Gallbladder Disease 1

A number sign (#) is used with this entry because low phospholipid-associated cholelithiasis (LPAC), referred to here as gallbladder disease-1 (GBD1), is caused by homozygous or heterozygous mutation in the ABCB4 gene (171060) on chromosome 7q21.

Description

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).

Clinical Features

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.

Inheritance

Nonspecific Gallstone Disease

Reports of familial gallstone disease (e.g., Antero Kesaniemi et al., 1989) and the high incidence of cholesterol gallstones in Native American populations (Weiss et al., 1984) point to genetic factors. Bile from healthy sisters of female gallstone patients has been reported to be more lithogenic than that from controls (Danzinger et al., 1972; Antero Kesaniemi et al., 1989).

Sarin et al. (1995) used ultrasonography to observe the prevalence of gallstone disease in first-degree relatives of patients with cholelithiasis. Three groups were studied: group A, 105 index gallstone patients (male:female, 20:85); group B, 330 first-degree relatives of index patients; and group C, 105 matched controls for group A and 330 for group B. In 39 of 105 (37%) index cases, 1 or more additional family members had gallstones. The index cases with affected relatives were younger than the remaining index cases. Of the 330 first-degree relatives, 51 (15.5%) had gallstones, nearly 4.5 times the frequency in the matched control population (3.6%). No difference was detected in the diet, physical activity, and serum lipid profile between the index patients with affected relatives and those without and between the positive relatives and their controls. Sarin et al. (1995) interpreted the results as an indication that there is a strong familial predisposition for gallstone formation.

Kosters et al. (2003) reviewed the genetic background of cholesterol gallstone disease. The primary pathogenic factor in the multifactorial process of cholesterol gallstone formation is hypersecretion of free cholesterol into bile. They concluded that genetic factors clearly play a role. Analysis of the many pathways involved in biliary cholesterol secretion revealed many potential candidates for identification of 'gallstone genes.'

In general, gallbladder disease is a complex multifactorial disorder influenced by both genetic and environmental factors. Information on family data suggested that genetic factors play a key role in the development of GBD. Using data from a large Swedish study of 43,141 twin pairs, Katsika et al. (2005) determined that genetic influences are major contributors to the variation in symptomatic gallstone disease. According to this study, genetic factors accounted for 25%, shared environmental factors for 13%, and unique environmental factors for 62% of the phenotypic variance among twins. In addition, varying prevalence on the basis of ethnicity has been considered to be indirect evidence of the genetic determination of GBD. Weiss et al. (1984) proposed that there may be a genetic susceptibility association among complex diseases such as GBD, diabetes, and obesity, which cluster to form a 'New World syndrome' in populations with Native American ancestry.

Gallbladder Disease 1/Low Phospholipid-Associated Cholelithiasis

In families with low phospholipid-associated cholelithiasis, Rosmorduc et al. (2001) found evidence for both autosomal dominant and autosomal recessive inheritance.

Molecular Genetics

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 (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).

Pathogenesis

Defects in the ABCB4 gene compromise the transporter's ability to move phosphatidylcholine across the canalicular membrane, where it normally would be available for extraction into the canalicular lumen by bile salts. This lack of phospholipid protection in the bile against the detergent effect of the bile salts results in damage to the biliary epithelium, bile ductular proliferation, and potential progressive portal fibrosis. A decreased rate of phospholipid excretion can also be a cause of gallstone formation (summary by Pasmant et al., 2012).

Animal Model

The prevalence of cholesterol gallstones differs among inbred strains of mice fed on a lithogenic diet containing 15% dairy fat, 1% cholesterol, and 0.5% cholic acid. Khanuja et al. (1995) carried out a genetic analysis of the difference in gallstone prevalence rates between a no cholelithiasis strain (AKR) and a high prevalence strain (C57L) by using the AKXL recombinant inbred strain set (AKR x C57L)F1 x AKR backcross mice. Susceptibility to gallstone formation was found to be a dominant trait determined by at least 2 genes: a major gene, named Lith1, mapped to mouse chromosome 2. When examined after 6 weeks on the lithogenic diet, the activity of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase (142910; EC 1.1.1.88) was downregulated as expected in the gallstone-resistance strains, AKR and SJL, but this enzyme failed to downregulate in C57L and SWR, the gallstone-susceptible strains. This suggested to Khanuja et al. (1995) that regulation of the rate-limiting enzyme in cholesterol biosynthesis may be pivotal in determining the occurrence and severity of cholesterol hypersecretion and hence lithogenicity of gallbladder bile. The studies indicated that genetic factors are critical in determining gallstone formation and that the mouse model may permit identification of those genetic factors.

Several mouse models identifying various 'Lith' (i.e., lithogenic) loci influencing gallstone formation were identified by Lammert et al. (2001), Lyons et al. (2003, 2005), and others.