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.

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.