Background Cholangiocarcinomas are a heterogeneous group of malignancies arising from a number of cells of origin along the biliary tree. Although most cases in Western countries are sporadic, large population-based studies have identified a number of risk factors. This review summarises the evidence behind reported risk factors and current understanding of the molecular pathogenesis of cholangiocarcinoma, with a focus on inflammation and cholestasis as the driving forces in cholangiocarcinoma development. Risk Factors for cholangiocarcinogenesis Cholestatic liver diseases (e.g. primary sclerosing cholangitis and fibropolycystic liver diseases), liver cirrhosis, and biliary stone disease all increase the risk of cholangiocarcinoma. Certain bacterial, viral or parasitic infections such as hepatitis B and C and liver flukes also increase cholangiocarcinoma risk. Other risk factors include inflammatory disorders (such as inflammatory bowel disease and chronic pancreatitis), toxins (e.g. alcohol and tobacco), metabolic conditions (diabetes, obesity and non-alcoholic fatty liver disease) and a number of genetic disorders. Molecular pathogenesis of cholangiocarcinoma Regardless of aetiology, most risk factors cause chronic inflammation or cholestasis. Chronic inflammation leads to increased exposure of cholangiocytes to the inflammatory mediators interleukin-6, Tumour Necrosis Factor-ɑ, Cyclo-oxygenase-2 and Wnt, resulting in progressive mutations in tumour suppressor genes, proto-oncogenes and DNA mismatch-repair genes. Accumulating bile acids from cholestasis lead to reduced pH, increased apoptosis and activation of ERK1/2, Akt and NF-κB pathways that encourage cell proliferation, migration and survival. Other mediators upregulated in cholangiocarcinoma include Transforming Growth Factor-β, Vascular Endothelial Growth Factor, Hepatocyte Growth Factor and several microRNAs. Increased expression of the cell surface receptor c-Met, the glucose transporter GLUT-1 and the sodium iodide symporter lead to tumour growth, angiogenesis and cell migration. Stromal changes are also observed, resulting in alterations to the extracellular matrix composition and recruitment of fibroblasts and macrophages that create a microenvironment promoting cell survival, invasion and metastasis. Conclusion Regardless of aetiology, most risk factors for cholangiocarcinoma cause chronic inflammation and/or cholestasis, leading to the activation of common intracellular pathways that result in reactive cell proliferation, genetic/epigenetic mutations and cholangiocarcinogenesis. An understanding of the molecular pathogenesis of cholangiocarcinoma is vital when developing new diagnostic biomarkers and targeted therapies for this disease.

Acute pancreatitis (AP) is characterised by inflammation of the exocrine pancreas and is associated with acinar cell injury and both a local and systemic inflammatory response. AP may range in severity from self-limiting, characterised by mild pancreatic oedema, to severe systemic inflammation with pancreatic necrosis, organ failure and death. Several international guidelines have been developed including those from the joint International Association of Pancreatology and American Pancreatic Association, American College of Gastroenterology and British Society of Gastroenterology. Here we discuss current diagnostic and management challenges and address the common dilemmas in AP.

IntroductionIgG4-related disease (IgG4-RD) is a relapsing multisystem fibro-inflammatory disease, which may involve the kidney (IgG4-related kidney disease [IgG4-RKD]) and retroperitoneum (IgG4-related retroperitoneal fibrosis [IgG4-RPF]). The aim of this study was to describe IgG4-RKD and IgG4-RPF in the United Kingdom.MethodsWe conducted a retrospective observational study of patients with IgG4-RKD and IgG4-RPF in a multicenter IgG4-RD cohort. Data were collected through review of medical records. We describe clinical parameters at baseline, histological and radiological findings, treatment, and patient outcomes.ResultsOf 154 patients with IgG4-RD, 14 (9.1%) had IgG4-RKD, 10 (6.5%) had IgG4-RPF, and 4 (2.6%) had both. Patients were aged 58.2 ± 14.2 years, and 26 (92.9%) were male. Creatinine at presentation was worse in those with intrinsic renal disease (229 μmol/l vs. 110 μmol/l; P = 0.0076). Serum IgG4 was elevated in the majority of patients (87.5%), and hypocomplementemia was present in half of those with IgG4-RKD. Fifteen patients underwent renal biopsy; tubulointerstitial nephritis with abundant IgG4+ plasma cells was the most common finding (n = 14; 93.3%), and 4 (26.7%) patients had membranous nephropathy. Most patients (89.3%) were treated with corticosteroids, and 4 (16.0%) with additional azathioprine as initial management. Thirteen patients (46.4%) relapsed over 60 ± 48 months of follow-up, at median 18 (12–36) months after renal/RPF diagnosis; 61.5% of relapses were in the kidney. Renal function deteriorated in 5 patients (20.8%), including 2 (8.3%) who reached end-stage renal disease (ESRD).ConclusionIgG4-RKD and IgG4-RPF represent major organ manifestations of IgG4-RD, and should be identified early with prompt treatment to prevent progression to ESRD.