Alagille Syndrome: Symptoms, Treatment and Life Expectancy

Syndromes are medical conditions where a group of symptoms or signs occur consistently together. The reason behind such association is that they have a common cause, whether genetic, acquired, or both. What is important to understand in syndromes, and in medicine in general, is that they have a cause, and managing the cause is key to controlling the condition. In some cases, however, the cause cannot be controlled, and managing symptoms is the best we can do. However, as long as the syndrome is not life-threatening, controlling its manifestations can be enough.

What is Alagille syndrome and why does it occur?

Alagille syndrome is a genetic disorder, which means that the main problem occurs at the level of genes, and is inherited as an autosomal dominant trait, which means that if a person has Alagille syndrome, and regardless of their partner, half their offspring will have the condition if he has both copies of the gene, and quarter of their offspring will have the condition if he has one defective copy of the gene. It is worth noting, however, that not all of their children who have the disease will manifest it to the fullest, and that the gene has variable expression. The gene that is affected is either the JAG-1 gene or the NOTCH gene. Alagille syndrome nearly affects all body systems, and its manifestations can start early in life.

Symptoms of Alagille syndrome

There is a wide variation in the presentation of Alagille syndrome, owing to its genetic nature and the number of body systems it affects. The most common presentations include:

Delayed growth in children, which can be the first presentation of the syndrome. Linear growth is usually the one affected rather than gaining weight.

Abnormalities of vision, where children may complain of blurry vision. It results from the swelling of the optic disc, which is a sign of increased pressure in the skull.

Liver abnormalities

Some infants present with jaundice, which is usually deep in color, reflecting its cholestatic nature, which means that the liver is normal but the flow of bile is obstructed, along with the enlargement of the liver and the spleen.

Rickets

Rickets is the manifestation of vitamin D deficiency in children. It presents with bone pains and bowing of the legs. The reason behind this deficiency is the abnormality of bile secretion by the liver, since vitamin D is a fat-soluble vitamin.

Severe pruritis and itching

One of the manifestations of bile acid stagnation and the reflux of bile salts into the blood is the severe itching and pruritis they cause.

Hypertension

Although hypertension is largely asymptomatic, it can be detected with routine physical examination the first time the child visits a doctor. Hypertension results from the narrowing of the artery supplying the kidney.

Mental retardation

Although not usually present, developmental delay and mental retardation can be present in many children with Alagille syndrome.

Facial features

Although perhaps the first noticeable sign, facial features are not striking in Alagille syndrome. They include a broad forehead and a narrow chin. Again, they are not suggestive of the disease, but combined with the above can help establish the diagnosis.

Diagnosis of Alagille syndrome

Diagnosing any syndrome is challenging, and extensive investigations along with a good clinical sense are essential for correct diagnosis. Your doctor will ask questions about the symptoms and then perform a thorough clinical examination. One of the detectable signs of Alagille syndrome is heart murmurs, owing to the problems that can be present in the heart including heart defects and valvular problems. They will also perform an ophthalmic examination to detect retinal problems, which is also commonly associated with Alagille syndrome. Afterwards, they will ask for a number of investigations:

Liver function tests

Liver function tests are ordered routinely once the condition is diagnosed. They include liver enzymes, which are signs of liver damage as well as coagulation tests. There are abnormalities of coagulation in patients with Alagille syndrome due to vitamin K deficiency, which is also a fat-soluble vitamin.

Bilirubin level and GGT

Bilirubin level is needed when there is jaundice, and GGT is a special lab investigation that is related to problems in the biliary tree and is usually elevated in Alagille syndrome.

Levels of vitamins including vitamin D and K are usually reduced for the lack of adequate bile flow, impairing absorption.

Gene analysis

If the diagnosis is not clear or if confirmation is needed, your doctor will order a gene analysis to detect the mutation of the JAG-1 gene.

Imaging studies

Those lab tests may be complemented with other tests and imaging studies to confirm the diagnosis or to detect the extent of damage to different body systems. The most commonly done imaging studies include:

Xray

Xray imaging is needed in children with leg bowing, to confirm the diagnosis of rickets.

Abdominal ultrasound: Abdominal ultrasound can assess the condition of the liver and kidneys, two organs commonly affected by Alagille syndrome.

Echocardiography

Echocardiography is a special kind of ultrasound for the heart and is done in patients with Alagille syndrome. It is used to detect defects in the heart and problems with the heart valves.

CT scan

CT scanning is a special type of Xray that is used to get a cross-section of the body and is used in Alagille to detect problems of the blood vessels whether the aorta, blood vessels of the brain or the kidney.

Doppler scan

Doppler scan is a type of ultrasound that can detect the flow of blood and its pattern within blood vessels and is also used to detect narrowing of blood vessels of the kidney.

OCT

Ocular coherent tomography is a type of scanning for the retina of the eye for detachment or swelling of the optic disc.

Even after all of the above investigations -with the exception of genetic analysis- there are several conditions that are similar to Alagille syndrome including all the causes of jaundice in children and the newborn, cystic fibrosis, and biliary atresia.

Treatment

Unfortunately, and since the cause of Alagille syndrome is genetic, there is no cure for the condition. However, most of its manifestations can be controlled either medically or surgically. Medical care includes:

Medications to decrease itching and pruritis, such as hydrazine.

Giving fat soluble vitamins, such as vitamin A, D, E, and K to compensate for deficiency.

For the treatment of stagnation of bile acid, and the resultant jaundice and vitamin deficiencies, artificial bile acids are given such as Urso deoxycholic acid. They act to prevent stone formation and improve bile flow.

Other medications can decrease the absorption of bile salts to reduce symptoms of pruritis such as maralixibat.

After screening for cardiac and vascular problems, such conditions can be managed medically or surgically by the relevant specialists. Although hypertension due to renal artery stenosis is resistant to medications, some antihypertensive medications may be tried first.

One of the commonest complications of heart problems is bacterial endocarditis, which is a severe bacterial infection of the lining of the heart and heart valves. It can be managed by aggressive antibiotic therapy and antibiotics can be given for protection against future attacks.

Vaccinations should be given to children with the condition, to protect them against infections, as they are usually more susceptible.

Surgical care

Surgical treatment is mainly directed towards abnormalities of the liver and the heart. Patients with severe pruritis from the cholestasis may need liver transplantation so are those with impaired liver functions. In addition, those born with biliary atresia, which is the absence of a part or the whole biliary tree may need a special operation called Kasai operation to establish bile flow.

Heart conditions including septal defects and valvular problems may need cardiothoracic surgery to repair such defects. In addition, long term follow-up following any procedure is mandatory to monitor the condition.

Outcome of patients with Alagille syndrome

There is no concrete number for the morbidity and mortality of people with Alagille syndrome. However, the main determinant of such numbers is the affection of the liver and the heart. Patients with heart conditions associated with the syndrome usually have a shorter lifespan compared to those without them. In addition, patients needing liver transplantation usually have a worse quality of life until they undergo the procedure, and they usually also need lifetime medications after performing it.

In raw numbers, up to 80% of Alagille syndrome patients without heart abnormalities survive past adulthood, compared to about 40% with significant heart problems.