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PubMed2003

Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis.

BACKGROUND & AIMS: The pathogenesis of nonalcoholic steatohepatitis (NASH) remains poorly understood. Although apoptosis is a common mechanism of liver injury, the extent and clinical significance of apoptosis in NASH has not been examined. Thus, the aims of this study were to quantify hepatocyte apoptosis in NASH, correlate it with disease severity, and identify possible mechanisms of apoptosis induction. METHODS: Hepatocyte apoptosis was assessed in NASH, simple steatosis, alcoholic hepatitis, and controls without liver disease using the TUNEL assay and immunohistochemistry for activated caspases 3 and 7. Liver specimens were also graded according to the magnitude of inflammation and fibrosis. RESULTS: TUNEL-positive cells were significantly increased in liver biopsy specimens from patients with NASH compared with simple steatosis and controls. Unexpectedly, TUNEL-positive cells were also greater in NASH vs. alcoholic hepatitis. Immunohistochemistry demonstrated active caspases 3 and 7 in NASH specimens, confirming the occurrence of apoptosis in this disease. A positive correlation was observed between hepatocyte apoptosis and hepatic fibrosis and inflammatory activity, respectively. The Fas receptor was strongly expressed in hepatocytes in liver specimens from NASH patients as compared with controls. CONCLUSIONS: Hepatocyte apoptosis is significantly increased in patients with NASH and correlates with disease severity, suggesting that antiapoptotic therapy may be useful in this syndrome.

Adult↗

PubMed2001

Role of non-alcoholic steatohepatitis in methotrexate-induced liver injury.

BACKGROUND AND AIMS: Hepatotoxicity, especially liver fibrosis, is the major concern with long-term, 'low-dose' oral methotrexate (MTX) therapy for psoriasis. The histological features are non-specific and resemble those of non-alcoholic steatohepatitis (NASH). Moreover, most of the risk factors of MTX-induced liver injury are also associated with NASH. In this study, we investigate whether NASH contributes to the prevalence and progression of MTX-induced liver injury in patients receiving MTX for psoriasis. METHODS: Clinical details, including MTX dosage schedules and risk factors for liver injury, was documented for 24 patients on long-term MTX therapy for psoriasis. Serial liver biopsies were graded according to the Roenigk classification scale and a recently proposed grading and staging system for NASH. RESULTS: Thirteen of the 17 patients who had a NASH-like pattern of liver injury also had the risk factors for NASH obesity and/or diabetes, and all had progressive liver injury. The other four patients had no risk factors, but a mean cumulative dose of 6.5 g. Seven patients, who did not have a NASH-like pattern of injury, had a mean cumulative dose of 3.8 g. There was a positive correlation between the cumulative dose, risk factors and progression when the biopsies were scored by the modified grading and staging classification for NASH, but not with the Roenigk system. CONCLUSIONS: Non-steatohepatitis, probably aggravated by MTX, is an important cause of liver injury in patients on long-term, 'low-dose' MTX treatment for psoriasis. In addition, MTX alone can cause a NASH-like pattern of injury that is at least, in part, caused by a higher cumulative dose.

Adult↗

PubMed2001

Nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a condition characterized by hepatomegaly, elevated serum aminotransferase levels, and a histologic picture similar to alcoholic hepatitis in the absence of alcohol abuse. Most patients with NASH are obese women, and many have diabetes mellitus, hypercholesterolemia, or hypertriglyceridemia. NASH has also been associated with a number of metabolic conditions, surgical procedures, and drug treatments. Most patients are asymptomatic. The most common sign of NASH is hepatomegaly. Stigmata of chronic liver disease are rare. Laboratory abnormalities include a 2-4-fold elevation of serum aminotransferase levels; other liver function test results are usually normal. Histologically, there is moderate to severe macrovesicular steatosis and lobular hepatitis with necrosis or ballooning degeneration and/or fibrosis. The pathogenesis of NASH is poorly understood, but lipid peroxidation and oxidative stress are the leading culprits. The natural history of NASH is unknown, but NASH seems to be a stable disease in most patients. Treatment of NASH is unproven, but weight reduction is recommended in obese patients. Small pilot studies of several drugs have shown promise, but large randomized clinical trials are awaited. Orthotopic liver transplantation is the treatment of choice for end-stage liver disease secondary to NASH.

Fatty Liver↗

PubMed2001

Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients.

The main objective of this study was to analyze the pathogenic role of the tumor necrosis factor alpha (TNF-alpha) system in the development of nonalcoholic steatohepatitis (NASH). Fifty-two obese patients were studied. We investigated: (1) the expression of mRNA of TNF-alpha and their p55 and p75-receptors by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) in hepatic and adipose tissues; and (2) the relationship between TNF-alpha, p55, and p75 and the severity of NASH. Obese patients without NASH were the control group. A remarkable increase in the expression of mRNA of TNF-alpha was found in patients with NASH in hepatic tissue (0.65 +/- 0.54) and in peripheral fat (0.43 +/- 0.45); in the control samples, the mRNA expression was 0.28 +/- 0.32, P <.007, and 0.26 +/- 0.22, P <.018, respectively. Furthermore, we found a significant increase in the mRNA levels of p55 receptor (2.42 +/- 1.81 vs. 1.56 +/- 1.17; P <.05); however, the mRNA expression of the p75 receptor was similar in both patients. Those patients with NASH with significant fibrosis presented an increase in the expression of mRNA TNF-alpha in comparison with those with a slight or nonexistent fibrosis. An overexpression of TNF-alpha mRNA is found in the liver and in the adipose tissue of NASH patients. The levels of mRNA-p55 are increased in the liver tissue of NASH patients. This overexpression is more elevated in patients with more advanced NASH. These findings suggest that the TNF-alpha system may be involved in the pathogenesis of NASH.

Adipose Tissue↗

PubMed1999

Nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is an hepatic disorder with histologic features of alcohol-induced liver disease that occurs in individuals who do not consume significant alcohol. NASH is believed to be one of the most common explanations for abnormal liver chemistries in American adults. Risk factors for NASH include obesity, type II diabetes, hyperlipidemia, total parenteral nutrition, jejuno-ileal bypass surgery, and the use of certain drugs. However, some patients with NASH have no identifiable risk factors for the disease. Clinically, NASH is a diagnosis of exclusion that should be suspected as a cause of chronic hepatitis in patients who deny significant alcohol consumption and have negative serologic tests for congenital and other acquired causes of liver disease. The identification of fatty liver on imaging studies supports the diagnosis of NASH, which can be established definitively by liver biopsy. The latter also provides useful prognostic information since most patients with simple steatosis follow an indolent clinical course, whereas those with steatohepatitis, fibrosis, or cirrhosis are more likely to develop clinically significant complications of liver disease. Weight reduction and treatment of confounding medical conditions are the mainstays of therapy for NASH. However, there is little evidence that any of the current treatments prevent progression to more histologically advanced stages of NASH. Several experimental therapies, including treatment with bile acids, antibiotics, nutritional supplements, and antioxidants, have had anecdotal success in selected patients, but improved understanding of the pathogenesis and natural history of NASH will be required to develop generally effective therapy for the disorder.

Adult↗

PubMed2003

Is hypothyroidism a risk factor for non-alcoholic steatohepatitis?

PURPOSE: Thyroid hormones play an important role in the regulation of lipid and carbohydrate metabolism, both of which are affected in patients with non-alcoholic steatohepatitis (NASH). Anecdotally, we have observed that a number of patients with NASH carried a diagnosis of hypothyroidism. However, it is unknown if thyroid dysfunction plays any role in the pathogenesis of NASH. To further investigate this observation, we conducted a case-control study to determine the association between hypothyroidism and NASH. SUBJECTS AND METHODS: Cases were defined as patients with well-documented NASH attending hepatology clinics at Indiana University Hospital from January 1, 1995 to December 31, 2000. Age, gender, race, and body-weight matched individuals seen during the same period in the general medical clinics served as controls. Patients with a previous diagnosis of hypothyroidism who are currently on synthetic T4 replacement were considered to be "hypothyroid". The strength of association was assessed by logistic regression analysis after controlling for the frequency of diabetes mellitus, hyperlipidemia, and hypertension. RESULTS: One hundred seventy-four patients with NASH (cases) and 442 controls were included. The mean age of cohort was 49 +/- 13 years, 59% were female, and 98% were white. The prevalence of hypothyroidism in patients with NASH was 15% was significantly higher than in the controls (7.2%, P < 0.001). By multivariate analysis, the prevalence of hypothyroidism in the NASH group was significantly higher than in control group (OR: 2.3, 95% CI: 1.2-4.2, P = 0.008). CONCLUSION: These data suggest that hypothyroidism is associated with human NASH. Further research is needed to confirm this finding and to understand its implications.

Adult↗

PubMed2005

Is adiponectin involved in the pathogenesis of nonalcoholic steatohepatitis? A preliminary human study.

BACKGROUND: Animal studies have suggested that adiponectin may play a role in the pathogenesis of alcoholic and nonalcoholic fatty liver disease. Studies are limited that evaluated the role of adiponectin in the pathogenesis of nonalcoholic steatohepatitis (NASH). METHODS: To further our understanding of the role of adiponectin in the pathogenesis of NASH, the following studies were conducted. Serum adiponectin was measured and correlated with anthropometric and nutritional variables in 21 patients with biopsy-proven NASH and 19 age-, gender-, body mass index-, and body fat-matched controls. The effect of a mixed meal on serum adiponectin levels in a subgroup of patients (n = 24) with NASH and controls was assessed. In a separate cohort, liver samples belonging to healthy (n = 11), steatotic (n = 12), and NASH (n = 12) patients were used to further explore the role of adiponectin by measuring the expression of adiponectin and adiponectin receptor (AdipoR2) mRNA. RESULTS: Patients with NASH had significantly lower levels of serum adiponectin than controls (4.9 +/- 2.7 vs. 7.3 +/- 3.5 microg/mL, P = 0.02). While no significant correlation existed between serum adiponectin and anthropometric or nutritional variables, it was independently associated with age, high density lipoprotein, and triglycerides. Mixed meal had no effect on serum adiponectin either in patients with NASH or in controls. There was no expression of adiponectin mRNA in any of liver samples studied. However, AdipoR2 mRNA expression was higher in NASH than in steatotic and normal liver tissue. CONCLUSION: These data show that adiponectin may have a role in the pathogenesis of human NASH and should be investigated further.

Adiponectin↗

PubMedDate not supplied

Depression, anxiety, and nonalcoholic steatohepatitis.

OBJECTIVE: Nonalcoholic steatohepatitis (NASH) is a morbid liver disease with limited treatment. Depression and anxiety have been associated recently with insulin resistance and inflammatory states, factors that are relevant to the development of NASH. We hypothesized that depression and anxiety would be more prevalent in NASH patients and predict more severe histological findings on liver biopsy. METHODS: Histories of major depressive disorder (MDD) and generalized anxiety disorder (GAD) were determined using a structured interview and DSM-IV criteria in 36 NASH subjects and 36 matched controls without liver disease who had undergone cholecystectomy. Histological changes on liver biopsy in NASH subjects were age-adjusted and compared in subjects with and without psychiatric disorders. A multivariate model incorporating other potential risk factors for NASH (female sex, body mass index, waist-to-hip ratio, and presence of diabetes) was used to determine independent effects of MDD and GAD on severity of histological findings. RESULTS: NASH subjects had significantly increased lifetime rates of MDD (odds ratio [OR], 3.8; 95% confidence interval [CI], 1.4-10.2; p = .018) and GAD (OR 5.0, 95% CI, 1.7-14.9; p = .005). The onset of psychiatric illness preceded diagnosis of liver disease by 18 to 20 years. Each psychiatric disorder was associated with more severe histological features (p < .05 for each), the effect of GAD on fibrosis stage persisting in the multivariate model. CONCLUSIONS: MDD and GAD are overrepresented in NASH subjects and are associated with more advanced liver histological abnormalities. Additional investigation will be required to determine if depression and anxiety affect the development or progression of NASH and serve as modifiable risk factors.

Anxiety Disorders↗

PubMedDate not supplied

Computed tomography features of nonalcoholic steatohepatitis with histopathologic correlation.

OBJECTIVE: This study was conducted to describe the computed tomography (CT) features of nonalcoholic steatohepatitis (NASH) and to evaluate if the CT features could be used to diagnose and stage NASH. METHODS: From 1994 until 2004, pathology records revealed 68 patients with NASH. Of these, 12 patients underwent CT scans before (n=6), on the same day as (n=3), or after (n=3) a liver biopsy. Using the same database, 9 patients with steatosis alone evaluated with a CT scan before (n=2), on the same day as (n=3), or after (n=4) the liver biopsy were selected as a control group. Two radiologists measured liver attenuation (compared with spleen) and assessed the pattern of steatosis, craniocaudal liver span, caudate-to-right lobe ratio, preportal space distance, and presence of porta hepatis lymph nodes and ascites. Biopsy specimens were assessed by a pathologist, and the degree of necroinflammatory activity, steatosis, and fibrosis was determined. Histopathologic and CT findings were compared between patients with NASH and patients with steatosis alone using the Mann-Whitney U test and Fisher exact test. RESULTS: In patients with NASH, the mean liver-to-spleen attenuation ratio was 0.66 (range: 0.1-1.1). Steatosis was diffuse (n=9), geographic or nonlobar (n=2), or diffuse with an area of focal sparing (n=1). The liver craniocaudal span varied from 17.5 to 25.5 cm (mean=21.4 cm), and hepatomegaly was present in 11 (91.7%) patients. The caudate-to-right-lobe ratio (mean=0.43) and preportal space (mean=4.5 mm) were normal in all cases. Porta hepatis lymph nodes were present in 7 (58.3%) patients; their mean dimensions were 16 mmx11 mm. Ascites was absent in all patients. On histopathology, the degree of necroinflammatory activity was mild (n=9), moderate (n=1), or severe (n=2). The degree of steatosis was 33% to 66% (n=5) or >67% (n=7). All but 3 patients had fibrosis; 6 had focal nonbridging fibrosis, 1 had multifocal nonbridging fibrosis, and 2 had bridging fibrosis. There was a significant correlation between the degree of steatosis on pathologic examination and the liver-to-spleen attenuation ratio on CT (P=0.048). The severity of inflammation and stage of fibrosis on pathologic examination did not correlate with the CT features. Among patients with steatosis alone, the mean liver-to-spleen attenuation ratio was 0.80 (range: 0.3-1.2); the craniocaudal liver span varied from 12 to 20 cm (mean=16 cm); hepatomegaly was present in 2 (22.2%) patients; the caudate-to-right lobe ratio was normal in all patients, with a mean of 0.36 (range: 0.22-0.47); the preportal space distance was enlarged in 2 cases (mean=7.5 mm, range: 1-16 mm); porta hepatis lymph nodes were present in 7 (77.8%) patients, and their mean dimensions were 11 mmx8 mm (large axis range: 6-19 mm, short axis range: 4-14 mm); and no patient had ascites. There was a significant difference in the craniocaudal liver span between patients with NASH (mean=21 cm) and patients with steatosis (mean=16 cm) (P<0.05). The caudate-to-right-lobe ratio was also significantly different between patients with NASH (mean=0.43) and patients with steatosis (mean=0.36) (P<0.05). There were no significant differences in liver-to-spleen attenuation ratios, measurements of preportal space, or the presence of porta hepatic lymph nodes. CONCLUSION: The CT features of NASH include steatosis, hepatomegaly, and porta hepatis lymph nodes, and the liver-to-spleen attenuation ratio correlated with the degree of steatosis on histopathology. Patients with NASH had a greater liver span and increased caudate-to-right-lobe-ratio compared with patients with steatosis alone.

Adult↗

PubMed2005

Hepatic gene expression in patients with obesity-related non-alcoholic steatohepatitis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is among the most common causes of chronic liver disease. NAFLD includes a spectrum of clinicopathologic syndromes that includes non-alcoholic steatohepatitis (NASH) that has potential for progression. The pathogenesis of NASH is poorly characterized. AIM: This study was designed to identify differences in hepatic gene expression in patients with NASH and to relate such differences to their clinical characteristics. DESIGN: Consecutive patients undergoing bariatric surgery were prospectively recruited. Extensive clinical data and two liver biopsy specimens were obtained at the time of enrollment. A single hepatopathologist reviewed and classified the liver biopsies. Patients with excessive alcohol use and other causes of liver disease were excluded. A group of 29 NASH patients, 12 with steatosis alone, seven obese controls and six non-obese controls were selected for further investigation. Customized cDNA microarrays containing 5220 relevant genes were designed specifically for this study. Microarray experiments were run in triplicate for each sample and a selected group of genes were confirmed using real-time PCR. OUTCOME MEASURE: Differential hepatic gene expressions in patients with NASH as compared with controls. RESULTS: Thirty-four genes with significant differential expression were identified in patients with NASH when compared with non-obese controls. Moreover, 19 of these genes showed no significant expression differences in obese vs. non-obese controls, suggesting a stronger association of these genes to NASH. CONCLUSIONS: Several differentially expressed genes in patients with NASH are related to lipid metabolism and extracellular matrix remodeling. Additionally, genes related to liver regeneration, apoptosis, and the detoxification process were differentially expressed. These findings may help clarify the molecular pathogenesis of NASH and identify potential targets for therapeutic intervention.

Adult↗

PubMed2006

Serum cytokine and soluble cytokine receptor levels in patients with non-alcoholic steatohepatitis.

BACKGROUND: Although the pathogenesis of non-alcoholic steatohepatitis (NASH) remains poorly understood, proinflammatory cytokines seem to play an important role in the process of NASH. We have undertaken this study in order to elucidate the role of proinflammatory cytokines and their soluble receptors in NASH patients. METHODS: Serum cytokines and soluble cytokine receptors levels were determined using an enzyme-linked immunosorbent assay kit in 23 patients with NASH, 21 patients with simple steatosis, and 18 healthy volunteers. RESULTS: Patients with NASH had significantly higher serum tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels than did the simple steatosis patients. Similarly, when compared with simple steatosis, NASH was associated with higher soluble TNF receptor 1 (sTNFR1) and soluble IL-6 receptor (sIL-6R) levels, and a significant positive correlation was seen between the levels of sTNFR1 and aminotranferases in NASH patients. CONCLUSIONS: This study shows that circulating TNF-alpha/sTNFR1 and IL-6/sIL-6R levels are significantly increased in NASH patients as compared with simple steatosis patients and healthy volunteers, and that these increased levels may be implicated in the pathogenesis of NASH.

Adult↗

PubMed2004

Polymorphisms of interleukin-1 beta and beta 3-adrenergic receptor in Japanese patients with nonalcoholic steatohepatitis.

BACKGROUND: Obesity, hypertriglyceridemia, and diabetes have been reported as frequent complications observed in patients with nonalcoholic steatohepatitis (NASH) in Western countries. The aim of this study was to investigate the genetic predisposition on NASH pathogenesis in the Japanese population. METHODS: Genotypes of two previously described functional polymorphisms-beta3-adrenergic receptor 190 T/A polymorphism, which results in Trp64Arg (W64R) amino acid replacement, and interleukin-1beta-511 T/C polymorphism in the promoter sequence-were determined in 63 Japanese NASH patients and 100 healthy volunteers using polymerase chain reaction and restriction fragment length polymorphism. RESULTS: beta3-adrenergic receptor R allele frequency and the R/- (W/R and R/R) genotype frequency were significantly higher in NASH patients than those in control subjects. Interleukin-1beta-511 T allele frequency and the T/T genotype frequency were significantly higher in NASH patients than those in control subjects. Obesity, hypertriglyceridemia, and hyperinsulinemia were associated with NASH patients with the R/- genotype, whereas an increase in fasting plasma glucose level and a decrease in insulinogenic index were associated with NASH patients with the W/W genotype. CONCLUSION: This study confirmed the contribution of obesity, glucose intolerance, and hypertriglyceridemia to NASH development in the Japanese population. In addition to these factors, genetic predispositions to obesity and inflammation in the Japanese population were shown to contribute much to the development of NASH.

Aged↗

PubMed2003

Does leptin play a role in the pathogenesis of human nonalcoholic steatohepatitis?

OBJECTIVES: Obesity is a risk factor for nonalcoholic steatohepatitis (NASH). Leptin plays an important role in the regulation of food intake, body composition, energy expenditure, and body weight. It has been suggested that leptin plays a role in the pathogenesis of NASH; however, adequate studies are lacking. We therefore conducted a study to explore the role of serum leptin in the pathogenesis of human NASH. METHODS: We measured the levels of serum leptin and its anthropometric, biochemical, metabolic, and histological correlates in a cohort of patients with NASH (n = 26) and well-matched controls (n = 20). Furthermore, we measured the levels of leptin in the serum and hepatic leptin and leptin receptor messenger RNA (mRNA) expression in liver biopsy specimens of patients with NASH (n = 5) and simple steatosis (n = 5). RESULTS: Serum leptin was not statistically different between patients with NASH and their controls (21 +/- 13 vs 18 +/- 11 ng/ml, respectively, p = 0.5). There was no correlation between serum leptin and hepatic histology, serum transaminases, fasting insulin levels, or a measure of insulin resistance. After adjusting for covariates in a multiple regression analysis, only percent body fat (p = 0.04) and subcutaneous abdominal fat area (p = 0.04) had significant correlation with serum leptin. There was no expression of leptin mRNA in the cell lysate of liver biopsy specimens of subjects with NASH or steatosis. Additionally, the serum leptin levels and the hepatic leptin receptor mRNA expression were not statistically different between patients with NASH and those with simple steatosis. CONCLUSION: These data do not support a direct role for leptin in the pathogenesis of human NASH.

Adult↗

PubMed2005

Fibrosis heterogeneity in nonalcoholic steatohepatitis and hepatitis C virus needle core biopsy specimens.

We examined 46 nonalcoholic steatohepatitis (NASH) and 52 hepatitis C virus (HCV) biopsy specimens to determine the magnitude of fibrosis heterogeneity and minimum length for accurate fibrosis staging. Three fibrosis scores were recorded: lowest regional, highest regional, and most common overall. Mean specimen lengths were 1.6 and 1.8 cm in NASH and HCV, respectively (P = .283). Mean (highest minus lowest) fibrosis heterogeneity scores (highest regional fibrosis - lowest regional fibrosis) were 3.7 and 2.0 in NASH and HCV, respectively (P < .001). Of 36 NASH specimens longer than 1.0 cm, 31 (86%) had the highest regional fibrosis in the deepest sampled parenchyma. Shorter specimens were associated significantly with greater fibrosis heterogeneity in NASH (coefficient, -1.3; P < .001) but not in HCV (P = .901). NASH specimens longer than 1.6 cm had significantly lower mean heterogeneity scores than specimens 1.6 cm or shorter (1.2 vs 3.4; P = .012). In NASH, fibrosis heterogeneity can be substantial and is greater than in HCV, and parenchymal injury, fibrosis, and healing might vary in different regions of the liver. The fibrosis stage in patients with NASH might not be assessed accurately in short specimens. Individual needle cores should be longer than 1.6 cm in NASH for accurate fibrosis staging.

Biopsy, Needle↗

PubMed2004

The importance of routine liver biopsy in diagnosing nonalcoholic steatohepatitis in bariatric patients.

BACKGROUND: Nonalcoholic Steatohepatitis (NASH) commonly occurs in obese patients and predisposes to cirrhosis. Prevalence of NASH in bariatric patients is unknown. Our aim was to determine the role of routine liver biopsy in managing bariatric patients. METHODS: Prospective data on patients undergoing Roux-en-Y gastric bypass (RYGBP) was analyzed. One pathologist graded all liver biopsies as mild, moderate or severe steatohepatitis. NASH was defined as steatohepatitis without alcoholic or viral hepatitis. Consecutive liver biopsies were compared to those liver biopsies selected because of grossly fatty livers. RESULTS: 242 patients underwent open and laparoscopic RYGBP from 1998-2001. Routine liver biopsies (68 consecutive patients) and selective liver biopsies (additional 86/174, 49%) were obtained. Findings of cirrhosis on frozen section changed the operation from a distal to a proximal RYGBP. The two groups were similar in age, gender, and BMI. The group with the routine liver biopsies showed a statistically significant larger preponderance of NASH (37% vs 32%). Both groups had a similar prevalence of cirrhosis. Neither BMI nor liver enzymes predicted the presence or severity of NASH. CONCLUSIONS: Routine liver biopsy documented significant liver abnormalities in a larger group of patients compared with selective liver biopsies, thereby suggesting that liver appearance is not predictive of NASH. Liver biopsy remains the gold-standard for diagnosing NASH. We recommend routine liver biopsy during bariatric operations to determine the prevalence and natural history of NASH, which will have important implications in directing future therapeutics for obese patients with NASH and for patients undergoing bariatric procedures.

Adult↗

PubMed2005

Predictors of nonalcoholic steatohepatitis and advanced fibrosis in morbidly obese patients.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a common form of chronic liver disease in the United States. It is commonly associated with the components of the metabolic syndrome including obesity. From the spectrum of NAFLD, only patients with nonalcoholic steatohepatitis (NASH) have been convincingly shown to have a potential for progression to cirrhosis. We report the prevalence of NAFLD and NASH as well as predictors of NASH and advanced fibrosis in morbidly obese patients. METHODS: 212 consecutive patients who underwent bariatric surgery were enrolled in the study. A liver biopsy was performed at the time of the surgery. Causes of chronic liver disease other than NAFLD were excluded by clinical and laboratory evaluation. RESULTS: The prevalence of NAFLD was 93%. Of those with NAFLD, 26% had NASH. 17 patients (9%) had advanced fibrosis (i.e., bridging fibrosis or cirrhosis). Male gender, AST, and type 2 diabetes mellitus were independently associated with NASH. Waistto-hip ratio, AST, and focal hepatocyte necrosis on liver biopsy were independently associated with advanced fibrosis. Interestingly, while AST was associated with NASH and advanced fibrosis, the majority of the patients with either NASH or advanced fibrosis had normal AST. CONCLUSIONS: NAFLD and NASH are very common in morbidly obese patients undergoing bariatric surgery. Features associated with the metabolic syndrome and liver cell injury are independently associated with either NASH or advanced fibrosis.

Adult↗

PubMed2003

[Non-alcoholic steatohepatitis].

Nonalcoholic steatohepatitis (NASH) is a condition characterized histologically by macrovesicular steatosis and lobular hepatitis with necrosis or ballooning degeneration and/or fibrosis--a picture resembling alcoholic hepatitis, in the absence of alcohol abuse. Most patients with NASH are asymptomatic, and the disease is detected incidentally. The most common signs of NASH are hepatomegaly and laboratory abnormalities, which include a 2-4-fold elevation of serum aminotransferase levels, while other liver function test results are usually normal. Most patients with NASH are obese, many have diabetes mellitus, hypercholesterolemia, or hypertriglyceridemia. NASH has also been associated with a number of metabolic derrangements, conditions, surgical procedures, and drug treatments. The pathogenesis of NASH is poorly understood, but lipid peroxidation and oxidative stress seem to be the leading culprits. The natural history of NASH is unknown, but it seems to be a stable disease in most patients. Still, the progress to cirrhosis is possible. There is no established treatment for NASH. Treatment is usually directed towards optimizing body weight, and pharmacologic agents are mostly experimentally used. Orthotopic liver transplantation is the treatment of choice for end-stage liver disease secondary to NASH.

Fatty Liver↗

PubMed2005

Design and validation of a histological scoring system for nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in the absence of a history of significant alcohol use or other known liver disease. Nonalcoholic steatohepatitis (NASH) is the progressive form of NAFLD. The Pathology Committee of the NASH Clinical Research Network designed and validated a histological feature scoring system that addresses the full spectrum of lesions of NAFLD and proposed a NAFLD activity score (NAS) for use in clinical trials. The scoring system comprised 14 histological features, 4 of which were evaluated semi-quantitatively: steatosis (0-3), lobular inflammation (0-2), hepatocellular ballooning (0-2), and fibrosis (0-4). Another nine features were recorded as present or absent. An anonymized study set of 50 cases (32 from adult hepatology services, 18 from pediatric hepatology services) was assembled, coded, and circulated. For the validation study, agreement on scoring and a diagnostic categorization ("NASH," "borderline," or "not NASH") were evaluated by using weighted kappa statistics. Inter-rater agreement on adult cases was: 0.84 for fibrosis, 0.79 for steatosis, 0.56 for injury, and 0.45 for lobular inflammation. Agreement on diagnostic category was 0.61. Using multiple logistic regression, five features were independently associated with the diagnosis of NASH in adult biopsies: steatosis (P = .009), hepatocellular ballooning (P = .0001), lobular inflammation (P = .0001), fibrosis (P = .0001), and the absence of lipogranulomas (P = .001). The proposed NAS is the unweighted sum of steatosis, lobular inflammation, and hepatocellular ballooning scores. In conclusion, we present a strong scoring system and NAS for NAFLD and NASH with reasonable inter-rater reproducibility that should be useful for studies of both adults and children with any degree of NAFLD. NAS of > or =5 correlated with a diagnosis of NASH, and biopsies with scores of less than 3 were diagnosed as "not NASH."

Adult↗