RARE DISEASE
Progressive familial intrahepatic cholestasis
Progressive familial intrahepatic cholestasis
Progressive familial intrahepatic cholestasis
Synonyms: PFIC
Synonyms: PFIC
Synonyms: PFIC
Drug discovery
9
drugs
With orphan designations
Overview
Progressive Familial Intrahepatic Cholestasis (PFIC) is a group of rare autosomal recessive disorders caused by defects in hepatobiliary transport proteins (ATP8B1, ABCB11, or ABCB4), leading to impaired bile formation, cholestasis, and progressive liver injury. Clinical hallmarks include severe pruritus, jaundice, failure to thrive, and fat-soluble vitamin deficiencies. Untreated, PFIC progresses to cirrhosis and liver failure, often requiring transplantation. Diagnosis involves genetic testing, serum bile acid profiling, and liver histology [1][2][14].
Burden
Severe pruritus causes sleep disturbances, skin mutilation, and impaired cognitive/social development [4][7][15].
50–87% progress to liver failure before adulthood, often requiring transplantation [1][10][18].
Caregiver burden: Reduced quality of life, financial strain, and emotional distress due to complex care needs [4][15][17].
Therapies
Pharmacologic: Ursodeoxycholic acid (first-line), ileal bile acid transporter (IBAT) inhibitors (odevixibat, maralixibat) [3][12][19], rifampicin, and cholestyramine [16].
Surgical: Partial external biliary diversion (PEBD) for pruritus relief; liver transplantation for end-stage disease [1][8][16].
Supportive: Fat-soluble vitamin supplementation, medium-chain triglycerides [16][18].
Categories: rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare transplant-related disorders
Research Papers
584 drug discovery papers about Progressive familial intrahepatic cholestasis, with 5 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
584 drug discovery papers about Progressive familial intrahepatic cholestasis, with 5 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-11 | Liver-directed gene therapy results in amelioration of progressive familial intrahepatic cholestasis type 2 in mice.
Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare disease affecting the ABCB11 gene, encoding the bile salt export pump (BSEP). BSEP dysfunction impairs bile acid (BA) secretion, causing hepatic damage and leading to pruritus, cholestasis, hepatomegaly, and often fibrosis and end-stage hepatic disease. Treatments include ileal BA transporter inhibitors, surgical bile diversion, or ultimately, liver transplantation. Our aim was to develop a PFIC2 gene therapy approach based on the restoration of BSEP hepatocyte expression. We designed several expression cassettes containing the human ABCB11 gene downstream of either a liver-specific constitutive promoter or a BA-inducible promoter. After in vitro screening, the AAV vectors with the best expression cassette for each promoter were tested in a PFIC2 mouse model. The AAV vector containing the constitutive promoter, named VTX-802, showed higher BSEP expression, resulting in better restoration of BA secretion 3 and 7 weeks post-treatment. We then performed a dose-range-finding study of VTX-802 in 5-week-old female PFIC2 mice in which the therapeutic efficacy was monitored until 5 months of age. Treated mice showed a sustained dose-dependent improvement in serum transaminase levels. These mice also exhibited significant, but partial, correction of hepatomegaly, and increased BA levels in bile and small intestine, indicating partial restoration of normal BA secretion. VTX-802 restores hepatic BSEP expression and partially corrects disease phenotype in PFIC2 mice. To our knowledge, VTX-802 is the first gene therapy approach that could potentially benefit PFIC2 patients.
2026-08-07 | PFIC Type 4 Presenting As Biliary Atresia-like Neonatal Cholestasis: a Case With Persistent Truncus Arteriosus and Horseshoe Kidney
Introduction Progressive familial intrahepatic cholestasis (PFIC) comprises an important group of monogenic disorders causing neonatal and infantile cholestasis. In the evaluation of cholestatic jaundice in infants, current algorithms emphasize prompt assessment and timely exclusion of biliary atresia (BA) because outcomes are strongly time-dependent; nevertheless, several genetic cholestatic disorders may clinically and radiologically mimic BA, creating a significant diagnostic challenge in critically ill neonates [ 1 ]. PFIC type 4 results from biallelic pathogenic variants in TJP2 (tight junction protein 2), an essential component of epithelial tight junctions; loss of function disrupts the canalicular barrier, leading to hepatocellular injury and progressive cholestatic liver disease [ 2 ] [ 3 ]. PFIC-4 has a broad clinical spectrum, and early hepatocellular carcinoma has been reported in some children with TJP2 deficiency [ 4 ]. As next-generation sequencing (NGS) has become more accessible, panel-based testing has improved diagnostic yield in suspected monogenic cholestasis and can shorten the diagnostic journey when conventional evaluation is inconclusive [ 5 ]. Co-existing complex congenital heart disease can further confound cholestasis work-up through prolonged intensive care, hemodynamic instability, nutritional challenges, and exposure to multiple medications (including potentially hepatotoxic antibiotics), thereby complicating interpretation of cholestatic laboratories and imaging. In our review of the available literature, we did not identify any previous report of genetically confirmed PFIC-4 coexisting with persistent truncus arteriosus; therefore, this association appears to be exceptionally rare. The aim of this case report is to highlight (i) BA-mimicking, dynamic ultrasonographic findings in PFIC-4, (ii) the confounding impact of severe cardiac comorbidity on cholestasis evaluation, and (iii) the clinical value of early NGS-based testing in complex neonatal cholestasis. Publication History Received: 19 February 2026 Accepted after revision: 24 July 2026 Article published online: 07 August 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2026-08-05 | Contrasting Impacts of Two ABCB11 Variants Affecting the Same Residue in Progressive Familial Intrahepatic Cholestasis Type 2.
Progressive Familial Intrahepatic Cholestasis Type 2 (PFIC2) is a severe autosomal recessive cholestatic liver disease due to variations in ABCB11. Clinical and molecular consequences of two missense variations affecting the same ABCB11 residue (T463) were characterized, and pharmacological strategies were investigated. Clinical and genetic data were collected from two PFIC2 patients carrying p.T463I or p.T463P substitution. A three-dimensional (3D) structure analysis was performed to predict substitution impacts. ABCB11T463I and ABCB11T463P variants were expressed in HepG2 and Madin-Darby canine kidney cells to assess their subcellular localization and functional activity. Pharmacological modulators were tested to correct the defects. The patient carrying ABCB11T463I exhibited a mild phenotype and responded to surgical biliary diversion. Conversely, the patient carrying ABCB11T463P required a liver transplantation before age one. 3D structure and in vitro analyses predicted a functional defect in both variants, and a folding defect for the T463P variant. In vitro, ursodeoxycholic acid combined with glycerol phenylbutyrate increased ABCB11T463P canalicular expression (40.2 ± 7.7% of the wild-type, p <0.0001) and improved transport activity (32.4 ± 10.3% of the wild-type, p <0.0001). VX-770 and SBC040 increased ABCB11T463I function from 37.9 ± 2.5% (DMSO) to 73.2 ± 12.3% and 76.1 ± 17.5%, respectively, of the wild-type activity (p <0.0001). ABCB11 missense variations, even affecting the same residue, can cause various molecular defects, resulting in mild to severe phenotypes. 3D structure and in vitro analyses could be used to predict the severity of missense variants and guide the treatment of PFIC2 patients with pharmacological modulators.
2026-07-29 | From one-size-fits-all to on-demand: personalized crispr gene editing for rare genetic liver diseases.
Rare genetic liver diseases collectively affect millions of individuals worldwide and encompass a heterogeneous group of monogenic disorders including Wilson disease, alpha-1 antitrypsin deficiency, glycogen storage diseases, urea cycle disorders, progressive familial intrahepatic cholestasis, and acute hepatic porphyrias. While conventional management relies on dietary modification, pharmacotherapy, and ultimately liver transplantation, the advent of clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing has opened transformative therapeutic avenues. This review provides a comprehensive and critical appraisal of the current landscape of CRISPR-based therapies for genetic liver diseases, from preclinical proof-of-concept studies to landmark clinical trials. We examine the evolution from conventional Cas9 nuclease-mediated editing to precision tools including base editors and prime editors, which enable single-nucleotide corrections without inducing double-strand DNA breaks. The role of lipid nanoparticle delivery systems in achieving efficient hepatocyte-targeted delivery is discussed, alongside emerging challenges in pediatric dosing and immunogenicity. We highlight the paradigm shift toward personalized, patient-specific CRISPR therapies, exemplified by the first-in-human bespoke gene editing treatment delivered in 2025. Competing nucleic acid technologies, including RNA interference and antisense oligonucleotides, are compared in terms of durability, safety, and cost-effectiveness. Finally, we critically evaluate the evolving regulatory landscape and propose a priority framework for selecting genetic liver diseases most amenable to CRISPR-based correction. This review underscores that CRISPR gene editing is transitioning from experimental promise to clinical reality for genetic liver diseases, with personalized approaches poised to redefine the treatment paradigm.
2026-06-19 | Progressive Familial Intrahepatic Cholestasis Type 7 in a 4 Month Old Female, Japanese Infant: A Case Report
Learning Points This case represents the first documented diagnosis of PFIC Type 7 in a Japanese infant, expanding the understanding of the ethnic demographics and geographical distributions of USP53 associated cholestasis. This case highlights an unusual clinical presentation of PFIC Type 7, which may present with initial complications including coagulopathy and intracranial haemorrhage as seen in this case rather than typical features such as jaundice or pruritus. This highlights the importance of considering hepatobiliary disorders as a differential diagnosis in the investigation of unexplained bleeding in infants. The diagnosis of PFIC Type 7 in this patient was made via trio exome sequencing, as the USP53 gene is not routinely included in standard genetic panels for cholestasis. Incorporating USP53 into these panels could facilitate earlier recognition of and subsequent intervention for this condition. Long term management involves correction of fat‐soluble vitamin deficiency and supportive management of cholestasis. Improvement with rifampicin, as observed in this case, supports its potential therapeutic role, though the mechanism remains uncertain.
2026-08-11 | Liver-directed gene therapy results in amelioration of progressive familial intrahepatic cholestasis type 2 in mice.
Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare disease affecting the ABCB11 gene, encoding the bile salt export pump (BSEP). BSEP dysfunction impairs bile acid (BA) secretion, causing hepatic damage and leading to pruritus, cholestasis, hepatomegaly, and often fibrosis and end-stage hepatic disease. Treatments include ileal BA transporter inhibitors, surgical bile diversion, or ultimately, liver transplantation. Our aim was to develop a PFIC2 gene therapy approach based on the restoration of BSEP hepatocyte expression. We designed several expression cassettes containing the human ABCB11 gene downstream of either a liver-specific constitutive promoter or a BA-inducible promoter. After in vitro screening, the AAV vectors with the best expression cassette for each promoter were tested in a PFIC2 mouse model. The AAV vector containing the constitutive promoter, named VTX-802, showed higher BSEP expression, resulting in better restoration of BA secretion 3 and 7 weeks post-treatment. We then performed a dose-range-finding study of VTX-802 in 5-week-old female PFIC2 mice in which the therapeutic efficacy was monitored until 5 months of age. Treated mice showed a sustained dose-dependent improvement in serum transaminase levels. These mice also exhibited significant, but partial, correction of hepatomegaly, and increased BA levels in bile and small intestine, indicating partial restoration of normal BA secretion. VTX-802 restores hepatic BSEP expression and partially corrects disease phenotype in PFIC2 mice. To our knowledge, VTX-802 is the first gene therapy approach that could potentially benefit PFIC2 patients.
2026-08-07 | PFIC Type 4 Presenting As Biliary Atresia-like Neonatal Cholestasis: a Case With Persistent Truncus Arteriosus and Horseshoe Kidney
Introduction Progressive familial intrahepatic cholestasis (PFIC) comprises an important group of monogenic disorders causing neonatal and infantile cholestasis. In the evaluation of cholestatic jaundice in infants, current algorithms emphasize prompt assessment and timely exclusion of biliary atresia (BA) because outcomes are strongly time-dependent; nevertheless, several genetic cholestatic disorders may clinically and radiologically mimic BA, creating a significant diagnostic challenge in critically ill neonates [ 1 ]. PFIC type 4 results from biallelic pathogenic variants in TJP2 (tight junction protein 2), an essential component of epithelial tight junctions; loss of function disrupts the canalicular barrier, leading to hepatocellular injury and progressive cholestatic liver disease [ 2 ] [ 3 ]. PFIC-4 has a broad clinical spectrum, and early hepatocellular carcinoma has been reported in some children with TJP2 deficiency [ 4 ]. As next-generation sequencing (NGS) has become more accessible, panel-based testing has improved diagnostic yield in suspected monogenic cholestasis and can shorten the diagnostic journey when conventional evaluation is inconclusive [ 5 ]. Co-existing complex congenital heart disease can further confound cholestasis work-up through prolonged intensive care, hemodynamic instability, nutritional challenges, and exposure to multiple medications (including potentially hepatotoxic antibiotics), thereby complicating interpretation of cholestatic laboratories and imaging. In our review of the available literature, we did not identify any previous report of genetically confirmed PFIC-4 coexisting with persistent truncus arteriosus; therefore, this association appears to be exceptionally rare. The aim of this case report is to highlight (i) BA-mimicking, dynamic ultrasonographic findings in PFIC-4, (ii) the confounding impact of severe cardiac comorbidity on cholestasis evaluation, and (iii) the clinical value of early NGS-based testing in complex neonatal cholestasis. Publication History Received: 19 February 2026 Accepted after revision: 24 July 2026 Article published online: 07 August 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2026-08-05 | Contrasting Impacts of Two ABCB11 Variants Affecting the Same Residue in Progressive Familial Intrahepatic Cholestasis Type 2.
Progressive Familial Intrahepatic Cholestasis Type 2 (PFIC2) is a severe autosomal recessive cholestatic liver disease due to variations in ABCB11. Clinical and molecular consequences of two missense variations affecting the same ABCB11 residue (T463) were characterized, and pharmacological strategies were investigated. Clinical and genetic data were collected from two PFIC2 patients carrying p.T463I or p.T463P substitution. A three-dimensional (3D) structure analysis was performed to predict substitution impacts. ABCB11T463I and ABCB11T463P variants were expressed in HepG2 and Madin-Darby canine kidney cells to assess their subcellular localization and functional activity. Pharmacological modulators were tested to correct the defects. The patient carrying ABCB11T463I exhibited a mild phenotype and responded to surgical biliary diversion. Conversely, the patient carrying ABCB11T463P required a liver transplantation before age one. 3D structure and in vitro analyses predicted a functional defect in both variants, and a folding defect for the T463P variant. In vitro, ursodeoxycholic acid combined with glycerol phenylbutyrate increased ABCB11T463P canalicular expression (40.2 ± 7.7% of the wild-type, p <0.0001) and improved transport activity (32.4 ± 10.3% of the wild-type, p <0.0001). VX-770 and SBC040 increased ABCB11T463I function from 37.9 ± 2.5% (DMSO) to 73.2 ± 12.3% and 76.1 ± 17.5%, respectively, of the wild-type activity (p <0.0001). ABCB11 missense variations, even affecting the same residue, can cause various molecular defects, resulting in mild to severe phenotypes. 3D structure and in vitro analyses could be used to predict the severity of missense variants and guide the treatment of PFIC2 patients with pharmacological modulators.
2026-07-29 | From one-size-fits-all to on-demand: personalized crispr gene editing for rare genetic liver diseases.
Rare genetic liver diseases collectively affect millions of individuals worldwide and encompass a heterogeneous group of monogenic disorders including Wilson disease, alpha-1 antitrypsin deficiency, glycogen storage diseases, urea cycle disorders, progressive familial intrahepatic cholestasis, and acute hepatic porphyrias. While conventional management relies on dietary modification, pharmacotherapy, and ultimately liver transplantation, the advent of clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing has opened transformative therapeutic avenues. This review provides a comprehensive and critical appraisal of the current landscape of CRISPR-based therapies for genetic liver diseases, from preclinical proof-of-concept studies to landmark clinical trials. We examine the evolution from conventional Cas9 nuclease-mediated editing to precision tools including base editors and prime editors, which enable single-nucleotide corrections without inducing double-strand DNA breaks. The role of lipid nanoparticle delivery systems in achieving efficient hepatocyte-targeted delivery is discussed, alongside emerging challenges in pediatric dosing and immunogenicity. We highlight the paradigm shift toward personalized, patient-specific CRISPR therapies, exemplified by the first-in-human bespoke gene editing treatment delivered in 2025. Competing nucleic acid technologies, including RNA interference and antisense oligonucleotides, are compared in terms of durability, safety, and cost-effectiveness. Finally, we critically evaluate the evolving regulatory landscape and propose a priority framework for selecting genetic liver diseases most amenable to CRISPR-based correction. This review underscores that CRISPR gene editing is transitioning from experimental promise to clinical reality for genetic liver diseases, with personalized approaches poised to redefine the treatment paradigm.
2026-06-19 | Progressive Familial Intrahepatic Cholestasis Type 7 in a 4 Month Old Female, Japanese Infant: A Case Report
Learning Points This case represents the first documented diagnosis of PFIC Type 7 in a Japanese infant, expanding the understanding of the ethnic demographics and geographical distributions of USP53 associated cholestasis. This case highlights an unusual clinical presentation of PFIC Type 7, which may present with initial complications including coagulopathy and intracranial haemorrhage as seen in this case rather than typical features such as jaundice or pruritus. This highlights the importance of considering hepatobiliary disorders as a differential diagnosis in the investigation of unexplained bleeding in infants. The diagnosis of PFIC Type 7 in this patient was made via trio exome sequencing, as the USP53 gene is not routinely included in standard genetic panels for cholestasis. Incorporating USP53 into these panels could facilitate earlier recognition of and subsequent intervention for this condition. Long term management involves correction of fat‐soluble vitamin deficiency and supportive management of cholestasis. Improvement with rifampicin, as observed in this case, supports its potential therapeutic role, though the mechanism remains uncertain.
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Drug Discovery Landscape
9 orphan drug designations for Progressive familial intrahepatic cholestasis, including 4 approved therapies.
9 orphan drug designations for Progressive familial intrahepatic cholestasis, including 4 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
modified human ATP binding cassette subfamily B member 4 (ABCB4) mRNA encoding multidrug resistance protein 3 (MDR3) | RNAs | FDA | 2024-11-18 | — | INNORNA USA INC. |
modified human ATP binding cassette subfamily B member 11 (ABCB11) messenger RNA encoding bile salts export pump | RNAs | FDA | 2024-07-29 | — | INNORNA USA INC. |
3alpha,6beta,7beta,12alpha-tetrahydroxy-5beta-cholan-24-oic acid | small molecules | FDA | 2020-10-22 | — | Qing Bile Therapeutics, Inc. |
Adeno-associated viral vector serotype 3B encoding human multidrug resistance protein 3A | gene therapies | EMA | 2020-04-22 | — | Vivet Therapeutics S.A.S. |
Adeno-associated viral vector encoding human multidrug resistance protein 3A (MDR3A) | gene therapies | FDA | 2020-03-16 | — | Vivet Therapeutics SAS |
(4R,5R)-1-[[4-[[4-[3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-4-aza-1-azoniabicyclo[2.2.2]octane chloride [Livmarli] | small molecules | EMA | 2013-12-18 | 2024-07-01 | Mirum Pharmaceuticals International B.V. |
maralixibat [Livmarli] | small molecules | FDA | 2013-09-04 | 2024-03-13 | Mirum Pharmaceuticals, Inc. |
odevixibat [Bylvay] | small molecules | FDA | 2012-10-31 | 2021-07-20 | Ipsen Biopharmaceuticals, Inc. |
(2S)-2-{[(2R)-2-[({[3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro- 1,2,5-benzothiadiazepin-8-yl]oxy}acetyl)amino]-2-(4-hydroxyphenyl)acetyl]amino}butanoic acid [Bylvay] | small molecules | EMA | 2012-07-17 | 2021-07-19 | Ipsen Pharma |
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