Genotype-phenotype relationships in the low-phospholipid-associated cholelithiasis syndrome: A study of 156 consecutive patients

Abstract

The low-phospholipid-associated cholelithiasis syndrome (LPAC; OMIM 171060) is a peculiar form of intrahepatic cholelithiasis occurring in young adults, associated with ABCB4/MDR3 gene sequence variations. Our aim was to determine the genotype-phenotype relationships in 156 consecutive patients with the criteria of LPAC syndrome. A variant was detected in 79 (61 missense and 18 truncating sequence variants), 63 being monoallelic. The clinical features (age at onset, high prevalence in women, frequency and severity of acute and chronic complications, intrahepatic cholestasis of pregnancy [ICP]) were similar in the patients with or without ABCB4 gene sequence variation. Truncating variations were associated with an earlier onset of symptoms both in women and men. Acute and chronic biliary complications were variant-independent. Half of the women who had pregnancy developed ICP. The frequency of ICP and fetal complications were similar in patients with missense and truncating variants. Conclusion: The LPAC syndrome is more frequent in women and highly associated with ICP. Half of the patients harbored missense or truncating variants of the ABCB4 gene. The characteristics of the patients without detectable variant are similar to those with variant, indicating that yet unexplored regions of the ABCB4 and other genes may be involved.

Pregnancy and ABCB4 gene mutation: risk of recurrent cholelithiasis

“…The degree (and types) of symptoms depends on the location of the mutation and whether the mutation is heterozygous or homozygous 11. The mutation detected in our patient has been described in a previous study of 156 patients 3. Most patients in this series had heterogenous missense mutations.…”

“…Pregnancy and ATP-binding cassette B4 (ABCB4) gene mutations are associated with gallstone disease at young ages 3 4…”

A Complex Case of Cholestasis in a Patient with ABCB4 and ABCB11 Mutations

“…Although LPAC syndrome was originally described in association with ABCB4 mutations, in a study with 156 patients who fulfilled the diagnostic criteria, a genetic Abdominal ultrasound identified two foci of hepatolithiasis in segment II, the largest measuring 11 mm (arrow), with upstream dilation of the left intrahepatic ducts variant was only found in half of the patients; clinical features were similar in the groups with and without these variants, suggesting that unexplored regions of the ABCB4 gene or different genes could be involved [6].…”

“…The recommended medical therapy is ursodeoxycholic acid (UDCA) [5]. In the rare cases progressing to end-stage liver disease [2,6], a liver transplant may be indicated.…”

Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades

“…Such mice (and patients) lack this ATP-activated PC extruder in the canaliculus of the hepatocyte and are believed to have essentially no phospholipid in ductular bile. The micellar bile acids, if suffi ciently hydrophobic, attack the membranes of the cholangiocytes, leading to ductal infl ammation in mice ( 362 ) and to a variety of biliary problems in patients ( 363 ). Nonetheless, the bile of many vertebrate species has an extremely low ratio of phospholipids to bile acids ( 181 ) without any sign of biliary ductule injury.…”