Pathophysiology of Diabetes Insipidus

Pathophysiology of Diabetes Insipidus

Last updated on July 19th, 2016

Diabetes Insipidus is a heterogenous disorder, wherein large volumes of dilute urine are excreted. The body loses its capacity to concentrate excreted urine. The hormone responsible for regulating fluid balance is called arginine vasopressin (AVP), also called vasopressin or anti-diuretic hormone. In diabetes Insipidus, patients could have either a deficiency in this hormone or a resistance to its function. Another reason for developing diabetes insipidus is excessive water intake, which is often seen in several psychiatric conditions.

It is a rare condition with an estimated incidence of 1:25,000. However, it’s epidemiologic data among post-traumatic head injuries could vary from 2-16%. Fewer than 10% of diabetes insipidus is familial in origin, and 90% of which is sex-linked and 10% is autosomal in inheritance pattern. This syndrome is characterized by a 24-hr urine volume that is more than 50ml/kg body weight and serum osmolarity of less than 300 mosm/L. Polyuria produces symptoms of urinary frequency, enuresis and nocturia, which may cause sleep disturbances and daytime somnolence or fatigue. Due to the excessive fluid loss, patients experience excessive thirst with a commensurate increase in fluid intake.

Pathophysiology

Fluid balance is a product of an equalized input and output of the body. This is regulated by sensing of plasma osmolality by osmoreceptors of the anterior hypothalamus, which project to the thirst and vasopressin centers of the brain.

Arginine Vasopressin and Fluid homeostasis

Arginine vasopressin is an endogenously produced hormone in the hypothalamus and is delivered via the pituitary stalk to the posterior pituitary gland where it is stored and released to the systemic circulation. This hormone is secreted when serum osmolality is detected to be increased by the osmoreceptors of the kidney. Due to this, the net physiologic effect is conservation of water to balance out the increasing osmolality, thereby restoring fluid homeostasis.

Arginine Vasopressin and Fluid homeostasis
Arginine vasopressin acts on the AVP2 receptors, primarily in the kidneys to increase the water permeability of the collecting ducts. This process occurs through the generation of more water channels, called aquaporin-2 into the apical membrane of the collecting ducts, thereby resulting in reabsorption of water back to the systemic circulation. Due to this, excreted urine is concentrated. AVP2 receptors are also found to be present in various extra-renal tissues such as the vascular and pulmonary endothelial cells, inner ear, the parathyroid, non-keratinized squamous epithelia, exocrine pancreas, salivary glands, smooth muscle, breast, and Leydig cells.

Primary vasopressin deficiency

The deficient secretion of arginine vasopressin in diabetes insipidus may be primary or secondary. The primary form results from any condition that causes impaired production, transportation, release and function of vasopressin. Primary impaired production results from agenesis or irreversible destruction of the neurohypophysis and is referred to as central DI, neurogenic, pituitary DI or neurohypophyseal DI. This is often caused by a surgical intervention or head injury, which causes traumatic injury to the hypothalamus and posterior pituitary gland with resultant destruction or degeneration of neurons originating from the hypothalamic nuclei.

Primary vasopressin deficiencyPrimary impaired metabolism of vasopressin results in gestational DI. These patients have increased metabolism of arginine via the production of a placental enzyme called, cysteineaminopeptidase. This enzyme is responsible for metabolizing vasopressin, thereby decreasing the hormonal concentration and function in the systemic circulation. The concentration of this enzyme is higher for pregnant women, most especially in twin pregnancies. It usually presents in the third trimester and resolves spontaneously until three weeks after delivery. Primary impaired anti-diurectic action of arginine results in nephrogenic DI.  This results from various conditions, which impairs the ability of the renal collecting duct to respond to arginine vasopressin. This condition may be genetic, acquired or caused by exposure to certain medications. Children usually present with the inherited form of nephrogenic DI, while adults usually present with the acquired form.

When the secretion or function of arginine vasopressin is reduced to less than 80-85% of physiologic levels, the kidney’s ability to concentrate urine ceases and the rate of urine output increases. In patients with primary vasopressin deficiency, the polyuria is not marked, with an approximately 1-2% decrease in total body water and a commensurate increase in serum osmolarity and sodium concentration which stimulate a compensatory polydipsia. This does not result in overt clinical signs of dehydration unless the patient fails to drink or respond to thirst for any particular reason.

Secondary vasopressin deficiency

Secondary deficiencies in arginine vasopressin result from inhibition of secretion by the excessive intake of fluids. This is referred to as primary polydipsia, which can be subcategorized into three categories. Dipsogenic diabetes insipidus is characterized by inappropriate thirst due to a defective osmoregulatory mechanism, causing profound thirst. Psychogenic polydipsia is excessive fluid intake due to psychiatric conditions such as obsessive-compulsive disorder or overt psychosis. It is not associated with thirst or any derangement in the osmoregulatory pathway. Iatrogenic polydipsia results from recommendations from medical personnel or media to increase fluid intake for its presumed preventive or therapeutic benefits for various disease states.

In patients with secondary deficiency of arginine vasopressin, the excessive intake of fluids slightly increases total body water. This causes a reduction in plasma osmolarity, secretion of vasopressin and impaired urinary concentration. A dilute urine results in a compensatory increase in urine free-water clearance that varies in proportional to fluid input. Due to this, clinical signs of overhydrationis infrequent unless compensatory diuresis is impaired by a pre-existing medical condition or medication intake that could mimic the function of anti-diuretic hormone.

 Reference:

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