Progressive familial intrahepatic cholestasis

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Progressive familial intrahepatic cholestasis (PFIC) is a broad term for a group of disorders that cause liver disease that worsens over time. Cholestasis is a condition that impairs the release of a digestive fluid called bile, which is made and released by the liver. In people with cholestasis, bile builds up in the liver, impairing its function and causing liver damage. Because the problems with bile release occur within the liver, the condition is described as intrahepatic.

The signs and symptoms of PFIC can vary, but they typically begin in infancy or early childhood. Itching (pruritus) is a characteristic feature of PFIC and may be severe enough to significantly impact a person’s quality of life. Additional signs and symptoms of PFIC often include yellowing of the skin and the whites of the eyes (jaundice), an inability to gain weight and grow at the expected rate (faltering weight), and urine that is darker than usual. Progressive liver damage can lead to high blood pressure in the vein that supplies blood to the liver (portal hypertension), an enlarged liver and spleen (hepatosplenomegaly), and scarring of the liver (cirrhosis). Many people with PFIC eventually develop liver failure and require a liver transplant.

Researchers have discovered more than 10 types of PFIC, each with a different genetic cause. The most common types are:

The signs and symptoms of FIC1 deficiency typically begin in infancy and can range from mild to severe. In addition to the features listed above, people with FIC1 deficiency may have short stature, hearing loss, diarrhea, inflammation of the pancreas (pancreatitis), and low levels of fat-soluble vitamins (vitamins A, D, E, and K) in the blood. People with severe FIC1 deficiency may not survive past childhood. Those with mild to moderate FIC1 deficiency may have episodes of cholestasis, jaundice, and severe itching followed by intervals without signs and symptoms. In these individuals, liver disease may not develop until later in life, if at all. Mild to moderate FIC1 deficiency is sometimes called benign recurrent intrahepatic cholestasis type 1 or BRIC1.

BSEP deficiency is the most common type of PFIC. The signs and symptoms of BSEP deficiency typically begin in infancy and can be severe. People with BSEP deficiency often develop liver failure before reaching adulthood. Additionally, affected individuals are at increased risk of developing certain cancers, including a type of liver cancer called hepatocellular carcinoma (HCC). Mild BSEP deficiency is sometimes called benign recurrent intrahepatic cholestasis type 2 or BRIC2.

The signs and symptoms of MDR3 deficiency may begin in early childhood or may not appear until after the age of 2 or 3 years. Some people with MDR3 deficiency develop liver failure. In these people, liver failure can occur in childhood or adulthood. Affected individuals have an increased risk of developing problems that involve the network of tubes that connect the liver, gallbladder, and small intestine (bile ducts). These problems can include gallstones and a type of cancer called cholangiocarcinoma (CCA).

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in more than 10 different genes can cause PFIC. Pathogenic variants in the ATP8B1, ABCB11, and ABCB4 genes cause the three most common forms of PFIC.

Many of the genes that are associated with PFIC provide instructions for producing proteins that help move a particular component of bile, called bile acids, in and out of the liver. Bile acids help break down fats from food so that they can be absorbed by the intestines.

Pathogenic variants in the ATP8B1 gene cause FIC1 deficiency. The ATP8B1 gene provides instructions for making a protein that helps protect liver cells from the damaging effects of bile acids as they are moved out of the liver. The pathogenic variants in the ATP8B1 gene that cause FIC1 deficiency likely alter the makeup of the liver cell membrane, impairing the membrane's ability to transport bile acids. However, it is not clear exactly how these variants cause the cholestasis and liver damage seen in people with FIC1 deficiency.

Pathogenic variants in the ABCB11 gene cause BSEP deficiency. The ABCB11 gene provides instructions for making a protein called the bile salt export pump (BSEP). This protein is found in the liver, and its main role is to move bile acids out of liver cells. Pathogenic variants in the ABCB11 gene can result in a buildup of bile acids, which damages liver cells and causes liver disease.

Pathogenic variants in the ABCB4 gene cause MDR3 deficiency. These variants reduce the number of molecules called phospholipids that are available to bind to bile acids. These phospholipids act as a buffer. Large amounts of free (unbuffered) bile acids are potentially harmful to cells. However, when bile acids are bound to phospholipids, they are less toxic. When fewer phospholipids are available to bind to bile acids, bile acids can build up and cause liver damage.

Some people with PFIC do not have an identified pathogenic variant in the genes that are currently associated with PFIC. In these cases, the cause of the condition is unknown.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

PFIC is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a pathogenic variant to cause the disorder. Usually, the parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

Some adults with only one pathogenic variant in a gene that causes PFIC may be at increased risk for developing various conditions, including gallstones, a liver disorder that typically occurs during the second half of pregnancy (intrahepatic cholestasis of pregnancy or ICP), drug-induced cholestasis, or a temporary form of cholestasis that occurs in infants (transient neonatal cholestasis).

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

PFIC is estimated to affect 1 in 50,000 to 100,000 people.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormality of coagulation · Very frequent (99-80%)

An abnormality of the process of blood coagulation. That is, altered ability or inability of the blood to clot.

Cholestasis · Very frequent (99-80%)

Impairment of bile flow due to obstruction in bile ducts.

Cognitive impairment · Very frequent (99-80%)

Abnormal cognition is characterized by deficits in thinking, reasoning, or remembering.

Failure to thrive · Very frequent (99-80%)

Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.

Hepatomegaly · Very frequent (99-80%)

Abnormally increased size of the liver.

Jaundice · Very frequent (99-80%)

Yellow pigmentation of the skin due to bilirubin, which in turn is the result of increased bilirubin concentration in the bloodstream.

Malabsorption · Very frequent (99-80%)

Impaired ability to absorb one or more nutrients from the intestine.

Short stature · Very frequent (99-80%)

A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).

Other findings in the same source

From: Orphanet

Additional reported features include Splenomegaly (Very frequent (99-80%)); Abnormality of thrombocytes (Frequent (79-30%)); Delayed skeletal maturation (Frequent (79-30%)); Hypocalcemia (Frequent (79-30%)); Reduced bone mineral density (Frequent (79-30%)); Neoplasm (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Progressive familial intrahepatic cholestasis is Hepatology, with a hepatologist / gastroenterologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• What is known about the cause and extent of liver involvement?
• Which medicines, supplements or exposures should be reviewed?
• What follow-up is appropriate for the specific diagnosis and stage?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Progressive familial intrahepatic cholestasis. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.