Diabetes insipidus pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathogenesis
Genetics
Associated Conditions
Gross Pathology
Microscopic Pathology
- Diabetes insipidus (DI) is an endocrine disorder involving deficient production or lack of effective action of pituitary antidiuretic hormone (ADH, AVP, arginine vaopressin)
- DI is characterized by chronic excretion of very large amounts of urine
- DI is coupled with dehydration and excessive thirst
Electrolyte and volume homeostasis is a complex mechanism that balances the body's requirements for blood pressure and the main electrolytes sodium and potassium. In general, electrolyte regulation precedes volume regulation. When the volume is severely depleted, however, the body will retain water at the expense of deranging electrolyte levels. The regulation of urine production occurs in the hypothalamus, which produces antidiuretic hormone (ADH or vasopressin) in the supraoptic and paraventricular nuclei. After synthesis, the hormone is transported in neurosecretory granules down the axon of the hypothalamic neuron to the posterior lobe of the pituitary gland where it is stored for later release. In addition, the hypothalamus regulates the sensation of thirst in the ventromedial nucleus by sensing increases in serum osmolarity and relaying this information to the cortex. The main effector organ for fluid homeostasis is the kidney. ADH acts by increasing water permeability in the collecting ducts, specifically it acts on proteins called aquaporins which open to allow water into the collecting duct cells. This increase in permeability allows for reabsorption of water into the bloodstream, thus concentrating the urine. There are several forms of DI:
- Central diabetes insipidus is due to damage to the hypothalamus or pituitary due to a tumor, stroke, neurosurgery or some rather rare causes (which include hemochromatosis, sarcoidosis, histiocytosis, diseases that can form masses in the vicinity like a tuberculoma or syphilis and some genetic disorders). If the hypothalamus is damaged, the feeling of thirst may be completely absent.
- Nephrogenic diabetes insipidus is due to the inability of the kidney to respond normally to ADH. There are hereditary causes (90% are due to mutations of the ADH V2 receptor, and 10% mutations of the aquaporin 2 water channel), but these are rare (incidence is around 4 per million live births). Most are male, because V2 receptor mutations are x-linked recessive defects. More common are acquired forms of NDI, which occur as a side-effect to some medications (such as lithium citrate and amphotericin B), as well as in polycystic kidney disease (PKD) and sickle-cell disease, and electrolyte disturbances such as hypokalaemia and hypercalcaemia. In some cases, no cause is found.
- Dipsogenic DI is due to a defect or damage to the thirst mechanism, which is located in the hypothalamus. This defect results in an abnormal increase in thirst and fluid intake that suppresses ADH secretion and increases urine output. Desmopressin is ineffective, and can lead to fluid overload as the thirst remains.
- Gestational DI only occurs during pregnancy. While all pregnant women produce vasopressinase in the placenta, which breaks down ADH, this can assume extreme forms in GDI. Most cases of gestational DI can be treated with desmopressin. In rare cases, however, an abnormality in the thirst mechanism causes gestational DI, and desmopressin should not be used.