Alagille syndrome is the name given to a particular type of liver condition called biliary hypoplasia in association with at least two other signs in other parts of the body.

It affects approximately one child in every 100,000 live births and occurs equally between boys and girls. It is also sometimes called arterio-hepatic dysplasia or syndromic biliary hypoplasia.

The number of features and their severity varies and many people reach adulthood with mild forms of the condition, are completely well and unaware that they have Alagille syndrome. However, some babies can be quite unwell and be diagnosed when very young.

What causes Alagille syndrome?

The cause is not fully understood, but it is at least partly caused by genetic changes. Many children with the syndrome have a mutation or change in one particular gene but not everyone with this mutation has the syndrome. Research continues to try to find all the answers.

Features associated with the syndrome may include:

• Poor bile blow, causing some degree of liver dysfunction and sometimes jaundice
• Typical facial features such as prominent forehead, deep-set eyes and small chin
• Cardiovascular (heart or blood vessel) abnormalities
• Eye abnormalities - these do not affect vision but provide a clue to diagnosis
• Abnormal shape to some spinal bones - only visible on x-ray and does not cause problems

What are the signs and symptoms to look for?

The abnormality of the bile ducts causes chronic cholestasis, which means poor bile flow from the liver into the bowel. The effects can vary considerably from mild to severe symptoms of the following:

• Jaundice
• Pale stools
• Malabsorption (poor absorption of nutrients and vitamins from food)
• Pruritus (itching) Xanthelasma/Xanthomata (high levels of cholesterol in the blood/deposits in the skin)
• Nose bleeds/bleeding gums

And, less commonly:

• Hepatomegaly (enlarged liver)
• Splenomegaly (enlarged spleen)

How is Alagille syndrome diagnosed?

Jaundice, a yellow colouring of the whites of the eyes and often the skin, is usually the first sign of Alagille syndrome. This mostly occurs before six months of age but is sometimes not noticed up to the age of three years.

Any one or a combination of the following investigations may be required:

• Physical examination
• Heart tests
• x-ray
• eye examination
• blood tests
• liver biopsy

Treatment options

There is no cure for Alagille syndrome, but there are treatments that aim to improve the quality of life, including:

Vitamins - supplements of vitamins A, D, E, and K may be given.

Medication - Phenobarbitone, Rifampicin and Cholestyramine may be given to reduce itching and increase bile flow.

Diet - Good bile flow is needed to break down fat in milk and food therefore if you have Alagille syndrome you may not gain weight as you should. Your dietitian will advise on any necessary dietary changes.

Liver transplant - only considered for a small group of patients who have severe liver disease causing cirrhosis or persistent symptoms which cannot be controlled in other ways.

Heart problems - around 90% of children with Alagille syndrome have associated heart features, which will be monitored and appropriate treatment given.

Want to know more?

For further information on Alagille syndrome, please click here.

Alpha-1 antitrypsin is one of the many proteins and related substances which the body makes from food. It is produced mainly by the liver and circulated in the bloodstream.

It's not fully understood why we need it or what its main task is, but research has shown that it has a protective role in preventing tissue damage from the over-activity of enzymes called proteases. People with alpha-1 antitrypsin deficiency produce a slightly different form of the protein which becomes trapped in the liver.

What causes alpha-1 ATD?

A child's ability to make alpha-1 antitrypsin is inherited through the genes passed on from both parents. Apha-1 ATD occurs when a baby inherits from both parents a gene which leads to the production of abnormal alpha-1 antitrypsin protein.

What are effects of Alpha-1 ATD?

There may be one of three effects:

• 1. Some people seem to suffer no ill effects
• 2. Others remain healthy for years, but then may develop breathing difficulties due to emphysema, leading to lung damage and an early death.
• 3. You can develop inflammation of the liver, which can cause liver damage. This usually becomes apparent in the first four months of your life. Symptoms at this time may include:
• Jaundice
• Persistently yellow urine
• Poor weight gain
• Abnormal bleeding from the nose or umbilicus
• Enlargement of the liver and possibly the spleen

When you are older, alpha-1 ATD may produce the following symptoms:

• Jaundice
• Ascites (abnormal collection of fluid in the abdomen)
• Portal hypertension (increased blood vessel pressure caused by scarring of the liver, which may cause blood being vomited or passed in the stools)

What are the treatments for alpha-1 ATD?

There is no specific treatment and no cure for alpha-1 ATD, although research is providing some promising results. Treatments currently seek to make symptoms less troublesome for you and include:

Diet - a dietitian will advise on changes to your diet and may include a special milk formula; extra calories; extra vitamins

Regular monitoring - it is important to regularly monitor your growth and development as well as liver function. As a result, any complications will be recognised at an early stage and treated quickly.

What your parents had to look out for?

Your diagnosis may have been made when you a newly born baby.  You may have become jaundiced (which is very common) but then the jaundice did not disappear.  Prolonged jaundice should be investigated and may have resulted in the diagnosis of alpha 1 antitrypsin deficiency.  

There is no treatment for alpha 1 and often the jaundice subsides and then the doctors will just monitor you to check that your liver is working. 

The first signs of deteriorating liver function are usually found during medical examination and in blood tests. Signs which you and/or your parents should be aware of and seek medical advice for are:

Failure to gain weight or weight loss

Persistent tiredness or lethargy

Deepening or recurrence of jaundice

Swollen abdomen

Recurrent nose bleeds

Any vomiting of blood

Any blood in the stool - may be black or red

Swollen ankles, especially in the evening

The future

The likelihood of someone with alpha-1 ATD developing serious problems is very variable. Follow-up of children with liver disease at major centres showed that of all the babies with liver disease and alpha-1 ATD:

• 25% had no disease symptoms at the age of 10
• 45% had continuing but variable evidence of liver disease
• 5% needed a liver transplant in the first year of life
• 25% needed a liver transplant at some point in childhood

Want to know more?

There are two types of autoimmune liver disease: autoimmune hepatitis and autoimmune sclerosing cholangitis.

It is often diagnosed in adolescence but occasionally in younger children.  In teenagers they may have been entirely well up until they show the signs and symptoms. 

What is autoimmune hepatitis?

Autoimmune hepatitis (AIH) is a condition in which the body's defence or immune system malfunctions and attacks the liver, causing inflammation. Continuing cell destruction results in scarring of the liver and can lead to cirrhosis.

It is not fully understood why the immune system malfunctions in this way, but it is known that there is a genetically inherited tendency to develop autoimmune disorders. Research suggests that the trigger of autoimmunity may be a viral infection, which may have happened a long time, even years, before the liver disease appears.

What are the signs and symptoms to look for?

Symptoms may vary, ranging between those who are outwardly well and active through to those who are acutely ill and may also have signs of liver failure.

The most common symptoms are:

• Tiredness and generally feeling unwell
• Loss of appetite
• Deterioration of school performance

Other symptoms are

• Spider naevi -small, red spider-like markings on the skin due to dilated blood vessels.
• Nausea and/or vomiting
• Weight loss
• Itching
• Fever
• Nose bleeds, bleeding gums, bruising easily
• Amenorrhoea (delayed starting of periods or stopping once started)
• Diarrhoea
• Jaundice with dark urine and pale coloured stools
• Abdominal pain

How is AIH diagnosed?

It is unusual for a diagnosis to be made in the very early stages due to the vague nature of the symptoms. Investigation may be started because of:

• A large liver or spleen being found on routine medical
• An abnormal liver function noted on blood tests taken for another reason
• The appearance or persistence of the symptoms

A diagnosis is often made by excluding all other causes of liver disease and the doctors finding:

• Abnormal liver function on blood tests and scans
• High level of immunoglobulins (a particular type of protein) in the blood and, in most cases, autoantibodies (antibodies to parts of the body). Both suggest that the immune system is not working properly.
• Characteristic features on liver biopsy
• Normal bile ducts when examined by a special X-ray test.

What are the treatments for AIH?

The main treatment is by immunosuppressive medicines, particularly steroids, which make the immune system less active. They are used in an attempt to control the disease process. In some cases the malfunction eventually stops and treatment can be stopped.

The future:

Treatment length varies but it usually needs to be continued for a long time, often many years with medicine doses decreased over time in order to avoid side effects. 

Want to know more?

To find out more about AILD, download CLDF's leaflet here

What is autoimmune sclerosing cholangitis?

This is very similar to AIH, the only difference being that the immune system attacks not only the liver cells, but also the bile ducts inside and/or outside the liver. It is often referred to as sclerosing cholangitis.

Signs and symptoms to look for

Similar to AILD, with the exception that inflammation of the bowel (colitis) and diarrhoea are more common. A major symptom may be itching (pruritis - find out more here).

How is sclerosing cholangitis diagnosed?

The diagnosis is made with blood tests, physical examination, liver biopsy and a special x-ray performed under general anaesthetic.

Treatment of sclerosing cholangitis

As with AILD, treatment is by immunosuppression medicine, alongside medicine to improve bile flow if appropriate. If colitis is present, this will be treated with special medicines.

Want to know more?

To find out more about sclerosing cholangitis, download CLDF's leaflet here.

It is helpful to also read the information about the liver and bile

What is biliary atresia?

Biliary atresia is a condition in which inflammation develops within the bile ducts around the time of birth. The inflammation can occur in any of the bile ducts both inside and outside the liver. This leads to bile duct damage, reducing the flow of bile, which causes scarring of the liver.

Bile is a liquid which passes into the gut through small tubes called bile ducts and is necessary for the proper digestion of fat within the diet.

Biliary atresia can only occur in babies. 

What causes biliary atresia?

The cause of biliary atresia is currently unknown. Research is being carried out, but it has not yet provided any answers.

What are the signs and symptoms to look for?

In the first weeks of life babies with biliary atresia often seem well, apart from being jaundiced (yellowing of the skin and whites of the eyes). Jaundice is very common in babies and mostly clears within the first two weeks of birth. What is important to pick up is if the baby's jaundice continues - that's called prolonged jaundice. 

In addition to prolonged jaundice, other signs for parents to look out for in their babies are:

• Yellow coloured urine
• Pale stools
• Bleeding from the umbilicus or frequent nosebleeds may be an indication of liver disease

CLDF's Yellow Alert campaign highlights the signs and symptoms for parents, parents to be and healthcare professionals. Visit CLDF's dedicated Yellow Alert website here to find out more.

Getting a diagnosis can be a really stressful time for parents because the doctor's are looking for something very rare (1 in 16,000 birth chance) and jaundice (one of the signs) is really common and doesn't mean a baby has a liver disease. 

How is biliary atresia diagnosed?

The signs above are not really very specific so there will need to be a number of investigations. Tests have to be carried out in hospital and include blood tests, scans and liver biopsy. Once other causes of liver disease have been excluded and investigations indicate biliary atresia the baby is scheduled for surgery.

Treatment

The first and vital treatment is an operation called the ‘Kasai procedure' after the Japanese surgeon who pioneered the operation. The aim of the Kasai procedure is to allow bile to drain from the liver into the gut.  This is done when the baby is weeks old,the idea being before the liver becomes badly damaged.  By the time a baby is about 16 weeks old, the team may need to decide that a transplant is the best procedure. 

Babies with biliary atresia will often need a special milk formula so they can absorb nutrients more fully.  The doctor may prescribe extra vitamins and other medicines like Ursodeoxycholic acid and antiobiotics 

Are there any other problems to be aware of?

Even after a successful Kasai operation a number of problems may occur:

Cholangitis (an infection of the bile ducts in the liver, resulting in inflammation)

Ascites (an abnormal collection of fluid in the abdomen)

Portal hypertension (increased blood vessel pressure caused by scarring of the liver, which may cause blood being vomited or passed in the stools)

Pruritis (itching)

Failure to thrive

The future

As a baby or child grows up they will need to be seen regularly by the doctor.  And this will continue in adulthood too - even if you have not had a transplant.  Blood tests will be needed to monitor liver function and periodically an ultrasound will be performed to assess the size of the liver and other structures in the abdomen.  Routine endoscopy may be undertaken to monitor the development of oesophageal varices.

Want to know more?

More information on the biliary atresia, the Kasai operation and post-operative treatment can be found in CLDF's leaflet on biliary atresia, which can be downloaded here.

A choledochal cyst is a swelling/widening or dilation of the bile ducts. It usually affects the bile ducts outside the liver, but sometimes it also affects those inside the liver.

The exact cause is unknown but it happens because of a malformation of the bile duct when a baby is developing in early pregnancy.

What are the signs and symptoms to look for?

Most choledochal cysts are detected in childhood and some are found before birth during ultrasound scans. Everyone is different, but they may have some or all of the following:

• Jaundice
• Intermittent abdominal pain
• Cholangitis
• Peritonitis
• An abdominal swelling

How is a diagnosis made?

A choledochal cyst is most often suspected if an abdominal ultrasound scan shows a dilated bile duct in a baby or child with jaundice or severe abdominal pain. Extra tests are carried out to get more information. These may include:

• A more detailed ultrasound scan
• MRCP (Magnetic Resonance Cholangio-Pancreatography)
• ERCP (Endoscopic Retrograde Cholangio-Pancreatography)

Treatment options

Common types of choledochal cysts should be treated by a surgeon experienced in this kind of operation. The best operation involves the cyst being completely removed, which means removing most of the bile ducts outside the liver, together with the gall bladder.

Want to know more?

Download CLDF's leaflet on choledochal cysts here.

Cystic fibrosis and liver disease

Some children and young people with cystic fibrosis may have had prolonged jaundice as a baby . This usually disappears a few months after birth. However, a number of children and young people with cystic fibrosis develop liver problems later in life regardless of whether they had prolonged jaundice in infancy.

It is not possible to predict who will be affected, but boys seem to be affected more than girls. The development of liver disease may be more likely in children who, as a baby, had had "meconium ileus" - thickened meconium.  Meconium are the first stools of a new born baby,  Normally they are sticky, dark green and made up of cell debris, mucus and bile pigments. 

What happens to the liver in cystic fibrosis?

Damage to the liver starts in the small bile ducts. The bile produced by the liver cells into these ducts becomes stickier than normal and blockage of the ducts follows (this very occasionally causes jaundice). The surrounding liver tissue then becomes damaged and scarred, which may be referred to as biliary fibrosis. This is not unlike the underlying process occurring in the lungs. In time the fibrosis progresses and eventually spreads throughout the liver. This causes the liver to become hard and the blood flow through it more difficult.

How is a diagnosis made?

Most children and young people with cystic fibrosis have regular check-ups which include:

• Physical examination
• Liver function tests
• Abdominal ultrasound

What are the main effects of liver disease in children with cystic fibrosis?

• Portal hypertension
• Enlarged spleen
• Disturbance of the normal working of the liver

Treatments may include:

• Medication
• Nutrition

Diagnosis and treatment of varices, including:

• Endoscopy
• Sclerotherapy
• Banding
• TIPS
• Medication

Transplant

For more information, click here.

PFIC is the name given to a group of inherited conditions causing cholestasis (reduced bile flow) in children. 

The bile flow is reduced either because the liver cannot make bile properly or because it cannot get it out of the liver cells into the bile ducts, or both. The bile ducts themselves may also be abnormal reducing the flow of bile through them.

Recent research has led to a better understanding of these conditions but the research is still continuing.

What are the possible effects of PFIC?

The type and severity of effects vary greatly - they may include:

• Jaundice (yellowing of skin and whites of the eyes)
• Discolouration of teeth
• Darker urine
• Pale, smelly, greasy stools, frequently loose (diarrhoea)
• Failure to thrive
• Vitamin deficiencies - especially the fat soluble vitamins A, D, E and K
• Enlarged liver
• Pruritis (itching)
• Gall stones

Tests will be carried out to help make a diagnosis - you can find out more by downloading CLDF's Routine Investigations guide.

Treatment options

Dietary treatments will depend on the specific symptoms and characteristics of the individual. Medicine and/or surgical treatment can reduce the effects and complications of PFIC. Medicines given may include:

Choestyramine

This combines with the bile acids in the small intestine and reduces reabsorption. Some side effects may be experienced, such as abdominal distension and constipation. The medicine may also bind with the fat soluble vitamins A, D, E and K, further decreasing their absorption.

Ursodeoxycholic Acid (URSO)

This is a substance which naturally occurs in bile, and works by increasing the proportion of watery bile salts, helping the bile to flow more easily.

Rifampicin

An antibiotic commonly used to treat tuberculosis, Rifampicin is used in patients with cholestatic liver disease and gives complete relief from pruritis in some patients and significantly reduces it in others.

Vitamin supplements

Especially A, D, E and K are usually given by mouth, but injections are sometimes needed.

Phenobarbitone, naltrexone and ondansetron are other medicines which have been used with varying degrees of itch reduction.

Surgical options

A number of operations have been tried in an attempt to reduce the effects of PFIC with varying degrees of success. The procedures below may not be appropriate in all cases, and your medical team will assess your condition before any procedures are recommended.

• Partial external biliary diversion: only suitable if you have not developed cirrhosis. A short section of the bowel is used to make a channel for some of the bile to drain away. One end is attached to the gall bladder and the other is brought out through the skin for an opening on the surface of the abdomen (stoma).
• Internal ileal exclusion: a bypass is created around the distal ileum, which is the section of bowel where bile salts are usually reabsorbed.
• Liver transplant: a major operation, with some risks but a successful transplant can restore good quality of life. Find out more in CLDF's ‘Liver Transplantation - an Overview' leaflet, which you can download here.

Want to know more?

Download CLDF's leaflet on PFIC

Wilson's disease is an inherited condition where copper is not excreted properly from the body. As a result, excess copper can build up in the liver and/or brain causing liver damage and/or neurological problems. It can also collect in other parts of the body, including the eyes and kidneys.

It is often diagnosed in adolescence. 

Copper is essential to life and is found in many foods and in drinking water. Foods particularly rich in copper include:

• Liver
• Shellfish
• Nuts
• Seeds

What are the signs to look for?

Signs and symptoms of Wilson's disease can be very mild and may include:

• Tiredness
• Loss of appetite
• Abdominal pain
• Vomiting
• Weight loss
• Nose bleeds
• Anaemia
• Chronic joint or kidney problems

In some cases, symptoms may be more severe and you will need to be admitted to hospital.

Wilson's disease can cause chronic or acute hepatitis, acute liver failure and cirrhosis.  It may mean that an urgent liver transplant is necessary.   It can also cause a range of neurological problems, which may include deteriorating school or college performance; changed behaviour and deterioration of motor skills.

Want to know more?

Download CLDF's leaflet on Wilson's disease here.