A comprehensive assessment of environmental exposures among 1000 North American patients with primary sclerosing cholangitis, with and without inflammatory bowel disease

BACKGROUND: The relationships between primary sclerosing cholangitis (PSC) and the environment are largely unknown. AIM: To validate associations reported in previous studies and to identify novel environmental exposures among PSC patients. METHODS: We performed a multicenter, case-control analysis utilising self-administered questionnaires. Responses between cases (n = 1000) and controls (n = 663) were compared using multivariable logistic regression adjusted for age and gender. The model was further stratified based on inflammatory bowel disease (IBD) status (with IBD n = 741 without IBD n = 259). RESULTS: Smoking was associated with PSC only when IBD was present (OR, 0.5; 95% CI 0.4-0.7) but not among those PSC patients without IBD (OR, 0.9; 95% CI 0.7-1.2). Compared to controls, women with PSC (irrespective of the presence of IBD) were less likely to have received hormone replacement therapy (HRT; OR, 0.5; 95% CI 0.4-0.7) and were more likely to have recurrent urinary tract infections (OR, 1.6; 95% CI 1.2-2.3). PSC patients regardless of gender or IBD status were less likely to eat fish (OR, 0.4; 95% CI 0.3-0.6) and grilled/barbecued meat (OR, 0.8; 95% CI 0.7-0.9). In contrast, PSC patients with and without IBD were more likely to consume steak/burgers that were more well done (OR, 1.3; 95% CI 1.2-1.5). CONCLUSIONS: IBD (rather than PSC) is associated with smoking. Women with PSC are more likely to have recurrent urinary tract infections and less likely to receive HRT. Dietary intake and methods of food preparation differ in PSC patients when compared to controls

Increased Diacylglycerols Characterize Hepatic Lipid Changes in Progression of Human Nonalcoholic Fatty Liver Disease; Comparison to a Murine Model

The spectrum of nonalcoholic fatty liver disease (NAFLD) includes steatosis, nonalcoholic steatohepatitis (NASH), and progression to cirrhosis. While differences in liver lipids between disease states have been reported, precise composition of phospholipids and diacylglycerols (DAG) at a lipid species level has not been previously described. The goal of this study was to characterize changes in lipid species through progression of human NAFLD using advanced lipidomic technology and compare this with a murine model of early and advanced NAFLD.Utilizing mass spectrometry lipidomics, over 250 phospholipid and diacylglycerol species (DAGs) were identified in normal and diseased human and murine liver extracts.Significant differences between phospholipid composition of normal and diseased livers were demonstrated, notably among DAG species, consistent with previous reports that DAG transferases are involved in the progression of NAFLD and liver fibrosis. In addition, a novel phospholipid species (ether linked phosphatidylinositol) was identified in human cirrhotic liver extracts.Using parallel lipidomics analysis of murine and human liver tissues it was determined that mice maintained on a high-fat diet provide a reproducible model of NAFLD in regards to specificity of lipid species in the liver. These studies demonstrated that novel lipid species may serve as markers of advanced liver disease and importantly, marked increases in DAG species are a hallmark of NAFLD. Elevated DAGs may contribute to altered triglyceride, phosphatidylcholine (PC), and phosphatidylethanolamine (PE) levels characteristic of the disease and specific DAG species might be important lipid signaling molecules in the progression of NAFLD

Resveratrol inhibits nonalcoholic fatty liver disease in rats

<p>Abstract</p> <p>Background</p> <p>The prevalence of nonalcoholic fatty liver disease (NAFLD) is high. NAFLD is linked to obesity, diabetes mellitus, and hypertriglyceridemia. Approximately 20% of patients with NAFLD will eventually develop cirrhosis. Our purpose was to investigate whether resveratrol decreased hepatic steatosis in an animal model of steatosis, and whether this therapeutic approach resulted in a decrease in tumor necrosis factor α (TNF-α) production, lipid peroxidation and oxidative stress.</p> <p>Methods</p> <p>Male Wistar CRL: Wi (Han) (225 g) rats were randomized into three groups. A control group (n = 12) was given free access to regular dry rat chow for 4 weeks. The steatosis (n = 12) and resveratrol (n = 12) groups were given free access to feed (a high carbohydrate-fat free modified diet) and water 4 days per week, and fasted for the remaining 3 days for 4 weeks. Rats in the resveratrol group were given resveratrol 10 mg daily by the oral route. All rats were killed at 4 weeks and assessed for fatty infiltration and bacterial translocation. Levels of TNF-α in serum, hepatic malondialdehyde (MDA), oxidative stress (superoxide dismutase, glutathione peroxidase, catalase and nitric oxide synthase) and biochemical parameters were measured.</p> <p>Results</p> <p>Fat deposition was decreased in the resveratrol group as compared to the steatosis group (Grade 1 vs Grade 3, P < 0.05). TNF-α and MDA levels were significantly increased in the steatosis group (TNF-α; 33.4 ± 5.2 vs 26.24 ± 3.47 pg/ml and MDA; 9.08 ± 0.8 vs 3.17 ± 1.45 μM respectively, <it>P </it>< 0.05). This was accompanied by increased superoxide dismutase, glutathione peroxidase and catalase and decreased nitric oxide synthase in the liver of resveratrol group significantly (<it>P </it>< 0.05 vs steatosis group). Bacterial translocation was not found in any of the groups. Glucose levels were decreased in the group of rats given resveratrol (<it>P </it>< 0.05).</p> <p>Conclusion</p> <p>Resveratrol decreased NAFLD severity in rats. This effect was mediated, at least in part, by TNF-α inhibition and antioxidant activities.</p

High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo

NAFLD (non-alcoholic fatty liver disease), associated with obesity and the cardiometabolic syndrome, is an important medical problem affecting up to 20% of western populations. Evidence indicates that mitochondrial dysfunction plays a critical role in NAFLD initiation and progression to the more serious condition of NASH (non-alcoholic steatohepatitis). Herein we hypothesize that mitochondrial defects induced by exposure to a HFD (high fat diet) contribute to a hypoxic state in liver and this is associated with increased protein modification by RNS (reactive nitrogen species). To test this concept, C57BL/6 mice were pair-fed a control diet and HFD containing 35% and 71% total calories (1 cal≈4.184 J) from fat respectively, for 8 or 16 weeks and liver hypoxia, mitochondrial bioenergetics, NO (nitric oxide)-dependent control of respiration, and 3-NT (3-nitrotyrosine), a marker of protein modification by RNS, were examined. Feeding a HFD for 16 weeks induced NASH-like pathology accompanied by elevated triacylglycerols, increased CYP2E1 (cytochrome P450 2E1) and iNOS (inducible nitric oxide synthase) protein, and significantly enhanced hypoxia in the pericentral region of the liver. Mitochondria from the HFD group showed increased sensitivity to NO-dependent inhibition of respiration compared with controls. In addition, accumulation of 3-NT paralleled the hypoxia gradient in vivo and 3-NT levels were increased in mitochondrial proteins. Liver mitochondria from mice fed the HFD for 16 weeks exhibited depressed state 3 respiration, uncoupled respiration, cytochrome c oxidase activity, and mitochondrial membrane potential. These findings indicate that chronic exposure to a HFD negatively affects the bioenergetics of liver mitochondria and this probably contributes to hypoxic stress and deleterious NO-dependent modification of mitochondrial proteins

Modeling the Hepatology Workforce in the United States: A Predicted Critical Shortage.

BACKGROUND & AIMS: Liver disease is prevalent in the United States, and as the population ages, an increasing number of patients are anticipated to present for care. The state of the current hepatology workforce and future demand for hepatology providers is not known. The aim of this study was to model future projections for hepatology workforce demand. Approach & Results A workforce study of hepatology providers in the U.S. was completed using primary and secondary data sources. An integrated workforce framework model was used that combined socio-economic factors that drive economic demand, epidemiological factors that drive need, and utilization rates of healthcare services. Supply and demand projections were calculated for adult and pediatric hepatology professionals. Sensitivity analyses were conducted to cover the feasible range of these assumptions. An electronic survey of AASLD members whose practice included 50% or more hepatology was conducted. In 2018 the adult and pediatric workforce included 7,296 and 824 hepatology providers, composed of hepatologists, gastroenterologists, and advanced practice providers whose practice was ≥50% hepatology. The modeling analysis projects that in 2023, 2028, 2033 there will be a shortage of 10%, 23%, and 35% adult hepatology providers, respectively, and 19%, 20%, and 16% pediatric hepatology providers, respectively. In sensitivity analyses, a shortage of hepatology providers is predicted even under optimistic assumptions. Among respondents to the survey the median age was higher among gastroenterologists and general hepatologists compared to transplant hepatologists. The most common category treated by transplant hepatologists was general hepatology. CONCLUSIONS: There is an impending critical shortage of adult and pediatric hepatology providers. Strategies are needed to encourage clinicians to pursue hepatology, especially in areas outside of transplant centers

Evaluation of Liver Transplantation Among Advanced Age Recipients in a Large Multicenter U. S. Cohort

Purpose: The proportion of adults \u3e70 years (y) listed for liver transplant (LT) in the U. S. is rising. Outcomes in this growing population are limited to small, single-center cohorts or national database studies that lack granularity. We aimed to better characterize outcomes in LT recipients \u3e70y in a large multicenter cohort. Methods: All primaty LT recipients (LTR) \u3e65y~who underwent LT from 2010-16 at 13 centers were included. For LTRs \u3e70y, survival was estimated using Kaplan-Meier methods; other outcomes were assessed within ly post-LT and compared toLTRs\u3c70y. Results: Of 179 LTRs \u3e70y, median was age 71y (range 70-78), 64% were male. and 770/c Caucasian. Leading indications for LT were NASH (27%), alcohol (11%). HCV (17%). 52% had HCC, of which 63% had MELD exceptions. Median laboratory MELDNa at LT was 19 (IQR 13-26), and median allocation MELD was 22 (IQR16-29). Comorbidities included diabetes (39%), congestive heart failure (8%), cerebrovascular disease (6%), chronic pulmonaty disease (11%), renal disease (38%). and osteoporosis/osteopenia (42%). The median donor age was 48y (33-62); 8% were donations after cardiac death, 10% living donation LT, and 6% SLK During LT, 1. 70/0 received induction with a T-cell depleting agent compared to 9% of LTRs \u3c70y in the cohort. At discharge, 77% were on calcineurin inhibitors and 73% on steroids vs 85% and 84% respectively, of LTRs \u3c70y. Within ly post-LT, graft rejection occurred in 18% and biliary strictures in 26%. Cardiovascular complications occurred in 25% (12% afib, 3% MI, 8% stroke and 9% heart failure), delirium in 16% and seizures in 3%. Viral, bacterial and fungal infections occurred ly post-LT in 17% 39% and 7% respectively. Solid organ cancers ly post-LT occurred in 10% with recurrent HCC (40/0) and lung cancer (2%) being the most common; this is compared to 4% in the cohort \u3c70y (p=0. 002). One-year and three-year patient survival was 89% and 76% respectively, vs 90% and 84% in \u3c70y. Conclusions: In a large US multicenter cohort, ly and 3y survival in LTRs \u3e70y were acceptable. De novo solid organ cancers within ly post-LT occurred in 10% of LTRs \u3e70y, more frequently than in those \u3c70y. Our data provide further understanding of the comorbidities experienced in advanced age LTRs and lay the foundation for improved selection and management of older LTRs