Control of salt balance

Regulation of salt balance is achieved primarily through activation of the renin–angiotensin–aldosterone system and the release of atrial natriuretic peptide. Renin is secreted by the juxtaglomerular cells of the kidney in response to sodium depletion or extracellular fluid volume restriction. Renin converts angiotensinogen to angiotensin I which, in turn, is converted by angiotensin‐converting enzyme to angiotensin II. Angiotensin II stimulates the production of aldosterone from the zona glomerulosa of the adrenal cortex. Adrenocorticotrophic hormone (ACTH) does not play a role in the physiological regulation of aldosterone secretion although serum aldosterone increases upon acute intravenous (IV) ACTH administration. Potassium ions also facilitate the secretion of aldosterone. By contrast, the secretion of both renin and aldosterone may be inhibited by atrial natriuretic peptide.

Aldosterone binds to the mineralocorticoid receptor, resulting in increased reabsorption of sodium in the kidney, sweat and salivary glands. Sodium ions are exchanged for potassium and hydrogen ions in the distal tubule. Cortisol also has a strong binding affinity for the mineralocorticoid receptor but is prevented from doing so as a result of metabolism to inactive cortisone by 11‐β‐hydroxysteroid dehydrogenase‐2 in aldosterone‐sensitive tissues.

Control of water balance

Water balance is maintained by the interrelation between thirst, renal function, and the antidiuretic hormone arginine vasopressin (AVP). Vasopressin is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus in a pre‐pro‐hormone form consisting of vasopressin, neurophysin II, and copeptin. These peptides are then cleaved during transport along the supraoptic–hypophyseal tract to be stored in the posterior pituitary. Vasopressin release is regulated by osmoreceptors in the hypothalamus which detect changes in plasma osmolality from 280 to 295 mOsm/kg as may occur with loss of extracellular water. High concentrations of vasopressin may also be secreted following baroreceptor‐detected reductions in blood volume or blood pressure of 5–10%. Baroreceptors are located in the carotid arch, aortic sinus, and left atrium and modulate vasopressinergic neuronal function via vagal and glossopharyngeal stimulation of the brainstem.

Vasopressin binds to a V2 receptor in the renal collecting tubule which regulates the insertion of water channel proteins (aquaporin 2) into the cell membrane. These allow water to flow along an osmotic gradient from the tubular lumen into the cells lining the collecting duct. Other aquaporins (aquaporin 4) allow this water to pass to the renal interstitium and circulation. This regulatory mechanism maintains plasma osmolality between 282 and 295 mOsm/kg. When the plasma osmolality exceeds 295 mOsm/kg, vasopressin secretion cannot be increased further and fluid balance is maintained by increased thirst leading to increased fluid intake. The vasopressin effect is under negative feedback modulation by locally generated prostaglandins in the medullary collecting duct cells. Glucocorticoids are also required for free water excretion so that initiation of glucocorticoid replacement in hypopituitary patients may unmask diabetes insipidus (DI).

Aetiology

Hyponatraemia may occur either as a result of salt and water depletion in which salt loss exceeds water loss or following fluid overload resulting in relatively more water than salt. The general mechanisms for the development of hyponatraemia are shown in Table 9.1.

Hyponatraemia associated with extracellular fluid loss is not always a direct consequence of the fluid loss per se, which is frequently hypotonic or isotonic by comparison with plasma, but may be caused by replacement of these fluid losses with hypotonic fluid (e.g. drinking water alone or use of hypotonic IV fluids).

History and examination

When a child presents with hyponatraemia for which the cause is not immediately apparent, the following points should be highlighted in the history:

1. Features suggestive of salt loss:
   
   
   
   • The presence of symptoms causing excess fluid and sodium loss (e.g. weight loss, vomiting, diarrhoea, polyuria) or a compensatory decrease in urine production which may occur when sodium loss has occurred from the skin or gut.
     
   • Evidence that hyponatraemia is precipitated by intercurrent illness and associated with hyperkalaemia and hypoglycaemia which might suggest adrenal failure.
     
   • Symptoms of malabsorption or recurrent chest infections or a tendency for hyponatraemia to develop during hot weather which may be indicative of cystic fibrosis.
     
   • The use of medication (e.g. diuretics) which predispose to hyponatraemia.
     
   • Family history of consanguinity and of specific disorders such as cystic fibrosis, congenital adrenal hyperplasia or hypoplasia, and pseudohypoaldosteronism.
   
   
2. Features suggestive of water retention:
   
   
   
   • Excess daily fluid intake.
     
   • Symptoms suggestive of an underlying central nervous system (CNS) or respiratory disorder (e.g. meningitis, raised intracranial pressure, pneumonia) associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH).
     
   • Symptoms suggestive of heart failure, renal, liver or thyroid disease.

The following points should be highlighted in the clinical examination:

1. The patient should always be weighed.
   
2. If sodium loss has occurred, clinical signs of volume depletion may be present as shown in Table 9.2. Evidence of growth impairment may suggest a long‐standing cause of hyponatraemia resulting from sodium loss. Careful clinical examination should be undertaken of all systems for signs suggestive of intracranial or respiratory disease, cardiac, hepatic, renal or adrenal failure, or hypothyroidism.
   
3. If signs of volume depletion are absent, this may imply either previous fluid replacement with hypotonic fluids or the presence of water retention. In the latter circumstances, there may be evidence of oedema or rapid recent weight gain. The clinical signs of volume overload are shown in Table 9.2. The rapid onset of a hypo‐osmolar state may be associated with neurological manifestations including anorexia, apathy, confusion, headaches, weakness, and muscle cramps. More severe symptoms may include vomiting, depressed deep tendon reflexes, bulbar or pseudobulbar palsy, Cheyne–Stokes breathing, psychotic behaviour, seizures, coma, and death.

Investigations

• Serum and urine electrolytes and creatinine to calculate urinary sodium losses.
  
• Serum and urinary osmolalities.
  
• Plasma renin activity, aldosterone, 17‐hydroxy progesterone and cortisol.
  
• Thyroid function tests (TFT).
  
• Other investigations as indicated for cardiac, respiratory, hepatic, renal, or intracranial disease.
  
• If the patient is normo‐osmolar, plasma proteins, lipids, and glucose.

Differential diagnosis

Hyponatraemia can be spurious either as a result of contamination of the blood sample taken from an IV cannula with hypotonic IV fluids or because of interference with the flame photometer assay by excess serum lipids or proteins.

The key requirement in the assessment of a patient with hyponatraemia is to distinguish between causes associated with excess sodium loss and those associated with water retention, for example, in SIADH. The clinical distinction between these two states is summarized in Table 9.2.

If the cause of the hypo‐osmolar state is not clear at presentation, urine osmolalities >100 mOsm/kg associated with urinary sodium concentrations >20 mmol/L suggest acute SIADH or renal, adrenal, or cerebral salt wasting. Urine osmolalities >100 mOsm/kg associated with urinary sodium concentrations <20 mmol/L suggest hypovolaemia or longer‐standing SIADH. Plasma renin is usually suppressed in SIADH but elevated in hypovolaemia.

Diagnosis

The causes of hyponatraemia are summarized in Table 9.1. Mineralocorticoid deficiency may be a consequence of idiopathic congenital adrenal hypoplasia or aplasia, biosynthetic defects of aldosterone synthesis (e.g. congenital adrenal hyperplasia) or acquired primary adrenal failure (e.g. Waterhouse–Friderichsen syndrome, autoimmune disease, or following surgical removal). While combined mineralocorticoid and glucocorticoid deficiency will cause hyponatraemia through salt loss, glucocorticoid deficiency (e.g. in hypopituitarism) will cause hyponatraemia due to impaired water excretion. Resistance to aldosterone may occur as a result of inactivation of the mineralocorticoid receptor or of the epithelial sodium channel. Abnormalities of mineralocorticoid physiology are discussed in more detail in Chapter 8.

The various causes of SIADH are summarized in Table 9.3.

Treatment

Where hyponatraemia is a consequence of sodium loss and in the context of clinical signs of significant hypovolaemia, IV colloid or 0.9% saline should be given until there is clinical evidence of circulatory improvement. Adrenal insufficiency should be treated with fludrocortisone and glucocorticoids (see Chapter 8).

SIADH should be anticipated in individuals who have experienced significant head trauma or intracranial surgery and careful postoperative supervision of fluid balance is required. SIADH should be treated by fluid restriction which may range from only 40% to two‐thirds of normal intake. Where severe or symptomatic hyponatraemia or excessive thirst makes this approach impractical, then treatment to either increase water excretion or to raise the plasma sodium should be used. Water excretion will be enhanced by the tetracycline antibiotic demeclocycline which impairs the renal response to vasopressin and has been used in adults, giving 3–5 mg/kg eight‐hourly. An alternative is the relatively newly available V2 receptor antagonist tolvaptan, though trials of its efficacy in children are ongoing. Plasma sodium can be raised using hypertonic (3%) saline (0.1 ml/kg/min for two hours), aiming to increase plasma sodium concentration by about 10 mmol/L. In this context, it may be necessary to give furosemide with replacement of excreted urinary electrolytes to prevent hypervolaemia. This treatment should be reserved for those with significant neurological symptoms following the relatively acute onset of SIADH, as there is a risk of lethal pontine myelinolysis if serum sodium concentrations rise too rapidly (>10 mmol/L per day).

Aetiology

Hypertension in childhood as a result of endocrine pathology is usually a consequence of either glucocorticoid or catecholamine excess, as shown in Table 9.4.

History and examination

Key points to highlight in the history and on clinical examination include the following:

• A history of intermittent headaches, sweating, flushes, nausea or vomiting is suggestive of a phaeochromocytoma.
  
• Other affected family members. An autosomal recessive inheritance suggests congenital adrenal hyperplasia caused by 11β‐hydroxylase or 17α‐hydroxylase deficiency whereas an autosomal dominant pattern might suggest a phaeochromocytoma associated with a multiple endocrine neoplasia syndrome or hereditary phaeochromocytoma‐paraganglioma syndrome.
  
• Virilization in a girl might suggest congenital adrenal hyperplasia.
  
• Clinical signs of Cushing’s syndrome (see Chapter 8).
  
• The presence of cutaneous signs suggestive of neurofibromatosis, or of mucosal neuromas, which are associated with von Hippel–Lindau disease, may suggest the presence of an associated phaeochromocytoma.

Investigations

The following preliminary investigations should be considered if an endocrine cause of hypertension is suspected:

• serum electrolytes and creatinine;
  
• three 24‐hour urinary‐free cortisol (and creatinine) collections;
  
• urinary steroid metabolite profiling;
  
• plasma free metanephrine and urinary catecholamine metabolites;
  
• abdominal ultrasound.

If Cushing’s syndrome seems likely, additional investigations to confirm the diagnosis and treatment are described (see Chapter 8). If the urinary excretion of catecholamine metabolites is increased, then a blood sample should be taken for the measurement of free metanephrine. Two‐thirds of phaeochromocytomas are located in the adrenal medulla but they may also be found anywhere in the sympathetic chain, most commonly close to the renal hilum or aortic bifurcation. Abdominal imaging, preferably with computerized tomography (CT), magnetic resonance imaging (MRI), ¹²³I‐metaiodobenzylguanidine (MIBG) scanning and, possibly, selective venous catecholamine sampling by catheterization may be necessary to locate the site(s).

Diagnosis

The various causes of endocrine hypertension are shown in Table 9.4. Hypertension in 11β‐hydroxylase‐ and 17α‐hydroxylase‐deficient congenital adrenal hyperplasia results from accumulation of the potent mineralocorticoid deoxycorticosterone, resulting in sodium and water retention with suppression of renin and aldosterone. 11β‐hydroxylase deficiency is also associated with excess androgen production and virilization, whereas 17α‐hydroxylase deficiency leads to female external genitalia in 46,XY subjects and lack of development of secondary sexual characteristics in both sexes.

Primary aldosteronism is associated with hypernatraemia, increased plasma volume, hyporeninaemia, and hypokalaemia. Hypertension is common in childhood Cushing’s syndrome. The syndrome of apparent mineralocorticoid excess (AME) is characterized by low plasma renin and aldosterone concentrations and is associated with a deficiency of 11β‐hydroxysteroid dehydrogenase 2 which is responsible for metabolizing cortisol to cortisone to prevent high concentrations of cortisol from binding to the mineralocorticoid receptor.

Liddle’s syndrome arises from an abnormality of renal tubular transport caused by an activating mutation of the amiloride‐sensitive sodium channel, resulting in increased sodium reabsorption and potassium loss with a biochemical and clinical picture similar to that of AME. Glucocorticoid‐suppressible hyperaldosteronism is a rare disorder in which primary aldosteronism is regulated by ACTH rather than renin–angiotensin because of the fusion of regulatory sequences of the 11β‐hydroxylase gene to coding sequences of the aldosterone synthase gene.

Treatment

In 11β‐hydroxylase‐ and 17α‐hydroxylase‐deficient congenital adrenal hyperplasia, hypertension responds to glucocorticoid therapy which suppresses ACTH secretion and thus deoxycorticosterone production. The treatment of Cushing’s syndrome is discussed in detail in Chapter 8.

A phaeochromocytoma requires surgical removal in an experienced specialist centre with skilled anaesthetic support. Pre‐ and perioperative control of blood pressure must be achieved by the initial use of an adequate alpha blockade such as phenoxybenzamine. As this is achieved, supplemental salt intake is needed to expand the extracellular fluid volume. Beta blockers are also necessary to treat alpha‐blocker‐induced tachycardia. When a neuroblastoma causes catecholamine‐induced hypertension, similar medical management will be necessary in the pre‐operative period.

Aetiology

Diabetes insipidus may occur either as a result of inadequate secretion of AVP (cranial or central diabetes insipidus) or when there is resistance to the antidiuretic effect of AVP (nephrogenic diabetes insipidus). Cranial diabetes insipidus may be congenital due to a gene defect or to a cerebral malformation (e.g. septo‐optic dysplasia (SOD), holoprosencephaly); or caused by acquired disease (e.g. craniopharyngioma, Langerhans cell histiocytosis, or surgery) of the hypothalamo–pituitary axis (Table 9.5). Autosomal dominant cranial diabetes insipidus may be caused by a mutation of the AVP–neurophysin II gene which leads to impaired processing of the AVP hormone precursor, causing progressive damage to the neurosecretory neurones of the hypothalamus and the development of increasingly severe symptoms of diabetes insipidus with advancing age. In the much less common autosomal recessive form, the symptoms occur earlier. Nephrogenic diabetes insipidus may occur as a consequence of mutations affecting the V2 receptor gene (X‐linked) or aquaporin 2 gene (autosomal recessive) or because of disorders of the kidney which impair the function of other components of the urinary concentrating mechanism (Table 9.5).

History and examination

The cardinal symptoms of diabetes insipidus are polyuria and polydipsia. Other causes of these symptoms must be considered – osmotic diuresis from glycosuria in diabetes mellitus and reduced nephron mass in chronic renal failure; excessive intake in habit drinking (psychogenic polydipsia); and impaired renal tubular function in hypercalcaemia and hypokalaemia. Additional clinical features of diabetes insipidus include constipation, fever, vomiting, loss of weight, failure to thrive, and dehydration.

The following points should be highlighted in the history and clinical examination:

• The nature and severity of the polyuria and polydipsia. Excess consumption of flavoured liquids only as opposed to water suggests habitual excess drinking. Drinking from unusual places, such as from the toilet or bath, or unusual fluids, such as shampoo, suggests severe thirst due to an underlying organic disorder.
  
• Whether the symptoms were present from birth, suggesting a congenital abnormality, or developed later in life, suggesting an acquired disorder.
  
• Associated neurological symptoms (e.g. blindness, neurodevelopmental delay, headache) and signs (e.g. optic atrophy) or history of a recent neurological disorder suggesting risk factors for hypothalamo–pituitary dysfunction.
  
• Past medical history of renal disease.
  
• Symptoms suggestive of diabetes mellitus (weight loss and hyperphagia within the past six weeks) or hypercalcaemia (anorexia, abdominal pain, constipation).
  
• Medication (e.g. lithium treatment).
  
• Family history of similarly affected cases.
  
• Congenital abnormalities especially in the mid‐line of the brain and face.
  
• Blood pressure or presence of enlarged kidneys.
  
• Growth status – short stature suggestive of associated growth hormone (GH) deficiency in hypopituitarism.

Investigations

Habitual excess drinking is common in toddlers and preschool children, and if often part of a wider management problem including a poor sleeping pattern. The child is otherwise healthy and the problem can usually be both diagnosed and cured by asking parents to stop flavoured fluids but allow the child unrestricted access to water. If symptoms persist, the child should be admitted for observation and the severity of the polyuria and polydipsia be confirmed by measurement of the 24‐hour fluid intake and urinary losses. A fasting blood sample should be taken for the measurement of plasma glucose and serum sodium, potassium, calcium, and creatinine concentrations. Urine should be tested for glycosuria and proteinuria.

In a significantly symptomatic individual, simultaneous early morning blood and urine samples should be taken for the measurement of serum electrolytes and osmolality and urinary osmolality. Diabetes insipidus may be confirmed by the presence of a hyperosmolar state (i.e. serum osmolality >295 mOsm/kg) with inappropriately dilute urine (urine osmolarity around <750 mOsm/kg). The plasma or urine sample should then be sent for the measurement of AVP or plasma copeptin concentrations to confirm whether the cause is cranial or nephrogenic (Figure 9.1). In these circumstances, a water deprivation test would be dangerous and is contraindicated. Furthermore, a water deprivation test is not required when there is a clear history of polydipsia and polyuria in the context of underlying disease or treatment (e.g. craniopharyngioma, histiocytosis, and postoperative phase of craniopharyngioma) which is known to cause cranial diabetes insipidus.

Diagnosis

If during the water deprivation test, the plasma osmolality remains between 282 and 295 mOsm/kg and the urine osmolality increases to >750 mOsm/kg, the patient does not have diabetes insipidus and the possibility of primary polydipsia because of abnormal drinking habits should be considered.

A diagnosis of cranial diabetes insipidus is suggested by the development of increased plasma osmolality >295 mOsm/kg in the presence of a urine osmolality <300 mOsm/kg which is then increased to >750 mOsm/kg following the administration of DDAVP. Failure of the urine to respond to DDAVP is indicative of nephrogenic diabetes insipidus. A partial urinary response (300–750 mOsm/kg) to water deprivation or DDAVP suggests partial cranial or nephrogenic diabetes insipidus.

Treatment