The outcome of liver injury is dictated by the effectiveness of repair. Successful repair (i.e., regeneration) results in replacement of dead epithelial cells with healthy epithelial cells, and ...reconstructs normal hepatic structure and function. Liver regeneration is known to involve replication of surviving mature hepatocytes and bile duct cells. This review discusses recent evidence for other mechanisms that might also replace dead hepatic epithelial cells and repair liver damage, particularly during chronic injury. According to this theory, certain epithelial cells in developing livers and/or injured adult livers undergo epithelial‐to‐mesenchymal transition (EMT) and move into the hepatic mesenchyme where they exhibit fibroblastic features. Some of these epithelia‐derived mesenchymal cells, however, may be capable of undergoing subsequent mesenchymal‐to‐epithelial transition (MET), reverting to epithelial cells that ultimately become hepatocytes or cholangiocytes. Although these concepts remain to be proven, the theory predicts that the balance between EMT and MET modulates the outcome of chronic liver injury. When EMT activity outstrips MET, repair is mainly fibrogenic, causing liver fibrosis. Conversely, predominance of MET favors more normal liver regeneration. In this review, we summarize evidence that certain resident liver cells are capable of EMTs in vitro and during chronic liver injury. (HEPATOLOGY 2009.)
Pathogenesis of Nonalcoholic Steatohepatitis Machado, Mariana Verdelho; Diehl, Anna Mae
Gastroenterology (New York, N.Y. 1943),
06/2016, Letnik:
150, Številka:
8
Journal Article
Recenzirano
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Nonalcoholic steatohepatitis (NASH) is a necro-inflammatory response that ensues when hepatocytes are injured by lipids (lipotoxicity). NASH is a potential outcome of nonalcoholic fatty liver (NAFL), ...a condition that occurs when lipids accumulate in hepatocytes. NASH may be reversible, but it can also result in cirrhosis and primary liver cancer. We are beginning to learn about the mechanisms of progression of NAFL and NASH. NAFL does not inevitably lead to NASH because NAFL is a heterogeneous condition. This heterogeneity exists because different types of lipids with different cytotoxic potential accumulate in the NAFL, and individuals with NAFL differ in their ability to defend against lipotoxicity. There are no tests that reliably predict which patients with NAFL will develop lipotoxicity. However, NASH encompasses the spectrum of wound-healing responses induced by lipotoxic hepatocytes. Differences in these wound-healing responses among individuals determine whether lipotoxic livers regenerate, leading to stabilization or resolution of NASH, or develop progressive scarring, cirrhosis, and possibly liver cancer. We review concepts that are central to the pathogenesis of NASH.
Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis. Currently, there is no established treatment for this disease.
We randomly assigned 247 adults with nonalcoholic ...steatohepatitis and without diabetes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 weeks. The primary outcome was an improvement in histologic features of nonalcoholic steatohepatitis, as assessed with the use of a composite of standardized scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indicate statistical significance.
Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P=0.001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; P=0.04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone, as compared with placebo (P<0.001 for both comparisons), and both agents were associated with reductions in hepatic steatosis (P=0.005 for vitamin E and P<0.001 for pioglitazone) and lobular inflammation (P=0.02 for vitamin E and P=0.004 for pioglitazone) but not with improvement in fibrosis scores (P=0.24 for vitamin E and P=0.12 for pioglitazone). Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups.
Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes. (ClinicalTrials.gov number, NCT00063622.)
Factors that determine disease severity in nonalcoholic fatty liver disease (NAFLD) are unclear, but exercise is a recommended treatment. We evaluated the association between physical activity ...intensity and histological severity of NAFLD.
We conducted a retrospective analysis of adults with biopsy-proven NAFLD enrolled in the NASH CRN (Nonalcoholic Steatohepatitis Clinical Research Network). Using self-reported time spent in physical activity, we classified participants as inactive or as meeting the US guidelines for either moderate or vigorous exercise. Histology was reviewed by a central pathology committee. Frequency and odds of steatohepatitis (NASH) and advanced fibrosis were compared between subjects who either met or did not meet exercise recommendations, and by the total amount of exercise per week.
A total of 813 adults (males=302, females=511) with NAFLD were included, with a mean age of 48 years. Neither moderate-intensity exercise nor total exercise per week was associated with NASH or stage of fibrosis. Meeting vigorous recommendations was associated with a decreased adjusted odds of having NASH (odds ratio (OR): 0.65 (0.43-0.98)). Doubling the recommended time spent in vigorous exercise, as is suggested for achieving additional health benefits, was associated with a decreased adjusted odds of advanced fibrosis (OR: 0.53 (0.29-0.97)).
These data support an association of vigorous but not moderate or total exercise with the severity of NAFLD. Optimal doses of exercise by duration and intensity for the prevention or treatment of NASH have not been established; however, intensity may be more important than duration or total volume.
Background/Aims While the rise in non-alcoholic fatty liver disease (NAFLD) parallels the increase in obesity and diabetes, a significant increase in dietary fructose consumption in industrialized ...countries has also occurred. The increased consumption of high fructose corn syrup, primarily in the form of soft drinks, is linked with complications of the insulin resistance syndrome. Furthermore, the hepatic metabolism of fructose favors de novo lipogenesis and ATP depletion. We hypothesize that increased fructose consumption contributes to the development of NAFLD. Methods A dietary history and paired serum and liver tissue were obtained from patients with evidence of biopsy-proven NAFLD ( n = 49) without cirrhosis and controls ( n = 24) matched for gender, age (±5 years), and body mass index (±3 points). Results Consumption of fructose in patients with NAFLD was nearly 2- to 3-fold higher than controls 365 kcal vs 170 kcal ( p < 0.05). In patients with NAFLD ( n = 6), hepatic mRNA expression of fructokinase (KHK), an important enzyme for fructose metabolism, and fatty acid synthase, an important enzyme for lipogenesis were increased ( p = 0.04 and p = 0.02, respectively). In an AML hepatocyte cell line, fructose resulted in dose-dependent increase in KHK protein and activity. Conclusions The pathogenic mechanism underlying the development of NAFLD may be associated with excessive dietary fructose consumption.
The Hedgehog (HH)‐signaling pathway mediates several processes that are deregulated in patients with metabolic syndrome (e.g., fat mass regulation, vascular/endothelial remodeling, liver injury and ...repair, and carcinogenesis). The severity of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome generally correlate. Therefore, we hypothesized that the level of HH‐pathway activation would increase in parallel with the severity of liver damage in NAFLD. To assess potential correlations between known histologic and clinical predictors of advanced liver disease and HH‐pathway activation, immunohistochemistry was performed on liver biopsies from a large, well‐characterized cohort of NAFLD patients (n = 90) enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) Database 1 study. Increased HH activity (evidenced by accumulation of HH‐ligand–producing cells and HH‐responsive target cells) strongly correlated with portal inflammation, ballooning, and fibrosis stage (each P < 0.0001), supporting a relationship between HH‐pathway activation and liver damage. Pathway activity also correlated significantly with markers of liver repair, including numbers of hepatic progenitors and myofibroblastic cells (both P < 0.03). In addition, various clinical parameters that have been linked to histologically advanced NAFLD, including increased patient age (P < 0.005), body mass index (P < 0.002), waist circumference (P < 0.0007), homeostatic model assessment of insulin resistance (P < 0.0001), and hypertension (P < 0.02), correlated with hepatic HH activity. Conclusion: In NAFLD patients, the level of hepatic HH‐pathway activity is highly correlated with the severity of liver damage and with metabolic syndrome parameters that are known to be predictive of advanced liver disease. Hence, deregulation of the HH‐signaling network may contribute to the pathogenesis and sequelae of liver damage that develops with metabolic syndrome. (HEPATOLOGY 2012;55:1711–1721)
Recent progress has allowed a more comprehensive study of the gut microbiota. Gut microbiota helps in health maintenance and gut dysbiosis associates with chronic metabolic diseases. Modulation of ...short-chain fatty acids and choline bioavailability, lipoprotein lipase induction, alteration of bile acid profile, endogenous alcohol production, or liver inflammation secondary to endotoxemia result from gut dysbiosis. Modulation of the gut microbiota by pre/probiotics gives promising results in animal, but needs to be evaluated in human before use in clinical practice. Gut microbiota adds complexity to the pathophysiology of nonalcoholic fatty liver disease but represents an opportunity to discover new therapeutic targets.
It is now well established that gut flora and chronic liver diseases are closely interrelated. This association is most evident at late stages of the disease: cirrhosis and impaired liver function ...are associated with intestinal bacterial overgrowth, small bowel dysmotility, increased gut permeability, and decreased immunological defenses, all of which promote bacterial translocation from the gut to the systemic circulation, leading to infections that in turn aggravate liver dysfunction in a vicious circle 1. For a long time, the implication of gut flora in the pathophysiology of less advanced chronic liver diseases has been underestimated because technical limitations allow only for the culture of a small fraction of gut bacteria. Recent technological progress and next-generation DNA sequencing have allowed for more sophisticated analysis and sampling of the gut microbiota by culture-independent methods 2. Thanks to these recent technological advances, knowledge about the role of gut microbiota disruption (dysbiosis) in gut diseases such as colon cancer, inflammatory bowel diseases, and irritable bowel syndrome has greatly increased, with possible new therapeutic strategies. More surprisingly, gut dysbiosis has been implicated in chronic metabolic disorders such as obesity, metabolic syndrome, diabetes, and cardiovascular diseases 3. Nonalcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome and thus evolves in the same context as these metabolic diseases 4. It is therefore not surprising that recent literature emphasizes a potential role for gut dysbiosis in the pathophysiology of NAFLD. ...
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