To read the full text of this article, go to http://www.fasebj.org/cgi/ SPECIFIC AIMSToxic by-products of lipid peroxidation and oxidative stress associated with increased fat deposition in the liver, cytokine-mediated injury, and hyperglycemia are among proposed mechanisms that trigger fatty liver disease. It is uncertain why only a subgroup of patients with nonalcoholic steatohepatitis (NASH) may progress to liver fibrosis. Fatty livers of obese fa/fa rats are vulnerable to injury when challenged by endotoxin, ischemia-reperfusion, or acute ethanol treatment. Since the prevalence of obesity is expected to rise in the near future due to high saturated fat consumption, the objective of this study was to evaluate whether a high fat diet (HFD) can act as a "second hit" and cause progression to liver injury in obese fa/fa rats compared with lean Fa/? rats. PRINCIPAL FINDINGS A high saturated fat diet (HFD) contributes to the progression of NASH to fibrosisFifteen-wk-old obese fa/fa Zucker rats and their lean littermates, Fa/? rats, were fed a control or a high fat diet (12% vs. 60% total calories, respectively) for 8 wk. Hyperglycemia occurred to the greatest extent in fa/fa rats fed the HFD. Liver injury appeared in fa/fa rats fed the HFD. Hematoxylin and eosin staining showed steatohepatitis, ballooning degeneration, significant macrosteatosis extending beyond the periportal area into the lobule and the central zone, and foci of lobular inflammation only in the fa/fa rats fed the HFD (Fig. 1A-D). Nonesterified fatty acid levels were elevated 2-fold in fa/fa rats fed the HFD compared with control diet (Fig. 1E). ALT values were 5-fold higher than in Fa/? rats (Fig. 1F ). Stellate cell-derived TGF␤, which actively participates in liver fibrosis and collagen deposition, and plasma TNF␣ increased in fa/fa rats fed HFD compared with fa/fa rats fed control diet or to Fa/? rats fed HFD.Sirius red/Fast green staining for collagenous proteins showed mild periportal fibrosis only in fa/fa rats fed HFD. Western blot analysis for collagen type I, a marker of liver fibrosis, revealed increased collagen I expression in the liver of fa/fa rats fed HFD; no change was observed with Fa/? rats. ␣-Smooth muscle actin, representative of stellate cell activation, was elevated in fa/fa rats fed HFD. Expression of matrix metalloproteinases (MMPs) that participate in collagen degradation as well as their inhibitors (tissue inhibitors of metalloproteinases, TIMPs) was analyzed. A decrease in pro-MMP13 and active MMP13 was found in fa/fa rats regardless of diet. TIMP1 (which inhibits MMP13, preventing collagen I degradation) was similar in both genotypes fed control diet but elevated in rats fed HFD, especially in fa/fa rats. Along with elevated TGF␤ production, this may contribute to collagen accumulation in fa/fa rats fed HFD. MMP2 and MMP9 were detected only as latent forms by Western blot analysis; pro-MMP9 was increased 2-fold in fa/fa rats regardless of diet. Oxidative stress in obese fa/fa rats fed HFDFormation of malondialdehyde, a...

No abstract

Chronic hyperammonemia may negatively affect attention. Eating breakfast improves attention and executive functions of patients with MHE. Prolonged periods of starvation may be partly responsible for these changes. This trial was registered at clinicaltrials.gov as NCT01083446.

Retransplantation (re-LT) of patients with recurrent hepatitis C virus (HCV) carries significant morbidity and mortality, negatively impacting on an already scarce donor allograft pool. In this study, we investigated the outcome of allografts and patients after re-LT due to recurrent HCV. Between 1989 and 2002, 47 patients were retransplanted at our institution due to HCV-related graft failure. Clinical HCV recurrence after re-LT was diagnosed when patients had acute liver enzyme elevation correlated with histological recurrence. The independent influence of these variables on survival was tested using Cox regression model. Chi-squared tests were used to examine the influence of individual demographic and pre/perioperative variables on recurrence. Thirty-one (66%) patients died after re-LT (median 2.2 months). Donor age >60, clinical HCV recurrence, and graft failure due to cirrhosis were significant risk factors for mortality (risk ratios of 3.6, 3.3, and 2.4, respectively). Pre-LT MELD score was lower among survivors (22+/- 5 vs. 27+/- 8). Following re-LT, 38 patients had at least one biopsy due to acute liver dysfunction; 19 of them (50%) had recurrence within the first 3 months. High-dose solumedrol was correlated with early recurrence. No association was found between time of recurrence after the first LT and time of recurrence after re-LT. In conclusion, patients with cirrhosis due to recurrent HCV undergoing re-LT have an extremely high mortality rate; older allografts should be avoided in retransplanting these patients. The timing of clinical recurrence after initial liver transplantation is not predictive of the timing of recurrence after re-LT. Patients experiencing early graft failure due to accelerated forms of HCV should not be denied re-LT with the expectation that a similar disease course will occur after re-LT.