Characterization of pathogenic and prognostic factors of nonalcoholic steatohepatitis associated with obesity

García‐Monzón, Carmelo; Martín-Pérez, Elena; Iacono, Oreste Lo; Fernandez–Bermejo, Miguel; Majano, Pedro L.; Apolinario, A.; Larrañaga, Eduardo; Moreno–Otero, Ricardo

doi:10.1016/s0168-8278(00)80301-3

Cited by 244 publications

(149 citation statements)

References 47 publications

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“…Among these, age greater than 40 to 50 years, and the severity of obesity, diabetes, or hyperlipidemia (especially hypertriglyceridemia) are among the most reliable. 5,14,[26][27][28][29]36,37 The role of female gender has been more variable in reported series, but the relatively increased prevalence of women in patients with more advanced disease supports female gender as a risk for progression. 8,11,27,28,36 Other reported predictors of advanced disease include elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and an AST: ALT ratio greater than 1.…”

Section: Clinical Aspectsmentioning

confidence: 99%

“…5,14,[26][27][28][29]36,37 The role of female gender has been more variable in reported series, but the relatively increased prevalence of women in patients with more advanced disease supports female gender as a risk for progression. 8,11,27,28,36 Other reported predictors of advanced disease include elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and an AST: ALT ratio greater than 1. 5,8,20,26,27,38 However, it is well known that significant liver disease may exist with liver enzymes in the normal range among NAFLD patients.…”

Section: Clinical Aspectsmentioning

confidence: 99%

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Nonalcoholic steatohepatitis: Summary of an AASLD Single Topic Conference

2003

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Section: Clinical Aspectsmentioning

confidence: 99%

Section: Clinical Aspectsmentioning

confidence: 99%

Nonalcoholic steatohepatitis: Summary of an AASLD Single Topic Conference

2003

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“…Increased lipid peroxidation was demonstrated in both animal models of fatty liver [110][111][112] and patients with nonalcoholic fatty liver diseases (NAFLD) [113][114][115][116][117]. NASH patients have increased levels of oxidative stress as compared with patients with steatosis alone [113,115].…”

Section: Lipid Peroxidationmentioning

confidence: 99%

Role of free radicals in liver diseases

2009

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Reactive oxygen and nitrogen species (ROS and RNS) are produced by metabolism of normal cells. However, in liver diseases, redox is increased thereby damaging the hepatic tissue; the capability of ethanol to increase both ROS/RNS and peroxidation of lipids, DNA, and proteins was demonstrated in a variety of systems, cells, and species, including humans. ROS/RNS can activate hepatic stellate cells, which are characterized by the enhanced production of extracellular matrix and accelerated proliferation. Cross-talk between parenchymal and nonparenchymal cells is one of the most important events in liver injury and fibrogenesis; ROS play an important role in fibrogenesis throughout increasing platelet-derived growth factor. Most hepatocellular carcinomas occur in cirrhotic livers, and the common mechanism for hepatocarcinogenesis is chronic inflammation associated with severe oxidative stress; other risk factors are dietary aflatoxin B 1 consumption, cigarette smoking, and heavy drinking. Ischemia-reperfusion injury affects directly on hepatocyte viability, particularly during transplantation and hepatic surgery; ischemia activates Kupffer cells which are the main source of ROS during the reperfusion period. The toxic action mechanism of paracetamol is focused on metabolic activation of the drug, depletion of glutathione, and covalent binding of the reactive metabolite N-acetyl-pbenzoquinone imine to cellular proteins as the main cause of hepatic cell death; intracellular steps critical for cell death include mitochondrial dysfunction and, importantly, the formation of ROS and peroxynitrite. Infection with hepatitis C is associated with increased levels of ROS/RNS and decreased antioxidant levels. As a consequence, antioxidants have been proposed as an adjunct therapy for various liver diseases.

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“…[2][3][4][5][6] Therefore, it has become important to characterize independent determinants of hepatic fibrosis in these individuals. Although host characteristics such as older age, female sex, type 2 diabetes mellitus, and obesity are recognized as important predictors of fibrotic severity, [7][8][9] there is conflicting evidence regarding the influence of intrahepatic iron deposition. Related to this, controversy exists about whether inheritance of the major hemochromatosis alleles (C282Y, H63D) influences severity of hepatic fibrosis in patients with NASH.…”

Section: N Onalcoholic Steatohepatitis (Nash) Is Charac-mentioning

confidence: 99%

HFE mutations, hepatic iron, and fibrosis: Ethnic-specific association of NASH with C282Y but not with fibrotic severity

et al. 2002

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There is conflicting evidence regarding inheritance of hemochromatosis gene (HFE) mutations and influence of hepatic iron deposition as cofactors for development of fibrosis in patients with nonalcoholic steatohepatitis (NASH). We studied hepatic iron content (Perls' stain grade), frequency of HFE mutations, and serum iron indices in 93 patients with NASH from a multiethnic background; 59 (63%) were of Anglo-Celtic origin. Data on C282Y mutations were available for all 93 patients and on H63D for 69 patients. Respective controls were 206 (for C282Y, 141 [69%] of whom were Anglo-Celtic) and 180 (for H63D) blood donors. Hyperferritinemia was present in 38 patients (40%) with NASH, but transferrin saturation was increased (>55%) in only 5 (5%). Liver biopsy specimens showed advanced fibrosis in 31 (33%) (cirrhosis in 20%). Altogether, 9 biopsy specimens (10%) showed increased iron: 7 (8%) with grade 2 and 2 (2%) with grade 3 iron staining. Only 1 biopsy specimen with increased iron showed advanced fibrosis. The frequency of C282Y heterozygosity was increased in Anglo-Celtic patients with NASH compared with ethnic blood donor controls (22% vs. 9.2%; P ‫؍‬ .035); there were no C282Y homozygotes in the NASH cohort. Although there was a trend toward higher serum ferritin levels among C282Y heterozygotes with NASH, there were no differences in histologic grades of steatosis, inflammation, or fibrosis between individuals with and without C282Y. The frequencies of compound C282Y/H63D heterozygotes (n ‫؍‬ 1) or H63D heterozygotes (n ‫؍‬ 10) were not increased in NASH. Multivariate analysis identified female sex, diabetes mellitus, and more severe liver inflammation but not HFE mutations, serum ferritin, iron saturation, or hepatic iron staining as independent predictors of hepatic fibrosis. In conclusion, hepatic iron is not a factor linked to hepatic fibrogenesis in patients with NASH. HFE mutations do not confer an additional risk of hepatic fibrosis in this disorder. (HEPATOLOGY 2002;36:142-149.)

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Characterization of pathogenic and prognostic factors of nonalcoholic steatohepatitis associated with obesity

Cited by 244 publications

References 47 publications

Nonalcoholic steatohepatitis: Summary of an AASLD Single Topic Conference

Nonalcoholic steatohepatitis: Summary of an AASLD Single Topic Conference

Role of free radicals in liver diseases

HFE mutations, hepatic iron, and fibrosis: Ethnic-specific association of NASH with C282Y but not with fibrotic severity

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