Diabetes Insipidus & ADH hypersecretion Dr. Abdulmoein Eid Al-Agha Assistant Professor & Consultant Pediatric Endocrinologist, King AbdulAziz University & Dr. Erfan Hospital - Jeddah

The Pituitary Gland

The pituitary composed of 2 lobes: –anterior lobe “ adenohypophysis” –posterior lobe “neurohypophysis” Posterior Pituitary: Hormones synthesized in the hypothalamus are transported down the axons to the endings in the posterior pituitary Hormones are stored in vesicles in the posterior pituitary until release into the circulation Principal Hormones: Vasopressin & Oxytocin

Posterior Pituitary Hormones Antidiuretic Hormone (ADH) ADH is a polypeptide hormone, synthesized in the supraoptic & paraventricular nuclei in the hypothalamus &is released in response to a number of stimuli ADH is rapidly metabolized in the liver and kidneys and has a half-life of minutes The primary effect of ADH is to increase water retention by the kidney The result of this is to decrease urine volume and increase the volume of extracellular fluid

Hypothalamic regulation of the Posterior pituitary lobe The posterior pituitary secretes oxytocin & (ADH), both are synthesized in the supraoptic & para- ventricular nuclei of the hypothalamus They are transported to the posterior pituitary through axons of the same neurons that produced them

Posterior Pituitary: Regulation of Osmolality Plasma Osmolality is monitored by osmoreceptor in the hypothalamus Increases in plasma Osmolality stimulates secretion of vasopressin Small changes above the normal plasma osmotic pressure (290 mosm/kg) stimulate release of vasopressin

ADH is released by the posterior pituitary when – water deprivation causes increased plasma Osmolality – the cardiovascular system is challenged by hypovolemia and/or hypotension Functions: increases the passive water permeability of the cell membrane of the nephron collecting ducts Is a potent vasoconstrictor is a neurotransmitter in CNS regulation of –the secretion of ACTH –the cardiovascular system, –temperature and other visceral functions. Promotes hemostasis – the release of endothelial coagulation factors. – increases platelet aggregability

Water regulation 1)Osmoreceptors are neurons in the CNS 2)Baroreceptors in left atrium, left ventricle, and pulmonary veins sense blood volume (filling pressures), and baroreceptors in the carotid sinus and aorta monitor arterial blood pressure

What are the differences between the V1 & V2 receptors? Vasopressin has antidiuretic activity mediated by V2 receptor on renal tubule cells Also has vasopressor actions mediated by the V1 receptor on vascular smooth muscle cells Causes constriction Production of ADH is regulated by the Osmolarity of the circulating blood When the fluid content of the blood is high in comparison to the concentration of solute, ADH production will decrease

The word diabetes is derived from the Greek verb diabainein, which means to stand with legs apart, as in urination, or to go through Diabetes mellitus (DM), which describes the excretion of sweet urine Diabetes insipidus (DI) describes the passing of tasteless urine because of its relatively low sodium content Central diabetes insipidus is due to defective ADH secretion from posterior pituitary gland Nephrogenic diabetes insipidus can occur when kidneys are unable to properly respond to ADH hormone

Causes of central DI Secretion of vasopressin is regulated at the paraventricular & supraoptic nuclei, which sense changes in osmolarity Destruction of the paraventricular or supraoptic nuclei or of the posterior pituitary results in decreased vasopressin secretion –Brain tumor – pituitary / cranial surgery – closed head trauma – granulomatous disease –Histiocytosis X – CNS infections DI may be idiopathic or inherited either as an autosomal dominant or as autosomal recessive trait (locus 20p13)

Nephrogenic DI (NDI) NDI arises from defective or absent receptor sites at the cortical collecting duct segment of the nephron (X- linked, vasopressin V2 receptor deficiency, locus Xq28) or defective or absent aquaporin, the protein that transports water at the collecting duct (autosomal recessive, locus 12q13) The X-linked variety of NDI accounts for about 90% of all cases Aquaporin enhances water entry into the cell from the lumen Absence of the vasopressin receptor does not allow this process to take place, causing inhibition of water uptake and polyuria Alternatively, defective or absent aquaporin impairs the process in the presence of normal V2 receptors

Signs and symptoms The most common symptom of diabetes insipidus are: –Polydepsia –Polyuria –Nocturia & bed-wetting Infants and young children who have diabetes insipidus may have the following signs and symptoms: –Unexplained fussiness or inconsolable crying –Unusually wet diapers –Unexplained fever –Dry skin with cool extremities

Diabetes insipidus can cause dehydration which can cause: –Dry mouth –Muscle weakness –Hypotension (low blood pressure) –Sunken appearance of the eyes Rapid heart rate Weight loss Diabetes insipidus can also cause an electrolyte imbalance (Hypernatremia& hyperchloremia) Electrolyte imbalance can cause symptoms such as headache, fatigue, irritability and muscle pains Seizure secondary to Hypernatremia can happen

Complications Growth failure Nocturia and enuresis Hypernatremic dehydration Seizures Mental retardation

Diagnostic Studies Diagnosis should be suspected in any patient with sudden increased thirst & urination Laboratory examination will reveal very diluted urine, made up mostly of water with no solute Examination of the blood will reveal very concentrated blood, high in solute and low in fluid volume –The serum sodium may be as high as 170 mEq/L –Specific gravity of < (low) –Urine osmolality of < 100 mOsm/kg (low) –Serum osmolality > 290 mOsm/kg (High)

A water deprivation test may be performed In children, the water deprivation test is performed under close medical supervision so that they don't lose more than 5 % of their body weight during the test The test is stopped when: –patient has lost > 5% of original body weight –patient has reached certain limits of low blood pressure & increased heart rate –urine is no longer changing significantly from one sample to the next in terms of solute concentration The next step of the test involves injecting a synthetic form of ADH, with one last urine sample examined 60 minutes later –Comparing plasma and urine osmolarity allows to diagnose either central DI, Nephrogenic DI, partial DI, or psychogenic polydepsia

Treatment Desmopressin –(DDAVP) –(desamino-desarginino-vasopressin) –V2-selective analogue –Little V1 (vasoconstrictor) activity –Drug of choice in Diabetes insipidus Administration: –Oral, sub-cut, nasal spray

Syndrome of Inappropriate antidiuretic Hormone (SIADH)

The syndrome of inappropriate secretion of ADH (SIADH) is characterized by the non-physiologic release of ADH, resulting in impaired water excretion with normal sodium excretion SIADH is associated with disease that affect osmoreceptor in the hypothalamus SIADH is characterized by: –fluid retention –serum hypo-osmolarity –dilutional hyponatraemia –hypchloremia –concentrated urine in the presence of normal or increased intravascular volume –normal renal function

Symptoms are headache, nausea, vomiting, abnormal neurological signs and impaired consciousness In severe cases there can be coma & death Neurological signs may be present if hyponatraemia is severe or if it develops rapidly These signs include: – Cheyne-Stokes respiration, drowsiness, disorientation, delirium, seizures, and coma Hyponatraemia and hypo-osmolarity lead to acute edema of the brain cells An increase in brain water content of more than 5-10% is incompatible with life

Associated clinical manifestations correlate with serum sodium levels –initially thirst, dyspnea on exertion, fatigue and changed sensorium –as serum sodium falls below 120mEq/l symptoms are more severe with vomiting abdominal cramps, muscle twitching Seizures Diagnosis of SIADH is made by simultaneous measurement of urine & serum osmolarity –A serum osmolarity lower than the urine osmolarity indicates the inappropriate excretion of concentrated urine in the presence of very dilute serum –Dilutional hyponatraemia is indicated by serum sodium –other Labs include decreased BUN, creatinine

Causes The causes of SIADH are as follows: Increased hypothalamic production –Infections - Meningitis, encephalitis, abscess –Vascular - Thrombosis, subarachnoid or subdural hemorrhage –Neoplasm –Other - HIV, Guillain-Barré syndrome, acute intermittent porphyria, autonomic neuropathy, post–pituitary surgery, multiple sclerosis, psychosis –Drugs Chemotherapeutic - Cyclophosphamide, vincristine, vinblastine Antipsychotic - Thiothixene, thioridazine, haloperidol Antidepressants - Monoamine oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors Miscellaneous – Bromocriptine –Pulmonary diseases, Pneumonia, Tuberculosis, Acute respiratory failure,Positive pressure ventilation, Asthma & Atelectasis –Postoperative complications –Idiopathic

Treatment If symptoms are mild & serum sodium >125 meq: –treatment may be fluid restriction of ml/day –This restriction should result in a gradual daily reduction in weight, progressive rise in serum sodium concentration and osmolality, and symptomatic improvement If fluid restriction alone does not improve the symptoms –3-5% saline solution (hypertonic) is administered IV & diuretic therapy may be indicated to promote diuresis

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