Alagille Syndrome

Autosomal dominant - en[1]

Alagille syndrome (AS), also known as arteriohepatic dysplasia, is an autosomal dominant multisystem disorder associated with abnormalities of the liver, heart, skeleton, eye, kidneys and a characteristic facial appearance.

The disease is the consequence of this process: congenital.

Presentation

Patients suffering from Alagille Syndrome present with the following main clinical abnormalities: poor bile flow, heart disease, eye abnormalities, skeletal abnormalities, and characteristic facial features.1 The severity of these signs and symptoms vary among individuals, even if they came from the same family. In some patients, they are very mild and can go unnoticed, while for others, they are so severe that transplantations, particularly of the liver, become necessary.

In children, where the disease is more pronounced, the signs and symptoms become apparent on or before the age of 2. In most cases, the disease manifests much earlier—at birth or right after.

Poor Bile Flow
The most common signs and symptoms of Alagille Syndrome include jaundice, pruritus, and xanthomas. All three are related to poor bile flow and liver dysfunction.

Jaundice is the very first sign seen in patients with Alagille Syndrome. It results from the elevated amounts of bilirubin in the blood, causing yellowing of the skin, sclera, and nail beds. The mild form of jaundice that appears on the second or third day of life is known as physiological jaundice, and it disappears a few weeks after birth. Jaundice in Alagille Syndrome, on the other hand, tends to persist much longer.

Pruritus is also present in moderate to severe degree. It occurs due to the deposition of salts in the skin. It is felt at around three months of age.

Xanthomas are fatty, yellowish deposits in the skin. They are caused by the abnormally high levels cholesterol in the blood and often seen on the skin over the hands, elbows, knees, and sometimes, around the eyes.

Heart Disease
Aside from the liver, another organ that is almost always involved in Alagille Syndrome is the heart. The most common heart-related finding in most patients is the presence of the so-called Tetralogy of Fallot—a disorder which, as its name suggests, is made up of these four heart abnormalities: pulmonary infundibular stenosis, overriding aorta, ventricular septal defect, and right ventricle hypertrophy. Treatment of this heart disorder significantly improves the quality of life of Alagille Syndrome patients [7].

Eye Abnormalities
Eye defects are also observed in 90% of patients with Alagille Syndrome. The defect is specifically known as the posterior embryotoxon, which is characterized by the presence of an opaque ring around the cornea. Although common, it doesn't affect the patient’s vision.

Skeletal Abnormalities
Skeletal abnormalities, frequently described as the "butterfly-shaped" vertebrae, can be seen radiographically. Nevertheless, like the eye abnormality, it doesn't cause any problems—it does not affect the function of the nerves in the spine.

Characteristic Facial Features
There are also some characteristic facial features seen in majority of the patients. These include a small pointed chin, deep-set widely-spaced eyes, wide forehead, and malformed ears [7].

Other Signs and Symptoms
Poor kidney function, loose stools, pale skin, difficulty breathing, nose and gum bleeding, and growth retardation are also indicative of Alagille Syndrome. In rare occasions, hepatomegaly and splenomegaly occurs. In the worst cases, internal bleeding and stroke could happen, leading to death.3

Workup

Being a very rare disease, in addition to its varying symptoms and severity, Alagille Syndrome is difficult to diagnose. Physical examination and laboratory tests are usually prescribed for the initial diagnosis. Laboratory tests include blood tests, urine test, and liver and kidney function tests. Blood and urine tests measure the amount of bilirubin in the blood, while function tests determine whether or not the liver and kidneys are still working well.

Some more common diagnostic methods for Alagille Syndrome are liver biopsy and abdominal ultrasound. Biopsy results will show decreased number of bile ducts, especially in infants aged six months and below. Abdominal ultrasound, on the other hand, will reveal an enlarged liver.

An x-ray of the spine may help to identify the presence of bone deformities. The x-ray will reveal abnormal, butterfly hemivertebrae.

Other organs are also evaluated to identify any defect. Examinations of the eyes, kidneys, and heart, are also used to come up with the diagnosis of Alagille Syndrome.

However, in cases where the methods above prove to be inconclusive, gene testing is also ordered to confirm the diagnosis. This diagnostic method is also used to find out if a patient with only mild or no symptoms at all, carries a mutated gene. Anyone who is found to have a mutated gene will be advised to undergo genetic counselling.

Treatment

Treatment is non-specific and includes diets higher in carbohydrates, medium chain triglyceride diets and vitamin supplementation (ADEK). Pruritus may be reduced by ursodiol, hydroxyzine, cholestyramine or rifampicin [7].

Cardiac or vascular procedures may be needed for significant symptomatic lesions and liver transplantation is still often necessary.

Prognosis

The cure for Alagille Syndrome is yet to be found. All treatments available are only meant to prevent, or at least alleviate, the signs and symptoms related to the disease.

If treated early enough, patients, children most especially, tend to lead long, quality, and productive lives. However, shorter lifespan is expected for those with advanced heart problems that require surgery. The same is expected in those with severe blood vessel abnormalities, as such can lead to bleeding in and around the brain. In most cases, complications as serious as this ultimately lead to death [2].

Liver disease, on the other hand, tends to improve over time in some patients. However, 50% percent of patients with Alagille Syndrome will eventually need a liver transplant at some point in their lives. Transplantation can produce excellent results, but take note that other symptoms might also impact the procedure itself and its outcome. For instance, heart disease and kidney problems could make transplantation more difficult to perform. Also remember that transplantation will contribute very little to the improvement of non-liver symptoms.

Generally, patients who meticulously take their medications, follow their physician's advice, and live a healthy lifestyle will lead a normal life.

Etiology

Alagille Syndrome is an inherited disease passed through an autosomal dominant gene. Some individuals with no family history of the disease may also suffer from Alagille Syndrome. It happens when the gene associated with it becomes mutated. The cause of the mutation is not exactly understood, but as with any other gene mutations, it is believed to be induced by chemical and radiation damage.

It must be noted, however, that not all people with the mutated gene presents with Alagille Syndrome.

Epidemiology

Alagille Syndrome is a relatively rare liver disease, with only one patient affected for every 100,000 live births. No gender predilection is reported. Neither does it have any specific age of onset, but it is mostly seen in newborns and infants. Adults of any age can also have the disease.

In young patients, the signs and symptoms of Alagille Syndrome appear on or before the age of 2 (or even earlier). In adults, on the other hand, the onset of the disease is hard to determine, since the signs and symptoms are often mild in nature; in fact, most of the time, the patients look completely well and are not even aware that they have the disease.

Sex distribution
Age distribution

Pathophysiology

Alagille Syndrome, mainly a disease of the liver, occurs when the bile ducts are either malformed or are reduced in number. In some cases, they may even be absent at all.

The Normal Bile Duct System
Bile ducts, otherwise known as the hepatic ducts, are small tubes found in the liver. Their main function is to deliver the bile produced by the liver to the gallbladder, and then to the small intestines where it exerts its effects.

Once in the small intestines, bile serves the following purposes:

  • It aids in the digestion of fats and vitamins A, D, E, and K (the fat-soluble vitamins).
  • It facilitates elimination of toxins and other harmful substances from the body.


In Alagille Syndrome...
In Alagille Syndrome, bile accumulates in the liver because there are very few or no bile ducts at all to carry it to the sites where it should be working. As a result, the liver becomes less and less functional, and may stop working eventually.

As bile continues to damage the liver, other organs become affected—the heart, blood vessels, kidneys, eyes, and bones. The effects on the heart and blood vessels are the worst and most life-threatening.

The decrease in number of bile ducts, or their malformation, is brought about by the mutation in the genes JAG1 (in more than 90% of the cases) or NOTCH2. Both JAG1 and NOTCH2 play a major role in embryonic development. Any alteration in at least one of them, especially JAG1, leads to developmental defects of the bile ducts and liver, and of other important organs given above [5] [6].

The signs and symptoms seen in Alagille Syndrome are mostly related to the defects of bile ducts. Scarring, and eventual dysfunction of the liver is caused by accumulation of bile, and other non-liver signs and symptoms are produced as a result of build-up of substances (i.e. bile salts, bilirubin, cholesterol, toxins, etc.) normally expelled from the body [7].

Prevention

There are no guidelines for prevention of Alagille Syndrome.

Summary

Alagille Syndrome pertains to a hereditary disorder that affects multiple organs, including the liver, heart, eyes, and kidney [4]. It is primarily a disease of the liver, but the cardiovascular-related signs and symptoms are deemed to be the main cause of concern.

The disease is named after Dr. Daniel Alagille, the French hepatologist who first recognized it. He first described Alagille Syndrome in 1969, in the French medical literature, and termed it Syndromic Bile Duct Paucity.

Patient Information

Alagille Syndrome refers to an inherited disorder that affects the liver, and other important organs such as the heart, eyes, and kidney. Physicians also refer to it as Syndromic Bile Duct Paucity. It is a rare disease that is mostly seen in newborns and infants, although adults of any age can also be affected.

The signs and symptoms of Alagille Syndrome are mostly related to the problems in the bile ducts. The bile ducts pertain to the small tubes found in the liver; their main job is to carry bile from the liver to the small intestine. Bile refers to the substance that helps digest fats and eliminate toxins and harmful wastes from the body.

In Alagille Syndrome, the bile ducts are either malformed, reduced in number, or totally absent. As a result, bile cannot be transported to the small intestine, causing it to accumulate in the liver. Over time, the liver becomes less functional, and it may stop working eventually. The heart, eyes, and kidneys will also get affected.

Some of the most common symptoms of Alagille Syndrome include jaundice (yellowing of the skin, white of the eyes, nails), itching, and yellowish deposits on the skin of the hands, elbows and knees. A patient could also present with heart disease, kidney problems, and eye abnormalities (particularly the presence of an opaque ring around the cornea). Growth retardation is also indicative of the disease. In worst cases of Alagille Syndrome, internal bleeding and stroke occurs, leading to death.

The symptoms mentioned tend to be more severe in younger patients than in adults. In fact, adult patients won't even know that they have the disease because the signs and symptoms are so mild that they go unnoticeable.

Diagnosing Alagille Syndrome is quite a challenge, due to its various symptoms and degree of severity. To come up with an accurate diagnosis, physicians rely on physical examination, blood and organ function tests, liver biopsy, and abdominal ultrasound. Sometimes, gene testing is also prescribed to detect the disease in patients who are susceptible, but do not show any symptoms at all.

There is no definite cure for Alagille Syndrome. All available treatments are only meant to address the symptoms, and not the root cause of the disease. Treatments mostly include medications; surgery and liver transplantation are reserved for more severe cases. Patients who are treated early enough could have long, normal lives.

Self-assessment

References

  1. Alagille DM. Alagille Syndrome today. Clinical and Investigative Medicine 1996, 19(5), 325-330.
  2. Emerick KM, Rand EB, Goldmuntz E. Krantz ID, Spinner NB, Piccoli DA. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology 1999, 29(3), 822–829.
  3. Kamath BM, Spinner NB, Emerick KM, Chudley AE, Booth C, Piccoli DA,  Krantz ID. Vascular Anomalies in Alagille Syndrome: A Significant Cause of Morbidity and Mortality. Circulation 2004, 109, 1354-1358.
  4. Krantz ID, Piccoli DA, Spinner NB. Alagille Syndrome. Journal of Medical Genetics 1997, 34, 152-157.
  5. McDanielle R, Warthen DM, Sanchez-Lara PA, Pai A, Krantz ID, Piccoli DA, Spinner NB. NOTCH2 Mutations Cause Alagille Syndrome, a Heterogenous Disorder of the Notch Signaling Pathway. The American Journal of Human Genetics 2006, 79(1), 169-173.
  6. Oda T, Elkahloun AG, Pike BP, Okajima K, Krantz ID, Genin, A, et al. Mutations in the human Jagged1 are responsible for Alagille Syndrome. Nature Genetics 1997, 16 (3), 235-242.
  7. Cynamon HA, Andres JM, Iafrate RP. Rifampin relieves pruritus in children with cholestatic liver disease. Gastroenterology. Apr 1990;98(4):1013-6.

  • A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency - B McCright, J Lozier, T Gridley - Development, 2002 - dev.biologists.org


Media References

  1. Autosomal dominant - en, CC BY-SA 3.0

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