RARE DISEASE
Benign recurrent intrahepatic cholestasis type 2
Benign recurrent intrahepatic cholestasis type 2
Benign recurrent intrahepatic cholestasis type 2
Synonyms: BRIC type 2, BRIC2
Synonyms: BRIC type 2, BRIC2
Synonyms: BRIC type 2, BRIC2
Drug discovery
38
papers
On emerging therapies
Overview
Benign Recurrent Intrahepatic Cholestasis Type 2 (BRIC2) is an autosomal recessive disorder caused by ABCB11 mutations, impairing bile salt export pump function. It manifests as recurrent episodes of pruritus, jaundice, and cholestasis with normal/low gamma-glutamyl transferase (GGT) levels. Attacks resolve spontaneously without chronic liver damage, though rare progression to PFIC2 or cirrhosis occurs. Diagnosis requires genetic testing, exclusion of other cholestatic disorders, and liver biopsy showing centrilobular cholestasis. Management focuses on symptom relief and preventing triggers [1][3][7][14].
Burden
Recurrent episodes (weeks–months) cause debilitating pruritus, fatigue, and hospitalization, impairing quality of life.
Risk of progression to PFIC2/cirrhosis (~10% cases) and hepatobiliary malignancy (15% lifetime risk) [4][6][7].
Triggers (e.g., infections, stress) and psychosocial impacts necessitate long-term monitoring and multidisciplinary care [3][11][18].
Therapies
Symptom control: Rifampicin (induces bile acid detoxification), cholestyramine (bile acid sequestration), ursodeoxycholic acid (improves bile flow).
Severe cases: Plasmapheresis, MARS therapy, or endoscopic nasobiliary drainage [1][4][8][12].
Refractory disease: Partial biliary diversion; liver transplantation rare but considered in progressive cases [1][3][16].
Categories: rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare transplant-related disorders
Research Papers
38 drug discovery papers about Benign recurrent intrahepatic cholestasis type 2, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
38 drug discovery papers about Benign recurrent intrahepatic cholestasis type 2, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-06-14 | An ABCB11 variant registry and novel knockin mouse model of PFIC2 based on the clinically relevant ABCB11 E297G variant.
Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare pediatric cholestatic liver disease caused by genetic deficiency in the bile salt export pump (BSEP, ABCB11). BSEP is an ATP-binding cassette transporter and the primary regulator of hepatic bile acid efflux. Loss of BSEP function in PFIC2 leads to cholestasis and intrahepatic accumulation of bile acids, the native toxicity of which drives progressive liver injury, in a manner that correlates with ABCB11 genotype. Here, to support ongoing PFIC2 research, we present two novel translational tools, 1) a codified evidence-based catalog of published disease relevant ABCB11 mutations and 2) a knockin mouse model of the PFIC2-associated missense variant E297G. Using a combination of AI-based indexing of the literature and manual review, we identified 476 nonbenign ABCB11 variants in published patients with cholestatic disease, of which 240 were associated with PFIC2. Additionally, we present phenotypic validation of a novel knockin mouse model of the cholestasis-associated ABCB11 E297G variant. BsepE297G homozygous mice recapitulate the core molecular and pathophysiological aspects of PFIC2, including perturbed Bsep processing and membrane trafficking, cholestasis, and hepatotoxicity. Moreover, and consistent with clinical data, pharmacological ileal bile acid transporter inhibition improved the cholestatic phenotype of BsepE297G mice through increased fecal bile acid excretion. Together, these tools can support clinical and translational efforts to advance understanding and treatment of PFIC2.
2025-06-13 | Correction of a Traffic-Defective Missense ABCB11 Variant Responsible for Progressive Familial Intrahepatic Cholestasis Type 2.
Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a severe hepatocellular cholestasis due to biallelic variations in the ABCB11 (ATP-binding cassette B11) gene encoding the canalicular bile salt export pump (BSEP). Some missense variants identified in patients with PFIC2 do not traffic properly to the canalicular membrane. However, 4-phenybutyrate (4-PB) has been shown in vitro to partially correct the mis-trafficking of selected variants, resulting in an improvement of the medical conditions of corresponding PFIC2 patients. Herein, we report the ability of 4-PB analogous or homologous drugs and of non-4-PB related chemical correctors to rescue the canalicular expression and the activity of the folding-defective Abcb11R1128C variant. New compounds, either identified by screening a chemical library or designed by structural homology with 4-PB (or its metabolites) and synthesized, were evaluated in vitro for their ability to (i) correct the canalicular localization of Abcb11R1128C after transfection in hepatocellular polarized cell lines; (ii) restore the 3H-taurocholate transport of the Abcb11R1128C protein in Madin-Darby canine kidney (MDCK) cells stably co-expressing Abcb11 and the sodium taurocholate co-transporting polypeptide (Ntcp/Slc10A1). Glycerol phenylbutyrate (GPB), phenylacetate (PA, the active metabolite of 4-PB), 3-hydroxy-2-methyl-4-phenylbutyrate (HMPB, a 4-PB metabolite analog chemically synthesized in our laboratory) and 4-oxo-1,2,3,4-tetrahydro-naphthalene-carboxylate (OTNC, from the chemical library screening) significantly increased the proportion of canalicular Abcb11R1128C protein. GPB, PA, ursodeoxycholic acid (UDCA), alone or in combination with 4-PB, suberoylanilide hydroxamic acid (SAHA), C18, VX-445, and/or VX-661, significantly corrected both the traffic and the activity of Abcb11R1128C. Such correctors could represent new pharmacological insights for improving the condition of patients with ABCB11 deficiency due to missense variations affecting the transporter's traffic.
2025-02-24 | Hepatoprotective Effects of Cilnidipine in Cholestatic Liver Disease: Role of FXR and NRF2 Signalling.
Bile acid (BA) is a type of cholesterol derivative that has long been established for its crucial role in the breakdown and absorption of fat from food. Cholestasis occurs when the liver fails to transfer BAs to the intestines. Chronic cholestatic diseases can lead to liver cirrhosis. Ursodeoxycholic acid (UDCA) treatment is ineffective for certain cholestatic diseases like benign recurrent intrahepatic cholestasis (BRIC), despite increasing the hydrophilic bile acid pool. Moreover, studies indicate that UDCA and other bile acids affect liver cell functions, such as biotransformation through CYP enzymes. In hepatitis B virus transgenic mice, a UDCA-rich diet promoted hepatocyte proliferation and tumor growth. Hepatologists advise against using UDCA in patients with severe obstructive cholangiopathies. Given the foregoing, new medications are required to treat these illnesses. Twenty-four male Wistar albino rats were separated into three groups (8 rats for each group): negative control group I, positive control group II (ANIT-induced cholestasis), and treatment group III (Cil and ANIT). The mRNA and protein expression levels of FXR, small heterodimer partner (SHP), bile salt export pump (BSEP), nuclear factor erythroid 2-related factor 2 (NRF2), hepatocyte nuclear factor 1α (HNF1α), sirtuin 1 (SIRT1), NADPH dehydrogenase-quinone-1 (NQO-1), and heme oxygenase-1 (HO-1) were assessed post euthanasia. Additionally, other tissue oxidative stress markers were measured. Cil significantly increased the mRNA expression levels of FXR, SHP, BSEP, HNF1α, and NRF2 and the protein expression levels of FXR, BSEP, SIRT1, NQO-1, and HO-1 in the treatment group compared with those in the positive control group. Additionally, Cil decreased the oxidative stress level compared with that in the ANIT-treated group. The results suggest that Cil effectively treats cholestasis by affecting the FXR signaling system and the NRF2 pathway.
2023-12-28 | Benign recurrent intrahepatic cholestasis – case series and literature review
Benign recurrent intrahepatic cholestasis (BRIC) is a rare form of intrahepatic cholestasis seen in patients with genetic predispositions. It is a rare disease of unknown prevalence and is transmitted as an autosomal recessive pattern of inheritance. The available literature for BRIC is limited. It is hard to formulate the true prevalence of the disorder. Often precipitated by a trigger like viral infections and drugs, this condition results in a self-limiting episode of cholestasis. We present a case series of three patients with the clinical picture of BRIC. All three cases were fully evaluated for the cause of cholestasis and thereafter treated with ursodeoxycholic acid and rifampicin, which showed complete recovery.
2023-09-28 | Clinicopathologic Features, Genetics, Treatment, and Long-Term Outcomes in Japanese Children and Young Adults with Benign Recurrent Intrahepatic Cholestasis: A Multicenter Study.
Few reports of benign recurrent intrahepatic cholestasis (BRIC) have focused on East Asian patients. We describe the clinicopathologic features, genetics, treatment, and outcomes in Japanese BRIC patients. We recruited patients with BRIC type 1 (BRIC-1) or 2 (BRIC-2) treated at four pediatric centers and one adult center between April 2007 and March 2022. Demographics, clinical course, laboratory results, molecular genetic findings concerning ATP8B1 and ABCB11 genes, histopathology, and treatment response were examined retrospectively. Seven Japanese patients with BRIC were enrolled (four male, three female; four BRIC-1 and three BRIC-2). The median age at onset for BRIC-1 was 12 years; for BRIC-2, it was 1 month. Intermittent cholestatic attacks numbered from one to eight during the 11 years of median follow-up. Six patients received a mainstream education; only one patient attended special education. None developed cirrhosis. Three with BRIC-1 showed compound heterozygosity for a variant ATP8B1 gene, while one was heterozygous; two BRIC-2 patients showed compound heterozygosity in ABCB11 and one was heterozygous. Liver biopsy specimens obtained during cholestatic attacks showed fibrosis varying from none to moderate; inflammation was absent or mild. Rifampicin administered to three patients for cholestatic attacks was effective in all, as was cholestyramine in two of three. To our knowledge, this is the first East Asian multicenter study of BRIC patients. Onset age and number of cholestatic attacks varied. Rifampicin and cholestyramine were effective against attacks. No patient developed cirrhosis; most had normal growth and development. The long-term outcomes were satisfactory.
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
2025-06-14 | An ABCB11 variant registry and novel knockin mouse model of PFIC2 based on the clinically relevant ABCB11 E297G variant.
Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare pediatric cholestatic liver disease caused by genetic deficiency in the bile salt export pump (BSEP, ABCB11). BSEP is an ATP-binding cassette transporter and the primary regulator of hepatic bile acid efflux. Loss of BSEP function in PFIC2 leads to cholestasis and intrahepatic accumulation of bile acids, the native toxicity of which drives progressive liver injury, in a manner that correlates with ABCB11 genotype. Here, to support ongoing PFIC2 research, we present two novel translational tools, 1) a codified evidence-based catalog of published disease relevant ABCB11 mutations and 2) a knockin mouse model of the PFIC2-associated missense variant E297G. Using a combination of AI-based indexing of the literature and manual review, we identified 476 nonbenign ABCB11 variants in published patients with cholestatic disease, of which 240 were associated with PFIC2. Additionally, we present phenotypic validation of a novel knockin mouse model of the cholestasis-associated ABCB11 E297G variant. BsepE297G homozygous mice recapitulate the core molecular and pathophysiological aspects of PFIC2, including perturbed Bsep processing and membrane trafficking, cholestasis, and hepatotoxicity. Moreover, and consistent with clinical data, pharmacological ileal bile acid transporter inhibition improved the cholestatic phenotype of BsepE297G mice through increased fecal bile acid excretion. Together, these tools can support clinical and translational efforts to advance understanding and treatment of PFIC2.
2025-06-13 | Correction of a Traffic-Defective Missense ABCB11 Variant Responsible for Progressive Familial Intrahepatic Cholestasis Type 2.
Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a severe hepatocellular cholestasis due to biallelic variations in the ABCB11 (ATP-binding cassette B11) gene encoding the canalicular bile salt export pump (BSEP). Some missense variants identified in patients with PFIC2 do not traffic properly to the canalicular membrane. However, 4-phenybutyrate (4-PB) has been shown in vitro to partially correct the mis-trafficking of selected variants, resulting in an improvement of the medical conditions of corresponding PFIC2 patients. Herein, we report the ability of 4-PB analogous or homologous drugs and of non-4-PB related chemical correctors to rescue the canalicular expression and the activity of the folding-defective Abcb11R1128C variant. New compounds, either identified by screening a chemical library or designed by structural homology with 4-PB (or its metabolites) and synthesized, were evaluated in vitro for their ability to (i) correct the canalicular localization of Abcb11R1128C after transfection in hepatocellular polarized cell lines; (ii) restore the 3H-taurocholate transport of the Abcb11R1128C protein in Madin-Darby canine kidney (MDCK) cells stably co-expressing Abcb11 and the sodium taurocholate co-transporting polypeptide (Ntcp/Slc10A1). Glycerol phenylbutyrate (GPB), phenylacetate (PA, the active metabolite of 4-PB), 3-hydroxy-2-methyl-4-phenylbutyrate (HMPB, a 4-PB metabolite analog chemically synthesized in our laboratory) and 4-oxo-1,2,3,4-tetrahydro-naphthalene-carboxylate (OTNC, from the chemical library screening) significantly increased the proportion of canalicular Abcb11R1128C protein. GPB, PA, ursodeoxycholic acid (UDCA), alone or in combination with 4-PB, suberoylanilide hydroxamic acid (SAHA), C18, VX-445, and/or VX-661, significantly corrected both the traffic and the activity of Abcb11R1128C. Such correctors could represent new pharmacological insights for improving the condition of patients with ABCB11 deficiency due to missense variations affecting the transporter's traffic.
2025-02-24 | Hepatoprotective Effects of Cilnidipine in Cholestatic Liver Disease: Role of FXR and NRF2 Signalling.
Bile acid (BA) is a type of cholesterol derivative that has long been established for its crucial role in the breakdown and absorption of fat from food. Cholestasis occurs when the liver fails to transfer BAs to the intestines. Chronic cholestatic diseases can lead to liver cirrhosis. Ursodeoxycholic acid (UDCA) treatment is ineffective for certain cholestatic diseases like benign recurrent intrahepatic cholestasis (BRIC), despite increasing the hydrophilic bile acid pool. Moreover, studies indicate that UDCA and other bile acids affect liver cell functions, such as biotransformation through CYP enzymes. In hepatitis B virus transgenic mice, a UDCA-rich diet promoted hepatocyte proliferation and tumor growth. Hepatologists advise against using UDCA in patients with severe obstructive cholangiopathies. Given the foregoing, new medications are required to treat these illnesses. Twenty-four male Wistar albino rats were separated into three groups (8 rats for each group): negative control group I, positive control group II (ANIT-induced cholestasis), and treatment group III (Cil and ANIT). The mRNA and protein expression levels of FXR, small heterodimer partner (SHP), bile salt export pump (BSEP), nuclear factor erythroid 2-related factor 2 (NRF2), hepatocyte nuclear factor 1α (HNF1α), sirtuin 1 (SIRT1), NADPH dehydrogenase-quinone-1 (NQO-1), and heme oxygenase-1 (HO-1) were assessed post euthanasia. Additionally, other tissue oxidative stress markers were measured. Cil significantly increased the mRNA expression levels of FXR, SHP, BSEP, HNF1α, and NRF2 and the protein expression levels of FXR, BSEP, SIRT1, NQO-1, and HO-1 in the treatment group compared with those in the positive control group. Additionally, Cil decreased the oxidative stress level compared with that in the ANIT-treated group. The results suggest that Cil effectively treats cholestasis by affecting the FXR signaling system and the NRF2 pathway.
2023-12-28 | Benign recurrent intrahepatic cholestasis – case series and literature review
Benign recurrent intrahepatic cholestasis (BRIC) is a rare form of intrahepatic cholestasis seen in patients with genetic predispositions. It is a rare disease of unknown prevalence and is transmitted as an autosomal recessive pattern of inheritance. The available literature for BRIC is limited. It is hard to formulate the true prevalence of the disorder. Often precipitated by a trigger like viral infections and drugs, this condition results in a self-limiting episode of cholestasis. We present a case series of three patients with the clinical picture of BRIC. All three cases were fully evaluated for the cause of cholestasis and thereafter treated with ursodeoxycholic acid and rifampicin, which showed complete recovery.
2023-09-28 | Clinicopathologic Features, Genetics, Treatment, and Long-Term Outcomes in Japanese Children and Young Adults with Benign Recurrent Intrahepatic Cholestasis: A Multicenter Study.
Few reports of benign recurrent intrahepatic cholestasis (BRIC) have focused on East Asian patients. We describe the clinicopathologic features, genetics, treatment, and outcomes in Japanese BRIC patients. We recruited patients with BRIC type 1 (BRIC-1) or 2 (BRIC-2) treated at four pediatric centers and one adult center between April 2007 and March 2022. Demographics, clinical course, laboratory results, molecular genetic findings concerning ATP8B1 and ABCB11 genes, histopathology, and treatment response were examined retrospectively. Seven Japanese patients with BRIC were enrolled (four male, three female; four BRIC-1 and three BRIC-2). The median age at onset for BRIC-1 was 12 years; for BRIC-2, it was 1 month. Intermittent cholestatic attacks numbered from one to eight during the 11 years of median follow-up. Six patients received a mainstream education; only one patient attended special education. None developed cirrhosis. Three with BRIC-1 showed compound heterozygosity for a variant ATP8B1 gene, while one was heterozygous; two BRIC-2 patients showed compound heterozygosity in ABCB11 and one was heterozygous. Liver biopsy specimens obtained during cholestatic attacks showed fibrosis varying from none to moderate; inflammation was absent or mild. Rifampicin administered to three patients for cholestatic attacks was effective in all, as was cholestyramine in two of three. To our knowledge, this is the first East Asian multicenter study of BRIC patients. Onset age and number of cholestatic attacks varied. Rifampicin and cholestyramine were effective against attacks. No patient developed cirrhosis; most had normal growth and development. The long-term outcomes were satisfactory.
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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