Alagille’s syndrome

Introduction

Alagille’s syndrome is a syndrome in which the number of intrahepatic bile ducts is markedly reduced, bile stasis is present, and cardiovascular, skeletal, eye, facial, pancreatic and neurodevelopmental disorders may be accompanied.

The prevalence of the disease is reportedly one in 100,000, but the frequency is expected to be greater if the symptoms of the disease include milder patients.

Symptoms

Clinical symptoms of Alagille’s syndrome usually develop within three months. Most cases of jaundice and cholestasis persist in the neonatal period and require differential diagnosis between biliary atresia and non-symptomatic hepatobiliary insufficiency. Later in childhood, chronic liver disease can be found and later in adulthood. Diagnosis can be difficult because the clinical symptoms are diverse and can be inherited incompletely.

Hepatobiliary Problems

Most patients develop symptoms of jaundice, bile stasis, itching and progressive liver failure during infancy. However, the degree of liver disease is not proportional to the symptoms of other organs. Hepatomegaly may occur, and blood tests raise bile acid, direct bilirubin, alkaline phosphatase, and glutamyl transpeptidase, indicating impaired bile excretion. Jaundice is observed in most patients, lasting until late childhood in more than half of patients. Itching occurs due to cholestasis, and some children develop xanthoma in the subcutaneous tissue. Hepatic synthesis is relatively well preserved but can progress to cirrhosis and liver failure in about 20% of patients.

Nutrition Problems and Growth Disorders

The excretion of bile acids is not smooth, so there is a lack of fat, essential fatty acids, and fat-soluble vitamins. Growth disorders occur in 50-90% of patients and are accompanied by delayed puberty, which is known to be associated with malformations of the spine and skeletal system and endocrine disorders, in addition to nutritional imbalances.

Cardiovascular Problems

Heart noise is a symptom found in 97% of patients. The most common lesion is stenosis of the pulmonary artery, which is known to invade both the proximal and distal parts. Other lesions may be associated with the Tetralogy of Fallot (TOF) and other lesions include truncus arteriosus, atrial septal defect, and arteriovascular patency. Heart disease is an important factor that can affect the prognosis when liver transplantation is performed due to liver failure. Therefore, when examining the patients with allergy syndrome, heart noise should be checked and echocardiography should be performed.

Characteristic Face Shape

Facial features in children with Alagille’s syndrome are characteristic. The forehead is protruding, the gap between the eyebrows is wide, the eye is deep, the chin is small and has a saddle shape or a straight nose. These facial appearances may appear prominent upon birth or may become apparent as they grow up. Characteristic facial features are very important for the diagnosis of allergy syndrome and should be considered when diagnosing newborn cholestasis.

Spinal and Musculoskeletal Abnormalities

A typical aspect of spinal malformations is the butterfly-shaped vertebrae, a lesion in which the torso part of the spine is divided vertically. Usually these lesions are asymptomatic and have no structural significance. Other musculoskeletal disorders include narrowing of the lumbar spine or lesions such as spina bifida occulta.

Ocular Abnormalities

Chronic vitamin deficiency can lead to a variety of eye-related symptoms, including the cornea, iris, retina, and optic nerve papilla. The primary ocular abnormality associated with Alagille’s syndrome is the posterior embryotoxon, a structure that should be removed embryologically but remains at the corneal border of Alagille’s syndrome. Posterior embryotoxon is known to be present in 89% of children with Alagille’s syndrome.

Central and Peripheral Nervous System Symptoms

When Alagille’s syndrome was first reported, it was known that IQ was less than 80, but in later reports, only 2% reported mild intelligence decline, and 15% also reported a decrease in motor area development. Recent studies have highlighted that chronic liver disease can affect brain development. Intracranial hemorrhage may occur in 14% of children with Alagille’s syndrome. Intracranial hemorrhage can be caused by a coagulation disorder, or it can be caused by an aneurysm of the intracranial vessel.

Causes

Alagille’s syndrome is caused by an abnormality of the JAG1 gene located on chromosome 20. It is now known that genetic testing can detect causal mutations in 50-70% of cases.

Diagnoses

The diagnosis of Alagille’s syndrome consists mainly of clinical symptoms. Alagille and his colleagues diagnosed five main symptoms and histopathological findings of the liver. The five main symptoms were chronic cholestasis, characteristic facial features, heart murmur, spinal malformation, and ectopic disease. Most of the patients develop liver disease and jaundice during neonatal period. Therefore, it is necessary to distinguish between neonatal hepatitis and biliary atresia. DISIDA scans and liver biopsies to confirm normal excretion of bile are helpful for differential diagnosis. In particular, liver biopsy is the most helpful test to distinguish from cholestasis. In case of allergy syndrome, intrahepatic bile duct loss is characteristic. JAG1 (jagged 1) and NOTCH2 genes were identified as genes related to Alagille’s syndrome, and more than 89% of the patients who met clinical diagnostic criteria were able to identify mutations in the JAG1 gene by sequencing method. Fluorescence in situ Hybridization ( FISH) was able to identify microdefects in the 20p12 region containing the entire JAG1 gene in about 7% of patients. Mutations in the NOTCH2 gene have been identified in less than 1% of all Alagille’s syndrome patients.

Treatments

Infants with cholestasis are severely affected by the absorption of fat. Infants, in particular, are high in calories from fat, so this disorder of fat absorption can lead to severe malnutrition. Medium-chain triglycerides (MCT) can be an important source of fat in these children because they can be absorbed by the intestine without the help of bile acids. Since fat-soluble vitamin deficiency occurs, supplementation with fat-soluble vitamins through oral preparations is necessary. In particular, vitamin K deficiency may cause blood clotting disorders and rickets. Lack of vitamins E and A can lead to nervous system symptoms. If bile stagnation persists, severe itching can lead to disturbances in daily life, so antihistamines can be administered as a symptomatic treatment. Ursodeoxycholic acid (UDCA) can be administered because it can alleviate bile stasis. In the case of liver failure due to persistent cholestasis and progression of cirrhosis, it is an indication of liver transplantation.