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 autosom ...

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

high blood pressure Hypertension (HTN or HT), also known as high blood pressure (HBP), 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. Long-term high bl ...

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 ...

activity,

metabolic alkalosis Metabolic alkalosis is a metabolic condition 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 direct resu ...

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

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...

function, with excess reabsorption of

sodium Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable ...

and loss of

potassium Potassium is the chemical element with the symbol K (from Neo-Latin '' kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmos ...

from the renal tubule, 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 (HTN or HT), also known as high blood pressure (HBP), 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. Long-term high b ...

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

nonspecific symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showi ...

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

shortness of breath Shortness of breath (SOB), also medically 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 di ...

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

/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's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the chan ...

(

ENaC The epithelial sodium channel (ENaC), (also known as amiloride-sensitive sodium channel) is a membrane-bound ion channel that is selectively permeable to sodium ions (). It is assembled as a heterotrimer composed of three homologous subunits α ...

) 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 1980s. Fo ...

proteasome Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by whi ...

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 one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellu ...

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 system is the last part of nephron and participates in elect ...

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 a c ...

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 In cell biology, extracellular fluid (ECF) denotes all body fluid outside the cells of any multicellular organism. Total body water in healthy adults is about 60% (range 45 to 75%) of total body weight; women and the obese typically have a lower ...

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 Hyperaldosteronism is a medical condition wherein too much aldosterone is produced by the adrenal glands, which can lead to lowered levels of potassium in the blood ( hypokalemia) and increased hydrogen ion excretion (alkalosis). This cause of m ...

(also known as

Conn's syndrome Primary aldosteronism (PA)'','' also known as primary hyperaldosteronism or Conn's syndrome, refers to the excess production of the hormone aldosterone from the adrenal glands, resulting in low renin levels and high blood pressure. This abnormalit ...

), is due to an aldosterone-secreting adrenal tumor (

adenoma An adenoma is a benign tumor of epithelial tissue with glandular origin, glandular characteristics, or both. Adenomas can grow from many glandular organs, including the adrenal glands, pituitary gland, thyroid, prostate, and others. Some adenom ...

) or

adrenal hyperplasia The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex which ...

. 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 refers 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 steroidal aldosteron ...

, 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 a medication that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It is also used in the treatment of high blood press ...

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 American(s) may refer to: * American, something of, from, or related to the United States of America, commonly known as the "United States" or "America" ** Americans, citizens and nationals of the United States of America ** American ancestry, pe ...

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 research university in Nashville, Tennessee. Founded in 1873, it was named in honor of shipping and rail magnate Cornelius Vanderbilt, who provided the school its initial $1-million ...

, 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 symptoms of low potassium, renin, and aldosterone.

References

External links

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