Treatment of nonalcoholic steatohepatitis with colestimide

Aim: To clarify the usefulness of colestimide in patients with nonalcoholic steatohepatitis (NASH) with hyperlipidemia. Methods: In an open‐label randomized controlled trial, 17 NASH patients with hyperlipidemia received colestimide (3 g/day) for 24 weeks. There were 21 control patients. All patients received lifestyle modification therapy. Efficacy was assessed based on metabolic profile, insulin resistance, transaminases, serum hepatic fibrosis markers, adipokine levels, visceral fat on computed tomography (CT), and the fatty liver grade on CT. NASH patients with moderate to severe steatosis by histology were also evaluated separately. Results: Baseline clinical characteristics of the two groups were similar. Both groups experienced a significant decrease of BMI with no difference between them. However, visceral fat decreased significantly more in the colestimide group (P = 0.046). Aspartate aminotransferase (AST) showed a significantly greater decrease in the colestimide group compared with the control group (P = 0.042). In patients with moderate to severe histological steatosis, there were significant differences between the two groups regard to HbA_1c, transaminases, and hyaluronic acid (P = 0.018 for HbA_1c, P = 0.003 for AST, P = 0.042 for alanine aminotransferase, and P = 0.042 for hyaluronic acid). Steatosis significantly improved in patients in the colestimide group who had fatty liver on CT (P = 0.049). In the colestimide group, abdominal distension and/or constipation were seen, but mostly tolerable, no other clinical or laboratory adverse events associated with the use of this medicine were not observed. Conclusions: Colestimide seems to increase the efficacy of lifestyle modification in NASH patients with hyperlipidemia. Its beneficial effects were more prominent in NASH patients with moderate to severe histological steatosis.     

非酒精性脂肪性肝炎的病理临床观察

目的 观察非酒精性脂肪性肝炎的病理及临床特点。方法 经血清学、肝组织免疫组织化学和原位杂交检测，排除甲一戊型肝炎病毒感染的不明原因肝炎患者对其肝组织进行光镜观察，并对相应的临床资料进行了分析。结果 97例不明原因肝炎患者肝组织中检出非酒精性脂肪性肝炎15例(15．5％)。病变的特点是小叶内3区为主的大泡性脂肪变性，邻近的肝细胞呈气球样变。小叶内有弥漫的单个核和分叶核细胞浸润，以及窦周纤维化。肝组织的病变按Brunt标准进行了分级和分期后，计有7例GlS1，3例G2S2，4例G1S1，1例G3S2。其中14例患者有轻—中度的转氨酶升高，10例有高脂血症，8例患有糖尿病，9例于B超下检出脂肪肝。结论 非酒精性脂肪性肝炎是一种较为常见的、具有一定临床病理特点的原因不明性慢性肝病。     

A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease for which there is no known effective therapy. A proportion of patients with NASH progress to advanced fibrosis and cirrhosis. NASH is considered one of the clinical features of the metabolic syndrome in which insulin resistance plays a central role. This prospective study evaluates the role of insulin-sensitizing agent in treatment of NASH. Eighteen nondiabetic patients with biopsy-proven NASH were treated with pioglitazone (30 mg daily) for 48 weeks. Tests of insulin sensitivity and body composition as well as liver biopsies were performed before and at the end of treatment. By 48 weeks, serum alanine aminotransferase values fell to normal in 72% of patients. Hepatic fat content and size as determined by magnetic resonance imaging decreased, and glucose and free fatty acid sensitivity to insulin were uniformly improved. Histological features of steatosis, cellular injury, parenchymal inflammation, Mallory bodies, and fibrosis were significantly improved from baseline (all P < 0.05). Using strict criteria, histological improvement occurred in two-thirds of patients. Pioglitazone was well tolerated; the main side effects were weight gain (averaging 4%) and an increase in total body adiposity. In conclusion, these results indicate that treatment with an insulin-sensitizing agent can lead to improvement in biochemical and histological features of NASH and support the role of insulin resistance in the pathogenesis of this disease. The long-term safety and benefits of pioglitazone require further study.     

Pathology of nonalcoholic steatohepatitis.

To date, histologic evaluation, most commonly in the form of liver biopsy, remains the gold standard in evaluation of nonalcoholic fatty liver disease (NAFLD). Histologic evaluation was fundamental to the initial studies that introduced and defined the concept of fatty liver as a liver disease. Currently, liver biopsy in NAFLD serves multiple roles: confirmation (or exclusion) of the diagnosis; distinction of steatohepatitis from "simple steatosis"; assessment of extent of necroinflammatory activity, fibrosis, and architectural alterations. Histopathologic studies have underscored the fact that not all obese and/or diabetic individuals with elevated liver tests have fatty liver disease; for example, hepatic glycogenosis and hepatosclerosis have been described in diabetics, and other significant liver diseases have been documented. Likewise biopsy studies have documented lesions of steatosis or steatohepatitis in unusual patient groups or clinical settings, such as lean individuals, individuals with normal liver tests, patients taking certain medications, patients with co-existent serologically-diagnosed liver disease, and pediatric patients. Biopsy studies have shown that the lesions of NASH may or may not persist in cirrhosis; prior evidence of NASH on liver biopsy serves as a benchmark for the concept that many cases of otherwise cryptogenic cirrhosis developed from NAFLD/NASH. Liver biopsy remains a significant feature of studies delineating long-term outcome of NAFLD, some of which have shown that "simple steatosis" is not always non-progressive and benign. Finally, investigators have noted correlations of proposed pathophysiologic processes in NASH with particular histologic features. Therapeutic trials for NASH rely on histologic evaluation as the most sensitive analysis to document effects of treatment. Treatment trials afford an opportunity to evaluate histologic features of resolution, and these trials have also provided an opportunity for correlations of particular histologic lesions with clinical and laboratory features in well-characterized patient populations. These kinds of studies are currently relatively few, but results of a recent study have reinforced the concept of necessary criteria for diagnosis. Current discussions in pathology include identification of lesions of concern for progression, reproducible methods of diagnosis and semiquantification of lesions, and appropriate nomenclature. Matteoni et al. proposed NAFLD types 1-4 based on long-term outcome studies; Brunt et al. proposed a system of grading and staging for NASH that follows methods of separate assessment for necroinflammatory lesions (grade) and fibrosis (stage) accepted in other forms of non-biliary chronic liver disease. Recently, the Pathology Committee of the NIDDK NASH Clinical Research Network has proposed a system of evaluation that encompasses the entire spectrum of NAFLD from steatosis to steatohepatitis with fibrosis for use in upcoming treatment trials. And, just as the clinician cannot distinguish steatosis and steatohepatitis, the pathologist cannot discern if alcohol abuse may be an underlying cause of the lesions. Proposed nomenclature to align with either extant terminology in other forms of chronic liver disease, or to align with our knowledge of underlying cause(s) (such as metabolic syndrome) will be discussed.     

Open-label pilot study of folic acid in patients with nonalcoholic steatohepatitis.

BACKGROUND/AIMS: Folate deficiency disturbs hepatic methionine metabolism and promotes the development of steatohepatitis in animal models. Our aims were (1) to determine the safety and efficacy of folic acid treatment in patients with nonalcoholic steatohepatitis (NASH) on changes in liver biochemistries, and (2) to investigate the presence of subclinical folate deficiency in this population. METHODS: Patients with biopsy-proven NASH were treated with folic acid 1 mg/day for 6 months. Liver enzymes and adverse events were monitored every 3 months until completion. RESULTS: Ten patients (one male and nine females) with a median age of 54 years were enrolled in this study. At baseline, the median steatosis grade was 2 (range 1-3), the median necroinflammatory grade was 1 (1-3), and the median fibrosis stage was 2 (0-4). The median level of red cell folate was 526 ng/ml (range 99-708); the normal level was 268-616 ng/ml. One compensated cirrhotic patient had folate deficiency. No serious adverse events occurred. After 6 months of therapy, no significant reductions in serum aspartate and alanine aminotransferase levels (60+/-25 vs. 54+/-29, P=0.5 and 86+/-29 vs. 83+/-42, P=0.6, respectively), were observed. Serum levels of bilirubin, alkaline phosphatase, albumin, and prothrombin time remained in the normal range during treatment in all patients. CONCLUSION: Six months of therapy with folic acid at a dose of 1 mg/day, although safe and well tolerated, does not lead to a significant biochemical improvement in patients with NASH. In a small number of patients, folate deficiency was present in only a cirrhotic patient.     

Steatosis and nonalcoholic steatohepatitis. A comparative analysis

Liver biopsies with a main histological diagnosis of steatosis were selected from 3,422 liver biopsies carried out in our department between January 1995 and December 1998. Patients with known risk factors for steatosis, such as excessive alcohol consumption, hepatitis C infection, treatment with amiodarone, perhexiline maleate, tamoxifen, antiviral drugs (didanosine, zidovudine) methotrexate, sodium valproate or total parenteral nutrition, Wilson's disease and organ transplant were subsequently excluded. Of the 43 liver biopsies finally included in the study, 23 showed simple steatosis and 20 steatohepatitis. Eighty-one per cent of the patients were male (mean age of 44 years) and the majority were asymptomatic. The most frequent indication for liver biopsy was hypertransaminasemia. No differences were observed between the two groups in terms of frequency and severity of classical risk factors for steatosis (diabetes mellitus, dyslipemia and obesity). Thirty-five percent of patients with steatohepatitis and 26% of those with simple steatosis had none of these risk factors. Patients with steatohepatitis were older than those with simple steatosis. They presented more severe symptomatology, the degree of steatosis was more intense and laboratory investigations showed greater alterations. These results suggest that simple steatosis and nonalcoholic steatohepatitis are two different phases of the same disease. The difficulty in clinical differentiation justifies carrying out liver biopsy, especially in patients with more severe symptomatology whose laboratory results show greater alterations, since these patients present more marked histological lesions, are at risk of developing liver cirrhosis and require therapy.     

Hepatocellular carcinoma with nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) was originally believed to be a benign disease. However, it has been recently revealed that NASH could lead to irreversible liver disease in some patients. We report an unusual case of hepatocellular carcinoma (HCC) in a 76-year-old man with NASH. He had no history of alcohol consumption, drug use, or blood transfusion. He was negative for all serological viral markers and autoantibodies. In addition, he was obese (body mass index [BMI], 30.75kg/m²) and had type 2 diabetes mellitus. A liver biopsy specimen showed moderate steatosis with necroinflammatory changes, ballooning degeneration, Mallory bodies, pericellular fibrosis, and evidence of nodular regeneration. He was diagnosed with NASH with cirrhosis. Simultaneously, a liver tumor, measuring 19mm in diameter, was detected in segment 6. A tumor biopsy specimen revealed well-differentiated HCC, and imaging modalities confirmed the characteristics of HCC. To our knowledge, ten patients who had HCC with NASH were reported. In all patients with NASH and HCC, cirrhosis was present. Patients with NASH and cirrhosis may progress to HCC, and regular screening, based on tumor markers and imaging modalities, is needed to detect HCC in patients with NASH and cirrhosis.     

Laparoscopic findings in patients with nonalcoholic steatohepatitis.

BACKGROUND/AIMS: Laparoscopic observation of the liver is important to diagnose liver conditions accurately. However, the laparoscopic findings of nonalcoholic steatohepatitis (NASH) have not been characterized. The aim of this study was to clarify the laparoscopic characteristics of NASH. METHODS: Twenty-four patients were enrolled. The degrees of hepatomegaly, color and irregularity of the liver surface, and the presence of depressions, patches, and vesicles were investigated. These laparoscopic findings were compared among NASH, alcoholic liver disease (ALD), and autoimmune hepatitis (AIH). RESULTS: Mild hepatomegaly, dullness of the liver edge, increased fat accumulation of the round ligament, and whitish markings were found in most of the patients with NASH. Small depressions were observed in approximately 70% of the patients. As fibrosis developed, the liver surface became whiter and more uneven. Compared with patients with ALD and AIH, increased fat accumulation of the round ligament and dullness of the liver edge were observed more frequently in those with NASH. However, coarse and groove-like depressions were rare in NASH patients. CONCLUSIONS: Several findings, including mild hepatomegaly, increased fat accumulation of the round ligament, rounded liver edge, whitish markings, and small depressions were common in patients with NASH. However, coarse and groove-like depressions were rare. These findings may be helpful for confirming a diagnosis of NASH.     

非酒精性脂肪性肝炎发病机制的实验研究

建立大鼠非酒精性脂肪性肝炎 (NASH)动物模型 ,探讨NASH发病机制。雄性SD大鼠随机分为对照组及模型组 ,检测血清转氨酶、空腹血糖 (FBG)、胰岛素 (FBI)及肿瘤坏死因子α(TNFα)水平 ,肝组织匀浆MDA、SOD水平 ,肝组织学改变。于 9周末模型组大鼠已产生胰岛素抵抗 ,血清TNFα水平明显升高 ,肝细胞出现脂肪变及气球样变 ;14周末血清转氨酶水平及肝组织匀浆MDA水平明显升高 ,SOD水平明显下降 ,肝组织出现炎细胞浸润。胰岛素抵抗与TNFα在肝脏脂肪变的发生中起到重要作用 ,而炎症产生与脂质过氧化的关系更为密切     

脂联素及受体与非酒精性脂肪性肝炎

胰岛素抵抗是非酒精性脂肪性肝炎(NASH)发病机制的关键因素。细胞因子脂联素(adiponectin) 具有增加胰岛素敏感性、抗炎症和抗动脉粥样硬化的作用。而脂联素受体(AdipoR)在adiponectin激活AMPK、增加PPARα配体活性、增加葡萄糖摄取和脂肪酸氧化时发挥介导作用。因此,对adiponectin及AdipoR的进一步研究有助于对NASH的机制和治疗有更好的认识。     

Pediatric nonalcoholic steatohepatitis associated with hypopituitarism

We experienced two cases of pediatric nonalcoholic steatohepatitis (NASH) associated with hypopituitarism. The first patient was diagnosed with a craniopharyngioma at 5 years of age. After an operation to treat the condition, the patient gradually became obese, and an elevation of transaminases was observed. At 16 years of age, the patient was diagnosed as having NASH with liver cirrhosis. He was started on hormone replacement therapy; however, his insulin resistance and liver fibrosis, as evaluated by hyaluronic acid and platelet count, progressed. In addition, his hyperleptinemia continued. The second patient was diagnosed, at 10 years of age, as having pituitary dysfunction due to fetal asphyxia, and he was started on hormone replacement therapy. This patient was noted to have been obese throughout his life. He was diagnosed as having NASH with advanced fibrosis at 18 years of age. It is important for both hepatologists and endocrinologists to be aware of the association between pituitary dysfunction and 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.     

Primary liver cancers with nonalcoholic steatohepatitis

Nine patients with hepatocellular carcinoma (HCC) in nonalcoholic steatohepatitis (NASH) (six men and three women, median age 71.5 years) and one patient with intrahepatic cholangiocarcinoma (ICC), a 50-year-old man, in NASH are described. Most patients were associated with obesity, diabetes, hypertension, hypercholesterolemia, or hypertriglyceridemia. Seven patients showed insulin resistance and hyperinsulinemia. All patients except one met the criteria for metabolic syndrome. An HCC or ICC diagnosis was confirmed by tumor biopsy, surgery or autopsy except in two patients, who were diagnosed by computed tomography or hepatic angiography. The underlying liver disease was liver cirrhosis in six patients and chronic liver disease including mild hepatic fibrosis in four patients. The treatment of liver cancers consisted of surgery, radio-frequency ablation (RFA), transcatheter arterial embolization and transcatheter arterial infusion. Although the follow-up period was relatively short (median 27.5 months, average 32.1 months), all postoperative and post-RFA patients have not had a recurrence of HCC to date, except for one patient who had a palliative operation with intra-arterial infusion of anticancer drugs through an implanted reservoir port. Older age and liver cirrhosis are considered risk factors for HCC in NASH, and regular screening of these patients is necessary. Diabetes may contribute to the development of ICC in NASH. Curative therapy (surgery or RFA) and weight loss by the active therapeutic intervention (nutritional care and exercise therapy) after curative therapy may help us improve the prognosis of HCC in NASH.     

A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis

OBJECTIVES: Troglitazone is a thiazolidinedione and peroxisome proliferator-activated receptor gamma (PPARgamma) ligand used to treat diabetes mellitus type II. Because hyperinsulinemia may be a factor in nonalcoholic steatohepatitis (NASH), we postulated that troglitazone could have beneficial effects in this disorder. Our study was initiated before reports of idiosyncratic hepatitis induced by this agent and was completed before its recent withdrawal from the market. METHODS: We studied 10 female patients (age 44 +/- 16) with histological NASH. All but two were obese (mean body mass index, BMI = 38 +/- 6). One had type 2 diabetes, and three had well-compensated cirrhosis with NASH. Troglitazone was given at a dose of 400 mg/day for < or = 6 months. Responders (defined as normal ALT at the end of treatment) were rebiopsied. Paired specimens were compared in blinded fashion. Mitochondria were quantitated using ultrathin electron microscopy. RESULTS: Seven of ten patients responded with normal ALT at the end of treatment. One of three nonresponders initially normalized ALT but returned to pretreatment level at 3 months. In this patient, therapy was stopped, and the ALT has remained at the baseline level with no other clinical or laboratory findings. In the responders, ALT fell from 87 +/- 38 before to 39 +/- 9 at the end of treatment (p = 0.01), and AST decreased from 77 +/- 23 to 30 +/- 8 (p = 0.002). Biopsy comparisons before and after therapy showed persistent steatohepatitis in all cases, although four of seven showed a one-point improvement in the necroinflammatory grade. Electron microscopy revealed elongation of the mitochondria after therapy. CONCLUSIONS: Normal ALT was seen in 70% of NASH patients at the end of treatment, but this biochemical response was associated with only mild histological improvement, and all follow-up biopsies had evidence of NASH. Normalization of the liver enzymes in patients with NASH who are treated with thiazolidinediones should be viewed with reservation. Follow-up biopsy is essential to evaluate the efficacy of these agents, which, at the histological level, appears to be relatively modest.     

上海地区非酒精性脂肪性肝炎患者肿瘤坏死因子-α的基因多态性研究

目的:了解非酒精性脂肪性肝炎(NASH)患者肿瘤坏死因子-α(Tumor necrosis factor-alpha,TNF-α)启动子基因多态性在上海人群中的分布及其与疾病的相关性。方法:用聚合酶链反应-限制性片段长度多态性技术检测400例NASH患者和50例健康对照者外周血的TNF-α基因启动子区域-308、-238位点基因多态性。结果:TNF-α基因-308位点在NASH组中变异的G/A基因型频率比健康对照组明显升高(P<0.01,OR=14.667,95%CI 4.436～48.497),而-238位点其基因变异频率两组差异无显著性意义(P>0.05)。结论:TNF-α基因-308位点G/A的突变与NASH易感性相关。