only clinical findings to occur in at least 60% of patients with hypernatremia were orthostatic blood pressure and abnormal subclavicular and forearm skin turgor (poor specificity and sensitivity for all physical findings).

Causes

Several risk factors exist for hypernatremia. The greatest risk factor is age older than 65 years. In addition, mental or physical disability may result in impaired thirst sensation, an impaired ability to express thirst, and/or decreased access to water.15,16

Hypernatremia often is the result of several concurrent factors. The most prominent is poor fluid intake. Normally, an increase in osmolality of just 1-2% stimulates thirst, as do hypovolemia and hypotension. For clinical purposes, hypernatremia can, in a simplified view, be classified on the basis of the concurrent water loss or electrolyte gain and on corresponding changes in extracellular fluid volume:

Hypotonic fluid deficits (loss of water and electrolytes) Nearly pure-water deficits

Hypertonic sodium gain (gain of electrolytes in excess of water).

Loss of hypotonic fluid (loss of water in excess of electrolytes)

Patients who lose hypotonic fluid have a deficit in free water and electrolytes (low total body sodium and potassium) and have decreased extracellular volume. In these patients, hypovolemia may be more life threatening than hypertonicity. When physical evidence of hypovolemia is present, fluid resuscitation with normal saline is the first step in therapy.

Renal hypotonic fluid loss - Results from anything that will interfere with the ability of the kidney to concentrate the urine or osmotic diuresis

o Diuretic drugs (loop and thiazide diuretics)

o Osmotic diuresis (hyperglycemia, mannitol, urea [tube feeding])

o Renal salt wasting

o Postobstructive diuresis

o Diuretic phase of acute tubular necrosis

Nonrenal hypotonic fluid loss

o Gastrointestinal - Vomiting, diarrhea, lactulose, cathartics, nasogastric suction,

gastrointestinal fluid drains, and fistulas

o Cutaneous - Sweating (extreme sports, marathon runs), burn injuries

Pure-water deficits

Patients with pure-water deficits in the majority of cases have a normal extracellular volume with normal total body sodium and potassium. This condition most commonly develops when impaired intake is combined with increased insensible (eg, respiratory) or renal water losses.

Free-water loss will also result from an inability of the kidney to concentrate the urine. The cause of that can be either from failure of the hypothalamic-pituitary axis to synthesize or release adequate amounts of AVP (central diabetes insipidus) or a lack of responsiveness of the kidney to AVP (nephrogenic diabetes insipidus). Patients with diabetes insipidus and intact thirst mechanisms most often present with normal plasma osmolality and serum NA +, but with symptoms of polyuria and polydipsia.

Water intake less than insensible losseso Lack of access to water (through incarceration, restraints, intubation, immobilization)

o Altered mental status (through medications, disease)

o Neurologic disease (dementia, impaired motor function)

o Abnormal thirst

Geriatric hypodipsia

“Essential” hypernatremia with osmoreceptor dysfunction (reset of the osmotic threshold).

Injury to the thirst centers by any lesions to the hypothalamus, including from metastasis, granulomatous diseases, vascular abnormalities, and trauma.

o Loss of pure water through the respiratory tract

Vasopressin (AVP) deficiency (diabetes insipidus)

Central diabetes insipidus17 can be caused by any pathologic process that destroys the anatomic structures of the hypothalamic-pituitary axis involved in AVP production and secretion. Such processes include the following:

Pituitary injury - Posttraumatic, neurosurgical, hemorrhage, ischemia (Sheehan’s), idiopathic-autoimmune

Tumors - Craniopharyngioma, pinealoma, meningioma, germinoma, lymphoma, metastatic disease, cysts

Aneurysms - Particularly anterior communicating

Inflammatory states and granulomatous disease - Acute meningitis/encephalitis, Langerhans cell histiocytosis, neurosarcoidosis, tuberculosis

Drugs - Ethanol (transient), phenytoin

Genetic - Neurophysin-AVP gene defect

Nephrogenic diabetes insipidus (decreased responsiveness of the kidney to vasopressin) 

Genetic - V2-receptor defects, aquaporin defects (AQP2 and AQP1) Structural - Urinary tract obstruction, papillary necrosis, sickle-cell nephropathy

Tubulointerstitial disease - Medullary cystic disease, polycystic kidney disease, nephrocalcinosis, Sj ö gren’s syndrome, lupus, analgesic-abuse nephropathy, sarcoidosis, M-protein disease

Electrolyte disorders -Hypercalcemia, hypokalemia

Any prolonged state of severe polyuria - By washing out the renal medullary- intramedullary concentration gradient needed for urinary concentration, and by down-regulating kidney AQP2 water channels

Medications that induce nephrogenic diabetes insipidus

o Lithium

o Amphotericin B

o Demeclocycline

o Dopamine

o Ofloxacin

o Orlistat

o Ifosfamide

Medications that possibly cause nephrogenic diabetes insipidus

o Contrast agents

o Cyclophosphamide

o Cidofovir

o Ethanol

o Foscarnet

o Indinavir

o Libenzapril

o Mesalazine

o Methoxyflurane

o Pimozide

o Rifampin

o Streptozocin

o Tenofir

o Triamterene hydrochloride

o Cholchicine

Gestational diabetes insipidus 

In this form of diabetes insipidus, AVP is rapidly degraded by a high circulating level of oxytocinase/vasopressinase. It is a rare condition, because increased AVP secretion will compensate for the increased rate of degradation. Gestational diabetes insipidus occurs only in combination with impaired AVP production.

Hypertonic sodium gain

Patients with hypertonic sodium gain have a high total-body sodium and an extracellular volume overload (rare, mostly iatrogenic). When thirst and renal function are intact, this condition is transient.

Administration of hypertonic electrolyte solutions - Eg, sodium bicarbonate solutions, hypertonic alimentation solutions

Sodium ingestion - NaCl tablets, seawater ingestion

Sodium modeling in hemodialysis

Hyperphosphatemia

Introduction

Background

Phosphate is critical for a vast array of cellular processes. Phosphate is one of the major components of the skeleton, providing mineral strength to bone. Phosphate is an integral component of the nucleic acids that make up DNA and RNA. The phosphate bonds of ATP carry the energy required for all cellular functions. Phosphate functions as a buffer in bone, serum, and urine. The addition and deletion of phosphate groups to enzymes and proteins are common mechanisms for the regulation of their activity. In view of the sheer breadth of influence of this mineral, phosphate homeostasis (as depicted in the image below) is understandably a highly regulated process.

Approximately 60-70% of dietary phosphate, 1000-1500 mg/d, is absorbed in the small

intestine. Although vitamin D can enhance the absorption, especially under conditions of

dietary phosphate depletion, intestinal phosphate absorption is generally unregulated.

Specifically, high serum phosphate and high dietary phosphate intake do not significantly

impair intestinal uptake. The movement of phosphate in and out of bone, the reservoir

containing most of the total body phosphate, is generally balanced. Renal excretion of

excess dietary phosphate intake ensures maintenance of phosphate homeostasis,

maintaining serum phosphate at a level of approximately 4.5 mg/dL in the serum.

Phosphate in the body

The bulk of total body phosphate (85%) is in the bone as part of the mineralized extracellular matrix. This phosphate pool is accessible, albeit in a somewhat limited fashion. Approximately 300 mg of phosphate enters and exits bone tissue each day. Excessive losses or failure to add phosphate to bone leads to osteomalacia.

Phosphate is a predominantly intracellular anion with a concentration of approximately 100 mmol/L, although determination of the precise intracellular concentration has been difficult. Most intracellular phosphate is either complexed or bound to proteins or lipids. In response to kinases and phosphatases, these phosphate ions attach and detach from different molecules, forming a constantly shifting pool. Intracellular phosphate is essential for most, if not all, cellular processes; however, because the intracellular concentration of phosphate is greater than the extracellular concentration, phosphate entry into cells requires a facilitated transport process.

Several sodium-coupled transport proteins have been identified that enable intracellular uptake of phosphate by taking advantage of the steep extracellular-to-intracellular sodium gradient. Type 1 sodium phosphate cotransporters are expressed predominantly in kidney cells on the apical membranes of proximal tubule cells and, possibly, the distal tubule cells. They are capable of transporting organic ions and stimulating chloride conductance in addition to phosphate. Their role in phosphate homeostasis is not clear. Other sites of expression include the liver and brain.

Type 2 sodium phosphate cotransporters are expressed in kidneys, bone, and intestines. In epithelial cells, these transporters are responsible for transepithelial transport, ie, absorption of phosphate from intestine and reabsorption of phosphate from renal tubular fluid. Type 2a transporters are expressed in the apical membranes of kidney proximal tubules, are very specific for phosphate, and are regulated by several physiologic mediators of phosphate homeostasis, such as parathyroid hormone (PTH), dopamine, and dietary phosphate. Currently, these transporters are believed to be most critical for maintenance of renal phosphate homeostasis. Impaired expression or function of these transporters is associated with nephrolithiasis.1 Renal regulation of phosphate is depicted in the image below.

The vast majority of filtered phosphate is reabsorbed by type 2a sodium phosphate

cotransporters located on the apical membrane of the renal proximal tubule. The

expression of these cotransporters is increased by low dietary phosphate intake and

several growth factors to enhance phosphate absorption. The expression is decreased by

high dietary phosphate intake, parathyroid hormone, and dopamine. Phosphate absorption

in the remainder of the nephron is generally mediated by type 1 or 3 sodium phosphate

cotransporters. No direct evidence related to regulation of these transporters in renal cells

under physiologic conditions has been found. The absorption in the proximal tubule is

regulated such that the final excretion matches the dietary excess in order to maintain

homeostasis.

Type 2b transporters are very similar but not identical to type 2a transporters. They are expressed in the small intestine and are also up-regulated under conditions of dietary phosphate deprivation. Type 2c transporters, a third member of the Type 2 sodium phosphate cotransporter family, were initially described as growth-related phosphate transporters. They are expressed exclusively on the S1 segment of the proximal tubule and together with Type 2a transporters are essential for normal phosphate homeostasis. Similarly to type 2a transporters, type 2c transporters are also regulated by diet and PTH. Loss of type 2c function results in hereditary hypophosphatemic rickets with hypercalciuria.2

Type 3 transporters were initially identified as viral transport proteins. Almost all cells express type 3 sodium phosphate cotransporters; therefore, these transporters presumably play a housekeeping role in ensuring adequate phosphate for all cells. The factors that regulate the activity of these transporter proteins are not completely understood. Evidence suggests, however, that these transporters may also participate in regulation of renal and intestinal transepithelial transport3,4 and in regulation of bone mineralization.5

Circulating phosphate exists as either the univalent or divalent hydrogenated species. Because the ionization constant of acid (pK) of phosphate is 6.8, at the normal ambient serum pH of 7.4 the univalent species is 4 times as prevalent as the divalent species. Serum phosphate concentration varies with age, time of day, fasting state, and season. Serum phosphate concentration is higher in children than adults; the reference range is 4-7 mg/dL in children compared with 3-4.5 mg/dL in adults. A diurnal variation exists, with the highest phosphate level occurring near noon.

Serum phosphate concentration is regulated by diet, hormones, and physical factors such as pH. Importantly, because phosphate moves in and out of cells under several influences, the serum concentration of phosphate may not reflect true phosphate stores. Often, persons with alcoholism who have severely deficient phosphate stores may present for medical treatment with a normal serum phosphate level. Only after refeeding will serum phosphate levels decline, often abruptly plummeting to dangerously low levels.

Phosphate homeostasis

Phosphate is plentiful in the diet. A normal diet provides approximately 1000 mg of phosphate, two thirds of which is absorbed, predominantly in the proximal small intestine. The absorption of phosphate can be increased by increasing vitamin D intake and by ingesting a very low–phosphate diet. Under these conditions, the intestine expresses sodium-coupled phosphate transporters to enhance phosphate uptake.

Regulation of intestinal phosphate transport overall is poorly understood. Although studies had suggested that the majority of small intestine phosphate uptake was accomplished through sodium-independent, unregulated pathways, subsequent investigations have suggested that regulated sodium-dependent mechanisms may play a greater role in overall intestinal phosphate handling than was previously appreciated. Furthermore, intestinal cells may have a role in renal phosphate handling through elaboration of circulating phosphaturic substances in response to sensing a phosphate load.6 

Absorption of phosphate can be blocked by commonly used over-the-counter aluminum-, calcium-, and magnesium-containing antacids. Mild-to-moderate use of such phosphate binders generally poses no threat to phosphate homeostasis because dietary ingestion greatly exceeds body needs. However, very heavy use of these antacids can cause significant phosphate deficits. Stool losses of phosphate are minor, ie, 100-300 mg/d from sloughed intestinal cells and gastrointestinal secretions. However, these losses can be increased dramatically in persons with diseases that cause severe diarrhea or intestinal malabsorption.

Bone losses are approximately 300 mg phosphate per day, but that loss is generally balanced by an uptake of 300 mg. Bone metabolism of phosphate is influenced by factors that determine bone formation and destruction, ie, PTH, vitamin D, sex hormones, acid-base balance, and generalized inflammation.

The excess ingested phosphate is excreted by the kidneys to maintain phosphate balance. Major sites of regulation of phosphate excretion are the early proximal renal tubule and the distal convoluted tubule. In the proximal tubule, phosphate reabsorption by type 2 sodium phosphate cotransporters is regulated by dietary phosphate, PTH, and vitamin D. High dietary phosphate intake and elevated PTH levels decrease proximal renal tubule phosphate absorption, thus enhancing renal excretion. Defense against hyperphosphatemia is depicted in the image below.

Hyperphosphatemia inhibits 1-alpha hydroxylase in the proximal tubule, thus inhibiting the

conversion of 25-hydroxy vitamin D3 to the active metabolite, 1,25 dihydroxyvitamin D3.

The decrease in active vitamin D production is somewhat offset by the ability of

hyperphosphatemia to stimulate the secretion of parathyroid hormone (PTH), which will

increase the activity of 1-alpha hydroxylase. The result is generally a neutral effect on

intestinal phosphate absorption. Hyperphosphatemia-stimulated PTH secretion is mediated

through an as yet unidentified pathway. With normal renal function, the transient increase

in PTH and decrease in vitamin D serve to inhibit renal and intestinal absorption of

phosphate, resulting in resolution of the hyperphosphatemia. In contrast, under conditions

of renal failure, sustained hyperphosphatemia results in sustained hyperparathyroidism.

The hyperparathyroidism enhances renal phosphate excretion but also enhances bone

resorption, releasing more phosphate into the serum. As renal failure progresses and the

ability of the kidney to excrete phosphate continues to diminish, the action of PTH on the

bone can exacerbate the already present hyperphosphatemia.

Conversely, low dietary phosphate intake, low PTH levels, and high vitamin D levels enhance renal proximal tubule phosphate absorption. To some extent, phosphate regulates its own regulators. High phosphate concentrations in the blood down-regulate the expression of some phosphate transporters, decrease vitamin D production, and increase PTH secretion by the parathyroid gland. Distal tubule phosphate handling is less well understood. PTH increases phosphate absorption in the distal tubule, but the mechanisms by which this occurs are unknown. Renal phosphate excretion can also be increased by the administration of loop diuretics.

PTH and vitamin D were the only recognized regulators of phosphate metabolism until the discovery several novel regulators of mineral homeostasis, identified through studies of serum factors associated with phosphate wasting syndromes, such as oncogenic osteomalacia and the hereditary forms of hypophosphatemic rickets.

The first to be discovered was a phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX), a neutral endopeptidase mutated in the syndrome of X-linked hypophosphatemic rickets. The characteristics of this syndrome (ie, hypophosphatemia, renal phosphate wasting, low 1,25-dihydroxyvitamin D levels) and the fact that PHEX was identified as an endopeptidase suggested the possibility that PHEX might be responsible for the catabolism of a non-PTH circulating factor that regulated proximal tubule phosphate transport and vitamin D metabolism. A potential substrate for PHEX was subsequently identified as fibroblast growth factor 23 (FGF23).

Several lines of evidence support a phosphaturic role for FGF23. Another syndrome of hereditary hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, is characterized by a mutation in theFGF23 gene that renders the protein resistant to proteolytic cleavage and thus, presumably more available for inhibition of renal phosphate transport. Administration of recombinant FGF23 produces phosphaturia, and FGF23 knockout mice exhibit hyperphosphatemia. The syndrome of oncogenic osteomalacia, characterized by acquired hypophosphatemic rickets and renal phosphate wasting in association with specific tumors, is associated with overexpression of FGF23. Interestingly, in this syndrome, overexpression of FGF23 is accompanied by 2 other phosphaturic agents, matrix extracellular phosphoglycoprotein (MEPE) and frizzled related protein-4. The roles of these 2 latter proteins and their relationship with FGF23 and PHEX are unknown.

The physiologic role for FGF23 in regulation of phosphate homeostasis is still under investigation. FGF23 is produced in several tissues, including heart, liver, thyroid/parathyroid, small intestine, and bone tissue. The source of circulating FGF23 has not been conclusively established; however, the highest mRNA expression for FGF23 in mice is in bone.7,8 

FGF23 production by osteoblasts is stimulated by 1,25 vitamin D.8 Conversely, individuals with X-linked hypophosphatemic rickets show inappropriately depressed levels of 1,25 vitamin D due to FGF23-mediated suppression of 1-alpha hydroxylase activity. Studies in patients with end-stage renal disease found that FGF23 levels rose with decreasing creatinine clearance rates and increasing plasma phosphorus levels. Klotho, a transmembrane protein, is an essential cofactor for the effects of FGF23 on renal proximal tubule cells.9Inactivation or deletion of Klotho expression results in hyperphosphatemia and accelerated aging. The relationship between these 2 functions of Klotho remains unknown.

A study also demonstrated that FGF23 levels rapidly decreased after kidney transplantation suggesting that FGF23 is cleared by the kidney.10 Thus, residual FGF23 could contribute to the hypophosphatemia frequently seen in posttransplant patients. In healthy young men without renal disease, phosphate intake did not significantly increase FGF23 levels, suggesting that FGF23 may not play a role in acute phosphate homeostasis.11 

One other family of phosphate-regulating factors is the stanniocalcins (STC1 and STC2). In fish, where it was first described, STC1 inhibits calcium entry into the organism through the gills and intestines. However, in mammals, STC1 stimulates phosphate reabsorption in the small intestine and renal proximal tubules and STC2 inhibits the promoter activity of the type 2 sodium phosphate cotransporter, while the effects on calcium homeostasis are of lesser magnitude. Very little is known about the clinical significance of these newly described mineral-regulating agents or about potential interactions either with the PTH-vitamin D axis or with the phosphatonin-PHEX system.

Pathophysiology

Hyperphosphatemia can occur because of 1 of 3 pathogenetic mechanisms.

The first is excessive intake. Excessive phosphate intake alone is an uncommon cause of hyperphosphatemia, particularly in the presence of normal renal function. The mechanisms for renal excretion allow a person with normal phosphate homeostatic mechanisms to ingest virtually unlimited quantities of phosphate. Most often, hyperphosphatemia is caused by a relatively high phosphate intake in the setting of impaired mechanisms for renal phosphate excretion (eg, renal failure, milk-alkali syndrome).

Vitamin D intoxication can produce hyperphosphatemia as a result of excessive gastrointestinal absorption and increased renal reabsorption. Reports indicate that patients have developed hyperphosphatemia because of excessive use of phosphate-containing laxatives or enemas. Short-term administration of large quantities of phosphate parenterally can also produce hyperphosphatemia but, again, most often in the setting of impaired renal function.

The second is decreased excretion. Decreased excretion of phosphate, especially when coupled with excessive intake, is by far the most common mechanism for the development of hyperphosphatemia. The most common cause of decreased renal phosphate excretion is renal failure, acute or chronic, of any cause. Once renal insufficiency progresses to the loss of 40-50% of renal function, the decrease in the

amount of functioning renal tissue does not allow excretion of the full amount of ingested phosphate required to maintain homeostasis, and hyperphosphatemia develops.

Hypoparathyroidism causes hyperphosphatemia through a failure to inhibit renal proximal tubule phosphate reabsorption. Syndromes of tubular resistance to PTH manifest hyperphosphatemia because of the same mechanism. These syndromes include the various types of pseudohypoparathyroidism (1a, 1b, 1c, and 2) and severe hypomagnesemia, which impairs PTH secretion and causes peripheral PTH resistance.

The syndromes of tumoral calcinosis produced by inactivating mutations of the phosphaturic hormone FGF23; GALNT3, an enzyme that controls FGF23 glycosylation and function; or Klotho, an essential cofactor for the phosphaturic effect of FGF23 in the renal tubule, also are characterized by decreased renal excretion of phosphate, resulting in hyperphosphatemia.12,13,14,15,16 Vitamin D intoxication, in addition to increasing gastrointestinal phosphate absorption, increases renal phosphate reabsorption, thus enhancing the hyperphosphatemic effect.

The third is a shift from intracellular to extracellular space. This pathogenetic mechanism alone is an uncommon cause of hyperphosphatemia, but it can exacerbate hyperphosphatemia produced by impaired renal excretion. Clinical situations in which this mechanism is the major cause of hyperphosphatemia include rhabdomyolysis and tumor lysis. Rarely, extracellular shifts of phosphate occur with insulin deficiency or acute acidosis.

Regardless of the cause, hyperphosphatemia produces similar signs and symptoms. Because phosphate is predominantly an intracellular cation and because a variety of factors can regulate the actual serum phosphate concentration, an individual can ingest a very substantial phosphate load without exhibiting frank hyperphosphatemia. Conversely, hyperphosphatemia does not always reflect a true increase in total body phosphate stores.

Frequency

United States

Hyperphosphatemia is rare in the general population; however, in patients with renal insufficiency or renal failure, the rate of hyperphosphatemia is at least 70%. Almost all patients with renal failure experience hyperphosphatemia at some time during the course of their disease. This is true for both acute and chronic renal failure.

International

The prevalence of hyperphosphatemia in the general population and in persons with renal failure is similar throughout the world.

Mortality/Morbidity

Hyperphosphatemia, even of a quite severe degree, is largely a clinically asymptomatic condition. The morbidity of hyperphosphatemia is more commonly associated with the underlying condition than with the actual hyperphosphatemia.

The short-term complications of hyperphosphatemia include acute hypocalcemia with possible tetany and, more rarely, acute deposition of calcium/phosphate complexes into joints, subcutaneous tissue, or

other soft-tissue areas. Acute hyperphosphatemia caused by excessive phospho-soda ingestion may cause acute renal failure and, at times, chronic kidney disease.17,18,19,20

The long-term complications of chronic hyperphosphatemia can be devastating and can affect any organ system. Organs most commonly affected include the vascular system and the bones, skin, joints, and heart. Changes in baseline phosphorus values beyond the recommended targets of the Kidney Disease Outcome Quality Initiative (KDOQI) were robust predictors of higher death risk.

Hyperphosphatemia is a risk factor for mortality in multiple populations, including kidney transplant recipients,21 patients with end-stage renal disease,22 and patients with chronic kidney disease.23  Serum phosphate level is associated with cardiovascular risk even in individuals without kidney disease where the serum phosphate is within the "normal" range.24 Interestingly, whether treatment to lower phosphate levels in patients with chronic kidney disease or end stage renal disease results in lower morbidity and mortality has not really been definitively demonstrated. A study showed that patients treated with phosphate binders had a decrease in 1-year mortality, but the effect did not correlate with the degree of hyperphosphatemia.14,25

Some experimental evidence indicates that high phosphate levels are toxic to some cells. Specifically, a high ambient phosphate level causes apoptosis of chondrocytes and osteoblasts in cell culture. During growth, high phosphate-stimulated apoptosis is critical for normal bone development.26  However, the effect of chronic hyperphosphatemia per se on bone and cartilage metabolism after closure of the growth plates is unknown. Studies have shown that acute phosphate loads obtained through dietary ingestion cause endothelial cell dysfunction, manifested as a decrease in flow-mediated dilation, in healthy men. This finding raises the possibility that prolonged and chronic hyperphosphatemia, as is seen with chronic kidney disease, could play a direct role in the enhanced cardiovascular morbidity and mortality seen in patients with chronic kidney disease.27

Phosphate is a major mineral component of bone; therefore, not surprisingly, chronic excess of phosphate results in bone pathology due to several different mechanisms.

o Hyperphosphatemia complexes serum calcium, leading to lower-than-normal levels of

ionized calcium. The decrease in ionized calcium triggers the release of PTH, resulting in a state of secondary hyperparathyroidism. High phosphate levels alone also stimulate PTH release. The elevated PTH levels lead to a high bone turnover state, releasing calcium to normalize the serum calcium level at the expense of bone calcium.

o High phosphate levels also inhibit the renal enzyme 1-alpha hydroxylase, which produces

active vitamin D by adding a hydroxyl group to circulating 25-hydroxycholecalciferol. This effect is most likely a result of hyperphosphatemia-stimulated increase in FGF23 levels. The decrease in active vitamin D results in impaired gastrointestinal absorption of calcium, decreased renal reabsorption of calcium and phosphate, and impaired bone mineralization. Over months to years, bone density decreases. Additionally, the PTH and vitamin D derangements result in abnormal bone architecture. Clinically, the skeletal manifestations of chronic hyperphosphatemia include bone pain and fractures.

Patients with renal failure who have chronically uncontrolled hyperphosphatemia develop progressively extensive soft tissue calcifications.

o Hyperphosphatemia is ultimately responsible for the increase in vascular calcifications,

but studies have also suggested that the process may additionally be influenced by 1,25 vitamin and an elevated calcium-phosphate product .

o Deposition of calcium/phosphate into skin causes a papular rash and may contribute to

uremic pruritus and ischemic ulcers.

o Large deposits can develop within joints, leading to pain and limitation of movement.

o Calcium deposition in tendons and ligaments results in a high frequency of spontaneous

rupture.

o Eye deposits have also been well described, producing the syndrome of band-shaped

keratopathy and red eye or conjunctivitis.

Undoubtedly the most significant long-term complication of chronic uncontrolled hyperphosphatemia is the development of vascular calcifications. Although the syndrome of calciphylaxis has been recognized and reported for many years in patients with renal failure, the full extent of vascular involvement, the widespread prevalence in the renal failure population, and the ominous significance of this complication have been appreciated only in the past decade. Vascular calcifications can assume 3 basic forms: capillary and small arteriole, medial arterial, and cardiac.

o Capillary and small arteriole deposition of calcium is generally the pathology detected in

classic calciphylaxis. Blood supply distal to the calcified vessels is impaired, leading to the development of necrotic skin lesions and hemorrhagic subcutaneous lesions. Many case reports have been published describing the syndrome, but only in a few series of more than several patients. The pathogenesis is not known. Several investigators have suggested a role for hyperparathyroidism, excessive vitamin D, vitamin K deficiency, and high calcium phosphate production. However, many patients may not demonstrate any of these abnormalities. However, most have a history of uncontrolled phosphate levels, implicating hyperphosphatemia as a particularly important pathogenetic or inciting factor.

o Medial arterial calcium deposition has been described in patients with renal failure. Some

investigators suggest that smooth muscle cells in the media dedifferentiate into cells with a more osteoblastic phenotype, allowing mineralization of the blood vessel. Support for this theory comes from studies demonstrating the expression of osteoblast-specific proteins, such as alkaline phosphatase and osteopontin, in the medial cells of calcified blood vessels. Other investigators suggest that loss of normal inhibitors of soft tissue calcification, such as matrix GLA protein or osteoprotegerin, may play a role in the pathogenesis.

o A study also demonstrated that phosphate uptake through Pit-1, a type III sodium-

dependent phosphate cotransporter, is essential for smooth muscle cell calcification in response to elevated phosphate. Studies comparing coronary calcification in patients with renal failure versus patients without renal failure uniformly show a higher degree of calcification at a younger age. This premature coronary calcification is thought to play a role in the accelerated cardiovascular mortality observed in patients with renal failure.

o Calcium deposited into the heart tissue itself can disrupt the cardiac conduction system,

producing significant arrhythmias. Calcium deposition into valves generally does not produce valve dysfunction, but it can serve as a marker for generalized vascular calcification. Aortic valve calcification detected using echocardiography is a poor prognostic factor in patients with renal failure and portends a high chance of mortality. The precise role of uremia in causing, facilitating, or exacerbating the incidence and effect of vascular calcifications associated with hyperphosphatemia has not been clarified.

Race

The development of hyperphosphatemia, per se, has no racial predilection. African Americans, people of Hispanic origin, and indigenous populations (eg, American Indians, aboriginal peoples) have a disproportionately high prevalence of renal failure, which can lead to hyperphosphatemia.

Sex

Susceptibility to hyperphosphatemia favors neither sex.

Age

Hyperphosphatemia can occur in persons of any age. The normally higher level of serum phosphate in neonates, infants, and children (sometimes >6 mg/dL) must be considered when making a diagnosis of hyperphosphatemia. Because hyperphosphatemia most commonly occurs in the setting of renal failure and because renal failure most commonly occurs in elderly persons, the incidence of hyperphosphatemia increases with age, proportionate to the increase in the incidence of renal failure.  Multiple investigators have suggested that the acute and chronic kidney disease resulting from the use of phosphate-containing bowel cleansing agents is far more prevalent in the elderly population. This observation may be due to the higher prevalence of chronic kidney disease in this population.

Clinical

History

Typically, most patients with hyperphosphatemia are asymptomatic. However, patients occasionally report hypocalcemic symptoms such as muscle cramps, tetany, and perioral numbness or tingling. Other symptoms include bone and joint pain, pruritus, or rash. More commonly, patients report symptoms related to the underlying cause of the hyperphosphatemia, generally uremic symptoms such as fatigue, shortness of breath, anorexia, nausea, vomiting, and sleep disturbances.

Therefore, important information to obtain is related to causes of hyperphosphatemia, such as a history of diabetes mellitus or hypertension (causes of renal failure), a history of neck surgery or irradiation (causes of hypoparathyroidism), or a history of excessive vitamin D or milk ingestion.

Physical

No aspects of the physical examination are specific to or pathognomonic of hyperphosphatemia. If the hyperphosphatemia is acute, especially if due to parenteral phosphate administration, the patient may be hypotensive or exhibit signs of hypocalcemia such as a positive Trousseau or Chvostek sign, hyperreflexia, carpopedal spasm, or seizure.

Causes

The most common cause of hyperphosphatemia is renal failure. Less common causes can be classified according to pathogenesis, ie, increased intake, decreased output, or shift from the intracellular to the extracellular space. Often, several mechanisms contribute. Impaired renal excretion is most frequently the major factor, with relatively increased intake or cell breakdown contributing to the problem.

Increased intakeo Excessive oral or rectal use of an oral saline laxative (Phospho-soda)

o Excessive parenteral administration of phosphate

o Milk-alkali syndrome

o Vitamin D intoxication

Decreased excretion

o Renal failure, acute or chronic

o Hypoparathyroidism

o Pseudohypoparathyroidism

o Severe hypomagnesemia

o Tumoral calcinosis

o Bisphosphonate therapy

Shift of phosphate from intracellular to extracellular space

o Rhabdomyolysis

o Tumor lysis

o Acute hemolysis

o Acute metabolic or respiratory acidosis

Spurious

o Blood sample taken from line containing heparin or alteplase28,29

o High concentrations of paraproteins30

o Hyperbilirubinemia31

o In vitro hemolysis

o Hyperlipidemia

Hyperuricemia

Introduction

Background

Uric acid is the final product of purine metabolism in human beings. Despite the fact that uric acid was first identified approximately 2 centuries ago, certain pathophysiologic aspects of hyperuricemia are still not clearly understood. For years, hyperuricemia has been identified with or thought to be the same as gout, but uric acid has now been identified as a marker for a number of metabolic and hemodynamic abnormalities

Unlike allantoin, the more soluble end product found in lower animals, uric acid is a poorly soluble end product of purine metabolism in humans. Human beings have higher levels of uric acid, in part, because of a deficiency of the hepatic enzyme, uricase, and a lower fractional excretion of uric acid. Approximately two thirds of total body urate is produced endogenously, while the remaining one third is accounted for by dietary purines. Approximately 70% of the urate produced daily is excreted by the kidneys, while the rest is eliminated by the intestines. However, during renal failure, the intestinal contribution of urate excretion increases to compensate for the decreased elimination by the kidneys.

The blood levels of uric acid are a function of the balance between the breakdown of purines and the rate of uric acid excretion. Theoretically, alterations in this balance may account for hyperuricemia, although clinically defective elimination accounts for most cases of hyperuricemia.

Pathophysiology

Uric acid in the blood is saturated at 6.4-6.8 mg/dL at ambient conditions, with the upper limit of solubility placed at 7 mg/dL. Urate is freely filtered at the glomerulus, reabsorbed, secreted, and then again reabsorbed in the proximal tubule. The recent cloning of certain urate transporters will facilitate the understanding of specific mechanisms by which urate is handled in the kidney and small intestines.

A urate/anion exchanger (URAT1) has been identified in the brush-border membrane of the kidneys and is inhibited by an angiotensin II receptor blocker, losartan. A human organic anion transporter (hOAT1) has been found to be inhibited by both uricosuric drugs and antiuricosuric drugs, while another urate transporter (UAT) has been found to facilitate urate efflux out of the cells. These transporters may account for the reabsorption, secretion, and reabsorption pattern of renal handling of urate.

Urate secretion does appear to correlate with the serum urate concentration because a small increase in the serum concentration results in a marked increase in urate excretion.

Hyperuricemia may occur because of decreased excretion (underexcretors), increased production (overproducers), or a combination of these two mechanisms.

Underexcretion accounts for most causes of hyperuricemia. Urate handling by the kidneys involves filtration at the glomerulus, reabsorption, secretion, and, finally, postsecretory reabsorption. Consequently, altered uric acid excretion can result from decreased glomerular filtration, decreased tubular secretion, or enhanced tubular reabsorption. While decreased urate filtration may not cause primary hyperuricemia, it can contribute to the hyperuricemia of renal insufficiency. Decreased tubular secretion of urate occurs in patients with acidosis (eg, diabetic ketoacidosis, ethanol or salicylate intoxication, starvation ketosis). The organic acids that accumulate in these conditions compete with urate for tubular secretion. Finally, enhanced reabsorption of uric acid distal to the site of secretion is the mechanism thought to be responsible for the hyperuricemia observed with diuretic therapy and diabetes insipidus.

Overproduction accounts for only a minority of patients presenting with hyperuricemia. The causes for hyperuricemia in overproducers may be either exogenous (diet rich in purines) or endogenous (increased purine nucleotide breakdown). A small percentage of overproducers have enzymatic defects that account for their hyperuricemia. These include a complete deficiency of hypoxanthine guanine phosphoribosyltransferase (HGPRT) as in Lesch-Nyhan syndrome, partial deficiency of HGPRT (Kelley-Seegmiller syndrome), and increased production of 5-phospho-alpha-d-ribosyl pyrophosphate (PRPP) activity. Accelerated purine degradation can result from rapid cell proliferation and turnover (blast crisis of leukemias) or from cell death (rhabdomyolysis, cytotoxic therapy). Glycogenoses types III, IV, and VII can result in hyperuricemia from excessive degradation of skeletal muscle ATP.

Combined mechanisms (underexcretion and overproduction) can also cause hyperuricemia. The most common cause under this group is alcohol consumption,1 which results in accelerated hepatic breakdown of ATP and the generation of organic acids that compete with urate for tubular secretion. Enzymatic defects such as glycogenoses type I and aldolase-B deficiency are other causes of hyperuricemia that result from a combination of overproduction and underexcretion.

New findings revealed that urate crystals can engage an intracellular pattern recognition receptor, the macromolecular NALP3 (cryopyrin) inflammasome complex.2,3 NALP3 inflammasome may result in interleukin 1 (IL-1) beta production, which, in turn, incites an inflammatory response. Inhibition of this pathway has the potential to be targeted for hyperuricemia-induced crystal arthritis.

Frequency

United States

The prevalence rate of asymptomatic hyperuricemia in the general population is estimated at 2-13%.

International

A Japanese study that used an administrative claims database to ascertain 10-year trends in the prevalence of hyperuricemia concluded that the prevalence of hyperuricemia in the overall study population increased during the 10-year follow-up. When stratified by age, the prevalence increased among groups older than 65 years in both sexes. In those younger than 65 years, men had a prevalence 4 times higher than that in women, but in those older than 65 years, the gender gap narrowed to 1:3 (female-to-male ratio) with gout and/or hyperuricemia.

Mortality/Morbidity

Hyperuricemia has been associated with increased morbidity4 in patients with hypertension and is associated with increased mortality in women and elderly persons. The cause for this is unknown, but

hyperuricemia is probably a marker for comorbid risk factors rather than a causative factor, per se.

Although observational studies on hyperuricemia and stroke have yielded conflicting results, a meta-analysis by Kim et al suggested that hyperuricemia may modestly increase the risk of stroke incidence and mortality.5 The authors reviewed 16 studies that together included 238,449 adults. Investigating risk ratios (RRs) for the incidence of stroke and mortality in relation to serum uric acid levels in adults, the authors found that in studies that adjusted for known risk factors, the RR for stroke in patients with hyperuricemia was 1.47 (4 studies; 95% confidence interval [CI] 1.19, 1.76) and the RR for mortality was 1.26 (6 studies; 95% CI 1.12, 1.39). Kim et al concluded that further research is needed to determine if reducing patients' uric acid levels will have beneficial effects relating to stroke.

Race

A high prevalence of hyperuricemia exists in indigenous races of the Pacific, which appears to be associated with a low fractional excretion of uric acid. African American persons develop hyperuricemia more commonly than white persons.

Sex

Hyperuricemia, and particularly gouty arthritis, are far more common in men than in women. Only 5% of patients with gout are female, but uric acid levels increase in women after menopause.

Age

The normal serum uric acid level is lower in children than in adults. The upper limit of the reference range for children is 5 mg/dL (0.30 mmol/L). The upper limit of the reference range for men is 7 mg/dL (0.42 mmol/L) and for women is 6 mg/dL (0.36 mmol/L). The tendency to develop hyperuricemia increases with age.

Clinical

History

In patients with hyperuricemia, the history involves determining whether the patient is symptomatic or asymptomatic and identifying causative etiologies and comorbid conditions.

Symptoms are those of gout and nephrolithiasis.

Gout typically manifests as an acute monoarthritis, most commonly in the great toe and less frequently in the tarsal joint, knee, and other joints.

Uric acid nephrolithiasis may manifest with hematuria; pain in the flank, abdomen, or inguinal region; and/or nausea and vomiting.

Physical

Patients are usually asymptomatic, and no specific physical findings are recognized.

In acute gouty arthritis, the affected joint is typically warm, erythematous, swollen, and exquisitely painful.

Patients with chronic gouty arthritis may develop tophi in the helix or antihelix of the ear, along the ulnar surface of the forearm, in the olecranon bursa, or in other tissues.

In uric acid nephrolithiasis, patients may present with abdominal or flank tenderness.

Causes

Hyperuricemia is generally divided into 3 pathophysiologic categories, ie, uric acid underexcretion, uric acid overproduction, and combined causes.

Underexcretion

Idiopathic Familial juvenile gouty nephropathy: This is a rare autosomal dominant condition characterized by

progressive renal insufficiency. These patients have a low fractional excretion of urate (typically 4%). Kidney biopsy findings indicate glomerulosclerosis and tubulointerstitial disease but no uric acid deposition.

Renal insufficiency: Renal failure is one of the more common causes of hyperuricemia. In chronic renal failure, the uric acid level does not generally become elevated until the creatinine clearance falls below 20 mL/min, unless other contributing factors exist. This is due to a decrease in urate clearance as retained organic acids compete for secretion in the proximal tubule. In certain renal disorders, such as medullary cystic disease and chronic lead nephropathy, hyperuricemia is commonly observed even with minimal renal insufficiency.

Syndrome X: This metabolic syndrome is characterized by hypertension, obesity, insulin resistance, dyslipidemia, and hyperuricemia. This is associated with a decreased fractional excretion of urate by the kidneys.

Drugs: Causative drugs include diuretics, low-dose salicylate, cyclosporine, pyrazinamide, ethambutol, levodopa, nicotinic acid, and methoxyflurane.

Hypertension

Acidosis: Types that cause hyperuricemia include lactic acidosis, diabetic ketoacidosis, alcoholic ketoacidosis, and starvation ketoacidosis.

Preeclampsia and eclampsia: The elevated uric acid associated with these conditions is a key clue to the diagnosis because uric acid levels are lower than normal in healthy pregnancies.

Hypothyroidism

Hyperparathyroidism

Sarcoidosis

Lead intoxication (chronic): History may reveal occupational exposure (eg, lead smelting, battery and paint manufacture) or consumption of moonshine (ie, illegally distilled corn whiskey) because some, but not all, moonshine was produced in lead-containing stills).

Trisomy 21

Overproduction

Idiopathic HGPRT deficiency (Lesch-Nyhan syndrome): This is an inherited X-linked disorder. HGRPT

catalyzes the conversion of hypoxanthine to inosinic acid, in which PRPP serves as the phosphate donor. The deficiency of HGPRT results in accumulation of PRPP, which accelerates purine biosynthesis with a resultant increase in uric acid production. In addition to gout and uric acid nephrolithiasis, these patients develop a neurologic disorder that is characterized by choreoathetosis, spasticity, growth, mental function retardation, and, occasionally, self-mutilation.

Partial deficiency of HGPRT (Kelley-Seegmiller syndrome): This is also an X-linked disorder. Patients typically develop gouty arthritis in the second or third decade of life, have a high incidence of uric acid nephrolithiasis, and may have mild neurologic deficits.

Increased activity of PRPP synthetase: This is a rare X-linked disorder in which patients make mutated PRPP synthetase enzymes with increased activity. These patients develop gout when aged 15-30 years and have a high incidence of uric acid renal stones.

Purine-rich diet: A diet rich in meats, organ foods, alcohol,1 and legumes can result in an overproduction of uric acid.

Increased nucleic acid turnover: This may be observed in persons with hemolytic anemia and hematologic malignancies such as lymphoma, myeloma, or leukemia.

Tumor lysis syndrome: This may produce the most serious complications of hyperuricemia.

Glycogenoses III, V, and VII

Combined causes

Alcohol1 : Ethanol increases the production of uric acid by causing increased turnover of adenine nucleotides. It also decreases uric acid excretion by the kidneys, which is partially due to the production of lactic acid.

Exercise: Exercise may result in enhanced tissue breakdown and decreased renal excretion due to mild volume depletion.

Deficiency of aldolase B (fructose-1-phosphate aldolase): This is a fairly common inherited disorder, often resulting in gout.

Glucose-6-phosphatase deficiency (glycogenosis type I, von Gierke disease): This is an autosomal recessive disorder characterized by the development of symptomatic hypoglycemia and hepatomegaly within the first 12 months of life. Additional findings include short stature, delayed adolescence, enlarged kidneys, hepatic adenoma, hyperuricemia, hyperlipidemia, and increased serum lactate levels.

Hypocalcemia

Introduction

Background

Hypocalcemia is frequently encountered in patients who are hospitalized. Presentations vary widely, from asymptomatic to life-threatening situations. A 70 kg person has approximately 1.2 kg of calcium in the body, most of which is stored as hydroxyapatite in bones (>99%). Less than 1% (5-6 g) of this calcium is located in the intracellular and extracellular compartments, with only 1.3 g located extracellularly. The total calcium concentration in the plasma is 4.5-5.1 mEq/L (9-10.2 mg/dL). Fifty percent of plasma calcium is ionized, 40% is bound to proteins (90% of which binds to albumin), and 10% circulates bound to anions (eg, phosphate, carbonate, citrate, lactate, sulfate).

At a plasma pH of 7.4, each gram of albumin binds 0.8 mg/dL of calcium. This bond is dependent on the carboxyl groups of albumin and is highly dependent on pH. Acute acidemia decreases calcium binding to albumin, whereas alkalemia increases binding, which decreases ionized calcium. Clinical signs and symptoms are observed only with decreases in ionized calcium concentration (normally 4.5-5.5 mg/dL).1,2

Pathophysiology

Ionized calcium is the necessary plasma fraction for normal physiologic processes. In the neuromuscular system, ionized calcium levels facilitate nerve conduction, muscle contraction, and muscle relaxation. Calcium is necessary for bone mineralization and is an important cofactor for hormonal secretion in endocrine organs. At the cellular level, calcium is an important regulator of ion transport and membrane integrity. The calcium turnover is estimated at 10-20 mEq/d. Approximately 500 mg of calcium are removed from the bones daily and replaced by an equal amount. Normally, the amount of calcium absorbed by the intestines is matched by urinary calcium excretion. Despite these enormous fluxes of

calcium, the levels of ionized calcium remain stable because of the rigid control of parathyroid hormone (PTH) and vitamin D levels. Normocalcemia requires PTH and normal target-organ response to PTH. The parathyroid gland has a remarkable sensitivity to ionized serum calcium changes.

These changes are recognized by the calcium-sensing receptor (CaSR), a 7-transmembrane receptor linked to G-protein with a large extracellular amino-terminal region. Binding of calcium to the CaSR induces activation of phospholipase C and inhibition of PTH secretion. On the other hand, a slight decrease in calcium stimulates the chief cells of the parathyroid gland to secrete PTH. CaSR is crucial in PTH secretion. A loss of CaSR function leads to pathological states, such as familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. In renal failure, CaSR agonists suppress the progression of hyperparathyroidism and parathyroid gland growth. PTH stimulates osteoclastic bone reabsorption and distal tubular calcium reabsorption and mediates 1,25-dihydroxyvitamin D (1,25[OH]2 D) intestinal calcium absorption.3

Vitamin D stimulates intestinal absorption of calcium, regulates PTH release by the chief cells, and mediates PTH-stimulated bone reabsorption. Patients with a decrease in total serum calcium may not have "true" hypocalcemia, which is defined as a decrease in ionized calcium. A reduction in total serum calcium can result from a decrease in albumin secondary to liver disease, nephrotic syndrome, or malnutrition. Hypocalcemia causes neuromuscular irritability and tetany. Alkalemia induces tetany due to a decrease in ionized calcium, whereas acidemia is protective. This pathophysiology is important in patients with renal failure who have hypocalcemia because rapid correction of acidemia or development of alkalemia may trigger tetany.4,5,6

Frequency

United States

Hypocalcemia is less frequent than hypercalcemia. In order of frequency, hypocalcemia occurs in patients with chronic and acute renal failure; vitamin D deficiency; magnesium (Mg) deficiency; acute pancreatitis; hypoparathyroidism and pseudohypoparathyroidism; and infusion of phosphate, citrate, or calcium-free albumin.

Mortality/Morbidity

Hypocalcemia can present with subtle findings, but it also can be associated with significant clinical manifestations.

Cardiovascular complications: In severe cases, hypocalcemia may lead to arrhythmias, hypotension, and heart failure. Some patients may manifest digitalis insensitivity.

Neurologic complications: In addition to acute seizures or tetany, hypocalcemia may lead to basal ganglia calcification, parkinsonism, hemiballismus, and choreoathetosis. Although some patients with hypocalcemia may improve with treatment, the calcification typically is not reversible.

Sex

Hypocalcemia occurs with similar frequency in men and women.

Age

The age distribution is contingent on the disorder that led to hypocalcemia. In children, nutritional deficiencies are more frequent; in adults, renal failure predominates. However, the recognition of the high

prevalence of vitamin D deficiency, particularly in elderly patients, may change our understanding of hypocalcemia in the general population.

Clinical

History

Once laboratory results demonstrate hypocalcemia, the first question is whether the hypocalcemia is true, that is, representative of a decrease in ionized calcium.

Patient historyo The presence of chronic diarrhea or intestinal disease, such as is observed with Crohn

disease, sprue, or chronic pancreatitis, suggests the possibility of hypocalcemia due to malabsorption of calcium and/or vitamin D.

o Previous neck surgery suggests hypoparathyroidism; a history of seizures suggests

hypocalcemia secondary to anticonvulsants.

o The length of time that a disorder is present is an important clue. Hypoparathyroidism

and pseudohypoparathyroidism are lifelong disorders. Instead, acute transient hypocalcemia may be associated with acute gastrointestinal illness, nutritional deficiency, or acute or chronic renal failure.

o In an elderly patient, a nutritional deficiency may be associated with a low intake of

vitamin D.

o A history of alcoholism can help diagnose hypocalcemia due to magnesium deficiency,

malabsorption, or chronic pancreatitis.

o Family history of hypocalcemia

o Low-calcium diet

o Lack of sun exposure

o Use of certain medications, such as the calcimimetic agent, cinacalcet, and

anticonvulsants

Clinical symptoms7

o Neuromuscular8

Numbness and tingling sensations in the perioral area or in the fingers and toes

Muscle cramps, particularly in the back and lower extremities; may progress to carpopedal spasm (ie, tetany)

Wheezing; may develop from bronchospasm

Dysphagia 

Voice changes (due to laryngospasm)

o Neurologic9

Irritability, impaired intellectual capacity, depression, and personality changes

Fatigue

Seizures (eg, grand mal, petit mal, focal) 

Other uncontrolled movements

o Cardiac

Shortness of breath

Symptoms of congestive heart failure (possible)

o Skin

Coarse hair

Brittle nails

Psoriasis

Dry skin

Physical

Physical examination findings may include the following:

General: Patients may appear confused or disoriented. They may exhibit signs of dementia or overt psychosis.

Head: Hair may appear coarse. Alopecia may be present.

Eyes: Subcapsular cataracts or papilledema can be seen.

Oral: If chronic (since childhood), patients may be at an increased risk of dental caries and enamel hypoplasia.

Respiratory: Inspiratory or expiratory wheezes may be present.

Cardiac: Signs of heart failure may be present (see Other Tests). 

Skin: Dry skin or patches of psoriasis and eczema may be present, particularly in patients with chronic hypocalcemia.

Neurologic 

o Chvostek sign: Tapping the skin over the facial nerve immediately in front of the external

auditory meatus will cause an ipsilateral contraction of the facial muscles. Up to 10% of the population will have a positive Chvostek sign. This test, while suggestive, is not diagnostic of hypocalcemia. 

o Trousseau sign: Place a blood pressure cuff on the patient’s arm and inflate to 20 mm Hg

above systolic blood pressure for 3-5 minutes. This increases the irritability of the nerves, and a flexion of the wrist and metacarpal phalangeal joints can be observed with extension of the interphalangeal joints and adduction of the thumb (carpal spasm). Trousseau sign is more specific than Chvostek sign, but the test result can be negative.

Movement abnormalities include the following:

o Choreoathetosis10

o Dystonic spasm

o Parkinsonism

o Hemiballism

Causes

Hypocalcemia has a variety of causes.

Hypoalbuminemia

The first step in evaluation of hypocalcemia it to measure the serum albumin levels, as low serum albumin levels can cause a reduction in total, but not the ionized, fraction of serum calcium. Patients do not have any signs or symptoms of hypocalcemia.

Each 1 g/dL reduction in the serum albumin concentration will lower the total calcium concentration by approximately 0.8 mg/dL without affecting the ionized calcium concentration. This is not a completely precise method, and ionized calcium measurements in the serum can confirm whether true hypocalcemia is present.

Pseudohypocalcemia

Gadolinium-based contrast agents (used in magnetic resonance imaging and angiography), gadodiamide and gadoversetamide, may interfere with the colorimetric assays for calcium that are frequently used in hospital laboratories. This effect is not observed with other gadolinium-based agents: dimeglumine gadopentetate, gadoteridol, or gadoterate meglumine.

The interaction can result in a marked reduction in the measured calcium concentration of as much as 6 mg/dL if a blood sample is obtained soon after the test. This effect is rapidly reversible as the gadolinium is excreted in the urine, and the patient has no symptoms or signs of hypocalcemia. Awareness of this phenomenon is particularly important in patients with renal insufficiency who may retain the contrast agent for prolonged periods. There is no reason to treat this type of hypocalcemia.11,12,13

Parathyroid hormone related

Hypoparathyroidism 

This condition can be hereditary or acquired. Both varieties share the same symptoms, although hereditary hypoparathyroidism tends to have a gradual onset.14

Acquired hypoparathyroidism may result from the following:

Neck irradiation/radioiodine therapy15

Postparathyroidectomy in dialysis patients16

Inadvertent surgical removal (can be transient or permanent)

Infiltrative disease is similar to hemachromatosis, granulomatous disease (sarcoidosis), thalassemia, amyloidosis, or metastatic malignant infiltration of the glands.

Late-onset hypoparathyroidism can be seen as a part of a complex autoimmune disorder involving ovarian failure and adrenal failure. Mucocutaneous candidiasis, alopecia, vitiligo, and pernicious anemia are associated with this disorder, which is referred to as polyglandular autoimmune disease (PGA I).

Hereditary hypoparathyroidism may be familial or sporadic, and it can occur as an isolated entity or can be associated with other endocrine manifestations.

The familial forms include autosomal dominant and autosomal recessive, as well as a sex-linked form of early onset, for which the gene has been located on the long arm of the X chromosome.

Sporadic, late-onset hypoparathyroidism is associated with DiGeorge syndrome, which is also associated with congenital heart disease, cleft palate/lip, and abnormal facies. Some cases are associated with Kearns-Sayre syndrome, which presents with heart block, retinitis pigmentosa, and ophthalmoplegia. Kenny-Caffey syndrome is associated with hypoparathyroidism and includes medullary stenosis of the long bones and growth retardation.

Pseudohypoparathyroidism 

This condition is characterized by end-organ resistance to the effects of PTH. PTH binds to the PTH receptor, which, in turn, activates cyclic adenosine monophosphate (cAMP) through guanine nucleotide regulatory proteins (Gs). These proteins consist of alpha, beta, and gamma subunits.

Pseudohypoparathyroidism is classified into types I and II. Type I is further subdivided into Ia, Ib, and Ic.14

Type Ia o Pseudohypoparathyroidism type Ia results from a decrease in the Gs-alpha protein. In

1942, Albright et al described a disorder, known as Albright hereditary osteodystrophy (AHO), comprised of short stature, mental retardation, obesity, round-shaped face, brachymetacarpia, brachymetatarsia, and subcutaneous bone formation. These somatic features of Albright hereditary osteodystrophy and the presence of the biochemical features of pseudohypoparathyroidism constitute type Ia.

o Laboratory findings include hypocalcemia, hyperphosphatemia (with normal or high PTH

levels), and low calcitriol. Vitamin D may be decreased because of inhibition by elevated levels of phosphorus and by decreased PTH stimulation of the 25-hydroxyvitamin D 1-alpha-hydroxylase. The low calcitriol levels, in turn, may cause the resistance to the hypercalcemic effects of PTH in the bone.

o The defect of the Gs-alpha protein is not confined to the effects of PTH but also affects

other hormonal systems (eg, resistance to glucagon, thyroid-stimulating hormone, gonadotropins). The gene for the Gs-alpha protein is located on chromosome 20. Some

family members carry the mutation and display the AHO phenotype but do not have pseudohypoparathyroidism. This is termed pseudo-pseudohypoparathyroidism.

Type Ib: These patients do not present with the somatic features of Albright hereditary osteodystrophy. These patients have normal Gs-alpha protein, with hormonal resistance to PTH—an impaired cAMP response to PTH, suggesting that the defect lies on the receptor. At what level the receptor is affected is not yet clear.

Type Ic: Patients with this type present with resistance to multiple hormonal receptors but have normal Gs-alpha protein expression.

Type II: In patients with this type of pseudohypoparathyroidism, PTH raises cAMP normally but fails to increase levels of serum calcium or urinary phosphate excretion, suggesting that the defect is located downstream of the generation of cAMP. If the patient presents with hypocalcemia, hypophosphaturia, and elevated immunoreactive parathyroid hormone (iPTH) levels, first rule out vitamin D deficiency, which has a similar presentation. In patients with a vitamin D deficiency, all parameters return to normal after vitamin D administration.

Hypomagnesemia 

Severe hypomagnesemia can lead to hypocalcemia, which is resistant to the administration of calcium and vitamin D. The usual cause of hypomagnesemia is due to loss through the kidney (eg, osmotic diuresis, drugs) or the gastrointestinal tract (eg, chronic diarrhea, severe pancreatitis, bypass or resection of small bowel). These patients present with low or inappropriately normal PTH levels in the presence of hypocalcemia. The mechanism of hypocalcemia includes resistance to PTH in the bone and kidneys, as well as a decrease in PTH secretion. Acute magnesium restoration rapidly corrects the PTH level, suggesting the hypomagnesemia affects the release of PTH, rather than its synthesis.

Ineffective PTH 

Vitamin D is a necessary cofactor for the normal response to PTH, and deficiency renders PTH ineffective. Poor nutritional intake, chronic renal insufficiency, or reduced exposure to sunlight may cause vitamin D deficiency.

Vitamin D related

Nutritional deficiency

Current federal guidelines recommend 200-600 IU of vitamin D per day for adults, depending upon age.

Studies have recognized that vitamin D insufficiency can still occur and lead to an increased PTH and subsequent bone turnover. Studies have also shown that dietary intake of vitamin D varies greatly by race and age. In one review of National Health and Nutrition Examination Survey (NHANES) III data, 42% of African American women had low blood levels of vitamin D compared to 4% in Caucasian women.17

Another observational study in elderly adults found that 74% of those studied were deficient in vitamin D, despite adequate intake.18 The authors of this study suggested that the current guidelines for the elderly be increased to 800-1000 IU per day. The recognition of mild hypovitaminosis D may not be trivial. In an

elderly population with an increased PTH and osteoporosis, response to alendronate was attenuated. This attenuation was improved when vitamin D was administered.19,20

Impaired absorption 

Numerous conditions can impair the absorption of vitamin D. Small bowel diseases, such as celiac disease, gastric bypass (particularly long limb Roux-en-Y gastric bypass), steatorrhea, and pancreatic diseases can all lead to low vitamin D levels.21

Inheritable conditions

Pseudovitamin D deficiency rickets (type I) or 1-alpha-hydroxylase deficiency: This condition is secondary to an autosomal mutation of the 1-hydroxylase gene. Ultimately, calcidiol is not hydroxylated to calcitriol and calcium is not absorbed appropriately. This condition is considered pseudovitamin D deficiency because high doses of vitamin D can overcome the clinical and biochemical findings of this disease.

Hereditary vitamin D resistance rickets: This condition is extremely rare and is caused by a mutation in the vitamin D receptor. Typically, this condition presents within the first 2 years of life.

Hepatic disease 

Liver disease with decreased synthetic function can cause vitamin D deficiency from several sources, as follows: impaired 25-hydroxylation of vitamin D, decreased bile salts with malabsorption of vitamin D, decreased synthesis of vitamin D–binding protein, or other factors. Patients with cirrhosis and osteomalacia have low or normal levels of calcitriol, suggesting that other factors may interfere with vitamin D function or are synergistic with malabsorption or decreased sun exposure. These patients require administration of calcidiol or calcitriol for the treatment of hypocalcemia.

Renal failure

Chronic kidney disease leads to a decrease in the conversion of 25-hydroxyvitamin D to its active form 1,25-dihydroxyvitamin D, particularly when the glomerular filtration rate (GFR) falls below 30 mL/min. This results in an increase in PTH. Ultimately, the increased absorption of phosphorus and calcium can lead to calcium-phosphorus mineral deposition in the soft tissues. In the early stages of renal failure, hypocalcemia can be seen due to the decrease in calcitriol production and a subsequent decrease in the intestinal absorption of calcium.

Critical illness and severe sepsis

A patient with acute illness may experience hypocalcemia for multiple reasons. In one study, the 3 most common factors identified in patients with hypocalcemia associated with acute illness were hypomagnesemia, acute renal failure, and transfusions. In gram-negative sepsis, there is a reduction in total and ionized serum calcium. The mechanism for this remains unknown, but it appears to be associated with multiple factors, including elevated levels of cytokines (eg, interleukin-6, interleukin-1, TNF-alpha), hypoparathyroidism, and vitamin D deficiency or resistance. Mortality rates increase among patients with sepsis and hypocalcemia, compared with patients who are normocalcemic.22,23 However, there is no clear evidence that treating critically ill patients with supplemental calcium alters outcomes.24

Hungry bone syndrome

Surgical correction of primary or secondary hyperparathyroidism may be associated with severe hypocalcemia due to a rapid increase in bone remodeling. Hypocalcemia results if the rate of skeletal mineralization exceeds the rate of osteoclast-mediated bone resorption. A less severe picture is also observed after correction of thyrotoxicosis, after institution of vitamin D therapy for osteomalacia, and with tumors associated with bone formation (eg, prostate, breast, leukemia). All of these disease states result in hypocalcemia due to mineralization of large amounts of unmineralized osteoid.25

Acute pancreatitis

Pancreatitis can be associated with tetany and hypocalcemia. It is caused primarily by precipitation of calcium soaps in the abdominal cavity, but glucagon-stimulated calcitonin release and decreased PTH secretion may play a role. When the pancreas is damaged, free fatty acids are generated by the action of pancreatic lipase. Insoluble calcium salts are present in the pancreas, and the free fatty acids avidly chelate the salts, resulting in calcium deposition in the retroperitoneum. In addition, hypoalbuminemia may be a part of the clinical picture, resulting in a reduction in total serum calcium. In patients with concomitant alcohol abuse, a poor nutritional intake of calcium and vitamin D, as well as accompanying hypomagnesemia, may predispose these patients to hypocalcemia.26

Hyperphosphatemia

Hyperphosphatemia (due to renal failure, phosphate administration, or excess tissue breakdown because of rhabdomyolysis or tumor lysis) causes acute hypocalcemia. In acute hyperphosphatemia, calcium is deposited mostly in the bone but also in the extraskeletal tissue. In contrast, in chronic hyperphosphatemia, which is nearly always due to chronic renal failure, calcium efflux from the bone is inhibited and the calcium absorption is low, due to reduced renal synthesis of 1,25-dihydroxyvitamin D. However, other consequences of renal failure, including a primary impairment in calcitriol synthesis, also contribute to hypocalcemia.

Medications and other causes

Cinacalcet (calcimimetic agent)

Patients receiving the calcimimetic agent to help control secondary hyperparathyroidism in renal failure may experience hypocalcemia as a result of acute inhibition of PTH release. Clinically significant hypocalcemia occurs in approximately 5% of patients treated with cinacalcet.27

Chemotherapy

Hypocalcemia can occur in patients treated with some chemotherapeutic drugs. Cisplatin can induce hypocalcemia by causing hypomagnesemia. Combination therapy with 5-fluorouracil and leucovorin can also cause mild hypocalcemia (65% of patients in one series), possibly by decreasing calcitriol production.28 

Bisphosphonates

Hypocalcemia may result from the treatment of hypercalcemia with bisphosphonates, particularly zoledronic acid, which is significantly more potent than other bisphosphates in suppressing the formation and function of osteoclasts. Patients who are affected appear to lack an adequate PTH response to

decreasing serum calcium levels.29 

Anticonvulsant therapy 

Hypocalcemia and osteomalacia have been described with prolonged therapy with anticonvulsants, such as phenytoin or phenobarbital.30 

Foscarnet

Foscarnet is a drug used to treat refractory cytomegalovirus and herpes infections in patients who are immunocompromised. It complexes ionized calcium and, therefore, lowers ionized calcium concentrations, potentially causing symptomatic hypocalcemia. Therefore, the ionized calcium concentration should be measured at the end of an infusion of foscarnet.

Citrated blood

Symptomatic hypocalcemia during transfusion of citrated blood or plasma is rare, because healthy patients rapidly metabolize citrate in the liver and kidney. However, a clinically important fall in serum ionized calcium concentration can occur if citrate metabolism is impaired due to hepatic or renal failure or if large quantities of citrate are given rapidly, for example, during plasma exchange or massive blood transfusion.

Sodium phosphate preparations 

These agents, which come in aqueous and tablet forms of preparation, are used to cleanse the bowel prior to GI procedures, such as colonoscopy. In certain populations (those consisting of persons with renal failure, advanced age, congestive heart failure, hepatic insufficiency, or volume depletion, or of individuals who use of other drugs, such as angiotensin-converting enzyme [ACE] inhibitors and nonsteroidal anti-inflammatory drugs [NSAIDS]), these agents can lead to acute hyperphosphatemia and subsequent hypocalcemia.31,32 

Ethylenediaminetetraacetic acid (EDTA) 

Some radiographic contrast dyes may contain EDTA, which chelates calcium in serum, thereby reducing serum ionized calcium concentration, resulting in hypocalcemia.

Fluoride poisoning 

Rarely, an excess intake of fluoride can cause hypocalcemia; this effect is presumably mediated by inhibition of bone resorption. Overfluorinated public water supplies and ingestion of fluoride-containing cleaning agents have been associated with low serum calcium levels. In this case, hypocalcemia is thought to be due to excessive rates of skeletal mineralization secondary to formation of calcium difluoride complex.

Hypokalemia

Introduction

Background

Potassium homeostasis

Potassium, the most abundant intracellular cation, is essential for the life of the organism. Potassium is obtained through the diet, and common potassium-rich foods include meats, beans, fruits, and potatoes.

Gastrointestinal absorption is complete, resulting in daily excess intake of approximately 1 mEq/kg/d (60-100 mEq). Ninety percent of this excess is excreted through the kidneys, and 10% is excreted through the gut. Potassium homeostasis is maintained predominantly through the regulation of renal excretion. The most important site of regulation is the collecting duct, where aldosterone receptors are present.

Excretion is increased by (1) aldosterone, (2) high sodium delivery to the collecting duct (eg, diuretics), (3) high urine flow (eg, osmotic diuresis), (4) high serum potassium level, and (5) delivery of negatively charged ions to the collecting duct (eg, bicarbonate).

Excretion is decreased by (1) absence or relative deficiency of aldosterone, (2) low sodium delivery to the collecting duct, (3) low urine flow, (4) low serum potassium level, and (5) renal failure.

Kidneys adapt to acute and chronic alterations in potassium intake. When potassium intake is chronically high, potassium excretion likewise is increased. In the absence of potassium intake, obligatory renal losses are 10-15 mEq/d. Thus, chronic losses occur in the absence of any ingested potassium. The kidney maintains a central role in the maintenance of potassium homeostasis, even in the setting of chronic renal failure. Renal adaptive mechanisms allow the kidneys to maintain potassium homeostasis until the glomerular filtration rate drops to less than 15-20 mL/min. Additionally, in the presence of renal failure, the proportion of potassium excreted through the gut increases. The colon is the major site of gut regulation of potassium excretion. Therefore, potassium levels can remain relatively normal under stable conditions, even with advanced renal insufficiency. However, as renal function worsens, the kidneys may not be capable of handling an acute potassium load.

Serum potassium level

Potassium is predominantly an intracellular cation; therefore, serum potassium levels can be a very poor indicator of total body stores. Because potassium moves easily across cell membranes, serum potassium levels reflect movement of potassium between intracellular and extracellular fluid compartments, as well as total body potassium homeostasis.

Mechanisms for sensing extracellular potassium concentration are not well understood. Evidence

suggests that adrenal glomerulosa cells and pancreatic beta cells may play a role in potassium sensing, resulting in alterations in aldosterone and insulin secretion.1,2   As both of these hormonal systems play important roles in potassium homeostasis, these new findings are no surprise; however, the molecular mechanisms by which these potassium channels signal changes in hormone secretion and activity have still not been determined.

Muscle contains the bulk of body potassium, and the notion that muscle could play a prominent role in the regulation of serum potassium concentration through alterations in sodium pump activity has been promoted for a number of years. Insulin stimulated by potassium ingestion increases the activity of the sodium pump in muscle cells, resulting in an increased uptake of potassium. Studies in a model of potassium deprivation demonstrate that acutely, skeletal muscle develops resistance to insulin-stimulated potassium uptake even in the absence of changes in muscle cell sodium pump expression. However, long term potassium deprivation results in a decrease in muscle cell sodium-pump expression, resulting in decreased muscle uptake of potassium.3,4,5 

Thus, there appears to be a well-developed system for sensing potassium by the pancreas and adrenal glands, resulting in rapid adjustments in immediate potassium disposal and for long-term potassium homeostasis. High potassium states stimulate cellular uptake via insulin-mediated stimulation of sodium-pump activity in muscle and stimulate potassium secretion by the kidney via aldosterone-mediated enhancement of distal renal expression of secretory potassium channels (ROMK). Low potassium states result in insulin resistance, impairing potassium uptake into muscle cells, and cause decreased aldosterone release, lessening renal potassium excretion.

Several factors regulate the distribution of potassium between the intracellular and extracellular space, as follows:

Glycoregulatory hormones: (1) Insulin enhances potassium entry into cells, and (2) glucagon impairs potassium entry into cells.

Adrenergic stimuli: (1) Beta-adrenergic stimuli enhance potassium entry into cells, and (2) alpha-adrenergic stimuli impair potassium entry into cells.

pH: (1) Alkalosis enhances potassium entry into cells, and (2) acidosis impairs potassium entry into cells.

An acute increase in osmolality causes potassium to exit from cells. An acute cell/tissue breakdown releases potassium into extracellular space.

Pathophysiology

Hypokalemia can occur due to 1 of 3 pathogenetic mechanisms.

The first is deficient intake. Poor potassium intake alone is an uncommon cause of hypokalemia but occasionally can be seen in very elderly individuals unable to cook for themselves or unable to chew or swallow well. Over time, such individuals can accumulate a significant potassium deficit. Another clinical situation where hypokalemia may occur due to poor intake is in patients receiving total parenteral nutrition (TPN), where potassium supplementation may be inadequate for a prolonged period of time.

The second is increased excretion. Increased excretion of potassium, especially coupled with poor intake, is the most common cause of hypokalemia. The most common mechanisms leading to increased renal

potassium losses include enhanced sodium delivery to the collecting duct, as with diuretics; mineralocorticoid excess, as with primary or secondary hyperaldosteronism; or increased urine flow, as with an osmotic diuresis.

Gastrointestinal losses, most commonly from diarrhea, also are common causes of hypokalemia. Vomiting is a common cause of hypokalemia, but the pathogenesis of the hypokalemia is complex. Gastric fluid itself contains little potassium, approximately 10 mEq/L. However, vomiting produces volume depletion and metabolic alkalosis. These 2 processes are accompanied by increased renal potassium excretion. Volume depletion leads to secondary hyperaldosteronism, which, in turn, leads to enhanced cortical collecting tubule secretion of potassium in response to enhanced sodium reabsorption. Metabolic alkalosis also increases collecting tubule potassium secretion due to the decreased availability of hydrogen ions for secretion in response to sodium reabsorption.

The third is due to a shift from extracellular to intracellular space. This pathogenetic mechanism also often accompanies increased excretion, leading to a potentiation of the hypokalemic effect of excessive loss. Intracellular shifts of potassium often are episodic and frequently are self-limited, for example, with acute insulin therapy for hyperglycemia.

Regardless of the cause, hypokalemia produces similar signs and symptoms. Because potassium is overwhelmingly an intracellular cation and because a variety of factors can regulate the actual serum potassium concentration, an individual can incur very substantial potassium losses without exhibiting frank hypokalemia. Conversely, hypokalemia does not always reflect a true deficit in total body potassium stores.

Frequency

United States

In the general population, data are difficult to estimate; however, probably fewer than 1% of people on no medications have a serum potassium level of lower than 3.5 mEq/L. Potassium intake varies according to age, sex, ethnic background, and socioeconomic status. Whether these differences in intake produce different degrees of hypokalemia or different sensitivities to hypokalemic insults is not known. Up to 21% of hospitalized patients have serum potassium levels lower than 3.5 mEq/L, with 5% of patients achieving potassium levels lower than 3 mEq/L. Of elderly patients, 5% demonstrate potassium levels lower than 3 mEq/L.

In patients on non – potassium-sparing diuretics, hypokalemia is present in 20-50%. African Americans and females are more susceptible. Risk is enhanced by concomitant illness such as heart failure or nephrotic syndrome.

Other groups with a high incidence of hypokalemia include individuals with eating disorders, published incidence ranging from 4.6%6 to 19.7%7 in an outpatient setting; patients with AIDS, of which 23.1% of hospitalized patients are hypokalemic; and patients with alcoholism, where the incidence of hypokalemia in the inpatient setting is reportedly as high as 12.6%8 and is likely due to a hypomagnesemia-induced decrease in tubular reabsorption of potassium. A relatively new and emerging group of individuals who are at high risk for hypokalemia are patients who have undergone bariatric surgery.9

Mortality/Morbidity

Hypokalemia generally is associated with higher morbidity and mortality, especially due to cardiac arrhythmias or sudden cardiac death. However, an independent contribution of hypokalemia to increased morbidity/mortality has not been conclusively established.

Patients who develop hypokalemia often have multiple medical problems, making the separation and quantitation of the contribution by hypokalemia, per se, difficult. For further details, see Complications.

Race

Some suggestion is observed of increased frequency of diuretic-induced hypokalemia in African Americans. The higher frequency of hypokalemia in this group may be due to the lower intake of potassium among African American men (approximately 25 mEq/d) than in their white counterparts (70-100 mEq/d).

Sex

Some suggestion also is observed of increased frequency of diuretic-induced hypokalemia in women.

Age

With age, frequency increases, due to increased use of diuretics and poor diet, which often is low in potassium.

Clinical

History

Symptoms are nonspecific and predominantly are related to muscular or cardiac function.o Weakness and fatigue are the most common complaints. The muscular weakness that

occurs with hypokalemia can manifest in protean ways, ie, dyspnea, constipation or abdominal distention, or exercise intolerance. Rarely, muscle weakness progresses to frank paralysis.

o Occasionally, a patient may complain of worsening diabetes control or polyuria due to a

recent onset of hyperglycemia or nephrogenic diabetes insipidus.

o The patient also may complain of palpitations.

o With severe hypokalemia or total body potassium deficits, muscle cramps and pain can

occur with rhabdomyolysis.

When the diagnosis of hypokalemia is discovered, investigate potential pathophysiologic mechanisms.

o Poor intake may result from the following:

Eating disorders

Dental problems

Poverty

o Increased excretion may be due to the following:

Medications, including diuretics, AIDS therapy, or antibiotics

Polyuria

Vomiting or diarrhea

o Shift of potassium into the intracellular space may occur due to the following:

Recurrent episodes of paralysis

Use of high doses of insulin

High-dose beta agonist therapy (eg, for chronic obstructive pulmonary disease)

Physical

Vital signs generally are normal, except for occasional tachycardia or tachypnea due to respiratory muscle weakness.

o Hypertension may be a clue to primary hyperaldosteronism, renal artery stenosis, licorice

ingestion, or the more unusual forms of genetically transmitted hypertensive syndromes such as congenital adrenal hyperplasia, glucocorticoid remediable hypertension, or Liddle syndrome.

o Relative hypotension should suggest occult laxative use, diuretic use, bulimia, or one of

the unusual tubular disorders such as Bartter syndrome or Gitelman syndrome (see Bartter Syndrome). Bear in mind that occult diuretic use is far more common than either congenital tubular disorder and is, in fact, also called "pseudo Bartter."

Muscle weakness and flaccid paralysis may be present.

Patients may have depressed or absent deep-tendon reflexes.

Causes

Pathophysiologic mechanisms include poor intake, increased excretion, or a shift of potassium from the extracellular to the intracellular space. Mechanisms causing increased excretion are the most common. Singly, poor intake or an intracellular shift is a distinctly uncommon cause. Often, several disorders are present simultaneously.

Poor intakeo Eating disorders: Anorexia, bulimia, starvation, pica, and alcoholism

o Dental problems: Inability to chew or swallow

o Poverty: Lack of food, ie, "tea-and-toast" diet of elderly individuals

o Hospitalization: Potassium-poor TPN

Increased excretion

o Endogenous mineralocorticoid excess

Cushing disease

Primary hyperaldosteronism, most commonly due to adenoma or bilateral adrenal hyperplasia

Secondary hyperaldosteronism due to volume depletion, congestive heart failure, cirrhosis, or vomiting

Adrenocortical carcinoma

Tumor that is producing adrenocorticotropic hormone

Congenital disorders - Congenital adrenal hyperplasia (11-beta hydroxylase or 17-alpha hydroxylase deficiency) or glucocorticoid-remediable hypertension

o Hyperreninism due to renal artery stenosis

o Exogenous mineralocorticoid excess

Steroid therapy for immunosuppression

Glycyrrhizic  acid -  Inhibits 11-beta hydroxysteroid dehydrogenase; contained in licorice and Chinese herbal preparations

Renal tubular disorders - Type I and type II renal tubular acidosis

Hypomagnesemia

o Congenital disorders

Bartter syndrome: This is a group of autosomal-recessive disorders characterized by hypokalemic metabolic alkalosis and hypotension. Mutations in 6 different renal tubular proteins in the loop of Henle have been discovered in individuals with clinical Bartter syndrome.10,11 They are the NaKCl (NKCC2) transporter; the ROMK1 potassium channel; the chloride channel CLCKa either alone or in combination with the chloride channel CLCKb; the calcium sensing receptor; and barttin, a protein required for the surface expression of the chloride channels. The most severe cases present antenatally or neonatally with profound volume depletion and hypokalemia. Less severe cases present in childhood or early adulthood with persistent hypokalemic metabolic alkalosis that is resistant to replacement therapy. Type IV, a variant to the classic Bartter syndrome, is associated with sensorineural hearing loss.

Gitelman syndrome: This is an autosomal-recessive disorder characterized by hypokalemic metabolic alkalosis and low blood pressure. It is caused by a defect in the thiazide-sensitive sodium chloride transporter in the distal tubule. Compared to Bartter syndrome, it generally is milder, presents later, and is complicated by hypomagnesemia. In contrast, patients with Bartter syndrome generally do not develop hypomagnesemia. Hypocalciuria is also frequently

found in Gitelman syndrome, while the patients with Bartter syndrome are more likely to have increased urinary calcium excretion.

Liddle syndrome: This syndrome is an autosomal-recessive disorder characterized by a mutation in the epithelial sodium channel in the aldosterone-sensitive portion of the nephron, leading to unregulated sodium reabsorption, hypokalemic metabolic alkalosis, and severe hypertension.

o Osmotic diuresis: Mannitol and hyperglycemia can cause osmotic diuresis.

o Increased gastrointestinal losses: Losses can result from diarrhea or small intestine

drainage. The problem can be particularly prominent in tropical illnesses, such as malaria or leptospirosis.12 Severe hypokalemia has also been reported with villous adenoma or VIPomas.13

o Drugs

Diuretics (carbonic anhydrase inhibitors, loop diuretics, thiazide diuretics): Increased collecting duct permeability or increased gradient for potassium secretion can result in losses.

Some penicillins

Exogenous bicarbonate ingestion

Amphotericin B, azole class of antifungal agents, echinocandin class of antifungal agents14

Gentamicin

Cisplatin

Stacker 215

Beta-agonist intoxication16

Shift of potassium from extracellular to intracellular space

o Alkalosis, metabolic or respiratory

o Insulin administration or glucose administration: This stimulates insulin release.

o Intensive beta-adrenergic stimulation

o Hypokalemic periodic paralysis is a rare disorder with recurrent periods of hypokalemic

paralysis between periods of normal serum potassium levels. In most cases, it is due to an abnormality in the alpha 1 subunit of the dihydropyridine-sensitive calcium channel in the skeletal muscle. How a defect in a calcium channel produces hypokalemic paralysis is not well understood.

o Thyrotoxic periodic paralysis is an acquired form of hypokalemic periodic paralysis and is

most common in Asian males. The mechanism by which hyperthyroidism produces

hypokalemic paralysis is not yet understood, but theories include increased Na-K-ATPase activity, which has been found in patients with both thyrotoxicosis and paralysis. 

o Refeeding: This is observed in prolonged starvation, eating disorders, and alcoholism.

Hypomagnesemia

Background and Pathophysiology

Magnesium is the fourth most abundant cation in the body and the second most abundant intracellular cation after potassium.1Magnesium plays a fundamental role in many functions of the cell, including energy transfer, storage, and use; protein, carbohydrate, and fat metabolism; maintenance of normal cell membrane function; and the regulation of parathyroid hormone (PTH) secretion. Systemically, magnesium lowers blood pressure and alters peripheral vascular resistance. Abnormalities of magnesium levels can result in disturbances in nearly every organ system and can cause potentially fatal complications (eg, ventricular arrhythmia, coronary artery vasospasm, sudden death). Despite the well-recognized importance of magnesium, low and high levels have been documented in ill patients,2 as a result of which, magnesium has occasionally been called the "forgotten cation."

This article addresses the basic physiologic principles of magnesium distribution and handling, the causes of hypomagnesemia, disorders related to magnesium depletion, the assessment of magnesium status, and the treatment of magnesium deficiency.

Magnesium homeostasis

The total body magnesium level of an average adult is 25 g, or 1000 mmol. Approximately 60% of the body's magnesium is present in bone, 20% is in muscle, and another 20% is in soft tissue and the liver. Approximately 99% of total body magnesium is intracellular or bone-deposited, with only 1% present in the extracellular space; 80% of plasma magnesium is ionized or complexed to filterable ions (eg, oxalate, phosphate, citrate) and is available for glomerular filtration, while 20% is protein-bound. Normal plasma magnesium concentration is 1.7-2.1 mg/dL (0.7-0.9 mmol, or 1.4-1.7 mEq/L).1

The main controlling factors in magnesium homeostasis appear to be gastrointestinal absorption and renal excretion. The average American diet contains approximately 360 mg (ie, 15 mmol) of magnesium; healthy individuals need to ingest 0.15-0.2 mmol/kg/d to stay in balance. Magnesium is ubiquitous in nature and is especially plentiful in green vegetables, cereal, grain, nuts, legumes, and chocolate. Vegetables, fruits, meats, and fish have intermediate values. Food processing and cooking may deplete magnesium content, thus accounting for the apparently high percentage of the population whose magnesium intake is less than the daily allowance.

The plasma magnesium concentration is kept within narrow limits. Extracellular magnesium is in equilibrium with that in the bones and soft tissues (eg, those of the kidneys and intestines). In contrast with other ions, magnesium is treated differently in 2 major respects: (1) no hormonal modulation of urinary magnesium excretion occurs, and (2) bone, the principal reservoir of magnesium, does not readily exchange with circulating magnesium in the extracellular fluid space. This inability to mobilize magnesium stores means that in states of negative magnesium balance, initial losses come from the extracellular space; equilibrium with bone stores does not begin for several weeks.

Magnesium absorption

Magnesium is absorbed principally in the small intestine, through a saturable transport system and via passive diffusion through bulk flow of water. Absorption of magnesium depends on the amount ingested. When the dietary content of magnesium is typical, approximately 30-40% is absorbed. Under conditions

of low magnesium intake (ie, 1 mmol/d), approximately 80% is absorbed, while only 25% is absorbed when intake is high (25 mmol/d). The exact mechanism by which alterations in fractional magnesium absorption occur has yet to be determined. Presumably, only ionized magnesium is absorbed. Increased luminal phosphate or fat may precipitate magnesium and decrease absorption.

In the gut, calcium and magnesium intakes influence each other's absorption; a high calcium intake may decrease magnesium absorption and a low magnesium intake may increase calcium absorption. PTH appears to increase magnesium absorption. Glucocorticoids, which decrease the absorption of calcium, appear to increase the transport of magnesium. Vitamin D may increase magnesium absorption, but its role is controversial.

Renal handling of magnesium

The kidneys play a major role in magnesium homeostasis and in the maintenance of plasma magnesium concentration (see the image below). Approximately 80% of plasma magnesium is ultrafilterable. Under normal circumstances, approximately 95% of filtered magnesium is reabsorbed by various parts of the nephron.

A: Magnesium reabsorption in the thick ascending limb of the loop of Henle. The driving

force for the reabsorption against a concentration gradient is a lumen-positive voltage

gradient generated by the reabsorption of NaCl. Terms: FHHNC (familial hypomagnesemia

with hypercalciuria and nephrocalcinosis); ADH (autosomal-dominant hypocalcemia);

FHH/NSHPT (familial hypomagnesemia/neonatal severe hyperparathyroidism). B:

Magnesium reabsorption in the distal convoluted tubule. Active transcellular transport is

mediated by an apical entry through a magnesium channel and a basolateral exit,

presumably via a Na+/Mg2+ exchange mechanism. Terms: HSH (hypomagnesemia with

secondary hypocalcemia); GS (Gitelman syndrome); IDH (isolated dominant

hypomagnesemia). Source: Konrad M, Schlingmann KP, Gudermann T: Insights into the

molecular nature of magnesium homeostasis. Am J Physiol Renal Physiol 2004; 286: F599-

F605.

Unlike most ions, the majority of magnesium is not reabsorbed in the proximal convoluted tubule (PCT). Micropuncture studies, in which small pipettes are placed into different nephron segments, indicate that the thick ascending limb (TAL) of the loop of Henle is the major site of reabsorption (60-70%). The PCT accounts for only 15-25% of absorbed magnesium, and the distal convoluted tubule (DCT), for another 5-10%.3 There is no significant reabsorption of magnesium in the collecting duct.4,5 Inherited disorders of magnesium transport, although rare, may present through an array of underlying biochemical abnormalities.6,7

In the TAL, magnesium is passively reabsorbed with calcium through paracellular tight junctions; the driving force behind this reabsorption is a lumen-positive electrochemical gradient, which results from the reabsorption of sodium chloride. Claudin-16, also known as paracellin-1, has been identified as the renal tight junction protein in the TAL, where the reabsorption of magnesium occurs.8,9 Mutations in the paracellin-1 gene cause a human hereditary disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), which is characterized by excessive renal magnesium and calcium wasting, bilateral nephrocalcinosis, and progressive renal failure.10,11,12

In the distal convoluted tubule (DCT), magnesium is reabsorbed via an active, transcellular process that is thought to involve TRPM6, a member of the transient receptor potential (TRP) family of cation channels.13,14 Mutations in TRPM6 have been identified as the underlying defect in patients with hypomagnesemia with secondary hypocalcemia (HSH),3,15,16,17 an autosomal-recessive disorder that manifests in early infancy with generalized convulsions refractory to anticonvulsant treatment or with other symptoms of increased neuromuscular excitability, such as muscle spasms or tetany. Laboratory evaluation reveals extremely low serum magnesium and serum calcium levels.

Interestingly, mutations of the epithelial growth factor (EGF) have been associated with reduced expression of TRPM618 and thus, with hypomagnesemia; colorectal cancer treatment with cetuximab (an EGF receptor inhibitor) also causes hypomagnesemia.19,20,21

The mechanism of basolateral transport into the interstitium is unknown. Magnesium has to be extruded against an unfavorable electrochemical gradient. Most physiologic studies favor a sodium-dependent exchange mechanism driven by low intracellular sodium concentrations; these concentrations are generated by Na+/K+ -adenosine triphosphatase (ATPase), also known as the sodium-potassium pump.

A mutation in the gamma subunit of Na+/K+ -ATPase is responsible for isolated dominant hypomagnesemia (IDH), an autosomal-dominant condition associated with few symptoms other than chondrocalcinosis.22 Patients always have hypocalciuria and variable (but usually mild) hypomagnesemic symptoms. This mutation in the gamma subunit is thought to produce a disturbed routing of the Na+/K+ -ATPase complex to the basolateral membrane, leading to reduced expression of the Na+/K+ -ATPase on the cell surface.23,24 Consequently, the entry of K+ is reduced and the cell depolarizes to some extent, leading to closing of the TRPM6 channel and magnesium wasting.

The following factors influence the renal handling of magnesium1 :

Extracellular fluid volume - Expansion of the extracellular fluid volume increases the excretion of calcium, sodium, and magnesium. Magnesium reabsorption in the loop of Henle is reduced, probably due to increased delivery of sodium and water to the TAL and a decrease in the potential difference that is the driving force for magnesium reabsorption.

Glomerular filtration rate (GFR) - Changes in the GFR also influence tubular magnesium reabsorption. When the GFR and, thus, the filtered load of magnesium in chronic renal failure are reduced, fractional reabsorption is also reduced, such that the plasma magnesium value remains normal until the patient reaches end-stage renal disease (ESRD).

Plasma magnesium and calcium concentration - Hypercalcemia and hypermagnesemia inhibit magnesium reabsorption through activation of the calcium-sensing receptor (CaSR), a member of the family of G-protein – coupled receptors. The CaSR is expressed in the basolateral membrane of the TAL. When calcium or magnesium activates the receptor, there is a resultant enhancement

in the formation of arachidonic acid-derived 20-HETE, which reversibly inhibits apical potassium channels (ROMK2).25 Secretion of potassium into the lumen via these channels has 2 functions: it provides potassium for sodium chloride reabsorption by the Na-K-2Cl cotransporter (NKCC2), and it makes the lumen electropositive, which permits passive calcium and magnesium reabsorption.26 Thus, inhibition of ROMK2 channels in the TAL will reduce active sodium transport and passive calcium and magnesium reabsorption.

Activating mutations of the CaSR result in autosomal-dominant hypocalcemia with hypercalciuria (ADHH), a condition characterized by hypocalcemia, hypercalciuria, and hypomagnesemia, and by low, but detectable, parathyroid hormone (PTH).27,28 

Phosphate depletion can also increase urinary magnesium excretion, through a mechanism that is not clear.

Acid-base status - Chronic metabolic acidosis results in renal magnesium wasting, whereas chronic metabolic alkalosis is known to exert the reverse effects. Chronic metabolic acidosis decreases renal TRPM6 expression in the DCT, increased magnesium excretion, and decreased serum magnesium concentration, whereas chronic metabolic alkalosis results in the exact opposite effects.29

Hormones - No single hormone has been implicated in the control of renal magnesium reabsorption. In experimental studies, a number of hormones have been shown to alter magnesium transport in the TAL. These include PTH, calcitonin, glucagon, AVP, and the beta-adrenergic agonists, all of which are coupled to adenylate cyclase in the TAL. Postulated mechanisms include an increase in luminal positive voltage (via activation of basolateral membrane chloride conductance and NKCC2) and an increase in paracellular permeability (possibly by the phosphorylation of paracellular pathway proteins). It is not known if these effects have an important role in normal magnesium hemostasis.

Causes of Hypomagnesemia

Causes of hypomagnesemia related to decreased magnesium intake include the following1 :o Starvation

o Alcohol dependence

o Total parenteral nutrition

Causes related to the redistribution of magnesium from extracellular to intracellular space include the following:

o Hungry bone syndrome

o Treatment of diabetic ketoacidosis

o Alcohol withdrawal syndromes

o Refeeding syndrome

o Acute pancreatitis

Causes related to gastrointestinal magnesium loss include the following:

o Diarrhea

o Vomiting and nasogastric suction

o Gastrointestinal fistulas and ostomies

o Hypomagnesemia with secondary hypocalcemia (HSH)

Causes related to renal magnesium loss include the following:

o Inherited renal tubular defects10,12,30

Gitelman syndrome

Classic Bartter syndrome (Type III Bartter syndrome)

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC)

Autosomal-dominant hypocalcemia with hypercalciuria (ADHH)

Isolated dominant hypomagnesemia (IDH) with hypocalciuria

Isolated recessive hypomagnesemia (IRH) with normocalcemia

HSH

o Drugs31

Diuretics - Loop diuretics, osmotic diuretics, and chronic use of thiazides

Antimicrobials - Amphotericin B, aminoglycosides, pentamidine, capreomycin, viomycin, and foscarnet

Chemotherapeutic agents - Cisplatin

Immunosuppressants - Tacrolimus and cyclosporine

Proton-pump inhibitors32,33

o Ethanol34

o Hypercalcemia

o Chronic metabolic acidosis

o Volume expansion

o Primary hyperaldosteronism

o Recovery phase of acute tubular necrosis

o Postobstructive diuresis

Decreased intake

Alcoholics and individuals on magnesium-deficient diets or on parenteral nutrition for prolonged periods can become hypomagnesemic without abnormal gastrointestinal or kidney function. The addition of 4-12 mmol of magnesium per day to total parenteral nutrition has been recommended to prevent hypomagnesemia.

Redistribution from extracellular to intracellular

The transfer of magnesium from extracellular space to intracellular fluid or bone is a frequent cause of decreased serum magnesium levels. This depletion may occur as part of the hungry bone syndrome,35 in which magnesium is removed from the extracellular fluid space and deposited into bone following parathyroidectomy or total thyroidectomy.

Hypomagnesemia may also occur following insulin therapy for diabetic ketoacidosis and may be related to the anabolic effects of insulin driving magnesium, along with potassium and phosphorus, back into cells.

Hyperadrenergic states, such as alcohol withdrawal, may cause intracellular shifting of magnesium and may increase circulating levels of free fatty acids that combine with free plasma magnesium. The hypomagnesemia that sometimes is observed after surgery is attributed to the latter.

Hypomagnesemia is a manifestation of the refeeding syndrome, a condition in which previously malnourished patients are fed high carbohydrate loads, resulting in a rapid fall in phosphate, magnesium, and potassium, along with an expanding extracellular fluid space volume, leading to a variety of complications.

Acute pancreatitis can also cause hypomagnesemia. The mechanism may represent saponification of magnesium in necrotic fat, similar to that of hypocalcemia. However, postoperative states36 or critical illnesses in general are associated with low magnesium levels,37 without pancreatitis necessarily being present.

Gastrointestinal losses

Impaired gastrointestinal magnesium absorption is a common underlying basis for hypomagnesemia, especially when the small bowel is involved, due to disorders associated with malabsorption, chronic diarrhea, or steatorrhea, or as a result of bypass surgery on the small intestine. Because there is some magnesium absorption in the colon, patients with ileostomies can develop hypomagnesemia.

HSH is a rare autosomal-recessive disorder characterized by profound hypomagnesemia associated with hypocalcemia.38 Pathophysiology is related to impaired intestinal absorption of magnesium39 accompanied by renal magnesium wasting as a result of a reabsorption defect in the DCT. Mutations in the gene coding for TRPM6, a member of the transient receptor potential (TRP) family of cation channels, have been identified as the underlying genetic defect.15,16,17

Renal losses

Several inherited tubular disorders are responsible for urinary magnesium wasting. Gitelman syndrome is an autosomal-recessive condition caused by mutations of the SLC12A3 gene, which encodes the

thiazide-sensitive NaCl cotransporter (NCCT).40 This syndrome is characterized by hypokalemia, hypomagnesemia, and hypocalciuria.41 Hypomagnesemia is found in most patients with Gitelman syndrome and is assumed to be secondary to the primary defect in the NCCT, but some data points to magnesium wasting as a primary abnormality.42 Some studies have indicated that magnesium wasting in Gitelman syndrome may be due to down-regulation of TRPM6 in the DCT.

Classic Bartter syndrome is caused by mutations in CLCNKB encoding the basolaterally located renal chloride channel ClC-Kb, which mediates chloride efflux from the tubular epithelial cell to the interstitium along the TAL and DCT. It is unknown how hypomagnesemia is produced in this syndrome.

In FHHNC, an autosomal-recessive disorder, there is profound renal magnesium and calcium wasting. The hypercalciuria often leads to nephrocalcinosis, resulting in progressive renal failure.10,30,12 Other symptoms that have been reported in patients with FHHNC include urinary tract infections, nephrolithiasis, incomplete distal tubular acidosis, and ocular abnormalities.43 This syndrome is caused by mutations in the gene CLDN16, which encodes for paracellin-1, (claudin-16)11 a member of the claudin family of tight junction proteins that form the paracellular pathway for calcium and magnesium reabsorption in the TAL.

ADHH is another disorder of urinary magnesium wasting.27 Individuals who are affected present with hypocalcemia, hypercalciuria, and polyuria, and about 50% of these patients have hypomagnesemia. ADHH is produced by mutations of the CASR gene, the gene that encodes for the calcium-sensing receptor (CaSR) located basolaterally in TAL and DCT, which is involved in renal calcium and magnesium reabsorption.28 Activating mutations shift the set point of the receptor to a level of enhanced sensitivity by increasing the apparent affinity of the mutant receptor for extracellular calcium and magnesium. This results in diminished PTH secretion and decreased reabsorption of divalent cations in the TAL and DCT, which leads to loss of urinary calcium and magnesium.

IDH with hypocalciuria22 is an autosomal-dominant condition associated with few symptoms other than chondrocalcinosis. Patients always have hypocalciuria and variable (but usually mild) hypomagnesemic symptoms. A mutation in the gene FXYD2, which codes for the gamma subunit of the basolateral Na+/K+-ATPase in the DCT, has been identified. This mutation in the gamma subunit is thought to produce a disturbed routing of the Na+/K+-ATPase complex to the basolateral membrane, leading to reduced expression of the Na+/K+-ATPase on the cell surface.23,24 Consequently, the entry of potassium is reduced and the cell depolarizes to some extent, leading to closing of the TRPM6 channel and magnesium wasting.

IRH with normocalcemia is an autosomal-recessive disorder in which the individuals who are affected present with symptoms of hypomagnesemia early during infancy. Hypomagnesemia due to increased urinary magnesium excretion appears to be the only abnormal biochemical finding. IRH is distinguished from the autosomal-dominant form by the lack of hypocalciuria.44 The mechanism of hypomagnesemia remains unknown.

HSH, also called primary intestinal hypomagnesemia, is an autosomal-recessive disorder that is characterized by very low serum magnesium and low calcium levels.38 Mutations in the gene encoding for TRPM6, the active magnesium transporter in the DCT, have been identified.16,17 Patients usually present within the first 3 months of life with the neurologic symptoms of hypomagnesemic hypocalcemia, including seizures, tetany, and muscle spasms.

Untreated, HSH may result in permanent neurologic damage or may be fatal. Hypocalcemia is secondary

to parathyroid failure and peripheral parathyroid hormone resistance as a result of sustained magnesium deficiency. Usually, the hypocalcemia is resistant to calcium or vitamin D therapy. Normocalcemia and relief of clinical symptoms can be attained by administration of high oral doses of magnesium, up to 20 times the normal intake. As large oral amounts of magnesium may induce severe diarrhea and noncompliance in some patients, parenteral magnesium administration has to sometimes be considered. Alternatively, continuous nocturnal nasogastric magnesium infusions have been proven to efficiently reduce gastrointestinal adverse effects.

Several drugs, such as loop diuretics (including furosemide, bumetanide, and ethacrynic acid), produce large increases in magnesium excretion through the inhibition of the electrical gradient necessary for magnesium reabsorption in the TAL. Long-term thiazide diuretic therapy also may cause magnesium deficiency. Chronic thiazide administration has enhanced magnesium excretion and has specifically reduced renal expression levels of the epithelial magnesium channel TRPM6.45 Many nephrotoxic drugs, including aminoglycoside antibiotics, cisplatin, amphotericin B, cyclosporine, and pentamidine, can produce urinary magnesium wasting by a variety of mechanisms, some of which are still unknown. For instance, tacrolimus causes hypomagnesemia through down-regulation of TRPM6 channels.46 

On the other side, aminoglycosides are thought to induce the action of the CaSR on the TAL and DCT, producing magnesium wasting.47 Some data suggest that magnesium loss associated with cisplatin treatment is mainly the result of lowered intestinal absorption rather than, as presently thought, the result of increased renal elimination.

Other causes of renal magnesium wasting include aldosterone excess, most likely through chronic volume expansion, thereby increasing magnesium excretion; hypercalcemia, due to stimulation of the CaSR and inhibition of magnesium reabsorption; hypophosphatemia, for unknown reasons; and alcohol, most likely due to alcohol-induced tubular dysfunction that is reversible within 4 weeks of abstinence.34

Finally, magnesium wasting can be seen as part of the tubular dysfunction seen with recovery from acute tubular necrosis or during a postobstructive diuresis.

Clinical Manifestations of Magnesium Deficiency

Magnesium is critically important in maintaining normal cell function, and symptomatic magnesium depletion is often associated with multiple biochemical abnormalities, including hypokalemia, hypocalcemia, and metabolic acidosis. As a result, hypomagnesemia is sometimes difficult to attribute solely to specific clinical manifestations. The organ systems commonly affected by magnesium deficiency are the cardiovascular system and the central and peripheral nervous systems. The skeletal, hematologic, gastrointestinal, and genitourinary systems are affected less often.

Neuromuscular manifestations of hypomagnesemia may include the following1 :

Muscular weakness Tremors

Seizure

Paresthesias

Tetany

Positive Chvostek sign and Trousseau sign

Vertical and horizontal nystagmus

Cardiovascular manifestations may include the following:

Electrocardiographic abnormalitieso Nonspecific T-wave changes - U waves

o Prolonged QT and QU interval

o Repolarization alternans

Arrhythmias

o Premature ventricular contractions - Monomorphic ventricular tachycardia

o Torsade de pointes

o Ventricular fibrillation

o Enhanced digitalis toxicity

Metabolic manifestations may include the following:

Hypokalemia Hypocalcemia

Related Metabolic Abnormalities

Hypokalemia is a common event in patients with hypomagnesemia, occurring in 40-60% of cases.2 This is partly due to underlying disorders that cause magnesium and potassium losses, including diuretic therapy and diarrhea. The mechanism for hypomagnesemia-induced hypokalemia relates to the intrinsic biophysical properties of ROMK channels mediating K+ secretion in the TAL and the distal nephron. ROMK channels represent the first (Kir1.1) of 7 subfamilies making up the 2-transmembrane segment inward-rectifier potassium channel family. The channels are designated as inward rectifiers because they have a greater inward conductance of potassium ions than they do an outward conductance of them at negative membrane potentials (if external and internal K+ concentrations are equivalent).26

The mechanism for this differential conductance results from the binding and subsequent cytoplasmic block of the outward K+ movement through the inward-rectifier conduction pathway by cytoplasmic magnesium and polyamines. A reduction in intracellular magnesium (in the absence of polyamines) results in the loss of inward rectification, thus causing the greater outward conductance of K+ ions through the channel pore. Therefore, a decrease in intracellular magnesium concentration in the TAL and collecting duct cells results in increased K+secretion through the ROMK channels. Evidence also suggests that this wasting may be due to a hypomagnesemia-induced decline in adenosine triphosphate (ATP) and the subsequent removal of ATP inhibition of the ROMK channels responsible for secretion in the TAL and collecting duct.

The classic sign of severe hypomagnesemia (<1.2 mg/dL) is hypocalcemia. The mechanism is multifactorial. Parathyroid gland function is abnormal, largely because of impaired release of PTH. Impaired magnesium-dependent adenyl cyclase generation of cyclic adenosine monophosphate (cAMP) mediates the decreased release of PTH.48 Skeletal resistance to this hormone in magnesium deficiency has also been implicated. Hypomagnesemia also alters the normal heteroionic exchange of calcium and magnesium at the bone surface, leading to an increased bone release of magnesium ions in exchange for an increased skeletal uptake of calcium from the serum.

Cardiovascular Manifestations of Magnesium Deficiency

The cardiovascular effects of magnesium deficiency include effects on electrical activity, myocardial contractility, potentiation of digitalis effects, and vascular tone. Epidemiologic studies also show an association between magnesium deficiency and coronary artery disease (CAD).

Arrhythmia

Hypomagnesemia is now recognized to cause cardiac arrhythmia.49 Changes in electrocardiogram findings include prolongation of conduction and slight ST depression, although these changes are nonspecific. Patients with magnesium deficiency are particularly susceptible to digoxin-related arrhythmia. Intravenous magnesium supplementation may be a helpful adjunct when attempting rate control for atrial fibrillation with digoxin.50 Intracellular magnesium deficiency and digoxin excess act together to impair Na+/K+ -ATPase. The resulting decrease in intracellular potassium disturbs the resting membrane potential and repolarization phase of the myocardial cells, enhancing the inhibitory effect of digoxin.

Non–digitalis–associated arrhythmias are myriad. The clinical disturbance of greatest importance is the association of mild hypomagnesemia with ventricular arrhythmia in patients with cardiac disease. At-risk patients include those with acute myocardial ischemia, congestive heart failure, or recent cardiopulmonary bypass, as well as acutely ill patients in the intensive care unit.49

The ionic basis of the effect of magnesium depletion on cardiac arrhythmia may be related to impairment of the membrane sodium-potassium pump and the increased outward movement of potassium through the potassium channels in cardiac cells, leading to shortening of the action potential and increasing susceptibility to cardiac arrhythmia.51 Torsade de pointes, a repetitive, polymorphous ventricular tachycardia with prolongation of the QT interval, has been reported in conjunction with hypomagnesemia, and the American Heart Association now recommends that magnesium sulfate be added to the regimen used to manage torsade de pointes or refractory ventricular fibrillation.

Hypertension

It has been suggested that magnesium plays a role in blood pressure regulation, its therapeutic efficacy in the hypertensive syndromes of pregnancy having been demonstrated in the 19th century. Hypertension appears to be uniformly characterized by a decrease in intracellular free magnesium that, due to increased vascular tone and reactivity, causes an increase in total peripheral resistance. At a cellular level, increased intracellular calcium content is believed to account for this increased tone and reactivity. This increased cytosolic calcium concentration may be secondary to decreased activation of calcium channels, which may enhance calcium current into cells, decrease calcium efflux from cells, increase cellular permeability to calcium, or decrease sarcoplasmic reticulum reuptake of intracellularly released calcium.

Whatever the cause, intracellular accumulation leads to activation of actin-myosin contractile proteins, which increase vascular tone and total peripheral resistance. In contrast to experimental cellular physiology data supporting a role for magnesium deficiency in hypertension, results from clinical epidemiological studies have failed to confirm a relationship, and results from clinical trials examining the hypotensive effects of magnesium supplementation have been conflicting. Large, carefully performed, randomized clinical trials are needed.

CAD

In epidemiologic studies, patients with CAD have a higher incidence of magnesium deficiency than do control subjects.52,53 Mounting evidence suggests that magnesium deficiency may play a role in the pathogenesis, initiation, morbidity, and mortality associated with myocardial infarction. In experimental animals, arterial atherogenesis varied inversely with dietary magnesium intake. In humans, the level of serum magnesium is inversely related to the serum cholesterol concentration. Therefore, magnesium deficiency is associated with hypertension and hypercholesterolemia, which are well-recognized risk factors for atherogenesis and CAD. Magnesium deficiency is also known to be accompanied by thrombotic tendencies, increased platelet aggregatability, and increased coronary artery responsiveness to contractile stimuli. These factors are important in the initiation of acute myocardial infarction.

The incidence of cardiac arrhythmia also correlates with the degree of magnesium deficiency in patients with CAD. Preliminary data suggest that magnesium supplementation may reduce the frequency of potentially fatal ventricular arrhythmia, although this finding has not been conclusively proven. Hypomagnesemia can also develop during cardiopulmonary bypass and predispose to arrhythmia,54 and intravenous magnesium given after the termination of cardiopulmonary bypass has resulted in significantly fewer incidences of supraventricular and ventricular dysrhythmia in relatively small trials of adult55,56 and pediatric57 patients. Considering the above data, carefully assessing magnesium status in patients with CAD and supplementing patients deficient in magnesium seem prudent. The use of routine magnesium supplements in myocardial infraction remains controversial in the era of thrombolytics and percutaneous coronary interventions. 

Hypomagnesemia and Other Systems

Neuromuscular manifestations

The earliest manifestations of magnesium deficiency are usually neuromuscular and neuropsychiatric disturbances, the most common being hyperexcitability. Neuromuscular irritability, including tremor, fasciculations, tetany, Chvostek and Trousseau signs, and convulsions, has been noted when hypomagnesemia has been induced in volunteers. Other manifestations include convulsions, apathy, muscle cramps, hyperreflexia, acute organic brain syndromes, depression, generalized weakness, anorexia, and vomiting. Magnesium is required for stabilization of the axon. The threshold of axon stimulation is decreased and nerve conduction velocity is increased when serum magnesium is reduced, leading to an increase in the excitability of muscles and nerves. The cellular basis for these changes is due to increased intracellular calcium content by mechanisms similar to those described in Cardiovascular Manifestations of Magnesium Deficiency.

Magnesium and bone

Magnesium deficiency has also been implicated in osteoporosis.58 The magnesium content in trabecular bone is significantly reduced in patients with osteoporosis, and magnesium intake in people with

osteoporosis reportedly is lower than it is in control subjects.59 Magnesium intake frequently is lower than the recommended dietary intake in many groups, especially elderly persons.60

Postmenopausal women are encouraged to consume at least 1000 mg of calcium per day, which leads to altered dietary calcium-to-magnesium ratios. This calcium supplementation may reduce the efficacy of magnesium absorption and further aggravate the consequences of diminished estrogen and the greater demineralizing effects of PTH. The H+ -K+ -ATPase pump in the cells of the periosteum is magnesium-dependent, which may lead to decreased pH in the bone extracellular fluid and increased demineralization. In addition, because the formation of calcitriol involves a magnesium-dependent hydroxylase enzyme, calcitriol concentrations are reduced in magnesium deficiency, possibly affecting calcium reabsorption.

Magnesium supplementation may be beneficial in osteoporosis and may increase bone density, arrest vertebral deformity, and decrease osteoporotic pain. In the large joints, chondrocalcinosis is associated with long-term magnesium depletion.61

Magnesium and nephrolithiasis

Urinary magnesium is an inhibitor of urinary crystal formation in vivo, and some studies have shown a lower urinary excretion of magnesium in patients with stones. Magnesium deficiency due to etiologies other than renal wasting is associated with hypomagnesuria and, theoretically, could play a role in predisposition to urinary calculus formation.

Magnesium and diabetes

Patients with diabetes mellitus are often magnesium deficient, expressed by hypomagnesemia.62,63 Magnesium deficiency decreases insulin sensitivity and secretion.64 Moreover, magnesium deficiency is inherently related to the pathogenesis and development not only of diabetic microangiopathy but also of lifestyle-related diseases, such as hypertension and hyperlipidemia.65  Generally, modern people tend to live in a state of chronic dietary magnesium deficiency.66 There is a possibility that one of the major factors contributing to the drastic increase of type 2 diabetes mellitus is the drastically decreased intake of grains, such as barley or cereals rich in magnesium.67 This implies an association between the volume of dietary magnesium intake and the onset of type 2 diabetes, raising expectations that in the future, clinical trials will be performed to investigate the efficacy of magnesium supplementation therapy.

Miscellaneous Conditions

Magnesium deficiency has also been implicated in many other conditions. Low intracellular magnesium levels in the brain have been reported in migraine headache. In addition, magnesium status may have an influence on asthma, because magnesium deficiency is associated with increased contractility of smooth muscle cells. Magnesium supplementation in asthma remains controversial,68 but it has been shown to reduce bronchial hyperreactivity to methacholine and other measures of allergy.69 Magnesium deficiency has also been linked to chronic fatigue syndrome, sudden death in athletes, impaired athletic performance, and sudden infant death syndrome.

Assessment and Treatment of Magnesium Depletion

Assessment of magnesium status

The majority of patients with clinical manifestations of magnesium deficiency have hypomagnesemia. Measurement of serum magnesium is relatively easy, becoming the method of choice to estimate magnesium content, although its use in evaluating total body stores is limited. Magnesium assessment can also be made via red cell, mononuclear cell, or skeletal muscle intracellular content; 24-hour urinary excretion; fractional excretion of magnesium; and intracellular free magnesium ion concentration with fluorescent dye or nuclear magnetic resonance spectroscopy.

Two caveats should be considered when serum magnesium is used to diagnose magnesium deficiency. First, although only free magnesium is biologically active, most methods of assessing the serum content measure total magnesium concentration. Because 30% of magnesium is bound to albumin and is therefore inactive, hypoalbuminemic states may lead to spuriously low magnesium values. The second caveat is that the major physiologic role of magnesium occurs at an intracellular level. Excluding magnesium deposited in the bone, which is poorly mobilized, the extracellular fluid space contains only 2% of total body magnesium and may not always accurately reflect the intracellular magnesium status. A person may have normal serum levels of magnesium but be intracellularly depleted and exhibit signs of magnesium deficiency. Unfortunately, no quick, simple, and accurate test is available to measure intracellular magnesium.

A surrogate for direct intracellular magnesium is the measurement of magnesium retention after acute magnesium loading. This method is useful only when the clinical suggestion of magnesium deficiency is strong in the setting of normomagnesemia (eg, unexplained cardiovascular or neuromuscular abnormalities).

A magnesium deficiency is indicated if a patient has reduced excretion (<80% over 24 h) of an infused magnesium load (2.4 mg/kg of lean body weight given over the initial 4 h). However, the utility of this test is uncertain. Patients with malnutrition, cirrhosis, diarrhea, or long-term diuretic use typically have a positive test, whether or not they have signs or symptoms referable to magnesium depletion. It seems prudent, therefore, to simply administer magnesium to these patients if they have unexplained hypocalcemia and/or hypokalemia.

If hypomagnesemia is confirmed, the diagnosis can usually be obtained from the history. If no cause is apparent, the distinction between gastrointestinal and renal losses can be made by measuring the 24-hour urinary magnesium excretion or the fractional excretion (FE) of magnesium on a random urine specimen. The latter can be calculated from the following formula:

FEMg = [(UMg x PCr) / (PMg x UCr x 0.7)] x 100

In the above equation, U and P refer to the urine and plasma concentrations of magnesium (Mg) and creatinine (Cr). The plasma magnesium concentration is multiplied by 0.7, since only about 70% of the circulating magnesium is free (not bound to albumin) and therefore capable of being filtered across the glomerulus. The normal renal response to magnesium depletion is to lower magnesium excretion to very low levels. Thus, daily excretion of more than 1 mmol or a calculated fractional excretion of magnesium above 3% in a subject with normal renal function indicates renal magnesium wasting.

Treatment of magnesium depletion

The route of magnesium repletion varies with the severity of the clinical manifestations. For example, the hypocalcemic-hypomagnesemic patient with tetany or the patient who is suspected of having hypomagnesemic-hypokalemic ventricular arrhythmias should receive 50 mEq of intravenous

magnesium, given slowly over 8-24 hours. This dose can be repeated as necessary to maintain the plasma magnesium concentration above 1.0 mg/dL (0.4 mmol/L or 0.8 mEq/L). In the normomagnesemic patient with hypocalcemia, it has been suggested that this dose be repeated daily for 3-5 days.

It must be appreciated that the plasma magnesium concentration is the major regulator of magnesium reabsorption in the loop of Henle, the major site of active magnesium transport. Thus, an abrupt elevation in the plasma magnesium concentration will partially remove the stimulus to magnesium retention, and up to 50% of the infused magnesium will be excreted in the urine. Furthermore, because magnesium is subject to slow equilibration between serum and the intracellular spaces and tissues (eg, bone, red blood cells, muscle), the serum magnesium level could appear artificially high if measured too soon after a magnesium dose is administered. Large magnesium depletion requires sustained correction of the hypomagnesemia.

For these reasons, oral replacement should be given in the asymptomatic patient, preferably with a sustained-release preparation, given the ability of magnesium to induce diarrhea. Several preparations are available: Mag-Ox 400, containing magnesium oxide; Slow-Mag, containing magnesium chloride; and Mag-Tab, containing magnesium lactate. These preparations provide 5-7 mEq (2.5-3.5 mmol or 60-84 mg) of magnesium per tablet. Six to 8 tablets should be taken daily in divided doses for severe magnesium depletion. Two to 4 tablets may be sufficient for mild, asymptomatic disease. Mag-Ox 400 contains 242 mg (20 mEq) of elemental magnesium, but absorption is less efficacious.

Patients with concomitant hypokalemia or hypocalcemia should also receive potassium and calcium replacement, because these disorders may take several days to correct when treated with magnesium alone. Patients undergoing intravenous magnesium replacement should be monitored for evidence of acute hypermagnesemia (eg, respiratory depression, areflexia).

Patients with renal dysfunction are at a markedly increased risk, and 25-50% of the normal dose should be given to patients with plasma creatinine levels greater than 2 mg/dL. Intravenous calcium chloride or gluconate are the antidotes, and 1-2 ampules should be administered immediately if these complications develop. Calcium chloride (1000 mg, 13.6 mEq of calcium) should be infused via a central venous catheter over 10 minutes; calcium gluconate 1-3 grams (4.56-13.7 mEq of elemental calcium) can be infused via a peripheral intravenous catheter over 3-10 minutes.70  Whenever possible, the underlying cause of active magnesium loss should be corrected.

Patients with diuretic-induced hypomagnesemia who cannot discontinue diuretic therapy may benefit from the addition of a potassium-sparing diuretic (eg, amiloride or triamterene) or from changing plain thiazide diuretic medication to a thiazide diuretic/potassium-sparing diuretic combination. These drugs may decrease magnesium excretion by increasing its reabsorption in the collecting tubule. These drugs also may be useful in Bartter and Gitelman syndrome or in cisplatin nephrotoxicity. These patients should also be placed on a magnesium-rich diet, which includes such foods as meat, green vegetables, dairy products, nuts, cereals, and seafood. In addition, these patients should be examined frequently for evidence of magnesium deficiency and should be monitored for regular serum magnesium. If hypomagnesemia persists, these patients should be treated with an oral sustained-release preparation.

HyponatremiaIntroduction

Background

Hyponatremia is an important and common electrolyte abnormality that can be seen in isolation or, as most often is the case, as a complication of other medical illnesses.

Sodium is the dominant extracellular cation and cannot freely cross the cell membrane. Its homeostasis is vital to the normal physiologic function of cells. The normal serum sodium level is 135-145 mEq/L. Hyponatremia is defined as a serum level of less than 135 mEq/L and is considered severe when the serum level is below 125 mEq/L.

This article reviews the epidemiology, pathophysiology, differential diagnosis, evaluation, and treatment of this disorder.

Pathophysiology

Hypoosmolality (serum osmolality <260 mOsm/kg) always indicates excess total body water relative to body solutes or excess water relative to solute in the extracellular fluid (ECF), as water moves freely between the intracellular compartment and the extracellular compartment. This imbalance can be due to solute depletion, solute dilution, or a combination of both.

In the normal condition, renal handling of water is sufficient to excrete as much as 15-20 L of free water per day. Further, in the normal condition, the body's response to a decreased osmolality is decreased thirst. Thus, hyponatremia can occur only when some condition impairs normal free water excretion.1 Generally, hyponatremia is of clinical significance only when it reflects a drop in the serum osmolality (ie, hypotonic hyponatremia), which is measured directly via osmometry or is calculated as 2(Na) mEq/L + serum glucose (mg/dL)/18 + BUN (mg/dL)/2.8.

The recommendations for treatment of hyponatremia rely on the current understanding of CNS adaptation to an alteration in serum osmolality. In the setting of an acute drop in the serum osmolality, neuronal cell swelling occurs due to the water shift from the extracellular space to the intracellular space (ie, Frank Starling forces). Swelling of the brain cells elicits the following 2 osmoregulatory responses:

It inhibits both arginine vasopressin secretion from neurons in the hypothalamus and hypothalamic thirst center. This leads to excess water elimination as dilute urine.

There is an immediate cellular adaptation with loss of electrolytes, and over the next few days, there is a more gradual loss of organic intracellular osmolytes.2

Therefore, correction of hyponatremia must take into account the chronicity of the condition. Acute hyponatremia (duration <48h) can be safely corrected more quickly than chronic hyponatremia. Correction of serum sodium that is too rapid can precipitate severe neurologic complications. Most individuals who present for diagnosis, versus individuals who develop it while in an inpatient setting, have had hyponatremia for some time, so the condition is chronic, and correction should proceed accordingly.

Frequency

United States

The incidence of hyponatremia depends largely on the patient population and the criteria used to establish the diagnosis. A hospital incidence of 15-20% is common (defined as a serum sodium level of <135 mEq/L), while only 3-5% of patients who are hospitalized have a serum sodium level of less than 130 mEq/L. Hyponatremia's prevalence is lower in the ambulatory setting.

Mortality/Morbidity

Severe hyponatremia (<125 mEq/L) has a high mortality rate; for instance, when the serum sodium level is less than 105 mEq/L, the mortality is over 50%, especially in alcoholics.3 In patients with acute ST-elevation myocardial infarction, the presence of hyponatremia on admission or early development of hyponatremia is an independent predictor of 30-day mortality, and the prognosis worsens with the severity of hyponatremia.4 Similarly, cirrhotic patients with persistent ascites and a low serum sodium level awaiting transplant have a high mortality risk despite low severity (MELD) scores. The independent predictors ascites and hyponatremia are findings indicative of hemodynamic decompensation.5,6

Race

Hyponatremia affects all races.

Sex

No sexual predilection exists for hyponatremia. However, symptoms are more likely to occur in young women than in men.

Age

Hyponatremia is more common in elderly persons, because they have an increased incidence of comorbid conditions (eg, cardiac, hepatic, or renal failure) that can be complicated by it.

Clinical

History

Patients may present to medical attention owing to symptoms directly referable to low serum sodium concentrations. However, many patients present due to manifestations of other medical comorbidities, with hyponatremia being recognized only secondarily. For many people, therefore, the recognition is entirely incidental.

Patients may develop clinical symptoms due to the cause of hyponatremia or the hyponatremia itself.

Many medical illnesses, such as congestive heart failure, liver failure, renal failure, or pneumonia, may be associated with hyponatremia. These patients frequently present because of primary disease symptomatology (eg, dyspnea, jaundice, uremia, cough).

Symptoms range from nausea and malaise, with mild reduction in the serum sodium, to lethargy, a decreased level of consciousness, headache, and (if severe) seizures and coma. Neurologic symptoms most often are due to very low serum sodium levels (usually <115 mEq/L), resulting in intracerebral osmotic fluid shifts and brain edema. This neurologic symptom complex can lead to tentorial herniation with subsequent brain stem compression and respiratory arrest, resulting in death in the most severe cases.

The severity of neurologic symptoms correlates well with the rapidity and severity of the drop in serum sodium. A gradual drop in serum sodium, even to very low levels, may be tolerated well if it occurs over several days or weeks, because of neuronal adaptation. The presence of an underlying neurologic disease, like a seizure disorder, or nonneurologic metabolic abnormalities, like hypoxia, hypercapnia, or acidosis, also affects the severity of neurologic symptoms.

In interviewing the patient, obtaining a detailed medication history, including information on over-the-counter (OTC) drugs the patient has been using, is important, because many medications may precipitate hyponatremia (eg, antipsychotic medications). A dietary history with reference to salt, protein, and water intake is useful as well. For patients who are hospitalized, reviewing the records of parenteral fluids administered is crucial.

Physical

Examination should include orthostatic vital signs and an accurate assessment of volume status. This determination (ie, hypervolemic, euvolemic, hypovolemic) often guides treatment decisions.

A full assessment for medical comorbidity also is essential, with particular attention paid to cardiopulmonary and neurologic components of the examination.

Causes

Although the differential diagnosis is quite broad, hyponatremia can be divided into the following clinically useful groupings:

Hypertonic hyponatremia: Patients with hypertonic hyponatremia have normal total body sodium and a dilutional drop in the measured serum sodium due to the presence of osmotically active molecules in the serum, which cause a water shift from the intracellular compartment to the extracellular compartment.

o Glucose produces a drop in the serum sodium level of 1.6 mEq/L for each 100 mg/dL of

serum glucose greater than 100 mg/dL. This relationship is nonlinear, with greater reduction in plasma sodium concentrations with glucose concentrations over 400 mg/dL, making 2.4 mEq/L for each 100 mg/dL increase in glucose over 100 mg/dL a more accurate correction factor when the glucose is greater than 400 mg/dL.7

o Other examples of osmotically active molecules include mannitol (often used to treat

brain edema) or maltose (used with intravenous immunoglobulin administration).

Normotonic hyponatremia: Severe hyperlipidemia and paraproteinemia can lead to low measured serum sodium concentrations with normal serum osmolality. Normally, the plasma water comprises 92-94% of plasma volume. The plasma water fraction falls with an increase in fats and proteins. The measured sodium concentration in the total plasma volume is respectively reduced, although the plasma water sodium concentration and plasma osmolality are unchanged. This artifactually low sodium (so-called pseudohyponatremia) is secondary to measurement by flame photometry. It can be avoided by direct ion-selective electrode measurement.

Hyponatremia posttransurethral resection of the prostate (TURP) or hysteroscopy is caused by absorption of irrigants, glycine, sorbitol, or mannitol, contained in nonconductive flushing solutions used. The degree of hyponatremia is related to the quantity and the rate of fluid absorbed. The plasma osmolality is also variable and changes over time.

o The presence of a relatively large osmolal gap due to the excess organic solute is

diagnostic in the appropriate clinical setting. Symptomatic patients are treated depending on plasma osmolality and volume status of patients with either hypertonic saline in hypoosmolar state or loop diuretic in volume-overloaded patients with normal renal function.

o Hemodialysis, which will correct the hyponatremia and remove glycine and its toxic

metabolites, can be used in patients with end-stage renal disease. Use of isotonic saline as an irrigant instead of glycine with the new bipolar resectoscope for TURP in high-risk patients (with large prostates that require lengthy resection) could avoid this complication, making this disorder a diagnosis of the past.8

Hypotonic hyponatremia: Hypotonic hyponatremia always reflects the inability of the kidneys to handle the excretion of free water to match oral intake. It can be divided pathophysiologically into the following categories, according to the effective intravascular volume: hypovolemic,

hypervolemic, and euvolemic. These clinically relevant groupings aid in determination of likely underlying etiology and guiding treatment.

o Hypovolemic hypotonic hyponatremia: This usually indicates concomitant solute

depletion, with patients presenting with orthostatic symptoms. The pathophysiology underlying hypovolemic hypotonic hyponatremia is complex and involves the interplay of carotid baroreceptors, the sympathetic nervous system, the renin-angiotensin system, antidiuretic hormone (ADH) secretion (vasopressin), and renal tubular function. In the setting of decreased intravascular volume (eg, severe hemorrhage or severe volume depletion secondary to GI or renal loss, or diuretic use) owing to a decreased stretch on the baroreceptors in the great veins, aortic arch, and carotid bodies, an increased sympathetic tone to maintain systemic blood pressure generally occurs.

o This increased sympathetic tone, along with decreased renal perfusion secondary to

intravascular volume depletion, results in increased renin and angiotensin excretion. This, in turn, results in increased sodium absorption in the proximal tubules of the kidney and consequent decreased delivery of solutes to distal diluting segments, causing an impairment of renal free water excretion. There also is a concomitant increase in serum ADH production that further impairs free water excretion. Because angiotensin is also a very potent stimulant of thirst, free water intake is increased, and, at the same time, water excretion is limited. Together, these changes lead to hyponatremia.

o Cerebral salt wasting (CSW) is seen with intracranial disorders, such as subarachnoid

hemorrhage, carcinomatous or infectious meningitis, and metastatic carcinoma, but especially after neurologic procedures. Disruption of sympathetic neural input into the kidney, which normally promotes salt and water reabsorption in the proximal nephron segment through various indirect and direct mechanisms, might cause renal salt wasting, resulting in reduced plasma volume. Plasma renin and aldosterone levels fail to rise appropriately in patients with CSW despite a reduced plasma volume because of disruption of the sympathetic nervous system. In addition, the release of 1 or more natriuretic factors could also play a role in the renal salt wasting seen in CSW. Volume depletion leads to an elevation of plasma vasopressin levels and impaired free water excretion.

o Distinguishing between CSW and syndrome of inappropriate ADH secretion (SIADH) can

be challenging, because there is considerable overlap in the clinical presentation. Vigorous salt replacement is required in patients with CSW, whereas fluid restriction is the treatment of choice in patients with SIADH. Infusion of isotonic saline to correct the volume depletion is usually effective in reversing the hyponatremia in cerebral salt wasting, since euvolemia will suppress the release of ADH. The disorder is usually transient, with resolution occurring within 3-4 weeks of disease onset.9,10

o Salt-wasting nephropathy causing hypovolemic hyponatremia may rarely develop in a

range of renal disorders (eg, interstitial nephropathy, medullary cystic disease, polycystic kidney disease, partial urinary obstruction) with low salt intake.

o The treatment of choice for hypovolemic hypotonic hyponatremia is saline infusion.

o Hypervolemic hypotonic hyponatremia: This is characterized by clinically detectable

edema or ascites that signifies an increase in total body water and sodium. Paradoxically, however, a decrease in the effective circulating volume, critical for tissue perfusion, stimulates the same pathophysiologic mechanism of impaired water excretion by the kidney that is observed in hypovolemic hypotonic hyponatremia.

o Commonly encountered examples include liver cirrhosis, congestive heart failure,

nephrotic syndrome, and severe hypoproteinemia (albumin level <1.5-2 g/dL).

o The treatment of these patients is usually limited to free water restriction and diuresis to

induce negative water balance.

o Patients with renal failure and hyponatremia may have normal or high plasma osmolality

because of the urea retention. However, as urea is not an effective osmole, the patient should be treated as per hypotonic hyponatremia.

o Normovolemic (euvolemic) hypotonic hyponatremia: This is a very common cause of

hyponatremia in patients who are hospitalized. It is associated with nonosmotic and nonvolume related vasopressin (ADH) secretion (ie, SIADH) secondary to a variety of clinical conditions, including CNS disturbances, major surgery, trauma, pulmonary tumors, infection, stress, and certain medications.

o Common medications associated with SIADH are as follows: chlorpropamide

(potentiating renal action of ADH), carbamazepine (possesses antidiuretic property), cyclophosphamide (marked water retention secondary to SIADH and potentially fatal hyponatremia may ensue in selected cases; use of isotonic saline rather than free water to maintain a high urine output to prevent hemorrhagic cystitis can minimize the risk), vincristine, vinblastine, amitriptyline, haloperidol, selective serotonin reuptake inhibitors (particularly in elderly patients), and monoamine oxidase (MAO) antidepressants. In these circumstances, the ability of the kidney to dilute urine in the setting of serum hypotonicity is reduced.

o Diuretics may induce hypovolemic hyponatremia. Note that thiazide diuretics, in contrast

to loop diuretics, impair the diluting mechanism without limiting the concentrating mechanism, thereby impairing the ability to excrete a free water load. Thus, thiazides are more prone to causing hyponatremia than are loop diuretics.

o Hyponatremia is a relatively common adverse effect of desmopressin, a vasopressin

analogue that acts as a pure V2 agonist. Its common use in the treatment of central diabetes insipidus, von Willebrand disease, and nocturia in adults and of enuresis in children requires regular monitoring of serum sodium levels.

o The diagnostic criteria for SIADH are as follows:

Normal hepatic, renal, and cardiac function - Clinical euvolemia (absence of intravascular volume depletion)

Normal thyroid and adrenal function

Hypotonic hyponatremia

Urine osmolality greater than 100 mOsm/kg, generally greater than 400-500 mOsm/kg with normal renal function

o Urinary sodium concentrations are also typically greater than 20 mEq/L on a normal salt

diet. Serum uric acid levels are generally reduced; this is due to reduced tubular uric acid reabsorption, which parallels the decrease in proximal tubular sodium reabsorption associated with central volume expansion.

o Reset osmostat is another important cause of normovolemic hypotonic hyponatremia.

This may occur in elderly patients and during pregnancy. These patients regulate their serum osmolality around a reduced set point; however, in contrast to patients with SIADH (who also have a downward resetting of the osmotic threshold for thirst),11 they are able to dilute their urine in response to a water load to keep the serum osmolality around the preset low point.

o Severe hypothyroidism (unknown mechanism, possibly secondary to low cardiac output

and glomerular filtration rate) and adrenal insufficiency are also associated with nonosmotic vasopressin release and impaired sodium reabsorption, leading to hypotonic hyponatremia. Hyponatremia associated with cortisol deficiency, such as primary or secondary hypoadrenalism, commonly presents subtly and may go undiagnosed. A random cortisol level check, especially in acute illness, can be misleading if the level is normal (when it should be high). Testing for adrenal insufficiency and hypothyroidism should be part of the hyponatremic workup, as the disorders respond promptly to hormone replacement. Depending on the etiology, mineralocorticoid will also need replacement.

o Severe malnutrition seen in weight-conscious women (low protein, high water intake diet)

is a special condition in which a markedly decreased intake of solutes occurs, which limits the ability of the kidney to handle the free water. Because a mandatory solute loss of 50-100 mOsm/kg of urine exists, free water intake in excess of solute needs can produce hyponatremia.12 Another example is beer drinker's potomania, because a diet consisting primarily of beer is rich in free water but solute poor.

o Compulsive intake of large amounts of free water exceeding the dilutional capacity of the

kidneys (>20 L/d), even with a normal solute intake of 600-900 mOsm/d, may also result in hyponatremia, but in contrast to SIADH, the urine is maximally dilute. In addition to a central defect in thirst regulation, which plays an important role in the pathogenesis of primary polydipsia, different abnormalities in ADH regulation have been identified in psychotic patients, all impairing free water excretion. Transient stimulation of ADH release during acute psychotic episodes, an increase in the net renal response to ADH, downward resetting of the osmostat, and antipsychotic medication may contribute. Limiting water intake will rapidly raise the plasma sodium concentration as the excess water is readily excreted in dilute urine.13

o Hospitalized patients who are infected with human immunodeficiency virus (HIV) have a

high incidence of hyponatremia. In these individuals, hyponatremia is usually due to at least 1 of the following 3 disorders associated with an increased ADH level:

Increased release of ADH due to malignancy, to occult or symptomatic infection of the central nervous system, or to pneumonia resulting from infection with Pneumocystis carinii or other organisms.

Effective volume depletion secondary to fluid loss from the gastrointestinal tract, due primarily to infectious diarrhea.

Adrenal insufficiency often due to an adrenalitis, an abnormality that may be infectious in origin, perhaps being induced by cytomegalovirus, Mycobacterium avium-intracellulare, or HIV itself. Affected patients have a high risk of morbidity and mortality.

o Treatment generally is that of the underlying cause and free water restriction.

o The most common precipitant of hyponatremia in patients after surgery14 is the iatrogenic

infusion of hypotonic fluids. Inappropriate administration of hypotonic intravenous fluids after surgery increases the risk of developing hyponatremia in these vulnerable patients, who retain water due to nonosmotic release of ADH, which is typically elevated for a few days after most surgical procedures. Hospital-acquired acute hyponatremia is disturbingly common also among hospitalized children and adults.

o Acute hyponatremia is associated with ultra-endurance athletes and marathon runners.

With women making up a higher percentage, the strongest single predictor is weight gain during the race correlating with excessive fluid intake. Longer racing time and body mass index extremes are also associated with hyponatremia, whereas the composition of fluids consumed (plain water rather than sports drinks containing electrolytes) is not. Oxidization of glycogen and triglyceride during a race is associated with the production of "bound" water, which then becomes an endogenous, electrolyte-free water infusion contributing to hyponatremia induced by water ingestion in excess of water losses.

o Nonsteroidal anti-inflammatory drug (NSAID) use may increase the risk of development

of hyponatremia by strenuous exercise by inhibiting prostaglandin formation. Prostaglandins have a natriuretic effect. Prostaglandin depletion increases NaCl reabsorption in the thick ascending limb of Henle (ultimately increasing medullary tonicity) and ADH action in the collecting duct, leading to impaired free water excretion.15

o Some collapsed runners are normonatremic or even hypernatremic,16 making blanket

recommendations difficult. However, fluid intake to the point of weight gain should be avoided.16,17Athletes should rely on thirst as their guide for fluid replacement and avoid fixed, global recommendations for water intake. Symptomatic hyponatremic patients should receive 100 mL of 3% sodium chloride over 10 minutes in the field before transportation to hospital. This maneuver should raise the plasma sodium concentration an average of 2-3 mEq/L.18

o Symptomatic and potentially fatal hyponatremia can develop with rapid onset after

ingestion of the designer drug ecstasy (methylenedioxymethamphetamine, or MDMA), an amphetamine. A marked increase in water intake via direct thirst stimulation, as well as inappropriate secretion of ADH, contributes to the hyponatremia seen with even small amount of drug intake.

o Nephrogenic syndrome of inappropriate antidiuresis (or NSIAD) is an SIADH-like clinical

and laboratory picture seen in male infants who present with neurologic symptoms secondary to hyponatremia but who have undetectable plasma arginine vasopressin (AVP) levels. This hereditary disorder is secondary to mutations in the V2 vasopressin receptor, resulting in constitutive activation of the receptor with elevated cAMP production in the collecting duct principle cells. Treatment of NSIAD poses a challenge. Water restriction improves serum sodium levels and osmolality in infants, but it limits calorie intake in these formula-fed infants. The use of demeclocycline or lithium is potentially limited because of adverse effects. The current therapy of choice is fluid restriction and the use of urea to induce an osmotic diuresis.19

o Hyponatremic hypertensive syndrome, a rare condition, consists of severe hypertension

associated with renal artery stenosis, hyponatremia, hypokalemia, severe thirst, and renal dysfunction characterized by natriuresis, hypercalciuria, renal glycosuria, and proteinuria. Angiotensin-mediated thirst coupled with nonosmotic release of vasopressin provoked by angiotensin II and/or hypertensive encephalopathy are likely mechanisms for this syndrome. Sodium depletion due to pressure natriuresis and potassium depletion due to hyperaldosteronism with high plasma renin activity are also likely to play a role in the pathogenesis of hyponatremia. The abnormalities resolve with correction of the renal artery stenosis.20

Using a retrospective case note analysis, an Irish study examined the incidence of hyponatremia in a variety of neurologic conditions.21 The investigators found that the occurrence of hyponatremia was greater in persons with subarachnoid hemorrhage (62 out of 316 patients, or 19.6%; p <0.001), intracranial neoplasm (56 out of 355 patients, or 15.8%; p <0.001), traumatic brain injury (44 out of 457 patients, or 9.6%; p <0.001), and pituitary disorders (5 out of 81 patients, or 6.25%; p = 0.004) than it was in patients with spinal disorders (4 out of 489 patients, or 0.81%).

The investigators also determined that the median hospital stay for patients with hyponatremia was 19 days, compared with a median stay of 12 days for the study's other patients.

Hypophosphatemia

Introduction

Background

Hypophosphatemia is defined as a phosphate level of less than 2.5 mg/dL (0.8 mmol/L). Phosphate is critical for an incredible array of cellular processes. It is one of the major components of the skeleton, providing mineral strength to bone. Phosphate is an integral component of the nucleic acids that comprise DNA and RNA. Phosphate bonds of ATP carry the energy required for all cellular functions. It also functions as a buffer in bone, serum, and urine.

The addition and deletion of phosphate groups to enzymes and proteins are common mechanisms for the regulation of their activity. In view of the sheer breadth of influence of this mineral, the fact that phosphate homeostasis is a highly regulated process is not surprising.

Phosphate in the body

The bulk of total body phosphate resides in bone as part of the mineralized extracellular matrix. This phosphate pool is accessible, although in a somewhat limited fashion. Approximately 300 mg of phosphate per day enters and exits bone tissue. Excessive losses or failure to add phosphate to bone leads to osteomalacia.

Phosphate is a predominantly intracellular anion with a concentration of approximately 100 mmol/L, although determination of the precise intracellular concentration has been difficult. Most intracellular phosphate is either complexed or bound to proteins and lipids. In response to kinases and phosphatases, these phosphate ions attach and detach from different molecules, forming a constantly shifting pool. Intracellular phosphate is essential for most, if not all, cellular processes; however, because the intracellular concentration of phosphate is greater than the extracellular concentration, phosphate entry into cells requires a facilitated transport process.

Several sodium-coupled transport proteins have been identified that enable intracellular uptake of phosphate by taking advantage of the steep extracellular-to-intracellular sodium gradient. Type 1 sodium phosphate cotransporters are expressed predominantly in kidney cells on the apical membranes of proximal tubule cells and, possibly, the distal tubule cells. They are capable of transporting organic ions and stimulating chloride conductance in addition to phosphate. Their role in phosphate homeostasis is not clear. Other sites of expression include the liver and brain.

Type 2 sodium phosphate cotransporters are expressed in the kidneys, bones, and intestines. In epithelial cells, these transporters are responsible for transepithelial transport, ie, absorption of phosphate from intestine and reabsorption of phosphate from renal tubular fluid. Type 2a transporters are expressed in the apical membranes of kidney proximal tubules, are very specific for phosphate, and are regulated by several physiologic mediators of phosphate homeostasis, such as parathyroid hormone (PTH), dopamine, and dietary phosphate. Currently, these transporters are believed to be most critical for maintenance of renal phosphate homeostasis. Impaired expression or function of these transporters is associated with nephrolithiasis.1,2 

Type 2b transporters are very similar, but not identical, to type 2a transporters. They are expressed in the small intestine and are also up-regulated under conditions of dietary phosphate deprivation. Type 2c transporters, initially described as growth-related phosphate transporters, are a third member of the type 2 sodium phosphate cotransporter family. They are expressed exclusively on the S1 segment of the proximal tubule and together with Type 2a transporters are essential for normal phosphate homeostasis.3  Similarly to type 2a transporters, type 2c transporters are also regulated by diet and PTH. Loss of type 2c function results in hereditary hypophosphatemic rickets with hypercalciuria.4

Type 3 transporters were initially identified as viral transport proteins. Almost all cells express type 3 sodium phosphate cotransporters; therefore, these transporters presumably play a housekeeping role in ensuring adequate phosphate for all cells. The factors that regulate the activity of these transporter proteins are not completely understood. Evidence suggests, however, that these transporters also participate in the regulation of renal and intestinal transepithelial transport5,6 and in the regulation of bone mineralization.7

Circulating phosphate exists as either the univalent or divalent hydrogenated species. Because the ionization constant of acid (pK) of phosphate is 6.8, at the normal ambient serum pH of 7.4 the univalent species is 4 times as prevalent as the divalent species. Serum phosphate concentration varies with age, time of day, fasting state, and season. Serum phosphate concentration is higher in children than adults; the reference range is 4-7 mg/dL in children compared with 3-4.5 mg/dL in adults. A diurnal variation exists, with the highest phosphate level occurring near noon.

Serum phosphate concentration is regulated by diet, hormones, and physical factors such as pH, as discussed in the next section. Importantly, because phosphate enters and exits cells under several influences, the serum concentration of phosphate may not reflect true phosphate stores. Often, persons with alcoholism who have severely deficient phosphate stores may present for medical treatment with a normal serum phosphate concentration. Only after refeeding will serum phosphate levels decline, often abruptly plummeting to dangerously low levels.

Phosphate homeostasis

Phosphate is plentiful in the diet. A normal diet provides approximately 1000 mg of phosphate, two thirds of which is absorbed, predominantly in the proximal small intestine. The absorption of phosphate can be

increased by increasing vitamin D intake and by ingesting a very low–phosphate diet. Under these conditions, the intestine expresses sodium-coupled phosphate transporters to enhance phosphate uptake.

Regulation of intestinal phosphate transport overall is poorly understood. Although studies had suggested that the majority of small intestine phosphate uptake is accomplished through sodium-independent, unregulated pathways, subsequent investigations have suggested that regulated, sodium-dependent mechanisms may play a greater role in overall intestinal phosphate handling than was previously appreciated.  Furthermore, intestinal cells may have a role in renal phosphate handling through elaboration of circulating phosphaturic substances in response to sensing a phosphate load.8 

Absorption of phosphate can be blocked by commonly used over-the-counter aluminum-, calcium-, and magnesium-containing antacids. Mild-to-moderate use of such phosphate binders generally poses no threat to phosphate homeostasis because dietary ingestion greatly exceeds body needs. However, very heavy use of these antacids can cause significant phosphate deficits. Stool losses of phosphate are minor, ie, 100-300 mg/d from sloughed intestinal cells and gastrointestinal secretions. However, these losses can be increased dramatically in persons with diseases that cause severe diarrhea or intestinal malabsorption.

Bone loses approximately 300 mg of phosphate per day, but that is generally balanced by an uptake of 300 mg. Bone metabolism of phosphate is influenced by factors that determine bone formation and destruction, ie, PTH, vitamin D, sex hormones, acid-base balance, and generalized inflammation.

The excess ingested phosphate is excreted by the kidneys to maintain phosphate balance. Major sites of regulation of phosphate excretion are the early proximal renal tubule and the distal convoluted tubule. In the proximal tubule, phosphate reabsorption by type 2 sodium phosphate cotransporters is regulated by dietary phosphate, PTH, and vitamin D. High dietary phosphate intake and elevated PTH levels decrease proximal renal tubule phosphate absorption, thus enhancing renal excretion.

Conversely, low dietary phosphate intake, low PTH levels, and high vitamin D levels enhance renal proximal tubule phosphate absorption. To some extent, phosphate regulates its own regulators. High phosphate concentrations in the blood down-regulate the expression of some phosphate transporters, decrease vitamin D production, and increase PTH secretion by the parathyroid gland. Distal tubule phosphate handling is less well understood. PTH increases phosphate absorption in the distal tubule, but the mechanisms by which this occurs are unknown. Renal phosphate excretion can also be increased by the administration of loop diuretics.

PTH and vitamin D were previously the only recognized regulators of phosphate metabolism. However, several novel regulators of mineral homeostasis have been identified through studies of serum factors associated with phosphate wasting syndromes such as oncogenic osteomalacia and the hereditary forms of hypophosphatemic rickets, have been discovered.

The first to be discovered was a phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX), a neutral endopeptidase mutated in the syndrome of X-linked hypophosphatemic rickets. The characteristics of this syndrome (ie, hypophosphatemia, renal phosphate wasting, low 1,25-dihydroxyvitamin D levels) and the fact that PHEX was identified as an endopeptidase suggested the possibility that PHEX might be responsible for the catabolism of a non-PTH circulating factor that

regulated proximal tubule phosphate transport and vitamin D metabolism. A potential substrate for PHEX was subsequently identified as fibroblast growth factor 23 (FGF23).

Several lines of evidence support a phosphaturic role for FGF23. Another syndrome of hereditary hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, is characterized by a mutation in theFGF23 gene that renders the protein resistant to proteolytic cleavage and, thus, presumably more available for inhibition of renal phosphate transport. Administration of recombinant FGF23 produces phosphaturia, and FGF23 knockout mice exhibit hyperphosphatemia.

The syndrome of oncogenic osteomalacia, characterized by acquired hypophosphatemic rickets and renal phosphate wasting in association with specific tumors, is associated with overexpression of FGF23. Interestingly, in this syndrome, overexpression of FGF23 is accompanied by 2 other phosphaturic agents, matrix extracellular phosphoglycoprotein (MEPE) and frizzled related protein-4. The roles of these 2 latter proteins and their relationship with FGF23 and PHEX are unknown.

The physiologic role of FGF23 in the regulation of phosphate homeostasis is still under investigation. FGF23 is produced in several types of tissue, including heart, liver, thyroid/parathyroid, small intestine, and bone tissue. The source of circulating FGF23 has not been conclusively established; however, the highest mRNA expression for FGF23 in mice is in bone.9,10  FGF23 production by osteoblasts is stimulated by 1,25 vitamin D.9 Conversely, individuals with X-linked hypophosphatemic rickets show inappropriately depressed levels of 1,25 vitamin D due to FGF23-mediated suppression of 1-alpha hydroxylase activity.

Studies in patients with end-stage renal disease found that FGF23 levels rose with decreasing creatinine clearance rates and increasing plasma phosphorus levels. Klotho, a transmembrane protein, is an essential cofactor for the effects of FGF23 on renal proximal tubule cells.11  Inactivation or deletion of Klotho expression results in hyperphosphatemia and accelerated aging. The relationship between these 2 functions of Klotho remains unknown.

A study also demonstrated that FGF23 levels rapidly decreased after kidney transplantation suggesting that FGF23 is cleared by the kidney.12 Thus, residual FGF23 could contribute to the hypophosphatemia frequently seen in posttransplant patients. In healthy young men without renal disease, phosphate intake did not significantly increase FGF23 levels, suggesting that FGF23 may not play a role in acute phosphate homeostasis.13

One other family of phosphate-regulating factors is the stanniocalcins (STC1 and STC2). In fish, where it was first described, STC1 inhibits calcium entry into the organism through the gills and intestines. However, in mammals, STC1 stimulates phosphate reabsorption in the small intestine and renal proximal tubules and STC2 inhibits the promoter activity of the type 2 sodium phosphate cotransporter, while the effects on calcium homeostasis are of lesser magnitude. Very little is known about the clinical significance of these newly described mineral-regulating agents or about potential interactions with either the PTH-vitamin D axis or with the phosphatonin-PHEX system.

Pathophysiology

Any of 3 pathogenic mechanisms can cause hypophosphatemia.

Inadequate intake

Inadequate phosphate intake alone is an uncommon cause of hypophosphatemia. The ease of intestinal absorption of phosphate coupled with the ubiquitous presence of phosphate in almost all ingested food substances ensures that daily phosphate requirements are more than met by even a less-than-ideal diet.

Hypophosphatemia is most often caused by long-term, relatively low phosphate intake in the setting of a sudden increase in intracellular phosphate requirements such as occurs with refeeding. Intestinal malabsorption can contribute to inadequate phosphate intake, especially if coupled with a poor diet. Although generally not essential for adequate phosphate absorption, vitamin D deficiency can contribute to hypophosphatemia by failing to stimulate phosphate absorption in cases of poor dietary ingestion. Case reports also document patients developing hypophosphatemia due to excessive use of antacids, particularly calcium-, magnesium-, or aluminum-containing antacids.

Increased excretion

Increased excretion of phosphate is a more common mechanism for the development of hypophosphatemia. The most common cause of increased renal phosphate excretion is hyperparathyroidism due to the ability of PTH to inhibit proximal renal tubule phosphate transport. However, frank hypophosphatemia is not universal and is most often mild.

Increased excretion of phosphate can also be induced by forced saline diuresis due to the inhibitory effect of saline diuresis on all proximal renal tubule transport processes. Again, the degree of hypophosphatemia is generally minimal. Vitamin D deficiency not only impairs intestinal absorption, but also decreases renal absorption of phosphate. Several genetic and acquired syndromes of phosphate wasting and associated skeletal abnormalities have been described.

Shift from extracellular to intracellular space

This pathogenetic mechanism alone is an uncommon cause of hypophosphatemia, but it can exacerbate hypophosphatemia produced by other mechanisms. Clinical situations in which this mechanism is the major cause of hypophosphatemia are the treatment of diabetic ketoacidosis, refeeding, short-term increases in cellular demand (eg, hungry bones syndrome), and acute respiratory alkalosis.

Frequency

United States

Exact figures are difficult to determine, mainly because phosphate measurements are often not obtained with routine laboratory studies and are determined only when the care provider has a high index of suspicion for hypophosphatemia. In the general population of hospitalized patients, hypophosphatemia is observed in 1-5% of individuals and is usually mild and asymptomatic. The percentage rises steeply in patients with alcoholism, diabetic ketoacidosis, or sepsis, in whom studies have reported frequency rates of up to 40-80%.

Hypophosphatemia has been reported in a significant number of patients following partial hepatectomy for transplantation (up to 55%) and in acute hepatic failure, attributed to an increase in cell utilization due to regeneration of liver tissue. Hypophosphatemia in this setting is associated with a favorable prognosis. Hypophosphatemia is also seen in approximately one third of hematopoietic cell transplantation, but, in this setting, it correlates highly with mortality.

Hypophosphatemia occurs in a significant percentage of kidney transplant recipients (50-80%), in particular immediately after transplantation. In many patients it can persist for the life of the transplant. Hypophosphatemia has also been reported in association with the metabolic syndrome.

Mortality/Morbidity

The morbidity of hypophosphatemia is highly dependent on cause, duration, and severity.

Mild and transient hypophosphatemia is generally asymptomatic and is not accompanied by long-term complications.

Chronic hypophosphatemia that accompanies chronic phosphate deficiency can result in significant bone disease. This is seen most commonly in osteomalacia due to vitamin D deficiency, long-term antacid abuse, hereditary phosphate wasting syndromes, malnutrition, and tumor-induced osteomalacia. Frequently in these conditions, the hypophosphatemia is accompanied by significant bone pain, fracture rate, nephrocalcinosis, and renal insufficiency. In childhood phosphate wasting syndromes, long-term treatment with phosphate replacement frequently results in renal insufficiency and hyperparathyroidism.

Acute severe hypophosphatemia can manifest as widespread organ dysfunction. Hypophosphatemia in the ICU setting is associated with respiratory insufficiency due to impaired diaphragmatic contractility and depressed cardiac output due to decreased myocardial contractility that reverse with correction of the electrolyte abnormality. Severe hypophosphatemia is also associated with rhabdomyolysis, cardiac arrhythmias, altered mental status, seizures, hemolysis, impaired hepatic function, and depressed white cell function. The newest recommendation for the use of aggressive insulin therapy in the ICU setting has the potential for increasing the frequency and severity of and the morbidity of hypophosphatemia. Another factor increasing the frequency and severity of hypophosphatemia is the widespread use of continuous therapies for the treatment of acute renal failure.

Race

Hypophosphatemia has no race predilection except for the syndrome of X-linked hypophosphatemic rickets, which predominates in Caucasian populations.

Sex

Hypophosphatemia has no sex predilection except for the syndrome of X-linked hypophosphatemic rickets, which is seen in male children.

Age

Hypophosphatemia can occur in persons of any age. Acquired hypophosphatemia tends to occur in late adolescence to adulthood. Cases occurring in late adolescence are often related to eating disorders. With aging, hypophosphatemia is often related to alcoholism, tumors, malabsorption, or vitamin D deficiency.

The genetic syndromes of phosphate wasting manifest in infancy or childhood. These syndromes include X-linked hypophosphatemic rickets, vitamin D resistant rickets, autosomal dominant hypophosphatemic rickets, hereditary hypophosphatemia with hypercalciuria, and congenital Fanconi syndrome.

Acquired hypophosphatemia tends to occur in late adolescence to adulthood. Cases occurring in late adolescence are often related to eating disorders. With aging, hypophosphatemia is often

related to alcoholism, tumors, malabsorption, malnutrition, or vitamin D deficiency. Hypophosphatemia has been reported in up to 15% of geriatric patients undergoing refeeding. Hypophosphatemia has also been reported in up to 35% of adult patients undergoing open heart surgery and is associated with prolonged mechanical ventilation, increased use of cardiovascular drugs, and prolonged hospitalization.

Clinical

History

Most patients with hypophosphatemia are asymptomatic. History alone rarely alerts the physician to the possibility of hypophosphatemia. In cases of oncogenic osteomalacia or in some of the genetic causes of phosphate wasting, patients complain of bone pain and fractures. Otherwise, physicians must have a high index of suspicion and must be aware of the clinical conditions that might be complicated by hypophosphatemia.

Symptoms of hypophosphatemia are nonspecific and highly dependent on cause, duration, and severity.

Mild hypophosphatemia (ie, 2-2.5 mg/dL), whether acute or chronic, is generally asymptomatic. Occasionally, patients may complain of weakness, but whether the weakness is secondary to hypophosphatemia or is due to the underlying disorder causing the hypophosphatemia is not clear.

Acute mild hypophosphatemia commonly occurs with the treatment of diabetic ketoacidosis because of the sudden large doses of insulin used to treat the uncontrolled diabetes. However, mild hypophosphatemia is asymptomatic and rapidly reversed.

o Mild hypophosphatemia can also occur after renal transplantation and can last years

without any discernible symptoms.

o Primary hyperparathyroidism is also associated with mild hypophosphatemia; however,

the symptoms of hypercalcemia appear to be more prominent than those of mild hypophosphatemia.

Patients with severe and/or chronic hypophosphatemia are more likely to be symptomatic.

o Moderate degrees of hypophosphatemia are commonly observed in patients with the

refeeding syndromes. Most commonly, these individuals have a history of long-standing alcohol use and chronic malnutrition, resulting in the development of total body phosphate depletion.

o When these patients are admitted to the hospital, their serum phosphate level is most

often within the reference range. However, feeding stimulates insulin release, leading to a shift of phosphate from the extracellular to the intracellular compartment.

o At times, the ensuing hypophosphatemia can be profound. Depending on the severity of

the hypophosphatemia, the patient may complain of muscle weakness and generalized weakness or may develop the full-blown hypophosphatemic syndrome. In this particular clinical situation, if the practitioner does not have a high index of suspicion, the delirious state can be misinterpreted as delirium tremens.

o The acute hypophosphatemic syndrome occurs most commonly in persons with chronic

alcoholism, but it can also be observed in refeeding of patients who have eating disorders, patients who have been starved for any reason, or patients who are receiving parenteral nutrition with inadequate quantities of phosphate replacement.

Patients with chronic phosphate wasting syndromes frequently present with bone pain, muscle weakness, and skeletal disorders. In the genetic syndromes of renal phosphate wasting or acquired oncogenic osteomalacia, the serum phosphate level is generally moderately depressed. Symptoms are predominantly muscle weakness and bone pain or fractures.

In short, symptoms alone rarely alert the physician to the possibility of hypophosphatemia. Recognizing that hypophosphatemia can complicate specific clinical conditions allows the physician to make this diagnosis.

o Weakness, bone pain, rhabdomyolysis, and altered mental status are the most common

presenting features of persons with symptomatic hypophosphatemia.

o If considering the diagnosis of hypophosphatemia, the physician should attempt to elicit

the following clinical clues to conditions associated with hypophosphatemia:

Poor nutrition

Symptoms of malabsorption

Excessive antacid use

Bone pain or fractures

Symptoms suggestive of multiple myeloma or other paraproteinemia

Treatment with parenteral nutrition

Exposure to heavy metals

Use of drugs such as glucocorticoids, cisplatin, or pamidronate

Treatment of diabetic ketoacidosis

Extensive burns

Use of growth factors

Bone marrow transplant

Intensive care unit (ICU) setting

Physical

No physical signs are specific for hypophosphatemia. In fact, physical signs of mild hypophosphatemia are generally absent.

Chronic hypophosphatemia can be associated with short stature and evidence of rickets, with bowing of the legs, when caused by one of the genetically transmitted phosphate wasting

disorders. In adults, chronic hypophosphatemia is more commonly associated with bone pain upon palpation.

Severe acute hypophosphatemia can have a variety of signs, including disorientation, seizures, focal neurologic findings, evidence of heart failure, and muscle pain.

Myocardial contractility may be impaired with ATP depletion, and respiratory failure due to weakness of the diaphragm has been described. The reduction in cardiac output may become clinically significant, leading to congestive heart failure, when the plasma phosphate concentration falls to 1.0 mg/dL (0.32 mmol/L).14Acute hypophosphatemia superimposed upon preexisting severe phosphate depletion can lead to rhabdomyolysis. Although CPK elevations are fairly common in hypophosphatemia, clinically significant rhabdomyolysis has been described almost exclusively in alcoholics and in patients receiving hyperalimentation without phosphate supplementation.

Causes

The differential diagnosis of hypophosphatemia is most easily considered according to pathogenetic mechanisms. The following discussion conforms to this approach, but note that hypophosphatemia is frequently the result of more than one mechanism.

Inadequate intakeo Hypophosphatemia due to inadequate intake is uncommon but should be strongly

considered in certain patient populations. Inadequate ingestion can result from phosphate deficiency in the diet or from poor intestinal absorption. Patients who have had prolonged poor intake of phosphate develop true phosphate deficiency.

o Persons with alcoholism who ingest an inadequate diet comprise one population at risk

for this clinical scenario. Serum phosphate levels may be within reference ranges upon admission to the hospital, but refeeding stimulates cellular uptake and results in profound hypophosphatemia.

o Similarly, critically ill patients receiving a parenteral diet deficient in phosphate may

suddenly become hypophosphatemic as their catabolic condition resolves and they become more anabolic.

o People with eating disorders or dietary deficiencies due to socioeconomic, dental, or

swallowing difficulties may also become hypophosphatemic when fed an adequate diet.

o Malabsorption of intestinal phosphate can be severe enough to produce phosphate

deficiency and hypophosphatemia.

o Individuals who ingest large quantities of antacids can become hypophosphatemic

because of phosphate binding by the antacids, resulting in poor intestinal absorption.

o Primary intestinal disorders, such as Crohn disease or celiac sprue, can limit phosphate

absorption, leading to hypophosphatemia.

o Similarly, steatorrhea or chronic diarrhea can cause mild-to-moderate hypophosphatemia

due to decreased phosphate absorption from the gut and renal phosphate wasting; the

latter is caused by secondary hyperparathyroidism induced by concomitant vitamin D deficiency.

o Vitamin D deficiency causes hypophosphatemia by limiting intestinal and renal phosphate

absorption.

Excessive losses

o Phosphate wasting can result from genetic or acquired renal disorders. The genetic

disorders generally manifest in infancy, when the children exhibit short stature and bone deformities.

X-linked hypophosphatemic rickets is characterized by short stature, radiographic evidence of rickets, and bone pain. Patients with this condition also may have calcification of tendons, cranial abnormalities, and spinal stenosis. In addition to hypophosphatemia, these patients have relatively low levels of 1,25 dihydroxyvitamin D-3, levels that are inappropriately low for the degree of hypophosphatemia. The defective gene is PHEX, which encodes for a membrane-bound neutral endopeptidase. Present understanding of this disorder is that the inactive neutral endopeptidase is unable to cleave a circulating phosphaturic substance. Data suggest that this circulating substance might be FGF23. This results in impaired phosphate reabsorption by decreasing the sodium-phosphate cotransporter in the kidneys.

Autosomal dominant hypophosphatemic rickets has similar manifestations, with hypophosphatemia, clinical rickets, and inappropriately low levels of 1,25 dihydroxyvitamin D-3. The cause of this disorder is thought to be mutations of FGF23 that result in resistance to degradation, persistently high circulating levels of FGF23, and subsequent phosphaturia.

Hereditary hypophosphatemic rickets with hypercalciuria is a rare disorder characterized by hypophosphatemia, phosphate wasting, hypercalciuria, bone pain, muscle weakness, and high levels of 1,25 dihydroxyvitamin D-3. The cause of this disorder is an inactivating mutation in the type 2c sodium-phosphate cotransporter.

Vitamin D–resistant rickets is an autosomal recessive disorder. In type I, the defect is in renal 1-alpha-hydroxylation. Type II is characterized by end organ resistance to the effects of 1,25 dihydroxyvitamin D-3. These patients present in childhood with hypocalcemia, hypophosphatemia, hyperparathyroidism, rickets, bone pain, muscle weakness, and alopecia. The disease is caused by mutations in the vitamin D receptor that prevent normal responsiveness to circulating vitamin D-3.

Mutations in the type 2a sodium-phosphate cotransporter have been reported in some patients with hypophosphatemia and inappropriate urinary phosphate wasting associated with nephrolithiasis and/or osteoporosis.1,15

Rarely, significant renal phosphate wasting is observed in patients with fibrous dysplasia/McCune-Albright syndrome, disorders that result from mutations in the

alpha subunit of the stimulatory G protein. Excess production of FGF23 has been found in some of these patients.16

o Acquired phosphate wasting syndromes are of diverse etiologies.

Simple vitamin D deficiency results in hypophosphatemia, at least in part, from renal wasting. Vitamin D deficiency can result from several mechanisms, including poor oral intake, lack of sun exposure, drug-induced hypermetabolism of vitamin D precursors in the liver, or loss of vitamin D binding protein in the urine in persons with nephrotic syndrome. The loss of normal bone mineralization produces rickets in children and osteomalacia in adults.

Primary hyperparathyroidism is another cause of renal phosphate wasting.

Heavy metal intoxication and paraproteinemias can cause global proximal renal tubule dysfunction. These patients have hypophosphatemia along with type II renal tubular acidosis, renal glycosuria, aminoaciduria, and hypouricemia, ie, the condition referred to as Fanconi syndrome. Serum calcitriol concentrations can be either low or inappropriately normal. In children, cystinosis, Wilson disease, and hereditary fructose intolerance are the most common of the syndrome.

Drugs that can produce renal phosphate wasting include loop diuretics; acetazolamide; bisphosphonates, including pamidronate and zoledronate; and multiple chemotherapeutic and biologic agents, including cisplatinum; bevacizumab plus irinotecan17 ; everolimus plus octreotide LAR18 ; imatinib mesylate, a drug used in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors19,20 ; sorafenib21 ; carmustine22 ; and ifosfamide.23  In some circumstances, renal phosphate wasting is part of a more generalized, drug-induced Fanconi syndrome.24

Extracellular volume expansion or the administration of bicarbonate can cause loss of phosphate through the kidneys.

Oncogenic osteomalacia is a paraneoplastic syndrome characterized by osteomalacia, hypophosphatemia, renal phosphate wasting, bone pain, and muscle weakness. Several tumors that cause this syndrome have been described, most of which are benign tumors of mesenchymal origin.

Other factors that can increase urinary phosphate excretion are osmotic diuresis (most often due to glucosuria), proximally acting diuretics (acetazolamide and some thiazide diuretics that also have carbonic anhydrase inhibitory activity, such as metolazone), and acute volume expansion (which diminishes proximal sodium reabsorption).

Intracellular shift of phosphate

o Several physiologic agents stimulate phosphate uptake from the extracellular

environment into the cell. This phenomenon can exacerbate the hypophosphatemia caused by the previously described mechanisms and can result in profound

hypophosphatemia. However, in some circumstances, the shift alone may be enough to produce hypophosphatemia, albeit of a milder degree.

o Acute respiratory alkalosis or hyperventilation produces hypophosphatemia by

stimulating a shift of phosphate into the cells. This mechanism is responsible for the hypophosphatemia observed with salicylate overdose, panic attacks, and sepsis. Extreme hyperventilation in normal subjects can lower serum phosphate concentrations to below 1.0 mg/dL (0.32 mmol/L), and it is probably the most common cause of marked hypophosphatemia in hospitalized patients. Less pronounced hypophosphatemia may occur during the increase in ventilation after the successful treatment of severe asthma. The effects of respiratory alkalosis are exacerbated by concomitant glucose infusions and may persist after hyperventilation ceases. Respiratory alkalosis also may be the precipitating factor in the hypophosphatemia-induced acute rhabdomyolysis that can occur in alcoholic patients.25

o Insulin increases cell phosphate uptake and causes hypophosphatemia during treatment

of diabetic ketoacidosis, refeeding, and parenteral nutrition therapy.

o Exogenous epinephrine also stimulates cellular phosphate uptake.

o Several cytokines reportedly stimulate intracellular phosphate shifts. This mechanism is

perhaps responsible for the hypophosphatemia observed in the ICU setting of trauma, extensive burns, and bone marrow transplantation.

o In hungry bone syndrome, rapid uptake of phosphate into bone occurs after the initial

treatment of osteomalacia or rickets or postparathyroidectomy.

o Hypophosphatemia is a common complication of kidney transplantation. Tertiary

hyperparathyroidism has long been thought to be the etiology, but hypophosphatemia can occur despite low PTH levels and can persist after high PTH levels normalize. Furthermore, even in the setting of normal allograft function, hypophosphatemia, and hyperparathyroidism, calcitriol levels remain inappropriately low following transplantation, suggesting that mechanisms other than PTH contribute to phosphate homeostasis.

FGF23 induces phosphaturia, inhibits calcitriol synthesis, and accumulates in chronic kidney disease. This factor has been suggested as a possible mediator of posttransplantation hypophosphatemia. Dipyridamole enhances renal tubular phosphate reabsorption and has been shown to be effective in posttransplant hypophosphatemia in small studies.

Hyporeninemic Hypoaldosteronism

Introduction

Background

In chronic kidney disease (CKD), the kidney retains a remarkable ability to compensate for nephron loss by increasing single nephron excretion of various substances. This situation is particularly important in the renal adaptation to potassium handling. In fact, when compensation is intact, hyperkalemia is uncommon until renal function (glomerular filtration rate [GFR]) decays to an advanced stage (ie, GFR or creatinine clearance ≤ 15 cc/min); however, at times, tubular adaptation is impaired, and hyperkalemia is observed much earlier in the course of CKD.

This picture of hyperkalemia, often with mild acidosis, in the setting of mild-to-moderate CKD (stages 2-4) is quite common in clinical practice. Several pathophysiologic mechanisms are involved. However, the diagnostic workup does not always establish the precise mechanism, and, unfortunately, much confusion has arisen from the nomenclature employed.

The use of the term hyporeninemic hypoaldosteronism, strictly speaking, should be limited to those cases in which testing reveals the cause of hyperkalemia to be a deficiency of renin and aldosterone. Similarly, the term type IV renal tubular acidosis (RTA), or (more recently) hyperkalemic RTA or tubular hyperkalemia, should be employed for cases with normal renin and aldosterone production but impaired tubular responsiveness, usually caused by a distal tubular voltage defect. The term type IV RTA is in itself confusing because type III is rarely observed or discussed.

This article reviews some of the pathophysiologic aspects, the clinical picture, and the treatment strategies of hyporeninemic hypoaldosteronism from the standpoint of clinical presentation, evaluation, and treatment. These diagnoses often are less precise than they sound, and, in this article, the term type IV RTA is used in its broad sense as hyperkalemia due to some combination of derangements of renin or aldosterone production and/or of tubular responsiveness to aldosterone.

See Metabolic Acidosis for a detailed discussion of the regulation of acid-base balance.

Pathophysiology

The dietary potassium intake may exceed 120 mEq/d in patients in the United States and may be even higher elsewhere. Patients excrete 90% of this intake renally. Even with CKD, the kidneys usually can compensate and maintain potassium homeostasis, albeit with less ability to handle a surge of potassium intake. Potassium is filtered at the glomerulus and then reabsorbed in the proximal nephron. The main site of potassium excretion is located in the distal tubule, or, more precisely, the principal cells of the cortical collecting tubule (CCT). To achieve adequate potassium excretion, sodium delivery to that site must be adequate, aldosterone must be present to facilitate the sodium-potassium (Na-K) exchange, the principal cells must respond to aldosterone, and urine flow must be brisk enough to wash out the excreted potassium.1,2

The degree of acidosis is variable and may be related to the underlying chronic renal disease. Note that unlike type I (ie, distal) RTA, in which the defect is in proton secretion with resulting high urine pH (>5.3), in type IV RTA, the defect is primarily with ammoniagenesis. This defect, albeit significant, still permits the elaboration of acidic (pH <5.3) urine. Hyperkalemia inhibits renal ammoniagenesis is several ways. Furthermore, hyperkalemia may produce acidosis by a shift of protons out from cells to the extracellular space, as homeostatic mechanisms attempt to buffer potassium by intracellular uptake.

The first step in the renin release cascade involves the juxtaglomerular apparatus of the nephron. Here, renin is released, allowing angiotensin I to be cleaved from angiotensinogen; this is the rate-limiting step in the cascade. Angiotensin I, in turn, is broken down by angiotensin converting enzyme (ACE) into angiotensin II. Angiotensin II is a cofactor, along with potassium, in aldosterone synthesis by the adrenal gland.

Renal tubular damage may cause inadequate renin production and release; adrenal dysfunction may lead to inadequate aldosterone production; and the principal cells of the CCT may not respond normally to aldosterone. In true cases of hyporeninemic hypoaldosteronism, atrophy of the juxtaglomerular apparatus may be present; this may be more prevalent in diabetic patients. Any combination of these factors may cause the clinical picture commonly called hyporeninemic hypoaldosteronism or RTA type IV (see Background). Indeed, as demonstrated by Schambelan and colleagues, all 3 factors may be present together in some patients.3

Frequency

United States

Specifying incidence or prevalence of RTA type IV is difficult for several reasons: the condition (1) is often undetected, (2) may only manifest when the patient is challenged by dietary potassium excess, (3) is often iatrogenic (in the sense that an underlying proclivity is exposed by certain medications), and (4) improves with the removal of exacerbating agents. This condition involves a spectrum of symptom severity, and only the more severe cases provoke attention and therapy. In the broad perspective of an aging population with a high prevalence of diabetes and polypharmacy, the clinical picture of RTA type IV is not uncommon.

Mortality/Morbidity

Occasionally, a patient presents with hyperkalemia-induced cardiac arrhythmias, which may be fatal. Muscle weakness and dyspnea may also be presenting symptoms. More typically, the patient presents

with hyperkalemia on routine chemistry testing. If untreated, the risk of a fatal arrhythmia exists, but this risk is not quantified. Sublethal hyperkalemia, per se, is usually asymptomatic, but chronic acidosis contributes to bone demineralization over the long term.

Race

In the United States, renal disease is more common in blacks, Native Americans, and Hispanics; therefore, RTA type IV would be expected to show a higher prevalence in those groups. Diabetes also is more common in these groups, further compounding the problem of hyperkalemia.

Sex

No sexual predilection exists; however, a sexual prevalence does exist among the underlying renal diseases (eg, more systemic lupus erythematosus [SLE] occurs in women, more lead nephropathy occurs in men).

Age

This condition generally develops in middle-aged or older patients but can occur in younger patients with such disorders as diabetes type I or sickle cell anemia.

Clinical

History

RTA type IV generally is asymptomatic unless severe hyperkalemia leads to muscle weakness or life-threatening arrhythmia (see Hyperkalemia for further discussion). Acidosis usually is mild and asymptomatic.

The condition is usually discovered during routine laboratory evaluations. Because several commonly used drugs may unmask RTA type IV, hyperkalemia commonly is

discovered during follow-up testing of a patient started on one of those agents. Patient history may include the following:

o The above-mentioned drugs include medications affecting the renin-angiotensin-

aldosterone axis (seeCauses). Hyperkalemia with moderate doses of such agents may suggest a forme fruste of Type IV RTA. 

o If the patient is newly discovered to have hyperkalemia and mild-to-moderate renal

failure, focus the history on the causes of renal disease. In particular, consider long-term analgesic use, exposure to lead (industrial or from moonshine liquor), and obstructive symptoms.

o Other illnesses (eg, diabetes, sickle cell anemia, SLE) would likely have become

apparent earlier.

o Other important historical data consist of dietary intake (including pica, fad diets, and use

of salt substitutes) and current medication use (ie, over-the-counter [OTC] and prescription drugs).

Physical

The underlying renal disease and/or associated illnesses (eg, SLE, sickle cell disease) dominate the physical findings.

Except for arrhythmia and muscle weakness in severe cases, hyperkalemia produces no physical signs.

Mild acidosis may be present, but associated physical signs (eg, Kussmaul respiration) usually are absent. However, some cases of symptomatic acidosis with dyspnea have been described.

Patients demonstrate no signs of adrenal insufficiency, as glucocorticoid excretion is intact, by definition.

Patients usually are hypertensive, in association with their underlying renal disease.

The assessment of patient volume status is important because therapy commonly includes the use of diuretics.

Adrenal insufficiency is part of the differential diagnosis and manifests with findings, including fever, orthostatic changes, hyperpigmentation, and signs of illnesses (eg, SLE), that, when resulting in treatment with long-term corticosteroids, can lead to secondary hypoadrenalism.

Causes

As a rule, renal interstitial disorders are more likely to produce a picture of type IV RTA than glomerular diseases. Interstitial diseases produce more tubular damage, cause more renin production impairment (eg, in juxtaglomerular apparatus), and are more likely to compromise tubular potassium secretion in the distal nephron.

The tubulointerstitial diseases commonly associated with RTA type IV include the following:

o Sickle cell disease

o Analgesic nephropathy

o Lead nephropathy

o Chronic pyelonephritis

o Obstructive nephropathy

Diabetic nephropathy , although primarily a glomerular disease, is an exception because it is associated with decreased renin production. Furthermore, patients with diabetes may have impaired extrarenal potassium homeostasis, caused by a lack of insulin, and autonomic neuropathy with resulting impaired beta2-mediated influx of potassium into cells.

Patients with HIV disease are at risk for developing adrenal insufficiency, which may present as hyperkalemia.

o At times, the adrenal defect may be selective for mineralocorticoid production.

Furthermore, trimethoprim, a component of chemoprophylaxis regimens for patients with AIDS, may impair tubular potassium excretion.

Many commonly used drugs affect renin release, aldosterone production, or tubular potassium excretory capacity. In these cases, some confusion exists in the literature regarding nomenclature. For example, if beta-blockade reduces renin release and leads to hyperkalemia in a given patient who is usually normokalemic, some authors would declare that patient to have hyporeninemic hypoaldosteronism, while others would limit that diagnosis to cases in which drug effects have been excluded. In addition, some drugs either contain potassium or impair extrarenal potassium homeostasis. The following are some of the commonly used drugs affecting potassium excretion and homeostasis4,5 :

o Inhibitors of renin release:

Beta blockers, including beta1 selective blockers

Nonsteroidal anti-inflammatory agents, including cyclooxygenase-2 (COX-2) inhibitors

o Renin inhibitor: Aliskiren (Tekturna)6

o Inhibitors of aldosterone production: ACE inhibitors block formation of angiotensin II (a

cofactor in aldosterone production); this effect is similar to that of angiotensin II receptor blockers. Heparin interferes with adrenal gland aldosterone biosynthesis.

o Inhibitors of tubular potassium excretion: Spironolactone and eplerenone are direct

competitive inhibitors of aldosterone. Triamterene and amiloride inhibit the sodium channel necessary for potassium excretion. Triamterene has a mild effect on this channel. Calcineurin inhibitors, including cyclosporine A and tacrolimus, may interfere with the aldosterone receptor.

o Potassium-containing drugs include penicillin (oral or IV).

o Impaired potassium homeostasis: Nonselective beta blockers (and selective ones at

higher doses) block beta2-mediated potassium influx into cells, which is part of moment-to-moment potassium regulation. Acute osmotic loads (eg, mannitol, radiocontrast) impair potassium homeostasis by causing osmotic efflux of water from cells, with convective drag of potassium. This effect is mostly seen in diabetics, who lack the homeostatic protections of insulin release and an intact autonomic system.

o Some herbal products may be rich in potassium themselves or contain digitalis-like

substances that may inhibit tubular potassium excretion.

Metabolic Acidosis

Introduction

Background

Understanding the regulation of acid-base balance requires appreciation of the fundamental definitions and principles underlying this complex physiologic process.

Basic definitions

An acid is a substance that can donate hydrogen ions (H+), and a base is a substance that can accept H+ ions, regardless of the substance's charge.

H2 CO3 (acid)«H+ + HCO3 - (base)

Strong acids are those that are completely ionized in body fluids, and weak acids are those that are incompletely ionized in body fluids.

HCl«H+ + Cl- 

Hydrochloric acid (HCl) is considered a strong acid because it is present only in a completely ionized form in the body, whereas H2 CO3 is a weak acid because it is ionized incompletely, and, at equilibrium, all 3 reactants are present in body fluids.

The law of mass action states that the velocity of a reaction is proportional to the product of the reactant concentrations.

H2 CO3 (acid)«H+ + HCO3 - (base)

On the basis of this law, the addition of H+ or bicarbonate (HCO3 -) drives this reaction to the left.

In body fluids, the concentration of hydrogen ions ([H+]) is maintained within very narrow limits, with the normal physiologic concentration being 40 nEq/L. The concentration of HCO3 - (24 mEq/L) is 600,000 times that of [H+]. The tight regulation of [H+] at this low concentration is crucial for normal cellular activities because H+ at higher concentrations can bind strongly to negatively charged proteins, including enzymes, and impair their function. Under normal conditions, acids and, to a lesser extent, bases are being added constantly to the extracellular fluid compartment, and for the body to maintain a physiologic [H+] of 40 mEq/L, the following 3 processes must take place:

Buffering by extracellular and intracellular buffers Alveolar ventilation, which controls PaCO2

Renal H+ excretion, which controls plasma [HCO3 -]

Buffers

Buffers are weak acids or bases that are able to minimize changes in pH by taking up or releasing H+. Phosphate is an example of an effective buffer, as in the following reaction:

HPO4 2- + (H+)«H2 PO4 - 

Upon addition of an H+ to extracellular fluids, the monohydrogen phosphate binds H+ to form dihydrogen phosphate, minimizing the change in pH. Similarly, when [H+] is decreased, the reaction is shifted to the left. Thus, buffers work as a first-line of defense to blunt the changes in pH that would otherwise result from the constant daily addition of acids and bases to body fluids.

HCO3 -/H2 CO3 buffering system

The major extracellular buffering system is HCO3 -/H2 CO3; its function is illustrated by the following reactions:

H2 O + CO2 «H2 CO3 «H+ + HCO3 - 

One of the major factors that makes this system very effective is the ability to control PaCO2 by changes in ventilation. As can be noted from this reaction, increased carbon dioxide (CO2) concentration drives the reaction to the right, whereas a decrease in CO2 concentration drives it to the left. Put simply, adding an acid load to the body fluids results in consumption of HCO3 - by the H+ added and the formation of carbonic acid, which, in turn, forms water and CO2. CO2 concentration is maintained within a narrow range via the respiratory drive, which eliminates accumulating CO2. The kidneys regenerate the HCO3 - consumed during this reaction.

This reaction continues to move to the left as long as CO2 is constantly eliminated or until HCO3 - is significantly depleted, making less HCO3 - available to bind H+. That HCO3 - and PaCO2 can be managed independently (kidneys and lungs, respectively) makes this a very effective buffering system. At equilibrium, the relationship between the 3 reactants in the reaction is expressed by the Henderson-Hasselbalch equation, which relates the concentration of dissolved CO2 (ie, H2 CO3) to the partial pressure of CO2 (0.03 X PaCO2) in the following way:

pH = 6.10 + log ([HCO3 -]/0.03 X PaCO2)

Alternatively, [H+] = 24 X PaCO2/[HCO3 -]

Note that changes in pH or [H+] are a result of relative changes in the ratio of PaCO2 to [HCO3 -] rather than to absolute change in either one. In other words, if both PaCO2 and [HCO3 -] change in the same direction, the ratio stays the same and the pH or [H+] remains relatively stable. To diminish the alteration in pH that occurs when either HCO3 - or PaCO2 changes, the body, within certain limits, changes the other variable in the same direction.

In chronic metabolic acidosis, intracellular buffers (eg, hemoglobin, bone) may be more important than HCO3 -when the extracellular HCO3 - level is low.

Renal acid handling

Acids are added daily to the body fluids. These include volatile (eg, carbonic) and nonvolatile (eg, sulfuric, phosphoric) acids. The metabolism of dietary carbohydrates and fat produces approximately 15,000 mmol of CO2per day, which is excreted by the lungs. Failure to do so results in respiratory acidosis. The metabolism of proteins (ie, sulfur-containing amino acids) and dietary phosphate results in the formation of nonvolatile acids, H2SO4 and H3 PO4. These acids first are buffered by the HCO3 -/H2 CO3 system as follows:

H2 SO4 + 2NaHCO3 «Na2 SO4 + 2H2 CO3 «2H2 O + CO2 

The net result is buffering of a strong acid (H2 SO4) by 2 molecules of HCO3 - and production of a weak acid (H2CO3), which minimizes the change in pH. The lungs excrete the CO2 produced, and the kidneys, to prevent progressive HCO3 - loss and metabolic acidosis, replace the consumed HCO3 - (principally by

H+ secretion in the collecting duct). Some amino acids (ie, glutamate, aspartate) result in the formation of citrate and lactate, which, in turn, will be converted to HCO3 -. The net result, in a typical American diet, is an acid load in the range of 50-100 mEq of H+ per day.

To maintain normal pH, the kidneys must perform 2 physiological functions. The first is to reabsorb all the filtered HCO3 - (any loss of HCO3 - is equal to the addition of an equimolar amount of H+), a function principally of the proximal tubule. The second is to excrete the daily H+ load (loss of H+ is equal to addition of an equimolar amount of HCO3 -), a function of the collecting duct.

HCO3 - reabsorption

With a serum HCO3 - concentration of 24 mEq/L, the daily glomerular ultrafiltrate of 180 L, in a healthy subject, contains 4300 mEq of HCO3 -, all of which has to be reabsorbed. Approximately 90% of the filtered HCO3 - is reabsorbed in the proximal tubule, and the remainder is reabsorbed in the thick ascending limb and the medullary collecting duct.

The 3Na+ -2K+ «ATPase (sodium-potassium«adenosine triphosphatase) provides the energy for this process, which maintains a low intracellular Na+ concentration and a relative negative intracellular potential. The low Na+concentration indirectly provides energy for the apical Na+/H+ exchanger, NHE3 (gene symbol SLC9A3), which transports H+ into the tubular lumen. H+ in the tubular lumen combines with filtered HCO3 - in the following reaction:

HCO3 - + H+ «H2 CO3 «H2 O + CO2 

Carbonic anhydrase (CA IV isoform) present in the brush border of the first 2 segments of the proximal tubule accelerates the dissociation of H2 CO3 into H2 O + CO2, which shifts the reaction shown above to the right and keeps the luminal concentration of H+ low. CO2 diffuses into the proximal tubular cell perhaps via the aquaporin-1 water channel, where carbonic anhydrase (CA II isoform) combines CO2 and water to form HCO3 - and H+. The HCO3 - formed intracellularly returns to the pericellular space and then to the circulation via the basolateral Na+/3HCO3 - cotransporter, NBCe1-A (gene symbol SLC4A4).

In essence, the filtered HCO3 - is converted to CO2 in the lumen, which diffuses into the proximal tubular cell and is then converted back to HCO3 - to be returned to the systemic circulation, thus reclaiming the filtered HCO3 -.

Acid excretion

Excretion of the daily acid load (50-100 mEq of H+) occurs principally through H+ secretion by the apical H+«ATPase in A-type intercalated cells of the collecting duct.

HCO3 - formed intracellularly is returned to the systemic circulation via the basolateral Cl-/HCO3 - exchanger, AE1 (gene symbol SLC4A1), and H+ enters the tubular lumen via 1 of 2 apical proton pumps, H+ «ATPase or H+ -K+«ATPase. The secretion of H+ in these segments is influenced by Na+ reabsorption in the adjacent principal cells of the collecting duct. The reabsorbed Na+ creates a relative lumen negativity, which decreases the amount of secreted H+ that back-diffuses from the lumen.

Hydrogen ions secreted by the kidneys can be excreted as free ions but, at the lowest achievable urine pH of 5.0 (equal to free H+ concentration of 10 µEq/L), would require excretion of 5000-10,000 L of urine a

day. Urine pH cannot be lowered much below 5.0 because the gradient against which H+ «ATPase has to pump protons (intracellular pH 7.5 to luminal pH 5) becomes too steep. A maximally acidified urine, even with a volume of 3 L, would thus contain a mere 30 µEq of free H+. Instead, more than 99.9% of the H+ load is excreted buffered by the weak bases NH3 or phosphate.

Titratable acidity

The amount of secreted H+ that is buffered by filtered weak acids is called titratable acidity. Phosphate as HPO4 2-is the main buffer in this system, but other urine buffers include uric acid and creatinine.

H2 PO4 «H+ + HPO4 2- 

The amount of phosphate filtered is limited and relatively fixed, and only a fraction of the secreted H+ can be buffered by HPO4 2-.

Ammonia

A more important urine-buffering system for secreted H+ than phosphate, ammonia (NH3) buffering occurs via the following reaction:

NH3 + H+ «NH4 + 

Ammonia is produced in the proximal tubule from the amino acid glutamine, and this reaction is enhanced by an acid load and by hypokalemia. Ammonia is converted to ammonium (NH4 +) by intracellular H+ and is secreted into the proximal tubular lumen by the apical Na+/H+ (NH4 +) antiporter. The apical Na+/K+ (NH4 +)/2Cl- cotransporter in the thick ascending limb of the loop of Henle then transports NH4 + into the medullary interstitium, where it dissociates back into NH3 and H+. The NH3 diffuses into the lumen of the collecting duct, where it is available to buffer H+ ions and becomes NH4 +. NH4 + is trapped in the lumen and excreted as the Cl salt, and every H+ ion buffered is an HCO3 - gained to the systemic circulation.

The increased secretion of H+ in the collecting duct shifts the equation to the right and decreases the NH3concentration, facilitating continued diffusion of NH3 from the interstitium down its concentration gradient and allowing more H+ to be buffered. The kidneys can adjust the amount of NH3 synthesized to meet demand, making this a powerful system to buffer secreted H+ in the urine.

Pathophysiology

In healthy people, blood pH is maintained at 7.39-7.41, and because pH is the negative logarithm of [H+] (pH = - log10 [H+]), an increase in pH indicates a decrease in [H+] and vice versa. An increase in [H+] and a fall in pH is termed acidemia, and a decrease in [H+] and an increase in pH is termed alkalemia. The underlying disorders that lead to acidemia and alkalemia are acidosis and alkalosis, respectively. Metabolic acidosis is a primary decrease in serum HCO3 - concentration and, in its pure form, manifests as acidemia (pH <7.40).

Rarely, metabolic acidosis can be part of a mixed or complex acid-base disturbance in which 2 or more separate metabolic or respiratory derangements occur together. In these instances, pH may not be reduced or the HCO3 -concentration may not be low.

As a compensatory mechanism, metabolic acidosis leads to alveolar hyperventilation with a fall in PaCO2. Normally, PaCO2 falls by 1-1.3 mm Hg for every 1-mEq/L fall in serum HCO3 - concentration, a compensatory response that can occur fairly quickly. If the change in PaCO2 is not within this range, then a mixed acid-base disturbance is present. For example, if the decrease in PaCO2 is less than the expected change, then a primary respiratory acidosis also is present.

Often the first clue to metabolic acidosis is a decreased serum HCO3 - concentration observed when serum electrolytes are measured. Remember, however, that a decreased serum [HCO3 -] level can be observed as a compensatory response to respiratory alkalosis. An [HCO3 -] level less than 15 mEq/L, however, almost always is due, at least in part, to metabolic acidosis.

The only definitive way to diagnose metabolic acidosis is by simultaneous measurement of serum electrolytes and arterial blood gases (ABGs), which shows both pH and PaCO2 to be low; calculated HCO3 - also is low. (See the eMedicine article Metabolic Alkalosis for a discussion of the difference between measured and calculated HCO3 -concentrations.) A normal serum HCO3 - level does not rule out the presence of metabolic acidosis because a drop in HCO3 - from a high baseline (ie, preexisting metabolic alkalosis) can result in a serum HCO3 - level that is within the reference range, concealing the metabolic acidosis.

Anion gap in metabolic acidosis

Plasma, like any other body fluid compartment, is neutral; total anions match total cations. The major plasma cation is Na+, and major plasma anions are Cl- and HCO3 -. Extracellular anions present in lower concentrations include phosphate, sulfate, and some organic anions, while other cations present include K+, Mg2+, and Ca2+. The anion gap (AG) is the difference between the concentration of the major measured cation Na+ and the major measured anions Cl- and HCO3 -. Normal values for those ions are 140, 108, and 24 mEq/L, respectively, and the gap is usually between 6 and 12 mEq/L. The AG represents the difference between unmeasured anions and unmeasured cations, as shown in the following:

AG = [Na+]-([Cl-] + [HCO3 -]) = unmeasured anions - unmeasured cations

This equation indicates that an increase in the AG can result from either a decrease in unmeasured cations (eg, hypokalemia, hypocalcemia, hypomagnesemia) or an increase in unmeasured anions (eg, hyperphosphatemia, high albumin levels). In certain forms of metabolic acidosis, other anions accumulate; by recognizing the increasing AG, the clinician can formulate a differential diagnosis for the cause of that acidosis.

HA + NaHCO3 ↔ NaA + H2 CO3 ↔ CO2 + H2 O

This reaction indicates that the addition of an acid (HA, where H+ is combined with an unmeasured anion A-) results in the consumption of HCO3 - with an addition of anions that will account for the increase in the AG. Metabolic acidosis is classified on the basis of AG into normal- (also called non-AG or hyperchloremic metabolic acidosis1 ) and high-AG metabolic acidosis.

Urinary AG

Calculating the urine AG is helpful in evaluating some cases of non-AG metabolic acidosis. The major measured urinary cations are Na+ and K+, and the major measured urinary anion is Cl-.

Urine AG = ([Na+] + [K+]) - [Cl-]

The major unmeasured urinary anions and cations are HCO3 - and NH4 +, respectively. HCO3 - excretion in healthy subjects is usually negligible, and average daily excretion of NH4 + is approximately 40 mEq/L, which results in a positive or near-zero gap. In the face of metabolic acidosis, the kidneys increase the amount of NH3 synthesized to buffer the excess H+ and NH4 Cl excretion increases. The increased unmeasured NH4 + thus increases the measured anion Cl- in the urine, and the net effect is a negative AG, representing a normal response to systemic acidification. Thus, the finding of a positive urine AG in the face of non-AG metabolic acidosis points toward a renal acidification defect (eg, renal tubular acidosis [RTA]2 ).

Caveats

The presence of ketonuria makes this test unreliable because the negatively charged ketones are unmeasured and urine AG will be positive or zero despite the fact that renal acidification and NH4 + levels are increased. Moreover, severe volume depletion from extrarenal NaHCO3 loss causes avid proximal Na+ reabsorption, with little Na+reaching the lumen of the collecting duct to be reabsorbed in exchange for H+. Limiting H+ excretion reduces NH4

+ excretion and may make the urine AG become positive.

Effect of potassium balance on acid-base status

Renal acid secretion is influenced by serum [K+] and may result from the transcellular shift of K+ when intracellular K+ is exchanged for extracellular H+ or vice versa. In hypokalemia, an intracellular acidosis can develop; in hyperkalemia, an intracellular alkalosis can develop.

Hypokalemia

Renal production of NH3 is increased in hypokalemia, resulting in an increase in renal acid excretion. The increase in NH3 production by the kidneys may be significant enough to precipitate hepatic encephalopathy in patients who have advanced liver disease. Correcting the hypokalemia can reverse this process.

HCO3 - reabsorption is increased secondary to relative intracellular acidosis. The increase in intracellular H+concentration promotes the activity of the apical Na+/H+ exchanger.

Patients with hypokalemia may have relatively alkaline urine because hypokalemia increases renal ammoniagenesis. Excess NH3 then binds more H+ in the lumen of the distal nephron and urine pH increases, which may suggest RTA as an etiology for non-AG acidosis. However, these conditions can be distinguished by measuring urine AG, which will be negative in patients who have normal NH4 + excretion and positive in patients with RTA. The most common cause for hypokalemia and metabolic acidosis is GI loss (eg, diarrhea, laxative use). Other less common etiologies include renal loss of potassium secondary to RTA or salt-wasting nephropathy. The urine pH, the urine AG, and the urinary K+ concentration can distinguish these conditions.

Hyperkalemia

Hyperkalemia has an effect on acid-base regulation opposite to that observed in hypokalemia. Hyperkalemia impairs NH4 + excretion through reduction of NH3 synthesis in the proximal tubule and reduction of NH4 +reabsorption in the thick ascending limb, resulting in reduced medullary interstitial NH3 concentration. This leads to a decrease in net renal acid secretion and is a classic feature of primary

or secondary hypoaldosteronism. Consistent with the central role of hyperkalemia in the generation of the acidosis, lowering serum the K+concentration can correct the associated metabolic acidosis.

Mortality/Morbidity

The causes of metabolic acidosis are varied, and the morbidity and mortality of this disorder are primarily related to the underlying condition.

In a prospective, observational, cohort study, Maciel and Park looked at differences between survivors and nonsurvivors within a group of 107 patients suffering from metabolic acidosis on admission to an intensive care unit (ICU).3 The authors found that although acidosis was more severe in nonsurvivors than in survivors, the proportion of acidifying variables was similar on admission between the 2 groups (with hyperchloremia being the primary cause of the acidosis). The investigators also found that in nonsurviving patients, the degree of metabolic acidosis was similar on the day of death to the level measured when they were admitted to the ICU, but that the proportion of anions had changed. Specifically, the chloride levels in the patients had decreased, and the lactate levels had increased.

Clinical

History

Symptoms of metabolic acidosis are not specific. The respiratory center in the brain stem is stimulated, and hyperventilation develops in an effort to compensate for the acidosis. As a result, patients may report varying degrees of dyspnea. Patients, especially children, also may present with nausea, vomiting, and decreased appetite. The clinical history in metabolic acidosis is helpful in establishing the etiology when symptoms relate to the underlying disorder. The age of onset and a family history of acidosis may point to inherited disorders, which usually start during childhood. Important points in the history include the following:

Diarrhea - GI losses of HCO3 -

History of diabetes mellitus, alcoholism, or prolonged starvation - Accumulation of ketoacids

Polyuria, increased thirst, epigastric pain, vomiting - Diabetic ketoacidosis (DKA)

Nocturia, polyuria, pruritus, and anorexia - Renal failure4

Ingestion of drugs or toxins - Salicylates, acetazolamide, cyclosporine, ethylene glycol, methanol

Visual symptoms - Methanol ingestion

Renal stones - RTA or chronic diarrhea

Tinnitus - Salicylate overdose

Physical

The best recognized sign of metabolic acidosis is Kussmaul respirations, a form of hyperventilation that serves to increase minute ventilatory volume. This is characterized by an increase in tidal volume rather than respiratory rate and is appreciated as deliberate, slow, deep breathing. Chronic metabolic acidosis in children may be associated with stunted growth and rickets. Coma and hypotension have been reported

with acute severe metabolic acidosis. Other physical signs of metabolic acidosis are not specific and depend on the underlying cause. Some examples include the following:

Xerosis, scratch marks on skin, pallor, drowsiness, fetor, asterixis, pericardial rub - Renal failure Reduced skin turgor, dry mucous membranes, fruity smell - DKA

Causes

Metabolic acidosis is typically classified as having a normal AG (ie, non-AG) or a high AG. Non-AG metabolic acidosis is also characterized by hyperchloremia and is sometimes referred to as hyperchloremic acidosis.

Causes of non-AG metabolic acidosis can be remembered with the mnemonic ACCRUED (acid load, chronic renal failure, carbonic anhydrase inhibitors, renal tubular acidosis, ureteroenterostomy, expansion/extra-alimentation, diarrhea).

Causes of non-AG metabolic acidosis are discussed in more detail below.

The conditions that may cause a non-AG metabolic acidosis are outlined as follows:

GI loss of HCO3 - - Diarrhea, enterocutaneous fistula (eg, pancreatic), enteric diversion of urine (eg, ileal loop bladder), pancreas transplantation with bladder drainage

Renal loss of HCO3 - - Proximal RTA (type 2), carbonic anhydrase inhibitor

Failure of renal H+ secretion - Distal RTA (type 1), type 4 RTA, renal failure

Acid infusion - Ammonium chloride, hyperalimentation

Other - Rapid volume expansion with normal saline, urinary diverting surgical procedures (eg, ureteroenterostomy)

RTA is a term used to describe those conditions in which metabolic acidosis occurs from decreased net renal acid secretion. Three principal types of RTA occur; they are summarized in the Table.

Comparison of Types 1, 2, and 4 RTA

Open table in new window

Characteristics Proximal (Type 2) Distal (Type 1) Type 4

Primary defect Proximal HCO3 - reabsorption

Diminished distal H+ secretion

Diminished ammoniagenesis

Urine pH <5.5 when serum HCO3 - is low

>5.5 <5.5

Serum HCO3 - >15 mEq/L Can be <10 mEq/L >15 mEq/L

Fractional excretion of HCO3- (FEHCO3)

>15-20% during HCO3 - load

<5% (can be as high as 10% in children)

<5%

Serum K+ Normal or mild decrease

Mild-to-severe decrease* High

Associated features Fanconi syndrome ... Diabetes mellitus, renal insufficiency

Alkali therapy High doses Low doses Low doses

Complications Osteomalacia or rickets

Nephrocalcinosis, nephrolithiasis

...

*K+ may be high if RTA is due to volume depletion.

The following are common causes of high-AG metabolic acidosis:

Azotemia Ketoacidosis

Lactic acidosis

Salicylate overdose

Ethylene glycol poisoning

Methanol poisoning

Paraldehyde poisoning

A mnemonic to help remember this list is SLUMPED (salicylate, lactate, uremia, methanol, paraldehyde, ethylene glycol, diabetes).

Plasma osmolality can be calculated using the following equation:

Posm = [2 X Na+]+[glucose in mg/dL]/18+[BUN in mg/dL]/2.8

Posm can also be measured in the laboratory, and because other solutes normally contribute minimally to serum osmolality, the difference between the measured and the calculated value (osmolar gap) is no more than 10-15 mOsm/kg. In certain situations, unmeasured osmotically active solutes in the plasma can raise the osmolar gap (eg, mannitol, radioactive contrast agents). The osmolar gap can also help to determine the nature of the anion in high-AG acidosis because some osmotically active toxins also cause a high-AG acidosis. Methanol, ethylene glycol, and acetone are classic poisons that increase the osmolar gap and AG; measuring the osmolar gap can help narrow the differential diagnosis of high-AG acidosis.

The AG equation clearly indicates that for a patient with metabolic acidosis (with a decrease in HCO3 -) to maintain a normal AG, an equal increase in [Cl-] must occur, prompting this disorder to sometimes be called hyperchloremic metabolic acidosis.

AG = [Na+] - ([Cl-] + [HCO3 -])

Hyperchloremic metabolic acidosis occurs principally when HCO3 - is lost from either the GI tract or the kidneys or because of a renal acidification defect. Some of the mechanisms that result in a non-AG metabolic acidosis are the following:

Addition of HCl to body fluids: H+ buffers HCO3 - and the added Cl- results in a normal AG.

Loss of HCO3 - from the kidneys or the GI tract: The kidneys reabsorb sodium chloride to maintain volume.

Rapid volume expansion with normal saline: This results in an increase in the chloride load that exceeds the renal capacity to generate equal amounts of HCO3 -.

Specific causes of hyperchloremic metabolic acidosis 

Loss of HCO3 - via the GI tracto The secretions of the GI tract, with the exception of the stomach, are relatively alkaline,

with high concentrations of base (50-70 mEq/L). Significant loss of lower GI secretions results in metabolic acidosis, especially when the kidneys are unable to adapt to the loss by increasing net renal acid excretion.

o Such losses can occur in diarrheal states, fistula with drainage from the pancreas or the

lower GI tract, and sometimes vomiting if it occurs as a result of intestinal obstruction. When pancreatic transplantation is performed, the pancreatic duct is sometimes diverted into the recipient bladder, from where exocrine pancreatic secretions are lost in the final urine. Significant loss also occurs in patients who abuse laxatives, which should be suspected when the etiology for non-AG metabolic acidosis is not clear.

o Replacing the lost HCO3 - on a daily basis can treat this form of metabolic acidosis.

o Urine pH will be less than 5.3, with a negative urine AG reflecting normal urine

acidification and increased NH4 + excretion. However, if distal Na+ delivery is limited because of volume depletion, the urine pH cannot be lowered maximally.

Distal RTA (type 1)

o The defect in this type of RTA is a decrease in net H+ secreted by the A-type intercalated

cells of the collecting duct. As mentioned previously, H+ is secreted by the apical H+ –ATPase and, to a lesser extent, by the apical K+/H+ –ATPase. The K+/H+ –ATPase seems to be more important in K+regulation than in H+ secretion. The secreted H+ is then excreted as free ions (reflected by urine pH value) or titrated by urinary buffers, phosphate, and NH3. A decrease in the amount of H+ secreted results in a reduction in its urinary concentration (ie, increase in urine pH) and a reduction in total H+buffered by urinary phosphate or NH3.

o Type 1 RTA should be suspected in any patient with non-AG metabolic acidosis and a

urine pH greater than 5.0. Patients have a reduction in serum HCO3 - to various degrees, in some cases to less than 10 mEq/L. They are able to reabsorb HCO3 - normally, and their FE of HCO3 - is less than 3%. The disorder has been classified into 4 types—secretory, rate dependent, gradient, and voltage dependent—based on the nature of the defect.

o Several different mechanisms are implicated in the development of distal RTA. These

include a defect in 1 of the 2 proton pumps, H+ –ATPase or K+ -H+ –ATPase, that can be acquired or congenital. This may lead to loss of function (ie, secretory defect) or a reduction in the rate of H+ secretion (ie, rate-dependent defect).

o Another mechanism is a defect in the basolateral Cl-/HCO3 - exchanger, AE1, or the

intracellular carbonic anhydrase that can be acquired or congenital. This also causes a secretory defect.

o Back-diffusion of the H+ from the lumen via the paracellular or transcellular space is

another mechanism; this occurs if the integrity of the tight junctions is lost or permeability of the apical membrane is increased (ie, permeability or gradient defect). With a urine pH of 5.0 and an interstitial fluid pH of 7.4, the concentration gradient facilitating back-diffusion of free H+, under conditions of increased permeability of the collecting duct epithelia, is approximately 250-fold.

o A defect in Na+ reabsorption in the collecting duct would decrease the electrical gradient

favoring the secretion of H+ into the tubular lumen (ie, voltage-dependent defect). This can occur, for instance, in severe volume depletion with decreased luminal Na+ delivery to this site.

o The serum potassium level typically is low in patients with distal RTA because defects in

H+secretion or back-diffusion of H+ tend to increase urinary K+ wasting. Potassium wasting occurs from one or more of the following factors:

Decreased net H+ secretion results in more Na+ reabsorption in exchange for K+ secretion.

The drop in serum HCO3 - and, therefore, filtered HCO3 -, reduces the amount of Na+reabsorbed by the Na+/H+ exchanger in the proximal tubule, leading to mild volume depletion. The associated activation of the renin-angiotensin-aldosterone system increases K+ secretion in the collecting duct.

A possible defect in K+/H+ –ATPase results in decreased H+ secretion and decreased K+reabsorption.

o The serum K+ level can be high if the distal RTA is secondary to decreased luminal Na+ in

the distal nephron. Na+ reabsorption in the principal cells of the collecting duct serves as the driving force for K+ secretion. In this case, the patient has hyperkalemia and acidosis; the disorder is also called voltage-dependent or hyperkalemic type 1 acidosis.

o The causes of distal RTA are shown as follows. Type 1 RTA occurs sporadically,

although genetic forms have been reported.

Primary - Genetic or sporadic

Drug-related - Amphotericin B, lithium, analgesics, ifosfamide, toluene

Autoimmune disease - Systemic lupus erythematosus, chronic active hepatitis, Sjögren syndrome, rheumatoid arthritis, primary biliary cirrhosis

Related to other systemic disease - Sickle cell disease, hyperparathyroidism, light chain disease, cryoglobulinemia, Wilson disease, Fabry disease

Tubulointerstitial disease - Obstructive uropathy, transplant rejection, medullary cystic kidney disease, hypercalciuria

o The genetic forms of type 1 RTA are the following:

Autosomal dominant: Heterozygous mutations in the basolateral Cl-/HCO3 - exchanger, AE1, cause a dominant form of distal RTA with nephrocalcinosis and osteomalacia. Some patients with this disorder can be relatively asymptomatic and present in later years, while others present with severe disease in childhood. The disorder is allelic with one form of hereditary spherocytosis, but each disease is caused by distinct mutations in the same gene.

Autosomal recessive: This form of the disease may occur with or without sensorineural deafness. The type that occurs with deafness involves homozygous mutations in the B subunit of H+ –ATPase (gene symbol ATP6B1) in the A-type intercalated cells. The type that occurs without deafness involves homozygous mutations in the accessory N1 subunit of H+ –ATPase (gene symbol ATP6N1B). Homozygous or compound heterozygous mutations inAE1 also cause a recessive form of distal RTA that manifests in childhood with growth retardation and nephrocalcinosis that may lead to renal insufficiency. Heterozygous carriers have autosomal dominant ovalocytosis but normal renal acidification.

o Urine AG is positive secondary to the renal acid secretion defect. Urine pH also can be

high in patients with type 2 RTA if their serum HCO3 - level is higher than the renal threshold for reabsorption, typically when a patient with type 2 RTA is on HCO3 - replacement therapy. Administration of an HCO3 - load leads to a marked increase in urine pH in those who have type 2 RTA, while those with type 1 RTA have a constant urine pH unless their acidosis is overcorrected.

o Patients with type 1 RTA may develop nephrocalcinosis and nephrolithiasis. This is

thought to occur for the following reasons:

Patients have a constant release of calcium phosphate from bones to buffer the extracellular H+.

Patients have decreased reabsorption of calcium and phosphate, leading to hypercalciuria and hyperphosphaturia.

Patients have relatively alkaline urine, which promotes calcium phosphate precipitation.

Metabolic acidosis and hypokalemia lead to hypocitraturia, a risk factor for stones. Citrate in the urine complexes calcium and inhibits stone formation.

Proximal (type 2) RTA

o The hallmark of type 2 RTA is impairment in proximal tubular HCO3 - reabsorption. In the

euvolemic state and in the absence of elevated levels of serum HCO3 -, all filtered HCO3 - is reabsorbed, 90% in the proximal tubule. Normally, HCO3 - excretion occurs only when serum HCO3 - exceeds 24-28 mEq/L. Patients with type 2 RTA, however, have a lower threshold for excretion of HCO3 -, leading to a loss of filtered HCO3 - until the serum HCO3 - concentration reaches the lower threshold. At this point, bicarbonaturia ceases and the urine appears appropriately acidified. Serum HCO3 - typically does not fall below 15 mEq/L because of the ability of the collecting duct to reabsorb some HCO3 -.

o Type 2 RTA can be found either as a solitary proximal tubular defect, in which

reabsorption of HCO3 -is the only abnormality (rare), or as part of a more generalized defect of the proximal tubule characterized by glucosuria, aminoaciduria, and phosphaturia, also called Fanconi syndrome.

o Dent disease or X-linked hypercalciuric nephrolithiasis is one example of a generalized

proximal tubular disorder characterized by an acidification defect, hypophosphatemia, and hypercalciuria and arises from mutations in the renal chloride channel gene (CLCN5) .

o The proximal tubule is the site where bulk reabsorption of ultrafiltrate occurs, driven by

the basolateral Na+/K+ –ATPase. Any disorder that leads to decreased ATP production or a disorder involving Na+ -K+ –ATPase can result in Fanconi syndrome. In principle, loss of function of the apical Na+/H+ antiporter or the basolateral Na+/3HCO3 - cotransporter or the intracellular carbonic anhydrase results in selective reduction in HCO3 - reabsorption.

o The follow are causes of proximal RTA:

Primary - Genetic or sporadic

Inherited systemic disease - Wilson disease, glycogen storage disease, tyrosinemia, Lowe syndrome, cystinosis, fructose intolerance

Related to other systemic disease - Multiple myeloma, amyloidosis, hyperparathyroidism, Sjögren syndrome

Drug- and toxin-related - Carbonic anhydrase inhibitors, ifosfamide, gentamicin, valproic acid, lead, mercury, streptozotocin

o Isolated proximal RTA occurs sporadically, although an inherited form has recently been

described.

Homozygous mutations in the apical Na+/3HCO3 - cotransporter have been found in 2 kindreds with proximal RTA, band keratopathy, glaucoma, and cataracts.

A form of autosomal recessive osteopetrosis with mental retardation is associated with a mixed RTA with features of both proximal and distal disease (called type 3). The mixed defect is related to the deficiency of carbonic anhydrase (CA II isoform) normally found in the cytosol of the proximal tubular cells and the intercalated cells of the collecting duct.

The most common cause of acquired proximal RTA in adults follows the use of carbonic anhydrase inhibitors.

o Patients with type 2 RTA typically have hypokalemia and increased urinary K+ wasting.

This is thought, in part, to be due to an increased rate of urine flow to the distal nephron caused by the reduced proximal HCO3 - reabsorption and, in part, to be due to activation of the renin-angiotensin-aldosterone axis with increased collecting duct Na+ reabsorption from the mild hypovolemia induced by bicarbonaturia. Administration of alkali in those patients leads to more HCO3 - wasting and can worsen hypokalemia unless K+ is replaced simultaneously.

o The diagnosis of type 2 RTA should be suspected in patients who have a normal-AG

metabolic acidosis with a serum HCO3 - level usually greater than 15 mEq/L and acidic urine (pH <5.0).

Those patients have an FEHCO3 - less than 3% when their serum HCO3 - is low. However, raising serum HCO3 - above their lower threshold and closer to normal levels results in significant HCO3 - wasting and an FEHCO3 exceeding 15%.

FEHCO3 - = (urine [HCO3 -] X plasma [creatinine] / plasma [HCO3 -]) X urine [creatinine] X 100

o Some patients with type 2 RTA tend to have osteomalacia, a condition that can be

observed in any chronic acidemic state, although it is more common in persons with type 2 RTA. The traditional explanation is that the proximal tubular conversion of 25(OH)-cholecalciferol to the active 1,25(OH)2-cholecalciferol is impaired. Patients with more generalized defects in proximal tubular function (as in Fanconi syndrome) may have phosphaturia and hypophosphatemia, which also predispose to osteomalacia.

Type 4 RTA

o This is the most common form of RTA in adults and results from aldosterone deficiency

or resistance. The collecting duct is a major site of aldosterone action; there it stimulates Na+reabsorption and K+ secretion in the principal cells and stimulates H+ secretion in the A-type intercalated cells. Hypoaldosteronism, therefore, is associated with decreased collecting duct Na+reabsorption, hyperkalemia, and metabolic acidosis.

o Hyperkalemia also reduces proximal tubular NH4 + production and decreases

NH4 + absorption by the thick ascending limb, leading to a reduction in medullary interstitial NH3 concentration. This diminishes the ability of the kidneys to excrete an acid load and worsens the acidosis.

o Because the function of H+ –ATPase is normal, the urine is appropriately acidic in this

form of RTA. Correction of hyperkalemia leads to correction of metabolic acidosis in many patients, pointing to the central role of hyperkalemia in the pathogenesis of this acidosis.

o Almost all patients with type 4 RTA manifest varying degrees of hyperkalemia, which

commonly is asymptomatic. The etiology of hyperkalemia is multifactorial and related to the presence of hypoaldosteronism in conjunction with a degree of renal insufficiency.

The acidosis and hyperkalemia, however, are out of proportion to the degree of renal failure.

o The following findings are typical of type 4 RTA:

Mild-to-moderate chronic kidney disease (stages 2-3) in most patients, with a creatinine clearance of 30-60 mL/min

Hyperkalemia

Hypoaldosteronism

Diabetes mellitus (in approximately 50% of patients)

o The following are causes of type 4 RTA:

Hypoaldosteronism (low renin) - Hyporeninemic hypoaldosteronism (diabetes mellitus/mild renal impairment, chronic interstitial nephritis, nonsteroidal anti-inflammatory drugs, beta-blockers)

Hypoaldosteronism (high renin) - Primary adrenal defect (isolated: congenital hypoaldosteronism; generalized: Addison disease, adrenalectomy, AIDS), inhibition of aldosterone secretion (heparin, ACE inhibitors, AT1 receptor blockers)

Aldosterone resistance (drugs) - Diuretics (amiloride, triamterene, spironolactone), calcineurin inhibitors (cyclosporine, tacrolimus), antibiotics (trimethoprim, pentamidine)

Aldosterone resistance (genetic) - Pseudohypoaldosteronism (PHA) types I and II

o Although type 4 RTA occurs sporadically, familial forms have been reported. The genetic

forms are called PHA; PHA type 1 is characterized by hypotension with hyperkalemia and acidosis and includes an autosomal recessive and autosomal dominant form. PHA type 2 is characterized by hypertension with hyperkalemia and acidosis and is also known as Gordon syndrome and familial hyperkalemic hypertension.

Autosomal recessive PHA type 1: Homozygous mutations in the alpha, beta, or gamma subunits (gene symbols SCNN1A, SCNN1B, and SCNN1G) of the collecting duct epithelial sodium channel cause a syndrome that manifests in infancy with severe salt wasting, hypotension, hyperkalemia, and acidosis. A pulmonary syndrome characterized by recurrent respiratory infections, chronic cough, and increased respiratory secretions has also been noted in some individuals.

Autosomal dominant PHA type 1: Heterozygous mutations in the mineralocorticoid receptor lead to a milder phenotype that is restricted to the kidneys. Unlike the autosomal recessive form, the clinical symptoms improve with age.

Gordon syndrome (PHA type 2). This disorder is characterized by hypertension and hyperkalemia with variable degrees of metabolic acidosis. Heterozygous mutations in 1 of 2 kinases, WNK1 or WNK4, cause this syndrome. A third locus on band 1q has been described, but the genetic defect at this locus has not yet been identified.

o Type 4 RTA should be suspected in any patient with a mild non-AG metabolic acidosis

and hyperkalemia. The serum HCO3 - level is usually greater than 15 mEq/L, and the urine pH is less than 5.0 because these patients have a normal ability to secrete H+. The primary problem is hyperkalemia from aldosterone deficiency or end organ (collecting duct) resistance to the action of aldosterone. This can be diagnosed by measuring the transtubular potassium gradient (TTKG).

TTKG = urine K+ X serum osmolality/serum K+ X urine osmolality

A TTKG greater than 8 indicates that aldosterone is present and the collecting duct is responsive to it. A TTKG less than 5 in the presence of hyperkalemia indicates aldosterone deficiency or resistance. For the test to be interpretable, the urine Na+ level should be greater than 10 mEq/L and the urine osmolality should be greater than or equal to serum osmolality.

o The hyperkalemia suppresses renal ammoniagenesis, leading to a lack of urinary buffers

to excrete the total H+ load. The urine AG will be positive. Note that patients with hyperkalemic type 1 RTA have a urine pH greater than 5.5 and a low urine Na+.

Early renal failure

o Metabolic acidosis is usual in patients with renal failure, and, in early to moderate stages

of chronic kidney disease (glomerular filtration rate of 20-50 mL/min), it is associated with a normal AG (hyperchloremic). In more advanced renal failure, the acidosis is associated with a high AG.

o In hyperchloremic acidosis, reduced ammoniagenesis (secondary to loss of functioning

renal mass) is the primary defect, leading to an inability of the kidneys to excrete the normal daily acid load. In addition, NH3 reabsorption and recycling may be impaired, leading to reduced medullary interstitial NH3 concentration.

o In general, patients tend to have a serum HCO3 - level greater than 12 mEq/L, and

buffering by the skeleton prevents further decline in serum HCO3 -.

o Note that patients with hypobicarbonatemia from renal failure cannot compensate for

additional HCO3- loss from an extrarenal source (eg, diarrhea) and severe metabolic

acidosis can develop rapidly.

Urinary diversion

o Hyperchloremic metabolic acidosis can develop in patients who undergo a urinary

diversion procedure, such as a sigmoid bladder or an ileal conduit.

o This occurs through 1 of the following 2 mechanisms:

The intestinal mucosa has an apical Cl-/HCO3 - exchanger. When urine is diverted to a loop of bowel (as in patients with obstructive uropathy), the chloride in the urine is exchanged for HCO3 -. Significant loss of HCO3 - can occur, with a concurrent increase in serum Cl-concentration.

Intestinal mucosa reabsorbs urinary NH4 +, and the latter is metabolized in the liver to NH3and H+. This is particularly likely to occur if urine contact time with the intestinal mucosa is prolonged, as when a long loop of bowel is used or when the stoma is obstructed and when sigmoid rather than ileal loop is used. Presumably, the creation of a continent bladder also increases HCO3 - loss. This disorder is not observed very frequently anymore because short-loop incontinent ureteroileostomies are used now.

Infusion of acids

o The addition of an acid that contains Cl- as an ion (eg, NH4 Cl) can result in a normal-AG

acidosis because the drop in HCO3 - is accompanied by an increase in Cl-.

o The use of arginine or lysine hydrochloride as amino acids during hyperalimentation can

have the same result.

Specific causes of high-AG metabolic acidosis

Lactic acidosiso Briefly, L-lactate is a product of pyruvic acid metabolism in a reaction catalyzed by lactate

dehydrogenase that also involves the conversion of nicotinamide adenine dinucleotide (NADH) to the oxidized form of nicotinamide adenine dinucleotide (NAD+). This is an equilibrium reaction that is bidirectional, and the amount of lactate produced is related to the reactant concentration in the cytosol (pyruvate, NADH/NAD+).

o Daily lactate production in a healthy person is substantial (approximately 20 mEq/kg/d),

and this is usually metabolized to pyruvate in the liver, the kidneys, and, to a lesser degree, in the heart. Thus, production and use of lactate (ie, Cori cycle) is constant, keeping plasma lactate low.

o The major metabolic pathway for pyruvate is to acetyl coenzyme A, which then enters the

citric acid cycle. In the presence of mitochondrial dysfunction, pyruvate accumulates in the cytosol and more lactate is produced.

o Lactic acid accumulates in blood whenever production is increased or use is decreased.

A value greater than 4-5 mEq/L is considered diagnostic of lactic acidosis.

o Type A lactic acidosis occurs in hypoxic states, while type B occurs without associated

tissue hypoxia.

o D-lactic acidosis is a form of lactic acidosis that occurs from overproduction of D-lactate

by intestinal bacteria. It is observed in association with intestinal bacterial overgrowth syndromes. D-lactate is not measured routinely when lactate levels are ordered and must be requested specifically when such cases are suspected.

Ketoacidosis

o Free fatty acids released from adipose tissue have 2 principal fates. In the major

pathway, triglycerides are synthesized in the cytosol of the liver. In the less common pathway, fatty acids enter mitochondria and are metabolized to ketoacids (acetoacetic acid and beta-hydroxybutyric acid) by the beta-oxidation pathway. Ketoacidosis occurs when delivery of free fatty acids to the liver or preferential conversion of fatty acids to ketoacids is increased.

o This pathway is favored when insulin is absent (as in the fasting state), in certain forms of

diabetes, and when glucagon action is enhanced.

o Alcoholic ketoacidosis occurs when excess alcohol intake is accompanied by poor

nutrition. Alcohol inhibits gluconeogenesis, and the fasting state leads to low insulin and high glucagon levels. These patients tend to have a mild degree of lactic acidosis. This diagnosis should be suspected in alcoholic patients who have an unexplained AG acidosis, and detection of beta-hydroxybutyric acid in the serum in the absence of hyperglycemia is highly suggestive. Patients may have more than one metabolic disturbance (eg, mild lactic acidosis, metabolic alkalosis secondary to vomiting).

o Starvation ketoacidosis can occur after prolonged fasting and may be exacerbated by

exercise

o DKA is usually precipitated in patients with type 1 diabetes by stressful conditions (eg,

infection, surgery, emotional trauma), but it can also occur in patients with type 2 diabetes.

Hyperglycemia, metabolic acidosis, and elevated beta-hydroxybutyrate confirm the diagnosis.

The metabolic acidosis in DKA is commonly a high-AG acidosis secondary to the presence of ketones in the blood. However, after initiation of treatment with insulin, ketone production ceases, the liver uses ketones, and the acidosis becomes a non-AG type that resolves in a few days (ie, time necessary for kidneys to regenerate HCO3 -, which was consumed during the acidosis).

Advanced renal failure

o Patients with advanced chronic kidney disease (glomerular filtration rate of less than 20

mL/min) present with a high-AG acidosis. The acidosis occurs from reduced ammoniagenesis leading to a decrease in the amount of H+ buffered in the urine. The increase in AG is thought to occur because of the accumulation of sulfates, urates and phosphates from a reduction in glomerular filtration and from diminished tubular function.

o In persons with chronic uremic acidosis, bone salts contribute to buffering, and the serum

HCO3 -level usually remains greater than 12 mEq/L. This bone buffering can lead to significant loss of bone calcium with resulting osteopenia and osteomalacia.

Salicylate overdose

o Deliberate or accidental ingestion of salicylates can produce a high-AG acidosis,

although respiratory alkalosis is usually the more pronounced acid-base disorder.

o The increase in AG is only partly from the unmeasured salicylate anion. Increased

ketoacid and lactic acid levels have been reported in persons with salicylate overdose and are thought to account for the remainder of the AG.

o Salicylic acid ionizes to salicylate and H+ ion with increasing pH; at a pH of 7.4, only

0.004% of salicylic acid is nonionized, as follows:

Salicylic acid (HS)«salicylate (S) + H+ (H+)

o HS is lipid soluble and can diffuse into the CNS; with a fall in pH, more HS is formed. The

metabolic acidosis thus increases salicylate entry to the CNS, leading to respiratory alkalosis and CNS toxicity.

Methanol poisoning

o Methanol ingestion is associated with the development of a high-AG metabolic acidosis.

Methanol is metabolized by alcohol dehydrogenase to formaldehyde and then to formic acid.

o Formaldehyde is responsible for the optic nerve and CNS toxicity, while the increase in

AG is from formic acid and from lactic acid and ketoacid accumulation.

o Clinical manifestations include optic nerve injury that can be appreciated by funduscopic

examination as retinal edema, CNS depression, and unexplained metabolic acidosis with high anion and osmolar gaps.

Ethylene glycol poisoning

o Ingestion of ethylene glycol, a component of antifreeze and engine coolants, leads to a

high-AG acidosis. Ethylene glycol is converted by alcohol dehydrogenase first to glycoaldehyde and then to glycolic and glyoxylic acids. Glyoxylic acid then is degraded to several compounds, including oxalic acid, which is toxic, and glycine, which is relatively innocuous.

o The high AG is primarily from the accumulation of these acids, although a mild lactic

acidosis also may be present.

o Patients present with CNS symptoms, including slurred speech, confusion, stupor or

coma, myocardial depression, and renal failure with flank pain.

o Oxalate crystals are usually observed in the urine and are an important clue to the

diagnosis, as is an elevated osmolar gap.

Metabolic Alkalosis

Introduction

Background

For a general review of acid-base regulation, see Metabolic Acidosis.

Metabolic alkalosis is a primary increase in serum bicarbonate (HCO3 -) concentration. This occurs as a consequence of a loss of H+ from the body or a gain in HCO3 -. In its pure form, it manifests as alkalemia (pH >7.40). As a compensatory mechanism, metabolic alkalosis leads to alveolar hypoventilation with a rise in arterial carbon dioxide tension (PaCO2), which diminishes the change in pH that would otherwise

occur. 

Normally, arterial PaCO2 increases by 0.5-0.7 mm Hg for every 1 mEq/L increase in plasma bicarbonate concentration, a compensatory response that is very quick. If the change in PaCO2 is not within this range, then a mixed acid-base disturbance occurs. For example, if the increase in PaCO2 is more than 0.7 times the increase in bicarbonate, then metabolic alkalosis coexists with primary respiratory acidosis. Likewise, if the increase in PaCO2 is less than the expected change, then a primary respiratory alkalosis is also present.

The first clue to metabolic alkalosis is often an elevated bicarbonate concentration that is observed when serum electrolyte measurements are obtained. Remember that an elevated serum bicarbonate concentration may also be observed as a compensatory response to primary respiratory acidosis. However, a bicarbonate concentration greater than 35 mEq/L is almost always caused by metabolic alkalosis.

An algorithmic approach metabolic alkalosis is depicted in the image below.

Algorithm for metabolic alkalosis.

Calculation of the serum anion gap may also help to differentiate between primary metabolic alkalosis and the metabolic compensation for respiratory acidosis. The anion gap is frequently elevated to a modest degree in metabolic alkalosis because of the increase in the negative charge of albumin and the enhanced production of lactate. However, normal values for the anion gap vary in different laboratories and between individual patients, so it is important to know the range of normal for the particular clinical laboratory and know the prevailing baseline value for a particular patient.1 In any event, the only definitive way to diagnose metabolic alkalosis is to perform a simultaneous blood gases analysis, which reveals elevation of both pH and PaCO2 and increased calculated bicarbonate.

Serum bicarbonate concentration can be calculated from a blood gas sample using the Henderson-Hasselbalch equation, as follows:

pH = 6.10 + log (HCO3 - ÷ .03 X PaCO2)

Alternatively, HCO3 - = 24 X PaCO2 ÷ [H+]

Because pH and PaCO2 are directly measured, bicarbonate can be calculated.

Another means of assessing serum bicarbonate concentration is by measuring the total carbon dioxide content in serum, which is routinely measured with serum electrolytes obtained from venous blood. In this method, a strong acid is added to serum, which interacts with bicarbonate in the serum sample, forming carbonic acid. Carbonic acid dissociates to carbon dioxide and water; then, carbon dioxide is measured. Note that the carbon dioxide measured includes bicarbonate and dissolved carbon dioxide. The contribution of dissolved carbon dioxide is quite small (0.03 X PaCO2) and is usually ignored, although it accounts for a difference of 1-3 mEq/L between the measured total carbon dioxide content in venous blood and the calculated bicarbonate in arterial blood. Thus, at a PaCO2 of 40, a total carbon dioxide content of 25 means a true bicarbonate concentration of 23.8 (ie, 25 - 0.03 X 40).

The Henderson-Hasselbalch equation may fail to account for acid-base findings in critically ill patients. An alternative method of acid-base analysis, known as the quantitative, or strong ion, approach,2 determines pH on the basis of the following 3 independent variables (see Metabolic Acidosis):

Strong ion difference (SID): Ions almost completely dissociated at physiologic pH (the cations Na+, K+, Ca+, and Mg+, and the anions Cl- and lactate)

Total weak acid concentration: Ions that can be dissociated or associated at physiologic pH (albumin and phosphate)

pCO2 (mm Hg)

In a study of 100 patients with trauma who were admitted to a surgical intensive care unit, the conventional Henderson-Hasselbalch equation was compared with the strong ion approach to the diagnosis and treatment of acid-base disorders.3 The investigators concluded that the strong ion approach provides a more accurate means of diagnosing acid-base disorders, including metabolic alkalosis and tertiary disorders.Pathophysiology

The organ systems involved are mainly the kidneys and GI tract. The pathogenesis of metabolic alkalosis involves 2 processes, the generation of metabolic alkalosis and the maintenance of metabolic alkalosis, events that usually overlap.

The generation of metabolic alkalosis occurs with the loss of acid, the gain of alkali, or the contraction of the extracellular fluid compartment with a consequent change in bicarbonate concentration. The kidneys usually have an enormous capacity to excrete excess bicarbonate generated and to restore normal acid-base balance by the following mechanisms: (1) less reabsorption of bicarbonate because infused sodium bicarbonate (NaHCO3) leads to volume expansion, which reduces reabsorption of sodium ions and bicarbonate in the proximal tubule, and (2) bicarbonate secretion by B-type intercalated cells in the collecting duct that exchange bicarbonate for chloride via the apical chloride/bicarbonate (Cl-/HCO3 -) countertransporter. Therefore, to sustain metabolic alkalosis, the kidneys must participate to maintain the alkalosis by overriding these mechanisms.

Generation of metabolic alkalosis

Metabolic alkalosis may be generated by one of the following mechanisms:

Loss of hydrogen ions: Whenever a hydrogen ion is excreted, a bicarbonate ion is gained into the extracellular space. Hydrogen ions may be lost through the kidneys or the GI tract. Vomiting or nasogastric (NG) suction generates metabolic alkalosis by the loss of gastric secretions, which are rich in

hydrochloric acid (HCl). Renal losses of hydrogen ions occur whenever the distal delivery of sodium increases in the presence of excess aldosterone, which stimulates the electrogenic epithelial sodium channel (ENaC) in the collecting duct. As this channel reabsorbs sodium ions, the tubular lumen becomes more negative, leading to the secretion of hydrogen ions and potassium ions into the lumen.

Shift of hydrogen ions into the intracellular space: This mainly develops with hypokalemia. As the extracellular potassium concentration decreases, potassium ions move out of the cells. To maintain neutrality, hydrogen ions move into the intracellular space.

Alkali administration: Administration of sodium bicarbonate in amounts that exceed the capacity of the kidneys to excrete this excess bicarbonate may cause metabolic alkalosis. This capacity is reduced when a reduction in filtered bicarbonate occurs, as observed in renal failure, or when enhanced tubular reabsorption of bicarbonate occurs, as observed in volume depletion (see Maintenance of metabolic alkalosis).

Contraction alkalosis: Loss of bicarbonate-poor, chloride-rich extracellular fluid, as observed with thiazide diuretic or loop diuretic therapy or chloride diarrhea, leads to contraction of extracellular fluid volume. Because the original bicarbonate mass is now dissolved in a smaller volume of fluid, an increase in bicarbonate concentration occurs. This increase in bicarbonate causes, at most, a 2- to 4-mEq/L rise in bicarbonate concentration.

Maintenance of metabolic alkalosis

The following factors are believed to maintain the alkalosis:

Decrease in renal perfusion: Decreased perfusion to the kidneys, caused by either volume depletion or a reduction in effective circulating blood volume (eg, edematous states such as heart failure or cirrhosis) stimulates the renin-angiotensin-aldosterone system. This increases renal sodium ion reabsorption throughout the nephron, including the principal cells of the collecting duct. This results in enhanced hydrogen ion secretion via the apical proton pump H+ ATPase in the adjacent A-type intercalated cells. Aldosterone may also independently increase the activity of the apical proton pump. Whenever a hydrogen ion is secreted into the tubular lumen, a bicarbonate ion is gained into the systemic circulation via the basolateral Cl-/HCO3 - exchanger.

Chloride depletion may occur through the GI tract by loss of gastric secretions, which are rich in chloride ions, or through the kidneys with loop diuretics or thiazides. Chloride depletion, even without volume depletion, enhances bicarbonate reabsorption by different mechanisms, as follows:

Stimulation of the renin-angiotensin-aldosterone system: In the late thick ascending limb and early distal tubule, specialized cells called the macula densa are present. These cells have an Na+/K+/2Cl- cotransporter in the apical membrane, which is mainly regulated by chloride ions. When fewer chloride ions reach this transporter (eg, chloride depletion), the macula densa signals the juxtaglomerular apparatus (ie, specialized cells in the wall of the adjacent afferent arteriole) to secrete renin, which increases aldosterone secretion via angiotensin II.

Inhibition of bicarbonate secretion by the chloride/bicarbonate exchanger: In alkalemia, the kidneys secrete the excess bicarbonate via the apical chloride/bicarbonate exchanger in the B-type intercalated cells of the collecting duct. In this way, protons are gained to the systemic circulation via the basolateral

H+ ATPase. In chloride depletion, fewer chloride ions are available to be exchanged with bicarbonate, and the ability of the kidneys to excrete the excess bicarbonate is impaired.

Many of the causes of metabolic alkalosis are also associated with hypokalemia, which maintains metabolic alkalosis by different mechanisms. These include the following:

Shift of hydrogen ions intracellularly: Intracellular acidosis enhances bicarbonate reabsorption in the collecting duct.

Stimulation of the apical H+/K+ ATPase in the collecting duct: Increased activity of this ATPase leads to teleologically appropriate potassium ion reabsorption but a corresponding hydrogen ion secretion. This leads to a net gain of bicarbonate, maintaining systemic alkalosis.

Stimulation of renal ammonia genesis: Ammonium ions (NH4 +) are produced in the proximal tubule from the metabolism of glutamine. During this process, alpha-ketoglutarate is produced, the metabolism of which generates bicarbonate that is returned to the systemic circulation.

Impaired chloride ion reabsorption in the distal nephron: This results in an increase in luminal electronegativity, with subsequent enhancement of hydrogen ion secretion.

Reduction in glomerular filtration rate (GFR): This has been proven in animal studies. Hypokalemia by unknown mechanisms decreases GFR, which in turn decreases the filtered load of bicarbonate. In the presence of volume depletion, this impairs renal excretion of the excess bicarbonate.

Frequency

United States

Metabolic alkalosis is the most common acid-base disturbance observed in hospitalized patients, accounting for approximately 50% of all acid-base disorders.

Mortality/Morbidity

Severe metabolic alkalosis (ie, blood pH >7.55) is a serious medical problem. Mortality rates have been reported as 45% in patients with an arterial blood pH of 7.55 and 80% when the pH was greater than 7.65.

Severe alkalosis causes diffuse arteriolar constriction with reduction in tissue perfusion. By decreasing cerebral blood flow, alkalosis may lead to tetany, seizures, and decreased mental status. Metabolic alkalosis also decreases coronary blood flow and predisposes persons to refractory arrhythmias.

Metabolic alkalosis causes hypoventilation, which may cause hypoxemia, especially in patients with poor respiratory reserve, and it may impair weaning from mechanical ventilation.

Alkalosis decreases the serum concentration of ionized calcium by increasing calcium ion binding to albumin. In addition, metabolic alkalosis is almost always associated with hypokalemia, which can cause neuromuscular weakness and arrhythmias, and, by increasing ammonia production, it can precipitate hepatic encephalopathy in susceptible individuals.

Clinical

History

Symptoms of metabolic alkalosis are not specific. Because hypokalemia is usually present, the patient may experience weakness, myalgia, and polyuria. Hypoventilation develops because of inhibition of the respiratory center in the medulla. Symptoms of hypocalcemia (eg, jitteriness, perioral tingling, muscle spasms) may be present. The clinical history is helpful in establishing the etiology. Important points in the history include the following:

Vomiting or diarrhea - GI losses of HCl Age of onset and family history of alkalosis - Familial disorders (eg, Bartter syndrome, which

starts during childhood)

Renal failure - Alkali-loading alkalosis only develops when impairment of renal function occurs.

Drug use

o Loop or thiazide diuretics

o Licorice

o Tobacco chewing

o Carbenoxolone

o Fludrocortisone

o Glucocorticoids

o Antacids (eg, magnesium hydroxide)

o Calcium carbonate

Previous GI surgery4 (eg, ileostomy5 )

Physical

The physical signs of metabolic alkalosis are not specific and depend on the severity of the alkalosis. Because metabolic alkalosis decreases ionized calcium concentration, signs of hypocalcemia (eg, tetany, Chvostek sign, Trousseau sign), change in mental status, or seizures may be present. Physical examination is helpful to establish the cause of metabolic alkalosis. Important aspects of the physical examination include the evaluation of hypertension and volume status assessment. Hypertension accompanies several causes of metabolic alkalosis. See Summary of causes of metabolic alkalosis. Volume status assessment includes evaluation of orthostatic changes in blood pressure and heart rate, mucous membranes, presence or absence of edema, skin turgor, weight change, and urine output. Volume depletion usually accompanies chloride-responsive alkalosis, while volume expansion accompanies chloride-resistant alkalosis.

Bulimia : Because patients with bulimia frequently self-induce vomiting, they may have erosions of teeth enamel and dental caries because of repeatedly exposing their teeth to gastric acid.

Cushing syndrome

o Obesity

o Moon face

o Buffalo hump

o Hirsutism

o Violaceous skin striae

o Acne

Congenital adrenal hyperplasia (CAH): In CAH secondary to 11-hydroxylase deficiency, the infants have hypertension and growth retardation. Male infants have premature sexual development, while female infants develop virilization. In 17-hydroxylase deficiency, males develop sexual ambiguity, while females have sexual infantilism.

Causes

The most common causes of metabolic alkalosis are the use of diuretics and the external loss of gastric secretions. Causes of metabolic alkalosis can be divided into chloride-responsive alkalosis (urine chloride <20 mEq/L), chloride-resistant alkalosis (urine chloride >20 mEq/L), and other causes, including alkali-loading alkalosis.

Chloride-responsive Alkalosis (Urine Chloride <20 mEq/L)

Loss of gastric secretions

Gastric secretions are rich in HCl. The secretion of HCl by the stomach usually stimulates bicarbonate secretion by the pancreas once HCl reaches the duodenum. Ordinarily, these substances are neutralized, and no net gain or loss of hydrogen ions or bicarbonate occurs. When HCl is lost by vomiting or NG suction, pancreatic secretions are not stimulated and a net gain of bicarbonate into the systemic circulation occurs, generating a metabolic alkalosis. Volume depletion maintains alkalosis. In this case, the hypokalemia is secondary to the alkalosis itself and to renal loss of potassium ions from the stimulation of aldosterone secretion.

Ingestion of large doses of nonabsorbable antacids

Ingestion of large doses of nonabsorbable antacids (eg, magnesium hydroxide) may generate metabolic alkalosis by a rather complicated mechanism. Upon ingestion of magnesium hydroxide, calcium, or aluminum with base hydroxide or carbonate, the hydroxide anion buffers hydrogen ions in the stomach. The cation binds to bicarbonate secreted by the pancreas, leading to loss of bicarbonate with stools. In this process, both hydrogen ions and bicarbonate are lost, and, usually, no acid-base disturbance occurs. Sometimes, not all the bicarbonate binds to the ingested cation, which means that some bicarbonate is reabsorbed in excess of the lost hydrogen ions. This occurs primarily when antacids are administered with a cation-exchange resin (eg, sodium polystyrene sulfonate [Kayexalate]); the resin binds the cation, leaving bicarbonate unbound.

Thiazide or loop diuretics

Alkalosis occurs. However, urine chloride may not be less than 20 mEq/L. Thiazides and loop diuretics enhance sodium chloride excretion in the distal convoluted tubule and the thick ascending loop, respectively. These agents cause metabolic alkalosis by chloride depletion and by increased delivery of sodium ions to the collecting duct, which enhances potassium ion and hydrogen ion secretion. Volume depletion also stimulates aldosterone secretion, which enhances sodium ion reabsorption in the collecting duct and increases hydrogen ion and potassium secretion in this segment. Urine chloride is low after discontinuation of diuretic therapy, while it is high during active diuretic use.

Miscellaneous causes

Villous adenomas (rare cause of diarrhea) usually lead to metabolic acidosis from loss of colonic secretions that are rich in bicarbonate. Occasionally, these tumors cause metabolic alkalosis. The mechanism is not well understood. Some authors opine that the hypokalemia caused by these tumors is the etiology of metabolic alkalosis.

Congenital chloridorrhea (see Chloride Diarrhea, Familial. Online Mendelian Inheritance in Man [OMIM]) is a rare form of severe secretory diarrhea that is inherited as an autosomal recessive trait. Mutations in the down-regulated adenoma gene result in defective function of the chloride/bicarbonate exchange in the colon and ileum, leading to increased secretion of chloride and reabsorption of bicarbonate.

During respiratory acidosis, the kidneys reabsorb bicarbonate and secrete chloride to compensate for the acidosis. In the posthypercapnic state, urine chloride is high and can lead to chloride depletion. Once the respiratory acidosis is corrected, the kidneys cannot excrete the excess bicarbonate because of the low luminal chloride.

Infants with cystic fibrosis (see Cystic Fibrosis [OMIM]) may develop metabolic alkalosis because of loss of chloride in sweat. These infants are also prone to volume depletion.

Chloride-resistant Alkalosis (Urine Chloride >20 mEq/L)

Chloride-resistant alkalosis with hypertension

An adrenal adenoma (most common), bilateral adrenal hyperplasia, or an adrenal carcinoma may cause primary hyperaldosteronism. Another cause of primary hyperaldosteronism is glucocorticoid-remediable aldosteronism (seeHyperaldosteronism, Familial, Type 1 [OMIM]), an autosomal dominant disorder, in which ectopic production of aldosterone in the zona fasciculata of the adrenal cortex occurs. In this case, aldosterone production is controlled by adrenocorticotropic hormone (ACTH) rather than angiotensin II and potassium, its principal regulators. This type of primary hyperaldosteronism is responsive to glucocorticoid therapy, which inhibits aldosterone secretion by suppressing ACTH.

The mineralocorticoid receptor (MR) in the collecting duct usually is responsive to both aldosterone and cortisol. Cortisol has a higher affinity for MR and circulates at a higher concentration than aldosterone. Under physiological conditions, the enzyme 11-beta-hydroxysteroid dehydrogenase type 2 (11B-HSD2) inactivates cortisol to cortisone in the collecting duct, allowing aldosterone free access to its receptor. Deficiency of this enzyme leads to occupation and activation of the MR by cortisol, which, like aldosterone, then stimulates the ENaC. Cortisol behaves as a mineralocorticoid under these circumstances.

11B-HSD2 deficiency may be inherited as an autosomal recessive trait (see Cortisol 11-Beta-Ketoreductase Deficiency [OMIM]), ie, syndrome of apparent mineralocorticoid excess (AME), or the

enzyme may be inhibited by the use of licorice, carbenoxolone, or chewing tobacco. The active component in licorice is glycyrrhizic acid. This compound is found in certain candies and some chewing tobaccos. Inhibition or deficiency of 11B-HSD2 causes hypertension with low renin and low aldosterone, hypokalemia, and metabolic alkalosis. Serum cortisol is within the reference range because the negative feedback of cortisol on ACTH is intact.

Active use of thiazides or loop diuretics in hypertension is the most common cause of metabolic alkalosis in hypertensive patients. The mechanism of alkalosis is discussed in Thiazide or loop diuretics.

The enhanced mineralocorticoid effect in Cushing syndrome is caused by occupation of the MR by the high concentration of cortisol. Hypokalemia and metabolic alkalosis are more common in Cushing syndrome caused by ectopic ACTH production (90%) than in other causes of Cushing syndrome (10%). This difference is related to the higher concentration of plasma cortisol and the defective 11-beta-hydroxysteroid dehydrogenase (11B-HSD) activity found in ectopic ACTH production.

Liddle syndrome (see Liddle Syndrome [OMIM]) is a rare autosomal dominant disorder arising from a gain of function mutation in the beta (SCNN1B) or gamma subunit (SCNN1G) of the ENaC in the collecting duct. The channel behaves as if it is permanently open, and unregulated reabsorption of Na+ occurs, leading to volume expansion and hypertension. This unregulated Na+ reabsorption is responsible for secondary renal hydrogen ion and potassium ion losses and persists despite suppression of aldosterone.

Significant unilateral or bilateral renal artery stenosis stimulates the renin-angiotensin-aldosterone system, leading to hypertension and hypokalemic metabolic alkalosis.

Renin- or deoxycorticosterone-secreting tumors are rare. In renin-secreting tumors, excessive amounts of renin are secreted by tumors in the juxtaglomerular apparatus, stimulating aldosterone secretion. In the latter, deoxycorticosterone (DOC), rather than aldosterone, is secreted by some adrenal tumors and has mineralocorticoid effects.

Mutation in mineralocorticoid receptor (see Hypertension, Early-Onset, Autosomal Dominant, with Severe Exacerbation in Pregnancy [OMIM]) is a form of early-onset hypertension with autosomal dominant inheritance that has now been linked to a specific mutation of the MR. This mutation results in constitutive activation of the MR, making the MR responsive to progesterone. Activation of MR leads to unregulated sodium ion reabsorption via the collecting duct sodium ion channel, with accompanying hypokalemia and alkalosis. The disease is characterized by severe exacerbations of hypertension during pregnancy, and spironolactone can exacerbate hypertension.

CAH (see Adrenal Hyperplasia, Congenital, Due to 11-Beta-Hydroxylase Deficiency [OMIM] and Adrenal Hyperplasia, Congenital, Due to 17-Alpha-Hydroxylase Deficiency [OMIM]) can be caused by deficiency of either 11-beta-hydroxylase or 17-alpha-hydroxylase. Both enzymes are involved in the synthesis of adrenal steroids. Deficiency of either enzyme leads to increased levels of the mineralocorticoid 11-deoxycortisol, while cortisol and aldosterone production is impaired. 11-Hydroxylase deficiency differs from 17-hydroxylase deficiency by the presence of virilization.

Chloride-resistant alkalosis (urine chloride >20 mEq/L) with hypotension or normotension

Bartter syndrome (see Hypokalemic Alkalosis with Hypercalciuria [OMIM]) is an inherited autosomal recessive disorder, in which reabsorption of sodium ions and chloride ions in the thick ascending loop of Henle is impaired, leading to their increased delivery to the distal nephron. This condition and the

subsequent salt depletion and stimulation of the renin-angiotensin-aldosterone system lead to enhanced secretion of hydrogen and potassium ions. The impaired reabsorption of sodium chloride in the loop of Henle is secondary to loss of function of mutations of 1 of 3 transporters in this site of the nephron: (1) the furosemide-sensitive Na+/K+/2Cl- cotransporter (NKCC2), (2) the basolateral chloride ion channel (CLCNKB), or (3) the inwardly rectifying apical potassium ion channel (ROMK1).

Mutations of CLCNKB cause classic Bartter syndrome, while mutations of the other 2 transporters manifest with the antenatal form of Bartter syndrome. Edema and hypertension are absent, and hypercalciuria is common because the impaired reabsorption of sodium chloride inhibits the paracellular reabsorption of calcium. Because loop diuretics inhibit the Na+/K+/2Cl- transporter, the electrolyte abnormalities observed in Bartter syndrome and with loop diuretic use are similar.

Gitelman syndrome (see Potassium and Magnesium Depletion [OMIM]) is an inherited autosomal recessive disorder, in which loss of function of the thiazide-sensitive sodium/chloride transporter (NCCT) in the distal convoluted tubule occurs. The subsequent increased distal solute delivery and salt wasting with stimulation of the renin-angiotensin-aldosterone system lead to hypokalemic metabolic alkalosis. Other features of the syndrome are hypocalciuria and hypomagnesemia. The electrolyte abnormalities resemble those caused by thiazide diuretic use.

Pure hypokalemia (ie, severe potassium ion depletion) causes mild metabolic alkalosis, but, in combination with hyperaldosteronism, the alkalosis is more severe. Possible mechanisms of alkalosis in hypokalemia are enhanced proximal bicarbonate reabsorption, stimulated renal ammonia genesis, impaired renal chloride reabsorption, reduced GFR (in animals), and intracellular acidosis in the distal nephron with subsequent enhanced hydrogen secretion.

Magnesium depletion (ie, hypomagnesemia) may lead to metabolic alkalosis. The mechanism probably is caused by hypokalemia, which is usually caused by or associated with magnesium depletion.

Other Causes

Alkali-loading alkalosis

The kidneys are able to excrete any excess alkali load, whether it is exogenous (eg, infusion of sodium bicarbonate) or endogenous (eg, metabolism of lactate to bicarbonate in lactic acidosis). However, in renal failure or in any condition that maintains the alkalosis, this natural ability of the kidneys to excrete the excess bicarbonate is impaired. Examples include the following:

The components of milk-alkali syndrome are hypercalcemia, renal insufficiency, and metabolic alkalosis. Before the advent of H2-receptor antagonists, milk-alkali syndrome was observed in patients with peptic ulcers who ingested large amounts of milk and antacids. Currently, the syndrome is observed mainly in patients who chronically ingest large doses of calcium carbonate, with or without vitamin D (typically for osteoporosis prevention).6 Hypercalcemia that develops in some persons increases renal bicarbonate reabsorption. Renal insufficiency can occur secondary to nephrocalcinosis or hypercalcemia and contributes to maintaining the metabolic alkalosis.

Patients with end-stage renal disease (ESRD) are dialyzed with a high concentration of bicarbonate in the dialysate to reverse metabolic acidosis (ie, hemodialysis using high bicarbonate dialysate). Sometimes, this high bicarbonate exceeds is the amount needed to buffer the acidosis. Because the ability of the

kidneys to excrete the excess bicarbonate is absent or severely diminished, patients with ESRD maintain the alkalosis temporarily. The degree of alkalosis might be severe if they also have vomiting.

Metabolic alkalosis has been reported after regional citrate hemodialysis, which is used instead of heparin in patients who are at increased risk for bleeding. Citrate is infused in the blood inflow line in the hemodialysis circuit, where it prevents clotting by binding calcium. Because the dialyzer does not remove citrate completely, a fraction of the infused citrate might reach the systemic circulation. Citrate in the blood is metabolized to bicarbonate in the liver. The accumulated bicarbonate may lead to metabolic alkalosis.

Metabolic alkalosis may be a potential complication of plasmapheresis in patients with renal failure. The source of alkali is the citrate that is used to prevent clotting in the extracorporeal circuit and in the stored blood from which the fresh frozen plasma is prepared. Using heparin as the anticoagulant and using albumin instead of fresh frozen plasma as the replacement solution can prevent the metabolic alkalosis.

Recovery from lactic or ketoacidosis in the presence of volume depletion or renal failure typically occurs when exogenous bicarbonate is administered to correct the acidosis. When the patient recovers, the beta-hydroxybutyrate and lactate are metabolized to bicarbonate and the original bicarbonate deficit is recovered. The administered bicarbonate now becomes a surplus.

Refeeding with a carbohydrate-rich diet after prolonged fasting results in mild metabolic alkalosis because of enhanced metabolism of ketoacids to bicarbonate.

Massive blood transfusion results in mild metabolic alkalosis as the citrate in the transfused blood is converted to bicarbonate. Metabolic alkalosis is more likely to develop in the presence of renal insufficiency.

Hypercalcemia

Hypercalcemia may cause metabolic alkalosis by volume depletion and enhanced bicarbonate reabsorption in the proximal tubule. However, hypercalcemia from primary hyperparathyroidism is usually associated with a metabolic acidosis.

Intravenous penicillin

The administration of penicillin, carbenicillin, or other semisynthetic penicillins may cause hypokalemic metabolic alkalosis by distal delivery of nonreabsorbable anions with an absorbable cation such as Na+.

Hypoproteinemic alkalosis

Metabolic alkalosis has been reported in patients with hypoproteinemia. The mechanism of alkalosis is not clear, but it may be related to loss of negative charges of albumin. A decrease in plasma albumin of 1 g/dL is associated with an increase in plasma bicarbonate of 3.4 mEq/L.

Summary of Causes of Metabolic Alkalosis

Chloride-responsive alkalosis (urine chloride <20 mEq/L)

Loss of gastric secretions - Vomiting, NG suction Loss of colonic secretions - Congenital chloridorrhea, villous adenoma

Thiazides and loop diuretics (after discontinuation)

Posthypercapnia

Cystic fibrosis

Chloride-resistant alkalosis (urine chloride >20 mEq/L)

With hypertensiono Primary hyperaldosteronism - Adrenal adenoma, bilateral adrenal hyperplasia, adrenal

carcinoma, glucocorticoid-remediable hyperaldosteronism

o 11B-HSD2 - Genetic, licorice, chewing tobacco, carbenoxolone

o CAH - 11-Hydroxylase or 17-hydroxylase deficiency

o Current use of diuretics in hypertension

o Cushing syndrome

o Exogenous mineralocorticoids or glucocorticoids

o Liddle syndrome

o Renovascular hypertension

Without hypertension

o Bartter syndrome

o Gitelman syndrome

o Severe potassium depletion

o Current use of thiazides and loop diuretics

o Hypomagnesemia

Other causes

Exogenous alkali administration - Sodium bicarbonate therapy in the presence of renal failure, metabolism of lactic acid or ketoacids

Milk-alkali syndrome

Hypercalcemia

Intravenous penicillin

Refeeding alkalosis

Massive blood transfusion

Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Introduction

Background

Water balance is an important regulatory function involving the hypothalamus and the kidneys (among other organs). Various hormones are also involved, of which the antidiuretic hormone (ADH) arginine vasopressin is most important.

The syndrome of inappropriate secretion of ADH (SIADH) is characterized by the nonphysiologic release of ADH, resulting in impaired water excretion with normal sodium excretion.

SIADH was first described by Schwartz and associates in 2 patients with bronchogenic carcinoma and was later further characterized by Bartter and Schwartz.1

Pathophysiology

ADH is a polypeptide synthesized in the supraoptic and paraventricular nuclei in the hypothalamus and is released in response to a number of stimuli. ADH is rapidly metabolized in the liver and kidneys and has a half-life of 15-20 minutes.

In the kidneys, ADH acts on the principal cells of the cortical and medullary collecting tubules to increase water permeability. Other renal actions include local production of prostaglandins in a variety of renal cells, including the glomerulus and the thick ascending limb of the loop of Henle. Elsewhere, ADH causes vasoconstriction in a number of vascular beds and releases factor VIII and von Willebrand factor from vascular endothelium.

Three known receptors bind ADH at the cell membrane: V1a, V1b (also known as V3), and V2. The vasopressin (AVP, ADH) receptor subtypes belong to the G protein–coupled receptor superfamily. The V1a and V1b receptors signal by activation of phospholipase C and elevation in intracellular calcium, which, in turn, stimulates protein kinase C.

V1a subtype is ubiquitous and found on cells, such as vascular smooth muscle cells, hepatocytes, platelets, brain cells, and uterus cells. V1b receptors are found predominantly in the anterior pituitary.

V2 receptors are coupled to adenylate cyclase, causing a rise in intracellular cyclic adenosine monophosphate (cAMP), which serves as the second messenger. V2 receptors are found predominantly in the principal cells of the renal collecting duct, where they mediate antidiuretic response. V2 receptors are also found in endothelial cells and induce the secretion of von Willebrand factor.

ADH activates the V2 receptor on the basolateral membrane of the principal cells of the renal collecting duct. This activates cyclic adenosine monophosphate through heterotrimeric G proteins, which results in insertion of aquaporin-2 water channels in the luminal membrane, thus making it more permeable to water.

The major stimuli to ADH are hyperosmolality and effective circulating volume depletion. Normally, ADH secretion ceases when plasma osmolality falls below 275 mOsm/kg. This fall causes increased water excretion, which leads to a dilute urine with an osmolality of 40-100 mOsm/kg. In addition to the hypothalamic osmoreceptors, hypothalamic neurons secreting ADH also receive input from baroreceptors in the great vessels and the atria. This results in nonosmotic release of ADH. Other stimuli for ADH secretion include pain and nausea.

In general, the plasma sodium concentration is the primary osmotic determinant of ADH release. However, in persons with SIADH, a nonphysiologic secretion of ADH results in enhanced water reabsorption, leading to dilutional hyponatremia. Sodium excretion is intact, and the amount of sodium excreted in the urine varies with diet. Ingestion of water is an essential prerequisite to the development of dilutional hyponatremia; regardless of cause, hyponatremia does not occur if water is restricted.

The continued presence of ADH with water intake causes retention of ingested water. While a large fraction of this water is intracellular, the extracellular fraction causes volume expansion. Volume receptors are activated and peptides (eg, atrial natriuretic peptide) are secreted, which causes natriuresis with some degree of accompanying kaliuresis and diuresis. Thus, these patients are euvolemic or are slightly volume-expanded.

If water and sodium intake remain constant, a steady state is reached and sodium excretion equals sodium intake. Experimental evidence indicates that several days after ADH-induced water retention, escape from its effect occurs. This results in the establishment of a water balance and a newer, stable (although lower) sodium concentration. This is thought to be mediated via pressure-induced natriuresis and diuresis. Other authorities attribute this escape phenomenon to a decrease in the aquaporin-2 channel expression in the renal collecting duct.

In addition to the inappropriate ADH secretion, persons with this syndrome also may have an inappropriate thirst sensation, which leads to an intake of water that is in excess of the free water excreted. This increase in water ingested may then contribute to the maintenance of hyponatremia.

Before the diagnosis of SIADH is made, other causes for a decreased diluting capacity (eg, renal, pituitary, adrenal, thyroid, cardiac, or hepatic disease) must be excluded. In addition, nonosmotic stimuli for arginine vasopressin release, particularly hemodynamic derangements (eg, due to hypotension, nausea, uncontrolled pain, or drugs) must be excluded.

Frequency

United States

SIADH is usually observed in patients in hospital settings, and the frequency may be as high as 35%.

Mortality/Morbidity

The mortality rate for acute symptomatic hyponatremia has been noted to be as high as 55% and as low as 5%, depending on the reference source. The mortality rate associated with chronic hyponatremia has been reported to be 14-27%.

In a retrospective case note review by Clayton and colleagues, patients with a multifactorial cause for hyponatremia in an inpatient setting had a significantly higher mortality rate.2 The outcome was least favorable in patients who were normonatremic at admission and became hyponatremic during the course of their hospitalization. The etiology of hyponatremia was a more important prognostic indicator than the level of absolute serum sodium in the patients.

Clinical

History

SIADH is usually detected based on the results of laboratory testing.

Two important considerations related to the history include the following:o Note symptoms that may suggest increased secretion of ADH, such as chronic pain,

CNS or pulmonary tumors (eg, hemoptysis, chronic headaches), head injury, and drug use.

o Determine if the patient has had excessive fluid intake because of inappropriate thirst or

psychogenic polydipsia or because intravenous fluids were administered by health care providers.

Depending on the magnitude and rate of development, hyponatremia may or may not cause symptoms. In general, slowly progressive hyponatremia is associated with fewer symptoms than

a rapid drop of serum sodium to the same value. A recent paper by Decaux evaluating mild chronic hyponatremia suggests that it contributes to an increased rate of falls.3

When the serum sodium level is less than 125 mEq/L, mild CNS symptoms, such as lethargy, fatigue, anorexia, nausea, and muscle cramps, may develop. A further decrease in the serum sodium level can lead to drowsiness, confusion, seizures, and coma.

Physical

After the identification of hyponatremia, the approach to the patient depends on the clinically assessed volume status. In SIADH, the patient is typically euvolemic and hypertension, peripheral and pulmonary edema, dry mucous membranes, reduced skin turgor, and orthostatic hypotension are usually absent.

Neurologic signs may be present if hyponatremia is severe or if it develops rapidly.o These signs include Cheyne-Stokes respiration, drowsiness, disorientation, delirium,

seizures, and coma.

o Neurologic complications occur as a result of the brain's adaptation to changes in

osmolality. Hyponatremia and hypoosmolality lead to acute edema of the brain cells. An increase in brain water content of more than 5-10% is incompatible with life. The rigid calvarium prevents expansion of brain volume beyond a certain point, after which the brain cells must adapt to persistent hypoosmolality.

o In response to a decrease in osmolality, the brain rapidly loses electrolytes (eg, sodium

and chloride from interstitial fluid in minutes, potassium from intracellular space within 2-3 h) and intracellular organic osmolytes (eg, amino acids, such as glutamate, glutamine, taurine, polyhydric alcohol, myoinositol, methylamine, and creatinine). This occurs concurrently to prevent excessive brain swelling.

o Quantitative brain osmolyte modifications have been studied in humans in vivo (by proton

magnetic resonance spectroscopy), and results showed profound decreases in myoinositol.

Following correction of hyponatremia, the adaptive process does not match the extrusion kinetics.

o Electrolytes rapidly reaccumulate within 24 hours, resulting in a significant overshoot

above normal brain contents within the first 48 hours after correction.

o Organic osmolytes return to normal brain content very slowly over 5-7 days. Electrolyte

brain content returns to normal levels by the fifth day after correction, when organic osmolytes return to normal.

Irreversible neurologic damage and death may occur when the rate of correction of sodium exceeds 0.5 mEq/L/h for patients with severe hyponatremia. At this rate of correction, the osmolytes that have been lost in defense against brain edema during the development of hyponatremia cannot be restored as rapidly. The brain cells are thus subject to osmotic injury. This condition is called osmotic demyelination. Certain conditions, such as female sex (menstruating women), young age, and hypoxia, predispose patients to worse outcomes.

Causes

In most patients, the defect in urinary dilution is caused by ectopic production, exogenous administration, or osmotically inappropriate neurohypophyseal secretion of ADH. The causes of SIADH are as follows:

Increased hypothalamic productiono Neuropsychiatric

Infections - Meningitis, encephalitis, abscess

Vascular - Thrombosis, subarachnoid or subdural hemorrhage

Neoplasms

Other - HIV, Guillain-Barré syndrome, acute intermittent porphyria, autonomic neuropathy, post–pituitary surgery, multiple sclerosis, psychosis

o Drugs

Chemotherapeutic - Cyclophosphamide, vincristine, vinblastine

Antipsychotic - Thiothixene, thioridazine, haloperidol

Antidepressants - Monoamine oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors

Miscellaneous – Bromocriptine

Pulmonary diseases

o Pneumonia

o Tuberculosis

o Acute respiratory failure

o Positive pressure ventilation

o Asthma

o Atelectasis

Postoperative complications

Severe nausea, pain

Ectopic production of ADH

o Oat cell of lung

o Bronchogenic carcinoma

o Carcinoma of duodenum, pancreas, or thymus

o Olfactory neuroblastoma

Potentiation of ADH effect

o Chlorpropamide

o Tolbutamide

o Carbamazepine

o Intravenous cyclophosphamide

Exogenous administration of ADH

Idiopathic