Dysfunction of Biliary Sphincter of Oddi-Clinical, Diagnostic and Treatment Challenges.

Biliary Sphincter of Oddi dysfunction (SOD) is one of the main causes of post-cholecystectomy pain. In this review, we aimed to provide an update on the current knowledge on biliary SOD, with an emphasis on diagnostics and therapy. Overall, current but scarce data support biliary sphincterotomy for patients with type 1 and 2 SOD, but not for type 3. However, sphincterotomy is associated with post-treatment pancreatitis rates of from 10% to 15%, thus calling for improved diagnostics, patient selection and treatment modalities for SOD. The role of pharmacologic therapy for patients with SOD is poorly explored and only two randomized controlled trials are available. Currently, studies comparing treatment outcomes are few. There is an unmet need for randomized sham/placebo-controlled clinical trials related to both pharmacological and non-pharmacological treatments of SOD.

The Symptomatic Outcomes of Cholecystectomy for Gallstones.

Cholecystectomy is the definite treatment for symptomatic gallstones, and rates are rapidly rising. Symptomatic complicated gallstones are generally treated with cholecystectomy, but there is no consensus on the clinical selection of patients with symptomatic uncomplicated gallstones for cholecystectomy. The aim of this review is to describe symptomatic outcomes before versus after cholecystectomy in patients with symptomatic gallstones as reported in prospective clinical studies and to discuss patient selection for cholecystectomy. Following cholecystectomy, resolution of biliary pain is high and reported for 66-100%. Dyspepsia has an intermediate resolution of 41-91% and may co-exist with biliary pain but may also develop following cholecystectomy with an increase of 150%. Diarrhea has a high increase and debuts in 14-17%. Persisting symptoms are mainly determined by preoperative dyspepsia, functional disorders, atypical pain locations, longer duration of symptoms, and poor psychological or physical health. Patient satisfaction following cholecystectomy is high and may reflect symptom alleviation or a change in symptoms. Comparison of symptomatic outcomes in available prospective clinical studies is limited by variations in preoperative symptoms, clinical presentations, and clinical management of post-cholecystectomy symptoms. When selecting patients with biliary pain only in a randomized controlled trial, 30-40% still have persisting pain. Strategies for the selection of patients with symptomatic uncomplicated gallstones based on symptoms alone are exhausted. For the development of a selection strategy, future studies should explore the impact of objective determinants for symptomatic gallstones on pain relief following cholecystectomy.

One-step laparoscopic cholecystectomy with common bile duct exploration and stone extraction versus two-step endoscopic retrograde cholangiography with stone extraction plus laparoscopic cholecystectomy for patients with common bile duct stones: a randomised feasibility and pilot clinical trial-the preGallStep trial.

BACKGROUND: Endoscopic retrograde cholangiography (ERC) with stone extraction and papillotomy with subsequent laparoscopic cholecystectomy-the two-step approach-is the standard treatment of common bile duct stones in many countries. However, ERC is associated with a high risk of complications and more than half of patients require multiple ERCs. Meta-analyses of randomised clinical trials find no major differences of the two-step approach in comparison with laparoscopic cholecystectomy with intraoperative laparoscopic stone clearance-the one-step approach. Currently, there are insufficient data to ascertain superiority. METHODS: The preGallstep trial is an investigator-initiated, multicentre randomised feasibility and pilot clinical trial with blinded outcome assessment. Eligible patients are patients with common bile duct stones (identified by magnetic resonance cholagiopancreatography), age 18 years or above with the possibility to perform both interventions within a reasonable time. We intent to randomise 150 participants allocated 1:1. The experimental intervention is the one-step approach. This consists of laparoscopic common bile duct exploration plus laparoscopic cholecystectomy. The control intervention is the two-step approach which consists of ERC plus sphincterotomy (first step) and subsequent laparoscopic cholecystectomy (second step). Feasibility outcomes include the proportion of eligible patients not wanting to participate, reasons for rejection to participate, difficulties during the informed consent procedure, difficulties with randomisation, difficulties with data management, difficulties with blinding patient charts and forms and difficulties with maintaining blinding for the outcome assessors. The primary pilot outcome is the proportion of participants with at least one postoperative complication according to the Clavien-Dindo score grade II and above until 90 days after randomisation. This outcome will be used for a future sample size calculation of a larger pragmatic trial. Further, a range of clinical explorative outcomes will be assessed. DISCUSSION: As no sample size is estimated in this trial, there is a risk of wrongly assessing the effect on the patient-related outcome. The surgical procedures cannot be blinded. However, blinding will be employed in all other aspects of the trial, including the establishment of a blinded outcome adjudication committee with three independent assessors. Heterogeneity in screening, randomisation, diagnostics, treatment procedures, interventions and follow-up across trial sites may cause challenges in conducting a larger pragmatic trial. To monitor inter-site differences, we have implemented a central data monitoring scheme. TRIAL REGISTRATION: ClinicalTrials.gov identification: NCT04801238 , Registered on 16 March 2021.

National clinical practice guidelines for the treatment of symptomatic gallstone disease: 2021 recommendations from the Danish Surgical Society.

BACKGROUND AND OBJECTIVE: Gallstones are highly prevalent, and more than 9000 cholecystectomies are performed annually in Denmark. The aim of this guideline was to improve the clinical course of patients with gallstone disease including a subgroup of high-risk patients. Outcomes included reduction of complications, readmissions, and need for additional interventions in patients with uncomplicated gallstone disease, acute cholecystitis, and common bile duct stones (CBDS). METHODS: An interdisciplinary group of clinicians developed the guideline according to the GRADE methodology. Randomized controlled trials (RCTs) were primarily included. Non-RCTs were included if RCTs could not answer the clinical questions. Recommendations were strong or weak depending on effect estimates, quality of evidence, and patient preferences. RESULTS: For patients with acute cholecystitis, acute laparoscopic cholecystectomy is recommended (16 RCTs, strong recommendation). Gallbladder drainage may be used as an interval procedure before a delayed laparoscopic cholecystectomy in patients with temporary contraindications to surgery and severe acute cholecystitis (1 RCT and 1 non-RCT, weak recommendation). High-risk patients are suggested to undergo acute laparoscopic cholecystectomy instead of drainage (1 RCT and 1 non-RCT, weak recommendation). For patients with CBDS, a one-step procedure with simultaneous laparoscopic cholecystectomy and CBDS removal by laparoscopy or endoscopy is recommended (22 RCTs, strong recommendation). In high-risk patients with CBDS, laparoscopic cholecystectomy is suggested to be included in the treatment (6 RCTs, weak recommendation). For diagnosis of CBDS, the use of magnetic resonance imaging or endoscopic ultrasound prior to surgical treatment is recommended (8 RCTs, strong recommendation). For patients with uncomplicated symptomatic gallstone disease, observation is suggested as an alternative to laparoscopic cholecystectomy (2 RCTs, weak recommendation). CONCLUSIONS: Seven recommendations, four weak and three strong, for treating patients with symptomatic gallstone disease were developed. Studies for treatment of high-risk patients are few and more are needed. ENDORSEMENT: The Danish Surgical Society.

[Acute diverticulitis can be treated without antibiotics].

Diverticulitis is a complication to the common condition diverticulosis. Uncomplicated diverticulitis has traditionally been treated with antibiotics. Risk factors for diverticulitis, however, may suggest, that the condition is inflammatory rather than infectious. The evidence on antibiotic treatment for uncomplicated acute diverticulitis suggests, that antibiotics have no effect on complications, emergency surgery, recurrence, elective colonic resections and long-term complications. The evidence is based on three randomised clinical trials on the need for antibiotics, which is summarised in this review.

Male Circumcision Complications - A Systematic Review, Meta-Analysis and Meta-Regression.

OBJECTIVE: To determine the risk of complications requiring treatment following male circumcision by health-care professionals and to explore the impact of participant characteristics, type of circumcision and study design. METHODS: We identified studies through systematic searches in online databases (MEDLINE, EMBASE and CENTRAL) and hand searches. We performed random-effects meta-analysis to determine risk of circumcision complications and mixed-effects metaregression analyses to explore the impact of participant characteristics, type of circumcision and study design. Methods were prespecified in a registered protocol (Prospero CRD42020116770) and according to PRISMA guidelines. RESULTS: We included 351 studies with 4.042.988 participants. Overall complication risk was 3.84% (95% confidence interval 3.35-4.37). Our meta-analysis revealed that therapeutic circumcisions were associated with a 2-fold increase in complications as compared to nontherapeutic (7.47% and 3.34%, respectively). Adhesions, meatal stenosis and infections were the most frequent complication subgroups to therapeutic circumcisions. Bleeding, device removals and infections occurred more frequently in nontherapeutic circumcisions. Additionally, adjusted metaregression analyses revealed that children above 2 years, South American continent, older publication year and smaller study populations increased complication risk. Type of circumcision method, provider and setting were not associated with complication risk. Sensitivity analyses including only better-quality studies reporting indication, age at circumcision, treatment for complications, full-text articles, and adequate follow-up clinically for a minimum of one month or through databases confirmed our main findings while accounting better for heterogeneity. CONCLUSION: Circumcision complications occur in about 4 per hundred circumcisions. Higher risks of complications were determined by therapeutic circumcisions and by childhood age when compared to infant. Future studies should assess therapeutic and childhood circumcisions separately.

The clinical course of common bile duct stone clearance with endoscopic retrograde cholangio-pancreaticography.

Objectives: Two-stage treatment of common bile duct stones by Endoscopic Retrograde Cholangio-Pancreatography and subsequent laparoscopic cholecystectomy is well established. In many cases multiple procedures are needed before clearance of the common bile duct is obtained. This study aimed to describe the clinical course from common bile duct stone diagnosis to successful clearance. Materials and Methods: A prospective observational study from 2011 to 2014 of consecutive patients diagnosed with common bile duct stones undergoing Endoscopic Retrograde Cholangio-Pancreatography at a public university hospital. Results: In this study 297 patients with common bile duct stones were identified. More than one Endoscopic Retrograde Cholangio-Pancreatography was performed in 174 (59%) patients and more than two in 51(17%) before clearance. A sphincterotomy was performed in 269 (91%) patients and 189 (64%) had a stent inserted. Bleeding occurred in 17 (6%) requiring injection treatment and post procedure complications occurred in 38 (13%). Subsequent laparoscopic cholecystectomy was performed in 180 (61%) patients. Overall, the patients were hospitalized for 11 (8.5) days and the length of treatment from diagnose to stone clearance was 49 (84.5) days. Overweight, pancreatitis at admission, universal anesthesia, and expert level endoscopist inversely determined common bile duct clearance failure. Conclusions: Common bile duct clearance by Endoscopic Retrograde Cholangio-Pancreatography requires multiple procedures and complications are frequent leading to prolonged treatment and hospitalization suggesting a limited efficacy.

Association of alcohol consumption with allergic disease and asthma: a multi-centre Mendelian randomization analysis.

AIMS: To use the rs1229984 variant associated with alcohol consumption as an instrument for alcohol consumption to test the causality of the association of alcohol consumption with hay fever, asthma, allergic sensitization and serum total immunoglobulin (Ig)E. DESIGN: Observational and Mendelian randomization analyses using genetic variants as unbiased markers of exposure to estimate causal effects, subject to certain assumptions. SETTING: Europe. PARTICIPANTS: We included a total of 466 434 people aged 15-82 years from 17 population-based studies conducted from 1997 to 2015. MEASUREMENTS: The rs1229984 (ADH1B) was genotyped; alcohol consumption, hay fever and asthma were self-reported. Specific and total IgE were measured from serum samples. FINDINGS: Observational analyses showed that ever-drinking versus non-drinking, but not amount of alcohol intake, was positively associated with hay fever and inversely associated with asthma but not with allergic sensitization or serum total immunoglobulin (Ig)E. However, Mendelian randomization analyses did not suggest that the observational associations are causal. The causal odds ratio (OR) per genetically assessed unit of alcohol/week was an OR = 0.907 [95% confidence interval (CI) = 0.806, 1.019; P = 0.101] for hay fever, an OR = 0.897 (95% CI = 0.790, 1.019; P = 0.095) for asthma, an OR = 0.971 (95% CI =  0.804, 1.174; P = 0.763) for allergic sensitization and a 4.7% change (95% CI = -5.5%, 14.9%; P = 0.366) for total IgE. CONCLUSIONS: In observational analyses, ever-drinking versus not drinking was positively associated with hay fever and negatively associated with asthma. However, the Mendelian randomization results were not consistent with these associations being causal.

Percutaneous Cholecystostomy Versus Conservative Treatment for Acute Cholecystitis: a Cohort Study.

BACKGROUND: Percutaneous cholecystostomy is frequently used as a treatment option for acute calculous cholecystitis in patients unfit for surgery. There is sparse evidence on the long-term impact of cholecystostomy on gallstone-related morbidity and mortality in patients with acute calculous cholecystitis. This study describes the long-term outcome of acute calculous cholecystitis following percutaneous cholecystostomy compared to conservative treatment. METHODS: This was a cohort study of patients admitted at our institution from 2006 to 2015 with acute calculous cholecystitis without early or delayed cholecystectomy. Endpoints were gallstone-related readmissions, recurrent cholecystitis, and overall mortality. RESULTS: The investigation included 201 patients of whom 97 (48.2%) underwent percutaneous cholecystostomy. Patients in the cholecystostomy group had significantly higher age, comorbidity level, and inflammatory response at admission. The median duration of catheter placement in the cholecystostomy group was 6 days. The complication rate of cholecystostomy was 3.1% and the mortality during the index admission was 3.5%. The median follow-up was 1.6 years. The rate of gallstone-related readmissions was 38.6%, and 25.3% had recurrence of cholecystitis. Cox regression analyses revealed no significant differences in gallstone-related readmissions, recurrence of acute calculous cholecystitis, and overall mortality in the two groups. CONCLUSIONS: Percutaneous cholecystostomy in the treatment of acute calculous cholecystitis was neither associated with long-term benefits nor complications. Based on the high gallstone-related readmission rates of this study population and todays perioperative improvements, we suggest rethinking the indications for non-operative management including percutaneous cholecystostomy in acute calculous cholecystitis.

Quality of life, performance status, and work capacity after post-endoscopic retrograde cholangiopancreatography pancreatitis.

OBJECTIVES: This study evaluated the long-term consequences of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) on health related quality of life (HRQOL), performance status, and work capacity. MATERIALS AND METHODS: A follow-up study with prospective outcome measurements on patients with previous PEP and matched controls from a Danish cohort of 772 patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). HRQOL was evaluated by the short form 36 health surveys, performance status by the Zubrod score, and work capacity by employment status. Multivariable models were applied to adjust for potential confounders. RESULTS: Twenty-nine cases and 49 controls were included. Twelve (41%), eight (28%), and nine (31%) patients had mild, moderate, and severe PEP, respectively. Mean follow-up time was 4.8 ± 1.7 years. PEP was associated with long-term reduced mental HRQOL (-13.0 role-emotional score points, 95% CI: -25.4; -0.52). An increased Zubrod score representing reduced performance status was present in 12 of the 29 cases (41.4%) and in nine of the 49 controls (18.4%), p = .002. Reduced work capacity was present in 14 of the 29 cases (48.2%) and in 12 of the 49 controls (24.4%), p = .023. CONCLUSIONS: This study indicates that PEP has a detrimental effect on long-term HRQOL, performance score, and work capacity.

Screen-detected gallstone disease and autoimmune diseases - A cohort study.

BACKGROUND: Gallstone disease is highly prevalent and is associated with systemic inflammation. AIMS: To determine whether screen-detected gallstones or cholecystectomy are associated with the occurrence of autoimmune and autoinflammatory diseases and the most common subgroups thereof. METHODS: A cohort study of three randomly selected general population samples from Copenhagen was performed. Participants (n = 5928) were examined in the period 1982-1992, underwent abdominal ultrasound examination to detect gallstone disease, and followed through national registers until December 2014 (median 24.7 years) for occurrence of immunological diseases. Multivariable Cox regression analyses were performed. RESULTS: Gallstone disease was identified in 10% (591/5928) of participants, of whom 6.8% had gallstones and 3.2% had cholecystectomy at baseline. Gallstone disease was associated with incidence of autoimmune diseases (12.9% versus 7.92%; hazard ratio 1.46; 95% confidence interval [CI], [1.11;1.91]), diabetes mellitus type 1 (5.95% versus 3.67%; 1.53; [1.02;2.30]), and autoimmune thyroid disease (3.70% versus 1.59%; 2.06; [1.26;3.38]). Rheumatoid arthritis, autoinflammatory diseases, or any subgroups thereof were not associated. CONCLUSIONS: In a large general population sample, screen-detected gallstone disease was associated with the development of autoimmune diseases during long-term follow-up. Future research efforts are needed to further explore common disease mechanisms.

New determinants for gallstone disease?
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Gallstone disease is highly prevalent in Denmark and other countries of northern Europe, and cholecystectomy for the treatment of clinical gallstone disease is one the most frequently performed surgical procedures. Research efforts for the identification of mechanisms involved in gallstone formation have a long history and the most established include bile cholesterol saturation, gallbladder motor function, and the enterohepatic circulation of secondary bile salts produced by fecal microbiota. A small number of determinants that are believed to affect these mechanisms have been identified until now. However, much of this research on determinants for gallstone disease has been hampered by insufficient study designs and by insufficient assessment of gallstone disease by only assessing the selected minority of people with clinical gallstone disease. 
In a Danish general-population cohort screened for gallstone disease with multiple ultrasound examinations, it was possible to both confirm previously identified determinants and to identify new determinants for gallstone disease. Temporal associations for incident gallstone disease and female sex, BMI, non-HDL cholesterol, and inverse associations for increasing alcohol consumption and cessation of hormone replacement therapy in females were confirmed. New determinants included testosterone and increase in SHBG in males which had directly and inverse associations with incident gallstone disease, respectively. All of the identified determinants for incident gallstone disease found in this thesis can be linked to the three biological mechanisms of gallstone formation.
Other modifiable factors such as tobacco smoking, coffee consumption, dietary habits, physical activity, and blood pressure were not identified as determinants of incident gallstone disease in this thesis. Previous findings from other studies may be hampered by study design without exploration of temporal associations or due to selective assessment of gallstone disease. A common information bias for all existing literature exploring lifestyle habits and gallstone disease is the self-reported exposures which may cause misclassification bias. If explored in future studies, assessment of lifestyle habits should include objective measures in order to contribute any further to existing evidence on determinants for gallstone disease.
Associations for biomarkers of insulin resistance and gallstone disease prevalence were found. Insulin resistance probably mediates the association between BMI and gallstone disease. Although only cross-sectional, the association for both BMI and insulin resistance with gallstone disease seems well established based on existing experimental and observational evidence.
New cross-sectional associations for gallstone disease prevalence were identified for biomarkers of systemic inflammation, genetic risk for obesity or diabetes type 2, and for biomarkers of renal function. Levels of vitamin D were not identified as the cause of the higher northern European gallstone disease prevalence, although birth during season of low sun and vitamin D exposure seemed associated. 
Future clinical or larger population-based interventional trials aiming at changing body weight, circulating levels of non-HDL cholesterol, or alcohol consumption are supported by the findings of this PhD thesis. Screening of gallstone disease through ultrasound examinations should be performed in future interventional trials aiming at preventing cardiovascular disease in order to monitor the effects of such interventions on gallstone formation and, further, to avoid the selection bias caused by just assessing clinical gallstone disease. Screening for gallstone disease on the population-level is not recommended due to an assumed increase in clinical gallstone disease without a survival advantage of treatment. Explorations of male reproductive hormones, biomarkers of systemic inflammation, circulating levels of vitamin D, and genetic risk alleles should be repeated in future cohort studies before these possible determinants may be subject for future strategies for prevention or treatment of gallstone disease.

Incidence of gallstone disease and complications.

PURPOSE OF REVIEW: The purpose of this review was to describe the epidemiology of gallstone disease in the era of ultrasound screening and laparoscopic cholecystectomy. RECENT FINDINGS: Recent general population cohorts, including ultrasound screenings, have contributed to our understanding of formation and clinical course of gallstone disease. Cohorts of symptomatic gallstone disease have been informative about symptom recurrence and need of treatment. Preventive targets for gallstone formation may include obesity and the associated metabolic changes. The presence of gallstone disease is best described as a continuum from asymptomatic to symptomatic disease, with the latter including both pain attacks and complicated disease. Symptomatic disease causes a persistent high risk of symptom recurrence and need of cholecystectomy. The majority of gallstone carriers will remain asymptomatic and about one in five will develop symptoms. Determinants of disease progression from asymptomatic to symptomatic disease include sex, age, body mass index, and gallstone ultrasound characteristics. SUMMARY: Because of the absence of effective gallstone formation prevention, targets against the metabolic changes in obesity should be further explored in randomized controlled trials. To optimize patient selection for cholecystectomy, treatment algorithms including identified determinants of symptomatic disease in gallstone carriers should be explored in prospective clinical trials.

Associations of genetic determinants of serum vitamin B12 and folate concentrations with hay fever and asthma: a Mendelian randomization meta-analysis.

BACKGROUND/OBJECTIVES: Studies of the effect of vitamin B12 and folate on the risk of asthma and hay fever have shown inconsistent results that may be biased by reverse causation and confounding. We used a Mendelian randomization approach to examine a potential causal effect of vitamin B12 and folate on hay fever, asthma, and selected biomarkers of allergy by using 11 vitamin B12-associated single-nucleotide polymorphisms (SNPs) and 2 folate-associated SNPs as unconfounded markers. SUBJECTS/METHODS: We included 162,736 participants from 9 population-based studies including the UK Biobank. Results were combined in instrumental variable and meta-analyses and effects expressed as odds ratios (ORs) or estimates with 95% confidence interval (CI). RESULTS: Using genetic proxies for B12 and folate, instrumental variable analyses did not show evidence for associations between serum B12 and hay fever: OR = 1.02 (95% CI: 0.98, 1.05), asthma: OR = 0.99 (95% CI: 0.95, 1.04), allergic sensitization: OR = 1.02 (95% CI: 0.74, 1.40), or change in serum IgE: 10.0% (95% CI: -9.6%, 29.6%) per 100 pg/ml B12. Similarly, there was no evidence for association between serum folate and hay fever: OR = 0.74 (95% CI: 0.45, 1.21), asthma: OR = 0.80 (95% CI: 0.43, 1.49), or allergic sensitization: OR = 1.92 (95% CI: 0.11, 33.45), but there was a statistically significant association with change in serum IgE: 2.0% (95% CI: 0.43%, 3.58%) per 0.1 ng/ml serum folate. CONCLUSIONS: Our results did not support the hypothesis that levels of vitamin B12 and folate are causally related to hay fever, asthma, or biomarkers of allergy, but we found evidence of a positive association between serum folate and serum total IgE.

Alcohol, smoking and benign hepato-biliary disease.

Gallstone disease and pancreatitis are the most frequent benign hepato-biliary causes of hospital admissions. Gallstone disease is prevalent, but symptomatic disease develops only in about one out of five carriers. Alcohol intake seems to protect gallstone formation in cohort studies possibly through effects on bile cholesterol metabolism, the enterohepatic circulation, and gallbladder function. The impact of smoking on gallstone formation seems minor. Both alcohol intake and smoking do not alter the clinical course of gallstone disease carriers. Cholecystectomy is the preferred treatment for symptomatic gallstone disease. Studies about the impact of alcohol and smoking on the post-cholecystectomy state are few and future studies should be performed. Pancreatitis is associated with both excessive alcohol intake and smoking in observational studies. Interpretation of associations with pancreatitis is hampered by an incomplete understanding of underlying mechanisms and by the co-existence of excessive alcohol intake and smoking. Smoking cessation and alcohol abstinence is recommended in the treatment of pancreatitis, but higher-level evidence is needed.

Metabolic biomarkers and gallstone disease - a population-based study.

OBJECTIVES: The objectives for this study were to examine the associations between metabolic biomarkers of obesity including insulin resistance, vascular dysfunction, systemic inflammation, genetic susceptibility and ultrasound proven gallstone disease or cholecystectomy in a population-based cross-sectional study. MATERIAL AND METHODS: A total of 2650 participants were included, of whom 422 had gallstone disease. Associations between selected metabolic biomarkers and gallstone disease were estimated by multivariable logistic regression models and expressed as odds ratio (OR) and 95% confidence interval (CI). RESULTS: Gallstone disease was associated with fasting glucose (OR 1.14, 95% CI [1.05;1.24]), fasting insulin (OR 1.03, 95% CI [1.01;1.05]), homeostasis model assessment insulin resistance (OR 1.18, 95% CI [1.02;1.36]), the metabolic syndrome (OR 1.51, 95% CI [1.16;1.96]), white blood cell count (OR 1.07, 95% CI [1.00;1.15]) and C-reactive protein (OR 1.03, 95% CI [1.01;1.05]). A tendency towards an association for soluble urokinase plasminogen activator receptor was also found (OR 1.08, 95% CI [0.99;1.18]). The MC4R(rs17782313) (OR 1.27, 95% CI [1.02;1.58]), MAP2K5(rs2241423) (OR 1.80, 95% CI [1.04;3.41]), NRXN3(rs10146997) (OR 1.26, 95% CI [1.01;1.57]), HHEX(rs1111875) (OR 1.29, 95% CI [1.03;1.62]), FAIM2(rs7138803) (OR 0.66, 95% CI [0.48;0.91]), and apolipoprotein E4 allele (OR 0.76, 95% CI [0.59;0.98]) were associated with gallstone disease. Urinary albumin was not associated with gallstone disease. The association between BMI and gallstone disease was explained by insulin resistance. CONCLUSIONS: Biomarkers of insulin resistance, systemic inflammation and genetic obesity or type 2 diabetes risk alleles seem to be associated with gallstone disease. Future studies should explore temporal associations and genetic associations in other populations in order to clarify targets for prevention or intervention.

Screen-detected gallstone disease and cardiovascular disease.

Knowledge about temporal associations for screen-detected gallstone disease and cardiovascular disease is limited. The objective of this study was to determine if screen-detected gallstones or cholecystectomy was associated with development of cardiovascular disease. A cohort study of three randomly selected groups from the general population of Copenhagen was performed. Participants (n = 5928) were examined 1982-1992 and underwent abdominal ultrasound examination to detect gallstone disease and were not informed of their gallstone status. Participants were followed up for occurrence of cardiovascular disease through nationwide registers until December 2014. Multivariable Cox regression analyses were performed including traditional cardiovascular disease risk factors and apolipoprotein E genotype. Gallstone disease was identified in 10% (591/5928) of participants at baseline of whom 6.8% had gallstones and 3.2% had cholecystectomy. The study population was followed for a period of 32 years with only 1% lost to follow-up. Gallstone disease was associated with all cardiovascular disease (hazard ratio (HR) 1.36, 95% confidence interval (CI) [1.17;1.59]) and to the subgroups coronary artery (HR 1.34, 95% CI [1.10;1.64]), cerebrovascular (HR 1.22, 95% CI [0.97;1.52]), and peripheral artery disease (HR 1.57, 95% CI [1.15;2.13]). No differences in estimates were identified for gallstones detected at ultrasound or cholecystectomy. Adjustment did not change estimates substantially. Gallstone disease seems to be independently associated to cardiovascular disease. Associations cannot be explained through traditional cardiovascular disease risk factors, apolipoprotein E4 allele, or detection bias. Future studies should explore the link between gallstone and cardiovascular disease further and gut microbiota may be a candidate mechanism.

Association Between Screen-Detected Gallstone Disease and Cancer in a Cohort Study.

BACKGROUND & AIMS: Knowledge of temporal associations between screen-detected gallstone disease and specific cancers is limited. The objective of this study was to determine if screen-detected gallstones or cholecystectomy are associated with occurrence of gastrointestinal and nongastrointestinal cancers. METHODS: We performed a cohort study of 3 randomly selected groups from the general population of Copenhagen. Participants (N = 5928) were examined from 1982 through 1992 and underwent abdominal ultrasound examination to detect gallstone disease, but were not informed of their gallstone status. Participants were followed for the occurrence of cancers through national registers until December 2014. We performed multivariable Cox regression analyses to identify factors associated with development of cancer. RESULTS: Gallstone disease was identified in 10% of participants (591 of 5928); of these, 6.8% had gallstones and 3.2% had cholecystectomy at baseline. The population was followed for a median of 24.7 years (interquartile range, 18.9-32.4 years) with 1% lost. Pooled gastrointestinal cancers were associated with gallstone disease (11.2% of patients with gallstone disease vs 6.64% without; hazard ratio, 1.50; 95% confidence interval, 1.12-2.01). Right-side colon cancer was also associated with gallstone disease (2.57% of patients with gallstone disease vs 0.96% without; hazard ratio, 2.04; 95% confidence interval, 1.10-3.78). Pancreatic, esophageal, gastric, pooled colorectal, left-side colon, sigmoid colon, and rectal cancers were not associated with gallstone disease. Breast cancer had a weak association with gallstone disease depending on other factors (10.6% of patients with gallstone disease vs 7.41% without; hazard ratio, 1.44; 95% confidence interval, 0.99-2.11). Pooled nongastrointestinal and prostate cancers were not associated with gallstone disease. CONCLUSIONS: Screen-detected gallstone disease in the general population is associated with pooled gastrointestinal and right-side colon cancers. These associations are not due to detection bias or cholecystectomy. Further studies are needed to determine the mechanism of this association.

Which Abdominal Symptoms are Associated with Clinical Events in a Population Unaware of Their Gallstones? a Cohort Study.

BACKGROUND: High rates of persistent symptoms are found following cholecystectomy in patients with gallstones. The aim of this population based cohort study was to determine which symptoms were associated with the development of clinical gallstone events in a population unaware of their gallstones. MATERIAL AND METHODS: Three random population samples from Copenhagen (N = 6037) were examined with ultrasound during 1982-1994. Participants were not informed about gallstone status. Abdominal symptoms were assessed at baseline through a questionnaire. Follow-up for clinical events was performed through central registers until 2011. Multivariable Cox regression analyses were performed. RESULTS: Participants unaware of their gallstones (N = 595) were followed for median 17.5 years. A total of 16.6% participants developed clinical events. Both uncomplicated and complicated events were associated with high pain intensity at baseline. Complicated events were also associated with pain at night. Uncomplicated events were associated with pain localized in the epigastrium, of longer duration, and in need of pain medication. No associations were identified for dyspepsia or irritable bowel syndrome. CONCLUSIONS: In a population of unaware gallstone carriers, it was possible to identify abdominal symptoms associated with later clinical detection of the gallstones. These finding may contribute to a better selection of patients for surgery.