Sandbox:Vindhya

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2]

SIADH

Definition :The syndrome of inappropriate antidiuretic hormone (SIADH) is characterized by the excessive release of serum antidiuretic hormone (ADH) relative to serum osmolality. It typically results in excessive water reabsorption in the collecting ducts and hyponatremia

Historical perspective: Described by researchers from Boston, Massachusetts and Bethesda, Maryland (including Dr Frederic Bartter) in two patients with lung cancer.[1] Criteria were developed by Schwartz and Bartter in 1967,[2].

Pathogenesis:

Genetics: clinical picture of SIADH may result from genetic disorders that result in antidiuresis. A mutation affecting the gene for the renal V2 receptor, which some investigators have named nephrogenic syndrome of inappropriate antidiuresis, has been found to cause clinically significant hyponatremia. congenital nephrogenic diabetes insipidus is characterized by a resistance of the renal collecting duct to the action of the arginine vasopressin hormone responsible for the inability of the kidney to concentrate urine.He X-linked form is due to inactivating mutations of the vasopressin 2 receptor gene leading to a loss of function of the mutated receptors.conversely, the nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is linked to a constitutive activation of the V(2)-receptor due to activating mutations with clinical and biological features of inappropriate antidiuresis but with low or undetectable plasma arginine vasopressin hormone levels.

Causes: Intracranial:

• Tumor
• meningitis
• encephalitis
• abscess
• vasculitis
• subarachnoid hemorrhage
• subdural hemorrhage
• traumatic brain injury

Drugs :

• amiodarone
• tricyclic antidepressants
• bromocriptine
• quinolones
• chlorpropamide
• carbamazapine
• cyclophosphamide
• cisplatin
• SSRI
• vincristine
• vinblastine
• thioridazine
• thiothixene
• haloperidol
• MAOI
• melphalan
• methotrexate
• opiates
• NSAID
• IFN-alpha
• IFN-gamma
• clofibrate
• oxytocin
• hydrochlorthiazide
• desmopressin
• neuroleptic agents
• prostaglandins
• phenothiazines
• 3,4-methylenedioxymethamphetamines
• leveteiracetam

• Pulmonary disease: particularly pneumonia (leigonella ,mycoplasma, tuberculosis),abscess,vasculitis.

• Malignancy:
• small cell lung cancer
• pancreatic
• genitourinary
• gastrointestinal
• mesothelioma
• lymphoma
• sarcoma

• Miscellaneous:
• Multiple sclerosis
• Guillian barre syndrome
• Acute intermittent porphyria
• HIV
• Idiopathic
• surgery
• hormone deficiency: hypopituitirarism,hypothyroidism

6 Zilberberg MD, Exuzides A, Spalding J, Foreman A, Jones AG, Colby C & Shorr AF. Hyponatremia and hospital outcomes among patients with pneumonia: a retrospective cohort study. BMC Pulmonary Medicine 2008 8 16. 7 Sherlock M, O’Sullivan E, Agha A, Behan LA, Rawluk D, Brennan P, Tormey W & Thompson CJ. The incidence and pathophysiology of hyponatraemia after subarachnoid haemorrhage. Clinical Endocrinology 2006 64 250–254.

Classification

four different types of SIADH, defined by the pattern of AVP secretion across a range of plasma osmolalities.

Type A :is the commonest form of SIADH responsible for a much higher proportion of SIADH, at around 60–70%. Characteristically, type A patients exhibit excessive, random secretion of AVP, with loss of the close linear relationship between plasma osmolality and plasma AVP. Type A is common in lung cancer; in vitro studies have demonstrated that some lung tumours synthesize AVP, and that tumour tissue stains positive for AVP mRNA.Plasma AVP concentrations in type A SIADH are not suppressed physiologically by drinking , which makes patients vulnerable to the development of severe hyponatremia. Studies have also demonstrated a lower osmotic threshold for thirst appreciation in this type of SIADH. This type of SIADH is also characteristic of nasopharyngeal tumours, which also stain positive for AVP mRNA.

Type B: is also common (20–40%). The osmotic threshold for AVP release is lowered – a ‘reset osmostat’ – such that secretion of AVP occurs at lower plasma osmolalities than normal. Because AVP is suppressed at plasma osmolalities below the lower, reset threshold, further over-hydration leads to suppression of AVP release, which protects against the progression to severe hyponatraemia. Although most tumours manifest type A SIADH, some also present with type B SIADH, so the pattern of abnormal AVP secretion cannot be utilized to predict the causation of SIADH.

Type C :is a rare condition characterized by failure to suppress AVP secretion at plasma osmolalities below the osmotic threshold. Plasma AVP concentrations are thus inappropriately high at low plasma osmolalities, but there is a normal relationship between plasma osmolality and plasma AVP at physiological plasma osmolalities. This variant may be due to dysfunction of inhibitory neurons in the hypothalamus, leading to persistent low-grade basal AVP secretion.

Type D: is a rare clinical picture of SIADH with low or undetectable AVP levels and no detectable abnormality in circulating AVP response (45). It is thought that a nephrogenic SIADH (NSIAD) may be responsible for this picture (46). Gain-of-function mutations in the V2 receptor leading to a clinical picture of SIADH, with undetectable AVP levels, have been described. The identified mutations had different nucleotide substitutions causing different levels of V2 receptor activation (46). This syndrome appears to be inherited in an X-linked manner,although heterozygous females may have varying degrees of inappropriate antidiuresis. Owing to variable expressivity of the gene involved, NSIAD may be clinically undetectable for years, until other contributing factors in later life lead to clinically significant hyponatraemia .

6 Zilberberg MD, Exuzides A, Spalding J, Foreman A, Jones AG, Colby C & Shorr AF. Hyponatremia and hospital outcomes among patients with pneumonia: a retrospective cohort study. BMC Pulmonary Medicine 2008 8 16. 7 Sherlock M, O’Sullivan E, Agha A, Behan LA, Rawluk D, Brennan P, Tormey W & Thompson CJ. The incidence and pathophysiology of hyponatraemia after subarachnoid haemorrhage. Clinical Endocrinology 2006 64 250–254. 8 Sherlock M, O’Sullivan E, Agha A, Behan LA, Owens D, Finucane F, Rawluk D, Tormey W & Thompson CJ. Incidence and pathophysiology of severe hyponatraemia in neurosurgical patients. Postgraduate Medical Journal 2009 85 171–175.

• Signs and symptoms:

In patients with SIADH there is too much water in the blood,this leads to low sodium in the body.

Hyponatremia is the most common manifestation. The symptoms are based on level of sodium.(hyponatremia: sodium level below 135meq/l)

When symptoms do occur, they may include any of the following:

• headache

• altered mental status

• frequent falls

• neurological manifestations such as lethargy, confusion...

in severe cases,seizures and coma may result.

Diagnostic criteria of SIADH:

• Na<135mmol/litre
• decreased effective serum osmolality<275mosm/kg
• urine osmolality>100mosm/kg
• presence of underlying disorders;CNS,pulmonary,malignancies,medications
• normal adrenal and thyroid function
• urine Na concentration>40mmol/l,unless taking diuretics,(or) on a severe salt restriction.
• absence of edematous diseases(such as heart failure,nephrotic syndrome, liver cirrhosis)

Agents and means used in the treatment of SIADH.

Indirect modalities:

• treatment of underlying pathology
• salt restriction
• Hyper-tonic saline
• Loop diuretics
• Urea
• Demecloclycline, lithium
• Hemodialysis, CVVH(continuous veno-venous hemofiltration), SLED(slow, low-efficiency daily dialysis).

Direct modalities:

"Vaptan drugs": block action of vasopressin at it's receptors,(V1A,V1B,V2)

Prognosis:Patients with SIADH have different characteristics and a different prognosis according to SIADH etiology. Serum sodium concentration at short-term follow-up is predictive of long-term survival. These findings might have diagnostic and treatment-related implications. PMID:26563934