Differences between Bartter and Gitelman syndrome.
Metabolic alkalosis is a disorder where the primary defect, an increase in plasma bicarbonate concentration, leads to an increase in systemic pH. Here we review the causes of metabolic alkalosis with an emphasis on the inherited causes, namely Gitelman syndrome and Bartter syndrome and syndromes which mimic them. We detail the importance of understanding the kidney pathophysiology and molecular genetics in order to distinguish these syndromes from acquired causes. In particular we discuss the tubular transport of salt in the thick ascending limb of the loop of Henle, the distal convoluted tubule and the collecting duct. The effects of salt wasting, namely an increase in the renin-angiotensin-aldosterone axis are discussed in order to explain the biochemical phenotypes and targeted treatment approaches to these conditions.
- inherited tubulopathy
- renin-angiotensin-aldosterone axis
Metabolic alkalosis is a disorder where the primary defect, an increase in plasma bicarbonate concentration, leads to an increase in systemic pH. Various mechanisms underpin the pathophysiology of metabolic alkalosis, which is defined by an arterial bicarbonate concentration of over 28 mmol/L or a venous total carbon dioxide concentration of greater than 30 mmol/L. The body compensates for alkali retention and subsequent elevated arterial pH by inducing respiratory hypoventilation resulting in an accompanying rise in PaCO2. Normally the kidney, which has a protective mechanism against the development of significant increases in bicarbonate, will excrete excess alkali to restore the body to its homeostatic pH, but certain factors can impair this ability resulting in a sustained alkalotic state. Here we will review the pathophysiological mechanisms and clinical settings in which metabolic alkalosis may occur [1, 2, 3, 4] and give an overview of the causes of the inherited forms of metabolic alkalosis. The importance of defining a molecular genetic cause of metabolic alkalosis is reviewed alongside the common mimics of some of the inherited metabolic alkalosis syndromes.
2. Pathophysiology of metabolic alkalosis
The following mechanisms result in the elevation of serum bicarbonate; excessive loss of hydrogen ions by the kidney or via the GI tract, intracellular shift of hydrogen ions, retention of exogenous bicarbonate ions or volume contraction around a constant supply of extracellular bicarbonate (contraction alkalosis) .
As water dissociates in the body to hydrogen and hydroxyl ions, the hydroxyl ions combine with carbon dioxide, resulting in bicarbonate, as hydrogen ions are removed from extracellular fluid. Hydrogen ion removal in the kidney and GI tract is accompanied by loss of potassium and chloride so hypokalaemia and hypochloraemia often coexist with metabolic alkalosis.
Ability to excrete excess bicarbonate depends on the normal function of nephrons within the kidneys. The kidney therefore is implicated in the pathophysiology of most forms of metabolic alkalosis. The following scenarios result in a degree of impairment of this important mechanism: hypovolaemia, reduced glomerular filtration rate (GFR), reduced effective arterial volume, hypokalaemia, hypochloraemia or hyperaldosteronism.
2.1. Volume depletion
Both reduced extracellular volume and arterial pressure will reduce GFR and thus activate the renin-angiotensin-aldosterone and sympathetic nervous system. Decreased GFR reduces bicarbonate filtration by the kidney and angiotensin and sympathetic activation increases bicarbonate reabsorption and generation in addition to sodium reabsorption in the tubule. This is done in the following ways:
Angiotensin-2 stimulates apical sodium-hydrogen exchange and basolateral sodium bicarbonate co-transport in the proximal tubule. This increases bicarbonate and sodium reabsorption.
In the apical membrane of alpha-intercalated cells of the collecting duct angiotensin-2 and aldosterone increase H+-ATPase pump activity resulting in increased urinary excretion of hydrogen ions. This results in increased intracellular bicarbonate generation which exits the cell in exchange for chloride via the basolateral membrane.
Increases in aldosterone stimulate the apically located ENaC channel in the principal cells, which generates an electronegative potential in the tubular lumen. This enhances hydrogen and potassium ion excretion.
2.2. Sodium intake
A low sodium chloride diet will increase the bicarbonate reabsorption in the kidney enough to elevate serum pH although the reverse is not true with a high salt diet even though this will encourage the kidney to excrete sodium bicarbonate.
2.3. Chloride depletion
Chloride depletion secondary to vomiting or nasogastric suction leads to a metabolic alkalosis. Chloride depletion metabolic alkalosis causes concomitant potassium depletion through renal loss of potassium. A less severe chloride depletion metabolic alkalosis is seen with the use of thiazide and loop diuretics.
Hypokalaemia causes alkalosis by moving hydrogen ions into the intracellular space in exchange for extracellular movement of potassium and hypokalaemia maintains an alkalosis by increasing renal bicarbonate reabsorption. Hypokalaemia (and aldosterone) stimulates the distal Na+-K+-ATPase and H+-ATPase pumps in the apical membrane of alpha-intercalated cells to reabsorb potassium and secrete hydrogen and subsequently maintain alkalosis. Hypokalaemia also causes extracellular movement of potassium in exchange for intracellular movement of sodium and hydrogen which generates extracellular bicarbonate although co-existent intracellular acidosis. This intracellular acidosis stimulates renal bicarbonate reabsorption, hydrogen secretion and ammonium synthesis and excretion.
2.5. Increased aldosterone
Hyperaldosteronism in addition to increased distal tubule sodium delivery results in sodium reabsorption and hydrogen and potassium ion secretion. Any hyper-reninaemic state which will result in an increase in aldosterone production will have the same effects.
2.6. Volume contraction and beta-intercalated cells
Distal tubule chloride delivery is essential for the beta-intercalated cell to secrete bicarbonate as this occurs by an apical anion exchange protein called Pendrin (Figure 3). As volume contraction reduces distal chloride delivery, bicarbonate secretion will reduce as will chloride reabsorption. Urine pH becomes acidic with little chloride, sodium and potassium, so beta-intercalated cells are blunted from excreting bicarbonate and correcting the metabolic alkalosis [1, 2, 3, 4].
3. Causes of metabolic alkalosis
Loop diuretics (Furosemide, Bumetanide, Torsemide) inhibit the apical Na+–K+–2Cl− co-transporter in the thick ascending limb of the loop of Henle where 20–25% of sodium is typically reabsorbed. Metabolic alkalosis occurs in several ways [6, 7]:
Increased distal sodium delivery results in stimulation of the aldosterone sensitive sodium channel (ENaC) which increases hydrogen/potassium ion excretion.
Hypochloraemia will also contribute to the metabolic alkalosis.
The same principle also applies to other diuretics such as thiazides.
Patients who are chronic CO2 retainers typically develop a compensatory metabolic alkalosis due to renal bicarbonate retention. Once the hypercapnia is reversed with ventilatory support, the renal bicarbonate retention takes longer to correct and these patients usually have a chronically elevated bicarbonate .
3.3. Non-reabsorbable anion delivery
Antibiotics particularly Beta-lactams act as non-reabsorbable anions in the renal tubule which therefore promotes potassium and hydrogen excretion which results in metabolic alkalosis .
3.4. Inherited salt wasting alkaloses
Bartter and Gitelman syndromes are both autosomal recessive inherited disorders which result in characteristic features due to a hereditary dysfunction in a tubular salt handling . Both result in hypokalaemia, metabolic alkalosis, hyper-reninaemia and hyperaldosteronism with low blood pressure. The prevalence of Gitelman syndrome is about 1 in 40,000 compared with Bartter syndrome, which has a prevalence of 1 in 1,000,000. Bartter syndrome is more severe and may cause perinatal death due to salt wasting crises. The clinical phenotype that is seen with Gitelman syndrome mimics the chronic ingestion of a thiazide diuretic and that of Bartter syndrome mimics a chronic loop diuretic effect (Table 1). Bartter and Gitelman syndrome carriers (heterozygous for a mutation in causative gene) typically have lower blood pressure than that of the general population and may have mild biochemical phenotypes and some clinical symptoms.
|Bartter syndrome||Gitelman syndrome|
|Site of defect||NKCC2, ROMK, CLC-KB, CLC-KA and CaSR in the thick ascending limb of the loop of Henle||Apical sodium chloride co-transporter (NCCT) at the distal convoluted tubule|
|Hypocalcaemia||Rare (seen in Type 5 Bartter syndrome)||Absent|
|Urine chloride and sodium excretion||High||Normal/high|
|Urine potassium excretion||Normal/high||High|
|Urine calcium excretion||Normal/high||Low|
|Urinary concentrating ability||Impaired||Normal|
|Urine prostaglandin excretion||High||Normal|
|Age at presentation||Antenatal/neonatal periods||Childhood/adolescence/adult|
|Failure to thrive||Typically present||Absent|
|Growth retardation||Typically present||Rarely present|
|Polyuria and polydipsia||Present||Absent|
|Sensorineural deafness||Present in Type 4 Bartter syndrome||Absent|
|Nephrocalcinosis||Present in Type 1 and Type 2 Bartter syndrome||Absent|
|Muscle weakness/tetany||Occasionally present||Present|
Bartter syndrome results from a primary defect in sodium chloride reabsorption in the thick ascending limb of the loop of Henle (Figure 1). Salt (sodium) wasting results in volume depletion which activates juxtaglomerular secretion of renin and subsequent juxtaglomerular hyperplasia and hyperaldosteronism. Volume depletion and increased distal tubular sodium delivery result in tubular potassium and hydrogen secretion in the urine [11, 12]. Paracellular reabsorption of calcium and magnesium in the thick ascending limb of the loop of Henle is driven by sodium chloride reabsorption in this nephron segment. Reduced sodium absorption here results in hypercalciuria and hypomagnesaemia .
Type 1: mutations
Type 2: mutations in
Type 3: mutations in
Type 4: two mechanisms underlie type 4 Bartter syndrome. Both defects cause severe disease in the antenatal period and present with co-existent congenital deafness. Progressive renal failure is more common but nephrocalcinosis is less commonly seen. Type 4A is a consequence of a defect in the Barttin subunit that is essential to the function of both the chloride channels ClC-Ka and ClC-Kb which are present in both the renal tubule and the stria vascularis of the cochlear (inner ear). Bartter type 4b involves a second mechanism whereby digenic mutations affect both chloride channels (
Type 5: this form of Bartter syndrome is due to a gain of function mutation in
A transient form of Bartter syndrome exists as an X-linked pattern of inheritance which manifests in the antenatal period. This form presents with severe polyhydramnios and prematurity if the foetus survives to this stage. Severe salt wasting results in foetal polyuria and those that survive to birth have spontaneous resolution in symptoms over the first few months/years of life. Mutations in
The apically expressed furosemide sensitive co-transporter/sodium potassium chloride co-transporter (NKCC2) is shown. Mutations in Type 1 Bartter syndrome are associated with dysfunction in this channel, leading to salt wasting. Mutations in the apical potassium channel
Gitelman syndrome differs from Bartter syndrome due to the presence of hypocalciuria and does not typically manifest until adolescence or adulthood. Differentiating Gitelman syndrome from Type 3 Bartter syndrome can be difficult  due to expression of CLCKNB in distal nephron segments as well as the thick ascending limb of the loop of Henle.
Gitelman syndrome results from inactivating mutations in
EAST syndrome (alias SeSAME, OMIM #612780) is causes by mutations in
The apically expressed thiazide sensitive co-transporter/sodium chloride co-transporter (NCCT) is shown. Mutations in Gitelman syndrome are associated with dysfunction in this channel, leading to salt wasting. Mutations in the basolateral potassium channel
Treatment for these in inherited salt wasting alkaloses conditions, in addition to electrolyte replacement, can comprise of NSAIDs, typically indomethacin. Renal production of PGE2 is typically elevated in response to reduced entry of chloride into the macula densa in the end of the thick ascending limb in these conditions . Cyclooxygenase 2 expression is subsequently increased. PGE2 stimulates renin release by the juxtaglomerular apparatus contributing to the phenotype. PGE2 synthesis inhibition by NSAIDS will therefore reverse many of the clinical and biochemical abnormalities found in Bartter syndrome or phenotypically severe Gitelman syndrome (and EAST syndrome) .
4. Pendred Syndrome
Pendred syndrome is an autosomal recessive disorder resulting from biallelic mutations in
Pendrin is expressed on the apical membranes of type B intercalated cells (shown) as well as and non-A, non-B intercalated cells (not shown). Mutations in
4.1. Glucocorticoid remedial Aldosteronism
Glucocorticoid remediable aldosteronism (GRA) is an autosomal dominant inherited cause of hypertension and is one of three known forms of familial hyperaldosteronism. Normally, aldosterone synthesis occurs in the zona glomerulosa of the adrenal gland which intentionally lacks the 17-hydroxylase enzyme to synthesise cortisol. In GRA, aldosterone is synthesised in the ACTH-sensitive zona fasciculata. In the zona glomerulosa, the gene
4.2. Congenital adrenal hyperplasia
Over 95% of patients with congenital adrenal hyperplasia have defective conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol. This is because of a mutation in the
4.3. Apparent mineralocorticoid excess
Mineralocorticoid receptors in the collecting duct bind aldosterone and cortisol with similar affinity. Cortisol is normally converted into its inactive form cortisone by the enzyme 11-beta-hydroxysteroid type 2 at sites of aldosterone activity to prevent competitive inhibition with aldosterone. In AME, a mutation in 11-beta-hydroxysteroid type 2 results in a reduction of cortisol conversion to cortisone and subsequently the mineralocorticoid receptor is activated by excess cortisol. AME is autosomal recessive and causes severe hypertension in children in addition to hypercalciuria, nephrocalcinosis and renal failure due to an unknown mechanism. Nephrogenic diabetes insipidus can also occur due to chronic hypokalaemia. Defects in
4.4. Liquorice ingestion and carbenoxolone
Liquorice (root of
4.5. Liddle syndrome
Liddle syndrome is a rare autosomal dominant disorder associated with a gain of function mutation in the epithelial sodium channel (ENaC) situated on the luminal membrane of principal cells in the collecting duct. In Liddle syndrome, ENaC function is increased which results in hypokalaemia and metabolic alkalosis. Increased activity of ENaC results in increased sodium reabsorption and potassium secretion and subsequent hypertension, hypokalaemia and metabolic alkalosis. Most patients present at a young age and not all have hypokalaemia but their potassium does run at lower range of normal.
Net sodium reabsorption occurs down a concentration gradient in principle cells via both ENaC on the luminal membrane and the Na–K–ATPase on the basolateral membrane. The greater net sodium reabsorption enhances potassium secretion through basolateral Na–K–ATPase and subsequent open luminal potassium channels.
4.6. Cortisol excess
Excess cortisol may allow stimulation of the mineralocorticoid receptor to leading to hypertension and a hypokalemic metabolic alkalosis. Causes include excess exogenous administration of glucocorticoids such as hydrocortisone or secondary to endogenous cortisol hypersecretion either by Cushing’s syndrome or disease, ectopic ACTH production most commonly by small cell lung cancers or by a deoxycorticosterone-secreting tumour on the adrenal gland  (Figure 4).
Principal cells respond to a variety of stimuli to control Na+ and K+ transport. Aldosterone has the most pronounced effect. It acts through the mineralocorticoid receptor (MR) to increase surface expression of the epithelial sodium channel ENaC. Electrogenic Na+ reabsorption via ENaC is balanced by K+ secretion through ROMK and Cl− reabsorption through multiple pathways (not shown). The driving force that sets the electrochemical gradient for principal cell Na+ and K+ transport is the basolateral Na+–K+–ATPase.
5. Reasons to suspect and inherited cause of alkalosis
Clinical features of a metabolic alkalosis include muscle cramps, weakness, arrhythmias and seizures. Some of these signs and symptoms may be related to alterations in ionised calcium (increased pH causes plasma proteins to bind calcium more avidly, thus lowering ionised calcium concentration). The associated hypokalaemia may also give rise to many of these symptoms. Inherited forms of alkalosis are secondary to a heterogeneous group of renal tubulopathies. Typical manifestations range from asymptomatic biochemical disturbances to severe salt wasting leading in early life and may be complicated by renal failure. The important clues to diagnosing an inherited cause of metabolic alkalosis include consistent electrolyte abnormalities (versus acquired changes in serum biochemistry), nephrocalcinosis, renal stone formation and renal impairment. Historical blood values are invaluable in this regard. A detailed family history is required to look for autosomal dominant and recessive patterns of disease. In children, failure to thrive, short stature, learning difficulties and rickets may also be evident. A history of early onset hypertension and a family history of stroke at a young age provides clues to look for inherited forms of hypertension including Liddle syndrome and GRA.
Individual syndromes may be distinguished by distinct biochemical profiles but modern day molecular genetics allows a more robust means to come to a firm diagnosis. A very similar biochemical picture to Bartter and Gitelman syndromes can be induced by diuretic use or abuse, laxative abuse and chronic liquorice ingestion. However, urinary chloride will be raised in Bartter and Gitelman syndromes (>20 mmol/L) whereas vomiting, gastric drainage, diuretics and post-hypercapnia will all have a low urinary chloride concentration (<10 mmol/L). Therefore, obtaining a careful drug and food history is important together with urine electrolyte analysis and diuretic screening to make certain that the cause is not an acquired one. The optimal treatment of a metabolic alkalosis clearly depends on identifying the underlying cause. Treatment of life-threatening alkalosis may involve control of ventilation (sedation, intubation and controlled hypoventilation). Historically, administration of HCl or ammonium chloride/arginine chloride has been advocated. These are not advocated. Control of ventilation and correction of volume status and improvement of renal haemodynamics is effective in cases of chloride loss. Haemodialysis may be used in extreme cases. Hypokalaemia should be corrected alongside the alkalosis. Treatment of Bartter and Gitelman syndrome, as detailed above, relies upon electrolyte replacement, attempts at disrupting the renal production of renin with NSAIDs and blocking the effects of excess mineralocorticoids with spironolactone, eplerenone and amiloride. Treatment of Liddle syndrome relies on sodium restriction and potassium-sparing diuretics which block ENaC and allow the correction of blood pressure, hypokalaemia and metabolic alkalosis.
A systemic metabolic alkalosis is an important electrolyte disturbance which can have significant sequelae including neuromuscular irritability, tetany and cardiac rhythm disturbances. Hypokalaemia is a frequent accompanying electrolyte abnormality. Numerous inherited tubulopathies can cause this clinical and biochemical picture and acquired causes may mimic these. Molecular genetic testing allows a precise diagnosis and appropriate management to be given to patients with inherited salt wasting alkaloses.