metallothionein and Cholelithiasis

Carcinoma of the gallbladder has a very unusual geographical distribution with pockets of high incidence seen in Chile, Poland, India, Japan and Israel; it occurs rarely in the rest of the world. It is a common malignancy in the Western Bihar and Eastern Uttar Pradesh regions of India. Patients present with extremes of clinical symptoms, indicating benign biliary diseases on the one hand and incurable malignant disease on the other. Laboratory and roentgenographic data tend to confirm the clinical diagnosis of the advanced incurable disease at presentation, in most cases. Various aetiopathological agents have been proposed but none has stood the test of time. In this article, we have reviewed the aetiopathological agents proposed from time to time over the past two centuries, with special emphasis on the developments made in the last 25 years.

Topics: Carcinogens; Carcinoma; Cholelithiasis; Diet; Ethnicity; Gallbladder Neoplasms; Humans; Incidence; Infections; Life Style; Lipid Peroxidation; Metallothionein; Metals, Heavy; Neoplasm Staging; Occupational Exposure; Racial Groups; Risk Factors

Cholesterol Gallstone Disease (GSD) is a common multifactorial disorder characterized by crystallization and aggregation of biliary cholesterol in the gallbladder. The global prevalence of GSD is ~10-20% in the adult population but rises to 28% in Chile (17% among men and 30% among women). The small intestine may play a role in GSD pathogenesis, but the molecular mechanisms have not been clarified. Our aim was to identify the role of the small intestine in GSD pathogenesis. Duodenal biopsy samples were obtained from patients with GSD and healthy volunteers. GSD status was defined by abdominal ultrasonography. We performed a transcriptome study in a discovery cohort using Illumina HiSeq. 2500, and qPCR, immunohistochemistry and immunofluorescence were used to validate differentially expressed genes among additional case-control cohorts. 548 differentially expressed genes between GSD and control subjects were identified. Enriched biological processes related to cellular response to zinc, and immune and antimicrobial responses were observed in GSD patients. We validated lower transcript levels of metallothionein, NPC1L1 and tight junction genes and higher transcript levels of genes involved in immune and antimicrobial pathways in GSD patients. Interestingly, serum zinc and phytosterol to cholesterol precursor ratios were lower in GSD patients. A significant association was observed between serum zinc and phytosterol levels. Our results support a model where proximal small intestine plays a key role in GSD pathogenesis. Zinc supplementation, modulation of proximal microbiota and/or intestinal barrier may be novel targets for strategies to prevent GSD.

Topics: Adult; Biopsy; Cholelithiasis; Cholesterol; Duodenum; Female; Gene Expression Regulation; Humans; Inflammation; Male; Membrane Transport Proteins; Metallothionein; Microbiota; Prevalence; Risk Factors; RNA-Seq; Tight Junction Proteins; Tight Junctions; Transcriptome; Ultrasonography; Young Adult; Zinc