| Alagille syndrome | |
|---|---|
| Other names | Alagille–Watson syndrome (ALGS), hepatic ductular hypoplasia |
 | |
| Alagille syndrome is inherited in an autosomal dominant manner | |
| Specialty | Medical genetics,Gastroenterology,Cardiology |
| Named after | Daniel Alagille |
Alagille syndrome (ALGS) is agenetic disorder that affects primarily theliver and theheart. Problems associated with the disorder generally become evident in infancy or early childhood. The disorder is inherited in an autosomal dominant pattern, and the estimated prevalence of Alagille syndrome is 1 in every 30,000[1][2] to 1 in every 40,000 live births. It is named after the French pediatricianDaniel Alagille, who first described the condition in 1969.[3][4] Children with Alagille syndrome live to the age of 18 in about 90% of the cases.[5]
The severity of the disorder can vary within the same family, with symptoms ranging from so mild as to go unnoticed, to severe heart and/or liver disease that requirestransplantation.[6] It is uncommon, but Alagille syndrome can be a life-threatening disease with a mortality rate of 10%.[7] The majority of deaths from ALGS are typically due to heart complications or chronic liver failure.[8]
Signs and symptoms arising from liver damage in Alagille syndrome may include a yellowish tinge in theskin and the whites of the eyes (jaundice), itching (pruritus), pale stools (acholia), an enlarged liver (hepatomegaly), an enlarged spleen (splenomegaly) and deposits ofcholesterol in the skin (xanthomas).[9] Aliver biopsy may indicate too fewbile ducts (bile duct paucity) or, in some cases, the complete absence of bile ducts (biliary atresia). Bile duct paucity results in the reduced absorption of fat and fat-soluble vitamins (A, D, E and K), which may lead to rickets or afailure to thrive.Cirrhosis and eventualliver failure is fairly common among ALGS patients, and 15% of those with severehepatic manifestations require a liver transplant.[10]Hepatocellular cancer has been reported in a small number of cases, but it is extremely rare.[11]
Cardiac manifestations are a common feature of Alagille syndrome, and can be found in a majority of patients diagnosed with the condition. The most frequently occurring structural abnormality isstenosis/hypoplasia of the branchpulmonary arteries. This pulmonary artery stenosis can range in severity, and may progress over time. If left untreated, patients may developright ventricular hypertrophy, elevated right-sided pressures, and eventually right-sidedheart failure. Some other cardiac abnormalities associated with Alagille syndrome includeTetralogy of Fallot, pulmonary valve stenosis, interrupted aortic arch, or atrial and ventricular septal defects, but these are seen less frequently. Clinical presentations of these cardiac lesions can range from subtle murmurs to significantcyanotic heart disease. The severity of cardiac involvement has been shown to directly correlate to prognosis and long-term outcomes for patients. If the right-sided outflow obstruction orcongenital heart defect is considered too significant, then the risk of morbidity and mortality increases drastically. Thus, it is important for patients with cardiac symptoms to receive a comprehensive evaluation to start. Ongoing surveillance is needed going forward due to improved patient outcomes with early detection of cardiac disease and hemodynamic instability.
Other presentations of Alagille's syndrome includebutterfly vertebrae,ophthalmic defects, and distinct facial structures. Thebutterfly vertebrae can be detected with an x-ray, but there typically are no symptoms from this abnormality. Other skeletal defects common in ALGS patients are spina bifida and the fusion of vertebrae.[10] Most of the ophthalmological defects affect theanterior chamber of the eyeball, includingAxenfeld's anomaly and Rieger anomaly, butretina pigment changes are also common.[10] These anomalies can be beneficial in diagnosing Alagille syndrome. Many people with ALGS have similar facial features, including a broad, prominent forehead, deep-set eyes, and a small pointed chin. While these distinct facial features are often presented in ALGS patients, the features are presumably not due to Alagille syndrome, but they are characteristic of patients with intrahepaticcholestatic liver disease.[12] So while these facial characteristics are extremely common in ALGS patients, it is because many patients experience extreme liver complications or liver failure, but it is not caused by the disease itself. Thekidneys may also be affected because the mutations inJAG1 andNOTCH2 often lead torenal dysplasia, deformedproximal tubules, orlipidosis caused by the hindrance oflipid metabolism.[13]
ALGS is most commonly caused by a loss of function mutations inJAG1 (Jagged1), and less commonly inNOTCH2 (Notch homolog 2).[14][15] TheJAG1 mutation is either intragenic and found onchromosome 20p12, or it is a deletion of the entireJAG1 gene.[16] Mutations inNOTCH2 are much less likely to cause Alagille syndrome, but the primary type of ALGS-causing mutation inNOTCH2 is amissense mutation.[17] Amissense mutation is apoint mutation that changes onenucleotide, which results in acodon that codes for the wrongamino acid. Alagille syndrome is inherited in anautosomal dominant pattern, which means one copy of the altered gene is sufficient to cause the disorder. The "autosomal" aspect of the disease means that the gene mutation occurs in anautosome, which is one of the 44 chromosomes in the human body that is not asex chromosome (chromosome X or Y). Although the majority of cases are due to theautosomal dominant gene, there have been reports of a rare, autosomal recessive version of the disease.[16] In the autosomal recessive case, the ALGS patient must inherit two mutated genes: one from each parent. Although about 40% of the mutations are inherited from affected parents, most cases result from new, acquired mutations. These are caused by environmental factors that mutate one copy of the gene.[17] Environmental factors that can result in gene mutations may include radiation such as ultraviolet rays from the sun, or chemicals such asbenzene, which is found in cigarette smoke.[18]
JAG1 andNOTCH2 encode for proteins that are crucial to thenotch gene–signaling cascade. Specifically,JAG1 encodes for a surface-binding ligand that regulates the notch signaling pathway. It plays a crucial role in cell signaling during embryonic development. If the pathway is disrupted due to mutations, an infant will not develop properly.[6] Alagille syndrome causes bile duct paucity, which is characterized by narrow and malformed bile ducts. Bile duct paucity causes bile to build up in the liver, resulting in scarring of the liver which hinders the liver's normal functions, like blood filtration and drug metabolism.[6]
Alagille syndrome can be extremely difficult to diagnose. While people are born with ALGS, it is almost always diagnosed later during childhood. The diagnosis can be difficult because the severity of the disease varies widely among patients.[19] Some common clinical tests that are run in order to diagnose the disease include vertebral x-rays, heart exams to detect any defects such as aheart murmur, and aliver biopsy to detect liver disease or any precursors. If a patient presents with multiple symptoms such asjaundice,heart murmur, and the characteristic facial features discussed above (deep set eyes, broad brow, etc.), they are likely to be diagnosed with Alagille syndrome.[19] A more calculated and specific diagnosis can be done withgenetic testing.Next-generation sequencing can be utilized to detectsingle nucleotide polymorphisms (SNPs) in the affected gene(s).Multiplex ligation-dependent probe amplification (MLPA) can detect large deletions and/or insertions and microarray comparative genomic hybridization is used to improve the accuracy of MLPA.[20]
It is important to distinguish Alagille syndrome frombiliary atresia because the latter benefits from aKasai procedure in the early postnatal period, whereas this operation would make Alagille syndrome worse.[citation needed]. Indirect features on ultrasound of biliary atresia include abnormal and diminutive gallbladder shape, the triangular cord sign, andhepatic artery enlargement, though these can overlap with Alagille syndrome.[21]
Early treatment is possible once the disease is diagnosed. Treatments of Alagille syndrome typically involve medications, therapies, and/or surgical procedures. All treatments aim to improvebile excretion from the liver, reduce pain caused by the disease, and help improve nutritional deficiencies.[22] Diet can also be a crucial factor in improving quality of life when living with ALGS.[23]
Several medications are used to improve bile flow, includingursodiol (Actigall or Urso).[22] These medications differ in their rates of success. Certain drugs may be used to reduce itching (pruritus), such ascholestyramine andrifampin. While these medications can reducepruritus, the itching often is reduced when bile flow is improved viaursodiol orliver transplant.[22]
Many patients with Alagille syndrome have nutritional and/ormalabsorption issues which often hinders normal growth. Patients benefit fromvitamin A, D, E, and K supplements because the reduced bile flow makes it difficult to absorb and utilize these vitamins. A high-calorie diet is very important, and often requires agastrostomy tube to maintain the high caloric intake.[2]
Maralixibat (Livmarli) was approved for medical use in the United States in September 2021.[24][25]
Surgery is common in more severe cases on Alagille syndrome, especially for patients with liver disease or end-stage liver failure.Liver transplants can either be a complete liver transplant from a deceased organ donor, or a partial transplant from a living donor.[26][27]
Partial biliary diversion has been used to significantly reducepruritus,jaundice, andxanthoma caused by poor bile flow in patients with bile duct paucity. A portion of the bile produced by the liver is directed through a surgically createdstoma into a plastic pouch on the patient's lower right abdomen. The pouch is periodically drained as it fills with bile. Patients withbiliary atresia may require aKasai procedure to improve bile drainage; however, later liver transplantation is still often necessary.[28]
This article incorporates public domain text fromThe U.S. National Library of Medicine