Macrophage/neutrophil-specific IL-4 receptor alpha-deficient mice (LysM(Cre)IL-4Ralpha(-/flox)) were generated to understand the role of IL-4/IL-13 responsive myeloid cells during Type 2 immune responses. LysM(Cre)IL-4Ralpha(-/flox) mice developed protective immunity against Nippostrongylus brasiliensis accompanied by T(H)2 development and goblet cell hyperplasia. In contrast, LysM(Cre)IL-4Ralpha(-/flox) mice were extremely susceptible to Schistosoma mansoni infection with 100% mortality during acute infection. Mortality was not dependent on neutrophils and occurred in the presence of T(H)2/Type 2 responses, granuloma formation, and egg-induced fibrosis. Death was associated with increased T(H)1 cytokines, hepatic and intestinal histopathology, increased NOS-2 activity, impaired egg expulsion, and sepsis. IL-10 was not able to compensate for the absence of IL-4/IL-13-activated alternative macrophages. Together, this shows that alternative macrophages are essential during schistosomiasis for protection against organ injury through downregulation of egg-induced inflammation.

We have proposed that steatohepatitis results from reactive oxygen species (ROS) acting on accumulated fatty acids to form proinflammatory lipoperoxides. Cytochrome P450 4a (Cyp4a) and Cyp2e1 are potential hepatic sources of ROS. We tested the hypothesis that increasing Cyp4a through activation of peroxisome proliferator-activated receptor ␣ (PPAR␣) should aggravate steatohepatitis produced by feeding a methionine and choline deficient (MCD) diet. Conversely, we assessed dietary steatohepatitis in PPAR␣ ؊/؊ mice that cannot up-regulate Cyp4a. Male wild type (wt) or PPAR␣ ؊/؊ mice (C57BL6 background) were fed the MCD diet with or without Wy-14,643 (0.1% wt/wt), a potent PPAR␣ agonist. Controls were fed the same diet supplemented with methionine and choline. After 5 weeks, wt mice fed the MCD diet developed moderate steatohepatitis and alanine aminotransferase (ALT) levels were increased. Wy-14,643 prevented rather than increased liver injury; ALT levels were only mildly elevated whereas steatohepatitis was absent. Wy-14,643 up-regulated mRNA for liver fatty acid binding protein and peroxisomal ␤-oxidation enzymes (acyl-CoA oxidase, bifunctional enzyme, and ketothiolase), thereby reducing hepatic triglycerides and preventing steatosis. In wt mice, dietary feeding up-regulated Cyp4a14 mRNA 2.7-fold and increased hepatic lipoperoxides compared with controls. Wy-14,643 prevented hepatic lipoperoxides from accumulating despite an 18-fold increase in both Cyp4a10 and Cyp4a14 mRNA. PPAR␣ ؊/؊ mice fed the MCD diet developed more severe steatohepatitis than wt mice, and were unaffected by Wy-14,643. In conclusion, PPAR␣ activation both increases Cyp4a expression and enhances hepatic lipid turnover; the latter effect removes fatty acids as substrate for lipid peroxidation and is sufficiently powerful to prevent the development of dietary steatohepatitis. (HEPATOLOGY 2003;38:123-132.)

Nonalcoholic steatohepatitis (NASH) has multiple etiologic associations, but the pathogenesis is poorly understood. Cytochrome P450 (CYP) 2E1 is induced in the liver of patients who drink alcohol to excess and is important in the pathogenesis of alcoholic liver disease (ALD). We have previously shown that hepatic CYP2E1 is also increased in a rat dietary model of steatohepatitis. The aim of the present study was to test the hypothesis that hepatic CYP2E1 is induced in the liver of patients with NASH, defined on the basis of compatible liver histology and the exclusion of excessive alcohol intake. Sections of paraffin-embedded liver biopsy material from 31 subjects with NASH were evaluated and compared with sections from 10 histologically normal livers and 6 patients with ALD. Hepatic CYP2E1 and CYP3A were detected in liver sections by immunohistochemistry using specific anti-human CYP2E1 and CYP3A antibodies. As expected, normal livers showed CYP2E1 immunostaining confined to a rim, two to three cells thick, around terminal hepatic venule, while livers from alcoholic hepatitis patients showed increased CYP2E1 staining. CYP2E1 immunostaining was also increased in livers from patients with NASH, irrespective of the etiologic association. Further, the pattern of CYP2E1 distribution was similar to ALD, with increased perivenular intensity and more extensive acinar distribution of staining. As in the rat model, the hepatic distribution of CYP2E1 corresponded to that of steatosis. In contrast to CYP2E1, CYP3A immunostaining was decreased in patients with NASH. We conclude that hepatic CYP2E1 is increased in patients with NASH compared with normal livers. Thus, despite many possible etiologic factors for NASH, the pathogenetic mechanisms may be similar and, like alcoholic steatohepatitis, may involve induction of CYP2E1. (HEPATOLOGY 1998;27:128-133.)

No abstract

Data on the long-term outcome of nonalcoholic steatohepatitis (NASH)-associated cirrhosis are few, and most reports describe cases of cryptogenic cirrhosis associated with risk factors for NASH but without histologic definition. In this prospective cohort study, we describe the longterm morbidity and mortality of 23 patients with NASH-associated cirrhosis defined by strict clinicopathologic criteria. Outcomes were compared with 46 age-and gender-matched patients with cirrhosis from chronic hepatitis C virus (HCV) infection: 23 untreated and 23 nonresponders to antiviral therapy. During follow-up (mean, 84 months; median, 60 months; range, 5-177 months), 9 of the 23 NASH-associated cirrhosis cases developed liver-related morbidity (8 ascites and/or encephalopathy, 1 variceal bleeding). The probability of complication-free survival was 83%, 77%, and 48% at 1, 3, and 10 years, respectively, and the cumulative probability of overall survival was 95%, 90%, and 84% at 1, 3, and 10 years, respectively. Five deaths were from liver failure, 1 from a non-liver-related cause. By multivariate analysis, bilirubin (P ‫؍‬ .02) and platelet (P ‫؍‬ .04) were independent predictors of complication-free survival; bilirubin (P ‫؍‬ .05) was the only predictor for overall survival. After controlling for these factors, there was no difference in complication-free or overall survival between the NASH-cirrhosis cohort and either group of HCV-cirrhosis. However, 8 cases of liver cancer occurred in the HCV-cirrhosis groups compared with none among NASH cases. In conclusion, liver failure is the main cause of morbidity and mortality in NASH-associated cirrhosis. The prognosis is either similar or less severe than HCV-cirrhosis, except that HCC appears less common. (HEPATOLOGY 2003;38:420-427.) L iver-related morbidity and mortality in nonalcoholic steatohepatitis (NASH) occurs principally among those with cirrhosis, a finding similar to the natural history of hepatitis C. There is, however, a paucity of data on the natural history of cirrhosis attributable solely to host metabolic factors (NASH). In large part, this relates to the lack of accepted histologic and clinical criteria for the diagnosis of "NASH-associated cirrhosis" as opposed to "cryptogenic cirrhosis" occurring in people with risk factors for NASH. These definitional problems are compounded by reports that the features of steatohepatitis on liver biopsy may disappear with fibrotic progression. 1 Although disease progression in NASH is slow, 1 it is unclear whether clinical progression and liver complications are inevitable or whether the rate of progression is faster or slower than that in other liver diseases, such as hepatitis C. Prospective outcome studies of NASH are difficult to perform because of the need for extended follow-up, the possibility of death from other causes (especially cardiovascular disease and cancer), 2 and the reluctance to undertake serial liver biopsy because of the perceived benign natural history and lack of specific therapies.In chronic hepatit...

The Wistar strain and the male sex are associated with the greatest degree of steatosis in rats subjected to the MCD diet. Of the groups studied, male C57/BL6 mice develop the most inflammation and necrosis, lipid peroxidation, and ultrastructural injury, and best approximate the histological features of NASH.

Non-steatohepatitis, probably aggravated by MTX, is an important cause of liver injury in patients on long-term, 'low-dose' MTX treatment for psoriasis. In addition, MTX alone can cause a NASH-like pattern of injury that is at least, in part, caused by a higher cumulative dose.

The underlying mechanisms that perpetuate liver inflammation in nonalcoholic steatohepatitis are poorly understood. We explored the hypothesis that cyclooxygenase-2 (COX-2) can exert pro-inflammatory effects in metabolic forms of fatty liver disease. Male wild-type (WT) C57BL6/N or peroxisome proliferator-activated receptor ␣ knockout (PPAR-␣ ؊/؊ ) mice were fed a lipogenic, methionine-and choline-deficient (MCD) diet or the same diet with supplementary methionine and choline (control). COX-2 was not expressed in livers of mice fed the control diet. In mice fed the MCD diet, hepatic expression of COX-2 messenger RNA and protein occurred from day 5, continued to rise, and was 10-fold higher than controls after 5 weeks, thereby paralleling the development of steatohepatitis. Upregulation of COX-2 was even more pronounced in PPAR