University of Babylon



|Diabetes insipidus |

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|This uncommon disorder is characterised by the persistent excretion of excessive quantities of dilute urine and by thirst. |

|Diabetes insipidus is classified into two types: |

|cranial diabetes insipidus, in which there is deficient production of ADH by the hypothalamus |

|nephrogenic diabetes insipidus, in which the renal tubules are unresponsive to ADH. |

|Causes of diabetes insipidus |

|Cranial |

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|Structural hypothalamic or high stalk lesion |

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Idiopathic Genetic defect

|Dominant (AVP gene mutation) |

|Recessive (DIDMOAD syndrome-association of diabetes insipidus with diabetes mellitus, optic atrophy,|

|deafness) |

Nephrogenic Genetic defect

|V2 receptor mutation |

|Aquaporin-2 mutation |

|Cystinosis |

Metabolic abnormality

|Hypokalaemia |

|Hypercalcaemia |

Drug therapy

|Lithium |

|Demeclocycline |

Poisoning

|Heavy metals |

Chronic kidney disease

|Polycystic kidney disease |

|Sickle-cell anaemia |

|Infiltrative disease |

|Clinical features |

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|The most marked symptoms are polyuria and polydipsia. The patient may pass 5-20 L or more of urine in 24 hours. This is of |

|low specific gravity and osmolality. If the patient has an intact thirst mechanism, is conscious and has access to oral |

|fluids, then he or she can maintain adequate fluid intake. However, in an unconscious patient or a patient with damage to |

|the hypothalamic thirst centre, diabetes insipidus is potentially lethal. If there is associated cortisol deficiency, then |

|diabetes insipidus may not be manifest until glucocorticoid replacement therapy is given. The most common differential |

|diagnosis is primary polydipsia, caused by drinking excessive amounts of fluid in the absence of a defect in ADH or thirst |

|control. |

|Investigations |

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|Diabetes insipidus can be confirmed if serum ADH is undetectable or the urine is not maximally concentrated (i.e. is < 600 |

|mOsm/kg) in the presence of increased plasma osmolality (i.e. > 300 mOsm/kg). Sometimes, the diagnosis can be confirmed or |

|refuted by random simultaneous samples of blood and urine, but more often a dynamic test is required. The water deprivation|

|test is widely used, but an alternative is to infuse hypertonic (5%) saline and measure ADH secretion in response to |

|increasing plasma osmolality. Thirst can also be assessed during these tests on a visual analogue scale. |

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|How and when to do a water deprivation test |

|Use |

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|To establish a diagnosis of diabetes insipidus, and differentiate cranial from nephrogenic causes |

Protocol

|No coffee, tea or smoking on the test day |

|Free fluids until 0730 hrs on the morning of the test, but discourage patients from 'stocking up' |

|with extra fluid in anticipation of fluid deprivation |

|No fluids from 0730 hrs |

|Attend at 0830 hrs for body weight, plasma and urine osmolality |

|Record body weight, urine volume, urine and plasma osmolality and thirst score on a visual analogue |

|scale every 2 hrs for up to 8 hrs |

|Stop the test if the patient loses 3% of body weight |

|If plasma osmolality reaches > 300 mOsm/kg and urine osmolality < 600 mOsm/kg, then administer DDAVP|

|(see text) 2 μg i.m. |

Interpretation

|Diabetes insipidus is confirmed by a plasma osmolality > 300 mOsm/kg with a urine osmolality < 600 |

|mOsm/kg |

|Cranial diabetes insipidus is confirmed if urine osmolality rises by at least 50% after DDAVP |

|Nephrogenic diabetes insipidus is confirmed if DDAVP does not concentrate the urine |

|Primary polydipsia is suggested by low plasma osmolality at the start of the test |

In primary polydipsia, the urine may be excessively dilute because of chronic diuresis which 'washes out' the solute gradient across the loop of Henle, but plasma osmolality is low rather than high. DDAVP should not be administered to patients with primary polydipsia, since it will prevent excretion of water and risks severe water intoxication if the patient continues to drink fluid to excess. In nephrogenic diabetes insipidus appropriate further tests include plasma electrolytes, calcium and investigation of the renal tract

|Management |

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|Treatment of cranial diabetes insipidus is with des-amino-des-aspartate-arginine vasopressin (desmopressin, DDAVP), an |

|analogue of ADH which has a longer half-life. DDAVP is usually administered intranasally. An oral formulation is also |

|available but bioavailability is low and rather unpredictable. In sick patients, DDAVP should be given by intramuscular |

|injection. The dose of DDAVP should be adjusted on the basis of serum sodium concentrations and/or osmolality. The |

|principal hazard should be excessive treatment resulting in water intoxication and hyponatraemia. Conversely, inadequate |

|treatment results in thirst and polyuria. The ideal dose prevents nocturia but allows a degree of polyuria from time to |

|time before the next dose (e.g. DDAVP nasal dose 5 μg in the morning and 10 μg at night). |

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|The polyuria in nephrogenic diabetes insipidus is improved by thiazide diuretics (e.g. bendroflumethiazide 5-10 mg/day), |

|amiloride (5-10 mg/day) and NSAIDs (e.g. indometacin 15 mg 8-hourly), although the last of these carries a risk of reducing|

|glomerular filtration rate. |

|DISEASES AFFECTING MULTIPLE ENDOCRINE GLANDS |

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|Multiple endocrine neoplasia (MEN) |

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|These rare autosomal dominant syndromes are characterised by hyperplasia and formation of adenomas or malignant tumours in |

|multiple glands. They fall into two groups, Some other genetic diseases also have an increased risk of endocrine tumours; for |

|example, phaeochromocytoma is associated with von Hippel-Lindau syndrome and neurofibromatosis type 1. |

|Multiple endocrine neoplasia (MEN) syndromes |

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|MEN 1 (Werner's syndrome) |

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|Primary hyperparathyroidism |

|Pituitary tumours |

|Pancreatic neuro-endocrine tumours (insulinoma, gastrinoma) |

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MEN 2 (Sipple's syndrome)

|Primary hyperparathyroidism |

|Medullary carcinoma of thyroid |

|Phaeochromocytoma |

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In addition, in MEN 2b syndrome there are phenotypic changes (including marfanoid habitus, skeletal abnormalities, abnormal dental enamel, and multiple mucosal neuromas).

|MEN syndromes should be considered in all patients with two or more endocrine tumours and in patients with solitary tumours|

|who report other endocrine tumours in their family. MEN 1 results from inactivating mutations in MENIN, a tumour suppressor|

|gene on chromosome 11, whereas MEN 2 is caused by mutations in the RET proto-oncogene on chromosome 10. This causes |

|constitutive activation of the membrane-associated tyrosine kinase RET, which controls the development of cells that |

|migrate from the neural crest. Different mutations causing loss of function of the RET kinase are associated with |

|Hirschsprung's disease . Genetic testing can be performed on relatives of affected individuals, after appropriate |

|counselling . |

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|Individuals who carry mutations associated with MEN should be entered into a surveillance programme. In MEN 1, this |

|typically involves annual history, examination and measurements of serum calcium, gastrointestinal hormones and prolactin;|

|MRI of the pituitary is performed at less frequent intervals. In individuals with MEN 2, annual history, examination and |

|measurement of serum calcium and urinary catecholamine metabolites should be performed. Because the penetrance of medullary|

|carcinoma of the thyroid is 100% in individuals with a RET mutation, prophylactic thyroidectomy should be performed in |

|early childhood. |

|Autoimmune polyendocrine syndromes (APS) |

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|Two distinct autoimmune polyendocrine syndromes are known: APS types 1 and 2. |

|Autoimmune polyendocrine syndromes (APS)* |

|Type 1 (APECED) |

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|Addison's disease |

|Hypoparathyroidism |

|Type 1 diabetes |

|Primary hypothyroidism |

|Chronic mucocutaneous candidiasis |

|Nail dystrophy |

|Dental enamel hypoplasia |

Type 2 (Schmidt's syndrome)

|Addison's disease |

|Primary hypothyroidism |

|Graves' disease |

|Pernicious anaemia |

|Primary hypogonadism |

|Type 1 diabetes |

|Vitiligo |

|Coeliac disease |

|Myasthenia gravis |

|The most common is APS type 2 (Schmidt's syndrome) which typically presents in women between the ages of 20 and 60. It is |

|usually defined as the occurrence in the same individual of two or more autoimmune endocrine disorders, The mode of |

|inheritance is autosomal dominant with incomplete penetrance and there is a strong association with HLA-DR3 and CTLA-4. APS |

|type 2 may be further subdivided, depending on the precise combination of endocrine disorders observed, but this is of |

|limited value. |

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|APS type 1, which is also termed autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is much rarer and|

|is inherited in an autosomal recessive fashion. It is caused by mutations in the autoimmune regulator gene (AIRE). AIRE is |

|responsible for the presentation of self-antigens to thymocytes in utero, which is essential for the deletion of thymocyte |

|clones that react against self-antigens and hence for the development of immune tolerance . |

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