Browsing by Subject "nonalcoholic steatohepatitis"

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    Attribution of Nonalcoholic Steatohepatitis as an Etiology of Cirrhosis for Clinical Trials Eligibility: Recommendations from the Multi-stakeholder Liver Forum
    (Elsevier, 2020) Noureddin, Mazen; Chan, Jean L.; Barradas, Katherine; Dimick-Santos, Lara; Schabel, Elmer; Omokaro, Stephanie O.; Anania, Frank A.; Myers, Robert P.; Miller, Veronica; Sanyal, Arun J.; Chalasani, Naga; Medicine, School of Medicine
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    CHOP links endoplasmic reticulum stress to NF-κB activation in the pathogenesis of nonalcoholic steatohepatitis
    (2015) Willy, Jeffrey A.; Young, Sara K.; Stevens, James L.; Masuoka, Howard C.; Wek, Ronald C.; Department of Biochemistry and Molecular Biology, IU School of Medicine
    Free fatty acid induction of inflammation and cell death is an important feature of nonalcoholic steatohepatitis (NASH) and has been associated with disruption of the endoplasmic reticulum and activation of the Unfolded Protein Response (UPR). Following chronic UPR activation, the transcription factor CHOP (GADD153/DDIT3) triggers cell death; however, the mechanisms linking the UPR or CHOP to hepatoceullular injury and inflammation in the pathogenesis of NASH are not well understood. Using HepG2 and primary human hepatocytes, we found that CHOP induces cell death and inflammatory responses following saturated free fatty acid exposure by activating NF-κB through a pathway involving IRAK2 expression, resulting in secretion of cytokines IL-8 and TNFα directly from hepatocytes. TNFα facilitates hepatocyte death upon exposure to saturated free fatty acids and secretion of both IL-8 and TNFα contribute to inflammation. Interestingly, CHOP/NF-κB signaling is not conserved in primary rodent hepatocytes. Our studies suggest that CHOP plays a vital role in the pathophysiology of NASH through induction of secreted factors that trigger inflammation and hepatocellular death via a signaling pathway specific to human hepatocytes.
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    Enhanced Liver Fibrosis Score Can Be Used to Predict Liver-Related Events in Patients With Nonalcoholic Steatohepatitis and Compensated Cirrhosis
    (Elsevier, 2020) Are, Vijay S.; Vuppalanchi, Raj; Vilar-Gomez, Eduardo; Chalasani, Naga; Medicine, School of Medicine
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    Fibrosis Severity as a Determinant of Cause-Specific Mortality in Patients With Advanced Nonalcoholic Fatty Liver Disease: A Multi-National Cohort Study
    (Elsevier, 2018-08) Vilar-Gomez, Eduardo; Calzadilla-Bertot, Luis; Wong, Vincent Wai-Sun; Castellanos, Marlen; Aller-de la Fuente, Rocio; Metwally, Mayada; Eslam, Mohammed; Gonzalez-Fabian, Licet; Alvarez-Quiñones Sanz, María; Conde-Martin, Antonio Felix; De Boer, Bastiaan; McLeod, Duncan; Chan, Anthony Wing Hung; Chalasani, Naga; George, Jacob; Adams, Leon A.; Romero-Gomez, Manuel; Medicine, School of Medicine
    Background & Aims Little is known about the natural course of nonalcoholic fatty liver disease (NAFLD) with advanced fibrosis. We describe long-term outcomes and evaluate the effects of clinical and histologic parameters on disease progression in patients with advanced NAFLD. Methods We conducted a multi-national study of 458 patients with biopsy-confirmed NAFLD with bridging fibrosis (F3, n = 159) or compensated cirrhosis (222 patients with Child-Turcotte-Pugh scores of A5 and 77 patients with scores of A6), evaluated from April 1995 through November 2013 and followed until December 2016, death, or liver transplantation at hepatology centers in Spain, Australia, Hong Kong, and Cuba. Biopsies were re-evaluated and scored; demographic, clinical, laboratory, and pathology data for each patient were collected from the time of liver biopsy collection. Cox proportional and competing risk models were used to estimate rates of transplantation-free survival and major clinical events and to identify factors associated with outcomes. Results During a mean follow-up time of 5.5 years (range, 2.7–8.2 years), 37 patients died, 37 received liver transplants, 88 had initial hepatic decompensation events, 41 developed hepatocellular carcinoma, 14 had vascular events, and 30 developed nonhepatic cancers. A higher proportion of patients with F3 fibrosis survived transplantation-free for 10 years (94%; 95% confidence interval [CI], 86%–99%) than of patients with cirrhosis and Child-Turcotte-Pugh A5 (74%; 95% CI, 61%–89%) or Child-Turcotte-Pugh A6 (17%; 95% CI, 6%–29%). Patients with cirrhosis were more likely than patients with F3 fibrosis to have hepatic decompensation (44%; 95% CI, 32%–60% vs 6%, 95% CI, 2%–13%) or hepatocellular carcinoma (17%; 95% CI, 8%–31% vs 2.3%, 95% CI, 1%–12%). The cumulative incidence of vascular events was higher in patients with F3 fibrosis (7%; 95% CI, 3%–18%) than cirrhosis (2%; 95% CI, 0%–6%). The cumulative incidence of nonhepatic malignancies was higher in patients with F3 fibrosis (14%; 95% CI, 7%–23%) than cirrhosis (6%; 95% CI, 2%–15%). Death or transplantation, decompensation, and hepatocellular carcinoma were independently associated with baseline cirrhosis and mild (<33%) steatosis, whereas moderate alcohol consumption was associated with these outcomes only in patients with cirrhosis. Conclusions Patients with NAFLD cirrhosis have predominantly liver-related events, whereas those with bridging fibrosis have predominantly nonhepatic cancers and vascular events.
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    Vitamin E Improves Transplant‐free Survival and Hepatic Decompensation among Patients with NASH and Advanced Fibrosis
    (AASLD, 2018) Vilar-Gomez, Eduardo; Vuppalanchi, Raj; Gawrieh, Samer; Ghabril, Marwan; Saxena, Romil; Cummings, Oscar W.; Chalasani, Naga; Medicine, School of Medicine
    Vitamin E improves liver histology in non‐diabetic adults with nonalcoholic steatohepatitis (NASH), but its impact on long‐term patient outcomes is unknown. We evaluated whether vitamin E treatment improves clinical outcomes of NASH patients with bridging fibrosis or cirrhosis. Two hundred and thirty‐six patients with biopsy‐proven NASH and bridging fibrosis or cirrhosis seen at Indiana University Medical Center between October 2004, and January 2016 were included. Ninety of them took 800 IU/day of vitamin E for ≥ 2 years (vitamin E users) and were propensity matched to 90 adults who did not take vitamin E (controls) after adjusting for fibrosis severity, age, gender, body mass index, comorbidities and their treatment, LDL cholesterol, liver biochemistries and length of follow‐up on vitamin E. Covariate‐adjusted cox and competing risk regression models were assessed to evaluate association between vitamin E treatment and patient outcomes. The median follow‐up was 5.62 (IQR: 4.3‐7.5) and 5.6 (IQR: 4‐6.9) years for vitamin E users and controls respectively. Vitamin E users had higher adjusted transplant‐free survival (78% vs. 49%, P<.01) and lower rates of hepatic decompensation (37% vs. 62%, P=.04) than controls. After controlling for severity of fibrosis, calendar year of patient enrollment and other potential confounders, vitamin E treatment decreased the risk of death or transplant (adj. HR: 0.30, 95% CI: 0.12‐0.74, P<.01) and hepatic decompensation (adj. sHR: 0.52, 95% CI: 0.28‐0.96, P=.036). These benefits were evident in both diabetics as well as non‐diabetics. Adjusted 10‐year cumulative probability of HCC, vascular events and non‐hepatic cancers were not different between vitamin E exposed and controls.