Langerhans cell histiocytosis masquerading as acute appendicitis: Case report and review

Langerhans cell histiocytosis(LCH) is a rare syndrome characterized by unifocal,multifocal unisystem,or disseminated/multi-system disease that commonly involves the bone,skin,lymph nodes,pituitary,or sometimes lung(almost exclusively in smokers) causing a variety of symptoms from rashes and bone lesions to diabetes insipidus or pulmonary infiltrates.We present a previously unreported case of gastrointestinal LCH as well as a novel characteristic lesion affecting the colon of a young woman who presented with signs and symptoms mimicking acute on chronic appendicitis.Immunohistochemical analysis of appendectomy specimen and nodular specimens on colonoscopy demonstrated S-100,CD1a,and langerin reactivity.The patient underwent systemic chemotherapy with cytarabine and demonstrated excellent response to therapy.

Prolonged feeding with guanidinoacetate, a methyl group consumer, exacerbates ethanol-induced liver injury

AIM To investigate the hypothesis that exposure to guanidinoacetate(GAA, a potent methyl-group consumer) either alone or combined with ethanol intake for a prolonged period of time would cause more advanced liver pathology thus identifying methylation defects as the initiator and stimulator for progressive liver damage.METHODS Adult male Wistar rats were fed the control or ethanolLieber De Carli diet in the absence or presence of GAA supplementation. At the end of 6 wk of the feeding regimen, various biochemical and histological analyses were conducted. RESULTS Contrary to our expectations, we observed that GAA treatment alone resulted in a histologically normal liver without evidence of hepatosteatosis despite persistence of some abnormal biochemical parameters. This protection could result from the generation of creatine from the ingested GAA. Ethanol treatment for 6 wk exhibited changes in liver methionine metabolism and persistence of histological and biochemical defects as reported before. Further, when the rats were fed the GAA-supplemented ethanol diet, similar histological and biochemical changes as observed after 2 wk of combined treatment, including inflammation, macroand micro-vesicular steatosis and a marked decrease in the methylation index were noted. In addition, rats on the combined treatment exhibited increased liver toxicity and even early fibrotic changes in a subset of animals in this group. The worsening liver pathology could be related to the profound reduction in the hepatic methylation index, an increased accumulation of GAA and the inability of creatine generated to exert its hepato-protective effects in the setting of ethanol.CONCLUSION To conclude, prolonged exposure to a methyl consumer superimposed on chronic ethanol consumption causes persistent and pronounced liver damage.

Diagnosis of alcoholic liver disease

Alcohol is a hepatotoxin that is commonly consumed worldwide and is associated with a spectrum of liver injury including simple steatosis or fatty liver, alcoholic hepatitis, fibrosis, and cirrhosis. Alcoholic liver disease(ALD) is a general term used to refer to this spectrum of alcohol-related liver injuries. Excessive or harmful alcohol use is ranked as one of the top five risk factors for death and disability globally and results in 2.5 million deaths and 69.4 million annual disability adjusted life years. All patients who present with clinical features of hepatitis or chronic liver disease or who have elevated serum elevated transaminase levels should be screened for an alcohol use disorder. The diagnosis of ALD can generally be made based on history, clinical and laboratory findings. However, the diagnosis of ALD can be clinically challenging as there is no single diagnostic test that confirms the diagnosis and patients may not be forthcoming about their degree of alcohol consumption. In addition, clinical findings may be absent or minimal in early ALD characterized by hepatic steatosis. Typical laboratory findings in ALD include transaminase levels with aspartate aminotransferase greater than alanine aminotransferase as well as increased mean cor-puscular volume, gamma-glutamyltranspeptidase, and IgA to IgG ratio. In unclear cases, the diagnosis can be supported by imaging and liver biopsy. The histological features of ALD can ultimately define the diagnosis according to the typical presence and distribution of hepatic steatosis, inflammation, and Mallory-Denk bodies. Because of the potential reversible nature of ALD with sobriety, regular screening of the general population and early diagnosis are essential.

Alcohol,nutrition and liver cancer:Role of Toll-like receptor signaling

This article reviews the evidence that ties the development of hepatocellular carcinoma (HCC) to the natural immune pro-inflammatory response to chronic liver disease, with a focus on the role of Toll-like receptor (TLR) signaling as the mechanism of liver stem cell/progenitor transformation to HCC. Two exemplary models of this phenomenon are reviewed in detail. One model applies chronic ethanol/lipopolysaccharide feeding to the activated TLR4 signaling pathway. The other applies chronic feeding of a carcinogenic drug, in which TLR2 and 4 signaling pathways are activated. In the drug-induced model, two major methyl donors, S-adenosylmethionine and betaine, prevent the upregulation of the TLR signaling pathways and abrogate the stem cell/progenitor proliferation response when fed with the carcinogenic drug. This observation supports a nutritional approach to liver cancer prevention and treatment. The observation that upregulation of the TLR signaling pathways leads to liver tumor formation gives evidence to the popular concept that the chronic pro-inflammatory response is an important mechanism of liver oncogenesis. It provides a nutritional approach, which could prevent HCC from developing in many chronic liver diseases.

Chaperones in hepatitis C virus infection

The hepatitis C virus(HCV) infects approximately 3% of the world population or more than 185 million people worldwide. Each year, an estimated 350000-500000 deaths occur worldwide due to HCV-associated diseases including cirrhosis and hepatocellular carcinoma. HCV is the most common indication for liver transplantation in patients with cirrhosis worldwide. HCV is an enveloped RNA virus classified in the genus Hepacivirus in the Flaviviridae family. The HCV viral life cycle in a cell can be divided into six phases:(1) binding and internalization;(2) cytoplasmic release and uncoating;(3) viral polyprotein translation and processing;(4) RNA genome replication;(5) encapsidation(packaging) and assembly; and(6) virus morphogenesis(maturation) and secretion. Many host factors are involved in the HCV life cycle. Chaperones are an important group of host cytoprotective molecules that coordinate numerous cellular processes including protein folding, multimeric protein assembly, protein trafficking, and protein degradation. All phases of the viral life cycle require chaperone activity and the interaction of viral proteins with chaperones. This review will present our current knowledge and understanding of the role of chaperones in the HCV life cycle. Analysis of chaperones in HCV infection will provide further insights into viral/host interactions and potential therapeutic targets for both HCV and other viruses.

Epigenetics of proteasome inhibition in the liver of rats fed ethanol chronically

AIM:To examine the effects of ethanol-induced proteasome inhibition,and the effects of proteasome inhibition in the regulation of epigenetic mechanisms. METHODS:Rats were fed ethanol for 1 mo using the Tsukamoto-French model and were compared to rats given the proteasome inhibitor PS-341(Bortezomib, Velcade?)by intraperitoneal injection.Microarray analysis and real time PCR were performed and proteasome activity assays and Western blot analysis were performed using isolated nuclei. RESULTS:Chronic ethanol feeding caused a significant inhibition of the ubiquitin proteasome pathway in the nucleus,which led to changes in the turnover of transcriptional factors,histone-modifying enzymes, and,therefore,affected epigenetic mechanisms. Chronic ethanol feeding was related to an increase in histone acetylation,and it is hypothesized that the proteasome proteolytic activity regulated histone modifications by controlling the stability of histone modifying enzymes,and,therefore,regulated the chromatin structure,allowing easy access to chromatin by RNA polymerase,and,thus,proper gene expression.Proteasome inhibition by PS-341 increased histone acetylation similar to chronic ethanol feeding. In addition,proteasome inhibition caused dramatic changes in hepatic remethylation reactions as there was a significant decrease in the enzymes responsible for the regeneration of S-adenosylmethionine,and, in particular,a significant decrease in the betaine- homocysteine methyltransferase enzyme.This suggested that hypomethylation was associated with proteasome inhibition,as indicated by the decrease in histone methylation. CONCLUSION:The role of proteasome inhibition in regulating epigenetic mechanisms,and its link to liver injury in alcoholic liver disease,is thus a promising approach to study liver injury due to chronic ethanol consumption.

Staining for p53 and Ki-67 increases the sensitivity of EUS-FNA to detect pancreatic malignancy

AIM:To investigate whether tumor marker staining can improve the sensitivity of endoscopic ultrasound-guided fine needle aspiration(EUS-FNA)to diagnose pancreatic malignancy. METHODS:Patients who underwent EUS-FNA were retrospectively identified.Each EUS-FNA specimen was evaluated by routine cytology and stained for tumor markers p53,Ki-67,carcinoembryonic antigen(CEA) and CA19-9.Sensitivity,specificity,positive and negative predictive values(PPV and NPV),and positive and negative likelihood ratios(PLR and NLR)were calculated in order to evaluate the performance of each test to detect malignancy. RESULTS:Sixty-one specimens had complete sets of stains,yielding 49 and 12 specimens from pancreatic adenocarcinomas and benign pancreatic lesions due to pancreatitis,respectively.Cytology alone had sensitivity and specificity of 41%and 100%to detect malignancy, respectively.In 46%of the specimens,routine cytology alone was deemed indeterminate.The addition of either p53 or Ki-67 increased the sensitivity to 51%and 53%,respectively,with perfect specificity,PPV and PLR (100%,100%and infinite).Both stains in combination increased the sensitivity to 57%.While additional staining with CEA and CA19-9 further increased the sensitivity to 86%,the specificity,PPV and PLR were significantly reduced(at minimum 42%,84%and 1,respectively).Markers in all combinations performed poorly as a negative test(NPV 26%to 47%,and NLR 0.27 and 0.70).CONCLUSION:Immunohistochemical staining for p53 and Ki-67 can improve the sensitivity of EUS-FNA to diagnose pancreatic adenocarcinoma.

Mallory-Denk body pathogenesis revisited

This editorial reviews the recent evidence showing that Mallory-Denk bodies(MDBs)form in hepatocytes as the result of a drug-induced shift from the 26s proteasome formation to the immunoproteasome formation.The shift is the result of changes in gene expression induced in promoter activation,which is induced by the IFNγ and TNFa signaling pathway.This activates TLR 2 and 4 receptors.The TLR signaling pathway stimulates both the induction of a cytokine proinflammatory response and an up regulation of growth factors.The MDB-forming hepatocytes proliferate as a result of the increase in growth factor expression by the MDBforming cells,which selectively proliferate in response to drug toxicity.All of these mechanisms are induced by drug toxicity,and are prevented by feeding the methyl donors SAMe and betaine,supporting the epigenetic response of MDB formation.