The Chile Biliary Longitudinal Study: A Gallstone Cohort.

Gallbladder cancer (GBC) is a highly fatal cancer that can be cured through cholecystectomy if identified early. The presence of gallstones is the primary risk factor for GBC, but few people with gallstones develop GBC. A key question is what drives the development of GBC among persons with gallstones. We initiated the Chile Biliary Longitudinal Study (Chile BiLS) to address this question. From 2016 to 2019, Chile BiLS enrolled 4,726 women aged 50-74 years with ultrasound-detected gallstones from southern-central Chile, accounting for an estimated 36% of eligible women with gallstones in the study area. The median age was 59 years; 25% of the women were Amerindian (Mapuche), 60% were obese, 25% had diabetes, and 6% had cardiovascular disease. Participants will be followed for gallbladder dysplasia or cancer for 6 years. As of April 30, 2020, over 91% of those eligible completed the year 2 follow-up visit. Data being collected include epidemiologic and sociodemographic information, anthropometric measurements, blood pressure, and tooth counts. Biosamples being taken include baseline plasma, buffy coat, red blood cells, serum, blood clot from serum, and PAXgene whole blood (PreAnalytiX GmbH, Hombrechtikon, Switzerland). Complete gallbladder sampling is conducted for most participants undergoing cholecystectomy. The Chile BiLS cohort study will increase our understanding of GBC etiology and could identify potential risk stratification and early detection strategies in high-risk areas.

Variants in ABCG8 and TRAF3 genes confer risk for gallstone disease in admixed Latinos with Mapuche Native American ancestry.

Latin Americans and Chilean Amerindians have the highest prevalence of gallstone disease (GSD) and gallbladder cancer (GBC) in the world. A handful of loci have been associated with GSD in populations of predominantly European ancestry, however, they only explain a small portion of the genetic component of the disease. Here, we performed a genome-wide association study (GWAS) for GSD in 1,095 admixed Chilean Latinos with Mapuche Native American ancestry. Disease status was assessed by cholecystectomy or abdominal ultrasonography. Top-10 candidate variants surpassing the suggestive cutoff of P < 1 × 10-5 in the discovery cohort were genotyped in an independent replication sample composed of 1,643 individuals. Variants with positive replication were further examined in two European GSD populations and a Chilean GBC cohort. We consistently replicated the association of ABCG8 gene with GSD (rs11887534, P = 3.24 × 10-8, OR = 1.74) and identified TRAF3 (rs12882491, P = 1.11 × 10-7, OR = 1.40) as a novel candidate gene for the disease in admixed Chilean Latinos. ABCG8 and TRAF3 variants also conferred risk to GBC. Gene expression analyses indicated that TRAF3 was significantly decreased in gallbladder (P = 0.015) and duodenal mucosa (P = 0.001) of GSD individuals compared to healthy controls, where according to GTEx data in the small intestine, the presence of the risk allele contributes to the observed effect. We conclude that ABCG8 and TRAF3 genes are associated with GSD and GBC in admixed Latinos and that decreased TRAF3 levels could enhance gallbladder inflammation as is observed in GSD and GSD-associated GBC.

Clinical and ABCB11 profiles in Korean infants with progressive familial intrahepatic cholestasis.

AIM: To investigate clinical profiles and mutations of ABCB11 in Koreans with progressive familial intrahepatic cholestasis 2 and review the differences between Koreans and others. METHODS: Of 47 patients with neonatal cholestasis, five infants had chronic intrahepatic cholestasis with normal γ-glutamyl transpeptidase. Direct sequencing analyses of ABCB11, including exons and introns, were performed from peripheral blood. RESULTS: Living donor-liver transplantation was performed in four patients because of rapidly progressive hepatic failure and hepatocellular carcinoma. Three missense mutations were found in two patients: compound heterozygous 677C>T (S226L)/3007G>A (G1003R) and heterozygous 2296G>A (G766R). The mutations were located near and in the transmembranous space. CONCLUSION: Alterations in the transmembrane of the bile salt export pump in the Korean infants were different from those previously reported in Chinese, Japanease, Taiwanese, and European patients.

Variants and haplotypes in Flap endonuclease 1 and risk of gallbladder cancer and gallstones: a population-based study in China.

The role of FEN1 genetic variants on gallstone and gallbladder cancer susceptibility is unknown. FEN1 SNPs were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method in blood samples from 341 gallbladder cancer patients and 339 healthy controls. The distribution of FEN1-69G > A genotypes among controls (AA, 20.6%; GA, 47.2% and GG 32.2%) was significantly different from that among gallbladder cancer cases (AA, 11.1%; GA, 48.1% and GG, 40.8%), significantly increased association with gallbladder cancer was observed for subjects with both the FEN1-69G > A GA (OR = 1.73, 95% CI = 1.01-2.63) and the FEN1-69G > A GG (OR = 2.29, 95% CI = 1.31-3.9). The distribution of FEN1 -4150T genotypes among controls (TT, 21.8%;GT, 49.3% and GG 28.9%) was significantly different from that among gallbladder cancer cases (TT, 12.9%; GT, 48.4% and GG 38.7%), significantly increased association with gallbladder cancer was observed for subjects with both the FEN1-4150T GT(OR = 1.93, 95% CI = 1.04-2.91) and the FEN1-4150T GG(OR = 2.56, 95% CI = 1.37-5.39). A significant trend towards increased association with gallbladder cancer was observed with potentially higher-risk FEN1-69G > A genotypes (P < 0.001, χ2 trend test) and FEN14150G > T (P < 0.001, χ2 trend test) in gallstone presence but not in gallstone absence (P = 0.81, P = 0.89, respectively). In conclusion, this study revealed firstly that FEN1 polymorphisms and haplotypes are associated with gallbladder cancer risk.

Cholecystectomy is independently associated with nonalcoholic fatty liver disease in an Asian population.

AIM: To investigate the relationship between gallstone disease and nonalcoholic fatty liver disease (NAFLD) in a large Asian population. METHODS: A cross-sectional study including 17612 subjects recruited from general health check-ups at the Seoul National University Hospital, Healthcare System Gangnam Center between January 2010 and December 2010 was conducted. NAFLD and gallstone disease were diagnosed based on typical ultrasonographic findings. Subjects who were positive for hepatitis B or C, or who had a history of heavy alcohol consumption (> 30 g/d for men and > 20 g/d for women) or another type of hepatitis were excluded. Gallstone disease was defined as either the presence of gallstones or previous cholecystectomy, and these two entities (gallstones and cholecystectomy) were analyzed separately. Clinical parameters including body mass index, waist circumference, hypertension, diabetes, smoking status, and regular physical activity were reviewed. Laboratory parameters, including serum levels of gamma-glutamyl transpeptidase, alanine aminotransferase, aspartate aminotransferase, fasting glucose, fasting insulin, total cholesterol, triglycerides, and high-density lipoprotein, were also reviewed. RESULTS: The mean age of the subjects was 48.5 ± 11.3 years, and 49.3% were male. Approximately 30.3% and 6.1% of the subjects had NAFLD and gallstone disease, respectively. The prevalence of gallstone disease (8.3% vs 5.1%, P < 0.001), including both the presence of gallstones (5.5% vs 3.4%, P < 0.001) and a history of cholecystectomy (2.8% vs 1.7%, P < 0.001), was significantly increased in the NAFLD group. In the same manner, the prevalence of NAFLD increased with the presence of gallstone disease (41.3% vs 29.6%, P < 0.001). Multivariate regression analysis showed that cholecystectomy was associated with NAFLD (OR = 1.35, 95%CI: 1.03-1.77, P = 0.028). However, gallstones were not associated with NAFLD (OR = 1.15, 95%CI: 0.95-1.39, P = 0.153). The independent association between cholecystectomy and NAFLD was still significant after additional adjustment for insulin resistance (OR = 1.45, 95%CI: 1.01-2.08, P = 0.045). CONCLUSION: This study shows that cholecystectomy, but not gallstones, is independently associated with NAFLD after adjustment for metabolic risk factors. These data suggest that cholecystectomy may be an independent risk factor for NAFLD.

Roles of ApoB-100 gene polymorphisms and the risks of gallstones and gallbladder cancer: a meta-analysis.

BACKGROUND: Gallstones (GS) is the major manifestation of gallbladder disease, and is the most common risk factor for gallbladder cancer (GBC). Previous studies investigating the association between ApoB-100 gene polymorphisms and the risks of GS and GBC have yielded conflicting results. Therefore, we performed a meta-analysis to clarify the effects of ApoB-100 gene polymorphisms on the risks of GS and GBC. METHODS: A computerized literature search was conducted to identify the relevant studies from PubMed and Embase. Fixed or random effects model was selected based on heterogeneity test. Publication bias was estimated using Begg's funnel plots and Egger's regression test. RESULTS: A total of 10, 3, and 3 studies were included in the analyses of the association between ApoB-100 XbaI, EcoRI, or insertion/deletion (ID) polymorphisms and the GS risks, respectively, while 3 studies were included in the analysis for the association between XbaI polymorphism and GBC risk. The combined results showed a significant association in Chinese (X+ vs. X-, OR = 2.37, 95%CI 1.52-3.70; X+X+/X+X- vs. X+X+, OR = 2.47, 95%CI 1.55-3.92), but not in Indians or Caucasians. Null association was observed between EcoRI or ID polymorphisms and GS risks. With regard to the association between XbaI polymorphism and GBC risk, a significant association was detected when GBC patients were compared with healthy persons and when GBC patients were compared with GS patients. A significant association was still detected when GBC patients (with GS) were compared with the GS patients (X+X+ vs. X-X-, OR = 0.33, 95%CI 0.12-0.90). CONCLUSION: The results of this meta-analysis suggest that the ApoB-100 X+ allele might be associated with increased risk of GS in Chinese but not in other populations, while the ApoB-100 X+X+ genotype might be associated with reduced risk of GBC. Further studies with larger sample sizes are needed to confirm these results.

Gallstones in New Zealand: composition, risk factors and ethnic differences.

BACKGROUND: Gallstone disease is a worldwide problem causing morbidity, mortality and a drain on health-care resources. This prospective study aimed to investigate the spectrum of gallstone types in New Zealand and relate these to known risk factors. METHODS: Gallstone samples were collected from 107 patients undergoing surgery for gallstone disease at Auckland City Hospital between June 2009 and June 2010. Detailed chemical analyses were performed using Fourier Transform Raman spectroscopy. The relationship between gallstone type and age, gender, ethnicity, obesity and positive family history were analysed. RESULTS: Median age was 51 years (range 19-88), 75 (70%) were female, one third were obese (body mass index ≥ 30) and 41% had a positive family history. Major ethnic groups were European (51%), Asian (23%) and Maori/Pacific (18%). Gallstone types included pure or mixed cholesterol stones (74%), black pigment stones (20%) and brown pigment stones (5%). Asians had a higher proportion of black pigment stones and NZ Europeans had more cholesterol and mixed cholesterol stones (odds ratio 3.6 (95% CI 1.1 to 11.5)). The frequency of cholesterol/mixed cholesterol stones was not significantly different between NZ Europeans and Maori/Pacific groups (P = 0.7). Black pigment stones were more common in older patients (mean 68.0 years compared with 47.6 for cholesterol/mixed cholesterol stones) (P = 0.0001). There was no significant relationship between stone type and family history (P = 0.16) or gender (P = 0.17). CONCLUSION: This novel prospective study highlights risk factors and ethnic differences in gallstone composition in New Zealand. These may be important when considering gallstone prevention strategies.

Clinical characteristics and risk factors for symptomatic pediatric gallbladder disease.

OBJECTIVE: Our center previously reported its experience with pediatric gallbladder disease and cholecystectomies from 1980 to 1996. We aimed to determine the current clinical characteristics and risk factors for symptomatic pediatric gallbladder disease and cholecystectomies and compare these findings with our historical series. STUDY DESIGN: Retrospective, cross-sectional study of children, 0 to 18 years of age, who underwent a cholecystectomy from January 2005 to October 2008. RESULTS: We evaluated 404 patients: 73% girls; 39% Hispanic and 35% white. The mean age was 13.10 ± 0.91 years. The primary indications for surgery in patients 3 years or older were symptomatic cholelithiasis (53%), obstructive disease (28%), and biliary dyskinesia (16%). The median BMI percentile was 89%; 39% were classified as obese. Of the patients with nonhemolytic gallstone disease, 35% were obese and 18% were severely obese; BMI percentile was 99% or higher. Gallstone disease was associated with hemolytic disease in 23% (73/324) of patients and with obesity in 39% (126/324). Logistic regression demonstrated older age (P = .019) and Hispanic ethnicity (P < .0001) as independent risk factors for nonhemolytic gallstone disease. Compared with our historical series, children undergoing cholecystectomy are more likely to be Hispanic (P = .003) and severely obese (P < .0279). CONCLUSION: Obesity and Hispanic ethnicity are strongly correlated with symptomatic pediatric gallbladder disease. In comparison with our historical series, hemolytic disease is no longer the predominant risk factor for symptomatic gallstone disease in children.

Sterol transporter adenosine triphosphate-binding cassette transporter G8, gallstones, and biliary cancer in 62,000 individuals from the general population.

UNLABELLED: Gallstone disease, a risk factor for biliary cancer, has a strong heritable component, but the underlying genes are largely unknown. To test the hypothesis that ABCG8 (adenosine triphosphate-binding cassette transporter G8) Asp19His (D19H) genotype predicted risk of gallstones and biliary cancer in the general population, we studied 62,279 white individuals from The Copenhagen City Heart Study and The Copenhagen General Population Study, randomly selected to reflect the adult Danish population aged 20 to 80+ years. Endpoints were recorded from January 1976 through May 2009. During a mean follow-up of, respectively, 31 and 4.4 years, 3124 participants developed symptomatic gallstone disease and 30 developed biliary cancer. The multifactorially adjusted hazard ratio for symptomatic gallstone disease was 1.9 (95% confidence interval, 1.7-2.1) in DH heterozygotes (prevalence, 12%), and 3.3 (2.3-4.6) in HH homozygotes (0.4%) versus noncarriers (P for trend <0.001). Mean age at onset of symptomatic gallstone disease was 56 years for noncarriers, 54 for DH heterozygotes, and 52 for HH homozygotes (P for trend <0.001). The fraction of all gallstones attributed to D19H was 11%. The multifactorially adjusted hazard ratio for biliary cancer was 4.0 (1.9-8.4) in DH heterozygotes and HH homozygotes combined versus noncarriers (P < 0.001). The fraction of all biliary cancers attributed to the D19H genotype was 27%. Finally, D19H genotype associated with stepwise increases in plasma levels of alanine aminotransferase and gamma glutamyltransferase of up to 14% and 25% in HH homozygotes, and with corresponding stepwise reductions in plasma levels of total and low-density lipoprotein cholesterol of up to 5% versus noncarriers (all comparisons, P for trend <0.001). CONCLUSION: In this general population cohort, ABCG8 D19H genotype was an important predictor of both symptomatic gallstone disease and biliary cancer.

Genetic variants involved in gallstone formation and capsaicin metabolism, and the risk of gallbladder cancer in Chilean women.

AIM: To determine the effects of genetic variants associated with gallstone formation and capsaicin (a pungent component of chili pepper) metabolism on the risk of gallbladder cancer (GBC). METHODS: A total of 57 patients with GBC, 119 patients with gallstones, and 70 controls were enrolled in this study. DNA was extracted from their blood or paraffin block sample using standard commercial kits. The statuses of the genetic variants were assayed using Taqman SNP Genotyping Assays or Custom Taqman SNP Genotyping Assays. RESULTS: The non-ancestral T/T genotype of apolipoprotein B rs693 polymorphism was associated with a decreased risk of GBC (OR: 0.14, 95% CI: 0.03-0.63). The T/T genotype of cholesteryl ester transfer protein (CETP) rs708272 polymorphism was associated with an increased risk of GBC (OR: 5.04, 95% CI: 1.43-17.8). CONCLUSION: Genetic variants involved in gallstone formation such as the apolipoprotein B rs693 and CETP rs708272 polymorphisms may be related to the risk of developing GBC in Chilean women.

Prevalence and clinical features of chronic pancreatitis in China: a retrospective multicenter analysis over 10 years.

OBJECTIVES: A multicenter study was initiated by the Chinese Chronic Pancreatitis Study Group to determine the nature and magnitude of chronic pancreatitis (CP) in China. METHODS: Twenty-two hospitals representing all 6 urban health care regions in China participated in the study. The survey covered a 10-year period from May 1, 1994, to April 30, 2004. Multiple logistic regression was used for analyses. RESULTS: The analysis included 2008 patients (64.99% were men, and 35.01% were female; mean age, 48.9 years [SD, 15.0 years]). Chronic pancreatitis prevalence increased yearly from 1996 to 2003: 3.08, 3.91, 5.28, 7.61, 10.43, 11.92, 12.84, and 13.52 per 100,000 inhabitants. Chronic pancreatitis etiologies were alcohol (35.11%), biliary stones (34.36%), hereditary (7.22%), and idiopathic CP (12.90%). Clinical feature were pain (76.25%), maldigestion (36.11%), jaundice (13.40%), and steatorrhea (6.92%). Complications were pseudocyst (26.25%), diabetes (21.61%), bile duct strictures (13.40%), and ascites (1.74%). With regard to the diagnosis, the sensitivity and specificity of endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography were 88% and 93%, and 87% and 93%, respectively. Three hundred ninety-one patients (19.47%) received endoscopic therapy. Surgery was performed in 239 patients (11.90%). CONCLUSION: In China, the incidence of CP is rising rapidly; alcohol and biliary stones are the main causes. Endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography are highly sensitive and specific diagnostic methods.

Choledocholithiasis in Chinese immigrants with cholelithiasis.

During the period from January 1987 to December 1989, admissions for biliary tract disease at the New York Infirmary--Beekman Downtown Hospital were split almost evenly between Chinese immigrants from southeast Asia and all other ethnic groups (Caucasian, Hispanic, black, et cetera). However, the incidence of choledocholithiasis in patients undergoing cholecystectomy for cholelithiasis was much higher in the Chinese immigrant population, 37.2 versus 11.8 per cent, a highly significant difference (p = 0.001). In addition, we often found the disease to be of greater severity in Chinese patients. They were more likely to have large numbers of stones in the duct and more likely to have significant ductal enlargement. This increased risk was essentially constant regardless of age. Because of this threefold risk of choledocholithiasis when operating on a Chinese immigrant from southeast Asia for cholelithiasis, intraoperative cholangiography is mandatory, even in those without other indications for common bile duct exploration.