Endocrinology: Disorders of thirst and fluid balance

Hypernatraemia and diabetes insipidus

Posterior pituitary function and sodium homeostasis

The posterior pituitary is derived from a down-growth of primitive neural tissue and is anatomically distinct from the anterior pituitary gland. The posterior pituitary has a vital role in sodium and water balance, which is tightly regulated in health. Osmoreceptors in the hypothalamic supraoptic nucleus respond to high serum osmolality by stimulating vasopressin (ADH) release from the paraventricular nucleus in the hypothalamus (Figure 7.1), as well as stimulating thirst.
Vasopressin acts on aquaporin channels in the collecting duct of the kidney to allow water reabsorption. Osmolality quantifies the solute concentration of serum and can be measured directly or calculated (2 × [Na+] + urea + glucose). In the absence of high glucose and renal failure, osmolality amounts to approximately double serum sodium. Rapid changes in osmolality can lead to catastrophic CNS consequences.

Hypernatraemia

Hypernatraemia is mild (Na 145–150 mmol/L), moderate (150–159 mmol/L) or severe (>160 mmol/L). It is less common than hyponatraemia in clinical practice but is a sign of significant disease. The causes are pure water loss, hypotonic water loss or salt gain (Table 7.1). In patients with hypernatraemia who have a high urine output and low urine osmolality, diabetes insipidus (DI) should be considered.

Diabetes insipidus

DI is caused by vasopressin deficiency (cranial DI) or reduced action of vasopressin on the kidney (nephrogenic DI). The lack of water reabsorption from reduced vasopressin action leads to large volumes of dilute urine with profound unquenchable thirst (Figure 7.1). The biochemical hallmarks of DI are high serum osmolality, low urine osmolality and high urine volume.
Cranial DI is seen in inflammatory or infiltrative pituitary disease (Figure 7.1). A strong family history of cranial DI suggests a mutation in the arginine vasopressin (AVP) gene. DIDMOAD (Wolfram’s syndrome) is a rare genetic condition characterised by DI, diabetes mellitus, optic atrophy and deafness.
Nephrogenic DI is usually caused by metabolic and electrolyte disturbance, renal disease and drugs affecting the kidney. A rare congenital X-linked cause of nephrogenic DI has also been described.
Primary polydipsia is a behavioural condition leading to polydipsia, which drives polyuria. It is not associated with hypernatraemia, and can lead to dilutional hyponatraemia.
Some patients with primary polydipsia have an impaired ability to concentrate urine because of down-regulation of vasopressin release, and this can occasionally be difficult to distinguish from partial DI.

Investigation

DI is confirmed by demonstration of high urine volumes, high serum osmolality and low urine osmolality. The clinical diagnosis is usually obvious with complete vasopressin deficiency, due to the presence of extreme thirst and passing of large quantities of pale urine. DI is confirmed if serum osmolality >295 mosmol/kg, serum [Na+] >145 mmol/L and urine osmolality <300 mosmol/kg.

Water deprivation test

In partial DI, the diagnosis may be less clear-cut. In this situation a water deprivation test (WDT) can be useful. Patients with frank DI will have severe thirst and lose significant weight as a result of water loss. The test should be stopped if excessive weight loss occurs or symptoms are too severe. DI is excluded if patients concentrate urine osmolality >600 mosmol/kg and serum osmolality remains <300 mosmol/kg. In the second part of the WDT, synthetic vasopressin (1-desamino-8-d-arginine vasopressin; DDAVP) is given. In cranial DI, DDAVP leads to reduced urine volume and increased urine osmolality, while in nephrogenic DI there is no response.

Management

Patients with confirmed cranial DI should be investigated for pituitary disease, and managed as appropriate. Cranial DI responds well to DDAVP administration and results in good clinical improvement. Desmopressin can be given intranasally, orally, sublingually or parenterally. Overtreatment with DDAVP can lead to dilutional hyponatraemia, commonly characterised by headache and reduced cognitive ability, and, less commonly, seizures if there is a sudden drop in sodium. Signs of undertreatment with DDAVP are excessive thirst and polyuria.
Rarely, patients with DI have an impaired thirst mechanism if there is hypothalamic involvement, termed hypodipsic DI. This can be seen in hypothalamic infiltrative disorders and requires specialist care because of the risk of severe hypernatraemia and dehydration.
In nephrogenic DI, the underlying cause should be considered and reversed where possible. If symptoms persist, patients should drink according to thirst and keep up with water loss. Specific measures to treat nephrogenic DI include the use of low salt, low protein diet, diuretics, and non-steroidal anti-inflammatory drugs (NSAIDs).

Acute severe hypernatraemia

This is a medical emergency and requires inpatient management in a high dependency setting. Seizures and intracranial vascular haemorrhage as a result of brain shrinkage can occur. Severe hypernatraemia (Na >160 mmol/L) usually requires ITU discussion. The cause is most commonly excessive water loss, and the key aspect of treatment is aggressive fluid replacement.
Normal (0.9%) saline should be given as initial fluid replacement, as it is relatively hypotonic. An estimation of total body water deficit can be made according to weight. If urine osmolality is low, DI should be considered, and a trial of intramuscular or intravenous DDAVP given. In patients with known DI, it is essential to ensure DDAVP is given parenterally, and that close fluid balance is observed.

Hyponatraemia and SIADH

Hyponatraemia

Hyponatraemia is common, affecting approximately 30% of patients in hospital. It is classified as mild (>130 mmol/L), moderate (125–129 mmol/L) or severe (<125 mmol/L), according to either the degree of biochemical disturbance or the clinical state of the patient. The rate of change of sodium is more important than the absolute sodium value so patients with chronic hyponatraemia can be asymptomatic, while patients with a sudden drop can be very unwell. Early symptoms of hyponatraemia are headache, nausea, vomiting and general malaise. Later signs are confusion, agitation and drowsiness.
Acute severe hyponatraemia leads to seizures, respiratory depression, coma and can result in death.

Investigation

Making an accurate diagnosis of hyponatraemia requires full clinical assessment and a systematic approach. Drug history and hydration status are particularly important. Thiazide diuretics are a common cause of hyponatraemia and should be stopped if possible. Biochemical investigations include serum osmolality, urine osmolality, urine sodium, thyroid function and an assessment of cortisol reserve (09.00 cortisol or Synacthen test).
It is not possible to make an accurate diagnosis without all of these investigations (Figure 8.2).

Diagnostic approach

In acute severe hyponatraemia with neurological compromise, hypertonic saline should be considered whatever the cause. This is a senior decision and should only be carried out under close supervision. In mild or moderate hyponatraemia, the diagnostic algorithm should be followed (Figure 8.2).

Serum and urine osmolality

Confirmation of low serum osmolality is important to exclude non-hypo-osmolar hyponatraemia (e.g. hyperglycaemia). Once hypotonic hyponatraemia has been confirmed, urine osmolality should be checked. A low urine osmolality (<100 mosmol/kg) suggests primary polydipsia or inappropriate administration of IV fluids. If urine osmolality is >100 mosmol/kg, urine sodium will guide the differential diagnosis.

Urine sodium

A low urine sodium (<30 mmol/L) suggests a low effective arterial volume. This is seen either resulting from true volume depletion (e.g. gastrointestinal salt loss), or when patients are clinically overloaded but have intravascular depletion (e.g. congestive cardiac failure, cirrhosis or nephrotic syndrome). If urine sodium is >30 mmol/L and the patient is euvolaemic, syndrome of inappropriate ADH (SIADH) should be considered, although ACTH deficiency must be excluded. If urine sodium is 30 mmol/L and patients are hypovolaemic, Addison’s disease, renal and cerebral salt-wasting, or a history of vomiting should be considered – vomiting causes loss of hydrogen ions and a metabolic alkalosis, which is corrected by the renal excretion of sodium bicarbonate.
Severe hypothyroidism can cause hyponatraemia, although the mechanism is unclear.

Management

Cause-specific treatment leads to biochemical correction.
Appropriate fluid replacement in patients with hypovolaemic hyponatraemia with normal saline typically leads to improvement. In patients with hypervolaemic hyponatraemia, specialist treatment of cirrhosis, nephrotic syndrome or congestive cardiac failure is indicated.

Syndrome of inappropriate ADH

SIADH has many causes (Table 8.1). It is characterised by euvolaemic hypo-osmolar hyponatraemia in the context of low serum osmolality (<275 mosmol/kg), urine osmolality 100 mosmol/kg and urine sodium >30 mmol/L. SIADH can only be diagnosed after the exclusion of hypothyroidism, total salt depletion and ACTH deficiency.
ACTH deficiency appears identical to SIADH because it causes reduced excretion of free water, because cortisol deficiency leads to increased vasopressin activity. This is different from hyponatraemia caused by mineralocorticoid deficiency in Addison’s disease.
SIADH can be caused by underlying malignancy, most commonly lung cancer. Other respiratory and CNS pathology can also cause SIADH (Table 8.1). Many drugs can lead to SIADH, particularly anticonvulsants. If no cause for SIADH is found, cross-sectional imaging or bowel investigation may be necessary to search for an underlying malignancy. Idiopathic SIADH is a diagnosis of exclusion.

Management

Reversal or treatment of the cause of SIADH and fluid restriction are the key aspects of management. Strict fluid restriction (1–1.5 L/day) is poorly tolerated and difficult to achieve. Drug treatment of SIADH includes demeclocycline and ADH antagonists. Demeclocycline reduces renal response to ADH but its use is limited by side effects and unpredictable pharmacokinetics. ADH antagonists (vaptans) directly block ADH action and are of use in specific clinical situations.

Acute severe hyponatraemia

Patients with acute severe hyponatraemia and neurological compromise require urgent management and intensive monitoring (Figure 8.1). In life-threatening situations when patients are unconscious or fitting, hypertonic (3%) saline can be considered.