Aramchol improves hepatic fibrosis in MASH: Results of multimodality assessment using both conventional and digital pathology.

BACKGROUND AND AIMS: Antifibrotic trials rely on conventional pathology (CP) despite recognized limitations. We compared single fiber digital image analysis (DIA) with CP to quantify the antifibrotic effect of Aramchol, a stearoyl-CoA desaturase 1 inhibitor in development for metabolic-dysfunction associated steatohepatitis (MASH). APPROACH AND RESULTS: 51 MASH patients enrolled in the open-label part of the ARMOR trial received Aramchol 300 mg BID and had paired pre-post treatment liver biopsies scored by consensus among three hepatopathologists, and separately assessed by a DIA platform (PharmaNest®) that generates a continuous phenotypic Fibrosis Composite Severity Score (Ph-FCS). Fibrosis improvement was defined as: >1 NASH-CRN stage reduction; "improved" by ranked pair assessment (RPA); reduction in Ph-FCS ("any" for >0.3 absolute reduction, "substantial" for >25% relative reduction). Fibrosis improved in 31% of patients (NASH-CRN), 51% (RPA), 74.5% (any Ph-FCS reduction) and 41% (substantial Ph-FCS reduction). Most patients with stable fibrosis by NASH-CRN or RPA had a Ph-FCS reduction (a third with substantial reduction). Fibrosis improvement increased with treatment duration: 25% for <48 weeks vs. 39% for >48 weeks by NASH-CRN; 43% vs. 61% by RPA, mean Ph-FCS reduction -0.54 (sd 1.22) vs. -1.72 (sd 1.02); Ph-FCS reduction (any in 54% vs. 100%, substantial in 21% vs. 65%). The antifibrotic effect of Aramchol was corroborated by reductions in liver stiffness, Pro-C3 and ELF. Changes in Ph-FCS were positively correlated with changes in liver stiffness. CONCLUSIONS: Continuous fibrosis scores generated in antifibrotic trials by DIA quantify antifibrotic effects with greater sensitivity and larger dynamic range than CP.

Large platelet size is associated with poor outcome in patients with metastatic pancreatic cancer.

Background Platelets are a major cellular component of blood and their interaction with cancer cells is well-established to influence cancer progression and metastases. The physical size of platelets may have a critical impact on the interaction with cancer cells. In this study, we explored the potential prognostic role of platelet size measured by the determination of the mean platetlet volume (MPV) in patients with pancreatic ductal adenocarcinoma (PDAC). Methods Data from 527 patients with PDAC diagnosed and treated between 2004 and 2015 at a single center were evaluated retrospectively. Associations between MPV and baseline covariates were assessed with Wilcoxon's rank-sum tests, χ2-tests, and Fisher's exact tests. Median follow-up was estimated with a reverse Kaplan-Meier estimator according to Schemper and Smith. Analysis of time-to-death was performed with Kaplan-Meier estimators, log-rank tests and uni- and multivariable Cox proportional hazards models. Results The median MPV was 10.5 femto liter (fL) [9.8-11.3], ranged from 5.9 to 17.7 fL. A large platelet volume was associated with high-grade G3/4 tumors (p=0.004) and worse overall survival (OS) in patients with metastatic disease in univariable analysis (hazard ratio [HR] per fL increase in MPV=1.13 [95% CI: 1.04-1.23, p=0.005]). In multivariable analysis of metatatic PDAC patients, the adverse association between large platelets and a higher risk-of-death prevailed (adjusted HR per doubling of MPV=2.00; 95% CI: 1.10-3.62, p=0.02). Conclusions Large platelets represent a negative prognostic factor and add an independent prognostic information to well-established factors in PDAC patients. MPV should be considered for future individual risk assessment in patients with stage IV PDAC.

The role of liver biopsy in the diagnosis and prognosis of patients with acute deterioration of alcoholic cirrhosis.

BACKGROUND & AIMS: The aim of this study was to systematically assess the diagnostic and prognostic value of early liver biopsy in patients who require hospital admission with acute deterioration of alcoholic cirrhosis. METHODS: Sixty-eight patients with acute deterioration of alcoholic cirrhosis underwent a liver biopsy within 7 days and the biopsies were processed using routine stains and K8/18 immunohistochemistry to characterize balloon degeneration. The biopsies were scored by two independent histopathologists using pre-defined criteria. The patients were managed according to institutional protocols and followed until the time of hospital discharge or death. RESULTS: With use of K8/18 immunohistochemistry, very high concordance rate for the diagnosis of balloon degeneration was reached (r = 0.7; p = 0.0001). The presence of a systemic inflammatory response (SIRS) suggestive of acute alcoholic steatohepatitis (ASH), predicts severe ASH histologically in only 50% patients. Moreover, in 41% of SIRS negative patients who were thought not to have ASH, a diagnosis of ASH was subsequently confirmed on histological grading. Patients that have SIRS criteria but no evidence of histological ASH are more likely to develop infection which may be indicated by the severity of canalicular cholestasis. Nineteen patients died during follow up. Patients manifesting ASH on biopsy who were also SIRS positive, had a significantly greater risk of mortality compared to those that were SIRS positive but ASH negative (p < 0.01) and those that were SIRS negative (p < 0.0001). CONCLUSIONS: The use of K8/18 immunostaining allows grading of the severity of alcoholic steatohepatitis. Early liver biopsy in these patients presenting with acute deterioration of cirrhosis is safe and provides important diagnostic and prognostic information.

Ursodeoxycholic acid for treatment of fatty liver disease and dyslipidemia in morbidly obese patients.

Bile acids have recently been identified as major integrators of hepatic fatty acid and triglyceride metabolism. We explored potential mechanism(s) of action of ursodeoxycholic acid (20 mg/kg/day in 3 weeks) in 40 morbidly obese patients (mean BMI >40 kg/m(2)) with suggested fatty liver disease awaiting bariatric surgery. At follow-up half a year after surgery, patients had decreased their BMI by approximately 10 kg/m(2), which resulted in significant improvements of liver function tests, insulin sensitivity and glucose tolerance.

Nonalcoholic Fatty Liver Disease versus Alcohol-related Liver Disease: Is it Really so Different?

Nonalcoholic fatty liver disease and alcohol-related liver disease together, compose the majority of cases of liver disease and cirrhosis worldwide. Although in the last years, there has been much interest in the differentiation between the two entities, it is increasingly recognized that a large overlap exists between them. The main pathophysiological aspects are very similar, with the exceptions of mechanisms directly related to alcohol, acting as an added factor in the presence of metabolic risk factors. Genetic factors so far identified are also very similar. In both cases, the disease is more prevalent in males, the difference being more significant in the ALD group, having to do with harmful alcohol consumption, which is more frequent in males. NAFLD advanced stages usually present in older age than ALD. Regarding laboratory features, the ratio AST/ALT < 1 is more frequent in NAFLD than ALD, in the absence of cirrhosis. Histological aspects of both situations are very similar, but some are specific for ALD, such as alcoholic foamy degeneration or cholestasis, or fibroobliterative venous lesions. Regarding treatment, several drugs now included in clinical trials in NAFLD, could also be assayed in ALD, since similar mechanisms of action, are potentially acting in ALD. In summary, similarities seem to outnumber differences, and since so large overlap between risk factors exist, the use of a common designation such as Fatty Liver Disease (FLD) or Metabolic Fatty Liver disease (MEFLD), could better serve the field.

Intestine-Specific Overexpression of Carboxylesterase 2c Protects Mice From Diet-Induced Liver Steatosis and Obesity.

Murine hepatic carboxylesterase 2c (Ces2c) and the presumed human ortholog carboxylesterase 2 (CES2) have been implicated in the development of nonalcoholic fatty liver disease (NAFLD) in mice and obese humans. These studies demonstrated that Ces2c hydrolyzes triglycerides (TGs) in hepatocytes. Interestingly, Ces2c/CES2 is most abundantly expressed in the intestine, indicating a role of Ces2c/CES2 in intestinal TG metabolism. Here we show that Ces2c is an important enzyme in intestinal lipid metabolism in mice. Intestine-specific Ces2c overexpression (Ces2cint) provoked increased fatty acid oxidation (FAO) in the small intestine accompanied by enhanced chylomicron clearance from the circulation. As a consequence, high-fat diet-fed Ces2cint mice were resistant to excessive diet-induced weight gain and adipose tissue expansion. Notably, intestinal Ces2c overexpression increased hepatic insulin sensitivity and protected mice from NAFLD development. Although lipid absorption was not affected in Ces2cint mice, fecal energy content was significantly increased. Mechanistically, we demonstrate that Ces2c is a potent neutral lipase, which efficiently hydrolyzes TGs and diglycerides (DGs) in the small intestine, thereby generating fatty acids (FAs) for FAO and monoglycerides (MGs) and DGs for potential re-esterification. Consequently, the increased availability of MGs and DGs for re-esterification and primordial apolipoprotein B48 particle lipidation may increase chylomicron size, ultimately mediating more efficient chylomicron clearance from the circulation. Conclusion: This study suggests a critical role for Ces2c in intestinal lipid metabolism and highlights the importance of intestinal lipolysis to protect mice from the development of hepatic insulin resistance, NAFLD, and excessive diet-induced weight gain during metabolic stress.

Compound heterozygosity for two MSH6 mutations in a patient with early onset colorectal cancer, vitiligo and systemic lupus erythematosus.

Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC) is an autosomal dominant condition caused by heterozygous germline mutations in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. Rare cases have been reported of an inherited bi-allelic deficiency of MMR genes, associated with multiple café-au-lait spots, early onset CNS tumors, hematological malignancies, and early onset gastrointestinal neoplasia. We report on a patient with vitiligo in segments of the integument who developed systemic lupus erythematosus (SLE) at the age of 16, and four synchronous colorectal cancers at age 17 years. Examination of the colorectal cancer tissue showed high microsatellite instability (MSI-H) and an exclusive loss of expression of the MSH6 protein. Immunohistochemical analysis of normal colon tissue also showed loss of MSH6, pointing to a bi-allelic MSH6 mutation. Sequencing of the MSH6 gene showed the two germline mutations; c.1806_1809delAAAG;p.Glu604LeufsX5 and c.3226C > T;p.Arg1076Cys. We confirmed that the two mutations are on two different alleles by allele-specific PCR. To our knowledge, neither parent is clinically affected. They did not wish to be tested for the mutations identified in their daughter. These data suggest that bi-allelic mutations of one of the MMR genes should be considered in patients who develop early-onset multiple HNPCC-associated tumors and autoimmune disorders, even in absence of either hematological malignancies or brain tumors.

Elevated amylase in plasma represents an adverse prognostic marker in patients with metastatic pancreatic cancer : A retrospective analysis.

BACKGROUND AND AIM: The aim of this study was to investigate the prognostic relevance of plasma amylase and lipase concerning survival of patients suffering from metastatic pancreatic cancer (PC). METHOD: This retrospective study included 351 patients with metastatic PC, who were treated in a single academic institution. Cancer-specific survival (CSS) was analyzed using the Kaplan-Meier method. To further evaluate the prognostic significance of lipase and amylase, univariate and multivariate values were calculated using Cox proportional models. RESULTS: In univariate analysis, an increased amylase level was associated with shorter CSS in PC patients (hazard ratio HR = 1.258; 95% confidence interval CI = 1.011-1.566; p = 0.039). In multivariate analysis, including gender, age, CA19-9 and administration of chemotherapy, increased amylase levels prevailed as an independent prognostic factor for CSS (HR = 1.373; 95%CI = 1.004-1.878; p = 0.047). CONCLUSIONS: Plasma amylase was found to be an independent prognostic factor in patients with metastatic PC. The results indicate that amylase might represent a novel and useful marker for better patient stratification in PC management.