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PubMed2004

Factors associated or related to with pathological severity of nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has been more and more often regarded as a serious disorder, because nonalcoholic steatohepatitis (NASH), a part of NAFLD, may progress to the end stage of liver disease. Though an advanced age, obesity, diabetes mellitus (DM) etc. being not infrequent conditions in Korea, are known to exacerbate the severity of this disease, there are only a few Korean reports on this subject. The purpose of this study is to identify possible factors that might add up to the pathological severity of this disorder in Korean patients. METHODS: Of 60 patients with steatosis found at liver biopsy, 43 NAFLD patients were reviewed retrospectively after exclusion of other liver diseases. RESULTS: The cases of steatosis were mild, moderate, and severe in 9. 10, and 24 patients, respectively. The degree of necroinflammatory activity was mild, moderate, and severe in 33, 9, and 1 patients, respectively. There were no established factors directly related to these classes. As to fibrosis, the cases were classified as none, mild, moderate, severe, and cirrhotic in 9, 11, 16, 7, and 0 patients, respectively. The stage of fibrosis correlated with the age (p < 0.001), BMI (body mass index) (p = 0.032), and the platelet count (p = 0.009), but the presence of NASH was associated only with BMI (p = 0.002) and obesity (p = 0.001). CONCLUSION: It seems that there are no factors that are directly related to the degree of steatosis or necroinflammatory activity. BMI seems to be a unique factor directly related to both the severity of fibrosis and the presence of NASH. The age and the platelet count are factors that are directly related to the degree of fibrosis but not to the presence of NASH.

Adult↗

PubMed2000

Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study.

AIM: To determine whether supplemental oral vitamin E is effective in lowering serum aminotransferase and alkaline phosphatase levels in children with nonalcoholic steatohepatitis (NASH) associated with obesity. STUDY DESIGN: Open-label pilot study enrolling all children <16 years old with chronically elevated serum aminotransferase (alanine aminotransferase and aspartate aminotransferase) levels for greater than 3 months, who demonstrated a diffusely echogenic liver on ultrasonography, had no demonstrable reason for abnormal serum chemistry values other than obesity, and therefore were diagnosed to have NASH. Patients were prescribed oral vitamin E between 400 and 1200 IU per day. Serum chemistry values were monitored monthly during treatment. RESULTS: Eleven subjects with a mean age of 12.4 years were enrolled; treated patients were followed up for 4 to 10 months. The body mass index did not change significantly before and after treatment (32.8 +/- 3.8 kg/m(2) vs 32.5 +/- 4.4 kg/m(2), respectively). Serum alanine aminotransferase decreased from 175 +/- 106 IU/L to 40 +/- 26 IU/L (P <.001, paired Student t test), serum aspartate aminotransferase decreased from 104 +/- 61 IU/L to 33 +/- 11 IU/L (P <.002), and alkaline phosphatase decreased from 279 +/- 42 IU/L to 202 +/- 66 IU/L (P <.003) during treatment. Serum aminotransferase levels remained normal during treatment but returned to abnormal in those electing to stop treatment. Serum alpha-tocopherol levels were within the normal range before the commencement of therapy and increased significantly with supplementation. The liver remained diffusely echogenic during therapy, at the time serum aminotransferase levels were reduced. CONCLUSIONS: Daily oral vitamin E administration normalized serum aminotransferase and alkaline phosphatase levels in children with NASH. Obese children with NASH should be encouraged to lose weight as part of a comprehensive weight reduction program and to consider taking supplemental alpha-tocopherol.

Adolescent↗

PubMed2003

[A clinicopathological study on nonalcoholic steatohepatitis].

OBJECTIVE: To observe the pathological and clinical characters of nonalcoholic steatohepatitis (NASH). METHODS: Liver biopsy tissues taken from 97 patients negative for common viral detection with serological test and immunohistochemistry as well as in situ hybridization, were observed by routine light microscopic examination. And the clinical data of patients with NASH was analyzed. RESULTS: Among the chronic hepatitis patients with unknown etiology, the detection rate of NASH was 15.5% (15/97). The characteristic lesions in NASH patients included macrovesicular steatosis in zone 3 of lobules, hepatocytes ballooning degeneration, lobules diffused with acute and chronic inflammation, and perisinusoidal fibrosis. Grading and staging according to Brunt's method, histological lesions could be accounted for G1S1 in 7 patients, G2S2 in 3 patients, G3S1 in 4 patients and G3S2 in 1 patient. There were 14 patients with mild to moderate elevation of transaminase, 10 with hyperlipemia, 8 with diabetes and 9 with fatty liver by ultrasonography. CONCLUSION: Nonalcoholic steatohepatitis is a common form of unknown etiology chronic liver disease with certain clinic-pathological features.

Adult↗

PubMed2004

[Role of lipid peroxidation in non-alcoholic steatohepatitis].

The liver steatosis is a frequent human disease. The most frequent cause of the process is the alcohol consumption. But it also may arise without significant alcohol abuse. This pathogenetic process is called non-alcoholic steatohepatitis (NASH), that is characterized by the same conditions like the alcoholic steatohepatitis. In the pathogenesis of the NASH various factors participate i.e. obesity, diabetes mellitus type II, hyperlipidaemia, pregnancy, variable chemotoxins, parenteral nutrition, jejunoileal bypass, chronic inflammatory diseases, protein deficient nutrition and inborn metabolic diseases. Pathobiochemically the process consists of oxidative stress and lipid peroxidation. This condition comes from the progressive accumulation of the free fatty acids in mitochondria and from the induction of cytochrome P450, CYP 2E1 isoform in hepatocytes and Kupffer cells. The free fatty acids and ketons can cause the induction of CYP 2E1 system, that is why diabetes mellitus and obesity are the two most important factors in the NASH pathogenesis. This article is concerned mainly in the explanation of NASH pathomechanism.

Animals↗

PubMed2002

The risk factors of fibrosis in nonalcoholic steatohepatitis.

UNLABELLED: Nonalcoholic steatohepatitis (NASH) can be a severe progressive liver disease leading to the development of cirrhosis. The aim of this study was to assess the risk factors of fibrosis in NASH. METHODS: The clinical, biochemical and histological features of 80 patients with NASH admitted at University Hospital from 1998 to 2000, were analyzed. The patients had no alcoholic, viral, autoimmune, drug induced or genetic liver disease. The fibrosis and necroinflammatory activity was associated with clinico-biochemical parameters and with oxidative stress. The clinical and biochemical parameters consist of: age, sex, body mass index (BMI), serum glucose, tryglycerides, alanine aminotransferase (ALT) and serum iron study (transferring saturation and ferritin). Liver iron overload was assessed by Pearls'staining and graded in four classes. The oxidative stress was evaluated by the levels of serum malon-dyaldehide (MDA) and serum total gluthatione (GSI4). RESULTS: Septal fibrosis was present in 30 patients (27%) including cirrhosis in 4 patients (5%). Age > 45 years, B.M.I. >30 Kg/m2, serum tryglycerides >180 mg/dl, hyperglycemia > 220 mg/dl, serum ALT > 3N, increased hepatic iron and transferrin saturation percentage were independently associated with sepal fibrosis. Linear regression analysis showed that increased hepatic iron had the greatest association with the increase of lipid peroxidation (MDA > 250 nanomol/dl) and the decrease of serum gluthatione (< 40 micromol/dl). CONCLUSIONS: The clinical and biochemical parameters which consist of age, BMI, serum ALT, glucose and tryglycerides, Perls' grade and the serum index of oxidative stress (MDA and GSH) are independent risk factors for fibrosis in NASH raising therapeutic implications for the management of these patients.

Adult↗

PubMedDate not supplied

Nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is an underdiagnosed liver disease characterised by steatosis, necroinflammation and fibrosis. This disease may eventually develop into cirrhosis and hepatocellular carcinoma. NASH is highly prevalent among obese individuals and among patients with diabetes mellitus type 2. Nonalcoholic fatty liver (NAFL), a precursor of NASH, is the main cause of elevated serum liver enzymes among the general population. Insulin resistance is a major aetiological factor in NASH. Gradual weight loss, physical exercise and drugs that improve insulin sensitivity are potential therapies.

Carcinoma, Hepatocellular↗

PubMedDate not supplied

Steatosis and hepatocellular carcinoma risk.

The natural history of Non Alcoholic Fatty Liver Disease (NAFLD) is difficult to assess, but there is mounting evidence that patients with NAFLD may eventually develop cirrhosis and hepatocellular carcinoma (HCC). Retrospective, case-control studies have shown that features suggestive of Non Alcoholic SteatoHepatitis (NASH) are more frequent in HepatoCellular Carcinoma (HCC) complicating cryptogenic cirrhosis than in matched HCC patients with known etiology. In the only available prospective cohort study, there is the absence of HCC as a complication of NASH-associated cirrhosis after a mean follow up of 7 years (median 5 years). However prospective NASH studies are too short to exclude late complications. In fact the average lenght of cirrhosis before the diagnosis of HCC was 16 years. The prevalence of risk factors associated with NASH can account for the increasing incidence of cryptogenic cirrhosis and subsequent HCC. Obesity and diabetes per se are significantly associated with the development of HCC. In particular diabetes was found to be a risk factor for HCC independent of age, gender, and race. Chronic hyperinsulinaemia and insulin-like growth factor 1 (IGF-1) might be involved in hepato-carcinogenesis. Exposure to physiological insulin concentrations stimulate proliferation of human and rat hepatoma cell line. Changes in the expression pattern of IGF-system components has been observed in patients with HCC, in human hepatoma cell lines and in their conditioned culture medium.

Animals↗

PubMed2006

[Nonalcoholic steatohepatitis: a brief review on its concept].

Since the first report by Ludwig, considerable progress has been made in the understanding of NASH and it is not currently considered as a merely benign clinical entity, but is rather thought as a common disease with a variety of clinical sequelae including liver cirrhosis and even hepatocellular carcinoma. Thus, NASH is considered as a type of a larger spectrum of nonalcoholic fatty liver disease (NAFLD) that is a consequence of insulin resistance and other underlining factors with histological findings ranging from fatty change alone to fat plus inflammation, to fat plus ballooning degeneration, and to fat plus alcoholic hepatitis-like lesions including Mallory body and fibrosis, the latter two categories being considered as NASH. In this brief review article, particular emphasis has been paid to the clinical entity, namely cryptogenic cirrhosis in relation to the pathogenesis of NASH.

Disease Progression↗

PubMed2006

[Diagnostic criteria for non-alcoholic steatohepatitis].

Nonalcoholic fatty liver disease (NAFLD) is now emerging as the most common liver disease in Japan. NAFLD is mainly comprised of simple fatty liver that is considered benign, though some patients have nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma. The diagnosis of NASH was based on the following criteria: (1) intake of less than 20 g of ethanol per day, (2) biopsy proven steatohepatitis; steatosis, inflammatory infiltrates, and ballooning degeneration with or without Mallory bodies or pericellular/perivenular fibrosis, (3) appropriate exclusion of other liver diseases. The detection of NASH is usually delayed, since there are no serum surrogate markers for NASH, and a definitive diagnosis requires a liver biopsy.

Carcinoma, Hepatocellular↗

PubMed2006

[Hepatocyte-specific Pten deficient mice].

Histological findings of hepatocyte-specific Pten deficient(Pten KO) mice livers were consistent with the criteria of human nonalcoholic steatohepatitis(NASH). Therefore, Pten KO mice are a powerful animal model of NASH. In Pten KO mice livers, steatosis develops based on the increased expression of genes that promote fatty acids synthesis. The increased expression of beta, oxidation-related genes accumulates oxidative stress in Pten KO mice livers resulting in hepatitis based on lipid hyperoxidation of hepatocytes membranes. Onset and exacerbation of hepatitis are also related to endotoxins derived from intestinal bacteria. Oxidative DNA damage, hyperproliferation of hepatocytes induced by the activation of Akt and ERK, and the increasement of malignant potential based on the change of fatty acids composition in the livers contribute to the development of hepatocellular carcinoma in Pten KO mice. Since it is considered that the mechanism to induce hepatic lesions in some NASH patients is the same as that in Pten KO mice, the investigation using Pten KO mice gives us clues to clarify the pathogenesis or develop effective therapy of NASH.

Animals↗

PubMed2006

[Clinical utility of angiotensin II receptor antagonist].

Non-alcoholic steatohepatitis (NASH) can potentially progress to liver cirrhosis and hepatocellular carcinoma. The causes of this disease are not well defined, and although several therapies have been tried, the optimal treatment has not been established. Recently, a role for angiotensin II in insulin resistance, oxidative stress and hepatic stellate cell activation has been reported. We treated patients who had NASH and hypertension with losartan, an angiotensin II receptor antagonist for 48 weeks. The losartan treatment improved hepatic necroinflammation and fibrosis in NASH patients. Moreover, a disappearance of iron deposition in hepatocytes, and a decrease in activated hepatic stellate cells were detected after treatment. Our results suggest the therapeutic efficacy of angiotensin II receptor antagonist in patients with NASH.

Angiotensin II Type 1 Receptor Blockers↗

PubMedDate not supplied

[Non-alcoholic fatty liver: 10 years' experience at the Insituto Nacional de la Nutrición Salvador Zubirán].

AIM: To describe the characteristics of non-alcoholic steatohepatitis (NASH) at the Instituto Nacional de la Nutricion Salvador Zubiran. MATERIAL AND METHODS: We reviewed all liver biopsy reports from January 1982 to December 1991. From patient records we obtained the following data: clinical, biochemical, imaging studies and we reviewed the histological material. We correlated clinical, biochemical and histological data. RESULTS: From 2963 biopsies reviewed we obtained 16 cases of NASH. We found a 7:1 female/male ratio. Median age was 30 years and six patients were obese. Eleven patients had concomitant disease (diabetes in seven) and nine were using drugs. All had been studied for biochemical abnormalities and were asymptomatic. Ten patients had hepatomegaly and six splenomegaly. Ultrasound suggested the diagnosis in 50% of the cases. All had steatosis, inflammatory infiltrate, necrosis, fibrosis and Mallory bodies at different stages. One case had cirrhosis on initial biopsy and two developed cirrhosis on follow-up (one and eight years later). We did not find any correlation between clinical, biochemical or imaging characteristics and histological findings. When we compared these findings between obese and non obese patients and primary and secondary NASH we did not find any differences between groups. CONCLUSIONS: NASH is infrequent in our institution. The underlying pathogenesis seems to be multifactorial. There is no biochemical-histological correlation. Cirrhosis can develop in some cases.

Adolescent↗

PubMed2004

The zonal distribution of megamitochondria with crystalline inclusions in nonalcoholic steatohepatitis.

Megamitochondria with crystalline inclusions (MMC) have been previously described in nonalcoholic fatty liver; however, their distribution within hepatic zones is unknown. We sought to determine this distribution from the core liver biopsy specimens of 31 patients: 8 males and 23 females, age range 21 to 72 years. Twenty-nine showed evidence of nonalcoholic steatohepatitis (NASH) on biopsy with steatosis, inflammation, varying degree of fibrosis, ballooned hepatocytes, and Mallory hyaline, and two patients had cryptogenic cirrhosis thought to represent "burned out" NASH. Identified by transmission electron microscopy, the abundance of MMC was compared between low-stage (fibrosis stages 1 and 2) and high-stage (fibrosis stages 3 and 4) groups and between zones with or without difference in fibrosis stage. Regardless of stage, the MMC were distributed equally in all zones and were abundant similarly in low- and high-stage groups. This abundance did not correlate with the degree of oxidative stress (4-hydroxynonenal staining) or with the abundance of ballooned hepatocytes. Consistent with age as a risk factor for more severe disease, the median age for the low-stage group was significantly lower than that of the high-stage group (P =.003). In conclusion, in NASH, the MMC seem to be distributed randomly among zones and without variation in abundance, regardless of the fibrosis stage. The exact function of these structures remains to be defined. In this study, their presence did not seem to correlate with the light microscopic injury pattern represented by ballooned hepatocytes or degree of oxidative stress defined by immunostaining for 4-hydroxynonenal.

Adult↗

PubMed2004

Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis.

The therapeutic efficacy of angiotensin II receptor antagonist, losartan, was studied in patients with nonalcoholic steatohepatitis (NASH). Seven patients with both NASH and hypertension were treated with losartan (50 mg/d) for 48 weeks. Treatment with losartan resulted in a significant decrease in blood markers of hepatic fibrosis, plasma TGF-beta1 and serum ferritin concentration concurrently with an improvement in serum aminotransferase levels. Histological assessment showed improvement of hepatic necroinflammation in five patients, reduction of hepatic fibrosis in four patients, and disappearance of iron deposition in two patients. No side effect of treatment was noted at any time during the study. In conclusion, the present data raise the possibility that an angiotensin II receptor antagonist may be therapeutically efficacious for NASH.

Adult↗

PubMed2006

Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats.

Nonalcoholic steatohepatitis (NASH) may cause fibrosis, cirrhosis, and hepatocellular carcinoma (HCC); however, the exact mechanism of disease progression is not fully understood. Angiogenesis has been shown to play an important role in the progression of chronic liver disease. The aim of this study was to elucidate the role of angiogenesis in the development of liver fibrosis and hepatocarcinogenesis in NASH. Zucker rats, which naturally develop leptin receptor mutations, and their lean littermate rats were fed a choline-deficient, amino acid-defined diet. Both Zucker and littermate rats showed marked steatohepatitis and elevation of oxidative stress markers (e.g., thiobarbital acid reactive substances and 8-hydroxydeoxyguanosine). In sharp contrast, liver fibrosis, glutathione-S-transferase placental form (GST-P)-positive preneoplastic lesions, and HCC developed in littermate rats but not in Zucker rats. Hepatic neovascularization and the expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor, only increased in littermate rats, almost in parallel with fibrogenesis and carcinogenesis. The CD31-immunopositive neovessels were mainly localized either along the fibrotic septa or in the GST-P-positive lesions. Our in vitro study revealed that leptin exerted a proangiogenic activity in the presence of VEGF. In conclusion, these results suggest that leptin-mediated neovascularization coordinated with VEGF plays an important role in the development of liver fibrosis and hepatocarcinogenesis in NASH.

Animals↗

PubMed1997

Recurrence of nonalcoholic steatohepatitis in a liver transplant recipient.

A 42-year-old white man with morbid obesity and hypertriglyceridemia was noted to have nonalcoholic steatohepatitis (NASH) at the time of a laparoscopic cholecystectomy for presumed gallstone pancreatitis. His postoperative course was complicated by a 50-kg weight loss and continued right upper quadrant pain. Repeat liver biopsy revealed NASH with accompanying micronodular cirrhosis. Due to progressive fatigue, he underwent an orthotopic liver transplantation complicated by a 36-kg weight gain. Sixteen months posttransplantation, a liver biopsy revealed the recurrence of NASH. Screening for defects in fatty acid oxidation proved negative.

Adult↗

PubMed2006

Amelioration of non-alcoholic steatohepatitis and glucose intolerance in ob/ob mice by oral immune regulation towards liver-extracted proteins is associated with elevated intrahepatic NKT lymphocytes and serum IL-10 levels.

Non-alcoholic steatohepatitis (NASH) is a common cause of cryptogenic cirrhosis in the Western world. In an animal model of NASH, leptin-deficient ob/ob mice present with alterations in number and function of hepatic NKT and peripheral CD4 lymphocytes. Oral immune regulation is a method to alter the immune response towards orally administered antigens. To determine the effect of oral immune regulation towards liver-extracted proteins on the metabolic disorders in ob/ob mice, ob/ob mice and their lean littermates were orally administered liver extracts from wild-type or ob/ob mice or bovine serum albumin for 1 month. The effect of treatment on hepatic fat content was measured by magnetic resonance imaging (MRI) and using a histological steatohepatitis grading scale. Glucose tolerance was measured by an oral glucose tolerance test (GTT). T lymphocyte subpopulations were assessed by flow cytometry analysis. Induction of immune regulation by oral presentation of liver-extracted proteins resulted in a significant 18% reduction of the hepatic fat content in ob/ob mice fed with either wild-type or ob/ob liver extracts for 1 month. The MRI signal intensity index in treated mice decreased to 0.48 and 0.51, respectively, compared with 0.62 in BSA-fed controls (p = 0.037 and p = 0.019, respectively), while the histological steatohepatitis score decreased in both treated groups to 2.0, compared with 2.4 in BSA-fed controls (p = 0.05). A significant improvement in GTT was noted in treated ob/ob mice. These changes were accompanied by a marked increase in the intrahepatic NKT lymphocyte population in mice fed with proteins extracted from both wild-type and ob/ob mice (46.96% and 56.72%, respectively, compared with 26.21% in BSA-fed controls; p < 0.05) and a significant elevation in serum IL-10 levels. Oral immune regulation towards liver extracted proteins in leptin-deficient mice resulted in a marked reduction in hepatic fat content and improved glucose tolerance. This effect was associated with a significant increase in the intrahepatic NKT lymphocyte population and serum IL-10 levels, suggesting a Th1 to Th2 immune shift. Immune regulation towards disease-associated antigens holds promise as a new mode of therapy for NASH.

Adipose Tissue↗

PubMed2006

Nonalcoholic fatty liver disease and HIV infection.

As persons with HIV live longer, chronic liver disease is increasingly important. Nonalcoholic fatty liver disease (NAFLD) is characterized by excess fat in hepatocytes in patients without significant alcohol use. It can progress from steatosis to nonalcoholic steatohepatitis (NASH) to cirrhosis. Visceral obesity and insulin resistance are integral to the pathogenesis of NAFLD. Patients with HIV are at greater risk of NAFLD due to antiretroviral therapy and viral hepatitis coinfection. Antiretroviral therapy can lead to patterns of injury that include steatosis and NASH. Coinfection with hepatitis C virus increases the risk of insulin resistance and hepatic steatosis, and co-existent features of NASH have also been reported. Histological-based, longitudinal studies are needed that address the interactions of NAFLD and HIV infection, the effects of antiretroviral therapy and hepatotropic virus coinfection, and inform better management strategies.

Fatty Liver↗