Metabolic, Biliary Atresia & Related Diseases
Biliary atresia is a rare and life-threatening biliary tract disease that occurs exclusively in newborns. It is characterised by an obstruction of the bile ducts. This leads to a back-up of toxic bile (“cholestasis”) that damages the liver and, if left untreated, leads to cirrhosis of the liver.
The first descriptions of severely ill newborns who probably had this disease date back to the 18th and 19th centuries. However, the causes of biliary atresia are still largely unknown. It is thought that genetic or autoimmune/inflammatory factors in the patient, environmental factors or external infectious agents interact causing the disease to develop.
There is usually inflammation and scarring in the bile ducts (small tubes) that carry bile from the liver to the bowel. If left untreated, the disease is always fatal and the children do not live beyond the age of two to three years. It is critical that a child with biliary atresia receives prompt treatment.
An operation called the Kasai procedure is the first therapy of choice and can stop the disease from getting worse and in some cases, is a permanent solution. Nevertheless, a liver transplant is often necessary.
Children with biliary atresia are usually born without any recognisable symptoms. In most cases, ultrasound examinations before birth do not reveal any abnormalities. The disease usually becomes noticeable in the first one to six weeks after birth.
The symptoms include jaundice (a yellowish tinge ft he skin, whites ft he eyes and mucous membranes), pale/whitish stools, itching, dark yellow urine and a partially enlarged liver. Because of a lack of bile in the intestine, the absorption of fats and the fat-soluble vitamins A, D, E and K is impaired, which often leads to failure to thrive and vitamin deficiency. A vitamin K deficiency can cause bleeds (e.g. brain haemorrhages). In about one in ten cases, there is a biliary atresia with other malformations (e.g. malformation of the spleen, and the heart).
This form of the disease must be distinguished from the classic variant, which only affects the liver.ERN RARE-LIVER covers the following subtypes:
- Isolated Biliary Atresia
- Biliary atresia with splenic malformation syndrome
The combination of jaundice and (usually) light-coloured stools in infants over 14 days old must absolutely be recognised by the paediatrician.
A blood test must be carried out to determine the level of conjugated bilirubin in the blood, and if it is elevated, the infant must be referred to a paediatric liver centre. In the blood test, gamma-GT, AST and ALT are elevated in many cases. In addition, fat-soluble vitamin levels are often low, meaning that vitamin supplements are recommended. Since other liver diseases also cause abnormal blood test results, further tests are necessary to diagnose biliary atresia.
As with many rare liver diseases, the diagnosis is like a jigsaw puzzle: the more pieces that fit together, the clearer the diagnosis. A speedy procedure is very important here, as the course of biliary atresia is often much better with early diagnosis and early Kasai surgery.
Other tests to diagnose it include an ultrasound scan, a liver biopsy to examine the tissue or an ERCP to examine the appearance of the bile ducts. However, ERCP can be technically challenging in infants. Since biliary atresia must be treated urgently, surgery is performed if it is highly suspected. The operation is combined with an examination of the bile ducts (intraoperative visualisation of the bile ducts) to confirm the diagnosis. In the same operation, if the suspicion is confirmed, the Kasai operation can then be performed.
Besides the time-critical situation, an important aspect of the diagnosis is to exclude other causes of biliary obstruction in newborns such as: infections, an Alagille syndrome, alpha-1 antitrypsin deficiency, progressive familial intrahepatic cholestasis (PFIC) or hormone deficiency, e.g. in the case of thyroid dysfunction.
In addition to paediatric care close to home, it is extremely important to treat children with biliary atresia at specialised liver centres. Only at such centres is there broad experience in the diagnosis and therapy of these rare diseases, which can positively influence the course of the disease.
Currently, treatments are based on surgical interventions: Kasai surgery can support the regeneration of the liver and, at least in many cases, prevent the progression of the disease in the early years of life. Nevertheless, in cases with severe liver damage in the course of the disease, liver transplantation is necessary.
A targeted drug therapy for biliary atresia does not (yet) exist. Most children receive ursodeoxycholic acid (UDCA) to help the bile flow although it is unclear how or if it helps in the long term. New drugs are currently being tested in research trials to treat biliary atresia and promote regeneration of the liver.
The Kasai operation is named after the Japanese paediatric surgeon Morio Kasai, who developed this method in the late 1950s. The operation should be carried out as soon as possible after diagnosis because an operation in the first 45 to 60 days of life promises the most success. If the Kasai operation takes place later, a liver transplant is often necessary sooner. During the Kasai operation, the outer, scarred (blocked) bile ducts are removed. A loop of small intestine is removed and the shortened small intestine is sewn back together. The bile ducts are then directly connected to this eliminated loop of the small intestine. From then on, this serves as an artificial way to drain the bile into the intestine. However, this is not always successful in advanced disease, because by then the bile ducts are already too damaged. Other complications of the operation are, in particular, infections: bacteria can rise from the intestine via the drained intestinal loop and infect the liver. This leads to temporary inflammation of the bile ducts (cholangitis) which requires prompt treatment with antibiotics.
Surgery can often prevent or delay the progression of the disease. However, if the disease advances and the liver develops cirrhosis, a liver transplant will eventually become necessary. Overall, 60-80% of patients need a liver transplant in the first two decades of life. In almost half of the children, the transplantation becomes necessary within the first two years of life.
In addition to the surgery, other accompanying medical measures are important. A vitamin deficiency must be compensated for with an appropriate vitamin substitution. Antibiotics can be used to prevent and treat cholangitis. Anti-itch medicines are used for severe itching. Mothers may continue to breastfeed their children. If an age-appropriate diet is tolerated later, this should be continued. If fat digestion is affected, the diet should be enriched with certain fats (medium-chain triglycerides (MCTs) fats that are found in foods like coconut oil). In cases of severe malnutrition, tube feeding may be necessary for a short time.
How common is biliary atresia?
Biliary atresia is a rare condition, but it is the most common cause of liver transplantation in childhood and adolescence. About 270 cases are diagnosed each year in Europe, although there is probably a large number of unreported cases. Biliary atresia is estimated to affect one in 15,000 to 19,000 children in Europe and the US (source: Orphanet, 2020).
The future of biliary atresia
More research is needed to better understand and treat biliary atresia. Diagnosis is often late and only about half of affected children in Europe are treated in specialised centres. Drug approaches are being explored in early trials, and we await the results with great interest. The European Reference Network on Hepatological Diseases (ERN RARE-LIVER) has established its own working group on biliary atresia and is currently setting up a registry for children with this disease. This is an important step towards better understanding biliary atresia in the future, treating it more effectively and enabling young patients to live as normal lives as possible.