METABOLIC ACIDOSISHala Kilany, MD

ACIDEMIA

“-emia”= like in ischemia, anemia: blood. Acidemia = acid blood. “-osis”= pathologic process or condition. Acidosis: refers to the process that causes pH

to change. Acidosis is what causes acidemia.

ACIDEMIA VS ACIDOSIS

So, by definition, acidosis will affect blood pH. However, there is a special situation in which

pH does not change. This, “-osis” without “-emia” situation can occur

if an alkalosis and acidosis exist together in the same patient: if the processes are of equal magnitudes, the effects on pH cancel.

Each day:- 15,000 mmol of CO2( which can produce acid when combined to H2O)-50-100 meq of non-volatile acid( mostly from sulfur containing aa.)

are produced.

Acid-base balance is maintained by:-pulmonary-renalexcretion of CO2 and non-volatile acids.

RESPONSE TO AN ACID LOAD

The response of the body to an increase in the arterial [H+], involves 4 processes:-extracellular buffering-intracellular and bone buffering-respiratory compensation-renal excretion of an acid load

EXTRACELLULAR BUFFERING

HCO3 is the most important buffer in the extracellular fluid:

[H⁺] = 24 x PCO2\ [ HCO3¯]

INTRACELLULAR BUFFERING

H+ ions can enter the cells, and can be buffered by the cell and bone buffers:- proteins-phosphates-bone carbonate

On average, 55-60% of an acid load will be buffered by cells and bone buffers, with higher values occurring in severe acidemia, when HCO3- are severely reduced.

RESPIRATORY COMPENSATION

Metabolic acidosis stimulates:- central - peripheral, chemoreceptors controlling respiration, resulting in an increase in alveolar ventilation.

The ensuing decrease in PCO2 will increase the extracellular pH toward normal.

RESPIRATORY COMPENSATION

With metabolic acidosis:

PCO2 ⬇ 1.2mmHg for every 1 meq\l ⬇in [HCO3], down to a minimum of 10-15 mmHg.

The effect will only last few days.

RENAL ACID EXCRETION

The daily metabolism results in generation of 50-100 meq of H+\ day.

This load must be excreted. 2 steps:

- reabsorption of HCO3--secretion of the dietary acid load.

RENAL ACID EXCRETION

It involves the combination of H+ with:-urinary titrable acids,

ex; HPO4²¯ + H⁺ H2PO4¯OR-with ammonia to form ammonium:NH3 + H⁺ NH4⁺the primary adaptive response, since ammonia production from the metabolism of glutamine can be appropriately increased in the presence of an acid load.

DEFINITION AND ETIOLOGY

Definition:- low arterial pH: 7.40 (normal: 7.35- 7.45)

- low [ HCO3]: 24 meq\l ( normal: 22-24 meq\l)

MAJOR MECHANISMS

H⁺ + HCO3¯ ⇿ H2CO3 ⇿ H2O + CO2 Gain of acid:

-Increased endogenous acid production: ketoacidosis, lactic acidosis-Metabolism of ingested toxins: methanol, ethanol, paraldehyde.-Decreased renal acid excretion: uremic acidosis, type I RTA.

Loss of bicarbonate:-Renal loss in proximal RTA(type II)-Gastrointestinal loss in diarrhea

SYSTEM OF CLASSIFICATION

High anion gap.

Normal anion gap.

ANION GAP

It helps in the differential diagnosis of metabolic acidosis.

AG=Na⁺ - (Cl¯ + HCO3¯)= 5-11 meq\l.AG= UA – UC

HIGH AG METABOLIC ACIDOSIS

It results from:-production of an endogenous acid:+ketoacidosis+lactic acidosis+uremic acidosis+salicylate intoxication

It is caused by:+H+ buffered by HCO3-, leading to↓ in [HCO3-]+The unmeasured anion ↑ the AG.

The AG decreases by 2.5 meq\l for each 1 g\dl decrease in albumin.

It can increase due to a decrease in cations: calcium, magnesium, potassium.

∆AG \ ∆HCO3: IMPORTANT FOR DIAGNOSIS

In uncomplicated high AG metabolic acidosis, ∆AG\ ∆HCO3 is 1:1.

A value < 1:1= combined high AG and normal AG acidosis.

A value > 2:1= high AG acidosis and metabolic alkalosis.

HIGH ANION GAP METABOLIC ACIDOSIS

LACTIC ACIDOSIS Most cases of lactic acidosis are due to marked tissue hypoperfusion in shock or during cardiopulmonary arrest.

Hyperlactaemia: a level from 2 mmols/l to 5 mmol/l.

Severe Lactic Acidosis: when levels are greater than 5 mmols/l

TYPE A LACTIC ACIDOSIS : CLINICAL EVIDENCE OF INADEQUATE TISSUE OXYGEN DELIVERY:

Anaerobic muscular activity (eg sprinting, generalised convulsions)

Tissue hypoperfusion :(eg shock; cardiac arrest.)

Reduced tissue oxygen delivery or utilisation(eg: hypoxaemia, carbon monoxide poisoning)

TYPE B LACTIC ACIDOSIS: NO CLINICAL EVIDENCE OF INADEQUATE TISSUE OXYGEN DELIVERY type B1 : Associated with underlying diseases (eg

ketoacidosis, leukaemia, lymphoma, AIDS) type B2: Assoc with drugs & toxins (eg phenformin,

cyanide, beta-agonists, methanol, nitroprussideinfusion, ethanol intoxication in chronic alcoholics, anti-retroviral drugs)

type B3: Assoc with inborn errors of metabolism (eg congenital forms of lactic acidosis with various enzyme defects eg pyruvate dehydrogenase deficiency)

D-LACTIC ACIDOSIS

It occurs in jejunoileal bypass, or short bowel syndrome.

Glucose and starch are metabolized in the colon into D-lactic acid.

Symptoms: episodic metabolic acidosis, characteristic neurologic anomalies: confusion, cerebellar ataxia, slurred speech, loss of memory.

KETOACIDOSIS

The accumulation of ketones will lead to high AG metabolic acidosis.

Etiology: - uncontrolled DM- fasting- alcoholic ketoacidosis

RENAL FAILURE

The daily dietary acid load is primarily due to the generation of H2SO4 from the metabolism of sulphur containing amino acids. This acid is rapidly buffered by HCO3- and other buffers, leading to the formation of sodium sulphate salts.

H2SO4 + 2NaHCO3 ----- NA2SO4 + 2H2CO3 -----2CO2 + 2H2O + NA2SO4.

To maintain a steady state, both the 2H+ and the SO42- must be excreted in the urine. The excretion of H+ occurs via the excretion of titratable acids and more importantly, NH4+. Whilst, the excretion of SO42- anions depends on the capacity of the kidney to filter and reabsorb the anions.

RENAL FAILURE

With the initial reduction in GFR, H+ balance is maintained by increased ammonium excretion per functioning nephron.

Total ammonium excretion begins to decrease when the GFR is < 40-50 ml\min, because of the inability to excrete all of the daily acid load.

Result: Normal AG metabolic acidosis.

RENAL FAILURE In advanced kidney disease as GFR falls below

20ml/min, the kidneys capacity to filter the anions of organic acids is significantly diminished and thus there is retention of phosphates, sulphates, urate and hippurate anions in the plasma that significantly raise the anion gap resulting in an elevated anion gap metabolic acidosis.

To summarize: Early chronic kidney disease is associated with a hyperchloremic normal anion gap metabolic acidosis while end stage renal disease (uremia) is associated with an elevated anion gap metabolic acidosis.

[HCO3] stabilizes at 12-20 meq\l.

SALICYLATE INTOXICATION

Plasma levels> 40-50mg\dl Symptoms: tinnitus, vertigo, nausea, vomiting,

diarrhea, then altered mental status, noncardiac pulmonary edema, coma and death.

Respiratory alkalosis + high AG metabolic acidosis

ALCOHOL INTOXICATION

Lactic acidosis and diabetic ketoacidosis are the most common types of acute metabolic acidosis.

Less frequent but of great clinical significance are the alcohol intoxications.

Metabolic pathways for ethanol, methanol, and ethylene glycol.

Kraut J A , Kurtz I CJASN 2008;3:208-225

©2008 by American Society of Nephrology

OSMOLAL GAP

Serum osmolality= 2x Na+ + BUN(mg\dl)\2.8 + glucose \18.

Accumulation of low MW substances in the serum (alcohols) will raise :the measured osmolality > calculated osmolality= Osmolal gap. ( > 20 mosm\L)

Other causes of high osmolal gap: < 15-20 mosm\L- ketoacidosis-lactic acidosis-renal failure.

METHANOL

Present in:-windshield wiper fluid-anti-freeze-model airplane fluid.

Toxic dose: 15-500 ml Mortality: 8-36%, but reaches 50-80% when:

HCO3- < 10 meq\l, pH< 7.1.

PATHOPHYSIOLOGY

Metabolic acidosis + visual problems. Cause: Formic acid: metabolic acidosis, and visual

disturbances. Pancreatitis Treatment:

-fomepizole: Fomepizole is a competitive inhibitor of alcohol dehydrogenase, the enzyme that catalyzes the initial steps in the metabolism of ethylene glycol and methanol to their toxic metabolites.-dialysis.

ETHYLENE GLYCOL

Anti-freeze. Mortality: 1-22%. The accumulation of glycolic acid cause:

metabolic acidosis, and glycolate can cause lactic acidosis.

ETHYLENE GLYCOL

ARF, myocardial dysfunction, neurologic functions and possibly pulmonary dysfunction is due to accumulation of oxalate with calcium in several organs.

After 24- 72 hours, ARF, oliguric or non-oliguric develops.

TREATMENT:-Volume expansion with bicarbonate.-Hemodialysis.

OXALATE CRYSTALS

ALCOHOLIC KETOACIDOSIS

Uncommon < 10%. Ketogenesis has been

attributed to stimulation of lipolysis and free fatty acids generation, due to low insulin, high epinephrine, cortisol and glucagon.

HYPERCHLOREMIC METABOLIC ACIDOSIS

Table 2. Causes of Hyperchloremic ( Normal Anion Gap) Metabolic Acidosis

Gastrointestinal bicarbonate loss Diarrhea Urinary tract diversion to intestine

(ureterosigmoidoscopy, ileal conduit) Intestinal fistula Drugs (laxative abuse, magnesium sulfate,

cholestyramine)

Renal acidosis Hypokalemia (proximal and distal RTA) Hyperkalemia (type IV RTA, aldosterone deficiency,

aldosterone resistance) Normokalemia (early renal failure/stage Ill chronic

kidney disease)

Drug-induced hyperkalemia (with renal insuffi ciency) ACE inhibitors Potassium sparring diuretics (spironolactone, amiloride,

triamterene) Trimethoprim Pentamidine NSAIDS Cyclosporine

Administration of chloride containing fluid (ammonium chloride, hyperalimentation, rapid saline administration)

Others (hippurate, cation exchange resins)

RTA

Renal Tubular Acidosis (RTA) refer to a group of disorders intrinsic to renal tubules characterized by:-an impairment in urinary acidification which result in retention of H+ ions,-reduction in [HCO3-]-hyperchloremic metabolic acidosis with a normal serum anion gap.

TYPE-1 RTA

Type 1 or distal RTA is referred to as the classic RTA and is a disorder of acid excretion involving the collecting tubules. The disorder is characterized by: -hypokalemic, hyperchloremic metabolic acidosis.

The disorder is due to defective H+ ion secretion in the distal tubule. Impairment in H+ ions secretion result in an inability to acidify the pH beyond 5.5The plasma bicarbonate is significantly reduced and may fall below 10 meq/L.

IN CHILDREN

It is a primary entity. Prominent clinical features:

-impaired growth-polyuria-hypercalciuria-nephrocalcinosis-lithiasis-K+ depletion

TYPE-2 RTA

Type 2 RTA is characterized by an impairment in proximal HCO3- reabsorption resulting in: - hypokalemic hyperchloremic metabolic acidosis.

This condition usually appears as part of a generalized disorder of proximal tubular function known as Fanconi syndrome which also include defects in the absorption of glucose, amino acids, phosphate, uric acid, and other organic anions such as citrate.

Type 2 RTA is a self limiting disorder in which the plasma HCO3- concentration is usually between 14 and 20 meq/L .

Urinary K+ wasting and hypokalemia are common in type 2 RTA and is due to persistent hyperaldosteronism, leading to increased K secretion by the distal nephrons.

Hyperaldosteronism in these patients are related to the defect in proximal reabsorption of filtered HCO3- which in effect leads to decreased proximal NaCl reabsorption and a tendency for salt wasting.

TYPE IV RTA

Type IV RTA is the only type characterized by: - hyperkalemic, hyperchloremic acidosis.

The defect is thought to be Aldosterone deficiency or resistance.

Type 4 RTA due to aldosterone deficiency has multiple etiologies.

HYPORENINEMIC HYPOALDOSTERONISM

It is the most common cause and is usually associated with mild to moderate renal insufficiency.

It is most commonly found in:- diabetes nephropathy and -chronic interstitial nephritis.-NSAIDS, ACE inhibitors, Trimethoprim and heparin can all reduce aldosterone production and produce a type 4 RTA. Drug-induced type 4 RTA is usually seen in patients with pre-existing renal insufficiency.

FOR YOU:

Anion Gap= Na+-(Cl + HCO3)= 5-11= unmeasured( Anions – Cations)

Na\Cl=1.4-If<1.4: Hyperchloremia: -dehydration

-hyperchloremic metabolic acidosis -respiratory alkalosis-If >1.4: Hypochloremia: -combined metabolic alkalosis and respiratory acidosis

Combined metabolic acidosis and respiratory alkalosis:

-Sepsis-liver problem-Salicylate intoxication

In metabolic acidosis:∆PCO2=1.2 ∆HCO3

In uncomplicated high AG metabolic acidosis, ∆AG\ ∆HCO3 is 1:1.

A value < 1:1= combined high AG and normal AG acidosis.

A value > 2:1= high AG acidosis and metabolic alkalosis.