Syndrome of inappropriate antidiuretic hormone secretion

Gastro-intestinal • Anorexia (loss of appetite) • Nausea Musculoskeletal • Muscle aches • Generalized muscle weakness Neuro-muscular • Myoclonus • Decreased reflexes • Ataxia • Pathological reflexes • Tremor • Asterixis Respiratory • Cheyne-Stokes respiration Neurological • Dysarthria • Lethargy • Confusion • Delirium • Seizures • Coma (from brain swelling) • Death ==Causes==

Causes of SIADH include conditions that dysregulate ADH secretion in the central nervous system, tumors that secrete ADH, drugs that increase ADH secretion, among other causes. Cancer accounts for an estimated 24% of cases of SIADH, with 25% of those causes due to small cell lung cancer. ==Pathophysiology==

Normally there are homeostatic processes in the body which maintain the concentration of body solutes within a narrow range, both inside and outside cells. The process occurs as follows: in some hypothalamic cells there are osmoreceptors which respond to hyperosmolality in body fluids by signalling the posterior pituitary gland to secrete ADH. This keeps serum sodium concentration – a proxy for solute concentration – at normal levels, prevents hypernatremia and turns off the osmoreceptors. Specifically, when the serum sodium rises above 142 mEq/L, ADH secretion is maximal (and thirst is stimulated as well); when it is below 135 mEq/L, there is no secretion. ADH activates V2 receptors on the basolateral membrane of principal cells in the renal collecting duct, initiating a cyclic AMP-dependent process that culminates in increased production of water channels (aquaporin 2), and their insertion into the cells' luminal membranes. Excessive ADH causes an inappropriate increase in the reabsorption in the kidneys of solute-free water ("free water"): excess water moves from the distal convoluted tubules (DCTs) and collecting tubules of the nephrons – via activation of aquaporins, the site of the ADH receptors – back into the circulation. This has two consequences. First, in the extracellular fluid (ECF) space, there is a dilution of blood solutes, causing hypoosmolality, including a low sodium concentration – hyponatremia. [There is no expansion of the ECF volume because as it attempts to expand, aldosterone is suppressed and atrial natriuretic peptide (ANP) is stimulated: both of these hormones cause isotonic ECF fluid to be excreted by the kidneys sufficient to keep ECF volume at a normal level.] Also, virtually simultaneously to these ECF events, the intracellular space (ICF) volume expands. This is because the osmolality of the ECF is (transiently) less than that of the ICF; and since water is readily permeable to cell membranes, solute-free water moves from the ECF to the ICF compartment by osmosis: all cells swell. Swelling of brain cells – cerebral edema – causes various neurological abnormalities which in acute and/or severe cases can result in convulsions, coma, and death. The normal function of ADH on the kidneys is to control the amount of water reabsorbed by kidney nephrons. ADH acts in the distal portion of the renal tubule (distal convoluted tubule) as well as on the collecting duct and causes the retention of water, but not solute. Hence, ADH activity effectively dilutes the blood (decreasing the concentrations of solutes such as sodium), causing hyponatremia; this is compounded by the fact that the body responds to water retention by decreasing aldosterone, thus allowing even more sodium wasting. For this reason, a high urinary sodium excretion will be seen. The abnormalities underlying type D syndrome of inappropriate antidiuretic hormone hypersecretion concern individuals where vasopressin release and response are normal but where abnormal renal expression and translocation of aquaporin 2, or both are found. It has been suggested that this is due to abnormalities in the secretion of secretin in the brain and that "Secretin as a neurosecretory hormone from the posterior pituitary, therefore, could be the long-sought vasopressin independent mechanism to solve the riddle that has puzzled clinicians and physiologists for decades." Hyponatremia and inappropriately concentrated urine (UOsm >100 mOsm/L) are seen. ==Diagnosis==

Diagnosis is based on clinical and laboratory findings of low serum osmolality and low serum sodium. Urinalysis reveals a highly concentrated urine with a high fractional excretion of sodium (high sodium urine content compared to the serum sodium). A suspected diagnosis is based on a serum sodium under 138. A confirmed diagnosis has seven elements: 1) a decreased effective serum osmolality – <275 mOsm/kg of water; 2) urinary sodium concentration high – over 40 mEq/L with adequate dietary salt intake; 3) no recent diuretic usage; 4) no signs of ECF volume depletion or excess; 5) no signs of decreased arterial blood volume – cirrhosis, nephrosis, or congestive heart failure; 6) normal adrenal and thyroid function; and 7) no evidence of hyperglycemia (diabetes mellitus), hypertriglyceridemia, or hyperproteinia (myeloma). Cerebral salt wasting syndrome (CSWS) also presents with hyponatremia, there are signs of dehydration for which reason the management is diametrically opposed to SIADH. Importantly CSWS can be associated with subarachnoid hemorrhage (SAH) which may require fluid supplementation rather than restriction to prevent brain damage. Most cases of hyponatremia in children are caused by appropriate secretion of antidiuretic hormone rather than SIADH or another cause. ==Treatment==

Managing SIADH depends on whether symptoms are present, the severity of the hyponatremia, and the duration. Management of SIADH includes: Sodium correction should be no greater than 10 mEq/L/day, with a correction no greater than 8 mEq/L/day in those at high risk of osmotic demyelination. • Urea: oral daily ingestion has shown favorable long-term results with protective effects in myelinosis and brain damage. Limitations noted to be undesirable taste and is contraindicated in people with cirrhosis to avoid initiation or potentiation of hepatic encephalopathy. • Conivaptan – an antagonist of both V1A and V2 vasopressin receptors. • Tolvaptan – an antagonist of the vasopressin receptor 2. ==Epidemiology==

40% of all hospitalized adults aged 65 and older have hyponatremia, with an estimated 25–40% of those cases being due to inappropriate antidiuresis. ==History==

Through medullary lesioning in animals, Jungmann and Meyer from Germany induced polyuria and increased urinary salt excretion in 1913. Water intake restriction did not stop the polyuria, and salt continued to be excreted in the urine despite. In 1936, McCance defined the consequences of salt depletion in normal human. Patients with extra-renal salt losses complicated by hyponatremia were found to be common-place, and consistent with McCance's description, they excreted urine virtually free of sodium. In 1950, Sims et al, published their work that suggest observed relation between hyponatremia and pulmonary tuberculosis. Their work suggested that a primary reduction in cellular osmolarity may be the initiating factor in the development of this new syndrome (later called SIADH). The increased excretion of sodium at subnormal concentrations of this ion in the serum might represent an attempt to reduce extracellular tonicity to conform with a reduced cellular osmolarity. An eosinopenia response to epinephrine and the ability to reduce the excretion of sodium on a regime free of salt aids in differentiating this syndrome from Addison's disease. Almost a century after the pioneering work of Claude Bernard (1813–1878) in animals, Peters et al, in 1950, reported three patients seen at Yale New Haven Hospital with hyponatremia associated with varying cerebral pathologies and severe dehydration. In each patient, urine sodium losses persisted despite hyponatremia and a high-salt diet. All three patients were unable to prevent urinary sodium loss despite low serum sodium levels and no evidence of extrarenal sodium loss. Their hyponatremia responded to salt therapy. They postulated that this provided evidence of an extra-pituitary cerebral structure mediating normal sodium metabolism but were unsure of its location or mechanism of action. A subsequent paper from the group at Yale attributed hyponatremia in neurologic disease to SIADH. In 1952, Welt et al, described another six patients with cerebral lesions exhibiting severe clinical dehydration, hyponatremia, a negative sodium balance, but no potassium retention. All responded to sodium chloride administration but administering aldosterone precursor 11-deoxycorticosterone did not reverse renal sodium loss. The authors felt neither pituitary nor adrenal insufficiency was involved, but that direct neural control of renal proximal tubular reabsorption of sodium was disrupted. In 1953, Leaf et al, demonstrated that exogenous administration of the antidiuretic hormone vasopressin resulted in hyponatremia and a natriuresis dependent on water retention and weight gain. This was not "salt wasting"; it was a physiologic response to an expanded intravascular volume. Vasopressin-ADH administration to normal humans was shown to result in water retention and urinary loss of electrolytes (primarily sodium) in other studies at the time. William Schwartz (1922–2009) attended Duke University after serving in the US Army in World War II. He observed that sulfanilamide increased excretion of sodium in patients with heart failure. This observation was the basis for the discovery and development of modern diuretic drugs. Frederic Bartter (1914–1983) worked on hormones affecting the kidney that led to the discovery of syndrome of inappropriate antidiuretic hormone (SIADH) in 1957 and Bartter syndrome in 1963. Schwartz-Bartter syndrome is named after these two scientists. The first reports of hyponatremia and renal sodium loss corrected by fluid restriction in patients with bronchogenic carcinoma were published by Bartter. At that time, no direct measurement of vasopressin was done. In summary, the condition was first described at separate institutions by William Schwartz and Frederic Bartter in two people with lung cancer. ==Society and culture==

The condition is occasionally referred to by the names of the authors of the first report: Schwartz-Bartter syndrome. Because not all people with this syndrome have elevated levels of vasopressin, the term "syndrome of inappropriate antidiuresis" (SIAD) has been proposed as a more accurate description of this condition. ==References==