Transcriptomic profiles reveal differences in zinc metabolism, inflammation, and tight junction proteins in duodenum from cholesterol gallstone subjects.

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.

[Access to cholecystectomy among patients attended at primary family health centers]. / Acceso a colecistectomía en un programa de tamizaje ecográfico de colelitiasis en centros de medicina familiar.

BACKGROUND: Cholelithiasis (CL) represents a major health burden in Chile, with rates of cholecystectomy (CCT) of ~40.000 per year. The explicit health care guaranties (GES) program includes prioritized CCT for CL carriers between 35 and 49 years of age. AIM: To assess the access and opportunity of CCT in a screening program of CL in Family Medicine Centers, according to the age of the patients. MATERIAL AND METHODS: A systematic ultrasound screening program of CL was developed in Family Medicine Centers ANCORA-UC between March 2009 and March 2013 during which 1.450 individuals were assessed, (80% women) and 281 were identified as having CL (19.4%). After a minimum follow up interval of six months, patients with CL were contacted and surveyed by phone. They were categorized as being beneficiaries of the GES program (those aged between 35 to 49 years) or not (those aged < 35 o > 49 years). RESULTS: Two hundred thirteen patients were contacted (76%), 81 beneficiaries of the program and 132 non-beneficiaries. The attending physician indicated CCT to 191 patients (89.6%). During a mean follow-up time of 641 days/person, 100 patients had CCT, 11% of which were emergency interventions due to complications. A greater proportion of program beneficiaries than non-beneficiaries had an elective CCT (74 and 21% respectively). The waiting interval for elective CCT was longer in non-beneficiaries compared with beneficiaries (340 ± 247 and 229 ± 201 days respectively). Only 46% of the elective CCT in GES patients were done within deadlines determined by the program (≤ 150 days). CONCLUSIONS: The age of patients at the moment of CL diagnosis conditions the access and opportunity to CCT. Beneficiaries of the explicit health care guaranties program have higher rates of cholecystectomy with less waiting time.

Acceso a colecistectomía en un programa de tamizaje ecográfico de colelitiasis en centros de medicina familiar / Access to cholecystectomy among patients attended at primary family health centers

Background: Cholelithiasis (CL) represents a major health burden in Chile, with rates of cholecystectomy (CCT) of ~40.000 per year. The explicit health care guaranties (GES) program includes prioritized CCT for CL carriers between 35 and 49 years of age. Aim: To assess the access and opportunity of CCT in a screening program of CL in Family Medicine Centers, according to the age of the patients. Material and Methods: A systematic ultrasound screening program of CL was developed in Family Medicine Centers ANCORA-UC between March 2009 and March 2013 during which 1.450 individuals were assessed, (80% women) and 281 were identified as having CL (19.4%). After a minimum follow up interval of six months, patients with CL were contacted and surveyed by phone. They were categorized as being beneficiaries of the GES program (those aged between 35 to 49 years) or not (those aged < 35 o > 49 years). Results: Two hundred thirteen patients were contacted (76%), 81 beneficiaries of the program and 132 non-beneficiaries. The attending physician indicated CCT to 191 patients (89.6%). During a mean follow-up time of 641 days/person, 100 patients had CCT, 11% of which were emergency interventions due to complications. A greater proportion of program beneficiaries than non-beneficiaries had an elective CCT (74 and 21% respectively). The waiting interval for elective CCT was longer in non-beneficiaries compared with beneficiaries (340 ± 247 and 229 ± 201 days respectively). Only 46% of the elective CCT in GES patients were done within deadlines determined by the program (≤ 150 days). Conclusions: The age of patients at the moment of CL diagnosis conditions the access and opportunity to CCT. Beneficiaries of the explicit health care guaranties program have higher rates of cholecystectomy with less waiting time.

Effect of cholecystectomy on bile acid synthesis and circulating levels of fibroblast growth factor 19.

UNLABELLED: Background and rationale for the study. FGF19/15 is a gut-derived hormone presumably governing bile acid (BA) synthesis and gallbladder (GB) refilling. FGF19 mRNA is present in human GB cholangiocytes (hGBECs); however, the physiological significance of GB-derived FGF19 remains unknown. We investigated whether hGBECs secrete FGF19 and the effects of cholecystectomy on serum FGF19 ([FGF19]s) and BA synthesis. MATERIAL AND METHODS: FGF19 expression was assessed by qRT-PCRs and immunostaining in hGBECs and terminal ileum, and quantified in bile and serum by ELISA. Basal and BA (chenodexycholic acid, CDCA) induced FGF19 expression and secretion was analyzed in primary cultured hGBECs and GB-d1 cell line. Pre and postprandial serum changes in [FGF19]s, 7α-hydroxy-4-cholestene-3-one (C4, a marker of BA synthesis) and BA were evaluated in plasma of gallstone disease patients at baseline and after cholecystectomy. RESULTS: FGF19 mRNA levels were ~250-fold higher in hGBECs compared to distal ileum. GB bile contained ~23-fold higher FGF19 levels compared to serum (p < 0.0001). CDCA induced dose-dependent expression and secretion of FGF19 in hGBECs and GB-d1 cells. Cholecystectomy increased plasma BA synthesis ≥ 2-fold (p < 0.0001), and altered the diurnal rhythm and significantly reduced [FGF19]s noon peak. BA serum levels, serum cholesterol and triglyceride content remained unchanged. CONCLUSIONS: In conclusion human GB cholangiocytes constitutively express and secrete high levels of FGF19 in a process regulated by BA. Resection of this organ doubles BA synthesis concomitantly with changes in [FGF19]s. These findings suggest a potential connection between GB cholangiocytes-derived FGF19 and BA metabolism that could lead to metabolic dysregulation following cholecystectomy.