Alagille syndrome is a genetic disorder that affects primarily the liver and the heart.
The disorder generally become evident in infancy or early childhood.
The disorder is inherited in an autosomal dominant pattern.
Estimated prevalence of Alagille syndrome is 1 in every 30,000 to 1 in every 40,000 live births.
Symptoms ranging from so mild as to go unnoticed, to severe heart and/or liver disease that requires transplantation.
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.
Signs and symptoms arising from liver damage in Alagille syndrome: jaundice, pruritus, pale stools, hepatomegaly, splenomegaly and xanthomas.
Liver biopsy shows too few bile ducts or, in some cases, biliary atresia.
Bile duct paucity results in the reduced absorption of fat and fat-soluble vitamins (A, D, E, K).
Cirrhosis and eventual liver failure is fairly common.
15% of those with severe hepatic manifestations require a liver transplant.
Hepatocellular cancer is extremely rare.
Tetralogy of Fallot is a common heart associated defect in Alagille syndrome.
Common findings include congenital heart problems varying from heart murmurs to significant structural abnormalities, such as Tetralogy of Fallot, pulmonary stenosis, overriding aorta, ventricular septal defect, right ventricular hypertrophy, ventricular septal defect, atrial septal defect, patent ductus arteriosus, and coarctation of the aorta.
The mortality rate of Tetralogy of Fallot when untreated ranges from 70% by age 10 to 95% by age 40.
Surgical repair can significantly improve both longevity and quality of life in patients with Alagille syndrome.
Other aspects of Alagille’s syndrome include: asymptomatic butterfly vertebrae, ophthalmology defects, distinct facial structures, spina bifida, the fusion of vertebrae, ophthalmological defects affect the anterior chamber of the eyeball, and retina pigment changes.
Patients with ALGS may have similar facial features, including a broad, prominent forehead, deep-set eyes, and a small pointed chin.
These features are not due to Alagille syndrome, but are characteristic of patients with intrahepatic cholestatic liver disease.
Facial characteristics are extremely common in ALGS patients, due to 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.
It is caused by loss of function mutations in either JAG1 (Jagged1) or NOTCH2 homolog.
In the majority of people with ALGS, the gene mutation occurs in the JAG1 gene.
The JAG1 mutation is either found on chromosome 20p12, or it is a deletion of the entire JAG1 gene.
Mutations in NOTCH2 can cause Alagille syndrome, less commonly with a missense mutation.
The majority of cases are due to the autosomal dominant gene, there have been reports of a rare, autosomal recessive version of the disease.
About 40% of the mutations are inherited from affected parents.
Most cases of Alagille syndrome result from new, acquired mutations.
Environmental factors that can result in gene mutations include: radiation such as ultraviolet rays from the sun, or chemicals such as benzene, which is found in cigarette smoke.
JAG1 and NOTCH2 encode for proteins that are crucial to the notch gene–signaling cascade.
JAG1 encodes for a surface-binding ligand that regulates the notch signaling pathway, playing a crucial role in cell signaling during embryonic development.
If the notch signaling pathway is disrupted due to mutations, an infant will not develop properly.
Alagille syndrome causes bile duct paucity, with narrow and malformed bile ducts, resulting in bile build up in the liver, resulting in scarring of the liver which hinders the liver’s normal functions.
It impairs the liver’s, blood filtration and drug metabolism roles.
The notch gene–signaling cascade is also important for cell–cell recognition, involving gene regulation mechanisms that control multiple cell differentiation processes during embryonic and adult life, and is specially important for:
Atrioventricular (AV) canal development
Ventricular development
Ventricle outflow tract development
Angiogenesis
Pancreatic development
Intestinal development
Bone development
Respiratory system development
Neuron cell differentiation
Neurite development
Gliogenesis
Adult brain function
Diagnosis is extremely difficult.
It is is almost always diagnosed later during childhood.
The severity of the disease varies widely among patients, making diagnosis difficult.
Clinical testing include vertebral x-rays, heart exams, and a liver biopsy.
Suggested clinical findings are multiple symptoms such as jaundice, heart murmur, and the characteristic facial features of deep set eyes, and broad brow.
A specific diagnosis can be done with genetic testing.
Next-generation sequencing can be utilized to detect single nucleotide polymorphisms (SNPs) in the affected gene(s).
Treatment
Early treatment is possible.
Treatments involve medications, therapies, and/or surgical procedures.
Treatments aim to improve bile excretion from the liver, reduce pain caused by the disease, and help improve nutritional deficiencies.
Diet can improve quality of life.
Medications used to improve bile flow, including ursodeoxycholic acid.
Some drugs may be used to reduce pruritus, such as cholestyramine and rifampin.
Itching often is reduced when bile flow is improved via ursodeoxycholic acid or liver transplant.
Patients benefit from vitamin 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 required, and often requires
gastrostomy tube to maintain the high caloric intake.
Maralixibat (Livmarli) is an orally-administered, small-molecule ileal bile acid transporter inhibitor for the treatment of rare cholestatic liver diseases including Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC) and biliary atresia.
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.
Liver transplants can be difficult in ALGS patients because heart defects are common along with the liver failure.
Biliary diversion procedures have 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.
Patients with biliary atresia may require a Kasai procedure to improve bile drainage.