SIADH

SIADH SYNDROME OF INAPPROPRIATE SECRETION OF ANTI DIURETIC HORMONE 22.12.10

Outline Of The Presentation Introduction Prevalance of hyponatremia ADH SIADH Causes Classification Clinical features Laboratory features Treatment

Introduction Hyponatraemia is the commonest electrolyte abnormality found in hospital inpatients, and is associated with a greatly increased morbidity and mortality. The syndrome of inappropriate antidiuretic hormone (SIADH) is the most frequent cause of hyponatraemia in hospital inpatients. SIADH is the clinical and biochemical manifestation of a wide range of disease processes, and every case warrants investigation of the underlying cause.

Prevalance of hyponatremia A Belgian study reported that the prevalence of mild hyponatraemia (<135 mmol/l) was 4% in a randomly selected control group of healthy elderly patients. The population-based Copenhagen Holter study showed a higher prevalence of 11%, using a slightly higher cut-off of 137 mmol/l . Sajadieh A.AJEM 2009 122 679–686 . Gankam Kengne F.QJOM 2008 101 583–588

A large study of 7965 patients with pneumonia showed that 8% developed hyponatraemia during the course of hospital admission 56% of the patients admitted with subarachnoid haemorrhage develop hyponatraemia, with 20% developing clinically significant drops in plasma sodium concentration to <125 mmol/l Zilberberg MD BMC Pulmonary Medicine 2008 8 16. Sherlock M Endocrinology 2006 64 250–254

ADH: AntiDiuretic Hormone Formed in the supraoptic and paraventricular nuclei of the hypothalamus. Transported to the posterior lobe of the Pituitary Gland and stored. ADH is released in response to an increase in intravascular osmotic pressure, hypovolemia, decrease in pulse pressure, and also in response to fear, pain, anxiety.

Function of ADH ADH increases the permeability of the renal distal tubule and collecting ducts to water. Less free water is excreted in urine Urine volume is decreased Concentration of urine is increased

AVP action is mediated via binding to G protein–coupled V2 receptors on the serosal surface of the principal cell of collecting duct, activation of adenyl cyclase, and insertion into the luminal surface of water channels composed of a protein known as aquaporin 2 .

Syndrome of Inappropriate AntiDiuretic Hormone SIADH is a clinical condition involving excess of ADH secretion. The patient is hyponatremic with a low serum osmolality, which normally would inhibit ADH secretion.

…… .SIADH……. The first step in the diagnosis of SIADH is to differentiate it from other causes of hyponatraemia. Classification of causation is based on clinical and biochemical estimation of extracellular volume status. This divides hyponatraemia into hypovolaemic, euvolaemic and hypervolaemic aetiologies

Cardiac failure or cirrhosis on diuretic therapy Cirrhosis Cardiac failure Nephrotic syndrome Peripheral oedema Ascites Raised JVP Pulmonary oedema Underlying illness Hypervolaemic SIADH ACTH deficiency Hypothyroidism SIADH with ongoing fluid restriction Primary polydipsia Inappropriate fluid replacement Underlying illness Euvolaemic Diuretics Addison's disease Cerebral salt wasting Salt wasting nephropathy GI losses, Mucosal losses, Pancreatitis Sodium depletion post diuretics Dry mucous membranes, Decreased turgor, Tachycardia, Hypotension (orthostatic), Raised urea, rennin Hypovolaemic Urinary Na+>40 mmol/l Urinary Na+<20 mmol/l Clinical signs

Euvolaemic hyponatraemia is the commonest cause of hyponatraemia in hospitalised patients, An important cause of euvolaemic hyponatraemia, which must be excluded before the diagnosis of SIADH can be made, is ACTH deficiency

ACTH deficiency is manifested by cortisol deficiency. Cortisol is necessary for efficent excretion of free water and glucocorticoid deficiency is associated with retention of free water and development of hyponatraemia with a biochemical picture identical to SIADH. Patients with ACTH/cortisol deficiency and hyponatraemia have elevated plasma arginine vasopressin (AVP) concentrations, which further contribute to the tubular reabsorption of water.

Glucocorticoid therapy has been shown to suppress AVP secretion , which allows the excretion of free water and the normalisation of plasma sodium concentrations in patients with ACTH deficiency. Diagnosis can be aided by the fact that patients with ACTH deficiency have a lower serum bicarbonate and aldosterone concentration than those with SIADH

Normal approach followed could be to measure cortisol at 0900 h in all patients with apparent SIADH due to neurosurgical conditions such as traumatic brain injury, subarachnoid haemorrhage, subdural haematoma and intracranial haemorrhage. Commence empirical treatment with glucocorticoids if the reading is inappropriately low for the degree of expected stress–response (<300 nmol/l, and between 300 and 500 nmol/l if clinical suspicion is high). Important clinical clues that neurosurgical patients with apparent SIADH may have acute ACTH deficiency include the presence of hypoglycaemia or hypotension, particularly when the latter is resistant to pressor agents. M J Hannon. European Journal of Endocrinology,2010. Vol 162

Causes of SIADH Malignancy Small cell lung cancer Nasopharyngeal cancer MesotheliomaGI tract malignancy Pancreatic malignancy GU tract malignancy Lymphoma Sarcoma Drugs Desmopressin Selective serotonin reuptake inhibitors Carbamazepine Prostaglandins Tricyclic antidepressants Phenothiazines Haloperidol 3,4-Methylenedioxymethamphetamine Quinolones Leveteiracetam Cyclophosphamide Vincristine

Causes of SIADH Pulmonary Pneumonia, especially Legionella and Mycoplasma Tuberculosis Abscess Vasculitis Positive pressure ventilation Intracranial Tumour Meningitis Encephalitis Abscess Vasculitis Subarachnoid haemorrhage Subdural haemorrhage Traumatic brain injury

Miscellaneous : Multiple sclerosis Guillain–Barre syndrome Acute intermittent porphyria HIV Idiopathic

Classification of SIADH SIADH occurs by definition when AVP secretion is not suppressed when plasma sodium concentration falls below the osmotic threshold for physiological AVP secretion . Zerbe et al . were able to utilise the measurement of plasma AVP with an early RIA to describe four different types of SIADH, defined by the pattern of AVP secretion across a range of plasma osmolalities Zerbe R Annual Review of Medicine 1980 31 315–327

Type A SIADH Commonest form. Occurs in 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 synthesise 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 hyponatraemia. 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 Smith D American Journal of Physiology. Endocrinology and Metabolism 2004 287 E1019–E1023

Type B SIADH 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 overhydration 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 utilised to predict the causation of SIADH.

Type C SIADH Type C is a rare condition characterised 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 neurones in the hypothalamus, leading to persistent low-grade basal AVP secretion

Type D SIADH Type D is a rare clinical picture of SIADH with low or undetectable AVP levels and no detectable abnormality in circulating AVP response. It is thought that a nephrogenic SIADH (NSIAD) may be responsible for this picture. 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. 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

CLINICAL FEATURES Symptoms associated with hyponatraemia are varied, and are generally related to the severity of hyponatraemia, the rate of change in plasma sodium concentration, and the osmotic gradient between intracellular and extracellular fluids. Plasma sodium concentrations between 125 and 130 mmol/l, anorexia, nausea, vomiting and abdominal pain may develop. As plasma sodium concentration falls to between 115 and 125 mmol/l, agitation, confusion, hallucinations, incontinence and other neurological symptoms predominate.

CLINICAL FEATURES Hyponatraemia below 115 mmol/l may induce serious adverse neurological sequelae, such as seizures and coma, due to increased intracranial pressure. If there is intracranial illness, space-occupying lesion or neurosurgical intervention, the onset of symptoms may occur at higher plasma sodium concentrations than usual. In acute hyponatraemia, the main pathological consequence is the development of cerebral oedema, which may lead to raised intracranial pressure, cerebral herniation, hypoxia and even death

Laboratory Evaluation Serum osmolality Serum sodium levels Urine osmolality Urine spot sodium >40mEq/l Fractional excretion of sodium>0.5% FEurea >55% Low urea <30mg/dl Low uric acid

Table 1 Diagnostic criteria for SIADH Essential Plasma osmolality <270 mosmol/kg H2O Inappropriate urinary concentration (Uosm>100 mosmol/kg H2O) Patient is clinically euvolaemic Elevated urinary sodium (>40 mmol/l), with normal salt and water intake Exclude hypothyroidism and glucocorticoid deficiency Supplemental Abnormal water load test, i.e. inability to excrete at least 90% of a 20 ml/kg water load in 4 h and/or failure to dilute urine to Uosm<100 mosmol/kg H2O Plasma AVP levels inappropriately elevated relative to plasma osmolality Tests for supplemental criteria should only be performed in rare situations and in units with expertise in this area as they may aggravate hyponatraemia. Smith DM, McKenna K & Thompson CJ. Hyponatremia. Clinical Endocrinology 2000 52 679–678.

TREATMENT FLUID RESTRICTION Water restriction is regarded as first-line treatment for hyponatraemia due to SIADH In patients in whom there is no question of hypovolaemia, this treatment is safe Fluid restriction of 800–1200 ml/day is generally advised, according to severity of hyponatraemia

As long as background water losses from the kidney, skin and lungs exceed this amount, there is progressive depletion of total body water and a gradual rise in plasma sodium concentration The principal drawback is that patients find it extremely difficult to maintain fluid restriction, as thirst in SIADH is inappropriately normal due to a downward resetting of the osmotic thirst threshold .

Isotonic saline Plasma sodium concentration will rise in some patients with SIADH who are treated with i.v. normal (0.9%) saline, particularly if urine osmolality is <530 mosmol/kg However, treatment with normal saline is generally reserved for patients in whom the differentiation between hypovolaemia and euvolaemia is difficult. In this situation, i.v. saline is a safer first–line treatment than fluid restriction (as fluid restriction may exacerbate hypovolaemic hyponatraemia).

Hypertonic saline If a patient is symptomatic due to a rapid decrease in serum sodium concentration, treatment with hypertonic saline should be considered . Several formulae have been developed to estimate the effect of a given infusate on the serum sodium concentration.

The Adrogué–Madias formula This formula was shown to predict correction rates using hypertonic saline with reasonable accuracy, and is listed below. The formula derives the change in plasma sodium concentration (Δ[Na]) that is produced by 1 l of infusate with given sodium and potassium concentrations ([Na]infusate + [K]infusate) from the present serum sodium concentration and the (new) volume of distribution (total body water + 1).

Simple Rule Of Thumb In order to induce a correction rate of 1 mmol/L per hour, using 3% NaCl, one should infuse the body weight as millilitres per hour (i.e. a man with a body weight of 70 kg will increase by approximately 1 mmol/L per hour when infused with 3% NaCl at a rate of 70 mL/h Verbalis JG Am J Med. 2007;120(Suppl 1):S1–S21

Demeclocycline It is a tetracycline derivative which is utilised in the treatment of SIADH because it causes nephrogenic diabetes insipidus in about 60% of patientS. The mode of action is unknown and may interfere with the vasopressin-aquaporin signalling cascade . The onset of action is also unpredictable, usually occurring after 2–5 days, but occasionally taking longer.

In some patients, polyuria can be profound, and patients can become markedly symptomatic, occasionally developing hypernatraemia if access to water is compromised. Nephrotoxicity can arise, particularly in patients with cirrhosis, and although renal impairment is usually reversible with discontinuation, cases with permanent renal failure have been reported It has also been associated with photosensitive skin rash, leading to discontinuation of treatment and return of symptomatic hyponatraemia.

Lithium It also causes nephrogenic diabetes insipidus in 30% of patients , by downregulation of vasopressin-stimulated aquaporin-2 expression . An even larger proportion of patients have attenuation of maximal urine concentrating ability, and this property of lithium has been utilised by some centres to treat SIADH. Nephrogenic diabetes insipidus is usually but not always reversible , with chronic treatment sometimes producing interstitial nephritis and end-stage renal failure.

The efficacy of lithium is unpredictable. Additional side effects include hypothyroidism, tremor and rarely, hyperparathyroidism. Because of these side effects,the use of lithium to treat SIADH has been mostly abandoned.

Urea It is a major osmotic constituent of urine, accounting for half of the daily osmolar load excreted. Brodsy and Rapoport demonstrated that as solute excretion increases, the osmolality of urine decreases, despite maximal doses of vasopressin . This has led investigators to pursue the effects of increasing free water clearance by administering urea . Urea can be given by mouth, either as a powder or in capsules, and thus results in an osmotic diuresis. Due to its bitter taste, its use has not met wide acceptance. Brodsky WA J Clin Invest. 1951;30:282–291

Extracorporeal treatments Rapid correction of hyponatraemia may occur during haemodialysis, in some instances leading to pontine myelinolysis. Veno-venous haemofiltration has been shown to induce a more gradual correction of hyponatraemia and other forms of slow dialysis treatment, such as slow low-efficiency daily dialysis (SLEDD), may be equally effective. Cost is the limitation.

The vaptans A vasopressin-receptor antagonist Also called as ‘ aquaretics' Vasopressin exerts its antidiuretic effect by binding to the V2 receptors, which are situated in the basolateral surface of the cells of the collecting duct of the kidney. Receptor binding initiates an intracellular cascade which generates adenyl cyclase and an increase of intracellular cAMP. This causes protein synthesis, which leads to the production of mRNA for aquaporin-2, and insertion of pre-formed aquaporin into the apical membrane of the cell, allowing passage of free water across the cell, to be reabsorbed into the renal vasculature The vaptans competitively bind to the V2 receptors, preventing vasopressin-mediated generation of aquaporin-2, thus causing a solute-free aquaresis

V2 receptor antagonists in the treatment of SIADH. Drug Receptor Mode of Name Action administration Tolvaptan V2 Oral Conivaptan V1a and V2 I.v./oral Lixivaptan V2 Oral Mozavaptan V2 Oral Satavaptan V2 Oral V1 and V2, vasopressin receptors 1 and 2.

Indicaton- chronic SIADH and persistently elevated levels of vasopressin . Fluid restriction is usually a burden to the patient, unreliable, impractical and slow to work. Trials and proven data still lacking. Only marketed in Europe and US so far.

Contraindication - severe symptomatic hyponatraemia (serum sodium <120 mmol/L) hypovolaemic forms of hyponatraemia The problem is that volume status is not always easy to estimate clinically. If the sodium concentration in the urine is above 40 mmol/L, in a patient with preserved renal function, normal dietary salt intake and not on diuretics, one can assume with reasonable safety that the patient is not volume depleted.

Diuretic use and adrenal insufficiency should be excluded . Patients with anuria, volume depletion, hypernatraemia or in those who cannot perceive thirst, and, in addition, during pregnancy or breastfeeding also drug is contraindicated

How should treatment be monitored? Occurrence of hypernatraemia Increased thirst secondary to increase in serum osmolality could be limitation thus leading to increase water intake and prevent hypernatremia Discontinuation of a vaptan every 6–8 weeks, in order to observe whether hyponatraemia recurs, before treatment is continued.

SUMMARY SIADH is one of the most common cause of hyponatremia in in-hospital admissions. The patient is hyponatremic with a low serum osmolality, which normally would inhibit ADH secretion. Exclude hypothyroid and adrenal insufficiency. Look at the volume status of the patient.

sodium concentration in the urine >40 mmol/L, with preserved renal function, normal dietary salt intake and not on diuretics, essentially rules out hypovolemic state. Fluid restriction is the main stay of treatment which is practically tough. Hyertonic saline to be preferred in moderate to severe symptomatic hyponatremia . Future medical therapy like vaptans offer better treatment options but still safety and efficacy trials are lacking.

SIADH

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SIADH