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PubMed2005

Histopathology of pediatric nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are common in children and adolescents. However, standard histological criteria for pediatric NAFLD and NASH are undeveloped. We reviewed consecutive patients ages 2 to 18 years with biopsy-proven NAFLD diagnosed between 1997 and 2003. Biopsies were evaluated by two pathologists for individual features of steatohepatitis. Agglomerative hierarchical cluster analysis demonstrated two different forms of steatohepatitis. Type 1 was characterized by steatosis, ballooning degeneration, and perisinusoidal fibrosis; type 2 was characterized by steatosis, portal inflammation, and portal fibrosis. The study included 100 children with NAFLD. Simple steatosis was present in 16% of subjects, and advanced fibrosis was present in 8%. Type 1 NASH was present in 17% of subjects, and type 2 NASH was present in 51%. Boys were significantly (P < .01) more likely to have type 2 NASH and less likely to have type 1 NASH than girls. The NASH type differed significantly (P < .001) by race and ethnicity. Type 1 NASH was more common in white children, whereas type 2 NASH was more common in children of Asian, Native American, and Hispanic ethnicity. In cases of advanced fibrosis, the pattern was generally that of type 2 NASH. In conclusion, type 1 and type 2 NASH are distinct subtypes of pediatric NAFLD, and type 2 is the most common pattern in children. NASH subtypes should be considered when interpreting liver biopsies and planning studies of the pathophysiology, genetics, natural history, or response to treatment in pediatric NAFLD.

Adolescent↗

PubMed2001

Etiopathogenesis of nonalcoholic steatohepatitis.

The definable causes of nonalcoholic steatohepatitis (NASH) include jejunoileal bypass surgery (JIB), other causes of rapid and profound weight loss in obese subjects, total parenteral nutrition, drugs, industrial toxins, copper toxicity, and disorders characterized by extreme insulin resistance. However, the etiopathogenesis in most cases of NASH appears multifactorial. Obesity, type 2 diabetes, and hypertriglyceridemia are often associated with hepatic steatosis, and although this does not invariably lead to NASH, the fatty liver is vulnerable to hepatocellular injury initiated by reactive oxygen species (ROS). It is critical to understand not only the triggers for hepatitis (injury and inflammation) in NASH but also how this is perpetuated as chronic liver disease. The present focus is on whether the biochemical processes that generate oxidative stress lead to hepatocyte injury and secondary recruitment of inflammation or whether inflammation is the primary mediator of liver cell injury. Insulin resistance is a reproducible pathogenic factor in NASH. It favors accumulation of free fatty acids in the liver and predisposes to oxidative stress by stimulating microsomal lipid peroxidases and by the direct effects of high insulin levels in decreasing mitochondrial beta-oxidation. CYP2E1 is normally suppressed by insulin but is invariably increased in the livers of patients with NASH. In rodent dietary models of steatohepatitis, CYP2E1 is the catalyst of microsomal lipid peroxidation, while in Cyp 2e1 nullizygous mice, CYP4A proteins are induced and function as alternative microsomal lipid peroxidases. Other studies implicate activation of peroxisome proliferator-activated receptor-alpha (PPAR alpha) as leading to NASH; PPAR alpha is a transcription factor that governs both microsomal (via CYP4A) and peroxisomal (beta-oxidation) pathways of lipid oxidation and ultimately production of ROS. Increased lipid peroxidation is a crucial difference between the livers of rodents with experimental NASH and those of ob/ob genetically obese mice that have uncomplicated steatosis. Administration of endotoxin, through the release of tumor necrosis factor-alpha (TNF-alpha), provokes liver inflammation with hepatocyte injury in the steatotic liver. This may be particularly relevant in JIB and has been suggested as a pathogenic mechanism in primary NASH. It has been proposed that inheriting one or more copies of the hemochromatosis gene, C282Y, promotes fibrotic progression in NASH because of increased hepatic iron deposition, but recent studies have failed to confirm this. The relationship between the severity of hepatitis in NASH and progression to cirrhosis implies that products of the inflammatory infiltrate play a role in fibrogenesis. In summary, NASH can be regarded as the hepatic consequence of the metabolic syndrome (or syndrome X). Attention should now shift from steatosis, a generally benign process that is less evident in the advanced stages of cirrhosis, to the mechanisms for hepatocellular injury, inflammation, and hepatic fibrosis. In particular, the genetic, molecular, and cellular factors that ordain and moderate fibrosis in the context of steatohepatitis will be of greatest relevance to effective therapy and clinical outcome.

Chronic Disease↗

PubMed2005

Comparison of liver histology between patients with non-alcoholic steatohepatitis and patients with alcoholic steatohepatitis in Japan.

BACKGROUND: This study compared the liver histology of patients with NASH and patients with ASH. METHODS: Subjects consisted of 79 patients (41 in the NASH group and 38 in the ASH group). We performed physical and laboratory examinations as well as liver biopsy in all subjects, and we evaluated the differences between the NASH and ASH groups. In addition, we compared the liver histology of patients with obesity, diabetes or hyperlipidemia within the NASH group. RESULTS AND CONCLUSIONS: BMI was significantly higher in the NASH group than in the ASH group. Steatosis and nuclear vacuoles were more prevalent in the NASH group than in the ASH group. On the other hand, ballooning hepatocytes, lipogranuloma, focal necrosis, acidophilic bodies and fibrosis were more remarkable in the ASH group than in the NASH group. The degrees of steatosis and lipogranuloma gradually decreased as the stage of liver fibrosis progressed. Necro-inflammation and fibrosis tended to be more remarkable in the ASH group than in the NASH group. In the NASH group, ballooning hepatocytes and acidophilic bodies were significantly higher in the group with diabetes than in that without diabetes. Perivenular fibrosis, pericellular fibrosis and portal fibrosis were also higher in the NASH group with diabetes than in the NASH group without diabetes. These findings suggested that diabetes is deeply involved in the development and progression of NASH.

Adult↗

PubMed2006

Useful parameters for distinguishing nonalcoholic steatohepatitis with mild steatosis from cryptogenic chronic hepatitis in the Japanese population.

BACKGROUND/AIMS: As detecting mild steatosis is difficult by abdominal ultrasonography (US), nonalcoholic steatohepatitis (NASH) with mild steatosis may sometimes be confused with cryptogenic chronic hepatitis. We aimed to test this possibility and to isolate factors that may indicate NASH. METHODS: First, 53 Japanese patients diagnosed as having cryptogenic chronic hepatitis by laboratory examination and US were enrolled. These patients were histologically divided into NASH and non-NASH groups, and their clinical features were compared. Second, the diagnostic accuracy of predictors of NASH was examined prospectively. RESULTS: Fifteen patients (28%) were histologically diagnosed as having NASH with mild steatosis. Multivariable analysis revealed that body mass index (BMI) and serum ferritin level were independent predictors of NASH. The best cutoff values to detect NASH were assessed by using receiver-operating characteristic curves: BMI>25.2 kg/m(2) and serum ferritin level >142 ng/ml. When both markers were concomitantly negative, the negative predictive value to detect NASH was 100%. CONCLUSIONS: In cases of mild steatosis, US is not a perfect tool for the accurate diagnosis of NASH. BMI and serum ferritin level are useful discriminators of NASH from cryptogenic chronic hepatitis, and might be helpful markers for diagnosing NASH more accurately in Japanese patients.

Adolescent↗

PubMed2003

Treatment of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is very common in the United States, and in some patients it may lead to cirrhosis, liver failure, and liver cancer. NAFLD encompasses a spectrum of liver injury, ranging from steatosis to steatohepatitis, advanced fibrosis, and cirrhosis. Nonalcoholic steatohepatitis (NASH), an advanced form of NAFLD, histologically comprises steatosis, balloon degeneration, inflammation, and fibrosis in varying degrees. It is generally believed that simple steatosis is benign with minimal risk of progression, whereas NASH is progressive and can lead to cirrhosis. The commonly associated risk factors for NAFLD include obesity, hyperlipidemia, and diabetes mellitus. The pathogenesis of NAFLD and NASH is not fully known; however, current evidence suggests that insulin resistance and lipid peroxidation play a role in the pathogenesis of this condition. Currently, there are no proven effective therapies available for the treatment of NASH. Although there are numerous studies that have explored various treatments for NASH, these generally consist of small numbers of patients with suboptimal endpoints. Treatment strategies for NAFLD and NASH can be broadly divided into 1) treatment or control of underlying risk factors such as hyperlipidemia, diabetes mellitus, and obesity; and 2) specific pharmacologic therapy such as insulin sensitizers, antioxidants, or cytoprotective agents. Newer thiazolidinediones, such as rosiglitazone and pioglitazone, have shown promise in the treatment of NASH in pilot studies. However, these agents should not be used in clinical practice until their efficacy and safety are firmly established in larger studies. Despite encouraging initial studies, the recently completed multicenter, randomized, controlled trial failed to show any efficacy for ursodeoxycholic acid in the treatment of NASH. Other agents, such as vitamin E, betaine, probucol, and atorvastatin, have been explored as therapeutic agents for NASH. However, none of these studies have shown convincingly their utility in the treatment of NASH. Attempts to identify optimal therapy for patients with NASH are being vigorously pursued by the research community and important advances are expected within next several years. Until then, subjects should be advised to avoid alcohol, lose weight, and exercise regularly, and meticulous attention should be paid to the control of their risk factors such as diabetes and hyperlipidemia.

Journal Article↗

PubMed2000

Serum leptin levels in patients with nonalcoholic steatohepatitis.

OBJECTIVE: Leptin is a peptide hormone that mainly regulates food intake and energy expenditure of human body. A close correlation between serum leptin levels and the percentage of body fat stores is well known. Nonalcoholic steatohepatitis (NASH) is a common disorder which causes serum liver enzyme elevation. In this study, the serum leptin levels were investigated in patients with NASH to determine a possible role in the pathogenesis and in patients with chronic viral hepatitis to ascertain the effect of hepatic inflammation on serum leptin level. METHODS: Forty-nine patients (38 men, 11 women) with NASH diagnosed by biopsy, 32 patients with biopsy-proven chronic viral hepatitis (21 men and 11 women), and 30 healthy adults (17 men, 13 women) enrolled in the study. Fasting blood samples were obtained, and serum leptin levels were measured by ELISA. Body mass index (BMI) was calculated for all subjects, and serum insulin, C-peptide, and lipoprotein levels were also detected. RESULTS: The mean serum leptin levels (+/-SEM) were 6.62 +/- 0.71, 4.24 +/- 1.0, and 4.02 +/- 0.46 ng/ml in NASH, chronic hepatitis, and the control group, respectively. Mean serum leptin level in the NASH group was significantly higher than those in the other groups tested. BMI was also slightly higher in the NASH group when compared to the other groups (26.7 +/- 0.3, 23.7 +/- 0.6, and 24.6 +/- 0.3, respectively). There was a significant correlation between BMI and serum leptin levels when all the subjects were evaluated together (NASH, hepatitis, and control groups, r = 0.337, p = 0.012) but not in the NASH group when evaluated alone (r = 0.238, p = 0.1). Of the predisposing factors for NASH, obesity was observed in 24% of patients and hyperlipidemia in 67%. Serum cholesterol and triglyceride levels were significantly higher in the NASH group than those in controls (p < 0.05). It has been detected that most of these patients consumed high amounts of fat in their dietary habits. CONCLUSIONS: The serum leptin levels were significantly higher in patients with NASH, while they were not affected by chronic hepatitis. This elevation is out of proportion to BMI of these patients and may be related to hyperlipidemia in most. Elevated serum leptin levels, therefore, may promote hepatic steatosis and steatohepatitis.

Adult↗

PubMed2006

Diagnostic value of biochemical markers (NashTest) for the prediction of non alcoholo steato hepatitis in patients with non-alcoholic fatty liver disease.

BACKGROUND: Liver biopsy is considered the gold standard for assessing histologic lesions of non-alcoholic fatty liver disease (NAFLD). The aim was to develop and validate a new biomarker of non alcoholic steato hepatitis (NASH) the NashTest (NT) in patients with NAFLD. METHODS: 160 patients with NAFLD were prospectively included in a training group, 97 were included in a multicenter validation group and 383 controls. Histological diagnoses used Kleiner et al's scoring system, with 3 classes for NASH: "Not NASH", "Borderline", "NASH"). The area under the ROC curves (AUROC), sensitivity (Se), specificity (Sp), and positive and negative predictive values (PPV, NPV) were assessed. RESULTS: NT was developed using patented algorithms combining 13 parameters: age, sex, height, weight, and serum levels of triglycerides, cholesterol, alpha2macroglobulin, apolipoprotein A1, haptoglobin, gamma-glutamyl-transpeptidase, transaminases ALT, AST, and total bilirubin. AUROCs of NT for the diagnosis of NASH in the training and validation groups were, respectively, 0.79 (95%C I 0.69-0.86) and 0.79 (95% CI 0.67-0.87; P = 0.94); for the diagnosis of borderline NASH they were: 0.69 (95% CI 0.60-0.77) and 0.69 (95% CI 0.57-0.78; P = 0.98) and for the diagnosis of no NASH, 0.77 (95% CI 0.68-0.84) and 0.83 (95% CI 0.67-0.90; P = 0.34). When the two groups were pooled together the NashTest Sp for NASH = 94% (PPV = 66%), and Se = 33% (NPV = 81%); for borderline NASH or NASH Sp = 50% (PPV = 74%) and Se = 88% (NPV = 72%). CONCLUSION: In patients with non-alcoholic fatty liver disease, NashTest, a simple and non-invasive biomarker reliably predicts the presence or absence of NASH.

Algorithms↗

PubMed2006

Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C.

The objective of this study was to prospectively define outcomes of cirrhosis due to nonalcoholic steatohepatitis (NASH) and compare them with those associated with hepatitis C virus (HCV) infection. We compared 152 patients with cirrhosis due to NASH with 150 matched patients with cirrhosis due to HCV. Over 10 years, 29/152 patients with cirrhosis due to NASH died compared with 44/150 patients with HCV (P < .04). This was mainly due to the lower mortality rate in patients with Child class A cirrhosis due to NASH versus HCV (3/74 vs. 15/75; P < .004). There were no significant across-group differences in mortality in patients with Child class B or C cirrhosis. Sepsis was the most common cause of death in both groups; patients with NASH had a higher cardiac mortality (8/152 vs. 1/150; P < .03). Patients with Child class A cirrhosis due to NASH also had a significantly lower risk of decompensation, defined by a 2-point increase in Child-Turcotte-Pugh score (P < .007). Cirrhosis due to NASH was associated with a lower rate of development of ascites (14/101 vs. 40/97 patients at risk; P < .006). NASH also had a significantly lower risk of development of hepatocellular carcinoma (10/149 vs. 25/147 patients at risk; P < .01). In conclusion, compensated cirrhosis due to NASH is associated with a lower mortality rate compared with that due to HCV. It is also associated with a lower rate of development of ascites, hyperbilirubinemia, and hepatocellular carcinoma. However, cardiovascular mortality is greater in patients with NASH.

Ascites↗

PubMed2005

In vivo imaging of hepatic fatty acid metabolism in patients with nonalcoholic steatohepatitis using semiquantative (123)I-BMIPP liver scan.

Recent progress of studies in NASH displays multi-disciplinary characters of the pathogeneses. Despite these advances, the strategic use of imaging modalities such as CT, US, and MRI, remains a relatively low priority in clinical situations, because these can only visualize the presence of fatty infiltration to the hepatic parenchyma, impossible to figure out the dynamic function of NASH liver. Morphological alteration such as CT value, MR signal intensity and echo-grade do not distinguish NASH from simple fatty liver. In this presentation, from a radiologic viewpoint, we show the feasibility of in vivo fatty acid imaging with (123)I-beta-methyl-p-iodophenyl-pentadecanoic acid (BMIPP). BMIPP is an (123)I labeled fatty acid analog for imaging damaged myocardium, using conventional nuclear imaging equipment. Under normal conditions, the energy source for myocardial utilization is dependent on the beta-oxidation of fatty acids. For energy production in ischemic myocardium, the drastic switch from reduced beta-oxidation of fatty acids to glucose metabolism is well known. BMIPP can detect the area of reduced fatty acids metabolism on myocardial imaging and the data can be converted into semiquantitative analysis. Therefore, we speculate that the use of BMIPP to in vivo hepatic imaging in NASH could highlight a lot of matters of NASH. Details of this presentation include: (1) Hepatic imaging with BMIPP; (2) Clearance of BMIPP from NASH liver; (3) semiquantitative analysis of hepatic BMIPP clearance and clinical features of NASH; (4) Profiles of NASH categorized by BMIPP imaging and (5) Preliminary data of BMIPP clearance in patients with Tamoxifen-induced NASH. The core of our stance in this presentation is searching for valuable advice on clinical use of BMIPP in patients with NASH from specialists in the field of HEPATOLOGY.

Journal Article↗

PubMed2006

Dietary habits and nutrient intake in non-alcoholic steatohepatitis.

OBJECTIVE: Non-alcoholic steatohepatitis (NASH) is one of the most important emerging health issues. Insulin resistance and metabolic syndrome play a central role in the pathogenesis of NASH. Intake of nutrients strongly affects insulin resistance, carbohydrate and lipid metabolism, and hepatic steatosis. However, there are few reports about the intake of various nutrients in non-alcoholic fatty liver disease. In this work, we identified the characteristics of dietary habits and nutrient intake in patients with NASH. METHODS: Twenty-eight patients with NASH and 18 with simple steatosis (FL) were diagnosed from histologic findings, and their dietary habits and intake of nutrients were analyzed by detailed questioning by physicians and dieticians. RESULTS: There was an excess intake of carbohydrates/energy in patients with NASH 20-59 y of age compared with patients with FL. Among carbohydrates, intake of simple carbohydrates was higher in those with NASH. There also was a low intake of protein/energy in patients with NASH 40-59 y of age and a low intake of zinc in those 20-59 y of age compared with patients with FL. Ratio of intake of polyunsaturated fatty acid to saturated fatty acid was lower in patients with NASH and those with FL compared with the general Japanese subjects. CONCLUSION: These results suggest that imbalanced diets play important roles in development and progression of NASH and correction of these diets may be necessary in patients with NASH.

Adult↗

PubMed2003

Serum thioredoxin levels as a predictor of steatohepatitis in patients with nonalcoholic fatty liver disease.

BACKGROUND/AIMS: Thioredoxin (TRX) is a stress-inducible thiol-containing protein. The aim of this study was to evaluate the clinical significance of serum TRX in patients with nonalcoholic steatohepatitis (NASH) or simple steatosis. METHODS: Serum TRX levels were determined using an enzyme-linked immunosorbent assay kit in 25 patients with NASH, 15 patients with simple steatosis, and 17 healthy volunteers. RESULTS: Serum TRX levels (medians and (ranges), ng/ml) were significantly elevated in patients with NASH (60.3 (17.6-104.7)), compared to those in patients with simple steatosis (24.6 (16.6-69.7), P=0.0009) and in healthy controls (23.5 (1.3-50.7), P<0.0001). Serum ferritin levels in patients with NASH were also significantly higher than the levels in patients with simple steatosis. The receiver operating characteristic curve confirmed that serum TRX and ferritin levels were predictors for distinguishing NASH from simple steatosis. Higher grades of histological iron staining were observed in NASH than in simple steatosis. Serum TRX tended to increase in accordance with hepatic iron accumulation and the histological severity in patients with NASH. CONCLUSIONS: The pathogenesis of NASH may be associated with iron-related oxidative stress. The serum TRX level is a parameter for discriminating NASH from simple steatosis as well as a predictor of the severity of NASH.

Adolescent↗

PubMed2001

Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities.

BACKGROUND AND AIMS: The pathogenesis of nonalcoholic steatohepatitis (NASH) is unknown. We tested the hypothesis that NASH is associated with 2 defects: (1) peripheral insulin resistance, which increases lipolysis, delivery of free fatty acids (FFA) to the liver, and hepatic fatty acid beta oxidation, thereby creating oxidative stress; and (2) an abnormality within the hepatocytes that might render them more susceptible to injury from oxidative stress. METHODS: The hypothesis was tested by evaluation of (1) insulin resistance by a 2-step hyperinsulinemic (10 and 40 mU. m(-2). min(-1)) euglycemic clamp; (2) insulin effects on lipolysis by enrichment of [U-(13)C]glycerol; (3) frequency and severity of structural defects in hepatocyte mitochondria in vivo; (4) fatty acid beta oxidation from serum [beta-OH butyrate], release of water-soluble radioactivity from (3)H-palmitate by cultured fibroblasts and urinary dicarboxylic acid excretion; and (5) hepatic lipid peroxidation by immunohistochemical staining for 3-nitrotyrosine (3-NT). Subjects with NASH (n = 6-10 for different studies) were compared with those with fatty liver (n = 6) or normal controls (n = 6). RESULTS: NASH and fatty liver were both associated with insulin resistance, with mean glucose infusion rates (normal/fatty liver/NASH) of step 1, 4.5/1.6/0.9; step 2, 9.5/7.7/4.5 (P < 0.03 for both steps). Although baseline rates of glycerol appearance were higher in those with NASH than in those with fatty liver (means, 14.6 vs. 21.6 micromol. kg(-1). min(-1); P < 0.05), neither group significantly suppressed glycerol appearance at insulin infusion rates of 10 mU. m(-2). min(-1). NASH was associated with loss of mitochondrial cristae and paracrystalline inclusions in 9 of 10 subjects, compared with 0 of 6 subjects with fatty liver. However, no evidence of a generalized defect in fatty acid beta oxidation was noted in any group. Also, mean [beta-OH butyrate] was highest in those with NASH (means, 90 vs. 110 vs. 160 micromol/L; P < 0.04). Increased staining for 3-NT was present in fatty liver, and even greater staining was seen in NASH. CONCLUSIONS: These data indicate that peripheral insulin resistance, increased fatty acid beta oxidation, and hepatic oxidative stress are present in both fatty liver and NASH, but NASH alone is associated with mitochondrial structural defects.

Adult↗

PubMed2002

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.

Adult↗

PubMed2004

Non-alcoholic steatohepatitis in children.

Obesity has emerged as a significant new health problem in the pediatric population. Non-alcoholic steatohepatitis (NASH) is an entity in the spectrum of non-alcoholic fatty liver disease (NAFLD) ranges from fat in the liver -- simple steatosis, NASH/ steatohepatitis -- fat with inflammation and/or fibrosis to advanced fibrosis and cirrhosis when fat may no longer be present. NASH is associated with obesity, diabetes, insulin resistance (IR), and hypertriglyceridemia. While majority of individuals with risk factors like obesity and IR have steatosis only a minority develop steatohepatitis, possible mechanisms have been discussed. Clinical experience with pediatric NASH is limited. Children generally present in the prepubertal age group, have a male predominance with a higher incidence in children of Hispanic origin. Body mass index (BMI) of 25-29.9 is considered to be overweight and that > or =30 obese. Acanthosis nigricans as a marker of IR should be looked for. As NASH is a diagnosis of exclusion, other causes of chronic liver disease must be excluded. Increased echogenicity in the liver is noted on ultrasound. Liver biopsy is considered the gold standard in establishing the diagnosis. Histopathological lesions thought to be necessary for diagnosis of NASH include steatosis (macrovesicular > microvesicular), mixed mild lobular inflammation and hepatocyte ballooning. A system of grading depending on degree of steatosis and/or inflammation and staging depending on the extent of fibrosis has also been proposed. Although there is no consensus for the treatment for NASH, effort needs to be made to prevent development of fibrosis, which results in cirrhosis and portal hypertension. Slow, consistent weight loss has been shown to be effective in childhood NAFLD, based on improvement of serum aminotransferases or liver sonogram. A low glycemic index diet has been shown to be more effective than a low fat diet in lowering BMI. Family based behavioral intervention may also enhance success with diet. Several pharmacological agents have been used including ursodeoxycholic acid, vitamin E, betaine, n-acetyl cysteine, and insulin sensitizing agents like metformin, rosiglitazone, and pioglitazone. Transplantation for overt NASH is rare, accounting for < 1% of liver transplantations in the USA. The disease can recur after liver transplantation. A strong association exists between the presence of steatosis in a donor liver and poor graft function. As a result, cadaveric donor livers with macrovesicular steatosis >40% are not used routinely. Prognosis in NASH is dependent not only on severity and number of risk factors but also on the degree of histological damage. Clinical trials are needed to identify an effective treatment that halts the progression of NAFLD to NASH in both pretransplantation and post-transplantation patients.

Animals↗

PubMed2003

Clinical and pathological differences between alcoholic hepatitis and non-alcoholic steatohepatitis.

To determine the difference between alcoholic hepatitis (AH) and non-alcoholic steatohepatitis (NASH) in Japan, six patients with Ah and four patients with NASH, recently treated at our institute, were clinically and pathologically evaluated. Clinical features of the diseases differed: in NASH patients, mean age was higher, mean body mass index much higher, and the prevalence of diabetes mellitus was higher than in AH patients. The patients with NASH presented with unremarkable symptoms and signs. Abnormalities in liver function tests including prothrombin time and choline esterase were mild in NASH patients, except for the indocyanine green test. They had ALT-dominant hypertransaminasemia. AST, ALT and gamma GTP did not normalize as promptly as in AH patients after admission. However, there was no significant difference in the histological grade of fibrosis, inflammation or hepatocytic metamorphosis between NASH and AH patients. Stellate-form fibrosis was characteristic of AH, whereas pericellular and perivenular types were common in NASH patients. Focal cell necrosis was rather intense, and fatty deposits prominent, in NASH patients. However, it was difficult to histopathologically discriminate between NASH and AH patients. If AH is histologically suspected in non-alcoholic patients, the possibility of NASH should always be considered. Furthermore, even in patients with suspected simple fatty liver, a liver biopsy should be performed, especially in cases with prolonged abnormal liver function findings.

Adult↗

PubMed2005

[Antioxidant status in nonalcoholic steatohepatitis].

BACKGROUND/AIMS: Nonalcoholic steatohepatitis (NASH) is chronic liver disease that can potentially progress to end stage liver disease. Oxidative stress to the vulnerable fatty liver has been reported as a key mechanism in development of NASH. Several antioxidant pathways have been identified, but reports that involved quantitative analysis of each antioxidant systems are rare, and these reports have shown various results. So, we investigated antioxidant status and the degree of oxidative stress by measuring several antioxidant enzymes, the total antioxidant status (TAS), and the metabolites of superoxide in NASH patients. METHODS: Nineteen NASH patients who were confirmed by liver biopsy and fifteen controls were involved in this study. The levels of body mass index (BMI), AST, ALT, superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase, TAS, hydrogen peroxide (H2O2), and malondialdehyde (MDA) were compared between both groups. The relationship between the histologic severity and the levels of each antioxidants were analyzed in the NASH group. RESULTS: The activities of SOD and catalase were lower in the NASH group. The concentrations of TAS and H2O2 were higher in NASH group. The level of GPx and MDA showed no significant differences between both groups. There were no significant relationships between the above variables and the pathological severity. CONCLUSIONS: The disturbed metabolism of superoxide due to the decreased activities of SOD and catalase seem to be important in the pathogenesis of NASH. Further investigations about the nonenzymatic secondary antioxidant mechanism are necessary because the TAS was higher for the NASH group. The lack of difference between both groups for the concentration of MDA indicates that mechanisms other than lipid peroxidation also may be important in the pathogenesis of NASH.

Adult↗

PubMed2004

Portal fibrosis and hepatic steatosis in morbidly obese subjects: A spectrum of nonalcoholic fatty liver disease.

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that can lead to hepatic fibrosis and cirrhosis. Portal fibrosis in the absence of NASH, called isolated portal fibrosis (IPF), has received less attention and has not been classified as a spectrum of NAFLD. The aims of this study were to determine the prevalence of IPF in subjects undergoing gastric bypass surgery, to identify biochemical variables associated with IPF, and to assess the metabolic syndrome as defined by the AdultTreatment Panel III criteria. We analyzed liver biopsies from 195 morbidly obese subjects after excluding all other causes of liver disease. The prevalence of fatty liver (FL) only, IPF, and NASH was 30.3%, 33.3%, and 36.4%, respectively. Several biochemical parameters significantly trended across the 3 groups, with IPF falling between FL and NASH. Hyperglycemia was the only metabolic parameter associated with NASH (OR, 5.4; 95% CI, 2.4-12; P < .0001) and IPF (OR, 2.8; 95% CI, 1.2-6.5; P = .01). Subjects with diabetes had the greatest risk for NASH (OR, 8; 95% CI, 3.3-19.7; P < .0001) and IPF (OR, 4.3; 95% CI, 1.6-11.6; P = .003). The metabolic syndrome was identified in 78.5% of subjects, and a significant trend for the number of metabolic criteria was observed across the spectrum of FL, IPF, and NASH. In conclusion, a significant subset of morbidly obese individuals has portal fibrosis in the absence of NASH that is associated with glycemic dysregulation. Therefore, IPF should be considered a spectrum of NAFLD that may prelude NASH in morbid obesity.

Adult↗

PubMed2006

Clinical features of nonalcoholic steatohepatitis in Japan: Evidence from the literature.

Metabolic syndrome, that is, obesity, hypertension, hyperlipidemia, and insulin resistance with hyperinsulinemia, is a new disease entity prevailing worldwide, and nonalcoholic steatohepatitis (NASH) is believed to be a hepatic expression of this syndrome. NASH is characterized by zone 3-dominant hepatic steatosis with ballooned hepatocytes and Mallory bodies, zone 3 pericellular and perivenular fibrosis with or without bridging fibrosis, and lobular inflammatory cell infiltration. Indeed, 90% of NASH has been revealed to be complicated by visceral obesity, and two-thirds of NASH patients fulfill the criteria of metabolic syndrome. Therefore, a variety of lifestyle-related diseases such as obesity, hypertension, hyperlipidemia, and diabetes mellitus may share the same background. NASH is most prevalent and well characterized in Caucasians; however, little is known about its occurrence in Asia-Oceania, because obesity has not been frequent in countries in these areas. Obesity is expected to become a serious social problem in Asia-Oceania in the next two decades, so we need to prevent a corresponding increase of NASH. For that purpose, we need to know much about not only NASH but also ourselves. To elucidate the status of NASH in Japan, recent progress in the study of NASH in Japan is reviewed in this article.

Blood Glucose↗