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
592 drug discovery papers about Progressive familial intrahepatic cholestasis, with 5 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
592 drug discovery papers about Progressive familial intrahepatic cholestasis, with 5 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-22 | Decoding the Cellular Response to Methylthioadenosine Uncovers Novel Targets for Chronic Liver Disease
Progressive familial intrahepatic cholestasis type 3 (PFIC3), caused by MDR3 deficiency (MDR2 in mice), is a lethal pediatric liver disease characterized by early-onset persistent cholestasis, progressive fibrosis, cirrhosis, and eventual liver failure. MDR3 is a phosphatidylcholine transporter located in the canalicular membrane of hepatocytes, and its deficiency leads to the accumulation of free bile acids, which damage epithelial cells due to their detergent-like effect. Therapeutic options remain limited, highlighting the need to identify molecular drivers of disease progression and novel pharmacological strategies. To investigate the molecular alterations associated with this deficiency, our laboratory performed functional proteomic analyses in patient samples and murine hepatic organoids, revealing consistent reprogramming of one-carbon metabolism (OCM). Based on these findings, we explored the therapeutic potential and molecular mechanisms of 5′-methylthioadenosine (MTA), a metabolite involved in this pathway. Using hepatocellular carcinoma cells (PLCs), we combined quantitative shotgun proteomics with the proteome integral solubility alteration (PISA) assay to characterize functional responses and identify direct protein targets of MTA. To reinforce the physiological relevance of our findings, we extended the PISA analysis to liver protein extracts from the Mdr2−/− mouse model of chronic cholestatic injury, enabling validation of candidate target interactions observed in cellular extracts. Proteomic profiling revealed that MTA induces significant alterations in cell division processes, epigenetic regulatory networks, and energy metabolism, thereby promoting an adaptive phenotype characterized by metabolic plasticity, microenvironmental reorganization, and immunomodulation. These findings provide a robust molecular framework for understanding the hepatic response to MTA and shed new light on the mechanisms that may underlie its beneficial effects. In addition, they provide a valuable platform for further investigation of the therapeutic potential of this compound and its prospective translation into clinical practice.
2026-09-18 | Novel genetic variants and atypical phenotypes in pediatric progressive familial intrahepatic cholestasis.
Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders characterized by impaired bile formation and secretion, frequently progressing to cirrhosis and end-stage liver disease. This study characterized the genotypic and phenotypic spectrum of PFIC in a pediatric cohort. A retrospective cohort study with prospective enrollment of additional cases and longitudinal follow-up included 17 children with molecularly confirmed PFIC managed at Alexandria University Children's Hospital between 2017 and 2026. Clinical, biochemical, histopathological, genetic, therapeutic, and outcome data were reviewed. Three, ten, two, and two patients had PFIC types 1, 2, 3, and 8, respectively, with pathogenic variants in ATP8B1, ABCB11, ABCB4, and KIF12, including four novel variants. PFIC types 1 and 2 presented with early-onset low gamma-glutamyl transferase (GGT) cholestasis and severe pruritus; five patients underwent biliary diversion. PFIC type 2 showed more severe liver disease than PFIC type 1. PFIC types 3 and 8 presented later with atypical non-icteric presentations with hepatosplenomegaly and elevated GGT without classical histopathological cholestasis in three cases. Three patients underwent successful liver transplantation. PFIC exhibits marked phenotypic heterogeneity. Recognition of atypical and non-icteric presentations broadens its clinical spectrum and highlights the importance of comprehensive genetic testing for accurate diagnosis. The study identifies and characterizes novel variants in the ABCB11, ABCB4, and KIF12 genes within an Egyptian pediatric cohort, expanding the known mutational spectrum of the disease. The study reported unusual presentation for PFIC type 3 and 8 with rapid fibrotic progression even in the absence of clinical jaundice or histological evidence of bile plugs challenging the diagnostic reliance on overt cholestasis as the primary clinical marker for PFIC.
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.
2026-06-19 | 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.
2026-04-11 | Bile Acid Detergency as Determinant of Liver Pathology in a Humanized Mouse Model of Progressive Familial Intrahepatic Cholestasis Type 3.
Progressive familial intrahepatic cholestasis type 3 (PFIC3) is caused by impaired activity of ABCB4 that transports phosphatidylcholines (PC) from hepatocytes into bile. Abcb4-knockout (KO) mice have been generated, but hydrophilic muricholic acids in their bile acid (BA) pool may limit pathology and thereby hamper translation to human PFIC3. Therefore, we addressed whether Abcb4 knockdown (Abcb4-KD) in the livers of Cyp2c70-KO mice with a human-like BA composition leads to liver pathology that more closely resembles human PFIC3. Expression of Abcb4 gene was suppressed in livers of Cyp2c70-KO/L-Cas9tg mice and control-Cas9tg mice using CRISPR/Cas9-technology to assess short- and long-term consequences. The BA sequestrant colesevelam was mixed into the chow diet (2% w/w) of Cyp2c70-KO mice with or without Abcb4-KD, and the effects were evaluated after 6 weeks. Abcb4-KD strongly reduced biliary phospholipid:BA ratios in both Cyp2c70-KO and control mice. However, plasma transaminases elevations, liver fibrosis, and ductular reactions were markedly aggravated by Abcb4-KD in the context of a human-like BA composition. Importantly, the biliary lipid compositions differed markedly between the 2 Abcb4-KD models. Reduced biliary PC and increased concentrations of lysophosphatidylcholine, sphingomyelin, and ceramide were associated with the severity of liver disease only in Cyp2c70-KO/Abcb4-KD mice. Gene set enrichment analysis indicated that epithelial-mesenchymal transition was induced in the livers of Cyp2c70-KO/Abcb4-KD mice compared with control Abcb4-KD mice. BA sequestration reduced biliary BA secretion rates and mitigated liver pathology in Cyp2c70-KO/Abcb4-KD mice. The presence of a human-like BA composition profoundly aggravates liver pathology upon Abcb4 reduction in mice, conceivably due to the augmented extrusion of non-PC phospholipids by hydrophobic BAs from membranes into bile. This humanized PFIC3 model is anticipated to accelerate the development of novel therapies for PFIC3 and potentially other cholestatic liver diseases.
cell therapies
2026-06-01 |
Patients’ genotypes and types.
Background Progressive familial intrahepatic cholestasis (PFIC) refers to a group of inherited cholestatic liver diseases that affect children, often leading to liver failure and requiring liver transplantation (LT). Many studies have established correlations between the effect of the causal gene variant types and the severity of the PFIC phenotype, the treatment considered, or its outcomes in patients. Nevertheless, no selection criteria for LT based on genotypes have been adopted for patients affected by this group of diseases. Therefore, we conducted a meta-analysis to investigate the association between the main PFIC subtype genotypes and the treatment with LT. Methods Online databases were searched for articles on PFIC1–4 and LT. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. The genotypes of patients were extracted from the included studies and categorized into a group of cases, harboring null genotypes, and a group of controls, harboring non-null genotypes. The relationship between the genotype type and LT outcome was expressed as an OR by assessing the LT event among the case group and the control group. Results Eighteen studies involving 420 PFIC patients were included. A random-effects model was used to assess the OR. Overall, we observed a close relationship between the PFIC null genotype and the LT event; OR=2.79 (95% CI:1.63 to 4.77; p < 0.001). Subgroup analysis according to the PFIC subtype showed the same effect. Conclusions Our results provide evidence of a potential association between null genotypes in PFIC diseases and the indication of LT as a treatment. Further trials are needed to confirm our results and guide decisions regarding personalized and early preventive LT. Research protocol registration https://doi.org/10.17605/OSF.IO/MNQWB
2025-04-09 | Clinical and molecular genetic characteristics of pediatric PFIC3 patients: three novel variants and prognosis for parental liver transplantation.
Progressive Familial Intrahepatic Cholestasis Type 3 (PFIC3) is a rare inherited liver disease caused by a mutation in the ABCB4 gene, leading to dysfunction of multidrug resistance protein 3 (MDR3). The earlier the onset of PFIC3 in children is, the more severe the prognosis. The diagnosis of PFIC3 is typically based on clinical symptoms, laboratory tests, and imaging assessments, with final confirmation requiring genetic testing. The aim of this study was to investigate the associations between genetic mutations in PFIC3 and clinical features, molecular genetics, and liver histopathology to improve early recognition and understanding of this disease. By analysing the data of three children with PFIC3 who underwent parental liver transplantation, we were able to gain a deeper understanding of the complexity and diversity of the disease. With respect to molecular genetics, we identified five mutation sites in the ABCB4 gene, including three newly discovered mutations. Immunohistochemical analysis revealed reduced expression of the MDR3 protein in child 1 and no expression in child 2 or child 3, revealing an intrinsic link between the ABCB4 gene and the MDR3 protein. Histopathologically, all three patients presented with significant portal vein fibrosis or cholestatic liver cirrhosis. In conclusion, this study emphasizes the importance of molecular genetic and pathological evaluation of patients with PFIC3 mutations and elucidates the impact of these three mutations on the course of the disease in children, for whom early symptomatic treatment and early preparation for liver transplantation are options worth considering.
2024-02-15 | Novel approach for reconstruction of the three-dimensional biliary system in decellularized liver scaffold using hepatocyte progenitors
Reconstruction of the biliary system is indispensable for the regeneration of transplantable liver grafts. Here, we report the establishment of the first continuous three-dimensional biliary system scaffold for bile acid excretion using a novel method. We confirmed the preservation of the liver-derived extracellular matrix distribution in the scaffold. In addition, hepatocyte progenitors decellularized via the bile duct by slow-speed perfusion differentiated into hepatocyte- and cholangiocyte-like cells, mimicking hepatic cords and bile ducts, respectively. Furthermore, qRT-PCR demonstrated increased ALB , BSEP , and AQP8 expression, revealing bile canaliculi- and bile duct-specific genetic patterns. Therefore, we concluded that locally preserved extracellular matrices in the scaffold stimulated hepatic progenitors and provided efficient differentiation, as well as regeneration of a three-dimensional continuous biliary system from hepatic cords through bile ducts. These findings suggest that organ-derived scaffolds can be utilized for the efficient reconstruction of functional biliary systems.
2023-11-24 | The Modern Day Heracles
Rare pediatric liver disorders can be very destructive to the lives of patients and their families. Often, therapeutic options are limited to symptomatic care and precise disease mechanisms remain elusive. The relatively low incidence of each individual disease and the often widespread geographic distribution of patients complicate research and treatment development. In this thesis, we have investigated the potential of patient-derived liver organoids to study such rare pediatric liver diseases. We characterized intrahepatic cholangiocyte organoids (ICOs) from several monogenic liver disorders and showed that organoids express affected proteins of diseases such as cystic fibrosis, Wilson disease and methylmalonic acidemia. We uncovered that ICOs possess a hybrid phenotype, combining hepatocyte and cholangiocyte characteristics. This led us to investigate whether patient-derived liver organoids would be interesting to study the rare perinatal disease biliary atresia (BA), in which the hepatobiliary tree is occluded and becomes fibrotic. We found that organoids from different hepatobiliary regions (intrahepatic, extrahepatic and gallbladder) of BA patients can be cultured and biobanked. Further characterization showed that BA patient organoids display BA specific growth behavior and increased sensitivity to viral infections. While we showed that various hepatocyte and cholangiocyte functions can be studied in liver organoids, our data also indicated that several hepatocyte functions are currently limited in this in vitro system. Therefore, we devised a novel culture strategy to increase hepatic maturation in liver organoids. We found that hepatic functions, such as drug metabolism, improve when liver organoid cells are cultured on hollow fiber membranes coated with extracellular matrix proteins of the hepatic niche. Moreover, we demonstrated that hepatic transepithelial transporter defects such as progressive familial intrahepatic cholestasis type 3 can be studied in patient-derived liver organoids. In summary, we have demonstrated that patient-derived liver organoids are a useful tool to study various rare liver and metabolic disorders affecting the hepatobiliary tract. Several diseases such as BA, cystic fibrosis, Wilson disease, progressive familial intrahepatic cholestasis type 3 and methylmalonic acidemia can currently be studied with ICOs. Although ICOs were previously praised as a new break-through hepatocyte model, we have shown that organoids from all hepatobiliary regions are at least equally useful for researching cholangiopathies, such as BA. The development of new technologies, such as organ chips and co-culture strategies, are exciting not only to study the disease mechanisms of rare diseases but also to improve the hepatic maturity of ICOs. Applying the myriad of culture improvement strategies to ICOs will likely produce a fantastic patient-derived hepatocyte model. We have taken the first steps toward improving hepatic maturation of ICOs and in doing so have demonstrated that the ICO application range can be broadened to facilitate the study of (cholestatic) disease mechanisms. Similarly, we anticipate that these improvements in hepatic maturation of ICOs will aid in the development of safe therapeutics for (rare) liver diseases in a personalized manner in the future.
2022-08-26 | Recent Findings in the Gut-Liver Axis and Associated Disease Therapy
Several presentations at the recent International Liver Congress™ (ILC), held in London, UK, from 22nd–26th of June 2022, addressed the role of the gut microbiome in chronic liver disease. Debbie L. Shawcross from the Department of Inflammation Biology, School of Immunology and Microbial Sciences, Institute of Liver Studies, King’s College London, UK, outlined the role of the gut-liver axis in the pathogenesis of cirrhosis, and how existing and novel therapies manipulate gut microbes. Emina Halilbasic from the Medical University of Vienna, Austria, and Benjamin H. Mullish from the Division of Digestive Diseases, Imperial College London, UK. Focused on the use of gut-based therapies in cholestatic liver disease. They explained the current understanding of the interplay between bile acids, microbiota, and the mucosal immune system, and the ways in which this may be manipulated for therapeutic gain. The role of gut barrier impairment in alcohol-related liver disease (ArLD) was presented by Shilpa Chokshi from the Roger Williams Institute of Hepatology, Foundation for Liver Research, London, UK, and School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, UK. Charlotte Skinner from the Department of Metabolism, Digestion, and Reproduction, Division of Digestive Diseases, Imperial College London, UK, described the role of gut proteases in this process, while Jasmohan S. Bajaj from the Virginia Commonwealth University, Richmond, USA, and Central Virginia Veterans Healthcare System, Richmond, USA, illustrated new therapies that target the gut-liver axis in this condition. Yue Shen from Zhongshan Hospital, Fudan University, Shanghai, China, and the Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, China, described a combined microbiome-metabolome study to characterise the gut microbiome in hepatitis B virus infection-associated liver diseases (HBV-CLD), and how specific microbes might impact peripheral immunity. Finally, Bajaj outlined why the gut is a major target for hepatic encephalopathy (HE) treatment and described cutting edge research into therapies that show promise in this arena, such as soluble solid dispersion rifaximin, faecal microbiota transplantation (FMT), and rationally defined bacterial consortia. Overall, these presentations highlight an expanding knowledge of the gut-liver axis and promise an exciting future in liver treatment.
proteins
2026-09-10 | Impact of ATP8B1 Mutation and Maturation on CFTR Functionality and Gene Expression
Background/Objectives: Progressive familial intrahepatic cholestasis type 1 (PFIC1) is a rare autosomal recessive liver disorder caused by mutations in the ATP8B1 gene, leading to defective bile acid secretion and severe clinical outcomes. A milder, episodic form of the disease, benign recurrent intrahepatic cholestasis (BRIC), is also associated with ATP8B1 mutations. PFIC1 patients frequently present with extra-hepatic symptoms. Interestingly, cystic fibrosis (CF) patients also develop liver dysfunction, and we previously showed that CFTR expression is significantly reduced in PFIC1 patients. Methods: In this study, we investigated the relationship between ATP8B1 and CFTR by comparing gene expression and protein maturation in PFIC1 (Byler) and BRIC cell lines to wild-type controls. Results: Both ATP8B1 and CFTR transcripts were markedly decreased in mutant cells, resulting in lower protein synthesis. Distinct ATP8B1 isoforms were identified: a 140 kDa mature form in wild-type cells, a 145 kDa variant in BRIC cells, and a 180 kDa form in PFIC1 cells. Using antibodies targeting the N- and C-terminal domains, we demonstrated that wild-type ATP8B1 undergoes sequential maturation—first at Gly308 in the endoplasmic reticulum, then at Gly556, a region containing the D554N PFIC1 mutation site—yielding a 74 kDa nuclear peptide with transcriptional cofactor characteristics. This peptide contains an NR box flanked by STAT5 binding motifs and a potential PKA phosphorylation site, suggesting interaction with the Small Heterodimer Partner (SHP) and regulation of FXR and HNF1α expression, which are both known to modulate CFTR transcription. Immunoprecipitation experiments revealed a physical association between ATP8B1 and CFTR, supporting a chaperone role for ATP8B1 in CFTR trafficking and membrane insertion. PDZK1 was also found to interact with ATP8B1, potentially stabilizing CFTR at the apical membrane through PDZ-domain interactions. Conclusions: Collectively, our results identify ATP8B1 as a multifunctional protein that not only ensures the correct trafficking and membrane localization of CFTR but should also regulate its transcription via a nuclear signaling pathway. These findings provide new insights into the molecular link between PFIC1 and cystic fibrosis-associated liver disease.
2025-10-14 | Enigmatic functions of ATP8B1: cholestasis, inflammation, phosphoinositide flipping, and cellular homeostasis.
Mutations in ATP8B1 cause a spectrum of cholestatic liver disease, ranging from Progressive-Familial-Intrahepatic-Cholestasis type-1 (PFIC1) to Benign-Recurrent-Intrahepatic-Cholestasis type-1 (BRIC1). Manifestations of PFIC1 include severe pruritus, jaundice, and liver damage. Extrahepatic features sometimes observed in PFIC1 include sensorineural hearing loss, diarrhea, pancreatitis, and short stature. ATP8B1 was shown to translocate phospholipids across the plasma membrane; however, expression of ATP8B1 in many tissues and the range of pathological manifestations in ATP8B1 deficiency suggest diverse physiological functions of ATP8B1, and pleiotropic mechanisms regulating its activity. Recent studies suggest that phosphoinositides, including PIP2 and PIP3, can function as regulators, substrates, and binding partners of ATP8B1. New research shows that ATP8B1 modulates host immune system by regulating cleavage of pyroptotic-executioner Gasdermin D (GSDMD), and inflammation-resolution pathways such as phagocytosis/efferocytosis. Further mechanistic insights can accelerate development of new therapies for restoring membrane integrity, reducing inflammasome activity, and correcting metabolic imbalances caused by ATP8B1 dysfunction.
2025-06-12 | Liver-specific Nr1h4 deletion in mice with human-like bile acid composition causes severe liver injury.
The farnesoid X receptor, encoded by NR1H4, is crucial for bile acid, lipid, and glucose metabolism. NR1H4 mutations in humans cause a severe liver injury called progressive familial intrahepatic cholestasis 5. However, Nr1h4 deletion in mice did not cause severe liver damage at a young age, likely because of the higher levels of hydrophilic bile acids synthesized by the mouse-specific bile acid metabolic enzymes Cyp2a12 and Cyp2c70. We aimed to assess hepatic NR1H4 function by taking advantage of the recently established Cyp2a12/Cyp2c70 double-knockout (CYPDKO) mouse model, which has a human-like bile acid composition containing mainly hydrophobic bile acids. Liver-specific Nr1h4-deficient CYPDKO mice were established using an adeno-associated virus-derived genome-editing method. Nr1h4-deficient wild-type (WT) mice showed no significant changes in marker levels for serum liver injury. In contrast, Nr1h4-deficient CYPDKO mice showed an increase in the liver/body weight ratio and serum liver injury markers, suggesting that the combination of human-like bile acid composition and Nr1h4 deletion induces liver injury. Nr1h4 deletion increased total bile acid levels in the liver through the upregulation of bile acid metabolic genes and downregulation of bile acid transporters. Conversely, overexpression of a small heterodimer partner (Shp), a downstream gene of Nr1h4, suppresses liver injury induced by Nr1h4 deletion in CYPDKO mice. Overall, liver-specific Nr1h4 deficiency induced significant liver damage in mice with human-like bile acids, unlike in WT mice, validating its use as a new animal model for cholestatic liver disease. Therefore, Shp may be a potential target for the treatment of cholestasis.
2024-11-26 | Discovery and mechanism of K63-linkage-directed deubiquitinase activity in USP53.
Ubiquitin-specific proteases (USPs) represent the largest class of human deubiquitinases (DUBs) and comprise its phylogenetically most distant members USP53 and USP54, which are annotated as catalytically inactive pseudoenzymes. Conspicuously, mutations within the USP domain of USP53 cause progressive familial intrahepatic cholestasis. Here, we report the discovery that USP53 and USP54 are active DUBs with high specificity for K63-linked polyubiquitin. We demonstrate how USP53 mutations abrogate catalytic activity, implicating loss of DUB activity in USP53-mediated pathology. Depletion of USP53 increases K63-linked ubiquitination of tricellular junction components. Assays with substrate-bound polyubiquitin reveal that USP54 cleaves within K63-linked chains, whereas USP53 can en bloc deubiquitinate substrate proteins in a K63-linkage-dependent manner. Biochemical and structural analyses uncover underlying K63-specific S2 ubiquitin-binding sites within their catalytic domains. Collectively, our work revises the annotation of USP53 and USP54, provides reagents and a mechanistic framework to investigate K63-linked polyubiquitin decoding and establishes K63-linkage-directed deubiquitination as a new DUB activity.
2024-09-01 | P.352: Recombinant growth hormone treatment in two patients with progressive familial intrahepatic cholestasis.
Introduction: One of the reasons for growth failure in patients with chronic liver diseases is the disturbed growth hormone-insulin-like growth factor1 (GH-IGF1) axis.The expected catch-up growth after liver transplantation (LT) fails in some patients with progressive familial intrahepatic cholestasis type 1 (PFIC1), often due to the systemic nature of the disease and the worsening of diarrhea.Here, we presented our post–LT GH treatment experience for two patients with PFIC1 and growth retardation. Case 1: A 7,1-year-old female was referred to the pediatric endocrinology clinic for short stature.She was diagnosed with PFIC1 (a homozygous deletion in ATB8B1), and at the age of 4,9-year, a partial LT was performed.Following LT, she developed severe persistent diarrhea.Her weight was 17,4 kg (-1,9 SDS), height was 110 cm (-2,4 SDS), and BMI was 14,4 kg/m2 (-0,8 SDS). Tanner stage of puberty was 1, and bone age was 4 years.The midparental height (MPH) was 166 cm (0,5 SDS).She had mild hypertransaminasemia, hepatosteatosis.Considering the chronic disease, she had been followed without further treatment.However, the growth retardation even worsened.At the age of 14,5 years, she had a height of 143 cm (-3,06 SDS).Tanner stage of puberty was 4. Growth velocity (GV) was 4,9 cm/year.Bone age was 12 years.IGF-1 was 190 ng/mL (-1,5 SDS). The GH stimulation test (GHST) showed a peak GH response of 16,6 ng/mL, indicating GH resistance.rGH therapy was started at a dose of 40 mcg/kg, was increased to 60 mcg/kg per day.GV during the first year of treatment was 4,2 cm.At 15,5 years, her height was 147,2 cm (-2,5 SDS), her bone age was 13,5 years, and IGF was 132 ng/mL (-2,7 SDS)(Fig.1).Case 2: A 7-year-old female who was diagnosed with PFIC1 (a homozygous mutation in ATB8B1), and liver transplanted at the age of 3-year was referred to the pediatric endocrinology clinic for short stature.She presented with a weight of 18,9 kg (-1,3 SDS), a height of 99 cm (-4,5 SDS), and a BMI of 19,2 kg/m2 (1,5 SDS).The MPH was 154 cm (-1,5 SDS).Tanner stage of puberty was 1.Bone age was 4 years and 2 months. She had mild hypertransaminasemia, liver steatosis, and chronic diarrhea.At the age of 9,1 years, her height was 105,2 cm (-4,7 SDS).GV was 3.1 cm/year.Bone age was 5 years.IGF-1 was 26,7 ng/mL (-2,4 SDS).The GHST showed a peak GH response of 2,9 ng/mL. She was commenced on rGH therapy at a dose of 30 mcg/kg per day at the age of 9,1 years.GV was 8,1 cm during the first year of treatment.IGF-1 increased to 155 ng/mL (-0,6 SDS).rGH was administered over a period of 5 years.At the age of 15.1 years, her height was 146 cm (-2,7 SDS) (Fig.2).Conclusion: Patients who do not experience catch-up growth after LT should also be evaluated for disturbances in the GH-IGF1 axis. Although rGH had limited effectiveness in the patient with GH resistance, the patient with GH deficiency showed even greater improvement in height SDS and almost achieved the MPH.
gene therapies
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
2026-07-29 | 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.
2026-04-03 | Abstract 2266: Unexpected role of nuclear receptor CAR in cholangiocarcinoma development.
Abstract Cholangiocarcinoma (CCA), the second most common primary liver cancer, arises from the biliary epithelium, either within the liver parenchyma or in the hepatoduodenal ligament. Several cholestatic liver diseases, such as primary sclerosing cholangitis, developmental bile duct malformation, and progressive familial intrahepatic cholestasis (PFIC), have been implicated as CCA risk factors. Cholestatic conditions exhibit a cocarcinogenic effect when combined with chronic liver injuries, as supported by a recently reported CCA animal model in which partial bile duct ligation is combined with repeated treatments of the carcinogen diethylnitrosamine. The nuclear receptor Constitutive Androstane Receptor (CAR, NR1I3), a central regulator of xenobiotic metabolism, is known to drive hepatocellular carcinoma (HCC) when chronically activated, while CAR ablation prevents it in multiple liver cancer models. We have recently characterized the impact of endogenous CAR activation in a mouse model of human PFIC5 disease (i.e., Fxr;Shp double knockout, FS-DKO) that exhibits cholestatic liver injury and develops spontaneous HCC at 1 year of age. In this study, we demonstrated the role of endogenous CAR activation in cholestasis-driven liver cancer development. Based on the strong correlation between CAR activation and liver cancer development in FS-DKO liver, we initially hypothesized that chronic CAR activation mediates hepatic carcinogenesis in FS-DKO liver. However, in contrast to our expectations, further deletion of CAR in Fxr;Shp;Car triple knockouts (FSC-TKO) did not reduce tumor incidence compared to FS-DKO. Instead, highly hypertrophic as well as hyperplastic cholangiocytes became much more abundant in FSC-TKO livers than in FS-DKO livers. Accordingly, about half of the visible FSC-TKO tumor nodules were CCA or combined HCC-CCA types, while most tumors in FS-DKO livers were hepatocellular types. Using RNA-seq and TRRUST transcription factor analysis, we found that CAR/PXR targets were significantly depleted in FSC-TKO, while ETS1 targets were significantly enriched, consistent with emerging evidence that ETS1 biases liver tumor fate toward CCA lineage. These findings suggest that, under cholestatic stress, loss of CAR unexpectedly promotes CCA development by unleashing a microenvironment that favors CCA. Targeting the CAR-ETS1 axis may offer new opportunities to modulate HCC-CCA lineage specification and improve therapeutic strategies. Citation Format: Inyoung Cheon, Ji Ho Suh, Mi Jeong Heo, Sung Ho Lee, Hyun-Jung Jung, Young-Ho Ahn, David D. Moore, Kang Ho Kim. Unexpected role of nuclear receptor CAR in cholangiocarcinoma development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2266.
2026-03-11 | [Clinical features and genetic analysis of a child with Progressive familial intrahepatic cholestasis type 8 due to compound heterozygous variants of KIF12 gene].
To explore the clinical phenotype and genetic characteristics of a child with Progressive familial intrahepatic cholestasis type 8 (PFIC8). METHODS A child with PFIC diagnosed at Beijing Children's Hospital Affiliated to Capital Medical University in September 2025 was selected as the study subject. Peripheral venous blood samples were collected from the child and her parents. Following extraction of genomic DNA, whole-exome sequencing (WES) was carried out. Candidate variants were validated by Sanger sequencing. The pathogenicity of the candidate variants was classified based on the guidelines from American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of Beijing Children's Hospital Affiliated to Capital Medical University (Ethics No.: 2023-E-126-Y). The proband, a 2-month-old female infant, had manifested jaundice of the skin and sclera, and slightly distended abdomen. She had no visible abdominal wall varicose veins, soft abdomen, and no palpable masses. Biliary atresia was ruled out by intraoperative cholangiography. WES revealed that she has harbored compound heterozygous variants of KIF12 gene, namely c.809C>T (p.Ala270Val) and c.1313G>A (p.Arg438Lys), which were verified by Sanger sequencing to have derived from her mother and father, respectively. According to the ACMG guidelines, both variants were classified as variants of uncertain significance (VUS). Based on the pre-defined search strategy, 10 articles were retrieved, which involved 25 PFIC cases, including 5 from China. Together with the proband of this study, the 26 PFIC patients have primarily presented with high GGT cholestasis, with the genetic cause in all cases attributed to variants of the KIF12 gene. The c.809C>T and c.1313G>A compound heterozygous variants of the KIF12 gene probably underlay the pathogenesis of cholestatic liver disease in this child. Above findings have enriched the mutational and phenotypic spectra of PFIC8.
other
2026-02-02 | Evaluation of miRNA Expression in Pediatric Cirrhosis Caused by BA and PFIC.
Liver cirrhosis is one of the most common causes of death for pediatric patients with cholestasis. Because microRNA (miRNA) plays a part in the pathogenesis of the disease, comparing the changes in miRNA expression in cholestatic patients with liver cirrhosis could be helpful for therapeutic or prognostic purposes. miRNA levels in cirrhotic pediatric patients with progressive familial intrahepatic cholestasis (PFIC) and biliary atresia (BA) were studied in this research to comprehend the molecular distinctions and the significance of miRNA regulation in fibrosis and liver cirrhosis. Blood samples were collected from 43 PFIC patients and 84 BA patients, all of whom were confirmed to have liver cirrhosis. The in-house SYBR Green RT-qPCR techniques were established to assess the variations in the expressions of 12 miRNAs. Utilizing bioinformatics tools, the gene targets of the studied miRNAs were examined. Patients' expression of 12 miRNAs was higher than that of the healthy group. However, there was a notable distinction between the miRNAs in PFIC and BA. The levels of miR-34, miR-155, miR-199, miR-200b, and miR-222 were significantly higher in BA than in PFIC. PFIC showed a significantly higher level of miR-223 than BA. The predictive importance of distinct miRNAs in both diseases was revealed by the AUC values. In BA, miR-222 was associated with both liver transplantation and the PELD score. Death was correlated with miR-21, miR-155, miR-199, and miR-200 in BA and miR-34 in PFIC. The analysis showed the significance of the connection between miRNA expression and PI3K/Akt and TGF-β signaling in pediatric liver cirrhosis. Future investigations can evaluate the significance of the studied miRNAs as novel therapeutic targets and diagnostic options.
2025-10-02 | A farnesoid X receptor T296I variant disrupts ligand-induced FXR activation and thus bile acid transport in progressive familial intrahepatic cholestasis.
Nuclear receptor farnesoid X receptor (FXR) acts as a key regulator of bile acid pool homeostasis and metabolism. Within the enterohepatic circulation, reabsorbed bile acids act as FXR agonists. FXR, in turn, transcriptionally controls the synthesis and transport of bile acids. Binding occurs in the ligand binding domain (LBD), favoring a conformational change to the active state in which helix 12 interacts with the LBD to form an interaction surface for nuclear co-activators. The homozygous missense variant T296I, identified in a patient with progressive familial intrahepatic cholestasis (PFIC), is located close to the critical helix 12 interaction. Here, we identified reduced transcriptional activity of the variant protein on the downstream targets bile salt export pump (BSEP) and small heterodimer partner (SHP) in vitro, within the patient's liver, and in iPSC-derived hepatic organoids. BSEP-dependent Tauro-DBD transport was impaired in T296I patient-derived organoids, but could be rescued via lipid nanoparticle-mediated FXR WT mRNA delivery, indicating the variant is responsible for the identified reduced BSEP expression. Using molecular dynamics simulations, we observed a reduced transition from the inactive to the active state for the T296I variant, indicating a molecular mechanism underlying the reduced activity. To our knowledge, this is the first study to describe the conformational change from an inactive to an active state of the FXR LBD. This might be useful for new therapeutic approaches targeting the activation of FXR.
2024-02-14 | Management and outcomes after liver transplantation for progressive familial intrahepatic cholestasis: A systematic review and meta-analysis.
Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous rare congenital cholestatic liver disease. Disease progression might necessitate liver transplantation (LT). The aim of this study was to describe the outcome of PFIC1-4 patients after LT. Electronic databases were searched to identify studies on PFIC and LT. Patients were categorized according to PFIC type, genotype, graft type, age at LT, time of follow-up, and complications and treatment during follow-up. Seventy-nine studies with 507 patients met inclusion criteria; most patients were classified as PFIC1-3. The median age at LT was 50 months. The overall 5-year patient survival was 98.5%. PFIC1 patients with diarrhea after LT were at significant risk of developing graft steatosis ( p < 0.0001). Meta-analysis showed an efficacy of 100% [95% CI: 73.9%-100%] for surgical biliary diversion to ameliorate steatosis and 94.9% [95% CI: 53.7%-100%] to improve diarrhea (n = 8). PFIC2 patients with bile salt export pump (BSEP)2 or BSEP3-genotype were at significant risk of developing antibody-induced BSEP deficiency (AIBD) ( p < 0.0001), which was reported in 16.2% of patients at a median of 36.5 months after LT. Meta-analysis showed an efficacy of 81.1% [95% CI: 47.5%-100%] for rituximab-based treatment regimens to improve AIBD (n = 18). HCC was detected in 3.6% of PFIC2 and 13.8% of PFIC4 patients at LT. Fifty percent of PFIC1 patients develop diarrhea and steatosis after LT. Biliary diversion can protect the graft from injury. PFIC2 patients with BSEP2 and BSEP3 genotypes are at significant risk of developing AIBD, and rituximab-based treatment regimens effectively improve AIBD. PFIC3 patients have no PFIC-specific complications following LT.
2024-01-30 | Expression of miR-let7b and miR-19b in progressive familial intrahepatic cholestasis (PFIC) children.
MicroRNAs (miRNAs) are a group of small non-coding RNAs that bind to the target mRNA and regulate gene expression. Recently circulating microRNAs were investigated as markers of diseases and therapeutic targets. Although various studies analyze the miRNA expression in liver disease, these studies on PFIC are few. Progressive familial intrahepatic cholestasis (PFIC) is a rare liver disease with autosomal recessive inheritance. Most children with PFIC progress to cirrhosis and liver failure and consequently need to have a liver transplant. The aim of this study is the investigation of the miR-19b and miR-let7b expression levels in Iranian PFIC children. 25 PFIC patients, 25 healthy children and 25 Biliary Atresia patients were considered as case and two control groups respectively. Blood samples were obtained and Liver function tests (LFTs) were measured. After RNA extraction and cDNA synthesis, quantitative PCR was performed using specific primers for miR-19b and miR-let7b. The U6 gene is used as an internal control. qPCR on PFIC patients' samples demonstrated that the miR-19b and the miR-let7b expression were significantly decreased in patients compared to the control groups, with a p-value<0.0001 and p-value=0.0006 receptively. In conclusion, circulating micro-RNA like miR-19b and miR-let7b have a potential opportunity to be a non-invasive diagnostic marker or therapeutic target for PFIC in the future.
2023-06-05 | Iterative antibody-induced bile salt export pump deficiency after successive liver transplantations successfully treated with plasmapheresis and rituximab.
Post-transplantation evolution of progressive familial intrahepatic cholestasis type 2 patients can be complicated by antibody-induced bile salt export pump deficiency (AIBD). There is no consensus on its management. We describe a patient who presented two episodes, 9 years apart. The first episode was refractory to plasmapheresis and intravenous immunoglobulin (IVIG) started 2 months after AIBD onset, leading to graft loss. The second episode responded to plasmapheresis, IVIG and rituximab initiated less than 2 weeks after the beginning of symptoms, allowing for long-term recovery. This case suggests that intensive treatment with minimum delay after symptoms onset could sponsor a better evolution.
small molecules
2026-09-22 | Decoding the Cellular Response to Methylthioadenosine Uncovers Novel Targets for Chronic Liver Disease
Progressive familial intrahepatic cholestasis type 3 (PFIC3), caused by MDR3 deficiency (MDR2 in mice), is a lethal pediatric liver disease characterized by early-onset persistent cholestasis, progressive fibrosis, cirrhosis, and eventual liver failure. MDR3 is a phosphatidylcholine transporter located in the canalicular membrane of hepatocytes, and its deficiency leads to the accumulation of free bile acids, which damage epithelial cells due to their detergent-like effect. Therapeutic options remain limited, highlighting the need to identify molecular drivers of disease progression and novel pharmacological strategies. To investigate the molecular alterations associated with this deficiency, our laboratory performed functional proteomic analyses in patient samples and murine hepatic organoids, revealing consistent reprogramming of one-carbon metabolism (OCM). Based on these findings, we explored the therapeutic potential and molecular mechanisms of 5′-methylthioadenosine (MTA), a metabolite involved in this pathway. Using hepatocellular carcinoma cells (PLCs), we combined quantitative shotgun proteomics with the proteome integral solubility alteration (PISA) assay to characterize functional responses and identify direct protein targets of MTA. To reinforce the physiological relevance of our findings, we extended the PISA analysis to liver protein extracts from the Mdr2−/− mouse model of chronic cholestatic injury, enabling validation of candidate target interactions observed in cellular extracts. Proteomic profiling revealed that MTA induces significant alterations in cell division processes, epigenetic regulatory networks, and energy metabolism, thereby promoting an adaptive phenotype characterized by metabolic plasticity, microenvironmental reorganization, and immunomodulation. These findings provide a robust molecular framework for understanding the hepatic response to MTA and shed new light on the mechanisms that may underlie its beneficial effects. In addition, they provide a valuable platform for further investigation of the therapeutic potential of this compound and its prospective translation into clinical practice.
2026-09-18 | Novel genetic variants and atypical phenotypes in pediatric progressive familial intrahepatic cholestasis.
Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders characterized by impaired bile formation and secretion, frequently progressing to cirrhosis and end-stage liver disease. This study characterized the genotypic and phenotypic spectrum of PFIC in a pediatric cohort. A retrospective cohort study with prospective enrollment of additional cases and longitudinal follow-up included 17 children with molecularly confirmed PFIC managed at Alexandria University Children's Hospital between 2017 and 2026. Clinical, biochemical, histopathological, genetic, therapeutic, and outcome data were reviewed. Three, ten, two, and two patients had PFIC types 1, 2, 3, and 8, respectively, with pathogenic variants in ATP8B1, ABCB11, ABCB4, and KIF12, including four novel variants. PFIC types 1 and 2 presented with early-onset low gamma-glutamyl transferase (GGT) cholestasis and severe pruritus; five patients underwent biliary diversion. PFIC type 2 showed more severe liver disease than PFIC type 1. PFIC types 3 and 8 presented later with atypical non-icteric presentations with hepatosplenomegaly and elevated GGT without classical histopathological cholestasis in three cases. Three patients underwent successful liver transplantation. PFIC exhibits marked phenotypic heterogeneity. Recognition of atypical and non-icteric presentations broadens its clinical spectrum and highlights the importance of comprehensive genetic testing for accurate diagnosis. The study identifies and characterizes novel variants in the ABCB11, ABCB4, and KIF12 genes within an Egyptian pediatric cohort, expanding the known mutational spectrum of the disease. The study reported unusual presentation for PFIC type 3 and 8 with rapid fibrotic progression even in the absence of clinical jaundice or histological evidence of bile plugs challenging the diagnostic reliance on overt cholestasis as the primary clinical marker for PFIC.
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.
2026-06-19 | 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.
2026-04-11 | Bile Acid Detergency as Determinant of Liver Pathology in a Humanized Mouse Model of Progressive Familial Intrahepatic Cholestasis Type 3.
Progressive familial intrahepatic cholestasis type 3 (PFIC3) is caused by impaired activity of ABCB4 that transports phosphatidylcholines (PC) from hepatocytes into bile. Abcb4-knockout (KO) mice have been generated, but hydrophilic muricholic acids in their bile acid (BA) pool may limit pathology and thereby hamper translation to human PFIC3. Therefore, we addressed whether Abcb4 knockdown (Abcb4-KD) in the livers of Cyp2c70-KO mice with a human-like BA composition leads to liver pathology that more closely resembles human PFIC3. Expression of Abcb4 gene was suppressed in livers of Cyp2c70-KO/L-Cas9tg mice and control-Cas9tg mice using CRISPR/Cas9-technology to assess short- and long-term consequences. The BA sequestrant colesevelam was mixed into the chow diet (2% w/w) of Cyp2c70-KO mice with or without Abcb4-KD, and the effects were evaluated after 6 weeks. Abcb4-KD strongly reduced biliary phospholipid:BA ratios in both Cyp2c70-KO and control mice. However, plasma transaminases elevations, liver fibrosis, and ductular reactions were markedly aggravated by Abcb4-KD in the context of a human-like BA composition. Importantly, the biliary lipid compositions differed markedly between the 2 Abcb4-KD models. Reduced biliary PC and increased concentrations of lysophosphatidylcholine, sphingomyelin, and ceramide were associated with the severity of liver disease only in Cyp2c70-KO/Abcb4-KD mice. Gene set enrichment analysis indicated that epithelial-mesenchymal transition was induced in the livers of Cyp2c70-KO/Abcb4-KD mice compared with control Abcb4-KD mice. BA sequestration reduced biliary BA secretion rates and mitigated liver pathology in Cyp2c70-KO/Abcb4-KD mice. The presence of a human-like BA composition profoundly aggravates liver pathology upon Abcb4 reduction in mice, conceivably due to the augmented extrusion of non-PC phospholipids by hydrophobic BAs from membranes into bile. This humanized PFIC3 model is anticipated to accelerate the development of novel therapies for PFIC3 and potentially other cholestatic liver diseases.
cell therapies
2026-06-01 |
Patients’ genotypes and types.
Background Progressive familial intrahepatic cholestasis (PFIC) refers to a group of inherited cholestatic liver diseases that affect children, often leading to liver failure and requiring liver transplantation (LT). Many studies have established correlations between the effect of the causal gene variant types and the severity of the PFIC phenotype, the treatment considered, or its outcomes in patients. Nevertheless, no selection criteria for LT based on genotypes have been adopted for patients affected by this group of diseases. Therefore, we conducted a meta-analysis to investigate the association between the main PFIC subtype genotypes and the treatment with LT. Methods Online databases were searched for articles on PFIC1–4 and LT. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. The genotypes of patients were extracted from the included studies and categorized into a group of cases, harboring null genotypes, and a group of controls, harboring non-null genotypes. The relationship between the genotype type and LT outcome was expressed as an OR by assessing the LT event among the case group and the control group. Results Eighteen studies involving 420 PFIC patients were included. A random-effects model was used to assess the OR. Overall, we observed a close relationship between the PFIC null genotype and the LT event; OR=2.79 (95% CI:1.63 to 4.77; p < 0.001). Subgroup analysis according to the PFIC subtype showed the same effect. Conclusions Our results provide evidence of a potential association between null genotypes in PFIC diseases and the indication of LT as a treatment. Further trials are needed to confirm our results and guide decisions regarding personalized and early preventive LT. Research protocol registration https://doi.org/10.17605/OSF.IO/MNQWB
2025-04-09 | Clinical and molecular genetic characteristics of pediatric PFIC3 patients: three novel variants and prognosis for parental liver transplantation.
Progressive Familial Intrahepatic Cholestasis Type 3 (PFIC3) is a rare inherited liver disease caused by a mutation in the ABCB4 gene, leading to dysfunction of multidrug resistance protein 3 (MDR3). The earlier the onset of PFIC3 in children is, the more severe the prognosis. The diagnosis of PFIC3 is typically based on clinical symptoms, laboratory tests, and imaging assessments, with final confirmation requiring genetic testing. The aim of this study was to investigate the associations between genetic mutations in PFIC3 and clinical features, molecular genetics, and liver histopathology to improve early recognition and understanding of this disease. By analysing the data of three children with PFIC3 who underwent parental liver transplantation, we were able to gain a deeper understanding of the complexity and diversity of the disease. With respect to molecular genetics, we identified five mutation sites in the ABCB4 gene, including three newly discovered mutations. Immunohistochemical analysis revealed reduced expression of the MDR3 protein in child 1 and no expression in child 2 or child 3, revealing an intrinsic link between the ABCB4 gene and the MDR3 protein. Histopathologically, all three patients presented with significant portal vein fibrosis or cholestatic liver cirrhosis. In conclusion, this study emphasizes the importance of molecular genetic and pathological evaluation of patients with PFIC3 mutations and elucidates the impact of these three mutations on the course of the disease in children, for whom early symptomatic treatment and early preparation for liver transplantation are options worth considering.
2024-02-15 | Novel approach for reconstruction of the three-dimensional biliary system in decellularized liver scaffold using hepatocyte progenitors
Reconstruction of the biliary system is indispensable for the regeneration of transplantable liver grafts. Here, we report the establishment of the first continuous three-dimensional biliary system scaffold for bile acid excretion using a novel method. We confirmed the preservation of the liver-derived extracellular matrix distribution in the scaffold. In addition, hepatocyte progenitors decellularized via the bile duct by slow-speed perfusion differentiated into hepatocyte- and cholangiocyte-like cells, mimicking hepatic cords and bile ducts, respectively. Furthermore, qRT-PCR demonstrated increased ALB , BSEP , and AQP8 expression, revealing bile canaliculi- and bile duct-specific genetic patterns. Therefore, we concluded that locally preserved extracellular matrices in the scaffold stimulated hepatic progenitors and provided efficient differentiation, as well as regeneration of a three-dimensional continuous biliary system from hepatic cords through bile ducts. These findings suggest that organ-derived scaffolds can be utilized for the efficient reconstruction of functional biliary systems.
2023-11-24 | The Modern Day Heracles
Rare pediatric liver disorders can be very destructive to the lives of patients and their families. Often, therapeutic options are limited to symptomatic care and precise disease mechanisms remain elusive. The relatively low incidence of each individual disease and the often widespread geographic distribution of patients complicate research and treatment development. In this thesis, we have investigated the potential of patient-derived liver organoids to study such rare pediatric liver diseases. We characterized intrahepatic cholangiocyte organoids (ICOs) from several monogenic liver disorders and showed that organoids express affected proteins of diseases such as cystic fibrosis, Wilson disease and methylmalonic acidemia. We uncovered that ICOs possess a hybrid phenotype, combining hepatocyte and cholangiocyte characteristics. This led us to investigate whether patient-derived liver organoids would be interesting to study the rare perinatal disease biliary atresia (BA), in which the hepatobiliary tree is occluded and becomes fibrotic. We found that organoids from different hepatobiliary regions (intrahepatic, extrahepatic and gallbladder) of BA patients can be cultured and biobanked. Further characterization showed that BA patient organoids display BA specific growth behavior and increased sensitivity to viral infections. While we showed that various hepatocyte and cholangiocyte functions can be studied in liver organoids, our data also indicated that several hepatocyte functions are currently limited in this in vitro system. Therefore, we devised a novel culture strategy to increase hepatic maturation in liver organoids. We found that hepatic functions, such as drug metabolism, improve when liver organoid cells are cultured on hollow fiber membranes coated with extracellular matrix proteins of the hepatic niche. Moreover, we demonstrated that hepatic transepithelial transporter defects such as progressive familial intrahepatic cholestasis type 3 can be studied in patient-derived liver organoids. In summary, we have demonstrated that patient-derived liver organoids are a useful tool to study various rare liver and metabolic disorders affecting the hepatobiliary tract. Several diseases such as BA, cystic fibrosis, Wilson disease, progressive familial intrahepatic cholestasis type 3 and methylmalonic acidemia can currently be studied with ICOs. Although ICOs were previously praised as a new break-through hepatocyte model, we have shown that organoids from all hepatobiliary regions are at least equally useful for researching cholangiopathies, such as BA. The development of new technologies, such as organ chips and co-culture strategies, are exciting not only to study the disease mechanisms of rare diseases but also to improve the hepatic maturity of ICOs. Applying the myriad of culture improvement strategies to ICOs will likely produce a fantastic patient-derived hepatocyte model. We have taken the first steps toward improving hepatic maturation of ICOs and in doing so have demonstrated that the ICO application range can be broadened to facilitate the study of (cholestatic) disease mechanisms. Similarly, we anticipate that these improvements in hepatic maturation of ICOs will aid in the development of safe therapeutics for (rare) liver diseases in a personalized manner in the future.
2022-08-26 | Recent Findings in the Gut-Liver Axis and Associated Disease Therapy
Several presentations at the recent International Liver Congress™ (ILC), held in London, UK, from 22nd–26th of June 2022, addressed the role of the gut microbiome in chronic liver disease. Debbie L. Shawcross from the Department of Inflammation Biology, School of Immunology and Microbial Sciences, Institute of Liver Studies, King’s College London, UK, outlined the role of the gut-liver axis in the pathogenesis of cirrhosis, and how existing and novel therapies manipulate gut microbes. Emina Halilbasic from the Medical University of Vienna, Austria, and Benjamin H. Mullish from the Division of Digestive Diseases, Imperial College London, UK. Focused on the use of gut-based therapies in cholestatic liver disease. They explained the current understanding of the interplay between bile acids, microbiota, and the mucosal immune system, and the ways in which this may be manipulated for therapeutic gain. The role of gut barrier impairment in alcohol-related liver disease (ArLD) was presented by Shilpa Chokshi from the Roger Williams Institute of Hepatology, Foundation for Liver Research, London, UK, and School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, UK. Charlotte Skinner from the Department of Metabolism, Digestion, and Reproduction, Division of Digestive Diseases, Imperial College London, UK, described the role of gut proteases in this process, while Jasmohan S. Bajaj from the Virginia Commonwealth University, Richmond, USA, and Central Virginia Veterans Healthcare System, Richmond, USA, illustrated new therapies that target the gut-liver axis in this condition. Yue Shen from Zhongshan Hospital, Fudan University, Shanghai, China, and the Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, China, described a combined microbiome-metabolome study to characterise the gut microbiome in hepatitis B virus infection-associated liver diseases (HBV-CLD), and how specific microbes might impact peripheral immunity. Finally, Bajaj outlined why the gut is a major target for hepatic encephalopathy (HE) treatment and described cutting edge research into therapies that show promise in this arena, such as soluble solid dispersion rifaximin, faecal microbiota transplantation (FMT), and rationally defined bacterial consortia. Overall, these presentations highlight an expanding knowledge of the gut-liver axis and promise an exciting future in liver treatment.
proteins
2026-09-10 | Impact of ATP8B1 Mutation and Maturation on CFTR Functionality and Gene Expression
Background/Objectives: Progressive familial intrahepatic cholestasis type 1 (PFIC1) is a rare autosomal recessive liver disorder caused by mutations in the ATP8B1 gene, leading to defective bile acid secretion and severe clinical outcomes. A milder, episodic form of the disease, benign recurrent intrahepatic cholestasis (BRIC), is also associated with ATP8B1 mutations. PFIC1 patients frequently present with extra-hepatic symptoms. Interestingly, cystic fibrosis (CF) patients also develop liver dysfunction, and we previously showed that CFTR expression is significantly reduced in PFIC1 patients. Methods: In this study, we investigated the relationship between ATP8B1 and CFTR by comparing gene expression and protein maturation in PFIC1 (Byler) and BRIC cell lines to wild-type controls. Results: Both ATP8B1 and CFTR transcripts were markedly decreased in mutant cells, resulting in lower protein synthesis. Distinct ATP8B1 isoforms were identified: a 140 kDa mature form in wild-type cells, a 145 kDa variant in BRIC cells, and a 180 kDa form in PFIC1 cells. Using antibodies targeting the N- and C-terminal domains, we demonstrated that wild-type ATP8B1 undergoes sequential maturation—first at Gly308 in the endoplasmic reticulum, then at Gly556, a region containing the D554N PFIC1 mutation site—yielding a 74 kDa nuclear peptide with transcriptional cofactor characteristics. This peptide contains an NR box flanked by STAT5 binding motifs and a potential PKA phosphorylation site, suggesting interaction with the Small Heterodimer Partner (SHP) and regulation of FXR and HNF1α expression, which are both known to modulate CFTR transcription. Immunoprecipitation experiments revealed a physical association between ATP8B1 and CFTR, supporting a chaperone role for ATP8B1 in CFTR trafficking and membrane insertion. PDZK1 was also found to interact with ATP8B1, potentially stabilizing CFTR at the apical membrane through PDZ-domain interactions. Conclusions: Collectively, our results identify ATP8B1 as a multifunctional protein that not only ensures the correct trafficking and membrane localization of CFTR but should also regulate its transcription via a nuclear signaling pathway. These findings provide new insights into the molecular link between PFIC1 and cystic fibrosis-associated liver disease.
2025-10-14 | Enigmatic functions of ATP8B1: cholestasis, inflammation, phosphoinositide flipping, and cellular homeostasis.
Mutations in ATP8B1 cause a spectrum of cholestatic liver disease, ranging from Progressive-Familial-Intrahepatic-Cholestasis type-1 (PFIC1) to Benign-Recurrent-Intrahepatic-Cholestasis type-1 (BRIC1). Manifestations of PFIC1 include severe pruritus, jaundice, and liver damage. Extrahepatic features sometimes observed in PFIC1 include sensorineural hearing loss, diarrhea, pancreatitis, and short stature. ATP8B1 was shown to translocate phospholipids across the plasma membrane; however, expression of ATP8B1 in many tissues and the range of pathological manifestations in ATP8B1 deficiency suggest diverse physiological functions of ATP8B1, and pleiotropic mechanisms regulating its activity. Recent studies suggest that phosphoinositides, including PIP2 and PIP3, can function as regulators, substrates, and binding partners of ATP8B1. New research shows that ATP8B1 modulates host immune system by regulating cleavage of pyroptotic-executioner Gasdermin D (GSDMD), and inflammation-resolution pathways such as phagocytosis/efferocytosis. Further mechanistic insights can accelerate development of new therapies for restoring membrane integrity, reducing inflammasome activity, and correcting metabolic imbalances caused by ATP8B1 dysfunction.
2025-06-12 | Liver-specific Nr1h4 deletion in mice with human-like bile acid composition causes severe liver injury.
The farnesoid X receptor, encoded by NR1H4, is crucial for bile acid, lipid, and glucose metabolism. NR1H4 mutations in humans cause a severe liver injury called progressive familial intrahepatic cholestasis 5. However, Nr1h4 deletion in mice did not cause severe liver damage at a young age, likely because of the higher levels of hydrophilic bile acids synthesized by the mouse-specific bile acid metabolic enzymes Cyp2a12 and Cyp2c70. We aimed to assess hepatic NR1H4 function by taking advantage of the recently established Cyp2a12/Cyp2c70 double-knockout (CYPDKO) mouse model, which has a human-like bile acid composition containing mainly hydrophobic bile acids. Liver-specific Nr1h4-deficient CYPDKO mice were established using an adeno-associated virus-derived genome-editing method. Nr1h4-deficient wild-type (WT) mice showed no significant changes in marker levels for serum liver injury. In contrast, Nr1h4-deficient CYPDKO mice showed an increase in the liver/body weight ratio and serum liver injury markers, suggesting that the combination of human-like bile acid composition and Nr1h4 deletion induces liver injury. Nr1h4 deletion increased total bile acid levels in the liver through the upregulation of bile acid metabolic genes and downregulation of bile acid transporters. Conversely, overexpression of a small heterodimer partner (Shp), a downstream gene of Nr1h4, suppresses liver injury induced by Nr1h4 deletion in CYPDKO mice. Overall, liver-specific Nr1h4 deficiency induced significant liver damage in mice with human-like bile acids, unlike in WT mice, validating its use as a new animal model for cholestatic liver disease. Therefore, Shp may be a potential target for the treatment of cholestasis.
2024-11-26 | Discovery and mechanism of K63-linkage-directed deubiquitinase activity in USP53.
Ubiquitin-specific proteases (USPs) represent the largest class of human deubiquitinases (DUBs) and comprise its phylogenetically most distant members USP53 and USP54, which are annotated as catalytically inactive pseudoenzymes. Conspicuously, mutations within the USP domain of USP53 cause progressive familial intrahepatic cholestasis. Here, we report the discovery that USP53 and USP54 are active DUBs with high specificity for K63-linked polyubiquitin. We demonstrate how USP53 mutations abrogate catalytic activity, implicating loss of DUB activity in USP53-mediated pathology. Depletion of USP53 increases K63-linked ubiquitination of tricellular junction components. Assays with substrate-bound polyubiquitin reveal that USP54 cleaves within K63-linked chains, whereas USP53 can en bloc deubiquitinate substrate proteins in a K63-linkage-dependent manner. Biochemical and structural analyses uncover underlying K63-specific S2 ubiquitin-binding sites within their catalytic domains. Collectively, our work revises the annotation of USP53 and USP54, provides reagents and a mechanistic framework to investigate K63-linked polyubiquitin decoding and establishes K63-linkage-directed deubiquitination as a new DUB activity.
2024-09-01 | P.352: Recombinant growth hormone treatment in two patients with progressive familial intrahepatic cholestasis.
Introduction: One of the reasons for growth failure in patients with chronic liver diseases is the disturbed growth hormone-insulin-like growth factor1 (GH-IGF1) axis.The expected catch-up growth after liver transplantation (LT) fails in some patients with progressive familial intrahepatic cholestasis type 1 (PFIC1), often due to the systemic nature of the disease and the worsening of diarrhea.Here, we presented our post–LT GH treatment experience for two patients with PFIC1 and growth retardation. Case 1: A 7,1-year-old female was referred to the pediatric endocrinology clinic for short stature.She was diagnosed with PFIC1 (a homozygous deletion in ATB8B1), and at the age of 4,9-year, a partial LT was performed.Following LT, she developed severe persistent diarrhea.Her weight was 17,4 kg (-1,9 SDS), height was 110 cm (-2,4 SDS), and BMI was 14,4 kg/m2 (-0,8 SDS). Tanner stage of puberty was 1, and bone age was 4 years.The midparental height (MPH) was 166 cm (0,5 SDS).She had mild hypertransaminasemia, hepatosteatosis.Considering the chronic disease, she had been followed without further treatment.However, the growth retardation even worsened.At the age of 14,5 years, she had a height of 143 cm (-3,06 SDS).Tanner stage of puberty was 4. Growth velocity (GV) was 4,9 cm/year.Bone age was 12 years.IGF-1 was 190 ng/mL (-1,5 SDS). The GH stimulation test (GHST) showed a peak GH response of 16,6 ng/mL, indicating GH resistance.rGH therapy was started at a dose of 40 mcg/kg, was increased to 60 mcg/kg per day.GV during the first year of treatment was 4,2 cm.At 15,5 years, her height was 147,2 cm (-2,5 SDS), her bone age was 13,5 years, and IGF was 132 ng/mL (-2,7 SDS)(Fig.1).Case 2: A 7-year-old female who was diagnosed with PFIC1 (a homozygous mutation in ATB8B1), and liver transplanted at the age of 3-year was referred to the pediatric endocrinology clinic for short stature.She presented with a weight of 18,9 kg (-1,3 SDS), a height of 99 cm (-4,5 SDS), and a BMI of 19,2 kg/m2 (1,5 SDS).The MPH was 154 cm (-1,5 SDS).Tanner stage of puberty was 1.Bone age was 4 years and 2 months. She had mild hypertransaminasemia, liver steatosis, and chronic diarrhea.At the age of 9,1 years, her height was 105,2 cm (-4,7 SDS).GV was 3.1 cm/year.Bone age was 5 years.IGF-1 was 26,7 ng/mL (-2,4 SDS).The GHST showed a peak GH response of 2,9 ng/mL. She was commenced on rGH therapy at a dose of 30 mcg/kg per day at the age of 9,1 years.GV was 8,1 cm during the first year of treatment.IGF-1 increased to 155 ng/mL (-0,6 SDS).rGH was administered over a period of 5 years.At the age of 15.1 years, her height was 146 cm (-2,7 SDS) (Fig.2).Conclusion: Patients who do not experience catch-up growth after LT should also be evaluated for disturbances in the GH-IGF1 axis. Although rGH had limited effectiveness in the patient with GH resistance, the patient with GH deficiency showed even greater improvement in height SDS and almost achieved the MPH.
gene therapies
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
2026-07-29 | 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.
2026-04-03 | Abstract 2266: Unexpected role of nuclear receptor CAR in cholangiocarcinoma development.
Abstract Cholangiocarcinoma (CCA), the second most common primary liver cancer, arises from the biliary epithelium, either within the liver parenchyma or in the hepatoduodenal ligament. Several cholestatic liver diseases, such as primary sclerosing cholangitis, developmental bile duct malformation, and progressive familial intrahepatic cholestasis (PFIC), have been implicated as CCA risk factors. Cholestatic conditions exhibit a cocarcinogenic effect when combined with chronic liver injuries, as supported by a recently reported CCA animal model in which partial bile duct ligation is combined with repeated treatments of the carcinogen diethylnitrosamine. The nuclear receptor Constitutive Androstane Receptor (CAR, NR1I3), a central regulator of xenobiotic metabolism, is known to drive hepatocellular carcinoma (HCC) when chronically activated, while CAR ablation prevents it in multiple liver cancer models. We have recently characterized the impact of endogenous CAR activation in a mouse model of human PFIC5 disease (i.e., Fxr;Shp double knockout, FS-DKO) that exhibits cholestatic liver injury and develops spontaneous HCC at 1 year of age. In this study, we demonstrated the role of endogenous CAR activation in cholestasis-driven liver cancer development. Based on the strong correlation between CAR activation and liver cancer development in FS-DKO liver, we initially hypothesized that chronic CAR activation mediates hepatic carcinogenesis in FS-DKO liver. However, in contrast to our expectations, further deletion of CAR in Fxr;Shp;Car triple knockouts (FSC-TKO) did not reduce tumor incidence compared to FS-DKO. Instead, highly hypertrophic as well as hyperplastic cholangiocytes became much more abundant in FSC-TKO livers than in FS-DKO livers. Accordingly, about half of the visible FSC-TKO tumor nodules were CCA or combined HCC-CCA types, while most tumors in FS-DKO livers were hepatocellular types. Using RNA-seq and TRRUST transcription factor analysis, we found that CAR/PXR targets were significantly depleted in FSC-TKO, while ETS1 targets were significantly enriched, consistent with emerging evidence that ETS1 biases liver tumor fate toward CCA lineage. These findings suggest that, under cholestatic stress, loss of CAR unexpectedly promotes CCA development by unleashing a microenvironment that favors CCA. Targeting the CAR-ETS1 axis may offer new opportunities to modulate HCC-CCA lineage specification and improve therapeutic strategies. Citation Format: Inyoung Cheon, Ji Ho Suh, Mi Jeong Heo, Sung Ho Lee, Hyun-Jung Jung, Young-Ho Ahn, David D. Moore, Kang Ho Kim. Unexpected role of nuclear receptor CAR in cholangiocarcinoma development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2266.
2026-03-11 | [Clinical features and genetic analysis of a child with Progressive familial intrahepatic cholestasis type 8 due to compound heterozygous variants of KIF12 gene].
To explore the clinical phenotype and genetic characteristics of a child with Progressive familial intrahepatic cholestasis type 8 (PFIC8). METHODS A child with PFIC diagnosed at Beijing Children's Hospital Affiliated to Capital Medical University in September 2025 was selected as the study subject. Peripheral venous blood samples were collected from the child and her parents. Following extraction of genomic DNA, whole-exome sequencing (WES) was carried out. Candidate variants were validated by Sanger sequencing. The pathogenicity of the candidate variants was classified based on the guidelines from American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of Beijing Children's Hospital Affiliated to Capital Medical University (Ethics No.: 2023-E-126-Y). The proband, a 2-month-old female infant, had manifested jaundice of the skin and sclera, and slightly distended abdomen. She had no visible abdominal wall varicose veins, soft abdomen, and no palpable masses. Biliary atresia was ruled out by intraoperative cholangiography. WES revealed that she has harbored compound heterozygous variants of KIF12 gene, namely c.809C>T (p.Ala270Val) and c.1313G>A (p.Arg438Lys), which were verified by Sanger sequencing to have derived from her mother and father, respectively. According to the ACMG guidelines, both variants were classified as variants of uncertain significance (VUS). Based on the pre-defined search strategy, 10 articles were retrieved, which involved 25 PFIC cases, including 5 from China. Together with the proband of this study, the 26 PFIC patients have primarily presented with high GGT cholestasis, with the genetic cause in all cases attributed to variants of the KIF12 gene. The c.809C>T and c.1313G>A compound heterozygous variants of the KIF12 gene probably underlay the pathogenesis of cholestatic liver disease in this child. Above findings have enriched the mutational and phenotypic spectra of PFIC8.
other
2026-02-02 | Evaluation of miRNA Expression in Pediatric Cirrhosis Caused by BA and PFIC.
Liver cirrhosis is one of the most common causes of death for pediatric patients with cholestasis. Because microRNA (miRNA) plays a part in the pathogenesis of the disease, comparing the changes in miRNA expression in cholestatic patients with liver cirrhosis could be helpful for therapeutic or prognostic purposes. miRNA levels in cirrhotic pediatric patients with progressive familial intrahepatic cholestasis (PFIC) and biliary atresia (BA) were studied in this research to comprehend the molecular distinctions and the significance of miRNA regulation in fibrosis and liver cirrhosis. Blood samples were collected from 43 PFIC patients and 84 BA patients, all of whom were confirmed to have liver cirrhosis. The in-house SYBR Green RT-qPCR techniques were established to assess the variations in the expressions of 12 miRNAs. Utilizing bioinformatics tools, the gene targets of the studied miRNAs were examined. Patients' expression of 12 miRNAs was higher than that of the healthy group. However, there was a notable distinction between the miRNAs in PFIC and BA. The levels of miR-34, miR-155, miR-199, miR-200b, and miR-222 were significantly higher in BA than in PFIC. PFIC showed a significantly higher level of miR-223 than BA. The predictive importance of distinct miRNAs in both diseases was revealed by the AUC values. In BA, miR-222 was associated with both liver transplantation and the PELD score. Death was correlated with miR-21, miR-155, miR-199, and miR-200 in BA and miR-34 in PFIC. The analysis showed the significance of the connection between miRNA expression and PI3K/Akt and TGF-β signaling in pediatric liver cirrhosis. Future investigations can evaluate the significance of the studied miRNAs as novel therapeutic targets and diagnostic options.
2025-10-02 | A farnesoid X receptor T296I variant disrupts ligand-induced FXR activation and thus bile acid transport in progressive familial intrahepatic cholestasis.
Nuclear receptor farnesoid X receptor (FXR) acts as a key regulator of bile acid pool homeostasis and metabolism. Within the enterohepatic circulation, reabsorbed bile acids act as FXR agonists. FXR, in turn, transcriptionally controls the synthesis and transport of bile acids. Binding occurs in the ligand binding domain (LBD), favoring a conformational change to the active state in which helix 12 interacts with the LBD to form an interaction surface for nuclear co-activators. The homozygous missense variant T296I, identified in a patient with progressive familial intrahepatic cholestasis (PFIC), is located close to the critical helix 12 interaction. Here, we identified reduced transcriptional activity of the variant protein on the downstream targets bile salt export pump (BSEP) and small heterodimer partner (SHP) in vitro, within the patient's liver, and in iPSC-derived hepatic organoids. BSEP-dependent Tauro-DBD transport was impaired in T296I patient-derived organoids, but could be rescued via lipid nanoparticle-mediated FXR WT mRNA delivery, indicating the variant is responsible for the identified reduced BSEP expression. Using molecular dynamics simulations, we observed a reduced transition from the inactive to the active state for the T296I variant, indicating a molecular mechanism underlying the reduced activity. To our knowledge, this is the first study to describe the conformational change from an inactive to an active state of the FXR LBD. This might be useful for new therapeutic approaches targeting the activation of FXR.
2024-02-14 | Management and outcomes after liver transplantation for progressive familial intrahepatic cholestasis: A systematic review and meta-analysis.
Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous rare congenital cholestatic liver disease. Disease progression might necessitate liver transplantation (LT). The aim of this study was to describe the outcome of PFIC1-4 patients after LT. Electronic databases were searched to identify studies on PFIC and LT. Patients were categorized according to PFIC type, genotype, graft type, age at LT, time of follow-up, and complications and treatment during follow-up. Seventy-nine studies with 507 patients met inclusion criteria; most patients were classified as PFIC1-3. The median age at LT was 50 months. The overall 5-year patient survival was 98.5%. PFIC1 patients with diarrhea after LT were at significant risk of developing graft steatosis ( p < 0.0001). Meta-analysis showed an efficacy of 100% [95% CI: 73.9%-100%] for surgical biliary diversion to ameliorate steatosis and 94.9% [95% CI: 53.7%-100%] to improve diarrhea (n = 8). PFIC2 patients with bile salt export pump (BSEP)2 or BSEP3-genotype were at significant risk of developing antibody-induced BSEP deficiency (AIBD) ( p < 0.0001), which was reported in 16.2% of patients at a median of 36.5 months after LT. Meta-analysis showed an efficacy of 81.1% [95% CI: 47.5%-100%] for rituximab-based treatment regimens to improve AIBD (n = 18). HCC was detected in 3.6% of PFIC2 and 13.8% of PFIC4 patients at LT. Fifty percent of PFIC1 patients develop diarrhea and steatosis after LT. Biliary diversion can protect the graft from injury. PFIC2 patients with BSEP2 and BSEP3 genotypes are at significant risk of developing AIBD, and rituximab-based treatment regimens effectively improve AIBD. PFIC3 patients have no PFIC-specific complications following LT.
2024-01-30 | Expression of miR-let7b and miR-19b in progressive familial intrahepatic cholestasis (PFIC) children.
MicroRNAs (miRNAs) are a group of small non-coding RNAs that bind to the target mRNA and regulate gene expression. Recently circulating microRNAs were investigated as markers of diseases and therapeutic targets. Although various studies analyze the miRNA expression in liver disease, these studies on PFIC are few. Progressive familial intrahepatic cholestasis (PFIC) is a rare liver disease with autosomal recessive inheritance. Most children with PFIC progress to cirrhosis and liver failure and consequently need to have a liver transplant. The aim of this study is the investigation of the miR-19b and miR-let7b expression levels in Iranian PFIC children. 25 PFIC patients, 25 healthy children and 25 Biliary Atresia patients were considered as case and two control groups respectively. Blood samples were obtained and Liver function tests (LFTs) were measured. After RNA extraction and cDNA synthesis, quantitative PCR was performed using specific primers for miR-19b and miR-let7b. The U6 gene is used as an internal control. qPCR on PFIC patients' samples demonstrated that the miR-19b and the miR-let7b expression were significantly decreased in patients compared to the control groups, with a p-value<0.0001 and p-value=0.0006 receptively. In conclusion, circulating micro-RNA like miR-19b and miR-let7b have a potential opportunity to be a non-invasive diagnostic marker or therapeutic target for PFIC in the future.
2023-06-05 | Iterative antibody-induced bile salt export pump deficiency after successive liver transplantations successfully treated with plasmapheresis and rituximab.
Post-transplantation evolution of progressive familial intrahepatic cholestasis type 2 patients can be complicated by antibody-induced bile salt export pump deficiency (AIBD). There is no consensus on its management. We describe a patient who presented two episodes, 9 years apart. The first episode was refractory to plasmapheresis and intravenous immunoglobulin (IVIG) started 2 months after AIBD onset, leading to graft loss. The second episode responded to plasmapheresis, IVIG and rituximab initiated less than 2 weeks after the beginning of symptoms, allowing for long-term recovery. This case suggests that intensive treatment with minimum delay after symptoms onset could sponsor a better evolution.
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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 | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
modified human ATP binding cassette subfamily B member 4 (ABCB4) mRNA encoding multidrug resistance protein 3 (MDR3) | RNAs | FDA | — | INNORNA USA INC. |
modified human ATP binding cassette subfamily B member 11 (ABCB11) messenger RNA encoding bile salts export pump | RNAs | FDA | — | INNORNA USA INC. |
3alpha,6beta,7beta,12alpha-tetrahydroxy-5beta-cholan-24-oic acid | small molecules | FDA | — | Qing Bile Therapeutics, Inc. |
Adeno-associated viral vector serotype 3B encoding human multidrug resistance protein 3A | gene therapies | EMA | — | Vivet Therapeutics S.A.S. |
Adeno-associated viral vector encoding human multidrug resistance protein 3A (MDR3A) | gene therapies | FDA | — | 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 | Approved | Mirum Pharmaceuticals International B.V. |
maralixibat [Livmarli] | small molecules | FDA | Approved | Mirum Pharmaceuticals, Inc. |
odevixibat [Bylvay] | small molecules | FDA | Approved | 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 | Approved | Ipsen Pharma |
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