Evaluation of Suspected Diabetes Insipidus

David M. Slovik

When a patient presents with polyuria and polydipsia, the primary care physician needs to keep in mind the possibility of diabetes insipidus (DI), even though poorly controlled diabetes mellitus is the most common cause (see Chapter 102). DI is characterized clinically by the excretion of large volumes of inappropriately dilute urine. Although uncommon, DI may be a manifestation of important hypothalamic-pituitary disease or renal tubular dysfunction. The primary care physician needs to know how to screen for DI in a patient with polyuria and polydipsia and how to proceed with the basic elements of the diagnostic investigation.

PATHOPHYSIOLOGY AND CLINICAL PRESENTATION (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12)

Plasma osmolality is carefully regulated to maintain each individual’s normal value at a level between 285 and 290 mOsm/kg. When water is lost, even a 1% increase in plasma osmolality stimulates hypothalamic osmoreceptors to release antidiuretic hormone (ADH, vasopressin, AVP) from the posterior pituitary. This in turn stimulates water retention by the kidney. Osmoreceptor stimulation also triggers central thirst mechanisms. These actions serve to reestablish normal serum osmolality. The ability of ADH to stimulate water reabsorption is mediated by kidney aquaporins, which are ADH-responsive water channels; aquaporin-2 is the major one.

A lesion in any portion of this osmoregulatory system can result in DI and its attendant water diuresis. Dehydration and hypertonicity may ensue unless the thirst mechanism remains intact and access to water is adequate. Clinically, DI is characterized by the excretion of large volumes of dilute urine in conjunction with excessive thirst and polydipsia. Urinary frequency must be distinguished from true polyuria, which is generally defined as the excretion of more than 3 L/d or 50 mL/kg/d. Some patients may excrete as much as 15 to 20 L/d. Craving for ice water is common (especially with central DI) due to stimulation of osmoreceptors in the back of the throat. Nocturia is common.

The urine is almost always colorless, even in the morning, because of its dilute nature. Urine osmolality is inappropriately low (<250 mOsm/kg). Serum osmolality may be increased, especially if the thirst mechanism is impaired.

Central or Neurogenic Diabetes Insipidus

Central or neurogenic DI is the most common form of DI and is associated with deficient secretion of ADH. It can be due to complete or partial ADH deficiency and occurs in the context of an injury to the hypothalamus or posterior pituitary. Mechanisms for acquired central DI include trauma, destruction by malignant or granulomatous disease, autoimmune inflammatory processes, vascular insult, and pituitary surgery. Because the thirst
center is situated near the hypothalamic osmoreceptors, it, too, may be involved, although in many cases, the thirst mechanism is preserved and dehydration avoided. Anterior pituitary adenomas usually do not cause DI unless they are large and extend posteriorly or beyond the sella. Onset of polyuria is typically abrupt. Familial central DI is an autosomal dominant disease caused by mutation in the arginine vasopressin gene.

Nephrogenic Diabetes Insipidus

Nephrogenic DI is characterized by normal ADH secretion but impaired renal response to ADH. Acquired forms of nephrogenic DI result from conditions or medications that damage renal tubulointerstitial function and concentrating ability (most commonly hypercalcemia, hypokalemia, sickle cell disease, lithium use). Onset of polydipsia is usually gradual. Hereditary nephrogenic DI is primarily an X-linked disorder.

Primary Polydipsia

Primary polydipsia also produces polyuria, but unlike DI, this condition appears to originate with an altered perception of thirst and a primary increase in water intake. It is particularly prevalent among patients with chronic psychiatric disturbances (especially schizophrenia) but is also seen with organic brain disease (e.g., multiple sclerosis). Detailed study of such patients has revealed multiple defects in the regulation of osmolality, including problems with urinary dilution, regulation of water intake, and ADH secretion. Increased thirst and fluid intake are followed by polyuria, although some patients may hide this behavior. A fall in serum osmolality (<285 mOsm/kg) may be accompanied by hyponatremia. Symptoms tend to be episodic and onset of polydipsia gradual.

DIFFERENTIAL DIAGNOSIS (2,9, 10, 11 and 12)

The differential diagnosis for patients with polyuria and polydipsia in the outpatient setting includes diabetes mellitus (see Chapter 102), diuretic use, DI, and primary polydipsia. The differential can be organized as follows: (a) whether the diuresis is related to water or solute; (b) if related to water, whether it is a manifestation of DI or primary polydipsia; and (c) if DI, whether it is central or nephrogenic (Table 101-1). Other causes of urinary frequency unaccompanied by polydipsia (e.g., urinary tract infection, bladder dysfunction) need to be ruled out (see Chapters 133, 134, and 140).

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