diabetes insipidu1

7/30/2019 Diabetes Insipidu1

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Diabetes Insipidus

Last Updated: July 26, 2006

Synonyms and related keywords: diabetes insipidus, DI, hypernatremia, thirst, polydipsia, dehydration,central diabetes insipidus, CDI, nephrogenic diabetes insipidus, NDI

INTRODUCTION

Background: The word diabetes is derived from the Greek verb diabainein, which means to stand with legsapart, as in urination, or to go through. Insipidus comes from a Latin word meaning without taste. In contrastto diabetes mellitus (DM), which describes the excretion of sweet urine, diabetes insipidus (DI) describes

the passing of tasteless urine because of its relatively low sodium content.

Nephrogenic DI (NDI) reached North America in 1761, carried by Ulster Scots who arrived in Nova Scotia,Canada, on a ship named Hopewell. Scottish folklore reports the existence of the disease in Scotland before

1761. According to legend, a gypsy woman traveling with her thirsty son is denied water by a housewife.The gypsy woman curses the housewife, causing the housewife's sons to crave water while condemning herdaughters to pass the curse on to future generations.

Pathophysiology: The basis of water loss in DI is distinct from water loss caused by DM. The renal tubular

collecting ducts are unable to concentrate urine secondary to vasopressin deficiency or resistance. Thecollect ing duct concentrates urine by reabsorbing water, a function controlled by the posterior p ituitary

gland via secretion of vasopressin or antidiuretic hormone (ADH). Reabsorption of sugars, amino acids, andvirtually all electrolytes is completed by the time the urine has reached this segment of the nephron.Consequently, the inability to conserve water by reabsorption in the collecting duct depletes body water, but

leaves sodium unaffected. The net result is an extremely diluted, increased urine output resulting inhypernatremia. Polydipsia follows as the thirst mechanism urges replenishment of body water.

Secretion of vasopressin occurs in the posterior pituitary gland and is regulated at the paraventricular and

supraoptic nuclei, which sense changes in osmolality. Destruction of the paraventricular or supraoptic nucleior of the posterior pituitary by tumor, pressure, or surgical ablation results in decreased vasopressinsecretion and central diabetes insipidus (CDI). Alternatively, DI may be idiopathic or inherited either as an

autosomal dominant or as an autosomal recessive trait (locus 20p13).

NDI arises from defective or absent receptor sites at the cortical collecting duct segment of the nephron (X-linked, vasopressin V2 receptor deficiency, locus Xq28) or defective or absent aquaporin, the protein that

transports water at the collecting duct (autosomal recessive, locus 12q13). The X-linked variety of NDIaccounts for about 90% of all such cases.

As a consequence of one of these defects, the ducts do not respond appropriately to vasopressin. Normally,

vasopressin is transported in the blood to receptor sites on the basolateral surface of the collecting ductmembrane. Through a G proteinadenylate cyclase coupling, activat ion of the vasopressin receptor increasescyclic adenosine monophosphate (AMP) production and stimulates protein kinase A, leading to increased

recycling of the protein aquaporin in the plasma membrane.

In the presence of vasopressin stimulus, exocytic insertion of aquaporin into the apical, or luminal, surfaceof the tubule cell occurs. Aquaporin enhances water entry into the cell from the lumen. Absence of the

vasopressin receptor does not allow this process to take place, causing inhibition of water uptake andpolyuria. Alternat ively, defect ive or absent aquaporin impairs the process in the presence of normal V2receptors.


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Frequency:

In the US: Tumors, infiltrative lesions, malformations, and neurosurgical procedures are the mostcommon causes of CDI. Of the genetic etiologies, the overall incidence in the general population isestimated to be 3 cases per 100,000 population (0.003%.) The male-to-female ratio is 60:40. X-

linked NDI is very rare, although it exceeds the recessive variety by a ratio of 9:1. The mutation formales is 4 cases per million population.

Mortality/Morbidity:

Dehydration results from an inability to reabsorb free water at a site dista l to electrolyte reabsorption.

Any patient unable to continuously replace water loss is vulnerable to dehydration, especially inwarm weather when insensible water loss through perspiration and respiration substantially increases

risk. Electrolyte abnormalities are caused by the loss of urinary free water, which produceshyperosmolar dehydration, leading to hypernatremia, hyperchloremia, and prerenal azotemia.Diminished blood volume increases blood viscosity and the risk of sludging and thrombosis.

Failure to thrive occurs because of the patient's constant thirst conferring a sense of fullness thatoffsets the sense of hunger. The affected individual eats less than necessary for normal growth.

Seizures are a consequence of the electrolyte abnormalities introduced in the central nervous system

(CNS) by severe hypernatremia and hyperosmolar dehydration.

Mental retardation results from the damage to the CNS caused by severe hyperosmolarity, seizures,and potential hypoxia, all of which are thought to account for the frequent occurrence of mental

retardation.

Death can occur from a hypovolemic shock or a hypernatremic seizure.

Sex:

CDI secondary to hypothalamic-pituitary lesions occurs at random and should, therefore, be evenlydistributed between the sexes.

Autosomal dominant and autosomal recessive CDI occur equally in both sexes.

NDI caused by an X-linked mutation affects males only. Autosomal dominant and autosomalrecessive forms of NDI affect both sexes equally.

Age:

DI occurs in people of a wide age range.

Children who present with autosomal recessive CDI are generally younger than 1 year. Children who

present with autosomal dominant CDI are often older than 1 year.

NDI forms (including X-linked, autosomal dominant, and autosomal recessive forms) develop inearly infancy, often in neonates younger than 1 week.


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CLINICAL

History:

Diagnosis may be difficult in infants and children because of nonspecific presenting features (eg,

poor feeding, failure to thrive, irritability). Therefore, a high index of suspicion is necessary.

The earliest signs of diabetes insipidus (DI) include a vigorous suck with vomiting, fever withoutapparent cause, constipation, and excessively wet diapers from urination.

In older infants and young children, irritab ility is generally due to a borderline state of dehydration

coupled with hypernatremia and, sometimes, fever.

Nocturia is common and expected because of increased urine production.

CDI tends to develop suddenly.

Physical:

The typical examination shows an irritable infant with a dripping wet diaper, along with detectablesigns of dehydration (eg, dry mucous membranes, diminished skin turgor, decreased tearing,

tachycardia). Often, skin turgor is not diminished in individuals with hypernatremic dehydrationdespite significant dehydration.

In severely dehydrated patients, the pulse may be thready and rapid. Hypotension may be present

because of hypovolemic shock.

Mobile fecaliths may be palpable in the abdomen.

Causes: DI is due either to (1) deficiency of vasopressin secretion by the pituitary gland (CDI or neurogenicDI) or to (2) renal tubular unresponsiveness to vasopressin (NDI).

Nongenetic causes

o Typical injuries include head trauma, tumor, and neurosurgical procedures.o At all ages, destructive lesions of the pituitary and/or hypothalamus are the most common

cause of DI.

Genetic causes

o CDI with an autosomal dominant pattern inheritance is due to a mutation in the prepro-arginine vasopressin (prepro-AVP2) gene, mapped to locus 20p13.

o CDI with diabetes mellitus, optic atrophy, and mental retardation (Wolfram syndrome) maybe inherited in an autosomal recessive pattern (locus 4p16) or may be due to mitochondrialdeletions.

o X-linked NDI occurs from mutations in the antidiuretic arginine vasopressin V2 receptor(AVPR2) gene, mapped to Xq28.


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o NDI with an autosomal dominant or recessive pattern is due to mutations in the genedesignatedAQP2; this gene directs water channel formation in the distal membrane and hasnot yet been mapped.

DIFFERENTIALS

Head TraumaMedullary Cystic DiseaseSickle Cell Anemia

Other Problems to be Considered:

Histiocytosis X

Hypercalcemic nephropathyHypokalemic nephropathy

Interstitial nephritisPosterior fossa tumorNeurosurgical ablat ion of neurohypophysis

Psychogenic polydipsiaWater intoxication (excessive consumption)

WORKUP

Lab Studies:

The urine specific gravity of the first morning urine is helpful in assessing renal ability to concentrate

urine. Dilute urine with a relatively high serum sodium and osmolarity effectively establishes thediagnosis. The serum sodium may be as high as 170 mEq/L, while the serum osmolarity is greater

than 300 mOsm/kg. Patients with prerenal azotemia present with severe dehydration.

In young infants, finding a distinction between normal and pathological inability to concentrate theurine may be difficult because infants generally exhibit a constitutional hyposthenuria.

The definitive diagnostic study is the water deprivation test, which can be used both to confirm the

diagnosis and to distinguish between central diabetes insipidus (CDI) and NDI by response to a

vasopressin analogue. The water deprivation test is performed as follows:

o Collect baseline urine and blood for osmolality and electrolytes. Deprive the patient of waterafter breakfast until significant dehydration occurs. Weigh the patient every 2 hours and limit

dehydration to 2-5% loss of body weight.

o Monitor urine specific gravity hourly; if the specific gravity is 1.014 or greater, terminate thetest and obtain appropriate urine and blood specimens for osmolality. Limit water deprivation

to 4 hours for infants and 7 hours for children. If polyuria persists, administer intranasaldesmopressin (seeMedication) and replace urine output with fluids. After 4 hours (2 h ininfants), obtain urine and blood for osmolality.

o The normal response to dehydration or desmopressin acetate (DDAVP) includes urineosmolality greater than 450 mOsm/kg, urine/serum osmolality greater than or equal to 1.5,
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and an increase in urine/serum osmolality from baseline of 1.0 or more. A normal responseshould be observed in CDI and psychogenic DI but not in NDI.

An accurate 24-hour urine collection is important. The total urine output is high, and the number ofosmoles excreted per day is small.

Serum potassium and calcium concentrations are important to exclude the possibility of polyuria

secondary to hypokalemia or hypercalcemia, both of which interfere with renal concentratingmechanisms.

Imaging Studies:

Cranial MRI can be used to exclude pituitary cysts, hypoplasia, and destruction secondary to mass

lesions. Often, the bright spot that is thought to represent vasopressin-secreting neurons in theposterior pituitary is absent in CDI.

TREATMENT

Medical Care:

Treat patients in an inpatient setting because of the risk of severe dehydration. Destructive orcompressive intracranial lesions mandate inpatient stay.

Distinguishing between central and nephrogenic etiology is essential to the treatment modality.

Surgical Care: Demonstrat ion of an intracranial mass necessitates surgical care.

Consultations:

Nephrologist

Endocrinologist: The presence of central diabetes insipidus should prompt an evaluation of anteriorpituitary function.

Diagnostic radiologist

Diet:

Provide affected infants a breast milk diet to decrease solute load. Protein should comprise 6% ofcaloric intake, and sodium should be reduced to 0.7 mEq/kg/d.

Provide young children 8% of their caloric intake as protein to enable normal growth. Sodium intakemust be maintained at 0.7 mEq/kg/d.

Activity:

Activities resulting in increased insensible water loss should be moderated in the presence of massive

urinary water loss to prevent dehydration.

Heat exposure should be minimized, especially when participating in sports.


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MEDICATION

For central d iabetes insipidus (CDI), the treatment of choice is desmopressin (a synthetic vasopressinanalogue). It is available in parenteral, intranasal, and oral dosage forms. The doses are quite differentdepending upon the preparation used, so take care to calculate the dose correctly. Other useful medications

include chlorpropamide and thiazide diuretics. The latter 2 can result in a 25-75% reduction in urine volumeand can be used in combination with each other.

NDI cannot be treated effectively with desmopressin because the receptor sites are defect ive and the kidney

is prevented from responding. Thiazide diuretics, amiloride, and indomethacin or aspirin are useful whencoupled with a low-solute diet.

Drug Category:Pituitary hormones-- DI of central origin is due to absence of vasopressin secretion bythe pituitary. Consequently, use of a synthetic vasopressin analogue (ie, desmopressin) is required. Thenatural compound vasopressin (ie, ADH) may be used to diagnose NDI. It has a very short natural half-life.

This permits its safe use in distinguishing CDI from NDI by obviating prolonged fluid accumulation in theformer. As an aqueous preparation, it can be administered parenterally, IM, or SC.

Drug Name

Desmopressin acetate (DDAVP) -- A synthetic analogue (1-[3-mercaptopropionic

acid]-8-D-arginine vasopressin monoacetate trihydrate) of pituitary ADH.Increases cellular permeability of collecting ducts, resulting in reabsorption ofwater by kidneys.

Dosage must be individualized. Drug is supplied as parenteral (4 mcg/mL), nasal(100 mcg/mL rhinal tube), and PO (0.1- and 0.2-mg tab) preparations.

Adult Dose

0.5-1 mL/d (2-4 mcg/d) IV/SC divided bid0.1-0.4 mL/d (10-40 mcg) intranasally divided bid/tid0.1-1.2 mg/d PO divided bid/tid

Pediatric Dose

0.05-0.5 mL/d (0.2-2 mcg/d) IV/SQ divided bid0.05-0.3 mL/d (5-30 mcg/d) intranasally qd or divided bid/tid

>4 years: 0.05-0.2 mg/d PO divided bid/tid

ContraindicationsDocumented hypersensitivity; platelet-type von Willebrand disease; water loss dueto NDI

Interactions

Coadministration with demeclocycline and lithium decreases effects;fludrocortisone and chlorpropamide increase effects of desmopressin

Pregnancy B - Usually safe but benefits must outweigh the risks.

Precautions

Use carefully and monitor serum sodium and body weight because of the danger of

overdose and consequent water intoxication; hyponatremia may occur fromoverdose; every patient must be individually evaluated for optimal dose

Drug Name

Vasopressin (Pitressin) -- Has vasopressor and antidiuretic hormone (ADH)activity. Increases water resorption at d istal renal tubular epithelium (ADH effect)

and promotes smooth muscle contraction throughout vascular bed of renal tubularepithelium (vasopressor effects). However vasoconstriction also increased in

splanchnic, portal, coronary, cerebral, peripheral, pulmonary, and intrahepatic

vessels.Use only the aqueous preparation, which has a short half- life. Vasopressin tannate

in oil, which has a longer action, should not be used.


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Interactions

Concomitant therapy with potassium supplementation may increase serumpotassium levels so use caution and monitor serum potassium levels frequently ifconcomitant use of these agents is indicated because o f demonstrated

hypokalemia; lithium generally should not be administered with diuretics becausethey may reduce renal clearance and add a high risk of lithium toxicity;

administration of nonsteroidal anti-inflammatory agents can reduce diuretic,natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazidediuretics when used concomitantly, observe patient closely to determine if desired

effect of d iuretic is obtained; indomethacin and potassium-sparing diuretics,including amiloride, may be associated with increased serum potassium levels,

consider potential effects on potassium kinetics and renal function


Precautions

Monitor electrolytes and renal function carefully if evidence of renal functional

impairment is present, ie, BUN >30 mg/100 mL or serum creatinine levels >1.5mg/100 mL

Drug Category:Nonsteroidal anti-inflammatory agents-- These agents act synergistically withthiazides to diminish urine volume, although precise mechanism is unknown.

Drug NameIndomethacin (Indocin) -- Nonsteroidal prostaglandin inhibitor with antipyretic

properties.

Adult Dose 25 mg PO bid/tid; not to exceed 200 mg/d

Pediatric Dose2 years: 2 mg/kg/d PO divided bid/qid doses; not to exceed 150 mg/d

Contraindications Documented hypersensitivity; GI bleeding; renal insufficiency

Interactions

Coadministration with aspirin increases risk of inducing serious NSAID-relatedadverse effects; probenecid may increase concentrations and, possibly, toxicity ofNSAIDs; may decrease effect of hydralazine, captopril, and beta-b lockers; may

decrease diuretic effects of furosemide and thiazides; may increase PT whentaking anticoagulants (instruct patients to watch for signs of bleeding); mayincrease risk of methotrexate toxicity; phenytoin levels may be increased when

administered concurrently


Precautions

Category D in third tr imester of pregnancy; acute renal insufficiency,hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis mayoccur; increases risk of acute renal failure in patients with preexisting renal disease

or compromised renal perfusion; reversible leukopenia may occur (discontinue ifpersistent leukopenia, granulocytopenia, or thrombocytopenia is present)


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Drug Category: Sulfonylurea compounds-- These compounds are an alternative therapy todesmopressin and can be used in combination with thiazide diuretics. Sulfonylurea compounds have the

reported property of causing a syndrome identical to inappropriate ADH secretion.

Drug Name

Chlorpropamide (Diabinese) -- Promotes renal response to ADH. In CDI, ADHsecretion is absent, although ADH receptor sites remain present in the kidney.

Thus, interaction of the receptors with sulfonylurea compounds can produce aphysiologic antidiuresis.Dosage must be individualized. Available only in tablet form.

Adult Dose150-250 mg/d PO initially, slowly increase in 50 mg/d increments q3-5d ifhypoglycemia does not supervene; not to exceed 750 mg/d

Pediatric Dose

Not established; limited data suggests a starting dose of 50 mg/d PO, may increaseby 50 mg/d increments q3-5d; not to exceed 150 mg/d; carefully monitor bloodsugar

Contraindications Documented hypersensitivity; ketoacidosis; type 1 DM

Interactions

Clofibrate, fenfluramine, histamine (H2) antagonists, androgens, azole antifungals,

anticoagulants, chloramphenicol, fluconazole, gemfibrozil, magnesium sa lts,methyldopa, MAOIs, probenecid, salicylates, sulfinpyrazone, urinary acidifiers,and sulfonamides may enhance hypoglycemic effects; nicotinic acid, PO

contraceptives, isoniazid, hydantoins, estrogens, diazoxide, corticosteroids,cholestyramine, beta-blockers, calcium channel blockers, phenothiazines,

rifampin, thiazide diuretics, urinary alkalinizers, and sympathomimetics maydecrease hypoglycemic effects; may increase effects of digitalis glycosides

Pregnancy C - Safety for use during pregnancy has not been established.

PrecautionsMonitor carefully for hypoglycemia, hyponatremia, and fluid overload; caution inhepatic and renal impairment; cardiovascular disorders may occur

FOLLOW-UP

Further Inpatient Care:

Subsequent admissions are determined by the need for intravenous rehydration, especially during

intercurrent gastrointestinal illnesses.

Further Outpatient Care:

Regular follow-up visits with an endocrinologist (for central diabetes insipidus [CDI]) or anephrologist (for NDI) are necessary for dosage adjustment.

When indomethacin is used in long-term therapy, carefully observe renal function for any signs of

toxicity.

In/Out Patient Meds:

In addition to the medications already listed, aqueous vasopressin (Pitressin) and desmopressin(DDAVP) preparations are available for intravenous use in emergency circumstances.


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Transfer:

Transfer to an academic center is highly advised for initial diagnosis and treatment, especiallybecause CDI may require involved diagnostic studies and neurosurgical or oncologic treatment.

Subsequent episodes requiring intravenous rehydration can be treated by routine admission.

Deterrence/Prevention:

Reduce or eliminate activities resulting in increased insensible fluid losses.

Avoid creating barriers to drinking water.

Complications:

Growth failure

Nocturia and enuresis

Hypernatremic dehydration

Seizures

Mental retardation

Prognosis:

Long-term survival in cases of CDI depends on the precipitating cause. In primary CDI, the

prognosis is excellent with early recognition and appropriate DDAVP therapy.

The earlier onset of NDI and the reduced ability to treat this variety of the disease re nders the child

more prone to attention deficits, hyperactivity, learning disorders, and psychomotor delay.

As long as water remains available at all times to replace the massive losses, long-term survival isnot in question.

Patient Education:

Parents must replace water in infants and young children who cannot express thirst or access fluids

without assistance.

Gastrointestinal illnesses that cause decreased intake, increased stool losses, or both must receiveearly and serious attention to prevent life-threatening electrolyte and fluid balance abnormalities.


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MISCELLANEOUS

Medical/Legal Pitfalls:

Failure to recognize excessive fluid losses

Failure to diagnose an underlying condition causing secondary central diabetes insipidus

Overtreatment with DDAVP resulting in hyponatremia and seizures

Special Concerns:

Surgical procedures of any kind require replacement of fluids at a much higher rate than normalmaintenance; inattention to this may result in serious consequences.

diabetes insipidu1

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