Gallstones: Prevention, Diagnosis, and Treatment.

Gallstones are common and affect up to 20% of the general adult population and >20% of them will develop symptoms or complications of cholelithiasis. The high risk of gallbladder stone formation can be reduced by ursodeoxycholic acid in the case of significant weight reduction resulting from diet or bariatric surgery. Laparoscopic cholecystectomy is indicated for symptomatic gallstones, as the risk of recurrence or complications increases over the course of the disease. Biliary colic is treated with nonsteroidal anti-inflammatory drugs and spasmolytics; opioids can also be used in cases of severe acute pain. Acute cholecystitis represents a common complication of gallbladder stones and a cholecystectomy should be performed early electively, i.e., within 24 hours of admission to hospital. Symptomatic bile duct stones are primarily treated endoscopically. Immediate anti-infective therapy is mandatory in acute cholangitis. Although knowledge on the genetics and pathophysiology of gallstones has increased, current treatment algorithms remain predominantly invasive, based on interventional endoscopy and surgery. Future efforts should focus on novel strategies to prevent the development of gallstones.

A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis.

OBJECTIVE: To investigate the efficacy and safety of two different budesonide formulations (effervescent tablet for orodispersible use (BET) and viscous suspension (BVS)) with different daily dosages for short-term treatment of eosinophilic oesophagitis (EoE). DESIGN: Adults with active EoE (n=76) randomly received 14 days' treatment with either BET 2×1 mg/day (BET1, n=19) or BET 2×2 mg/day (BET2, n=19), or BVS 2×5 mL (0.4 mg/mL)/day (BVS, n=19) or placebo (n=19) in a double-blind, double-dummy fashion, with a 2-week follow-up. Primary end point was histological remission (mean of <16 eosinophils/mm(2 )hpf). Secondary end points included endoscopy score, dysphagia score, drug safety and patient's preference for drug formulation. RESULTS: Histological remission occurred in 100%, 94.7% and 94.7% of budesonide (BET1, BET2, BVS, respectively) and in 0% of placebo recipients (p<0.0001). The improvement in total endoscopic intensity score was significantly higher in the three budesonide groups compared with placebo. Dysphagia improved in all groups at the end of treatment; however, improvement of dysphagia persisted only in those treated with BET1 (p=0.0196 vs placebo). There were no serious adverse events. Local fungal infection (stained fungi) occurred in two patients of each budesonide group (10.5%). The effervescent tablet was preferred by 80% of patients. CONCLUSIONS: BET or BVS was highly effective and safe for short-term treatment of EoE. The 1 mg (twice daily) dosage was equally effective as the 2 mg twice daily dosage. The majority of patients preferred the effervescent tablet formulation. CLINICALTRIALSGOV NUMBER: NCT02280616; EudraCT number, 2009-016692-29.

Anastomotic leak in colorectal surgery: are 75 % preventable?

INTRODUCTION: Anastomotic leak (AL) is a significant cause of morbidity and mortality associated with complications of colorectal surgery. Furthermore, AL results in prolonged hospital stays and significant increase in costs of medical resources. MATERIALS AND METHODS: In this study, we investigated the impact of anastomosis technique on the rate of anastomotic leak. The rate of leak was compared between two groups performing end-to-end (E-E) vs. side-to-end (S-E) anastomosis. The impact of various risk factors was also compared between the two groups. RESULTS: There were 382 E-E and 363 S-E anastomoses after left colectomy or rectal resections. The anastomotic leak rate was 8.64 % using E-E compared to 1.93 % using S-E anastomosis technique (p < 0.001). CONCLUSIONS: These results indicate that the rate of anastomotic leak after left colon and rectum resections could be significantly reduced utilizing S-E anastomosis technique.

Genetic and functional identification of the likely causative variant for cholesterol gallstone disease at the ABCG5/8 lithogenic locus.

UNLABELLED: The sterolin locus (ABCG5/ABCG8) confers susceptibility for cholesterol gallstone disease in humans. Both the responsible variant and the molecular mechanism causing an increased incidence of gallstones in these patients have as yet not been identified. Genetic mapping utilized patient samples from Germany (2,808 cases, 2,089 controls), Chile (680 cases, 442 controls), Denmark (366 cases, 766 controls), India (247 cases, 224 controls), and China (280 cases, 244 controls). Analysis of allelic imbalance in complementary DNA (cDNA) samples from human liver (n = 22) was performed using pyrosequencing. Transiently transfected HEK293 cells were used for [(3) H]-cholesterol export assays, analysis of protein expression, and localization of allelic constructs. Through fine mapping in German and Chilean samples, an ∼250 kB disease-associated interval could be defined for this locus. Lack of allelic imbalance or allelic splicing of the ABCG5 and ABCG8 transcripts in human liver limited the search to coding single nucleotide polymorphisms. Subsequent mutation detection and genotyping yielded two disease-associated variants: ABCG5-R50C (P = 4.94 × 10(-9) ) and ABCG8-D19H (P = 1.74 × 10(-10) ) in high pairwise linkage disequilibrium (r(2) = 0.95). [(3) H]-cholesterol export assays of allelic constructs harboring these genetic candidate variants demonstrated increased transport activity (3.2-fold, P = 0.003) only for the ABCG8-19H variant, which was also superior in nested logistic regression models in German (P = 0.018), Chilean (P = 0.030), and Chinese (P = 0.040) patient samples. CONCLUSION: This variant thus provides a molecular basis for biliary cholesterol hypersecretion as the mechanism for cholesterol gallstone formation, thereby drawing a link between "postgenomic" and "pregenomic" pathophysiological knowledge about this common complex disorder. (HEPATOLOGY 2012).

Genetic susceptibility to hepatoxicity due to bosentan treatment in pulmonary hypertension.

BACKGROUND: Hepatotoxicity is a major side effect of treatment with bosentan in patients with pulmonary hypertension (PH). Bosentan is metabolized by the cytochrome CYP2C9 and inhibits the bile salt export pump, which is encoded by ABCB11. This suggests that genetic variants of CYP2C9 and/or ABCB11 may predispose patients to bosentan-induced liver injury. MATERIAL AND METHODS: PH patients with (n = 23) or without (n = 25) an increase of alanine aminotransferase (ALT) or aspartate-aminotransferase (AST) during bosentan therapy were included in our analysis. Functionally relevant alleles of CYP2C9 and 16 representative variants of ABCB11 were genotyped. Data were analyzed using logistic regression. RESULTS: Variants of ABCB11 were not associated with bosentan-induced liver injury. In contrast, variant alleles of CYP2C9 were more common in patients with elevated transaminases (allele frequency 52%) compared to controls (allele frequency 24%, P = 0.04, odds ratio 3.5, 95% confidence interval 1.01-11.8). CONCLUSION: Our data indicate hepatotoxicity of bosentan from decreased hepatic metabolism due to common variants of CYP2C9.

When in doubt, take it out? Cholestasis and obstructive gastric outlet syndrome in a patient with suspected chronic pancreatitis.

In some patients with tumors located in the pancreas or in the periampullary region, the decision to perform a surgical resection can be difficult. In patients with concomitant chronic pancreatitis this decision can be even more challenging, since a definitive preoperative differentiation between non-malignant and malignant tumors in many cases is not possible. Clinical symptoms or complications from the tumor often direct a rational treatment strategy. For therapeutic decisions, an interdisciplinary discussion of all diagnostic findings by experienced clinicians is needed. However, in rare cases, like the one presented here, an uncommon non-malignant entity like a periampullary hamartoma may be only diagnosed after surgical resection.

Heap of stones: an unusual cause for biliary colic and elevated liver function tests.

A 40-year old woman presented with symptomatic intrahepatic gallstones in one liver segment only four years after cholecystectomy for cholelithiasis. Multiple small, yellow and round calculi were completely removed from the intrahepatic bile ducts via ERCP. The young age of the patient, recurrence of gallstones after cholecystectomy and intrahepatic gallstones suggested a subtype of the low-phospholipid associated cholelithiasis syndrome, a monogenic form of cholesterol cholelithiasis due to variations of the ABCB4 gene that encodes the canalicular phospholipid transporter MDR3.

The mouse mutation "thrombocytopenia and cardiomyopathy" (trac) disrupts Abcg5: a spontaneous single gene model for human hereditary phytosterolemia/sitosterolemia.

The spontaneous mouse mutation "thrombocytopenia and cardiomyopathy" (trac) causes macrothrombocytopenia, prolonged bleeding times, anemia, leukopenia, infertility, cardiomyopathy, and shortened life span. Homozygotes show a 20-fold decrease in platelet numbers and a 3-fold increase in platelet size with structural alterations and functional impairments in activation and aggregation. Megakaryocytes in trac/trac mice are present in increased numbers, have poorly developed demarcation membrane systems, and have decreased polyploidy. The thrombocytopenia is not intrinsic to defects at the level of hematopoietic progenitor cells but is associated with a microenvironmental abnormality. The trac mutation maps to mouse chromosome 17, syntenic with human chromosome 2p21-22. A G to A mutation in exon 10 of the adenosine triphosphate (ATP)-binding cassette subfamily G, member 5 (Abcg5) gene, alters a tryptophan codon (UGG) to a premature stop codon (UAG). Crosses with mice doubly transgenic for the human ABCG5 and ABCG8 genes rescued platelet counts and volumes. ABCG5 and ABCG8 form a functional complex that limits dietary phytosterol accumulation. Phytosterolemia in trac/trac mice confirmed a functional defect in the ABCG5/ABCG8 transport system. The trac mutation provides a new clinically significant animal model for human phytosterolemia and provides a new means for studying the role of phytosterols in hematologic diseases and testing therapeutic interventions.

Effects of SLC10A2 variant rs9514089 on gallstone risk and serum cholesterol levels- meta-analysis of three independent cohorts.

BACKGROUND: Recently, a single nucleotide polymorphism (SNP) rs9514089 in SLC10A2 (apical sodium-dependent bile acid transporter gene) has been identified as a susceptibility variant for cholelithiasis in humans. METHODS: Here we assessed the effects of rs9514089 on gallstone risk and related phenotypes of the metabolic syndrome in the self-contained population of Sorbs (183 cases with gallstones/826 controls). Furthermore, we performed a meta-analysis for effects of rs9514089 on susceptibility for cholelithiasis in three independent cohorts (Stuttgart: 56 cases/71 controls, Aachen: 184 cases/184 controls and Sorbs). RESULTS: There was no significant association of rs9514089 with gallstone risk, serum lipid parameters and BMI in the Sorbs and in the meta-analysis of all three cohorts (p > 0.05). There was an effect trend in the subgroup of lean subjects but based on different effect directions in the three cohorts there was no significant association in the meta-analysis. CONCLUSIONS: We were not able to replicate the effect of rs9514089 on gallstone risk in the Sorbs. Further analyses in larger cohorts are required to finally assess the role of genetic variants in SLC10A2 in human gallstone development and lipid metabolism.

Sequence analysis of the human tyrosylprotein sulfotransferase-2 gene in subjects with chronic pancreatitis.

BACKGROUND/AIMS: Human trypsinogens are post-translationally sulfated on Tyr154 by the Golgi resident enzyme tyrosylprotein sulfotransferase-2 (TPST2). Tyrosine sulfation stimulates the autoactivation of human cationic trypsinogen. Because increased trypsinogen autoactivation has been implicated as a pathogenic mechanism in chronic pancreatitis, we hypothesized that genetic variants of TPST2 might alter the risk for the disease. METHODS: We sequenced the 4 protein-coding exons and the adjacent intronic sequences of TPST2 in 151 subjects with chronic pancreatitis and in 169 healthy controls. The functional effect of TPST2 variants on trypsinogen sulfation was analyzed in transfected HEK 293T cells. RESULTS: We detected 10 common polymorphic variants, including 6 synonymous variants and 4 intronic variants, with similar frequencies in patients and controls. None of the 8 common haplotypes reconstructed from the frequent variants showed an association with chronic pancreatitis. In addition, we identified 5 rare TPST2 variants, which included 3 synonymous alterations, the c.458G>A (p.R153H) nonsynonymous variant and the c.-9C>T variant in the 5' untranslated region. The p.R153H variant was found in a family with hereditary pancreatitis; however, it did not segregate with the disease. In functional assays, both the p.R153H and c.-9C>T TPST2 variants catalyzed trypsinogen sulfation as well as wild-type TPST2. CONCLUSION: Genetic variants of human TPST2 exert no influence on the risk of chronic pancreatitis.