Genetic Cholestasis in Adults: Making Sense of a PFIC-Related Diagnosis

by Chunyue Yin, Phd.

Genetic cholestatic liver diseases—once thought to affect only children—are now increasingly recognized in adults. In this blog, we’ll walk through the basics: what cholestasis means, when to consider genetic testing, which genes are involved, and current treatment options. A more detailed discussion of these topics can be found in the excellent recent review by Drs. Richard Thompson and Silvia Vilarinho et al.

What is cholestasis and what causes it?

Cholestasis occurs when the liver cannot properly drain bile—the fluid that helps digest fats and remove waste. When bile builds up, it can cause itching, jaundice, fatigue, and, over time, scarring of the liver that can progress to cirrhosis or liver cancer.

Cholestasis can arise from two cellular origins:

  1. Hepatocellular cholestasis: bile-producing liver cells (hepatocytes) cannot secrete bile normally.
  2. Cholangiocyte cholestasis: cells lining the bile ducts are damaged or dysfunctional, preventing normal bile flow.

Many conditions can cause cholestasis, including viral infections, medications, hormonal changes, autoimmune diseases, and physical blockage of the bile ducts. A smaller but important subset is caused by inherited genetic mutations. Among these are the progressive familial intrahepatic cholestasis (PFIC) disorders—an umbrella group of rare conditions caused by mutations in genes essential for bile transport and the structural integrity of hepatocytes and cholangiocytes. Although first recognized in children with severe early-onset disease, mutations in PFIC-related genes are now found to cause liver disease in individuals across all ages.

Can adults present with a genetic cholestatic liver disease? Why is it rarely discussed?

With modern genetic testing, it is clear that PFIC-related mutations are not limited to children. Up to 30% of adults with otherwise unexplained cholestasis may have an underlying genetic cause. Adult presentations vary widely. Some adults have only mild or intermittent liver test abnormalities, while others develop symptoms triggered by infections, hormonal changes, or medications. In some, disease can silently progress to fibrosis or cirrhosis.

Diagnosis in adults is difficult for several reasons: symptoms may come and go or be very mild, and standard imaging tests often look normal. Many other liver conditions share similar symptoms. In addition, interpretating genetic testing results in adults is complicated because lifestyle factors, other health conditions, and medications can all play a role.

When should adult patients be considered for genetic testing?

  • Common causes of cholestasis have been ruled out
    • Primary biliary cholangitis (PBC), Primary sclerosing cholangitis (PSC), viral hepatitis, medication side effects, overuse of alcohol, or bile duct blockage is not the cause.
  • There are ongoing or repeated liver problems
    • Persistent or recurring elevated liver tests
    • Elevated serum bile acid levels
    • Itching
    • Intrahepatic cholestasis during pregnancy
    • Unusually strong or unexpected reactions to medications that affect the liver
  • There is a history of gallstone disease that seems unusual
    • Early-onset gallstones, often requiring gallbladder removal
    • Gallstones that return even after gallbladder removal
  • Symptoms resemble PBC or PSC but do not fit the typical pattern
    • AMA-negative PBC
    • Small-duct PSC
    • Atypical PSC (particularly in the absence of inflammatory bowel disease)

Why is genetic testing important/helpful for evaluation of unexplained cholestasis in adults?

Beyond establishing a diagnosis, genetic testing also guides treatment and long-term management. The specific gene affected, and the type of mutation can have a significant impact on how well a patient responds to particular therapies. Some genetic mutations, especially in ABCB4 and ABCB11, also increase the risk of liver cancer, so individuals who carry these mutations may need personalized cancer surveillance.

Testing also benefits families. Parents and siblings of patients with PFIC or related disorders may be asymptomatic carriers of those mutations and develop cholestasis later in life, particularly during pregnancy, medication use, including estrogen enriched medications. Early identification supports preventive care and informs reproductive planning, including prenatal or preimplantation options.

How is genetic testing done?

As genetic testing has become more affordable and accessible, it is now much easier for doctors to evaluate whether cholestasis may have a genetic cause. Depending on the clinical situation, they may order a targeted gene panel, whole-exome sequencing (WES), or, in some cases, whole-genome sequencing (WGS). Regardless of the type of test, the results must be interpreted alongside the patient’s symptoms, liver tests, imaging, and sometimes liver biopsy findings to determine how the genetic findings relate to the patient’s disease. We will cover the different types of genetic tests and how to interpret the results in an upcoming blog.

Which genes have been associated with adult PFIC?

Genes that have been linked to cholestasis in adults are listed in the table below. In children, changes in these genes typically cause PFIC, a more severe and progressive form of cholestasis that often requires liver transplantation. In adults, however, milder changes in the same genes may lead to symptoms such as gallstones, unexplained abnormal liver tests, drug-induced liver injury, or cholestasis during pregnancy. These adult presentations are generally milder, and the majority are thought to be non-progressive forms of cholestasis.

GeneProteinFunction of the proteinSymptoms in adultsSymptoms outside the liver
ATP8B1FIC1Keeps hepatocyte membrane healthy to excrete bile to the bile ducts.Episodic cholestasis, ICP, elevated LFT, itchingIntestinal symptoms (diarrhea), hearing loss, pancreatitis
ABCB11BSEPPumps bile acids out of hepatocytes into bile ducts.Episodic cholestasis, DILI, ICP, HCC, elevated LFT, gallstones, itching
ABCB4MDR3Moves protective fats (phospholipids) into the bile to help prevent irritation and damage to the bile ducts.Sclerosing cholangitis, DILI, biliary fibrosis, LPAC, gallstones, ICP, CCA, elevated LFTs
TJP2TJP2Tight junction protein between hepatocytes to prevent bile from leaking where it shouldn’t.Episodic cholestasis, ICP, elevated LFT, gallstones, HCC, itchingIntestinal symptoms (diarrhea), pancreatitis, hearing loss
NR1H4FXRRegulates bile acid production and transportICP, gallstonesVitamin K-independent coagulopathy
MYO5BMYO5BHelps move the bile acid transporter to the correct spot inside liver cells so it can work properlyEpisodic cholestasisMVID, intestinal symptoms, neurodevelopmental delay and pyramidal syndrome
SEMA7ASemaphorin 7AMembrane protein linked to inflammation and tissue repairICP, MASLD
Abbreviations: CCA: cholangiocarcinoma; DILI: drug-induced liver injury; HCC: hepatocellular carcinoma; ICP: intrahepatic cholestasis of pregnancy; LFT: liver function test; MASLD, Metabolic dysfunction–Associated Steatotic Liver Disease; MVID: microvillus inclusion disease.

For a more extensive list of genes that are associated with genetic cholestasis and description of their function and disease mechanisms, please refer to Drs Thompson and Vilarinho review article. For genes detected in PFIC in children, please check our previous blog on PFIC subtypes.

Most genetic tests used in adults look only at the parts of a gene that directly give instructions to make proteins—these are called coding regions. But our DNA also contains large “non-coding” sections that act like on/off switches or control panels, helping the gene work properly. Changes in these non-coding areas can cause disease too, but they are usually not evaluated by standard tests. This means a person who seems to have only one genetic change may have another hidden one. We also still have more to learn about how additional genes or “epigenetic” influences—factors that affect how genes work without changing the DNA itself—shape why some people develop mild symptoms while others develop more serious disease.

Treatment of genetic cholestasis in adults

Because adult-onset genetic cholestasis has been unappreciated and underdiagnosed, there have not been large clinical trials in adults. Instead, current treatments are based on studies in pediatric patients andsmall groups of adult patients, as well as what doctors have learned over the years from caring for patients with similar conditions. While new treatments designed for specific gene mutations are being developed, today’s care mainly focuses on lowering the buildup of bile acids and protecting the bile ducts from further damage.

The most common treatments for PFIC/genetic cholestasis in adults are listed below:

Cholestyramine: As a bile acid–binding resin, it traps bile acids in the intestine so they can be removed from the body instead of reabsorbed. This may help lower bile acid levels and ease itching over time. It can cause stomach-related side effects, and because it may reduce absorption of fat-soluble vitamins, regular nutrition monitoring is important.

Ursodeoxycholic Acid (UDCA): It replaces part of the body’s bile acids with a gentler, more water-soluble form. In some conditions—such as PBC and certain types of MDR3/ABCB4-related cholestasis—this may help improve liver tests or symptoms. How well it works varies from person to person and depends on the specific genetic change.

Surgical Interruption of Bile Acid Recycling: Procedures like partial external biliary diversion or temporary nasobiliary drainage lower bile acids by rerouting or removing some of the bile. These surgeries are used mainly in children with severe PFIC but may be considered in carefully selected adults when symptoms remain difficult to control with medications alone.

Ileal bile acid transporter (IBAT) Inhibitors (such as odevixibat and maralixibat): These medications block the reabsorption of bile acids in the last part of the intestine, which can reduce itching and lower bile acid levels. They are approved for children with PFIC and Alagille syndrome. While studies focused on children, these drugs may also help adults with milder forms of these genetic conditions.

Supportive care is important for everyone with genetic cholestasis, no matter which gene is affected. Many people need ongoing treatment for itching, sometimes using more than one medication. Regular checks of fat-soluble vitamins, nutrition, and overall health are also important. Long-term follow-up helps doctors watch for possible complications of chronic cholestasis and address them early.

Call to action:

Acknowledging that genetic causes of cholestasis can present in adults is an important first step. Increased awareness and improved access to genetic testing will result in precise diagnosis and better management of adult cholestatic liver diseases, improving patient outcomes and quality of life.

Genetics of PFIC: Current Status and Implications

By Laura Bull, Ph.D

I am writing this summary in the spring of 2018. My Ph.D. training was in human genetics, and in the 25 years since then, I have performed research at the intersection of genetics and cholestatic liver disease. My work has focused on understanding the genetic factors contributing to inherited cholestasis, including PFIC and related diagnoses such as BRIC (benign recurrent intrahepatic cholestasis) and hypercholanemia, as well as ICP (intrahepatic cholestasis of pregnancy). I have also performed genetic and physiologic research using a mouse model of PFIC1, also called FIC1, or ATP8B1, deficiency.

In this article, I will try to provide an overview of our current understanding of the genetics of PFIC, based upon our work and that
of colleagues in the field. I will also indicate some of what still remains unknown.

Systematic Review of Progressive Familial Intrahepatic Cholestasis

Short Background:

Epidemiology is the study of how often and when diseases occur (prevalence), what the risk factors are, and how to control diseases. Epidemiology of rare diseases is challenging because the total number of patients in a study is often very small. For example getting precise percentages of subtypes of PFIC is difficult: if 10 PFIC patients participate in a study, and 6 out of the ten have PFIC2, then that results in a prevalence of 60%. Just one more PFIC2 patient (7 out of 10) would result in 70%.

Cholestasis is the reduction or complete stoppage of bile flow. Cholestasis within the liver is called intrahepatic cholestasis. Cholestasis does not only occur in PFIC but can also be part of other disorders.

Summary:

This paper is a review of 20 previous research studies of the epidemiology, history, health-related quality of life of PFIC. Of the 20 papers they found there were 17 on the history and epidemiology of PFIC, and 5 focused on quality of life. Two papers covered both topics.

            Prevalence of  PFIC: The authors wanted to know how often the different PFIC subtypes occur in the general population. One of the previous studies showed a rate of 1 in 18,000 for intrahepatic cholestasis, which includes PFIC but also other diseases. Among children with different liver diseases the percentage that have PFIC seemed to be between 9 and 13%. Looking at how often the different subtypes occur among children with PFIC, 9 previous studies showed that PFIC2 was the most common subtype but the numbers varied quite a bit: across these studies 37-90% of PFIC patients had PFIC2. The numbers for PFIC1 were 10-38%, and for PFIC3 28-38%.

            Symptoms of PFIC: Nine previous studies described the clinical symptoms of the different PFIC subtypes: jaundice, hepatomegaly (enlarged liver), pruritus (itch), pale stools, splenomegaly (enlarged spleen), diarrhea, discolored stools, failure to thrive, vitamin E and vitamin D deficiencies, and for PFIC 1 also pancreatitis. In PFIC1 and 2 patients these symptoms show within the first 3 months of life, while for PFIC3 patients jaundice, hepatomegaly and pruritus may only show after 2-3 years. Itch was often severe (76-80%). Symptoms outside the liver were reported for PFIC1 (diarrhea 61%, pancreatitis 8%, elevated sweat chloride 15%), for PFIC2 (vitamin D deficiency 3-22%, vitamin K deficiency 8%), and for PFIC3 (vitamin D deficiency 6%).

            Severity of PFIC: Progression to severe liver disease was more common and occurred earlier in patients with PFIC2 than in those with PFIC1. The authors also looked at mortality rates reported in previous studies, which varied a lot (0-87%). The high number (87%) is probably the mortality rate when PFIC is not treated. Causes of death include infections, liver failure, and complications related to liver transplant. 

            Quality of Life: Five previous studies looked at quality of life or itch in PFIC patients. Both children themselves and their parents consistently rated quality of life lower than (parents of) healthy children. Three studies reported that itch was the most bothersome symptom.

            Conclusion: The authors of this review conclude that data about prevalence, mortality rates, and health related quality of life are very limited, and studies of the economic burden for a family with a child with PFIC are lacking entirely. They recommend more studies to be done in the future.

Keywords:

PFIC subtypes, prevalence, symptoms, quality of life

Citation:

Baker et al. Systematic Review of Progressive Familial Intrahepatic Cholestasis. Clinics and Research in Hepatology and Gastroenterology, 43, 20-36. 2019

Short Background:

The ABCB11gene provides the code to build the bile salt export pump (BSEP) protein. In this paper, “genotype” refers to the type of mutations of the ABCB11gene that can cause severe BSEP deficiency. Liver disease caused by BSEP deficiency is known as PFIC 2. A “missense mutation” is a mutation of just one base pair of a gene. This can be thought of as just one wrong letter in the code, but the effects of such a missense mutation can still be very severe. It is possible that the protein is not built correctly, does not function correctly, or is not built at all.

Summary:

This article describes the largest study to date of patients with severe BSEP deficiency. The authors categorized a total of 264 patients into three groups according to their type of mutation. The first group, BSEP 1, consisted of 72 patients with at least one D482G or p.E297G mutation. If the ABCB11gene has either of these mutations it can still produce some BSEP protein but not enough. The second group, BSEP 2, had 136 patients with at least one missense mutation (but not D482G or p.E297G). The patients in this group differed a lot with respect to the type of missense mutation. The third group, BSEP 3, had mutations that were known to lead to absence of the BSEP protein or to a non-functioning BSEP protein. The authors suspected that the severity of the effect of the mutation was the least in the BSEP1 group, followed by the BSEP 2 group, and BSEP 3 group.

            The goal of the study was to look whether the groups indeed differed with respect to outcomes such as the success of surgical biliary diversions (SBD), how long a patient lived with the native liver after SBD, and liver carcinoma (cancer of the liver).

            All three groups of patients had symptoms of PFIC 2 within their first year of life, and had very similar lab data initially. However, the course of disease differed between the groups. The first group, BSEP 1, had the least severe outcomes. For instance, relief of pruritis (itch) after surgical biliary diversion (SBD) was better, the number of years living with the native liver after SBD was longer, and the risk of liver cancer was the least compared to the other two groups. The second group also seemed to benefit from SBD: relief from pruritis and numbers of years with the native liver after SBD were better than the third group. The third group, BSEP 3, had generally the worst outcomes. In this group the authors did not see any improvement in itch relief after SBD. Also, the risk of liver cancer was substantially higher (about 34%) in this group.

            The authors conclude the type of mutation of the ABCB11gene is related to the severity of the disease. The results of this large study are consistent with previous smaller studies. The authors also note that the BSEP 2 group lumped together patients with different missense mutations, and that it would be good to conduct more research to get a more detailed picture whether these differences play a role in the severity of PFIC 2.

Keywords:

PFIC 2, BSEP deficiency, type of mutation

Citation:

Van Wessel et al. Genotype Correlates with the Natural History of Severe Bile Salt Export Pump Deficiency. Journal of Hepatology, https://doi.org/10.1016/j.jhep.2020.02.007. 2020

Expanding etiology of progressive familial intrahepatic cholestasis (PFIC)

Short Background:

A gene is a part of a chromosome that provides the code to build a specific protein. Proteins are involved in pretty much all processes in the human body, including liver function. Mutations are changes in the code of a gene. Changes in the code can lead to proteins that do not function correctly, or even that the protein is not produced at all. The severity of the resulting symptoms often depends on the severity of the mutation. 

Summary:

This article is a review of research concerning the genetics and characteristics of the different PFIC subtypes. It includes more recent findings that go beyond the more classic PFIC1, PFIC2, and PFIC3 subtypes. The authors of this paper looked at over 900 scientific papers that involved genes associated with PFIC in order to select relevant research and provide an overview of the current status quo.  

            Bile is produced by the liver, transported out of the liver into the small intestine, and then reabsorbed and transported back to the liver. This circuit depends on several different proteins along the way that are coded by different genes. Mutations in any of these genes can cause a disruption of the normal bile flow, which can then result in liver damage. How and where the bile flow is disrupted depends on which protein is defective, and this is mainly why the different subtypes of PFIC have somewhat different characteristics.

            The first reported PFIC is PFIC1 (aka Byler’s disease). It is caused by mutations of the ATP8B1 gene, which encodes the FIC1 protein. The precise function(s) of this protein is not yet known. It is possible that it is involved in the transport of phospholipids, which are needed inside the liver cells to prevent bile acids from causing damage to the liver cells. Defects in the FIC1 protein can lead to low GGT cholestasis (bile built up in the liver). Since FIC1 is also found outside the liver, the spectrum of symptoms of PFIC1 is often broader than in other subtypes of PFIC.  In addition to jaundice, pruritus (itch), and in severe cases progressive liver disease, symptoms of PFIC1 children can also include severe diarrhea, poor growth, and problems with pancreas function. Medical treatment is challenging. Often surgical intervention is needed, which can result in improvement. Partial external biliary diversion (PEBD), ileal bypass, and partial internal biliary bypass (PIBD) are three options that all aim at reducing bile build up in the liver. As of right now neither procedure is clearly superior to the others. Patients who develop end stage liver disease need liver transplant, and it is important to consider that diarrhea can persist or even get worse post-transplant.

            PFIC2 results from mutations in the ABCB11 gene which encodes the Bile Salt Export Pump (BSEP) protein. The function of this protein is to transport bile salts out of the liver cells. Early symptoms of PFIC2 include jaundice, itch, and progressive liver damage which can result in an increase of pressure in the vein that carries blood from the intestines to the liver (“portal hypertension”). In addition, poor growth due to lack of fat absorption and fat-soluble vitamin deficiency can occur, but in general symptoms not directly related to the liver are less severe compared to PFIC1. Initial treatment is similar to PFIC1 and focuses on nutritional supplements and dealing with the itch. Success of biliary diversion seems to depend on the severity of the mutation of the ABCB11 gene. In addition to liver disease there a high chance of cancer (up to 15%) even in very young children.

            PFIC3 is caused by mutations in the ABCB4 gene, which encodes the MDR3 protein. MDR3 helps to incorporate a chemical (phosphatidylcholine) into the bile that neutralizes the detergent qualities of bile acids, which  if left unmitigated would otherwise cause harm. Similar to the other PFIC diseases, the severity of the symptoms seems to depend on the severity of the mutation. This subtype of PFIC often presents later in adolescence or early adulthood. Depending on the severity of the disease liver transplant is often the only therapy.

            More recently, several other proteins have been identified that can cause disease symptoms similar to PFIC if they are defective. The first protein listed in this paper is TJP2, which is a so-called tight junction protein. These types of proteins keep cells together and regulate the flow of specific molecules in between cells. More research is needed to figure out the exact function of TJP2, and why mutations can cause PFIC like disease. The second one is FXR , which regulates the BSEP protein. Without proper regulation of the BSEP protein patients have shown to rapidly develop end stage liver disease. The third protein is MYO5B. The BSEP protein depends on MYO5B to find its way to the cell membrane where it then transports bile salts out of the cell. The symptoms of defective MYO5B are similar to PFIC2, but the disease can include symptoms outside the liver because MYO5B also has other functions. Treatment is similar to PFIC 2 and starts with nutritional supplements and anti-itch medication. In case the itch remains PEBD has been somewhat successful. Finally, liver transplant has been carried out if PEBD is not solving the problems, but this does not resolve the symptoms that are not related directly to the liver. In addition to TJP2, FXR and MYO5B, two other proteins, USP53 and LSR have been found to be related to liver disease. Defects of USP53 were found in 3 children belonging to one family. This protein is thought to work together with TJP2. A mutation in the LSR coding gene was found in one boy, but more research is needed to uncover how this mutation can lead to liver disease. Importantly, these new PFIC-related disorders have only been described in a very small number of children, thus much more information is needed to truly understand how these diseases progress and what treatments may be best.

            This review paper also includes a short overview how the PFIC genes described above can contribute to disease in adults. In adults, disease is mostly limited to Benign Recurrent Intrahepatic Cholestasis (BRIC), and Intrahepatic Cholestasis of Pregnancy (ICP). BRIC in adults is characterized by episodes of more or less severe liver disease. ICP occurs in about 1% of pregnancies. While there are usually no harmful effects for the mother, there can be adverse effects for the child such as premature birth, and also in rare cases stillbirth. Medication has shown to decrease these risks.

Keywords:

PFIC subtypes, genetics

Citation:

Henkel et al. Expanding Etiology of Progressive Familial Intrahepatic Cholestasis. World Journal of Hepatology, 11(5), 450-463. 2019

About Us

Get Involved

The Disease