Alagille syndrome

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 requires transplantation. It is uncommon, but Alagille syndrome can be a life-threatening disease with a mortality rate of 10%. The majority of deaths from ALGS are typically due to heart complications or chronic liver failure. Liver Signs and symptoms arising from liver damage in Alagille syndrome may include a yellowish tinge in the skin and the whites of the eyes (jaundice), itching (pruritus), pale stools (acholia), an enlarged liver (hepatomegaly), an enlarged spleen (splenomegaly) and deposits of cholesterol in the skin (xanthomas). A liver biopsy may indicate too few bile 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 a failure to thrive. Cirrhosis and eventual liver failure is fairly common among ALGS patients, and 15% of those with severe hepatic manifestations require a liver transplant. Hepatocellular cancer has been reported in a small number of cases, but it is extremely rare. Heart 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 is stenosis/hypoplasia of the branch pulmonary arteries. This pulmonary artery stenosis can range in severity, and may progress over time. If left untreated, patients may develop right ventricular hypertrophy, elevated right-sided pressures, and eventually right-sided heart failure. Some other cardiac abnormalities associated with Alagille syndrome include Tetralogy 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 significant cyanotic 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 or congenital 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 Other presentations of Alagille's syndrome include butterfly vertebrae, ophthalmic defects, and distinct facial structures. The butterfly 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. 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. The kidneys may also be affected because the mutations in JAG1 and NOTCH2 often lead to renal dysplasia, deformed proximal tubules, or lipidosis caused by the hindrance of lipid metabolism. == Genetics ==

ALGS is most commonly caused by a loss of function mutations in JAG1 (Jagged1), and less commonly in NOTCH2 (Notch homolog 2). The JAG1 mutation is either intragenic and found on chromosome 20p12, or it is a deletion of the entire JAG1 gene. Mutations in NOTCH2 are much less likely to cause Alagille syndrome, but the primary type of ALGS-causing mutation in NOTCH2 is a missense mutation. A missense mutation is a point mutation that changes one nucleotide, which results in a codon that codes for the wrong amino acid. Alagille syndrome is inherited in an autosomal 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 an autosome, which is one of the 44 chromosomes in the human body that is not a sex chromosome (chromosome X or Y). Although the majority of cases are due to the autosomal dominant gene, there have been reports of a rare, autosomal recessive version of the disease. == Pathophysiology ==

JAG1 and NOTCH2 encode for proteins that are crucial to the notch 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. 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. == Diagnosis ==

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. 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 a heart murmur, and a liver biopsy to detect liver disease or any precursors. If a patient presents with multiple symptoms such as jaundice, heart murmur, and the characteristic facial features discussed above (deep set eyes, broad brow, etc.), they are likely to be diagnosed with Alagille syndrome. It is important to distinguish Alagille syndrome from biliary atresia because the latter benefits from a Kasai procedure in the early postnatal period, whereas this operation would make Alagille syndrome worse.. Indirect features on ultrasound of biliary atresia include abnormal and diminutive gallbladder shape, the triangular cord sign, and hepatic artery enlargement, though these can overlap with Alagille syndrome. == Treatment ==

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 improve bile excretion from the liver, reduce pain caused by the disease, and help improve nutritional deficiencies. Diet can also be a crucial factor in improving quality of life when living with ALGS. Medication Several medications are used to improve bile flow, including ursodiol (Actigall or Urso). Surgery 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. Partial biliary diversion has been used to significantly reduce pruritus, jaundice, and xanthoma 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 created stoma into a plastic pouch on the patient's lower right abdomen. The pouch is periodically drained as it fills with bile. Patients with biliary atresia may require a Kasai procedure to improve bile drainage; however, later liver transplantation is still often necessary. == See also ==