As part of the exclusive Endocrinology series for M3 India, experts- Dr. SK Wangnoo, Dr. Monika, and Dr. Asim Siddiqui, broach the topic of diabetes insipidus (DI), arriving at the type of DI using specific tests and the course of treatment to be followed for each.

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Diabetes insipidus (DI) is a disorder characterised by large volume of urine (diabetes) that is hypotonic, dilute and tasteless (insipid). It is differentiated from classic diabetes mellitus where the urine is hypertonic and sweet. It is defined as the passage of large volumes (>3 L/24 hr) of dilute urine (< 300 mOsm/kg). It occurs either due to absence of vasopressin (AVP) also called as antidiuretic hormone (ADH) or due to inadequate response to vasopressin.

It is primarily of four types i.e. primary polydipsia due to excess water intake, hypothalamic, or neuro-hypophyseal diabetes insipidus caused due to decreased synthesis or secretion of vasopressin. Diabetes insipidus of pregnancy is caused by accelerated metabolism of vasopressin by vasopressinase. Nephrogenic diabetes insipidus occurs due to lack of appropriate response by kidney.

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Causes of DI*

Central Diabetes Insipidus (involvement of pituitary and/or hypothalamus)
Neoplastic	Craniopharyngioma, germinoma, meningioma, pituitary macroadenoma (invasive), metastasis to the pituitary and/or the hypothalamus
Vascular	Hypothalamic infarction/haemorrhage, cerebral infarction/haemorrhage, anterior communicating artery ligation, anterior communicating artery aneurysm, Sheehan’s syndrome, sickle cell disease
Trauma	Deceleration injury, intracranial surgery, transsphenoidal pituitary surgery
Autoimmune / inflammatory	Lymphocytic hypophysitis, IgG4 disease xanthogranulomatous hypophysitis, anti-vasopressin neuron antibodies, Guillain-Barré syndrome
Infectious	Meningitis, encephalitis, tuberculosis, pituitary or hypothalamic abscess
Granulomatous	Sarcoidosis, granulomatous hypophysitis, Langerhans’ cell histiocytosis, Erdheim-Chester disease
Drug / toxin-induced	Phenytoin, ethyl alcohol, snake venom
Congenital / genetic	Autosomal dominant AVP-neurophysin II gene alterations, Wolfram (DIDMOAD) syndrome, septo-optic dysplasia, Schinzel-Giedion syndrome, Culler-Jones syndrome, Alstrom syndrome, Hartsfield syndrome, Webb-Dattani syndrome, X-linked recessive defects with subnormal AVP levels
Nephrogenic Diabetes Insipidus
Metabolic	Hypokalemia, hypercalcemia
Drug-induced	Lithium, demeclocycline, methoxyflurane, cisplatin, pemetrexed, aminoglycosides, amphotericin B
Renal disease	Chronic kidney disease, polycystic kidney disease, obstructive uropathy
Systemic disease	Amyloidosis, sarcoidosis, Sjogren’s syndrome, multiple myeloma
Vascular	Renal infarction, sickle cell disease
Congenital / genetic	Autosomal recessive aquaporin-2 channel gene alterations, X-linked recessive V-2 receptor gene alterations, polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE) syndrome,type 4b Bartter syndrome
Pregnancy-Induced/Gestational Diabetes Insipidus
Increased vasopressin metabolism induced by placental cysteine aminopeptidase
Primary Polydipsia
Psychogenic polydipsia
Drug-induced	Anticholinergics,Phenothiazines
Intracranial aetiology	Hypothalamic tumors,Tuberculous meningitis,Intracranial surgery/trauma,Sarcoidosis
Lowering of hypothalamic threshold for thirst (‘Dipsogenic DI’)

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Aetiology of DI

These patients primarily present with polyuria (increased urine output) and polydipsia (excessive water intake) as main symptoms of this disease. Also, there is excessive water loss through urine dehydration, and hypernatremia is usually absent because of intact thirst mechanism. Patients who have co-existing inadequate thirst mechanism may develop severe hypernatremia and thus hypertonic encephalopathy leading to altered sensorium, obtundation, seizure and rarely coma.

Other complications of dehydration include subarachnoid haemorrhage, intracerebral bleed or petechial haemorrhage. Apart from this, the patient may give history suggesting aetiological causes like any recent intracranial surgery of pituitary or history suggestive of systemic disorder, or malignancy or positive family history in cases of genetic disorder.

Any patient who complains of excessive urine output is advised to maintain a diary of 24-hour water intake and total urine volume to confirm if the patient has actual polyuria or not (defined by urine output >50 ml/kg). For patients with confirmed polyuria hyperosmotic states that are also known to cause polyuria need to ruled out like hyperglycaemia, use of mannitol by checking blood sugar and current treatment records of the patients.

Urine specific gravity and urine osmolarity is checked to confirm hypotonic polyuria which is less than 1.010 and <800 mOsm/l respectively (usually less than 300 mOsm/l). Renal function test along with serum calcium and serum potassium level should be checked as renal dysfunction, hypercalcemia and hypokalemia may stimulate clinical feature similar to DI.

Then serum sodium, serum osmolarity and urine osmolarity is checked to differentiate between type of DI i.e. central DI vs. nephrogenic DI vs. primary polydipsia. A high serum sodium (>146 mmol/L) with increased serum osmolarity >295 mOsm/l could point towards central or nephrogenic DI while a low normal or low sodium (<135 mmol/L) could indicate primary polydipsia as the underlying disorder .

Further, water deprivation test or the hypertonic saline infusion test is done to confirm the type. Water deprivation test is performed most commonly and is based on the principle that, deprivation of water intake should allow patients with primary polydipsia to concentrate their urine while those with central or nephrogenic DI continue to excrete dilute urine. Subsequent administration, the synthetic analogue of AVP(desmopressin), after water deprivation should help in differentiating patients with central DI from those with nephrogenic DI as the former should be able to concentrate the urine once AVP is replaced, while the latter doesn’t show a significant response to AVP administration. Interpretation of water deprivation test is done as per table given below.

Interpretation of water deprivation test

	Urine Osmolality (mOsm/kg)
Diagnosis	After fluid deprivation	After desmopressin
Central DI	<300	>800
Nephrogenic DI	<300	<300
Primary Polydipsia	>800	>800
Partial DI or Polydipsia	300-800	<800

Lastly, a detailed history and physical examination must be performed and appropriate laboratory and imaging studies must be undertaken to identify the underlying aetiology of DI.

Management includes treating underlying dehydration and electrolyte disturbances and if possible treating underlying aetiology. In case of central DI, a major goal of therapy is to decrease the thirst and polyuria to a level that allows the patient to maintain a normal lifestyle and treatment depends on case-to-case basis. The following drugs can be used to decrease polyuria^#:

1. ADH preparations:
   1. L-Arginine vasopressin
   2. Desmopressin, 1-(3-mercaptopropionic acid)-8-D-arginine, vasopressin
2. ADH potentiating drugs:
   1. Chlorpropamide
   2. Carbamazepine
   3. Indomethacin
3. ADH release stimulating drug: Clofibrate
4. Drugs and measures not requiring ADH: diuretics (thiazide and amiloride) and salt restriction

ADH preparation i.e. desmopressin, a synthetic analogue of vasopressin is the drug of choice. It can be given by oral, intranasal, and parenteral route. Starting oral dose is 0.1 mg orally twice a day to maximum dose rarely exceeds 0.2 mg orally three times a day. Similarly, starting intranasal dose is 5 μg (1 puff) in alternate nostril twice a day to 20 μg intranasally (two sprays) given two or three times a day.

Chlorpropramide, an ADH potentiating drug is used in mild to moderate cases. Its usual dose is 250 to 500 mg/day with a response noted in 1 to 2 days and a maximum antidiuresis in 4 days. It is contraindicated in pregnancy and children, especially with concurrent hypopituitarism, because of the possibility of severe hypoglycaemia.

Thiazide diuretics are the next group of drugs. They reduce urine ouput by 50% by causing volume depletion with enhanced proximal tubular sodium and water retention. Usually, hydrochlorthaizides are used in the dose of 50 to 100 mg/day. Clofibrate appear to enhance ADH secretion given in the dose 500 mg four times a day. Carbamazepine an anticonvulsant has been to potentiate release of ADH in the state of partial central DI.

Treatment of nephrogenic DI is more limited because only modalities that act independent of ADH are effective. The recommended treatment is to encourage water intake, eliminate nephrotoxic drugs, and follow salt restriction. Drugs that have been used include thiazide diuretics, NSAID (Indomethacin), Amiloride. NSAID by impairing renal prostaglandins synthesis potentiates ADH action and thus decreases urine volume. Amiloride is primarily used only for lithum-induced DI and acts by blocking entry of lithium into the collecting duct cell, thereby reducing its cellular toxicity.

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Diabetes and Pregnancy: Dr. SK Wangnoo & Dr. KW Yadwad

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

Dr. Subhash Kumar Wangnoo is a Senior Consultant Endocrinologist and Diabetologist for Obesity, Diabetes and Endocrinology (ACODE) in New Delhi.

Dr. Monica Sharma is a Consultant Endocrinologist at Apollo Hospital, New Delhi.

Dr. Asim Siddiqui is a Senior Consultant Endocrinologist at Apollo Hospital, New Delhi.