RARE DISEASE
Benign recurrent intrahepatic cholestasis
Benign recurrent intrahepatic cholestasis
Benign recurrent intrahepatic cholestasis
Synonyms: BRIC, Summerskill-Walshe-Tygstrup syndrome
Synonyms: BRIC, Summerskill-Walshe-Tygstrup syndrome
Synonyms: BRIC, Summerskill-Walshe-Tygstrup syndrome
Drug discovery
0
drugs
With orphan designations
Overview
Benign Recurrent Intrahepatic Cholestasis (BRIC) is a rare autosomal recessive disorder characterized by episodic intrahepatic cholestasis with pruritus, jaundice, and elevated conjugated bilirubin. Episodes resolve spontaneously without progressive liver injury, though rare progression to PFIC or cirrhosis occurs [1][10]. Caused by ATP8B1 (BRIC1) or ABCB11 (BRIC2) mutations, it presents with normal/low GGT and requires exclusion of other cholestatic etiologies [1][4][10].
Burden
Recurrent episodes cause hospitalization, work/school absenteeism, and reduced quality of life due to debilitating pruritus [10][15][18]
Risk of complications: steatorrhea, vitamin K deficiency, and BRIC2-associated hepatobiliary malignancies [1][10]
Economic impact from frequent healthcare utilization and invasive interventions in refractory cases [12][15][18]
Therapies
First-line: Rifampicin (induces bile acid metabolism) and cholestyramine (bile acid sequestration) [3][14][15]
Refractory cases: Plasmapheresis, nasobiliary drainage, or partial biliary diversion [1][15][18]
Emerging: Genetic testing guides personalized management; liver transplantation reserved for severe/progressive cases [1][10][15]
Categories: rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare transplant-related disorders
Research Papers
108 drug discovery papers about Benign recurrent intrahepatic cholestasis, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
108 drug discovery papers about Benign recurrent intrahepatic cholestasis, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-04 | Recurrent Cholestatic Jaundice in a Young Indian Adult: A Clinical Diagnosis of Benign Recurrent Intrahepatic Cholestasis
Benign recurrent intrahepatic cholestasis (BRIC) is a rare hereditary cholestatic disorder characterized by recurrent episodes of intermittent cholestatic jaundice and pruritus without causing detectable lasting liver damage. Owing to its rarity and the absence of pathognomonic findings, the diagnosis is often delayed and requires exclusion of more common causes of recurrent cholestasis. We report the case of a 25-year-old male who presented with recurrent episodes of severe cholestatic jaundice with intense generalized pruritus. The patient clinically and biochemically recovered after treatment with ursodeoxycholic acid (UDCA). Based on the characteristic recurrence pattern, severe pruritus, normal serum gamma-glutamyl transferase (GGT) levels during the current episode, normal hepatobiliary imaging, complete clinical recovery between attacks, and exclusion of alternative causes of cholestasis, a presumptive clinical diagnosis of BRIC was made. Although genetic confirmation was not done, the clinical features were most consistent with BRIC.
2026-07-10 | Data Sheet 1_Case Report: Recurrent intrahepatic cholestasis: two rare cases with their novel variants of ATB8B1 and atypical clinical findings.pdf
Recurrent intrahepatic cholestasis type 1 (RIC1), historically also known as BRIC 1 (benign recurrent intrahepatic cholestasis typr 1),is an autosomal recessive disorder presenting with intermittent episodes of cholestatic jaundice and caused by pathogenic variants of adenosine triphosphatase phospholipid transporting 8B1 (ATP8B1). Here, we describe two unusual RIC1-affected siblings, whose clinical courses and findings deviate from the classical RIC1 patients, emphasizing the potential adverse effects associated with recurrent cholestasis. Additionally, we have for the first time presented specific genetic, clinical and pathological evidence demonstrating that two novel compound heterozygous variants of ATP8B1 (c.749 T > C and c.3261 + 5G > A) had a significant effect on the expression of the ATP8B1 encoded protein, thereby contributing to cholestasis attacks.
2026-06-18 | Use of genetic analysis in adult cholestatic liver disease: lessons from progressive paediatric syndromes and cohort studies.
The increasing availability and decreasing costs of DNA sequencing have resulted in the re-grouping of rare, severe paediatric cases of progressive familial intrahepatic cholestasis (PFIC) with more frequent, later-onset cases of cholestasis (eg, intrahepatic cholestasis of pregnancy, benign recurrent intrahepatic cholestasis, low phospholipid-associated cholelithiasis) under the umbrella of genetic cholestasis. The common denominator is the presence of functional variants in the PFIC-associated genes, predominantly in ABCB4, ABCB11 and ATP8B1, which cause PFIC types 1-3. Several other congenital diseases such as Alagille syndrome and alpha1-antitrypsin deficiency comprise cholestatic pruritus as frequent symptoms.With the availability of intestinal bile acid transporter inhibitors (IBATi) as new and efficacious therapeutics for pruritus, the most debilitating symptom of PFIC, it is essential to envision their usefulness for patients with later-onset cholestatic liver disease suffering from pruritus.In this review, we summarise published studies on the genetic makeup of patients with paediatric, juvenile and adult-onset cholestasis, and discuss their findings with respect to genotype-specific treatment with IBATi, ursodeoxycholic acid, or alternative drugs. The aim is to provide an overview of the genetic variants likely to be encountered in future sequencing investigations of patients with cholestatic liver diseases, and how to translate this genetic information into personalised treatment recommendations.
2026-06-02 | Recurrent pruritus, jaundice, and pancreatitis in an adult due to a rare etiology: A case report
BACKGROUND Benign recurrent intrahepatic cholestasis type 1 (BRIC1) is an autosomal recessive disorder linked to mutations in ATP8B1 . We report a case of BRIC1 with the unusual combination of recurrent pancreatitis and hearing loss, features that extend beyond the classic hepatic phenotype. CASE SUMMARY An adult male with recurrent jaundice, pruritus, and pancreatitis from 2019 to 2025 underwent laboratory and imaging studies, liver biopsy, and genetic sequencing. Histology confirmed intrahepatic cholestasis. An ATP8B1 minigene plasmid was constructed to assess splicing effects in vitro . Sequencing identified compound heterozygous ATP8B1 variants: c.1214_1215delAT (p.Y405Cfs*24) and c.3015G>A (p.Q1005Q). Functional studies provided the evidence for reclassifying the c.3015G>A variant from uncertain significance to likely pathogenic (LP) in BRIC1. In addition, the patient appeared to show a favorable response to glucocorticoids therapy. CONCLUSION An adult with BRIC1 and relatively rare extrahepatic phenotype had functional evidence for the LP of a novel ATP8B1 variant.
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.
cell therapies
2025-06-08 | Plasmapheresis can improve clinical outcomes in patients with therapy resistant benign recurrent intrahepatic cholestasis: A case report.
Due to the rarity of benign recurrent intrahepatic cholestasis (BRIC), limited literature exists regarding the therapeutic benefit of plasmapheresis, particularly in the context of severe hyperbilirubinemia. A 25-year-old female presented with jaundice and severe pruritus. Laboratory findings revealed a total bilirubin of 37 mg/dL and a direct bilirubin of 27 mg/dL. Alanine aminotransferase (ALT) was 31 U/L, aspartate aminotransferase (AST) was 35 U/L, and alkaline phosphatase was 175 U/L. The patient had a five-year history of recurrent episodes, previously resolving spontaneously or with medical treatment. Following liver biopsy diagnosis and failure of conventional therapy, she underwent plasmapheresis on alternate days. Four sessions of one plasma volume exchange, using albumin, were performed concurrently with medical treatment. The patient demonstrated rapid and significant improvement in pruritus and urine color, with no adverse events or need for fresh frozen plasma. Total bilirubin decreased progressively to 5 mg/dL, and direct bilirubin to 4 mg/dL. Plasmapheresis appears to be a beneficial adjunct therapy for refractory BRIC, effectively reducing bilirubin levels and alleviating pruritus. This intervention may improve patient quality of life and potentially prevent renal complications associated with hyperbilirubinemia, serving as a bridge to liver transplantation, if necessary.
2025-03-03 | Early plasmapheresis in type 2 benign recurrent intrahepatic cholestasis: A case report and review of literature.
Benign recurrent intrahepatic cholestasis (BRIC) is a rare autosomal recessive liver disease, causing episodic cholestasis with intense pruritus. This case report highlights the effectiveness of early plasmapheresis as a therapeutic option for BRIC type 2, offering rapid symptom relief and early termination of cholestatic episodes. It contributes to the limited evidence supporting plasmapheresis as a treatment for BRIC flares resistant to conventional therapies. A 43-year-old male with BRIC type 2 presented with fatigue, jaundice, and severe pruritus, triggered by a recent mild severe acute respiratory syndrome coronavirus 2 infection. Laboratory results confirmed cholestasis with elevated bilirubin and alkaline phosphatase. First-line pharmacological treatments, including cholestyramine and rifampicin, failed. Endoscopic nasobiliary drainage was ineffective, prompting initiation of plasmapheresis. This intervention rapidly relieved pruritus, with complete biochemical normalisation after 11 sessions. Two years later, a similar episode occurred, and early reinitiation of plasmapheresis led to symptom resolution within two sessions and biochemical recovery within two weeks. The patient tolerated the procedure well, with no adverse effects observed. Follow-up showed no signs of cholestasis recurrence. Plasmapheresis is a safe and effective option for therapy-refractory BRIC type 2, particularly when initiated early in cholestasis.
2013-10-28 | Treatment of pruritus with Prometheus dialysis and absorption system in a patient with benign recurrent intrahepatic cholestasis.
Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disorder characterized by recurrent episodes of jaundice and itching. Episodes of cholestasis last variously from 1 week to several months, may start at any age and usually resolve spontaneously. No effective treatment has been found as yet. We report a case of genetically proven BRIC in a male patient who developed three episodes of pruritus and jaundice at the age of 14, 16 and 19 years. During the third episode, he did not respond to pharmacological medical therapy, and fractionated plasma separation and absorption (FPSA, Prometheus) was performed to manage intractable pruritus. The treatment immediately alleviated pruritus, lowered serum bilirubin concentration and induced sustained remission in the 5-year follow up. FPSA seems to be a safe and effective way of treatment for BRIC in patients with severe pruritus and prolonged jaundice.
1989-11-07 | Benign recurrent intrahepatic cholestasis. A report of 26 cases.
Benign recurrent intrahepatic cholestasis is characterized by attacks of cholestasis. The purpose of our study of 26 patients was to emphasize some features uncommonly or never reported in this disease: (a) in each patient, the attacks of cholestasis were stereotypic; (b) attacks of cholestasis were not associated with pruritus in 15% of our patients; (c) the occurrence of attacks of cholestasis during pregnancy or oral contraceptive use might be a fortuitous coincidence; (d) gallstones were found in several patients with benign recurrent intrahepatic cholestasis and might be present earlier than in the general population; (e) in some of our patients, during attacks of cholestasis, serum transaminases were very high, exceeding 15 times the upper limit of normal; (f) mild portal inflammatory infiltration was found in one third of our patients; (g) no treatment shortened the duration of cholestasis, and in a few patients, plasmapheresis seemed to diminish jaundice and improve biochemical disorders.
gene therapies
2025-09-29 | iPSC-based hepatic organoids reveal a heterozygous MYO5B variant as driver of intrahepatic cholestasis.
Hereditary intrahepatic cholestasis is caused by variants of various genes involved in enterohepatic bile circulation, metabolization, and conjugation. Originally classified into 3 groups, the number of contributing genes is still increasing, underlining the need for a deeper understanding of the molecular interaction during intrahepatic cholestasis. In the present study, we investigate the interplay of heterozygous variants in 3 cholestasis-associated genes (ABCB11, ABCB4, and MYO5B) by exploiting iPSC-based hepatic organoids from a patient suffering from recurrent intrahepatic cholestasis. Functional characterization of MRP2-mediated cholyl-lysyl-fluorescein (CLF) and BSEP-mediated Tauro-nor-THCA-24-DBD transport demonstrated a marked reduction of transport in MYO5B-deficient organoids, in comparison to unaffected control organoids. Moreover, iPSC-based organoids derived from the patient carrying 3 heterozygous variants in ABCB11, ABCB4, and MYO5B also exhibited absence of BSEP-mediated Tauro-nor-THCA-24-DBD transport, but functional MRP2-mediated CLF-transport. Interestingly, CRISPR/Cas9-mediated correction of the mutated ABCB11 allele could not restore the impaired BSEP function, suggesting the heterozygous MYO5B variant as the main driver of the transport deficiency. In fact, CRISPR/Cas-mediated correction of the MYO5B variant finally resulted in a restoration of the BSEP-mediated Tauro-nor-THCA-24-DBD transport. iPSC-based organoids serve as an authentic model for functional assessment of the hepatobiliary transport with fluorescent substrates. This allows the characterization of variants of uncertain significance and other variants in cholestasis-associated genes and revealed that a heterozygous MYO5B variant increases the susceptibility to defective hepatobiliary BSEP-mediated transport.
small molecules
2026-08-04 | Recurrent Cholestatic Jaundice in a Young Indian Adult: A Clinical Diagnosis of Benign Recurrent Intrahepatic Cholestasis
Benign recurrent intrahepatic cholestasis (BRIC) is a rare hereditary cholestatic disorder characterized by recurrent episodes of intermittent cholestatic jaundice and pruritus without causing detectable lasting liver damage. Owing to its rarity and the absence of pathognomonic findings, the diagnosis is often delayed and requires exclusion of more common causes of recurrent cholestasis. We report the case of a 25-year-old male who presented with recurrent episodes of severe cholestatic jaundice with intense generalized pruritus. The patient clinically and biochemically recovered after treatment with ursodeoxycholic acid (UDCA). Based on the characteristic recurrence pattern, severe pruritus, normal serum gamma-glutamyl transferase (GGT) levels during the current episode, normal hepatobiliary imaging, complete clinical recovery between attacks, and exclusion of alternative causes of cholestasis, a presumptive clinical diagnosis of BRIC was made. Although genetic confirmation was not done, the clinical features were most consistent with BRIC.
2026-07-10 | Data Sheet 1_Case Report: Recurrent intrahepatic cholestasis: two rare cases with their novel variants of ATB8B1 and atypical clinical findings.pdf
Recurrent intrahepatic cholestasis type 1 (RIC1), historically also known as BRIC 1 (benign recurrent intrahepatic cholestasis typr 1),is an autosomal recessive disorder presenting with intermittent episodes of cholestatic jaundice and caused by pathogenic variants of adenosine triphosphatase phospholipid transporting 8B1 (ATP8B1). Here, we describe two unusual RIC1-affected siblings, whose clinical courses and findings deviate from the classical RIC1 patients, emphasizing the potential adverse effects associated with recurrent cholestasis. Additionally, we have for the first time presented specific genetic, clinical and pathological evidence demonstrating that two novel compound heterozygous variants of ATP8B1 (c.749 T > C and c.3261 + 5G > A) had a significant effect on the expression of the ATP8B1 encoded protein, thereby contributing to cholestasis attacks.
2026-06-18 | Use of genetic analysis in adult cholestatic liver disease: lessons from progressive paediatric syndromes and cohort studies.
The increasing availability and decreasing costs of DNA sequencing have resulted in the re-grouping of rare, severe paediatric cases of progressive familial intrahepatic cholestasis (PFIC) with more frequent, later-onset cases of cholestasis (eg, intrahepatic cholestasis of pregnancy, benign recurrent intrahepatic cholestasis, low phospholipid-associated cholelithiasis) under the umbrella of genetic cholestasis. The common denominator is the presence of functional variants in the PFIC-associated genes, predominantly in ABCB4, ABCB11 and ATP8B1, which cause PFIC types 1-3. Several other congenital diseases such as Alagille syndrome and alpha1-antitrypsin deficiency comprise cholestatic pruritus as frequent symptoms.With the availability of intestinal bile acid transporter inhibitors (IBATi) as new and efficacious therapeutics for pruritus, the most debilitating symptom of PFIC, it is essential to envision their usefulness for patients with later-onset cholestatic liver disease suffering from pruritus.In this review, we summarise published studies on the genetic makeup of patients with paediatric, juvenile and adult-onset cholestasis, and discuss their findings with respect to genotype-specific treatment with IBATi, ursodeoxycholic acid, or alternative drugs. The aim is to provide an overview of the genetic variants likely to be encountered in future sequencing investigations of patients with cholestatic liver diseases, and how to translate this genetic information into personalised treatment recommendations.
2026-06-02 | Recurrent pruritus, jaundice, and pancreatitis in an adult due to a rare etiology: A case report
BACKGROUND Benign recurrent intrahepatic cholestasis type 1 (BRIC1) is an autosomal recessive disorder linked to mutations in ATP8B1 . We report a case of BRIC1 with the unusual combination of recurrent pancreatitis and hearing loss, features that extend beyond the classic hepatic phenotype. CASE SUMMARY An adult male with recurrent jaundice, pruritus, and pancreatitis from 2019 to 2025 underwent laboratory and imaging studies, liver biopsy, and genetic sequencing. Histology confirmed intrahepatic cholestasis. An ATP8B1 minigene plasmid was constructed to assess splicing effects in vitro . Sequencing identified compound heterozygous ATP8B1 variants: c.1214_1215delAT (p.Y405Cfs*24) and c.3015G>A (p.Q1005Q). Functional studies provided the evidence for reclassifying the c.3015G>A variant from uncertain significance to likely pathogenic (LP) in BRIC1. In addition, the patient appeared to show a favorable response to glucocorticoids therapy. CONCLUSION An adult with BRIC1 and relatively rare extrahepatic phenotype had functional evidence for the LP of a novel ATP8B1 variant.
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.
cell therapies
2025-06-08 | Plasmapheresis can improve clinical outcomes in patients with therapy resistant benign recurrent intrahepatic cholestasis: A case report.
Due to the rarity of benign recurrent intrahepatic cholestasis (BRIC), limited literature exists regarding the therapeutic benefit of plasmapheresis, particularly in the context of severe hyperbilirubinemia. A 25-year-old female presented with jaundice and severe pruritus. Laboratory findings revealed a total bilirubin of 37 mg/dL and a direct bilirubin of 27 mg/dL. Alanine aminotransferase (ALT) was 31 U/L, aspartate aminotransferase (AST) was 35 U/L, and alkaline phosphatase was 175 U/L. The patient had a five-year history of recurrent episodes, previously resolving spontaneously or with medical treatment. Following liver biopsy diagnosis and failure of conventional therapy, she underwent plasmapheresis on alternate days. Four sessions of one plasma volume exchange, using albumin, were performed concurrently with medical treatment. The patient demonstrated rapid and significant improvement in pruritus and urine color, with no adverse events or need for fresh frozen plasma. Total bilirubin decreased progressively to 5 mg/dL, and direct bilirubin to 4 mg/dL. Plasmapheresis appears to be a beneficial adjunct therapy for refractory BRIC, effectively reducing bilirubin levels and alleviating pruritus. This intervention may improve patient quality of life and potentially prevent renal complications associated with hyperbilirubinemia, serving as a bridge to liver transplantation, if necessary.
2025-03-03 | Early plasmapheresis in type 2 benign recurrent intrahepatic cholestasis: A case report and review of literature.
Benign recurrent intrahepatic cholestasis (BRIC) is a rare autosomal recessive liver disease, causing episodic cholestasis with intense pruritus. This case report highlights the effectiveness of early plasmapheresis as a therapeutic option for BRIC type 2, offering rapid symptom relief and early termination of cholestatic episodes. It contributes to the limited evidence supporting plasmapheresis as a treatment for BRIC flares resistant to conventional therapies. A 43-year-old male with BRIC type 2 presented with fatigue, jaundice, and severe pruritus, triggered by a recent mild severe acute respiratory syndrome coronavirus 2 infection. Laboratory results confirmed cholestasis with elevated bilirubin and alkaline phosphatase. First-line pharmacological treatments, including cholestyramine and rifampicin, failed. Endoscopic nasobiliary drainage was ineffective, prompting initiation of plasmapheresis. This intervention rapidly relieved pruritus, with complete biochemical normalisation after 11 sessions. Two years later, a similar episode occurred, and early reinitiation of plasmapheresis led to symptom resolution within two sessions and biochemical recovery within two weeks. The patient tolerated the procedure well, with no adverse effects observed. Follow-up showed no signs of cholestasis recurrence. Plasmapheresis is a safe and effective option for therapy-refractory BRIC type 2, particularly when initiated early in cholestasis.
2013-10-28 | Treatment of pruritus with Prometheus dialysis and absorption system in a patient with benign recurrent intrahepatic cholestasis.
Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disorder characterized by recurrent episodes of jaundice and itching. Episodes of cholestasis last variously from 1 week to several months, may start at any age and usually resolve spontaneously. No effective treatment has been found as yet. We report a case of genetically proven BRIC in a male patient who developed three episodes of pruritus and jaundice at the age of 14, 16 and 19 years. During the third episode, he did not respond to pharmacological medical therapy, and fractionated plasma separation and absorption (FPSA, Prometheus) was performed to manage intractable pruritus. The treatment immediately alleviated pruritus, lowered serum bilirubin concentration and induced sustained remission in the 5-year follow up. FPSA seems to be a safe and effective way of treatment for BRIC in patients with severe pruritus and prolonged jaundice.
1989-11-07 | Benign recurrent intrahepatic cholestasis. A report of 26 cases.
Benign recurrent intrahepatic cholestasis is characterized by attacks of cholestasis. The purpose of our study of 26 patients was to emphasize some features uncommonly or never reported in this disease: (a) in each patient, the attacks of cholestasis were stereotypic; (b) attacks of cholestasis were not associated with pruritus in 15% of our patients; (c) the occurrence of attacks of cholestasis during pregnancy or oral contraceptive use might be a fortuitous coincidence; (d) gallstones were found in several patients with benign recurrent intrahepatic cholestasis and might be present earlier than in the general population; (e) in some of our patients, during attacks of cholestasis, serum transaminases were very high, exceeding 15 times the upper limit of normal; (f) mild portal inflammatory infiltration was found in one third of our patients; (g) no treatment shortened the duration of cholestasis, and in a few patients, plasmapheresis seemed to diminish jaundice and improve biochemical disorders.
gene therapies
2025-09-29 | iPSC-based hepatic organoids reveal a heterozygous MYO5B variant as driver of intrahepatic cholestasis.
Hereditary intrahepatic cholestasis is caused by variants of various genes involved in enterohepatic bile circulation, metabolization, and conjugation. Originally classified into 3 groups, the number of contributing genes is still increasing, underlining the need for a deeper understanding of the molecular interaction during intrahepatic cholestasis. In the present study, we investigate the interplay of heterozygous variants in 3 cholestasis-associated genes (ABCB11, ABCB4, and MYO5B) by exploiting iPSC-based hepatic organoids from a patient suffering from recurrent intrahepatic cholestasis. Functional characterization of MRP2-mediated cholyl-lysyl-fluorescein (CLF) and BSEP-mediated Tauro-nor-THCA-24-DBD transport demonstrated a marked reduction of transport in MYO5B-deficient organoids, in comparison to unaffected control organoids. Moreover, iPSC-based organoids derived from the patient carrying 3 heterozygous variants in ABCB11, ABCB4, and MYO5B also exhibited absence of BSEP-mediated Tauro-nor-THCA-24-DBD transport, but functional MRP2-mediated CLF-transport. Interestingly, CRISPR/Cas9-mediated correction of the mutated ABCB11 allele could not restore the impaired BSEP function, suggesting the heterozygous MYO5B variant as the main driver of the transport deficiency. In fact, CRISPR/Cas-mediated correction of the MYO5B variant finally resulted in a restoration of the BSEP-mediated Tauro-nor-THCA-24-DBD transport. iPSC-based organoids serve as an authentic model for functional assessment of the hepatobiliary transport with fluorescent substrates. This allows the characterization of variants of uncertain significance and other variants in cholestasis-associated genes and revealed that a heterozygous MYO5B variant increases the susceptibility to defective hepatobiliary BSEP-mediated transport.
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