Association between glucagon-like peptide-1 receptor agonists and biliary-related diseases in patients with type 2 diabetes: A nationwide cohort study.

STUDY OBJECTIVE: Clinical trials have suggested that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may be associated with a higher risk of biliary-related diseases in patients with type 2 diabetes. Limited real-world studies have examined the comparative biliary safety of GLP-1RAs versus other antihyperglycemic drugs. We aimed to estimate the comparative risk of biliary-related diseases between GLP-1RAs and sodium glucose cotransporter 2 inhibitors (SGLT2is), which are indicated for patients with similar diabetes severity in Taiwan. DESIGN: Retrospective cohort study. DATA SOURCE: Taiwan National Health Insurance Database during 2011 to 2018. PATIENTS: Patients with type 2 diabetes who initiated GLP-1RAs or SGLT2is. INTERVENTION: GLP-1RAs versus SGLT2is. MEASUREMENTS AND MAIN RESULTS: We used an on-treatment approach to examine the effect of continuous use and an intention-to-treat approach to assess the effect of initiation of GLP-1RAs versus SGLT2is. We used Coxregression models to estimate the hazard ratios (HRs) and 95% confidenceintervals (CIs) for the composite hospitalized biliary-related diseases, including acute cholecystitis or cholecystectomy, choledocholithiasis, and acute cholangitis, after matching each GLP-1RA initiator to up to 10 SGLT2iinitiators using propensity scores (PSs). Among 78,253 PS-matched patients, GLP-1RA use was associated with a numerically higher risk of biliary-related diseases versus SGLT2i use in the on-treatment analysis, with an HR of 1.20 (95% CI, 0.93-1.56) for the composite outcome, an HR of 1.22 (95% CI, 0.92-1.62) for acute cholecystitis or cholecystectomy, an HR of 1.20 (95% CI, 0.69-2.07) for choledocholithiasis, and an HR of 1.14 (95% CI,0.82-2.42) for acute cholangitis. The HRs were more pronounced in theintention-to-treat analysis (1.27 [95% CI, 1.05-1.53] for the composite outcome, 1.29 [95% CI, 1.04-1.58] foracute cholecystitis or cholecystectomy, 1.74 [95% CI, 1.23-2.46] for choledocholithiasis, and 1.31 [95% CI, 0.89-1.94] for acute cholangitis). The increased risk of the composite outcome associated with GLP-1RAs was more evident in patients aged 〉60 years, women, and 120 days after treatment initiation. Liraglutide, but not dulaglutide, was associated with an elevated risk. CONCLUSIONS: GLP-1RAs might be associated with an elevated risk of biliary-related diseases compared to SGLT2is in Asian patients with type 2 diabetes.

Acute liver failure associated with Fructus Psoraleae: a case report and literature review.

BACKGROUND: Fructus Psoraleae is the seed of Psoralea corylifolia Linn. Fructus Psoraleae has been shown to be effective in treating some skin diseases, such as vitiligo. As a main ingredient in five types of herbs in the Qubaibabuqi tablet formula, Fructus Psoraleae plays an important role in the treatment of vitiligo. Fructus Psoraleae has potential hepatotoxicity, thus Qubaibabuqi tablets also have potential liver toxicity. CASE PRESENTATION: A 53-year-old woman who was diagnosed with vitiligo in September 2017 was treated with Qubaibabuqi tablets. After approximately 7 months of treatment, the patient developed a severe, diffuse yellow staining of the skin and sclera in March 2018. On admission, she was diagnosed with acute cholestatic hepatitis associated with Fructus Psoraleae. Despite receiving active treatment, her condition rapidly deteriorated and she died 5 days later due to acute liver failure and multiple organ dysfunction. To the best of our knowledge, there are only six reported cases of liver injury associated with Fructus Psoraleae described in the English language literature; however, cases of acute liver failure associated with the use of Fructus Psoraleae have not been described. CONCLUSION: As a main ingredient in the Qubaibabuqi tablet formula, Fructus Psoraleae has potential hepatotoxicity. This potentially fatal adverse effect should be considered when physicians prescribe Qubaibabuqi tablets.

FGFR3 mutation increases bladder tumourigenesis by suppressing acute inflammation.

Recent studies of muscle-invasive bladder cancer show that FGFR3 mutations are generally found in a luminal papillary tumour subtype that is characterised by better survival than other molecular subtypes. To better understand the role of FGFR3 in invasive bladder cancer, we examined the process of tumour development induced by the tobacco carcinogen OH-BBN in genetically engineered models that express mutationally activated FGFR3 S249C or FGFR3 K644E in the urothelium. Both occurrence and progression of OH-BBN-driven tumours were increased in the presence of an S249C mutation compared to wild-type control mice. Interestingly, at an early tumour initiation stage, the acute inflammatory response in OH-BBN-treated bladders was suppressed in the presence of an S249C mutation. However, at later stages of tumour progression, increased inflammation was observed in S249C tumours, long after the carcinogen administration had ceased. Early-phase neutrophil depletion using an anti-Ly6G monoclonal antibody resulted in an increased neutrophil-to-lymphocyte ratio at later stages of pathogenesis, indicative of enhanced tumour pathogenesis, which supports the hypothesis that suppression of acute inflammation could play a causative role. Statistical analyses of correlation showed that while initial bladder phenotypes in morphology and inflammation were FGFR3-dependent, increased levels of inflammation were associated with tumour progression at the later stage. This study provides a novel insight into the tumour-promoting effect of FGFR3 mutations via regulation of inflammation at the pre-tumour stage in the bladder. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Cholecystectomy during ceftriaxone therapy. A translational study with a new rabbit model

Abstract Purpose: To evaluate the actual incidence of both microlithiasis and acute cholecystitis during treatment with intravenous ceftriaxone in a new rabbit model. Methods: New Zealand rabbits were treated with intravenous ceftriaxone or saline for 21 days. Ultrasound monitoring of the gallbladder was performed every seven days until the 21st day when histopathology, immunohistochemistry for proliferating cell nuclear antigen (PCNA), pro-caspase-3 and CD68, liver enzyme biochemistry, and chromatography analysis of the bile and sediments were also performed. Results: All animals treated with ceftriaxone developed acute cholecystitis, confirmed by histopathology (P<0.05) and biliary microlithiasis, except one that exhibited sediment precipitation. In the group treated with ceftriaxone there was an increase in pro-caspase-3, gamma-glutamyl transpeptidase concentration, PCNA expression and in the number of cells positive for anti-CD68 (P<0.05). In the ceftriaxone group, the cholesterol and lecithin concentrations increased in the bile and a high concentration of ceftriaxone was found in the microlithiasis. Conclusion: Ceftriaxone administered intravenously at therapeutic doses causes a high predisposition for lithogenic bile formation and the development of acute lithiasic cholecystitis.

Cholecystectomy during ceftriaxone therapy. A translational study with a new rabbit model.

PURPOSE: To evaluate the actual incidence of both microlithiasis and acute cholecystitis during treatment with intravenous ceftriaxone in a new rabbit model. METHODS: New Zealand rabbits were treated with intravenous ceftriaxone or saline for 21 days. Ultrasound monitoring of the gallbladder was performed every seven days until the 21st day when histopathology, immunohistochemistry for proliferating cell nuclear antigen (PCNA), pro-caspase-3 and CD68, liver enzyme biochemistry, and chromatography analysis of the bile and sediments were also performed. RESULTS: All animals treated with ceftriaxone developed acute cholecystitis, confirmed by histopathology (P<0.05) and biliary microlithiasis, except one that exhibited sediment precipitation. In the group treated with ceftriaxone there was an increase in pro-caspase-3, gamma-glutamyl transpeptidase concentration, PCNA expression and in the number of cells positive for anti-CD68 (P<0.05). In the ceftriaxone group, the cholesterol and lecithin concentrations increased in the bile and a high concentration of ceftriaxone was found in the microlithiasis. CONCLUSION: Ceftriaxone administered intravenously at therapeutic doses causes a high predisposition for lithogenic bile formation and the development of acute lithiasic cholecystitis.

Incretin-based therapy and acute cholecystitis: a review of case reports and EudraVigilance spontaneous adverse drug reaction reporting database.

WHAT IS KNOWN AND OBJECTIVE: Glucagon-like peptide-1 (GLP-1) receptor agonists delay gastric and bowel emptying. A similar inhibitory effect of GLP-1 on gallbladder motility has been suggested, possibly leading to an increased risk of cholecystitis related to incretin-based medications, which include GLP-1 antagonists. Our objective was to review evidence in EudraVigilance, the European spontaneous reporting database and the scientific literature on this issue. COMMENT: Increasing evidence suggests an association of incretins with gallbladder adverse events. Pharmacovigilance data from EudraVigilance includes 200 serious ADR reports concerning cholecystitis related to the use of incretin-based therapies. Several mechanisms may explain this increased risk of cholecystitis, including rapid weight loss, inhibition of gallbladder contraction and emptying, reduced bile acids production, modulation of inflammation. WHAT IS NEW AND CONCLUSIONS: The available data suggest the possibility of gallbladder disease in diabetic subjects treated with incretins and highlight the importance of evaluating risk factors for cholelithiasis and gallbladder diseases in patients with diabetes before starting this therapy.

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.

Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial.

BACKGROUND: Autosomal dominant polycystic kidney disease slowly progresses to end-stage renal disease and has no effective therapy. A pilot study suggested that the somatostatin analogue octreotide longacting release (LAR) could be nephroprotective in this context. We aimed to assess the effect of 3 years of octreotide-LAR treatment on kidney and cyst growth and renal function decline in participants with this disorder. METHODS: We did an academic, multicentre, randomised, single-blind, placebo-controlled, parallel-group trial in five hospitals in Italy. Adult (>18 years) patients with estimated glomerular filtration rate (GFR) of 40 mL/min per 1·73 m(2) or higher were randomly assigned (central allocation by phone with a computerised list, 1:1 ratio, stratified by centre, block size four and eight) to 3 year treatment with two 20 mg intramuscular injections of octreotide-LAR (n=40) or 0·9% sodium chloride solution (n=39) every 28 days. Study physicians and nurses were aware of the allocated group; participants and outcome assessors were masked to allocation. The primary endpoint was change in total kidney volume (TKV), measured by MRI, at 1 year and 3 year follow-up. Analyses were by modified intention to treat. This study is registered with ClinicalTrials.gov, NCT00309283. FINDINGS: Recruitment was between April 27, 2006, and May 12, 2008. 38 patients in the octreotide-LAR group and 37 patients in the placebo group had evaluable MRI scans at 1 year follow-up, at this timepoint, mean TKV increased significantly less in the octreotide-LAR group (46·2 mL, SE 18·2) compared with the placebo group (143·7 mL, 26·0; p=0·032). 35 patients in each group had evaluable MRI scans at 3 year follow-up, at this timepoint, mean TKV increase in the octreotide-LAR group (220·1 mL, 49·1) was numerically smaller than in the placebo group (454·3 mL, 80·8), but the difference was not significant (p=0·25). 37 (92·5%) participants in the octreotide-LAR group and 32 (82·1%) in the placebo group had at least one adverse event (p=0·16). Participants with serious adverse events were similarly distributed in the two treatment groups. However, four cases of cholelithiasis or acute cholecystitis occurred in the octreotide-LAR group and were probably treatment-related. INTERPRETATION: These findings provide the background for large randomised controlled trials to test the protective effect of somatostatin analogues against renal function loss and progression to end-stage kidney disease. FUNDING: Polycystic Kidney Disease Foundation.

Acute ischemic cholecystitis after transarterial chemoembolization with drug-eluting beads.

Transarterial chemoembolization (TACE) is a widely used treatment choice for hepatocellular cancer. DC Bead microspheres are a new embolic material for TACE that doxorubicin can be loaded to. The tumor response rate of this well-tolerated treatment was changed between 60% and 81.8%. We report a case of ischemic cholecystitis after TACE with drug-eluting beads (DEB) that required cholecystectomy. The possibility of cholecystitis is always remembered during TACE-DEB for tumors in segment IV and/or V. Although selective catheterization is related with a lower risk for ischemic cholecystitis, the anatomic and vascular variability in patients with malignancy may lead to some unexpected conditions.

Spontaneous haemorrhagic perforation of gallbladder in acute cholecystitis as a complication of antiplatelet, immunosuppressant and corticosteroid therapy.

An older lady presented 1 week after being discharged from hospital with acute cholecystitis. She suffered a sudden onset lower abdominal pain and was in hypovolaemic shock upon arrival. It was noted that she had been on antiplatelet therapy after suffering a recent myocardial infarction, an immunosuppressor and steroids for rheumatoid arthritis. Her admission bloods revealed a platelet count of 83 with normal clotting factors. After resuscitation, a CT scan confirmed fluid in the abdomen possibly arising from the right subhepatic space. During laparotomy, bleeding was noted from a perforated and ischaemic-looking gallbladder, with an intact cystic artery and duct and no biliary calculi evident. The gallbladder was removed and the patient was transferred to intensive therapy unit. She recovered well within the subsequent 8 days and was discharged. Her histology described 'haemorrhage within the gallbladder wall along with oedema, fibrosis and patchy inflammation and no signs of malignancy or gangrene'.

Gallbladder hemorrhage mimicking acute cholecystitis in a patient under antiplatelet therapy.

Hemorrhage within the gallbladder is rare but potentially fatal. It can be easily overlooked and misdiagnosed because of its low incidence and presentation that is similar to other types of hepatobiliary disease. We present an unusual case of gallbladder hemorrhage in a 36-year-old male patient who was taking antiplatelet medication following cardiac surgery. The patient was misdiagnosed with acute primary cholecystitis and, in consideration of postoperative complications with cardiovascular comorbities, serial treatment with urgent percutaneous transhepatic gallbladder drainage and delayed laparoscopic cholecystectomy was prescribed. Unexpectedly, a gallbladder hemorrhage was intraoperatively confirmed as the gallbladder appeared filled with dark blood clot-like materials. The patient recovered well and was discharged on the 3rd postoperative day without complications. In patients who are on antiplatelet therapy, gallbladder hemorrhage should be considered in the differential diagnosis if they have symptoms typical of biliary colic. In addition, delayed surgery with prompt biliary diversion may represent a safe and effective treatment approach.

Acute cholecystitis in a patient with metastatic renal cell carcinoma treated with everolimus.

Everolimus (RAD001) is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), a therapeutic target for metastatic renal cell carcinoma. A 58-year-old woman was treated with everolimus as a third-line therapy for metastatic clear-cell renal carcinoma. She was given oral everolimus 10 mg once daily. During the fourth week of her first cycle, the patient was admitted to our hospital because of an acute-onset, right upper quadrant pain associated with nausea and vomiting. She was diagnosed with acute cholecystitis, which was treated with broad-spectrum antibiotics, and everolimus therapy was discontinued. A follow-up computed tomography scan of the abdomen revealed a complete resolution of gallbladder changes. Our patient did not have major risk factors for developing a cholecystitis except for a relative immunosuppressed state secondary to her advanced renal cancer. The Naranjo adverse drug reaction probability scale score for this event was 5, indicating a probable association of the event with everolimus. Because the use of everolimus is expanding in clinical practice, we want to alert the oncology community about this uncommon and life-threatening complication in patients receiving everolimus or another agent with antiangiogenic activity. To our best knowledge, only one case of an acute cholangitis associated with everolimus in a metastatic renal cell carcinoma has been reported. We report herein the first case of a metastatic renal cell carcinoma developed everolimus-associated cholecystitis that was completely reversed after drug withdrawal.

Hemorrhagic cholecystitis as a complication of anticoagulant therapy: role of CT in its diagnosis.

Hemorrhage within the gallbladder lumen is a rare but potentially fatal complication of acute cholecystitis. Concomitant anticoagulant therapy increases the chances of hemorrhage. In this case report we describe one such case which showed active extravasation of the contrast into the lumen of the gallbladder. Early diagnosis of this potentially fatal condition is important to facilitate urgent surgical treatment.

[Painless jaundice after holidays in Tanzania]. / Schmerzloser Ikterus nach Urlaub in Tansania.

The side effects caused by malaria prophylaxis with mefloquine (Lariam) are well known. We describe the case of a 42-year-old female Caucasian patient suffering from painless jaundice and showing elevated liver, cholestasis and inflammation laboratory findings 7 days after returning from Tanzania. Acute cholecystitis was diagnosed by ultrasound. Treatment with parenteral nutrition and antibiotic therapy did not show any beneficial effect. Excluding the possibility of infectious diseases, the elevated laboratory and ultrasound findings were normalized after the discontinuation of the malaria prophylaxis.

Endogenous endothelin increases gallbladder tone and leads to acute cholecystitis in the Australian possum.

Endothelins are bioactive peptides produced by gallbladder epithelial cells. We aimed to determine the role of endothelins in acute cholecystitis. Escherichia coli lipopolysaccharide vs saline (sham) was instilled into the gallbladder lumen of Australian possums. Some animals received the non-selective endothelin antagonist, tezosentan. At 4 or 24 h, plasma and gallbladder endothelins and white blood cell count (WBCC) were determined. Acute cholecystitis was assessed using a histopathology score. In other animals gallbladder tone was determined. At 4h, a dose-dependent 60-fold increase in gallbladder endothelin level occurred (P = 0.001) but other parameters remained comparable with sham animals. Epithelial cells were endothelin-immunoreactive. At 24 h, the WBCC rose (P < 0.007), and severe cholecystitis developed. Gallbladder but not plasma endothelin levels remained elevated. Tezosentan pre-treatment resulted in a histologically normal gallbladder, but the WBCC and gallbladder endothelin levels were elevated. Lipopolysaccharide or saline instillation also caused a time-dependent increase in gallbladder tone over 4 h (P < 0.001), but not in control animals. This increase was reduced by tezosentan treatment. Gallbladder endothelin production is an early event in acute cholecystitis, increases gallbladder tone and plays a crucial role in the inflammatory process.

Acute cholecystitis as a complication following percutaneous ethanol injection of a hepatocellular carcinoma.

UNLABELLED: Percutaneous ethanol injection is a useful option in the treatment of hepatocellular carcinoma which are not amenable to resection or transplantation. We describe a case of cholecystitis and tumour infiltration of the gallbladder after percutaneous ethanol injection, a complication not previously described in literature. The patient was a 70-year-old woman with a history of asymptomatic HCV+ hepatopathy and a 6 cm hepatocellular carcinoma nodule in segment V which had been treated two months before by percutaneous ethanol injection in another center. She attended our center due to febrile syndrome. Imaging studies suggested cholecystitis with an abscess on the wall of the gallbladder, purulent material obtained by means of a CT-guided puncture. Surgery revealed purulent and neoplasic material inside the gallbladder, with tumor invasion of the posterior wall; a partial cholecystectomy was therefore performed and a drainage inserted. The patient showed no post-operative complications and was discharged after seven days. CONCLUSION: we believe that the percutaneous ethanol injection of hepatocellular carcinomas located close to the gallbladder may occasionally lead to complications in the form of cholecystitis with neoplasic infiltration of the gallbladder. A case of cholecystitis secondary to radiofrequency treatment of a similarly-located tumor has previously been described and, therefore, the use of percutaneous local destructive treatments for tumors close to the gallbladder would seem unadvisable.