Mechanism of diarrhea in microscopic colitis

AIM: To search the pathophysiological mechanism of diarrhea based on daily stool weights, fecal electrolytes,osmotic gap and pH.METHODS: Seventy-six patients were included: 51 with microscopic colitis (MC) [40 with lymphocytic colitis (LC);11 with collagenous colitis (CC)]; 7 with MC without diarrhea and 18 as a control group (CG). They collected stool for 3 d. Sodium and potassium concentration were determined by flame photometry and chloride concentration by titration method of Schales. Fecal osmotic gap was calculated from the difference of osmolarity of fecal fluid and double sum of sodium and potassium concentration.RESULTS: Fecal fluid sodium concentration was significantly increased in LC 58.11±5.38 mmol/L (P＜0.01)and CC 54.14±8.42 mmol/L (P＜0.05) than in CG 34.28±2.98 mmol/L. Potassium concentration in LC 74.65±5.29 mmol/L (P＜0.01) and CC 75.53±8.78 mmol/L (P＜0.05) was significantly less compared to CG 92.67±2.99 mmol/L.Chloride concentration in CC 36.07±7.29 mmol/L was significantly higher than in CG 24.11±2.05 mmol/L (P＜0.05).Forty-four (86.7%) patients had a secretory diarrhea compared to fecal osmotic gap. Seven (13.3%) patients had osmotic diarrhea.CONCLUSION: Diarrhea in MC mostly belongs to the secretory type. The major pathophysiological mechanism in LC could be explained by a decrease of active sodium absorption. In CC, decreased Cl/HCO3 exchange rate and increased chloride secretion are coexistent pathways.

Hepatitis C-associated liver carcinogenesis:Role of PML nuclear bodies

Successful escape from immune response characterises chronic hepatitis C virus(HCV) infection,which results in persistence of infection in about 80% of the patients.The deleterious consequences are cirrhosis and hepatocellular carcinoma.HCV accounts the most frequent cause for hepatocellular carcinoma(HCC) and liver transplantation(LT) in the western world.The underlying molecular mechanisms how HCV promotes tumor development are largely unknown.There is some in vitro and in vivo evidence that HCV interferes with the tumor suppressor PML and may thereby importantly contribute to the HCV-associated pathogenesis with respect to the development of HCC.The tumor suppressor protein "promyelocytic leukemia"(PML) has been implicated in the regulation of important cellular processes like differentiation and apoptosis.In cancer biology,PML and its associated nuclear bodies(NBs) have initially attracted intense interest due to its role in the pathogenesis of acute promyelocytic leukemia(APL).More recently,loss of PML has been implicated in human cancers of various histologic origins.Moreover,number and intensity of PML-NBs increase in response to interferons(IFNs) and there is evidence that PML-NBs may represent preferential targets in viral infections.Thus,PML could not only play a role in the mechanisms of the antiviral action of IFNs but may also be involved in a direct oncogenic effect of the HCV on hepatocytes.This review aims to summarise current knowledge about HCV-related liver carcinogenesis and to discuss a potential role of the nuclear body protein PML for this this hard-to-treat cancer.

Eosinophilic cholangitis is a potentially underdiagnosed etiology in indeterminate biliary stricture

AIM To investigate presence and extent of eosinophilic cholangitis(EC) as well as Ig G4-related disease in patients with indeterminate biliary stricture(IBS).METHODS All patients with diagnosis of sclerosing cholangitis(SC) and histopathological samples such as biopsies or surgical specimens at University Hospital Frankfurt from 2005-2015 were included. Histopathological diagnoses as well as further clinical course were reviewed. Tissue samples of patients without definite diagnosis after complete diagnostic work-up were reviewed regardingpresence of eosinophilic infiltration and Ig G4 positive plasma cells. Eosinophilic infiltration was as well assessed in a control group of liver transplant donors and patients with primary sclerosing cholangitis.RESULTS One hundred and thirty-five patients with SC were included. In 10/135 (13.5%) patients, no potential cause of IBS could be identified after complete diagnostic work-up and further clinical course. After histopathological review, a post-hoc diagnosis of EC was established in three patients resulting in a prevalence of 2.2% (3/135) of all patients with SC as well as 30%(3/10) of patients, where no cause of IBS was identified. 2/3 patients with post-hoc diagnosis of EC underwent surgical resection with suspicion for malignancy. Diagnosis of Ig G4-related cholangitis was observed in 7/135 patients (5.1%), whereas 3 cases were discovered in post-hoc analysis. 6/7 cases with Ig G4-related cholangitis (85.7%) presented with eosinophilic infiltration in addition to Ig G4 positive plasma cells. There was no patient with eosinophilic infiltration in the control group of liver transplant donors (n=27) and patients with primary sclerosing cholangitis(n = 14).CONCLUSION EC is an underdiagnosed benign etiology of SC and IBS, which has to be considered in differential diagnosis of IBS.

Liver disease in the era of COVID-19: Is the worst yet to come?

The global social,economic and political crises related to coronavirus disease 2019(COVID-19)presumably had more indirect than direct negative impacts on health systems.Drastic lifestyle changes,social isolation and distancing,and individual and global financial crises resulted in robust populations forfeiting healthy habits and seeking comfort in alcoholic beverages,drugs and unhealthy diets.The inevitable consequences are increases in the incidence of nonalcoholic fatty liver disease,viral hepatitis,acute alcoholic hepatitis,liver cirrhosis decompensation and ultimately liver-related mortality.The inaccessibility of regular clinical and sonographic monitoring systems has caused difficulties in the treatment of patients with chronic liver disease(CLD)and has prevented prompt hepatocellular carcinoma detection and treatment.A dramatic reduction in the number of liver donors and the transformation of numerous transplantation centers into COVID-19 units drastically decreased the rate of orthotopic liver transplantation.The indirect,unavoidable effects of the COVID-19 pandemic in the following years have yet to be determined.Substantial efforts in the management of patients with liver disease in order to overcome the inevitable COVID-19-related morbidity and mortality that will follow have yet to be initiated.Several questions regarding the impact of the COVID-19 pandemic on liver disease remain.The most important question for general CLD patients is:How will the modification of clinical practice during this pandemic affect the outcomes of CLD patients?This article reviews the influence of COVID-19 on patients with liver disease during the pandemic,with particular emphasis on the disease course associated with pandemic resolution.

Myeloid-derived suppressor cells promote B-cell production of IgA in a TNFR2-dependent manner

Myeloid-derived suppressor cells(MDSCs)are well known for their capacity to suppress antitumor T-cell responses,but their effects on B-cell function and antibody production remain unclear.Here,we found that MDSCs that accumulated around the germinal center in the spleen of tumor-bearing mice co-located with B cells.In the presence of MDSCs,the antibody reaction to a surrogate antigen was significantly enhanced in mice,especially the immunoglobulin(Ig)A subtype.Co-culture with MDSCs promoted both proliferation and differentiation of B cells into IgA-producing plasma cells in vitro.Interestingly,the cross talk between MDSCs and B cells required cell-cell contact.MDSCs from tumor necrosis factor receptor(TNFR)2^(−/−)mice,but not from TNFR1^(−/−)mice,failed to promote B-cell responses.Further investigation suggested that interleukin-10 and transforming growth factor-β1 were crucial for the MDSC-mediated promotion of IgA responses.These results demonstrate a novel mechanism of MDSC-mediated immune regulation during tumor growth.