ATP-binding cassette transporter defects and their roles in hepatic diseases

ATP-binding cassette (ABC) transporters are transmembrane proteins essential for the biliary secretion of bilirubin, bile acids, phospholipids, and cholesterol. Mutations in genes encoding these transporters—including ABCB11 (BSEP), ABCB4 (MDR3), *ABCG5/8* (sterolin-1/2), and ABCC2 (MRP2)—lead to a spectrum of hepatobiliary disorders, ranging from benign conditions like Dubin-Johnson syndrome to severe progressive diseases such as progressive familial intrahepatic cholestasis (PFIC). Disease severity is influenced by zygosity, mutation type, and environmental modifiers. Next-generation genetic testing plays a crucial diagnostic and prognostic role, and understanding specific mutations opens avenues for targeted therapies. This review provides an updated overview of ABC transporter-related liver diseases, their genetic and phenotypic variability, diagnostic approaches, and treatment options.

Introduction
ABC transporters, classified into families ABCA–ABCG, utilize ATP hydrolysis to transport substrates across cellular membranes. In the liver, they are critical for biliary excretion. Mutations in ABCB11 (encoding BSEP) and ABCB4 (encoding MDR3) disrupt bile acid and phospholipid transport, leading to cholestatic syndromes. Similarly, defects in *ABCG5/8* impair sterol excretion, causing sitosterolemia, while ABCC2 mutations result in Dubin-Johnson syndrome. The clinical presentation varies widely based on genetic dosage (homozygous vs. heterozygous) and environmental factors, necessitating a nuanced understanding of genotype-phenotype correlations.

Specific Diseases Caused by ABCB11 Mutations
ABCB11 mutations lead to a cholestatic spectrum including intrahepatic cholestasis of pregnancy (ICP), benign recurrent intrahepatic cholestasis type 2 (BRIC2), and PFIC type 2.

• ICP: Presents with pruritus in the second trimester, elevated serum bile acids (>10 µmol/L), and increased fetal risks (preterm delivery, distress). Ursodeoxycholic acid (UDCA) is the primary treatment, improving symptoms and biochemical parameters.

• BRIC2: Characterized by recurrent, self-limiting episodes of jaundice and pruritus. Management includes UDCA, rifampicin, and, in refractory cases, biliary drainage or ileal bile acid transport inhibitors.

• PFIC2: Severe, early-onset cholestasis with low GGT, progressing rapidly to cirrhosis and hepatocellular carcinoma. Treatment involves UDCA, partial biliary diversion, or liver transplantation.

Specific Diseases Caused by ABCB4 Mutations
ABCB4 defects result in decreased biliary phospholipids, leading to ICP, low phospholipid-associated cholestasis (LPAC), and PFIC type 3.

• LPAC: Manifests as recurrent biliary symptoms before age 40, often with intrahepatic sludge or microlithiasis. UDCA is effective in preventing stone recurrence.

• PFIC3: Presents with high GGT cholestasis, progressing to cirrhosis in childhood or adulthood. UDCA is first-line therapy; rifampicin or FXR agonists may be considered.

Specific Diseases Caused by *ABCG5/8* Defects: Sitosterolemia
Loss-of-function mutations in *ABCG5/8* impair biliary cholesterol excretion, leading to accumulation of plant sterols. Sitosterolemia presents with xanthomas, premature atherosclerosis, and hematologic abnormalities. Diagnosis is confirmed by elevated plasma sitosterol and genetic testing. Treatment involves dietary restriction of plant sterols and pharmacotherapy with ezetimibe or bile acid sequestrants.

Specific Diseases Caused by ABCC2 Defects: Dubin-Johnson Syndrome
Autosomal recessive mutations in ABCC2 cause conjugated hyperbilirubinemia without pruritus or liver injury. The condition is benign but requires caution with drugs excreted via MRP2. No specific treatment is needed.

Discussion
The phenotypic expression of ABC transporter diseases is modulated by zygosity, mutation type (missense vs. truncating), and environmental triggers such as hormones (e.g., estrogen in ICP) and medications. Genetic testing—via targeted panels, next-generation sequencing, or whole-exome sequencing—is essential for diagnosis, especially in cases of unexplained cholestasis. Consanguinity and founder effects increase the prevalence of homozygous mutations in isolated populations. Genetic counseling is recommended for family planning and risk assessment.

Clinical Implications and Future Directions
Recognition of ABC transporter defects is critical for tailored management. UDCA remains a cornerstone for many cholestatic disorders, while surgical or transplant options are reserved for advanced disease. Emerging therapies include FXR agonists, PPAR ligands, and gene-editing approaches (e.g., AAV-mediated gene therapy) that show promise in preclinical models. Patient-derived iPSC models enable variant-specific drug testing. Future research should focus on translating these therapies into clinical practice and expanding genetic screening in diverse populations.

Conclusion
ABC transporter mutations underlie a heterogeneous group of cholestatic liver diseases, with severity strongly linked to genetic dosage and environmental factors. Advances in genetic diagnostics have improved identification and prognostication. While conventional treatments provide symptomatic relief, novel targeted and gene-based therapies offer hope for curative interventions. A multidisciplinary approach integrating genetics, hepatology, and counseling is essential for optimal patient care.

Full text

https://www.xiahepublishing.com/2310-8819/JCTH-2025-00476

The study was recently published in the Journal of Clinical and Translational Hepatology.

The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.

Follow us on X: @xiahepublishing

Follow us on LinkedIn: Xia & He Publishing Inc.