In general, gallbladder disease (GBD) is one of the major digestive diseases. GBD prevalence is particularly high in some minority populations in the United States, including Native and Mexican Americans. Gallstones composed of cholesterol (cholelithiasis) are the common ... In general, gallbladder disease (GBD) is one of the major digestive diseases. GBD prevalence is particularly high in some minority populations in the United States, including Native and Mexican Americans. Gallstones composed of cholesterol (cholelithiasis) are the common manifestations of GBD in western countries, including the United States. Most people with gallstones remain asymptomatic through their lifetimes; however, it is estimated that approximately 10 to 50% of individuals eventually develop symptoms. Significant risk factors associated with GBD are age, female sex, obesity (especially central obesity), lipids, diet, parity, type 2 diabetes (125853), medications, and Mexican American ethnicity. GBD appears to be strongly related to the metabolic syndrome (605552) and/or its major components, such as hyperinsulinism, dyslipidemia, and abdominal adiposity (Boland et al., 2002; Tsai et al., 2004). Infection, specifically by Helicobacter, has been implicated in cholelithiasis and cholecystitis (Silva et al., 2003; Maurer et al., 2005). Low phospholipid-associated cholelithiasis is a specific form of gallbladder disease characterized by young-adult onset of chronic cholestasis with intrahepatic sludge and cholesterol cholelithiasis. Affected individuals have recurrence of the disorder after cholecystectomy and show a favorable response to treatment with ursodeoxycholic acid (UDCA) (summary by Pasmant et al., 2012). Mutation in the ABCB4 gene can cause a spectrum of related diseases, including the more severe progressive familial intrahepatic cholestasis-3 (PFIC3; 602347), intrahepatic cholestasis of pregnancy-3 (ICP3; 614972), andoral contraceptive-induced cholestasis (OCIC; see 614972). - Genetic Heterogeneity of Gallbladder Disease Two major susceptibility loci for symptomatic gallbladder disease have been identified on chromosome 1p in Mexican Americans (GBD2, 609918; GBD3, 609919). In addition, variations in the ABCG8 gene (605460) on chromosome 2p21 confer susceptibility to gallbladder disease (GBD4; 611465).
Rosmorduc et al. (2001) reported 6 adult patients with gallbladder disease. There were 4 women and 2 men, including a mother and son. Common features were adult onset of symptoms related to chronic cholestasis and biliary pain, including ... Rosmorduc et al. (2001) reported 6 adult patients with gallbladder disease. There were 4 women and 2 men, including a mother and son. Common features were adult onset of symptoms related to chronic cholestasis and biliary pain, including biliary colic, pancreatitis, or cholangitis, recurrence of symptoms after cholecystectomy, presence of echogenic material in the intrahepatic bile ducts, and prevention of recurrence with UDCA therapy. One of the women first developed symptoms during pregnancy, consistent with ICP3 (614972), and 1 developed symptoms after beginning oral contraception, consistent with OCIC (see 614972). Another woman developed biliary pain, cholesterol gallstones, and sludge in the gallbladder at age 28 years. UDCA treatment was effective. During her first pregnancy at age 32, UDCA was discontinued. During the 24th week of pregnancy, she developed cholestasis and biliary pain and delivered a premature stillborn fetus. After delivery, the cholestasis and symptoms persisted and she underwent cholecystectomy. However, her symptoms recurred and she had increased liver enzymes and multiple intrahepatic gallstones. Treatment with UDCA resulted in remission, and she had a normal subsequent pregnancy and delivery while on UDCA therapy. A 26-year-old man, born of the woman who developed symptoms during pregnancy, developed acute cholangitis associated with multiple intrahepatic and extrahepatic cholesterol gallstones at age 24. He became free of symptoms after cholecystectomy and treatment with UDCA. An unrelated woman underwent cholecystectomy at age 15 years for cholesterol cholelithiasis. She continued to have recurrent episodes of biliary pain and chronic cholestasis, and received relief with UDCA therapy. A 60-year-old man developed biliary pain with cholestasis at age 55 years and underwent cholecystectomy. Liver biopsy showed portal inflammation, extensive fibrosis, and ductular proliferation, which were thought to be secondary to chronic cholestasis. Hepatic bile composition in 2 patients showed a high cholesterol/phospholipid ratio and cholesterol crystals. Rosmorduc et al. (2003) identified both heterozygous and homozygous ABCB4 gene mutations in 18 (56%) of 32 patients who presented with clinical criteria specific to LPAC. Three independent clinical features were strongly associated with ABCB4 mutations: recurrence of symptoms after cholecystectomy (odds ratio (OR) of 8.5); intrahepatic hyperechoic foci, intrahepatic sludge, or microlithiasis (OR of 6.1); and age less than 40 years at the onset of symptoms (OR of 3.0). No ABCB4 mutations were detected in 2 other groups of patients with classic cholelithiasis. Ziol et al. (2008) identified 11 patients, including 2 relatives, with chronic anicteric cholestasis associated with ABCB4 mutations. Six of 11 patients had had biliary symptoms, but only 4 patients met the full criteria for LPAC. The remaining patients were studied because of elevated liver enzymes. One woman had ICP and 2 had oral contraceptive-induced cholestasis. Compared to patients with cholestasis without ABCB4 mutations, patients with mutations had increased hepatic fibrosis, increased ductular reaction, and increased portal infiltration by macrophages on liver biopsy. Mutation carriers also showed decreased immunostaining for ABCB4. Cirrhosis was not observed. Ziol et al. (2008) concluded that unexplained anicteric cholestasis should be added to the spectrum of manifestations associated with ABCB4 mutations. Pasmant et al. (2012) reported 2 large families with LPAC. In 1 family, the proband presented at age 24 years with intrahepatic cholelithiasis with biliary pain. Despite cholecystectomy, she had recurrence of biliary pain and increased liver enzymes. Treatment with UDCA resulted in complex symptom relief and normalization of liver enzymes. Two paternal relatives had similar symptoms, with a later onset around age 60 years. Liver biopsy in 1 showed carcinoma in situ and bile ductular proliferation. In the second family, the proband presented at age 30 years with cholelithiasis with biliary pain and showed recurrence after cholecystectomy. Her mother, maternal grandmother, and 2 maternal aunts had cholecystectomy before age 40 years.
Rosmorduc et al. (2001) identified 4 different mutations in the ABCB4 gene (171060.0005-171060.0008) in 6 symptomatic adult patients with LPAC. Mutations occurred in both the homozygous and compound heterozygous state. One of the female patients presented during pregnancy, ... Rosmorduc et al. (2001) identified 4 different mutations in the ABCB4 gene (171060.0005-171060.0008) in 6 symptomatic adult patients with LPAC. Mutations occurred in both the homozygous and compound heterozygous state. One of the female patients presented during pregnancy, consistent with intrahepatic cholestasis of pregnancy (ICP3; 614972), and another presented after taking oral contraceptives, consistent with oral contraceptive-induced cholestasis (OCIC; see 614972). Rosmorduc et al. (2003) identified 14 heterozygous or homozygous ABCB4 gene mutations in 18 (56%) of 32 patients who presented with clinical criteria specific to LPAC. Ziol et al. (2008) identified 8 different mutations in the ABCB4 gene (see, e.g., 171060.0012-171060.0013) in 11 (34%) of 32 patients with chronic unexplained anicteric cholestasis. Eight patients carried a heterozygous mutation, whereas 3 were compound heterozygous for 2 mutations. In 16 (37%) of 43 adult patients with low phospholipid-associated cholelithiasis, Pasmant et al. (2012) identified heterozygous mutations in the ABCB4 gene. Three (7%) of the 43 patients were found to carry partial or complete deletions affecting the ABCB4 gene. The patients had intrahepatic cholelithiasis despite cholecystectomy before age 40 years. The disorder was associated with cholecystitis, cholangitis, acute pancreatitis, and intrahepatic hyperechoic foci; patients showed a favorable response to UDCA therapy. - Associations Pending Confirmation Among a total of 240 patients with gallstones and 255 controls from Stuttgart and Aachen, Renner et al. (2009) found an association between gallstones and an A-to-G SNP (dbSNP rs9514089) in the SLC10A2 gene (601295) (p = 0.00767, odds ratio of 2.04) on chromosome 2p21. A more frequent occurrence was observed for male gallstone carriers (22%) compared to controls (9%) (p = 0.01017, OR of 2.99), for the total normal weight group (p = 0.00754, OR of 2.90), and for male nonobese gallstone patients (p = 0.01410, OR of 6.85). In addition, minor allele carriers of the SNP had lower plasma cholesterol levels, especially in gallstone carriers (p = 0.05).