7 October 2026 Punjab Khabarnama Bureau : Progressive familial intrahepatic cholestasis, or PFIC, is a rare inherited liver disorder that primarily affects children and can lead to progressive liver damage. Researchers are increasingly focusing on treatments that address the underlying biological mechanisms of the disease rather than only managing symptoms.
Hisamitsu Hayashi, PhD, associate professor at the University of Tokyo Graduate School of Pharmaceutical Sciences, has been involved in research examining the role of bile salt export pump, or BSEP, in PFIC and how existing medicines could potentially be used to restore its function.
PFIC is a group of genetic disorders in which defects affecting bile formation and transport cause bile acids to accumulate in the liver. Patients can develop cholestasis, jaundice and severe itching during infancy or childhood. As the disease progresses, liver fibrosis, cirrhosis and, in some cases, liver failure can occur.
PFIC1 is associated with mutations in the ATP8B1 gene, while PFIC2 is linked to mutations in ABCB11, which produces the BSEP protein. BSEP plays a crucial role in transporting bile acids from liver cells into bile. When this process is disrupted, bile acids can build up and damage liver tissue.
According to Hayashi, an important challenge in PFIC treatment is that controlling symptoms such as severe itching does not necessarily stop the progression of liver disease. This has increased interest in therapies that can potentially preserve liver function and delay or prevent serious complications.
A major development in this area came from research into sodium phenylbutyrate, a medicine that has long been used for treating urea cycle disorders. Research led by Hayashi identified another pharmacological effect of the drug: it can increase the amount of functional BSEP present at the canalicular membrane of liver cells, helping improve bile acid transport.
This mechanism could be particularly relevant for certain patients with PFIC2. Some ABCB11 mutations result in BSEP proteins that retain some transport capability but do not reach or remain at the liver cell membrane in sufficient quantities. Increasing the amount of functional BSEP at the membrane could therefore improve bile acid export.
The research also found that sodium phenylbutyrate can increase membrane expression and transport capacity of normal BSEP. This finding may be relevant to PFIC1, where the primary genetic defect affects ATP8B1 rather than ABCB11 but can result in secondary impairment of BSEP function.
Japan approved sodium phenylbutyrate for PFIC types 1 and 2 in August 2026, providing a regulatory milestone for a disease-directed treatment approach. The approval followed clinical studies and research examining the drug’s effects on PFIC.
Clinical evidence remains limited because PFIC is a rare disease. A multicenter investigator-initiated study involving six patients with PFIC2 evaluated changes in liver histology after 24 weeks of treatment. Histological improvement was observed in three patients, while liver-related biochemical measures generally improved during treatment.
Long-term follow-up has also provided encouraging observations, although the available patient numbers are very small. Four patients who continued treatment were still receiving sodium phenylbutyrate as of March 2026 and had remained with their native livers for approximately 6.5 to 8 years. Researchers caution that these observations are not from a controlled comparison and therefore should be interpreted carefully.
Evidence for PFIC1 came from an exploratory study involving three patients. Researchers observed improvements in itching during treatment, with symptoms worsening again after treatment was stopped. However, the short study period did not clearly demonstrate changes in liver histology.
The potential role of sodium phenylbutyrate is different from that of IBAT inhibitors. Current IBAT inhibitor therapies are primarily used to control cholestatic pruritus associated with PFIC, whereas sodium phenylbutyrate is directed toward the underlying disease mechanism by increasing functional BSEP and improving bile acid export.
The different mechanisms could eventually allow treatments to be used alongside each other. Researchers are studying how therapies should be selected or combined based on disease subtype, genetic characteristics, residual BSEP function and the stage of liver disease.
Other treatment options, including biliary diversion, remain important for patients who do not respond adequately to medical therapy. Liver transplantation continues to be essential for patients who develop advanced or decompensated liver disease.
Hayashi’s research highlights the potential value of understanding the molecular mechanisms behind rare diseases. The development of sodium phenylbutyrate for PFIC followed a long path from laboratory research into BSEP biology to experimental models, clinical studies and regulatory approval.
Researchers now want to better understand which patients are most likely to respond, how genetic variants influence treatment response and whether early treatment can preserve native liver function over the long term.
Future research will also examine how disease-directed therapies can be integrated with existing treatments. For patients and families affected by PFIC, important outcomes include controlling severe itching, supporting normal growth and quality of life, slowing liver damage and delaying the need for transplantation.
The work on BSEP demonstrates how studying the underlying biology of an inherited disease can reveal new therapeutic possibilities. Continued research could help expand disease-directed treatment options for PFIC and potentially provide insights into other cholestatic liver conditions involving impaired bile acid transport.