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We thank Maringhini et al1Maringhini A. Gastroenterology. 2023; 164: 310-311Abstract Full Text Full Text PDF Scopus (1) Google Scholar for their support of the recommendations made in our article about liver disorders in pregnancy2Terrault N. Williamson C. Gastroenterology. 2022; 163: 97-117Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar and appreciate their concerns that biliary sludge and stones were not discussed. Indeed, we purposefully elected to focus our review only on liver conditions unique to pregnancy and omitted those for which pregnancy or postpartum is a risk factor but which occur in nonpregnant women, such as cholelithiasis and Budd-Chiari syndrome. However, as Maringhini et al highlight, cholelithiasis is quite common in pregnancy. A US study of 3254 women revealed either sludge or gallstones in 5% of women by the second trimester, 8% by the third trimester, and 10% by 4–6 weeks postpartum3Ko C.W. et al.Hepatology. 2005; 41: 359-365Crossref PubMed Scopus (167) Google Scholar; the prevalence in European women is similar.1Maringhini A. Gastroenterology. 2023; 164: 310-311Abstract Full Text Full Text PDF Scopus (1) Google Scholar Specific groups of pregnant women have an increased risk of cholelithiasis, including those with high body mass indices, elevated serum cholesterol, and higher parity.4Hess E.C.F. et al.Br J Hosp Med. 2021; 82: 1-8Crossref Scopus (2) Google Scholar Importantly, women with intrahepatic cholestasis of pregnancy (ICP) also have increased rates of gallstone disease during and subsequent to pregnancy.5Marschall H.U. et al.Hepatology. 2013; 58: 1385-1391Crossref PubMed Scopus (141) Google Scholar This is likely explained by shared genetic susceptibility to ICP and cholelithiasis; affected women more commonly have mutations in the ATP binding cassette subfamily B member 4 (ABCB4) gene and in the canalicular bile acid transporter ABCB11.6Turro E. et al.Nature. 2020; 583: 96-102Crossref PubMed Scopus (202) Google Scholar ABCB4 encodes the ABCB4 protein (also called multidrug resistance protein 3), a hepatic canalicular transport protein that translocates phospholipids into bile. In addition to ICP, genetic variation in ABCB4 can cause nonpregnancy-associated cholestasis and low phospholipid-associated cholelithiasis.7Stättermayer A.F. et al.J Hepatol. 2020; 73: 651-666Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar Genome-wide association studies demonstrated shared population susceptibility variants for ICP and gallstones in ABCB4 and several other genes, including a number involved in cholesterol uptake and metabolism (GAPDHS, ENPP7, SHROOM3) and bile acid metabolism (CYP7A1, SULT2A1)8Dixon P.H. et al.Nat Commun. 2022; 13: 4840Crossref PubMed Scopus (3) Google Scholar; such associations provide potential insights into the etiology of pregnancy-associated biliary sludge and stones in susceptible women. As Maringhini et al stated, cholelithiasis is associated with increased risk of morbidity, including subsequent gallstone pancreatitis and ascending cholangitis. We agree that hepatologists, gastroenterologists, and obstetricians need to be aware of the increased prevalence of cholelithiasis-associated adverse health outcomes during pregnancy and postpartum. Defining best practices in managing cholelithiasis during pregnancy is important. The potential protective benefit of breastfeeding was highlighted by Maringhini et al, and it would be of interest to investigate this further. Pharmacologic intervention also warrants consideration. As we highlighted in our review,2Terrault N. Williamson C. Gastroenterology. 2022; 163: 97-117Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar ursodeoxycholic acid (UDCA) has beneficial effects in treating ICP and has a good safety record in pregnancy and lactation. A meta-analysis of the use of UDCA after bariatric surgery, another group with increased risk of biliary sludge and stones, showed that UDCA treatment reduced gallstone formation, symptomatic gallstone disease, and cholecystectomy rate.9Mulliri A. et al.J Gastroenterol. 2022; 57: 529-539Crossref PubMed Scopus (2) Google Scholar Thus, UDCA may be a treatment to consider in pregnant women with gallstones and related biliary tract disorders. It is hoped that future work from Professor Maringhini’s team and others will illuminate the optimal interventions for this high-risk group of pregnant women. Bile and Liver in Pregnancy: No One Split Apart What God Has Joined TogetherGastroenterologyVol. 164Issue 2PreviewWe read the accurate and interesting review on liver diseases and pregnancy by Terrault and Williamson.1 The investigators highlight 5 liver disorders that are unique to pregnancy. In their introduction, they describe in detail non–pregnancy-specific liver diseases at their first presentation during pregnancy and acute liver insufficiency, which is coincidental but not specific to pregnancy, and finally discuss clinical conditions that are associated with physiologic changes that mimic liver disease. Full-Text PDF