PatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.
Hypokalaemic metabolic alkalosis may be caused by diarrhoea, vomiting, laxative or diuretic abuse, liquorice ingestion, antacid medication abuse or excess alcohol intake. Certain endocrine disorders (eg, primary hyperaldosteronism, congenital adrenal hyperplasia and Cushing's syndrome) may also cause hypokalaemic alkalosis. Hypokalaemia may cause metabolic alkalosis and metabolic alkalosis may cause hypokalaemia.
Liddle's syndrome is an autosomal dominant disorder characterised by early, and frequently severe, hypertension associated with hypokalaemic metabolic alkalosis, low plasma renin activity, and suppressed aldosterone secretion. Liddle's syndrome is caused by a genetic defect in the collecting tubule sodium channel, resulting in increased sodium reabsorption. Liddle's syndrome requires lifelong treatment with a potassium-sparing diuretic (but not spironolactone).
Hypokalaemic alkalosis may also be caused by rare salt-losing tubulopathies with secondary hyperaldosteronism, such as Bartter's syndrome and Gitelman's syndrome. The remainder of this article is about these rare conditions.
Gitelman's syndrome, also known as familial hypokalaemic hypomagnesaemia, is a rare autosomal recessive hereditary salt-losing tubulopathy, characterised by hypokalaemic metabolic alkalosis, hypomagnesaemia, and hypocalciuria, which is usually caused by mutations in the SLC12A3 gene encoding the thiazide-sensitive sodium chloride transporter.
Bartter's syndrome refers to a group of autosomal recessive disorders with impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalaemic metabolic alkalosis, and hypercalciuria.
Bartter's syndrome or Gitelman's syndrome can be differentiated by:
- Hypokalaemic alkalosis with hypercalciuria (true Bartter's syndrome).
- Hypokalaemic alkalosis with hypocalciuria (Gitelman's syndrome).
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- Gitelman's syndrome is the most common renal tubular disorder among Caucasians (prevalence of 1 in 40,000). Most patients have onset of symptoms as adults, but some can present in childhood.
- Bartter's syndrome is rare. Clinically, Bartter's syndrome can be classified into two variants, antenatal/neonatal and classic, according to the onset age. Genetically, Bartter's syndrome can be classified into at least five subtypes according to underlying mutant genes.
The primary problem is loss of excessive amounts of sodium and potassium in the urine. This leads to hypovolaemia and secondary hyperaldosteronism.
Patients with Bartter's syndrome may present with symptoms, often quite severe in the neonatal period. However, patients with classic Bartter's syndrome (type 3) present later in life and may be sporadically asymptomatic or mildly symptomatic. The severe, steady-state hypokalaemia in Bartter's syndrome and Gitelman's syndrome may abruptly become life-threatening under certain aggravating conditions.
- True Bartter's syndrome patients usually present aged >5 years with signs of vascular volume depletion, polyuria, and polydipsia.
- Most patients with Gitelman's syndrome have onset of symptoms as adults, but some can present in childhood. Clinical features include transient periods of muscle weakness and tetany, abdominal pains, and chondrocalcinosis.
- Other features include:
- Short stature.
- Hyperactive renin-angiotensin system (plasma renin increased, lack of effect of angiotensin on blood pressure, renal potassium wasting, increased renal prostaglandin production and, occasionally, hypomagnesemia).
- Impaired urinary concentrating ability.
- Muscle weakness and neuromuscular irritability may occur especially in Gitelman's syndrome.
- Can also present in utero with resulting prematurity or polyhydramnios.
- Biochemistry reveals hypokalaemia, hypochloraemic metabolic alkalosis, and increased urinary potassium and chloride (but normal blood pressure and no oedema).
- In Bartter's syndrome there is normocalcaemia and normomagnesaemia.
- Hypomagnesaemia is seen in Gitelman's syndrome.
- 12-lead ECG - half of Gitelman's syndrome patients have prolonged QT interval. This can lead to ventricular tachycardia and sudden death.
- Electrolyte replacement - eg, potassium, magnesium and sometimes sodium. This needs to be individualised and depends on symptoms.
- Non-steroidal anti-inflammatory drugs and selective cyclo-oxygenase-2 (COX-2) inhibitors have also been used.
- Other treatments have also been tried with differing results; for example, potassium-sparing diuretics - amiloride, angiotensin-converting enzyme (ACE) inhibitors, spironolactone and eplerenone.
In Bartter's syndrome, there is an over-activation of renin-angiotensin-aldosterone system and an over-production of prostaglandins, which are both due to sodium, chloride and potassium urinary wasting. Therefore, the recommended treatment has been based on potassium supplementation and a prostaglandin inhibitor; spironolactone1 is also an option, but with transient effect, and ACE inhibitors have been used in some studies. The treatment is similar for Gitelman's syndrome.
There have been reports of progressive renal impairment in Bartter's syndrome and Gitelman's syndrome. This may relate to chronic hypokalaemia (which can cause tubulo-interstitial damage) or glomerulosclerosis.
Frederic Crosby Bartter first described the syndrome of hypokalaemia, alkalosis, hyperaldosteronism and juxtaglomerular hyperplasia with normal blood pressure in two patients aged 5 and 25 years.
In 1966, Hillel J Gitelman described the variant which presents at a later age than Bartter's syndrome and with hypocalciuria.
Further reading & references
- Kim JB; Channelopathies. Korean J Pediatr. 2014 Jan;57(1):1-18. doi: 10.3345/kjp.2014.57.1.1. Epub 2014 Jan 31.
- Tabasum A, Shute C, Datta D, et al; A man with a worrying potassium deficiency. Endocrinol Diabetes Metab Case Rep. 2014;2014:130067. doi: 10.1530/EDM-13-0067. Epub 2014 Feb 1.
- Gawarammana IB, Coburn J, Greene S, et al; Severe hypokalaemic metabolic alkalosis following ingestion of gaviscon. Clin Toxicol (Phila). 2007;45(2):176-8.
- Liddle syndrome; Online Mendelian Inheritance in Man (OMIM)
- Seyberth HW, Schlingmann KP; Bartter- and Gitelman-like syndromes: salt-losing tubulopathies with loop or DCT defects. Pediatr Nephrol. 2011 Oct;26(10):1789-802. doi: 10.1007/s00467-011-1871-4. Epub 2011 Apr 19.
- Nakhoul F, Nakhoul N, Dorman E, et al; Gitelman's syndrome: a pathophysiological and clinical update. Endocrine. 2012 Feb;41(1):53-7. doi: 10.1007/s12020-011-9556-0. Epub 2011 Nov 15.
- Graziani G, Fedeli C, Moroni L, et al; Gitelman syndrome: pathophysiological and clinical aspects. QJM. 2010 Oct;103(10):741-8. doi: 10.1093/qjmed/hcq123. Epub 2010 Jul 22.
- Bartter syndrome Type 3 (Classic); Online Mendelian Inheritance in Man (OMIM)
- Gitelman syndrome; Online Mendelian Inheritance in Man (OMIM)
- Lee SE, Han KH, Jung YH, et al; Renal transplantation in a patient with Bartter syndrome and glomerulosclerosis. Korean J Pediatr. 2011 Jan;54(1):36-9. doi: 10.3345/kjp.2011.54.1.36. Epub 2011 Jan 31.
- Fremont OT, Chan JC; Understanding Bartter syndrome and Gitelman syndrome. World J Pediatr. 2012 Feb;8(1):25-30. doi: 10.1007/s12519-012-0333-9. Epub 2012 Jan 27.
- Pachulski RT, Lopez F, Sharaf R; Gitelman's not-so-benign syndrome. N Engl J Med. 2005 Aug 25;353(8):850-1.
- Zanolari Calderari M, Vigier RO, Bettinelli A, et al; Electrocardiographic QT prolongation and sudden death in renal hypokalemic Nephron. 2002 Aug;91(4):762-3.
- Unwin RJ, Capasso G; Bartter's and Gitelman's syndromes: their relationship to the actions of loop and thiazide diuretics. Curr Opin Pharmacol. 2006 Apr;6(2):208-13. Epub 2006 Feb 20.
- O'Shaughnessy KM, Karet FE; Salt handling and hypertension. Annu Rev Nutr. 2006;26:343-65.
- Nascimento CL, Garcia CL, Schvartsman BG, et al; Treatment of Bartter syndrome. Unsolved issue. J Pediatr (Rio J). 2014 May 27. pii: S0021-7557(14)00066-7. doi: 10.1016/j.jped.2014.01.012.
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Dr Colin Tidy
Dr Colin Tidy
Dr Adrian Bonsall