Diabetes Insipidus Pathophysiology

Diabetes insipidus is caused by abnormality in the functioning or levels of antidiuretic hormone (ADH), also known of as vasopressin. Manufactured in the hypothalamus and stored in the pituitary gland, ADH helps to regulate the amount of fluid in the body.

In healthy individuals, when the bodily fluids are depleted, ADH is released from the pituitary gland which prevents the excretion of fluids from the body in the form of urine. ADH acts on the kidneys to increase water permeability in the collecting duct and distal convoluted tubule. Specifically, ADH acts on transmembrane protein channels called aquaporins that open up to allow water into the collecting duct. Once the permeability rises, the water is re-absorbed into the blood, reducing urine volume and increasing its concentration.

The two forms of diabetes insipidus

In central (cranial) diabetes insipidus, the production or release of ADH is too low to stop the kidneys from passing dilute urine, which results in an increased loss of water and therefore more thirst. People with nephrogenic diabetes insipidus, however, have adequate amounts of ADH in the body but the kidneys fail to respond it, and again the urine is still not concentrated.

Causes of diabetes insipidus

Some of the causes of cranial diabetes insipidus include:

• Genetic inheritance of a mutation in the vasopressin gene, AVP-NPII. The pattern of inheritance is autosomal.
• Brain tumors such as pituitary adenoma and craniopharyngiomas
• Head injury causing damage to the pituitary gland or hypothalamus. Injury may also result after brain surgery.
• Meningitis and encephalitis or brain infections may also affect the pituitary gland and the hypothalamus.
• Sheehan's syndrome, deposition of iron (haemochromotosis) in pituitary/hypothalamic tissue, Langerhans' cell histiocytosis and Wolfram syndrome are other causes.
• Blood vessel complications such as those during pregnancy where the blood supply to the hypothalamus and pituitary gland may be compromised.
• Stroke or sudden loss of oxygen to the brain (e.g. during anesthesia or drowning) may also result in diabetes insipidus.

Causes of nephrogenic diabetes insipidus

• Familial or genetic causes resulting from mutation in the AQP2 gene that codes for the aquaporin-2 protein. This genetic mutation is has an autosomal recessive pattern of inheritance.
• Metabolic causes such as high blood sugar, high blood calcium and low potassium.
• The use of drugs such as lithium used to treat bipolar disorder can decrease the expression of aquaporin-2.
• Diseases such as amyloidosis, obstructive uropathy, chronic kidney disease and polycystic kidney disease.