肝星状细胞的活化与肝纤维化

肝纤维化是机体对损伤的一种修复作用，即使可以应用基因或其他疗法彻底消除纤维化，但机体对抑制或消除纤维化后将产生何种反应及后果尚难预测。肝星状细胞（hepatic stellate cells，HSC）是引起肝纤维化的主要细胞，对HSC与其活化型一肌成纤维细胞（myofibroblast，MF）在肝损伤中作用的研究已颇为深入，而HSC激活在肝纤维化发生、发展中的作用甚为重要。     

Liver inflammatory cells, apoptosis, regeneration and stellate cell activation in non-alcohol steatohepatitis

Background, The pathogenesis of non-alcoholic steatohepatitis remains unclear from several points of view. Minimal diagnostic criteria are still not defined. Aim. To gather information useful for diagnosis and to improve the understanding of pathogenic mechanisms.

Patients. A series of 14 patients with non-alcoholic steatohepatitis, identified among liver outpatients, were paired for age, sex and alanine amino transferase values with 14 patients with hepatitis C virus infection without steatosis.

Methods. Clinical, biochemical and immunohistological examination, including characterisation of inflammatory cell population, evaluation of type 111 collagen and tenascin deposition, activation of stellate cells, hepatocellular apoptosis and proliferation.

Results. Patients with non-alcoholic steatohepatitis were more frequently obese, had higher triglyceride concentrations and lower gamma-globulins. T lymphocytes outnumbered polymorphonuclear cells, both in hepatitis C and in steatohepatitis, with a larger number of CD8 lymphocytes in patients with viral hepatitis but a comparable number of granulocytes. This resulted in a higher granulocytes to T cells ratio in steatohepatitis, possibly making these cells more easily detectable in spite of similar absolute numbers. Portal fibrosis and piecemeal necrosis were prevalent in hepatitis C virus infection, pericentral fibrosis was similar. Hepatocellular, apoptosis and proliferation as well as stellate cell activation were less relevant in steatohepatitis than in hepatitis C virus infection in spite of similar alanine amino transferase levels.

Conclusions. These data provide a possible explanation for the relatively low tendency to progression of non-alcoholic steatohepatitis in most patients despite increased alanine amino transferase and suggest that non-death-related release of alanine amino transferase might occur in non-alcoholic steatohepatitis. This makes liver biopsy an essential part of the clinical setting supporting diagnosis, evaluation of severity and possibly definition of the evolutionary trend.     

Red cell distribution width and nonalcoholic steatohepatitis

Red cell distribution width is a measure of deviation of the volume of red blood cells.It is a marker of anisocytosis and often used to evaluate the possible causes of anemia.Elevated red cell distribution width levels are also associated with acute and chronic inflammatory responses.In nonalcoholic steatohepatitis,inflammation is accompanied with steatosis.For assuming red cell distribution width as a marker of nonalcoholic steatohepatitis,intervening factors such as levels of inflammatory markers should also be evaluated.     

Inhibitory effect of angiotensin Ⅱ receptor antagonist on hepatic stellate cell activation in non-alcoholic steatohepatitis

AIM: To investigate the efficacy of angiotensin II receptor antagonist on hepatic stellate cells (HSCs) activation in the patients with non-alcoholic steatohepatitis (NASH). METHODS: Seven patients with NASH were prescribed losartan, a selective angiotensin II type 1 receptor antagonist (50 mg/d) for 48 wk. Liver biopsies were performed both at the entry and end of the study in all patients. Quiescent and activated HSCs were identified by double immunostaining using anti-p75 and -smooth muscle actin antibodies, and the number of each phenotype was counted. Similarly, the liver specimens obtained from the eight patients with non-alcoholic fatty liver (NAFL) were also examined as controls. RESULTS: In NASH hepatic tissues, activated HSCs were dominantly distributed as compared with those in NAFL. The 48-wk losartan treatment induced a remarkable decrease in activated HSCs and a mild increase in quiescent phenotypes. CONCLUSION: Our data suggest the crucial involvement of HSCs in anti-fibrotic effect of angiotensin II receptor antagonist on patients with NASH.     

Hepatic stellate cell progenitor cells

Hepatic stellate cells (HSCs) are recognized as a major player in liver fibrogenesis. Upon liver injury, HSCs differentiate into myofibroblasts and participate in progression of fibrosis and cirrhosis. Additional cell types such as resident liver fibroblasts/myofibroblasts or bone marrow cells are also known to generate myofibroblasts. One of the major obstacles to understanding the mechanism of liver fibrogenesis is the lack of knowledge regarding the developmental origin of HSCs and other liver mesenchymal cells. Recent cell lineage analyses demonstrate that HSCs are derived from mesoderm during liver development. MesP1-expressing mesoderm gives rise to the septum transversum mesenchyme before liver formation and then to the liver mesothelium and mesenchymal cells, including HSCs and perivascular mesenchymal cells around the veins during liver development. During the growth of embryonic liver, the mesothelium, consisting of mesothelial cells and submesothelial cells, migrates inward from the liver surface and gives rise to HSCs and perivascular mesenchymal cells, including portal fibroblasts, smooth muscle cells around the portal vein, and fibroblasts around the central vein. Cell lineage analyses indicate that mesothelial cells are HSC progenitor cells capable of differentiating into HSCs and other liver mesenchymal cells during liver development.     

Inhibitory effect of angiotensin TT receptor antagonist on hepatic stellate cell activation in non-alcoholic steatohepatitis

AIM: To investigate the efficacy of angiotensin Ⅱ receptor antagonist on hepatic stellate cells (HSCs) activation in the patients with non-alcoholic steatohepatitis (NASH).METHODS: Seven patients with NASH were prescribed losartan, a selective angiotensin Ⅱ type 1 receptor antagonist (50 mg/d) for 48 wk. Liver biopsies were performed both at the entry and end of the study in all patients. Quiescent and activated HSCs were identified by double immunostaining using anti-p75 and α-smooth muscle actin antibodies, and the number of each phenotype was counted. Similarly, the liver specimens obtained from the eight patients with non-alcoholic fatty liver (NAFL) were also examined as controls.RESULTS: In NASH hepatic tissues, activated HSCs were dominantly distributed as compared with those in NAFL.The 48-wk losartan treatment induced a remarkable decrease in activated HSCs and a mild increase in quiescent phenotypes.CONCLUSION: Our data suggest the crucial involvement of HSCs in anti-fibrotic effect of angiotensin Ⅱ receptor antagonist on patients with NASH.     

Hepatic 11beta-HSD1 mRNA expression in fatty liver and nonalcoholic steatohepatitis

Context  Nonalcoholic fatty liver disease represents the hepatic manifestation of the metabolic syndrome. Nonalcoholic steatohepatitis (NASH) is the progressive form of liver injury. The pathophysiology that leads to NASH is not well understood.
Objective  We hypothesize that an altered cortisol metabolism in the liver may be a pathogenetic factor.
Design and patients  75 patients (28 men, 47 women) underwent liver biopsy for elevation in liver enzymes. Histological diagnosis identified normal liver in eight, fatty liver in 20, NASH grade 1 in 22, grade 2 in nine, grade 3 in three patients, and other forms of hepatitis or cirrhosis in 13 patients. We quantified hepatic 11β-hydroxysteroid dehydrogenase type1 (11β-HSD1) and hexose-6-phosphate-dehydrogenase (H6PDH) mRNA expression by real-time PCR. In addition, analysis of 24 h urinary excretion of cortisol metabolites using GCMS was performed and compared with healthy controls.
Results  11β-HSD1 mRNA expression correlated significantly ( R ²= 0·809; P  < 0·001) with H6PDH mRNA expression, negatively with waist-to-hip ratio in women ( R ²= 0·394; P = 0·005), but not with urinary (THF + 5α-THF)/THE ratio, total cortisol metabolite excretion, age, BMI, degree of fatty liver or NASH stages. Total cortisol metabolite excretion was increased in patients with fatty liver or NASH compared with healthy controls.
Conclusions  Our data suggest that expression of hepatic 11β-HSD1 and H6PDH are closely interlinked. 11β-HSD1 gene expression does not seem to be involved in the pathogenesis of fatty liver or NASH. However, those patients showed an increased 5α- and 5β-reduction of cortisol leading to an increased cortisol turnover rate and an activation of the HPA axis.     

Inflammation in nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) describes a range of disorders characterized by excess accumulation of triglyceride within the liver. While simple steatosis may be clinically stable, nonalcoholic steatohepatitis (NASH) can be progressive. Inflammation is believed to be the driving force behind NASH and the progression to fibrosis and subsequent cirrhosis. This article will review and interpret the current literature in an attempt to expand our understanding of the environmental and genetic causes of inflammation and its effects in NAFLD.     

Lipid peroxidation, stellate cell activation and hepatic fibrogenesis in a rat model of chronic steatohepatitis

BACKGROUND/AIMS: We explored the involvement of cell types, cytokines and lipid peroxidation in a rat dietary model of fibrosing steatohepatitis. METHODS: Male rats were fed a high fat diet deficient in methionine and choline (MCD) for up to 17 weeks. Whole liver, hepatocytes and non-parenchymal cells were analysed for reduced glutathione (GSH) levels, products of lipid peroxidation (thiobarbituric acid reactive substances, TBARS), liver injury, and fibrosis. RESULTS: MCD diet-fed rats developed hepatic steatosis at week 2 and focal necroinflammatory change by week 5, while pericellular fibrosis evolved and progressed between weeks 12 and 17. Collagen alpha(1)(1) gene expression was upregulated by week 5 and increased fivefold by week 17. Stellate cells were the unique source of collagen gene expression. TIMP-1 and -2 were increased at week 12. Livers of MCD diet-fed rats exhibited lowered levels of GSH and elevated TBARS. Hepatocytes were the source of lipid peroxidation, and mRNA levels for TGFbeta1 were increased only in this cell type. CONCLUSIONS: The MCD model of 'fibrosing steatohepatitis' replicates the histologic features of human steatohepatitis, and the sequence of steatosis, inflammatory cell injury and fibrogenesis. The temporal sequence is consistent with a concept for involvement of oxidative injury in inflammatory recruitment and pathogenesis of hepatic fibrogenesis.     

Hepatic fat quantification magnetic resonance for monitoring treatment response in pediatric nonalcoholic steatohepatitis

AIM: To evaluate the possibility of treatment effect monitoring using hepatic fat quantification magnetic resonance(MR) in pediatric nonalcoholic steatohepatitis(NASH).METHODS: We retrospectively reviewed the medical records of patients who received educational recommendations and vitamin E for NASH and underwent hepatic fat quantification MR from 2011 to 2013.Hepatic fat fraction(%) was measured using dual- and triple-echo gradient-recalled-echo sequences at 3T.The compliant and non-compliant groups were compared clinically,biochemically,and radiologically.RESULTS: Twenty seven patients(M:F = 24:3; mean age: 12 ± 2.3 years) were included(compliant group = 22,non-compliant = 5).None of the baseline findings differed between the 2 groups,except for triglyceride level(compliant vs non-compliant,167.7 mg/d L vs 74.2 mg/d L,P = 0.001).In the compliant group,high-density lipoprotein increased and all other parameters decreased after 1-year follow-up.However,there were various changes in the non-compliant group.Dualecho fat fraction(-19.2% vs 4.6,P 0.001),tripleecho fat fraction(-13.4% vs 3.5,P 0.001),alanine aminotransferase(-110.7 IU/L vs-10.6 IU/L,P = 0.047),total cholesterol(-18.1 mg/d L vs 3.8 mg/d L,P = 0.016),and triglyceride levels(-61.3 mg/d L vs 11.2 mg/d L,P = 0.013) were significantly decreased only in the compliant group.The change in body mass index and dual-echo fat fraction showed a positive correlation(ρ = 0.418,P = 0.030).CONCLUSION: Hepatic fat quantification MR can be a non-invasive,quantitative and useful tool for monitoring treatment effects in pediatric NASH.     

Current treatments in nonalcoholic steatohepatitis

Opinion statement Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the United States secondary to the growing obesity epidemic. Although most patients with NAFLD do not develop progressive liver disease, the subset of NAFLD patients with nonalcoholic steatohepatitis (NASH) are at risk for progression to cirrhosis and hepatocellular carcinoma, which necessitates appropriate follow-up and management. Unfortunately, proven treatment modalities for NASH that result in complete histopathologic regression of steatosis, inflammation, and fibrosis do not exist. Many therapeutic approaches to NAFLD management have been attempted, with varying degrees of success. However, most of these studies have been limited to small, single-center, uncontrolled trials. Based on our evolving understanding of the disease’s pathogenesis, it seems logical that a multidisciplinary approach addressing the underlying metabolic syndrome and the resultant intrinsic liver injury is necessary. Diet, exercise, surgical weight loss, diabetic medications, and hepatoprotective agents all have been studied and may serve as potential weapons in our armamentarium against this disease. Although most of these approaches have been studied as single-modality therapy, we believe that combination, multimodality therapy is required to treat this disease effectively.     

Apolipoprotein synthesis in nonalcoholic steatohepatitis

The pathophysiology of hepatic steatosis, a prerequisite of nonalcoholic fatty liver disease, is poorly understood. Because very-low-density lipoprotein (VLDL) formation is the chief route of hepatic lipid export, we hypothesized that the synthesis of apoB-100, a rate-determining step in hepatic VLDL formation, may be altered in patients with nonalcoholic steatohepatitis (NASH). This study evaluated the relative synthesis rates of apolipoprotein B-100 (apoB-100) in patients with NASH and in lean and body mass index (BMI)-matched (obese) controls without NASH. A primed continuous infusion of L-[1-(13)C] leucine was used to measure the absolute synthesis rates (ASR) of apoB-100 and fibrinogen in 7 patients with NASH and compared them with 7 lean and 7 obese (BMI-matched) controls without NASH. The ASRs of fibrinogen and albumin also were measured. The mean ASR of apoB-100 in patients with NASH was lower (31.5 +/- 3.4 mg/kg/d) than that of obese (115.2 +/- 7.2 mg/kg/d, P <.001) and lean controls (82.4 +/- 4.1 mg/kg/d, P =.002). In contrast, the mean ASR of fibrinogen was greater in subjects with NASH than in both control groups. These data indicate that NASH is associated with markedly altered hepatic synthesis of apoB-100. The finding that albumin synthesis was not similarly decreased in patients with NASH shows that the attenuation of apoB-100 synthesis is not on the basis of globally impaired hepatic protein synthesis. In conclusion, because apoB-100 synthesis is a rate-determining step in hepatocyte lipid export, decreased synthesis of this protein may be an important factor in the development of hepatic steatosis, a prerequisite for NASH.     

Pathophysiology of nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) affects approximately 30% of adults and 20% of children in the United States. Nonalcoholic steatohepatitis (NASH) is its most severe histologic form and progresses to cirrhosis in 20% of these patients. Once developed, 30% to 40% of patients with NASH cirrhosis will experience a liver-related death. Consequently, it has become extremely important to understand the pathophysiology of NASH to develop sound therapeutic interventions. It is now recognized that nonhepatic mechanisms are largely responsible for the development of insulin resistance, which causes hepatic steatosis. Once developed, oxidative stress and diminished antioxidants within the liver initiate the progression from steatosis alone to NASH and ultimately to cirrhosis. However, not all patients progress to cirrhosis. As is the case for other common complex metabolic diseases, it is the interaction between the environment and genetics that will determine the phenotypic expression of NAFLD and NASH in each individual patient. Which of the pathophysiologic factors (which are discussed in this review), either alone or in combination, will eventually provide the basis for the most effective therapy has yet to be determined.     

NASH -- nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis describes a hepatic disorder with the typical characteristics of an alcoholic pathogenesis without alcohol consumption. It was first described in 1962 and named NASH by Ludwig et al. 1980. Many researchers worked on this disease since this time. It represents the hepatic manifestation of the syndrome X. The pathogenesis is a two-hit phenomenon. The first hit leads to steatosis hepatis and makes the liver vulnerable to the second hit. Central factors of the second hit are oxygen-radicals, oxidative stress, lipid-peroxidation and cytokines. The exact pathogenic mechanisms are still unknown. NASH is a hepatic disease which can end up in liver cirrhosis and liver failure. Up to now a curative drug therapy does not exist. The poor prognosis in some cases, the increasing incidence in western populations and the lack of therapeutic options renders NASH to a serious problem. The aim of this article is to show the actual knowledge of this disease, especially focussed on the pathogenesis, by review of the literature from 1979 up to the present time.