Approach

The approach to the patient with hyponatraemia involves using a combination of clinical assessment and measurements of serum osmolality and urinary sodium. The cause is often apparent from the history and examination, but other conditions can only be diagnosed with the use of targeted investigations. The most common cause is syndrome of inappropriate antidiuretic hormone secretion (SIADH). However this is a diagnosis of exclusion. Cerebral salt-wasting syndrome produces a hypovolaemic clinical picture, with a high urine output and normal or low urine osmolality. By contrast, SIADH produces a euvolaemic clinical picture with a low urine output and increased urine osmolality. However, there are no clearly defined thresholds, and controversy exists as to whether the distinction between these 2 conditions is possible or meaningful.

A rapid decline in serum sodium levels over 24 to 48 hours can lead to severe cerebral oedema and central nervous system symptoms including headache, muscle cramps, reversible ataxia, psychosis, lethargy, apathy, anorexia, and agitation. This is an acute medical emergency. If no acute intervention is initiated to increase sodium level, patients can develop coma, brainstem herniation, and respiratory arrest, leading to death.

A slower decline in sodium levels over several days or weeks is usually asymptomatic; when it is symptomatic, it produces milder cerebral oedema, which does not lead to brainstem herniation.

Establishing the type of hyponatraemia

The first step is to measure effective serum osmolality (tonicity). If it is normal (275-295 mOsm/kg H₂O (275-295 mmol/kg H₂O)), the patient has pseudohyponatraemia (isotonic hyponatraemia), which is an artifact produced by high serum lipid or protein levels. Newer electrodes measure sodium directly and the measured sodium concentration will be normal if these electrodes are used. The most common cause of high protein levels is multiple myeloma; this diagnosis is already known in the majority of patients.

If the serum osmolality is >295 mmol/kg H₂O (>295 mOsm/kg H₂O), the patient has redistributive hyponatraemia (hypertonic), which is either due to hyperglycaemia or to the absorption or administration of a hypertonic fluid (e.g., mannitol, glycine, or sorbitol).

  • Hyperglycaemia is usually caused by diabetes but can also be caused by medications (beta-blockers, thiazide diuretics, corticosteroids, nicotinic acid, pentamidine, protease inhibitors, some antipsychotics) or by stress from a recent stroke, myocardial infarction, trauma, infection, or inflammation. A fasting or random serum glucose measurement establishes hyperglycaemia as the cause. The serum HbA1c is elevated in people with poorly controlled diabetes and may also be useful. Medication-induced hyponatraemia and hyperglycaemia should resolve once the causative agent is discontinued.

  • Hypertonic hyponatraemia due to mannitol, glycine, or sorbitol is usually easily established by examination of fluids administered intravenously or fluids used to irrigate the operative field during transurethral resection of prostate or hysteroscopy. However, it can be confirmed by calculation of the serum osmolar gap.[ Osmolal Gap Calculator (SI units) ] A difference of >10 indicates the presence of non-sodium effective osmoles such as mannitol, glycine, or sorbitol.

If the serum osmolality is <275 mmol/kg H₂O (<275 mOsm/kg H₂O), the patient has hypotonic hyponatraemia (hypovolaemic, euvolaemic, or hypervolaemic).

  • Patients with hypovolaemic hyponatraemia will have signs of volume depletion (decreased skin turgor, reduced jugular venous pressure, decreased blood pressure).

  • Patients with hypervolaemic hyponatraemia will have an elevated jugular venous pressure and peripheral oedema.

  • The absence of any of these signs indicates that the patient is euvolaemic.

Because hyponatraemia can arise in hypervolaemic, euvolaemic, and hypovolaemic states, hyponatraemia and its cause may not initially be clear.[24] The most important test to identify the aetiology in patients with hypovolaemic hypotonic hyponatraemia, euvolaemic hypotonic hyponatraemia, or hypervolaemic hypotonic hyponatraemia is measurement of urinary sodium. A spot urinary sodium test is available that allows urinary sodium to be quickly and conveniently measured in a random urine sample.

  • Hypovolaemic hyponatraemia: urinary sodium >20 mmol/L (>20 mEq/L) indicates renal sodium losses and urinary sodium ≤20 mmol/L (≤20 mEq/L) indicates extrarenal sodium losses.

  • Hypervolaemic hyponatraemia: urinary sodium >20 mmol/L (>20 mEq/L) suggests chronic renal failure and a urinary sodium ≤20 mmol/L (20 mEq/L) suggests oedematous disorders such as heart failure, cirrhosis, or nephrotic syndrome.

  • Patients with euvolaemic hyponatraemia always have a urinary sodium >20 mmol/L (>20 mEq/L).com.bmj.content.model.assessment.Caption@20e2880b[Figure caption and citation for the preceding image starts]: Algorithm for the diagnosis of hypotonic hyponatraemia. SIADH, syndrome of inappropriate antidiuretic hormoneProduced by the BMJ Knowledge Centre [Citation ends].

It is also important to measure urine osmolality. Urine osmolality is <100 mmol/kg H₂O (<100 mOsm/kg H₂O) in cases of excessive water intake, but >100 mmol/kg H₂O (>100 mOsm/kg H₂O) in all other causes. However, in general, urine osmolality is measured primarily to assess disease severity and is not useful for elucidating the underlying cause. It should be noted that causes such as endocrinopathies (glucocorticoid deficiency), potassium depletion, and diuretic use may present with either a euvolaemic or hypovolaemic state depending on the severity of the disease.

Hypovolaemic hyponatraemia with urinary sodium >20 mmol/L (>20 mEq/L)

Thiazide diuretics

  • The hyponatraemia may appear within days or even years of starting the medication, and will resolve once thiazide diuretics have been discontinued.

Renal disease

  • Salt-wasting nephropathy should be considered as a cause in all patients with hypovolaemic hyponatraemia with a urinary sodium >20 mmol/L (>20 mEq/L). Many patients will have a known diagnosis or a positive family history of tubulointerstitial disease (interstitial nephritis, medullary cystic kidney disease, partial urinary tract obstruction, and polycystic kidney disease). Salt-wasting nephropathy often precedes the onset of renal failure in these conditions. An abdominal mass is often present in polycystic kidney disease. Patients with medullary cystic kidney disease have early signs of severe anaemia such as pallor.

  • The serum creatinine may be normal or elevated with a normal or reduced glomerular filtration rate. Urinalysis reveals haematuria and/or proteinuria, depending on the underlying cause. Renal ultrasound will detect obstruction, hydronephrosis, kidney stones, or cysts. Contrast-enhanced abdominal CT scanning is a more definitive imaging tool for assessing the number, size, and location of the cysts in polycystic kidney disease and medullary cystic kidney disease. Genetic testing is the definitive method for distinguishing these conditions. Renal biopsy is required for the definitive diagnosis of interstitial nephritis, and should be considered in consultation with a renal specialist.

Central nervous system cause

  • If there is a history of recent head injury, intracranial surgery, subarachnoid haemorrhage, stroke, or brain tumours, cerebral salt-wasting syndrome should be considered as the cause. These conditions can also cause SIADH, but SIADH causes euvolaemic hyponatraemia and is a diagnosis of exclusion. A complete history and central nervous system examination should identify the cause.

  • A CT scan brain will identify signs of haemorrhage or skull fractures. An MRI brain is the preferred modality to detect intracranial tumours and to assess ischaemic stroke once haemorrhagic stroke has been excluded by CT.

Mineralocorticoid deficiency

  • Should also be excluded as a cause. Symptoms and signs are usually non-specific and include nausea, vomiting, myalgia, arthralgia, and clinical signs of volume depletion.

  • Serum potassium is usually elevated. A decreased morning serum cortisol is diagnostic. A decreased cortisol response to adrenocorticotropic hormone is seen.

Hypovolaemic hyponatraemia with urinary sodium ≤20 mmol/L (≤20 mEq/L)

This is produced by inappropriate replacement of extrarenal sodium and fluid losses with hypotonic fluids. This may be caused by replacement of excessive sweating (often due to prolonged exercise in a hot environment) by oral tap water or by intravenous hypotonic fluids. These causes are evident from the history and examination of fluid charts.

Other causes of fluid loss that may prompt inappropriate fluid replacement include vomiting, diarrhoea, gastrointestinal fistulas or drainage tubes, and third spacing of fluids caused by peritonitis, pancreatitis, burns, or small bowel obstruction.

Hypervolaemic hyponatraemia with urinary sodium ≤20 mmol/L (≤20 mEq/L)

Congestive heart failure

  • A history of myocardial infarction should prompt consideration of congestive heart failure. Symptoms include fatigue, decreased exercise tolerance, dyspnoea on exertion, orthopnoea, and paroxysmal nocturnal dyspnoea. Clinical signs include oedema, displaced cardiac apex, hepatojugular reflux, jugular venous distension, S3 gallop, pulmonary rales, and hepatomegaly.

  • Chest x-ray may show cardiomegaly, pulmonary oedema, or a pleural effusion. Elevated natriuretic peptide biomarkers (B-type and N-terminal pro-B-type) are a strong indicator for decompensated congestive heart failure.[25] An ECG may show anterior Q waves (indicating a previous myocardial infarction), bundle branch block, atrial arrhythmias, ventricular arrhythmias, left axis deviation, or left ventricular hypertrophy. An echocardiogram detects systolic and diastolic dysfunction. Valve lesions, signs of pericardial injury, or cardiomyopathy may also be seen.

Liver cirrhosis

  • A history of alcohol misuse, intravenous drug use, unprotected intercourse, obesity, blood transfusion, or known hepatitis infection should prompt suspicion of cirrhosis. Cirrhosis severe enough to cause hypervolaemic hyponatraemia is usually symptomatic. Symptoms include fatigue, weakness, weight gain, and pruritus. Signs include oedema, jaundice, ascites, collateral circulation, hepatosplenomegaly, leukonychia, palmar erythema, spider angiomata, telangiectasia, jaundiced sclera, hepatic fetor, and altered mental status.

  • LFTs are abnormal, and the pattern depends on the cause of cirrhosis.

  • An abdominal ultrasound can be used to detect signs of advanced cirrhosis such as liver surface nodularity, small liver, possible hypertrophy of left/caudate lobe, ascites, splenomegaly, and increased diameter of the portal vein (≥13 mm) or collateral vessels. Liver biopsy provides a definitive diagnosis, but is only necessary if the diagnosis cannot be established based on clinical features, investigations, and imaging.

Nephrotic syndrome

  • Should be suspected if there is a history of long-standing diabetes, malignancy, systemic lupus erythematosus, HIV infection, multiple myeloma, connective tissue diseases, or amyloidosis, or use of known causative medications (pamidronate, lithium, gold, penicillamine, or non-steroidal anti-inflammatory drugs, and, very rarely, interferon alfa, heroin, mercury, or formaldehyde). Patients present with leg or generalised oedema and foamy urine. Patients may also have Muehrcke's lines (due to hypoalbuminaemia) or xanthelasmas (due to hypertriglyceridaemia).

  • Serum albumin levels are low. The plasma creatinine may be normal or elevated depending on the stage of disease. A 24-hour urine collection for protein shows nephrotic range proteinuria (>3 g/24 hours). Renal biopsy is required for the definitive diagnosis of many of the underlying causes, and should be considered in consultation with a renal specialist.

Hypervolaemic hyponatraemia with urinary sodium >20 mmol/L (>20 mEq/L)

Indicates chronic renal failure with impaired sodium excretion. In most patients the diagnosis is already known, but further assessment is required if a new diagnosis of renal failure is made. Signs and symptoms of renal failure may be present and include jaundice, skin bruising, poor concentration/memory, or myoclonus.

Serum creatinine is elevated with a reduced glomerular filtration rate, and urinalysis reveals haematuria and/or proteinuria depending on the underlying cause. Renal ultrasound can be useful to assess the cause, and may reveal small kidneys, obstruction or hydronephrosis, and kidney stones. A kidney biopsy is required for the definitive diagnosis of intrinsic causes of renal failure, and should be considered in consultation with a renal specialist.

Euvolaemic hyponatraemia

Excessive oral fluid intake

  • If a history of schizophrenia or psychotic depression is present, psychogenic polydipsia should be considered. A history of polydipsia and polyuria is present. Patients usually complain of a persistent sensation of dry mouth. This may sometimes be due to phenothiazine medications and sometimes be due to the underlying condition. The clinical examination is usually normal, although weight gain due to high water intake may occur in extreme cases. The water intake is so excessive that it overwhelms the capacity of the kidney to resorb water, and urine osmolality is <100 mmol/kg H₂O (<100 mOsm/kg H₂O).

  • If a history of chronic alcohol abuse is present, beer drinker's potomania should be considered. The CAGE questionnaire can be helpful in identifying patients with alcohol abuse. CAGE Alcohol Questionnaire external link opens in a new window A CAGE score >2 is suspicious. Beer drinker's potomania is precipitated by drinking >6 litres of beer a day on a background of chronic poor dietary intake. Urine osmolality is <100 mmol/kg H₂O (<100 mOsm/kg H₂O). Serum bilirubin levels are typically elevated, and aspartate aminotransferase and alanine aminotransferase are rarely >200 units/L.

Postoperative period

  • A transient increase in antidiuretic hormone secretion occurs during this period. The hyponatraemia is self-limiting. However, administration of hypotonic fluids during this time can produce a more severe or prolonged hyponatraemia.

  • Large volumes of hypertonic fluids (glycine, mannitol, or sorbitol) are used to irrigate the operative field during transurethral resection of the prostate or hysteroscopy. If the fluid is absorbed without the solute, this can produce euvolaemic hypotonic hyponatraemia.

  • Large volumes of hypotonic fluids are used to irrigate the operative field during endometrial ablation. If absorbed, this can produce severe acute hyponatraemia.

SIADH

  • If all other causes of euvolaemic hyponatraemia have been excluded, the patient has SIADH.[26]

  • Known drug causes include vasopressin, non-steroidal anti-inflammatory drugs, nicotine, chlorpropamide, carbamazepine, tricyclic antidepressants, selective serotonin reuptake inhibitors, vincristine, thioridazine, cyclophosphamide, clofibrate, and ecstasy (MDMA) use.

  • Recent head injury, intracranial surgery, subarachnoid haemorrhage, stroke, brain tumours, meningitis, or brain abscess can cause SIADH.

  • A history of cough, shortness of breath, or pleuritic chest pain should prompt consideration of respiratory causes of SIADH. These include pneumonia, lung abscess, COPD, cystic fibrosis, and positive-pressure ventilation.

  • Ectopic ADH secretion by tumours is an important cause to exclude. The most common source is small cell lung cancer; other cancers are rare causes. These include cervical cancer, lymphoma, leukaemia, and pancreatic cancer.

  • Appropriate investigations depend on the cause identified by the clinical features. If there is no identifiable cause, the patient is diagnosed to have idiopathic SIADH.

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