ABCB4 – Low Phospholipid-Associated Cholelithiasis

Low phospholipid-associated cholelithiasis (LPAC) is a rare gallstone disorder characterized by early-onset (<40 years) recurrent cholelithiasis, intrahepatic microlithiasis, biliary sludge and a high cholesterol/phospholipid ratio in bile (PMID:35741809). Heterozygous variants in ABCB4 (HGNC:45), encoding the canalicular phosphatidylcholine floppase MDR3, underlie LPAC by reducing biliary phosphatidylcholine secretion and promoting cholesterol crystal precipitation.

LPAC follows an autosomal dominant inheritance pattern with variable penetrance. Familial segregation of ABCB4 variants has been documented, including two siblings with compound heterozygous mutations who developed LPAC and PFIC3 features before age 30 (PMID:19840255). A case report described a young woman with LPAC carrying a heterozygous c.56_58del (p.Gly19del) variant and a similarly affected sister (PMID:36324844).

Population screening of 60 female patients under 30 with symptomatic cholelithiasis identified LPAC in 14 (23%), with four cases harboring ABCB4 variants, confirming its frequent contribution to early gallstone disease (PMID:23684896). To date, over 158 distinct ABCB4 mutations and variants have been reported in LPAC patients, spanning missense, frameshift, splice‐site and large deletions, highlighting allelic heterogeneity (PMID:35741809).

Missense variants predominate, with recurrent alleles such as c.959C>T (p.Ser320Phe) and c.493T>A (p.Phe165Ile) reported in multiple unrelated probands. Loss-of-function alleles including frameshifts and nonsense mutations have also been described, and whole-gene deletions account for 7% of LPAC cases in mutation-negative patients screened by dosage analysis (PMID:21989363). No clear population-specific founder variants have been established.

Functional assays demonstrate that the p.Ser320Phe mutation reduces MDR3 transporter activity by ~50%, impairs cell-surface expression and lowers phosphatidylcholine transport in membrane vesicle assays (PMID:24381502). ABCB4 knockout mice recapitulate LPAC features, exhibiting biliary supersaturation with cholesterol and “anhydrous” crystal formation in bile (PMID:35741809). Rescue experiments show that pharmacological chaperones can restore maturation and function of select trafficking-defective mutants.

Collectively, strong genetic and experimental evidence support haploinsufficiency as the mechanism of ABCB4-related LPAC. While additional studies of large cohorts and genotype–phenotype correlations are ongoing, current data justify genetic testing in young patients with unexplained recurrent cholelithiasis. Key Take-home: Heterozygous ABCB4 mutations cause LPAC through reduced canalicular phosphatidylcholine secretion, and functional assays reliably predict pathogenicity, guiding diagnosis and potential targeted therapies.

References

• Liver international • 2010 • Combined features of low phospholipid-associated cholelithiasis and progressive familial intrahepatic cholestasis 3. PMID:19840255
• Digestive and liver disease • 2013 • Prevalence of low phospholipid-associated cholelithiasis in young female patients. PMID:23684896
• Radiology case reports • 2023 • Low phospholipids associated cholelithiasis syndrome in a young women: A rare case report. PMID:36324844
• Genes • 2022 • Genetic Analysis of ABCB4 Mutations and Variants Related to the Pathogenesis and Pathophysiology of Low Phospholipid-Associated Cholelithiasis. PMID:35741809
• The Korean journal of physiology & pharmacology • 2013 • Functional Characterization of ABCB4 Mutations Found in Low Phospholipid-Associated Cholelithiasis (LPAC). PMID:24381502

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