Dipeptidyl Peptidase-4 Inhibitors and the Risk of Gallbladder and Bile Duct Disease Among Patients with Type 2 Diabetes: A Population-Based Cohort Study.

INTRODUCTION: The use of dipeptidyl peptidase-4 (DPP-4) inhibitors may be associated with an increased risk of gallbladder and bile duct disease among patients with type 2 diabetes. METHODS: We conducted a population-based cohort study using an active comparator, new-user design. We used data from the United Kingdom Clinical Practice Research Datalink to identify patients newly treated with either a DPP-4 inhibitor or sodium-glucose cotransporter-2 (SGLT-2) inhibitor between January 2013 and December 2020. We fitted Cox proportional hazards models with propensity score fine stratification weighting to estimate the hazard ratio (HR) and its 95% confidence interval (CI) for incident gallbladder and bile duct disease associated with DPP-4 inhibitors compared to SGLT-2 inhibitors. RESULTS: DPP-4 inhibitors were associated with a 46% increased risk of gallbladder and bile duct disease (4.3 vs. 3.0 events per 1000 person-years, HR 1.46, 95% CI 1.17-1.83). At 6 months and 1 year, 745 and 948 patients, respectively, would need to be treated with DPP-4 inhibitors for one patient to experience a gallbladder or bile duct disease. CONCLUSIONS: In this population-based cohort study, the use of DPP-4 inhibitors, when compared with SGLT-2 inhibitors, was associated with a moderately increased risk of gallbladder and bile duct disease among patients with type 2 diabetes. This outcome was still quite rare with a high number needed to harm at 6 months and 1 year.

Short-term impact of air pollution, noise and temperature on emergency hospital admissions in Madrid (Spain) due to liver and gallbladder diseases.

BACKGROUND: Very few epidemiological studies have explored the environmental and meteorological risk factors that influence liver diseases and gallbladder disorders, and no studies have addressed the specific case of Spain. METHODS: This is a retrospective ecological study conducted during 2013-2018. We analysed emergency admissions in the central area of the Region of Madrid for the following causes: Liver and gallbladder diseases (L&GB) (ICD-10: K70-K81); disorders of gallbladder (DGB) (ICD 10: K80-K81); liver disease (LD) (ICD 10: K70-K77); alcoholic liver disease (ALD) (ICD-10: K70); viral hepatitis (VH) (ICD10:B15-B19); and hepatic failure, not elsewhere classified (HFNS) (ICD-10: K72). Independent variables used: meteorological (maximum daily temperature (Tmax in °C), minimum daily temperature (Tmin in °C), and relative humidity (RH in %)); chemical air pollution (8-hO3, NO2, PM10, PM2.5 in µg/m3); and noise pollution (equivalent level of daily noise (Ld in dB(A)). Transformed variables: extreme heat in degrees (Theat); wet cold (WC); and high ozone. We fitted Poisson models, negative binomials and zero-inflated Poisson controlled for seasonality, day of the week, holidays, trend, and autoregressive trend. Based on these models, the percentage of cases attributable to statistically significant risk factors was then estimated. RESULTS: In L&GB emergency admissions daily noise is related to 4.4% (CI95%: 0.8 7.9) of admissions; NO2 to 2.9% (CI95%: 0.1 5.7) and wet cold to 0.2% (CI95%: 0.8 7.9). Heat wave temperature was only related to ALD. In addition, the wet cold association with L&GB is also related to HFNS attributing 1.0% (CI95%: 0.3 1.8) of admissions for this cause. CONCLUSIONS: Daily noise and NO2 are associated with more than 7% of urgent L&GB admissions. Both pollutants, are mainly emitted by road traffic. A reduction of traffic in cities would result in a reduction of emergency admissions due to this cause.

Prenatal diethylstilbestrol exposure and risk of diabetes, gallbladder disease, and pancreatic disorders and malignancies.

Prenatal diethylstilbestrol (DES) exposure is associated with increased risk of hormonally mediated cancers and other medical conditions. We evaluated the association between DES and risk of pancreatic cancer and pancreatic disorders, type 2 diabetes, and gallbladder disease, which may be involved with this malignancy. Our analyses used follow-up data from the US National Cancer Institute DES Combined Cohort Study. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for age, sex, cohort, body mass index, smoking, and alcohol for the association between prenatal DES exposure and type 2 diabetes, gallbladder disease (mainly cholelithiasis), pancreatic disorders (mainly pancreatitis), and pancreatic cancer among 5667 exposed and 3315 unexposed individuals followed from 1990 to 2017. Standardized incidence rate (SIR) ratios for pancreatic cancer were based on age-, race-, and calendar year-specific general population cancer incidence rates. In women and men combined, the hazards for total pancreatic disorders and pancreatitis were greater in the prenatally DES exposed than the unexposed (HR = 11, 95% CI 2.6-51 and HR = 7.0, 95% CI 1.5-33, respectively). DES was not associated overall with gallbladder disease (HR = 1.2, 95% CI 0.88-1.5) or diabetes (HR = 1.1, 95% CI 0.9-1.2). In women, but not in men, DES exposure was associated with increased risk of pancreatic cancer compared with the unexposed (HR: 4.1, 95% CI 0.84-20) or general population (SIR: 1.9, 95% CI 1.0-3.2). Prenatal DES exposure may increase the risk of pancreatic disorders, including pancreatitis in women and men. The data suggested elevated pancreatic cancer risk in DES-exposed women, but not in exposed men.

Ceftriaxone-associated Pseudolithiasis in the Gallbladder and Bile Duct of an Elderly Patient.

A 78-year-old man had been undergoing treatment with Cefamezin for pyogenic spondylitis. Because of complication of a urinary tract infection, the medication was switched to ceftriaxone (CTRX) 2 g/day. On day 18 after starting CTRX, the patient began experiencing abdominal pain. Computed tomography (CT) and endoscopic ultrasound led to the identification of calculi in the gallbladder and extrahepatic bile duct with a peculiar formation. We suspected CTRX-associated pseudo-cholecystolithiasis and pseudo-choledocholithiasis, although CT performed at admission had shown no such findings. Therefore, CTRX was discontinued. By day 17 after CTRX cessation, both the pseudo-cholecystolithiasis and pseudo-choledocholithiasis had disappeared.

Repeated Perforation of the Gallbladder in a Patient with Hepatocellular Carcinoma Receiving Lenvatinib.

A 59-year-old man who was receiving lenvatinib as a third-line tyrosine kinase inhibitor to treat hepatocellular carcinoma and multiple bone metastases complained of general fatigue four months after starting lenvatinib. A blood examination showed unexpectedly elevated serum C-reactive protein (CRP) levels. Computed tomography (CT) revealed rupture of the gallbladder wall, indicating gallbladder perforation. After conservative treatment, the patient received lenvatinib again under informed consent; however, one month later, CT revealed repeated rupture of the gallbladder wall. Gallbladder perforation had again been induced by lenvatinib. For this reason, lenvatinib is strongly considered a causative drug for gallbladder perforation.

Gallbladder hemorrhage during orally administered edoxaban therapy: a case report.

BACKGROUND: Edoxaban is an orally administered anticoagulant treatment that is used in patients with cerebral infarction, venous thrombosis, or other conditions, with a reported incidence of gastrointestinal hemorrhage at approximately 1%. We encountered the rare case of a patient who developed a gallbladder hemorrhage after the administration of edoxaban. CASE PRESENTATION: An 86-year-old Japanese woman visited our gastrointestinal department due to the chief complaint of melena lasting for a week. Her medical history included hypertension and embolic cerebral infarction, and she was taking orally administered carvedilol (5 mg/day) and edoxaban (30 mg/day). Her palpebral conjunctiva was pale during a physical examination, indicating the possibility of anemia. Her blood test results confirmed severe anemia with red blood cells at 1.7 × 106/µL and hemoglobin at 4.7 g/dL. An upper gastrointestinal endoscopy revealed bile and fresh blood on the duodenal bulb and in more distal regions; hemobilia was suspected. A computed tomography scan on the ninth hospitalization day confirmed the hemobilia with a gallbladder fundus high-density signal. She was discharged on the 30th day of hospitalization with only fluid therapy and no progression of anemia. Moreover, she underwent a laparoscopic cholecystectomy 1 month after discharge, but the pathologist did not identify false aneurysms or neoplastic lesions. She has not been shown to develop anemia for 5 months after surgery. CONCLUSIONS: Our case suggests that gallbladder hemorrhage needs to be considered a possible complication for patients on direct oral anticoagulants.

[Hemocholecyst complicated by rupture of the gallbladder]. / Hémocholécyste compliquée d'une rupture de la vésicule biliaire.

Hemocholecyst is defined as a hemorrhage into the gallbladder. It is a rare complication of anticoagulant therapies which can progress to spontaneous rupture of the gallbladder with hemorrhagic shock. We report the case of a 75-year old hypertensive, dyslipidemic man with hypertensive heart disease initially hospitalized for left hemiplegia. The patient received antiplatelet and anticoagulant therapy with low molecular weight heparin (LMWH) as prevention strategy. After 5 days of treatment the patient developed hemocholecyst and hemoperitoneum, confirmed by angio-abdominal computerized tomography scan in emergency assessment. The patient underwent cholecystectomy, hemostasis of the gallbladder fossa and evacuation of the hemoperitoneum.

Computed tomography findings of ceftriaxone-associated biliary pseudocholelithiasis in adults.

PURPOSE: This study aimed to characterize the computed tomography (CT) findings of pseudolithiasis and investigate the outcomes and natural history in adult patients receiving CTRX therapy. METHODS: A total of 17 patients were diagnosed with CTRX-associated biliary pseudolithiasis on CT between April 2013 and March 2017. The medical records, characteristics, complications, treatment options, and outcomes of these patients were examined. Serial CT images and the form, density, and location of pseudolithiasis were reviewed by two radiologists. RESULTS: Of the 17 patients with CTRX-associated pseudolithiasis, seven were men and ten were women. The median patient age was 78 years (range 31-88 years). The median interval from CTRX administration to the diagnosis of pseudolithiasis was 10 days (range 4-32 days). The CT findings of pseudolithiasis included a sludge pattern (11 patients [64.7%]), stone pattern (two patients [11.8%]), and stone plus sludge pattern (four patients [23.5%]). Seven patients (41.2%) showed gall bladder enlargement along with a common bile duct (CBD) stone. Two patients with CBD stones underwent endoscopic CBD stone removal. The median time to pseudolithiasis resolution after CTRX cessation was 69 days. CONCLUSION: The high-density sludge pattern is the most common typical CT finding of CTRX-associated pseudolithiasis in adults.

Metformin treatment prevents gallstone formation but mimics porcelain gallbladder in C57Bl/6 mice.

Gallstone disease (GD) is highly correlated with metabolic syndrome and its related illnesses including type II diabetes (DMII) and polycystic ovary syndrome (PCOS). While previous studies claimed that metformin decreases the chance of developing GD in PCOS patients, this phenomenon has not been investigated in animal models to date. Here we fed a high fat diet (HFD) containing 2% of cholesterol and 1% of cholic acid to ten-week-old male C57Bl/6 mice for 105 days. The groups were as follows: Low fat diet; HFD; HFD + Ursodeoxycholic acid (UDCA) (day 1-105); HFD + Metformin (day 1-105); HFD + Metformin (Met) (day 64-105). All drugs were administered by oral gavage (Met = 300 mg/kg & UDCA = 750 mg/kg). Serum lipid profile and gross organ examination were performed after euthanasia. A microscopic evaluation of the paraffin-embedded gallbladders was done after hematoxylin & eosin and Von Kossa staining. HFD successfully induces gallstone (4 out of 4 of the HFD members). While both UDCA and metformin (d 1-105) prevented gallstone formation and cholecystitis, Metformin (d 64-105) group had a few small stones. Additionally, metformin induces mucosal calcification in gallbladder (porcelain GB) of more than 80% of the HFD + Met (day 1-105) and HFD + Met (day 64-105) groups, collectively, which can be a potential problem by itself. While metformin shows a noticeable benefit towards GB health by reducing the chance for gallstone formation, if it induces porcelain gallbladder in humans as well, it might inflict patients with preventable medical charges.

Association of Bile Duct and Gallbladder Diseases With the Use of Incretin-Based Drugs in Patients With Type 2 Diabetes Mellitus.

IMPORTANCE: The use of dipeptidyl-peptidase-4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) analogues-a group of drugs used in the management of type 2 diabetes mellitus-may be associated with an increased risk of bile duct and gallbladder disease. To date, no observational study has assessed this possible association. OBJECTIVE: To determine whether the use of DPP-4 inhibitors and GLP-1 analogues is associated with an increased risk of incident bile duct and gallbladder disease in patients with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS: A population-based cohort study linked the United Kingdom Clinical Practice Research Datalink with the Hospital Episodes Statistics database, yielding a cohort of 71 369 patients, 18 years or older, initiating an antidiabetic drug (including oral and injectable agents) between January 1, 2007, and March 31, 2014. EXPOSURES: Current use of DPP-4 inhibitors and GLP-1 analogues (alone or in combination therapy) compared with current use of at least 2 oral antidiabetic drugs. MAIN OUTCOMES AND MEASURES: Time-dependent Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% CIs of incident bile duct or gallbladder events (cholelithiasis, cholecystitis, cholangitis) causing hospitalization, comparing current use of DPP-4 inhibitors and GLP-1 analogues with current use of at least 2 oral antidiabetic drugs. RESULTS: During 227 994 person-years of follow-up, 853 of the 71 369 patients were hospitalized for bile duct and gallbladder disease (incidence rate per 1000 person-years, 3.7; 95% CI, 3.5-4.0). Current use of DPP-4 inhibitors was not associated with an increased risk of bile duct and gallbladder disease compared with current use of at least 2 oral antidiabetic drugs (3.6 vs 3.3 per 1000 person-years; adjusted HR, 0.99; 95% CI, 0.75-1.32). In contrast, the use of GLP-1 analogues was associated with an increased risk of bile duct and gallbladder disease compared with current use of at least 2 oral antidiabetic drugs (6.1 vs 3.3 per 1000 person-years; adjusted HR, 1.79; 95% CI, 1.21-2.67). In a secondary analysis, GLP-1 analogues were also associated with an increased risk of cholecystectomy (adjusted HR, 2.08; 95% CI, 1.08-4.02). CONCLUSIONS AND RELEVANCE: The use of GLP-1 analogues was associated with an increased risk of bile duct and gallbladder disease. Physicians should be aware of this potential adverse event when prescribing these drugs.

Tissue distribution and acute toxicity of silver after single intravenous administration in mice: nano-specific and size-dependent effects.

BACKGROUND: Silver nanoparticles (AgNPs) are an important class of nanomaterials used as antimicrobial agents for a wide range of medical and industrial applications. However toxicity of AgNPs and impact of their physicochemical characteristics in in vivo models still need to be comprehensively characterized. The aim of this study was to investigate the effect of size and coating on tissue distribution and toxicity of AgNPs after intravenous administration in mice, and compare the results with those obtained after silver acetate administration. METHODS: Male CD-1(ICR) mice were intravenously injected with AgNPs of different sizes (10 nm, 40 nm, 100 nm), citrate-or polyvinylpyrrolidone-coated, at a single dose of 10 mg/kg bw. An equivalent dose of silver ions was administered as silver acetate. Mice were euthanized 24 h after the treatment, and silver quantification by ICP-MS and histopathology were performed on spleen, liver, lungs, kidneys, brain, and blood. RESULTS: For all particle sizes, regardless of their coating, the highest silver concentrations were found in the spleen and liver, followed by lung, kidney, and brain. Silver concentrations were significantly higher in the spleen, lung, kidney, brain, and blood of mice treated with 10 nm AgNPs than those treated with larger particles. Relevant toxic effects (midzonal hepatocellular necrosis, gall bladder hemorrhage) were found in mice treated with 10 nm AgNPs, while in mice treated with 40 nm and 100 nm AgNPs lesions were milder or negligible, respectively. In mice treated with silver acetate, silver concentrations were significantly lower in the spleen and lung, and higher in the kidney than in mice treated with 10 nm AgNPs, and a different target organ of toxicity was identified (kidney). CONCLUSIONS: Administration of the smallest (10 nm) nanoparticles resulted in enhanced silver tissue distribution and overt hepatobiliary toxicity compared to larger ones (40 and 100 nm), while coating had no relevant impact. Distinct patterns of tissue distribution and toxicity were observed after silver acetate administration. It is concluded that if AgNPs become systemically available, they behave differently from ionic silver, exerting distinct and size-dependent effects, strictly related to the nanoparticulate form.

[CEFTRIAXONE-INDUCED GALLBADDER LITHIASIS IN CASE OF INTENSTINAL BACTERIAL INFECTIONS (CASE REPORTS)].

Ceftriaxone is a third generation cephalosporin antibiotic and is one of the most often applicable parenteral drug, which has wide antimicrobial activity range. According to the literature gall bladder lithiasis is a complication which is described in the first days of the treatment with this antibiotic. The cases are seen mostly as undergdiagnosed conditions when ultrasound examination is performed due to the abdominal colics. The aim of the study was to observe Cholelithiasis in ceftriaxone-treated patients. Last year few cases of Cholelithiasis were observed in Children's Infectious Diseases Hospital. All of them were related to the dysentery treatment with ceftriaxone. All of the cases of Cholelithiasis were diagnosed at the beginning of the antibiotic therapy (in first 2-3 days of hospitalization). Gall bladder concernments/sludge were found accidentally. Cholelithiasis in these cases was transitory and in 2 weeks ultrasound investigation revealed no calculi/sludge in the gall bladder. Further findings are supposed to be analyzed on a bigger number of the patients. It is necessary to follow up with gall bladder concernments till their absolute resolution.

Association of Gallbladder Mucocele Histologic Diagnosis with Selected Drug Use in Dogs: A Matched Case-Control Study.

BACKGROUND: The cause of gallbladder mucocele (GBM) formation in dogs currently is unknown. Many available drugs represent a newer generation of xenobiotics that may predispose dogs to GBM formation. OBJECTIVE: To determine if there is an association between the histologic diagnosis of GBM in dogs and administration of selected drugs. ANIMALS: Eighty-one dogs with a histologic diagnosis of GBM and 162 breed, age, and admission date-matched control dogs from a single referral institution. METHODS: Medical records of dogs with GBM and control dogs from 2001 to 2011 were reviewed. Owner verification of drug history was sought by a standard questionnaire. Reported use of heartworm, flea, and tick preventatives as well as nonsteroidal anti-inflammatory drugs, analgesics, corticosteroids, or medications for treatment of osteoarthritis was recorded. RESULTS: Dogs with GBM were 2.2 times as likely to have had reported use of thyroxine (as a proxy for the diagnosis of hypothyroidism) as control dogs (95% confidence interval [CI], 0.949-5.051), 3.6 times as likely to have had reported treatment for Cushing's disease (95% CI, 1.228-10.612), and 2.3 times as likely to have had reported use of products containing imidacloprid (95% CI, 1.094-4.723). Analysis of a data subset containing only Shetland sheepdogs (23 GBM and 46 control) indicated that Shetland sheepdogs with GBM formation were 9.3 times as likely to have had reported use of imidacloprid as were control Shetland sheepdogs (95% CI, 1.103-78.239). CONCLUSIONS AND CLINICAL IMPORTANCE: This study provides evidence for an association between selected drug use and GBM formation in dogs. A larger epidemiologic study of Shetland sheepdogs with GBM formation and exposure to imidacloprid is warranted.

Ceftriaxone-associated acute gallbladder enlargement - an unexpected diagnosis in the child with urinary tract infection.

UNLABELLED: Biliary sludge and/or biliary pseudolithiasis occur in patients treated with ceftriaxone with prevalence of 3-57%. Biliary obstruction can be the cause of the acute gallbladder enlargement. It is a minor complication, that usually does not give clinical symptoms and resolves once the drug is discontinued. The authors present a case of a 5-month old boy treated for the acute pyelonephritis. Routine ultrasound, performed on the 5th day of treatment with ceftriaxone, showed gallbladder enlargement. In the consecutive studies small gallblader sludge was visible. Patient had no symptoms related to the gallbladder enlargement. Ultrasound performed 6 weeks from the drug discontinuation was completely normal. CONCLUSIONS: Patients treated with ceftroiaxone should be monitored for biliary sludge and pseudolithiasis.

SIDE EFFECTS OF TUBERCULOSIS TREATMENT WITH FIXED-DOSE COMBINATIONS.

This paper aimed to explore the therapeutic effect and safety of Fixed-dose Combinations (FDCs) on tuberculosis. A computer search was carried out to review the literature related to clinical randomized controlled trials (RCTs) and clinical controlled trails (CCTs) on the curative effect and safety of treating pulmonary tuberculosis with FDCs. The results demonstrated that, in the 22 studies examined, comparison of sputum negative conservation rate of treating smear-positive pulmonary tuberculosis with FDCs and single drug, the relative risk (RR) value and 95% confidence interval (CI) were 1.02 (1.01, 1.03) and 1.01 (1.00, 1.02), respectively, at the end of the 2nd month and 6th month (P<0.05), while comparison of the relapse rate within six months showed that RR value and 95% CI was 1.72 (0.98, 3.02) (P>0.05). No statistically significant differences were found between the two groups in total occurrence of the rates of side effects pertaining to skin reaction, gastrointestinal tract side reaction, occurrence rate of liver and gall side reaction or occurrence rate of drug withdrawal because of side effects (P>0.05). After sensitivity analysis, it was found that occurrence rate of gastrointestinal tract side effects and occurrence rate of liver and gall side effects were unstable. All the findings suggest that the curative effect of treating tuberculosis with FDCs is better than that of a single drug. More reliable evidence is required since the safety evaluation results are not stable.

Novel finding of carbamazepine induced gall bladder granulomatous vasculitis.

We report a 63-year-old male patient who presented with eosinophilic granulomatous vasculitis of the gall bladder secondary to carbamazepine drug therapy. Following commencement of carbamazepine for treatment of partial seizures, the patient developed an allergic cutaneous drug rash. He continued to take carbamazepine postdischarge despite cessation by the treating team. He represented 7 weeks later with acute pancreatitis and cholecystis. Gall bladder histopathology showed a granulomatous vasculitis.

Gallbladder complications associated with molecular targeted therapies: clinical and imaging features.

OBJECTIVES: To evaluate the clinical and imaging features of molecular target therapies (MTT)-associated gallbladder complications. METHODS: The clinical presentation, imaging features, management, and outcome in six consecutive patients, who developed gallbladder complications while on monotherapy with MTT, were studied. RESULTS: Imaging features included gallbladder distension, edema, hyperemia, pericholecystic fluid, and stranding. Two of the six patients were asymptomatic and continued the drug due to good response. Four of the six patients developed acute cholecystitis and required drug discontinuation temporarily or permanently with 2/4 patients requiring surgery. CONCLUSION: MTT can be associated with gallbladder complications that may need temporary or permanent discontinuation of the associated drug.