Index of Suspicion

[Alon]

Постараюсь публиковать здесь интересные клинические случаи по детским болезням.
К участию и обсуждению приглашаются все желающие.
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Case 1
Presentation

A 21-month-old boy known to have chronic gastroesophageal reflux is brought to your office for a second opinion regarding poor growth. Born at term, he was diagnosed as having reflux at 3 weeks of age due to arching and crying with feedings. He was noticed to be failing to thrive initially at 12 months of age when, despite adequate caloric intake, his weight percentile had fallen from the 75th to the 5th percentile over 6 months. His height and head circumference have remained between the 10th and 25th percentiles. He has experienced intermittent episodes of constipation and frequent colds and ear infections. He walked at 15 months of age and says about 150 words.

His evaluation has included multiple laboratory tests, including cystic fibrosis and celiac disease screening, thyroid function tests, CBC, measurement of electrolytes, and urinalysis. He has been evaluated by pediatric gastroenterology, and despite a formula change and multiple antireflux medications, his weight has remained in the 5th percentile. A pH probe study and endoscopy performed at 20 months of age demonstrated only mild reflux. He has had negative skin testing for food allergies.

The diagnosis is revealed after additional history and a laboratory test are obtained.
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Case 1 Discussion

On further questioning, the child’s mother mentioned that he drinks about 70 to 80 oz of fluid a day! Generally, he drinks 40 oz of water, 16 oz of rice milk, and two to three cans of liquid dietary supplement. This excessive thirst started at about 6 months of age. He awakens three to five times a night asking for water, and his wet diapers are noted to be incredibly heavy.

Measurement of urine electrolytes demonstrated concentrations of sodium below 5 mEq/L (5 mmol/L) and chloride below 20 mEq/L (20 mmol/L), with urine osmolality below 50 mOsm/L while the serum osmolality was high-normal at 303 mOsm/L. In retrospect, previous urinalysis results had been abnormal because of a specific gravity of 1.005, although the other indices had been normal. His serum chloride value had been mildly elevated at 109 mEq/L (109 mmol/L), but his sodium value was normal at 144 mEq/L (144 mmol/L).

The boy was admitted to the hospital for a water deprivation test, which showed an increase of serum sodium (from 144 to 152 mEq/L [144 to 152 mmol/L]), increase in serum osmolality (from 297 to 310 mOsm/L), no change in urine osmolality (range, 64 to 77 mOsm/L), and continued passage of dilute urine (specific gravity below 1.003). His weight decreased 5% (9.4 kg to 8.95 kg), and his urine volume averaged 16 mL/kg per hour.

After an injection of arginine vasopressin (AVP), his urine osmolality and specific gravity remained low at 70 mOsm/L and 1.002, respectively. His urine output was more than 30 mL/kg per hour during the subsequent hour after injection. The diagnosis of congenital nephrogenic diabetes insipidus (CNDI) was confirmed.

The Signs
Causes of polyuria and polydipsia can be differentiated based on laboratory values. Solute diuresis can be identified by finding a urine-to-plasma osmolality ratio greater than 0.7. Examples of solute diuresis are diabetes mellitus and intrinsic renal disease, which can be determined by routine chemistries. Water diuresis, in addition to a urine-to-plasma osmolality of less than 0.7, demonstrates a urine specific gravity below 1.010. Three common causes of water diuresis are compulsive water drinking, central diabetes insipidus (CDI), and nephrogenic diabetes insipidus (NDI).

Compulsive water drinking can be differentiated from diabetes insipidus (DI) by laboratory testing, if the history is not forthcoming. Interestingly, compulsive water drinkers often have a preference for ice water and are less likely to have nocturia. Low serum osmolality combined with low urine osmolality suggests compulsive water drinking.

CDI often can be suspected on the basis of history, as when the patient manifests brain tumor, head trauma, or CNS infection. In approximately 25% of cases, no cause can be determined.

It is important to differentiate congenital from acquired causes of NDI, such as drug effects, electrolyte disorders, urinary tract obstruction, and systemic disorders such as sickle cell anemia. It is helpful to recall that acquired NDI can be caused by primary renal disease, systemic disease with renal involvement, medication effects, and miscellaneous conditions.

Making the Diagnosis
If the patient can drink freely, the baseline serum sodium concentration generally normalizes, and there is no evidence of dehydration. A first step to distinguish NDI from other causes of polydipsia is to collect a 24-hour urine sample. For a small child, a shorter collection period may be necessary. The finding of polyuria in a patient who is dehydrated and has an elevated serum sodium concentration as well as hypo-osmolar urine implies a renal concentration defect. The diagnosis of NDI is confirmed by a water deprivation test, with results showing the inability to concentrate the urine despite the release of vasopressin.

The water deprivation test involves dehydrating the patient and testing for changes in specific laboratory values. Generally, the criteria for dehydration are 3% to 5% weight loss, orthostasis, a plateau in urine osmolality, or hypernatremia. Urine volume, osmolality of plasma and urine, and electrolyte values are followed closely. A plasma vasopressin level is measured at the start and completion of dehydration.

Both types of DI are characterized by the inability to concentrate urine after water deprivation. The urine osmolality usually remains below 200 mOsm/kg H2O, and the urine specific gravity remains below 1.010. On the other hand, compulsive water drinkers pass concentrated urine (urine osmolality >500 mOsm/kg H2O) after being deprived of water. Patients who have CDI demonstrate inadequate concentrations of vasopressin after a water deprivation test, but concentrations are elevated in those having NDI. To distinguish CDI further from NDI, vasopressin is administered. Individuals who have CDI have a significant increase (usually >50%) in urine osmolality after vasopressin is administered either intranasally, subcutaneously, or intravenously. Patients having NDI maintain a low urinary osmolality (usually <200 mOsm/kg).

The Condition
CNDI is a genetically inherited error, with 90% of cases being X-linked and 10% involving an autosomal recessive or autosomal dominant mechanism. The distal nephron is insensitive to the antidiuretic effects of AVP, which leads to the production of large amounts of hypotonic urine. Normally, in the collecting duct, AVP from the posterior pituitary gland binds with the vasopressin type-2 receptor (V2R), which activates adenylate cyclase to increase cyclic AMP. This reaction stimulates protein kinase A, which redistributes aquaporin-2 water channels (AQP2), permitting the apical plasma membrane to become permeable to water. As a result, water flows from the tubular lumen to the medullary interstitium, which produces concentrated urine. In the X-linked form, the mutation exists in the V2R gene; in the autosomally inherited forms, the mutation is in the AQP2 gene.

Clinical Features
Classic features of DI are polyuria and polydipsia, which can lead to hypernatremic dehydration. The excessive fluid intake also may blunt the appetite. Nonspecific signs and symptoms include failure to thrive, recurrent fevers due to dehydration, vomiting or poor feeding, and constipation. More severe manifestations are seizures and mental retardation, which occurs rarely because awareness of the disorder has increased. Physical findings may be normal or the patient may show signs of dehydration and irritability.

Treatment
CNDI is treated by dietary restrictions and medication. Sodium intake is reduced to 0.7 mEq/kg per day, and protein intake is decreased to 8% of total caloric intake to decrease renal solute load and decrease the volume of urine required for solute excretion. Thiazide diuretics, often coupled with potassium supplements, or potassium-sparing diuretics with dietary changes paradoxically can reduce urine volume by 20% to 50%. Amiloride and prostaglandin synthetase inhibitors have been used in combination with thiazide diuretics. Nonsteroidal anti-inflammatory drugs are useful in the acute setting to reverse hyperosmolality. It is important to remember that an increase in urine osmolality to more than 200 mOsm/kg H2O has a dramatic effect on urinary losses.

Lessons for the Clinician
A comprehensive history is essential in determining a cause for failure to thrive. Growth failure can be a presenting sign of CNDI. It is important to ask not only about inadequate urination and oral intake, but also about polyuria and polydipsia.


Laurie Liang, MD
Kaiser Santa Clara Hospital, Santa Clara, Calif