Liddle's syndrome, also called Liddle syndrome, is a genetic disorder inherited in an

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosome ...

dominant manner that is characterized by early, and frequently severe,

high blood pressure Hypertension, also known as high blood pressure, is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms itself. It is, however, a major ri ...

associated with low plasma

renin Renin ( etymology and pronunciation), also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body's renin-angiotensin-aldosterone system (RAAS)—also known as the reni ...

activity,

metabolic alkalosis Metabolic alkalosis is an acid-base disorder in which the pH of tissue is elevated beyond the normal range (7.35–7.45). This is the result of decreased hydrogen ion concentration, leading to increased bicarbonate (), or alternatively a dire ...

, low blood potassium, and normal to low levels of aldosterone. Liddle syndrome involves abnormal

kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...

function, with excess reabsorption of

sodium Sodium is a chemical element; it has Symbol (chemistry), symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 element, group 1 of the peri ...

and loss of

potassium Potassium is a chemical element; it has Symbol (chemistry), symbol K (from Neo-Latin ) and atomic number19. It is a silvery white metal that is soft enough to easily cut with a knife. Potassium metal reacts rapidly with atmospheric oxygen to ...

from the

renal tubule The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure ...

, and is treated with a combination of low sodium diet and potassium-sparing diuretics (e.g. amiloride). It is extremely rare, with fewer than 30 pedigrees or isolated cases having been reported worldwide as of 2008.

Signs and symptoms

Children with Liddle syndrome are frequently asymptomatic. The first indication of the syndrome often is the incidental finding of hypertension during a routine physical exam. Because this syndrome is rare, it may only be considered by the treating physician after the child's

hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

does not respond to medications for lowering blood pressure. Adults could present with

nonspecific symptom Signs and symptoms are diagnostic indications of an illness, injury, or condition. Signs are objective and externally observable; symptoms are a person's reported subjective experiences. A sign for example may be a higher or lower temperature ...

s of low blood potassium, which can include weakness, fatigue, palpitations or muscular weakness (

shortness of breath Shortness of breath (SOB), known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that con ...

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...

/abdominal distention or exercise intolerance). Additionally, long-standing hypertension could become symptomatic.

Cause

This syndrome is caused by dysregulation of the epithelial

sodium channel Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell (biology), cell's cell membrane, membrane. They belong to the Cation channel superfamily, superfamily of cation channels. Classific ...

( ENaC) due to a genetic mutation at the 16p13-p12 locus. These channels are found on the surface of epithelial cells found in the kidneys, lungs, and sweat glands. The ENaC transports sodium ions from the adjacent lumen into the epithelial cells that line the lumen. The mutation changes a domain in the channel so it is no longer degraded correctly by the

ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 19 ...

proteasome Proteasomes are essential protein complexes responsible for the degradation of proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are found inside all e ...

system. Specifically, the PY motif in the protein is deleted or altered so the E3 ligase (Nedd4) no longer recognizes the channel. This loss of ability to be degraded leads to high amounts of the channel being chronically present on the apical membrane of the

epithelial Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...

cells that line the

collecting duct The collecting duct system of the kidney consists of a series of tubules and ducts that physically connect nephrons to a minor calyx or directly to the renal pelvis. The collecting duct participates in electrolyte and fluid balance through rea ...

s of the kidney. This results in a hyperaldosteronism-like state, since

aldosterone Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays ...

is typically responsible for creating and inserting these channels. The increased sodium resorption leads to increased resorption of water, and hypertension due to an increase in extracellular volume.

Diagnosis

Evaluation of a child with persistent high blood pressure usually involves analysis of blood electrolytes and an aldosterone level, as well as other tests. In Liddle's disease, the serum sodium is typically elevated, the serum potassium is reduced, and the serum bicarbonate is elevated. These findings are also found in hyperaldosteronism, another rare cause of hypertension in children. Primary hyperaldosteronism (also known as Conn's syndrome), is due to an aldosterone-secreting adrenal tumor (

adenoma An adenoma is a benign tumor of epithelium, epithelial tissue with glandular origin, glandular characteristics, or both. Adenomas can grow from many glandular organ (anatomy), organs, including the adrenal glands, pituitary gland, thyroid, prosta ...

) or adrenal hyperplasia. Aldosterone levels are high in hyperaldosteronism, whereas they are low to normal in Liddle syndrome. A genetic study of the ENaC sequences can be requested to detect mutations (deletions, insertions, missense mutations) and get a diagnosis.

Treatment

The treatment is a

potassium-sparing diuretic Potassium-sparing diuretics or antikaliuretics refer to drugs that cause diuresis without causing potassium loss in the urine. They are typically used as an adjunct in management of hypertension, cirrhosis, and congestive heart failure. The ster ...

, such as amiloride, that directly blocks the sodium channel. Potassium-sparing diuretics that are effective for this purpose include amiloride and triamterene;

spironolactone Spironolactone, sold under the brand name Aldactone among others, is classed as a diuretic medication. It can be used to treat edema, fluid build-up due to hepatic cirrhosis, liver disease or kidney disease. It is also used to reduce risk o ...

is not effective because it acts by regulating aldosterone and Liddle syndrome does not respond to this regulation. Amiloride is the only treatment option that is safe in pregnancy. Medical treatment usually corrects both the hypertension and the hypokalemia, and as a result these patients may not require any potassium replacement therapy. Liddle syndrome resolves completely after

kidney transplantation Kidney transplant or renal transplant is the organ transplant of a kidney into a patient with end-stage kidney disease (ESRD). Kidney transplant is typically classified as deceased-donor (formerly known as cadaveric) or living-donor transplantat ...

History

It is named after Dr. Grant Liddle (1921–1989), an American

endocrinologist Endocrinology (from ''endocrine'' + '' -ology'') is a branch of biology and medicine dealing with the endocrine system, its diseases, and its specific secretions known as hormones. It is also concerned with the integration of developmental events ...

Vanderbilt University Vanderbilt University (informally Vandy or VU) is a private university, private research university in Nashville, Tennessee, United States. Founded in 1873, it was named in honor of shipping and railroad magnate Cornelius Vanderbilt, who provide ...

, who described it in 1963.Liddle GW, Bledose T and Coppage Jr WS. A familial renal disorder simulating primary aldosteronism with negligible aldosterone secretion (1963). Trans. Assoc. Am. Physicians, 76, 199–213. Liddle described the syndrome in a family of people exemplifying a heritable, autosomal dominant hypertension with low potassium, renin, and aldosterone.

References

External links

* {{DEFAULTSORT:Liddle's Syndrome Autosomal dominant disorders Rare syndromes Endocrine diseases