What is Alagille syndrome?
Alagille Syndrome Life Expectancy, Information, Symptoms, Treatment & Causes: Alagille syndrome (English Alagille syndrome) is a rare genetic disease that is characterized by abnormalities of the hepatobiliary system and other malformations. The disease has an autosomal dominant mode of inheritance. The disease is characterized by an insufficient number or small diameter of the intrahepatic bile ducts, which remove bile from the liver. Bile performs important functions: it removes toxins and metabolic products from the liver to the gallbladder, and also helps to digest food, which is necessary for the absorption of fat and fat-soluble vitamins (these are A, D, E, K). Malformation of the bile duct leads to accumulation of bile in the liver. The resulting damage to the liver can be so severe that patients need a transplant. Alajille syndrome is a complex disease that can affect various organs and systems, including the heart, kidneys, blood vessels, eyes, face, and skeleton. The syndrome is recorded in approximately 1 case per 70,000 newborns. Boys and girls equally suffer from Alagille syndrome. Symptoms of the disease are usually noticeable in the first 2 years of a child’s life.
- What causes Alagille syndrome?
- What are the manifestations of Alagille syndrome?
- How is Alagille syndrome diagnosed?
- Alagille syndrome treatment
- What is the long-term prognosis for Alagille syndrome
What causes Alagille syndrome?
More than 90% of cases of Alagille syndrome are associated with a mutation of the JAG1 gene in chromosome 20. Another 7% of patients have small deletions in the genetic material of the 20th chromosome, which also captures the JAG1 gene.
The remaining people with Alagille syndrome have mutations in another gene, called NOTCH2. The JAG1 and NOTCH2 genes encode instructions for the synthesis of proteins involved in the so-called Notch signaling pathway, which is necessary for the normal construction of different structures of the human body during embryonic development. Mutations in these genes and, as a result, errors in the path of Notch, disrupt the development of the biliary tract, heart, bones of the skull, spine, etc.
Alajille syndrome has an autosomal dominant mode of inheritance. This means that one copy of a defective gene inherited from one of the parents is sufficient for the development of the disease in a child. Among patients with 30 to 50% inherited Alagille syndrome from the parent. Other cases are caused by new mutations and deletions in the genetic material that occur randomly at an early stage of intrauterine development. In these cases, of course, there is no talk of a family history of the disease — the parents of a sick child can be completely healthy.
What are the manifestations of Alagille syndrome?
Manifestations of Alajille syndrome vary greatly, even within the same family.
These symptoms, associated with poor bile flow, occur already in the first weeks of life. They are also observed in older children and adults. In children, jaundice occurs, the level of bilirubin in the blood increases significantly, the urine becomes dark, and the stool becomes gray due to insufficient excretion of bile into the intestinal lumen. Jaundice of newborns due to insufficient liver maturity occurs in many healthy children, but this type of jaundice disappears after the second or third week of life, while jaundice with Alagille syndrome remains, and this is cause for alarm.
Leather and soft tissue
The accumulation of large amounts of bilirubin in the blood causes intense pruritus. It can occur in children after the third month of life, and can be very strong, unbearable. Under the skin, with Alagille syndrome, fat accumulations, called xanthomas, can form. They are caused by abnormally high levels of cholesterol in the blood, which is a common problem in people with liver disease. Xanthomas look like yellow nodules of various shapes. They are formed on the abdomen, knees, elbows. In general, these formations are harmless.
Growth and metabolism
People with Alagille syndrome may suffer from diarrhea, which is caused by malabsorption, a condition in which the digestive system is unable to properly absorb nutrients, in this case, fats and fat-soluble vitamins. Malabsorption leads to delayed development and slow growth in children. Such patients often have broken bones, problems with vision, blood clotting, memory and learning. Characterized by delayed puberty.
Most patients with Alagille syndrome have a narrowing of the pulmonary arteries that carry blood from the heart to the lungs. This usually does not cause problems, but a small percentage of patients may have much more serious malformations of the walls and valves of the heart (Fallot’s tetrad), which require surgical correction.
Many people with Alajille syndrome have deep-set eyes (different scientists cite numbers from 70 to 96%). Other characteristic features: high, prominent forehead, straight nose, protruding auricles, protruding chin. These features are not very striking in the first years of life.
There is a posterior embryotoxon – an abnormality of development, which is corneal clouding. This is a common symptom in people with Alagille syndrome, which usually does not affect vision.
The shape of the spinal bones can be broken, which is found on x-rays, but it rarely causes back problems in patients.
In Alajille syndrome, there are many different pathologies of the kidneys. This may be renal hypoplasia, cysts, renal artery stenosis, etc. Often these disorders are accompanied by inadequate renal function.
The spleen is an organ that “cleanses” the blood and plays a role in protecting against infections. The blood from the spleen goes straight to the liver. When the liver damage reaches a certain stage, the blood flow in this system is disturbed and portal hypertension occurs. At the same time the spleen is enlarged. Patients with an enlarged spleen should avoid contact sports due to the risk of organ rupture.
Patients with Alagille syndrome may have abnormalities of the carotid arteries – blood vessels in the head and neck. This increases the risk of internal bleeding or stroke. In the US, all persons with this syndrome who have suffered a head injury are recommended to immediately take an MRI or CT scan as a precaution. Anomalies in other arteries (narrowing, aneurysm) are also possible.
How is Alagille syndrome diagnosed?
Since the symptoms of the disease are extremely variable, and it is very rare, the diagnosis can be difficult.
If the doctor suspects Alajille syndrome, he may rely on the results of such studies:
• Blood tests for liver function and nutrient content.
• Ultrasound examination of the liver, which will reveal an enlarged liver and help eliminate other diseases.
• Liver biopsy, which will confirm the pathology of the intrahepatic bile ducts.
• Examination by a cardiologist for the presence of malformations of the heart and blood vessels.
• Examination of the eye, which can reveal posterior embryotoxon
• X-ray of the spine to detect abnormal bone structure.
• Complete examination of the kidneys (ultrasound, angiography, blood and urine tests).
The doctor can send a blood sample for genetic analysis, which will determine the mutation of the JAG1 gene. Mutation of this gene is found in 95% of patients who are diagnosed with Alagille syndrome by American doctors only on the basis of symptoms.
Alagille syndrome treatment
The treatment of Alajille syndrome is mainly aimed at increasing the outflow of bile from the liver. This contributes to the normal absorption of nutrients, further growth and development of the child. In the US, the drug Ursodiol (Ursodiol, Actigall, Urso) is the only drug approved by the FDA to increase the flow of bile.
Pruritus may subside when the flow of bile begins to improve. In the US, cholestyramine preparations (Questran), naltrexone (ReVia, Depade), as well as antihistamines and moisturizers are used to relieve pruritus in Alagille syndrome.
If itching persists after conservative treatment, then a procedure called partial external biliary diversion (PEBD) is prescribed. It consists in creating an artificial pathway for the flow of bile and its removal through the stoma. In this case, the bile is collected outside the body in a special bag.
Liver transplantation may be required in patients who have developed severe liver failure. Some authors (Emerick et al. 1999) indicate that with proper treatment, only 15% of patients have such a need. In the US, patients with Alagille syndrome are considered poor candidates for a liver transplant due to the many potential complications after surgery.
Children with Alagille syndrome should receive special mixtures that allow them to absorb vital fats in the intestines. All patients need a high-calorie diet, calcium, additional vitamins A, D, E and K. If oral vitamin preparations are poorly tolerated, you can give them parenterally for a while.
Xanthomas, often occurring in this disease, usually grow rapidly in the first years of life, and then may decrease over time, and even disappear completely in response to PEBD and drug therapy.
What is the long-term prognosis for Alagille syndrome?
The prognosis depends on many factors, including the degree of liver damage, the presence of heart defects and the early correction of malabsorption. Predict the development of this disease for many years to come modern medicine can not. As a result, 15% of patients need liver transplantation, and their future life depends on the success of this risky procedure. Death with Alagille syndrome is usually caused by liver failure, pathologies of the heart and blood vessels.
Modern studies show that 75% of children diagnosed with Alagille syndrome live longer than 20 years. Thanks to the progress in hepatology and cardiology, their life expectancy is constantly increasing. In countries with advanced medicine, many patients can lead almost normal lives.