Kids with certain PFIC mutations more likely to need liver transplant

Children with progressive familial intrahepatic cholestasis (PFIC) who carry mutations that completely eliminate a protein’s production are nearly three times more likely to require a liver transplant than those with mutations that cause milder changes to that protein.

That’s according to a meta-analysis of published studies, the findings of which “underscore the importance of … synthesizing evidence related to types of [mutations] and the intervention of LT [liver transplant] for increasing the precision of the effect estimates and guiding decisions regarding personalized and early preventive LT before complications,” the researchers wrote.

The study, “Types of genotypes in progressive familial intrahepatic cholestasis and liver transplantation: A meta-analysis of observational studies,” was published in PLOS One.

PFIC is a group of rare liver disorders typically manifesting in infancy or early childhood. They are caused by genetic mutations that impair the liver’s ability to properly secrete bile, a digestive fluid. This results in cholestasis, when bile cannot flow properly from the liver, causing damage to the organ that can eventually lead to the need for a liver transplant.

Four of PFIC’s main types are caused by mutations in the ATP8B1 (PFIC1), ABCB11 (PFIC2), ABCB4 (PFIC3), and TJP2 genes (PFIC4). These genes encode proteins that help maintain the proper balance and transport of bile acids, bile’s main component. When these genes are mutated, the proteins they encode may function poorly or not at all.

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Mutations and disease severity

To understand whether genotpye (type of disease-causing mutation) is linked to PFIC severity and the risk of needing a liver transplant, a team of researchers in Tunisia combined data from 18 published studies reporting data on a total of 420 children and adolescents with PFIC types 1-4.

Half of the studies were conducted in Europe, and 27.8% in Asia. Three studies were conducted in the U.S. and other countries. The number of patients in each study ranged from three to 120.

Of the 420 children and adolescents, 193 (44%) eventually underwent liver transplant. The proportion of patients requiring a liver transplant varied by type of PFIC. It was highest in PFIC1 (61%), followed by PFIC2 (47%), PFIC4 (40%), and PFIC3 (39%).

Available data showed that the most common indications of liver transplant included chronic liver failure, severe cirrhosis (permanent liver scarring), persistent cholestasis, severe itching (a common PFIC symptom), and complications such as portal hypertension (high blood pressure in the major vein supplying the liver) and fluid buildup in the abdomen.

Many studies reported that patients received treatments before liver transplant. These included ursodeoxycholic acid (UDCA), a medication that helps bile flow, and biliary diversion surgery, a procedure that redirects bile to prevent bile from accumulating in the liver. However, information about treatment response was often incomplete.

A total of 105 participants (25%) had null genotypes, meaning their mutated gene produced little or no working protein, and 315 (75%) had non-null genotypes, meaning some protein function remained.

Statistical analyses of pooled data showed that participants with null genotypes were significantly more likely, by nearly threefold, to undergo liver transplant than those with non-null genotypes.

The increased odds remained consistent across PFIC types, suggesting that the type of mutation may be an important predictor of how disease will progress regardless of PFIC type. The team noted that the PFIC4 subgroup was excluded from this analysis because only one study included it.

Also, PFIC1 and PFIC3 subgroups were comprised of a smaller number of studies and participants relative to the PFIC2 subgroup, “meaning that the analysis may not be able to detect subgroup differences,” the researchers wrote.

“This meta-analysis contributed to shedding more light on a potential link between types of genotypes in PFIC diseases and the indication of LT,” the team concluded. “Particularly, LT was found to be performed more frequently in patients harboring null genotypes.”