Alagille syndrome is a rare genetic disease in which disorders of the hepatobiliary and cardiovascular systems are combined with abnormalities in the development of the skeleton. Characteristic symptoms appear in a child from the first months of life and include jaundice, itching, nutritional insufficiency, lagging rates of psychomotor development. Ultrasound and liver biopsy, echocardiography, biochemical and genetic testing are performed to diagnose the syndrome. Treatment consists of diet therapy, taking choleretic and antihistamine medications. According to the indications, surgical intervention is prescribed.
Q 44.7 Other congenital liver abnormalities
Alagille syndrome (arteriophepatic dysplasia) ranks second (17%) among all diseases of the hepatobiliary tract in children in the first 6 months after birth. It is detected with a frequency of 1 case per 70 thousand newborns. Pathology got its name after the French pediatrician Daniel Alagil, who described it in detail in 1975. In the medical literature, the disease is also known as arteriophepatic dysplasia. The polymorphism of symptoms, the complexity of diagnosis and a serious prognosis determine the significance of the syndrome in neonatology and pediatric gastroenterology.
Alagille syndrome is a hereditary disease that is transmitted by an autosomal dominant type. It is caused by a mutation on the short arm of chromosome 20, where the Jagged 1 (JAG1) gene is located. Given the type of inheritance, pathology occurs with the same frequency in boys and girls, it can be repeated in each generation of the family. Cases of the syndrome development in infants with trisomy on chromosome 21 (Down’s disease) are described.
The leading pathogenetic component is the narrowing of the intrahepatic bile ducts, which complicates the outflow of bile with its subsequent accumulation in hepatocytes. Bile acids have a toxic effect on liver cells, causing disruption of their functions and death, and also penetrate into the systemic bloodstream, provoking skin signs of the syndrome. Due to insufficient intake of bile into the intestine, malabsorption occurs.
In the mechanism of development of symptoms, an important role is played by heart defects, which are accompanied by circulatory disorders and tissue hypoxia. Hemodynamic disorders are associated with the absence of blood ejection from the right ventricle and myocardial hypotrophy. In case of untimely diagnosis, dilation of the right atrium and ventricle occurs. With a severe form of the syndrome, there may be a secondary opening of the oval window and venous-arterial discharge of blood.
The classic Alagille syndrome is characterized by a combination of 5 signs: cholestasis, pulmonary artery stenosis or other cardiac defects, disorders of the formation of the facial skeleton, eye lesions, non-infection of the vertebral bodies. To make a diagnosis, it is enough to have 3 symptoms from this list. In all cases, liver damage develops, and cardiovascular pathologies are in second place in frequency (up to 87-95%).
Clinical signs of the syndrome appear in the first 3 months of an infant’s life, with less severe anomalies, the onset of the disease occurs in the second half of life. The first symptom is moderate jaundice of the skin, sometimes with a greenish tinge. It is complemented by a painful itching of the skin, which makes the baby restless, constantly crying, sleeping poorly.
Disorders of bile production and excretion are accompanied by dyspeptic disorders, fecal discoloration, but this sign appears much later than jaundice. Violations of lipid metabolism can provoke the appearance of xanthomas — benign yellowish formations that rise above the skin level. They are mainly localized on the fingers, on the back of the neck, in the inguinal and popliteal zones.
For patients suffering from Alagille syndrome, the specific features of appearance due to facial dysmorphic disorder are specific. Parents and doctors pay attention to a too wide forehead, deep-set and widely spaced eyes, a long straight nose. The child may have protruding and low-lying ears, a protruding chin. Due to ophthalmopathy, the baby has difficulty recognizing his parents, he is not interested in bright toys.
Exacerbations of cholestasis in Alagille syndrome are often accompanied by infection, which provokes cholecystocholangitis, complicating the course of the disease. Liver damage by bile acids and chronic inflammation lead to periportal fibrosis, and cirrhosis of the liver is formed in 15% of children at an early age, which is a prognostically unfavorable sign.
Against the background of chronic malabsorption and maldigestion, protein-energy deficiency and vitamin deficiency occur. Severe growth retardation and physical development are observed in 50-87% of children. Cardiovascular complications also appear: without timely correction, the cardiac defect progresses rapidly. The 6-year survival rate of patients with intracardiac lesions is up to 40%, and without them it increases to 95%.
An experienced neonatologist or pediatrician may suspect Alagille syndrome by clinical manifestations, but with moderate severity of symptoms and their late development, diagnosis is accompanied by difficulties. During physical examination, the doctor reveals hepatomegaly, cardiac hump, rough systolic noise in the 2nd intercostal space. Instrumental and laboratory tests are carried out to confirm the syndrome:
- Ultrasound of the abdominal cavity. Screening noninvasive examination is performed to visualize the liver and determine the degree of hepatomegaly. Sonography is necessary to exclude other causes of jaundice, to assess the condition of the hepatobiliary system and the gastrointestinal tract of the child.
- Echocardiography. When visualizing the heart, the doctor determines the narrowing of the pulmonary artery at the level of the valves or the subvalvular space, hypertrophy of the right ventricle, dilation of the right chambers of the heart. If necessary, X-ray diagnostics is performed, which shows the protruding arch of the pulmonary artery, the expansion of the boundaries of the heart.
- Liver biopsy. A decrease in the number of intrahepatic ducts is a pathognomonic sign of Alagille syndrome, but it may not be detected in infancy. A biopsy is recommended to exclude other hepatobiliary pathologies if a pediatric gastroenterologist has difficulties with differential diagnosis.
- Blood test. In a biochemical study, an increase in typical markers of cholestasis is determined — cholesterol, alkaline phosphatase, direct bilirubin. The child has dyslipoproteinemia. Cytolysis enzymes in liver samples increase moderately. There are no deviations in the proteinogram in most patients.
- Genetic testing. Molecular diagnostics of JAG1 gene mutations is required for mild signs of the syndrome or its atypical course. With direct sequencing, characteristic gene disorders can be detected in 95% of children, but it is done only on a research basis.
To correct nutritional insufficiency, the child is prescribed enhanced therapeutic nutrition with a restriction of long-chain fats and an increase in the percentage of medium-chain fats, which are better absorbed with bile deficiency. The daily diet increases the content of fat-soluble vitamins. In severe eating disorders, special formulations are administered through a nasogastric probe. Medical treatment includes:
- Choleretic drugs. They are necessary to stimulate the outflow of bile from the hepatic ducts, which helps to relieve jaundice, improve digestion and eliminate discomfort. Ursodeoxycholic acid (UDCA) has a good effect on the hepatobiliary system.
- Antihistamines. They are indicated to relieve painful itching in children, but they are not always effective. In refractory cases, therapy is supplemented with sedatives, tranquilizers.
- Vitamins and minerals. Vitamin K in oral or parenteral form is effective for normalization of the blood clotting system. To improve calcium-phosphorus metabolism, cholecalciferol preparations are used, and with a decrease in bone density, calcium supplements are used.
In case of cardiac anomalies, minimally invasive correction methods are performed — valvuloplasty, balloon expansion of the lumen of the pulmonary artery and its stenting. In severe combined defects, open cardiac surgery is recommended. With cirrhosis, liver failure, chronic portal hypertension, the issue of liver transplantation is being considered.
Prognosis and prevention
The success of treatment depends on the severity of the syndrome: with minor arteriopepatic dysplasia, it is possible to compensate for the condition and ensure the normal development of the child, and severe forms of Alagille disease correlate with irreversible liver damage, cardiovascular disorders. Prevention of pathology consists in medical and genetic counseling of a couple at the stage of pregnancy planning.