Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) may present with increased hepatic fibrosis progressing to end‐stage liver disease. No factors that determine increasing fibrosis and histologically advanced disease have been recognized, thus, liver biopsy is recommended in all patients for diagnosis and prognosis. Our aim was to identify independent predictors of severe hepatic fibrosis in patients with NASH. One hundred and forty‐four patients were studied. All patients underwent liver biopsy. Clinical and biochemical variables were examined with univariate and multivariate analysis. Thirty‐seven (26%) patients had no abnormal fibrosis, 53 (37%) had mild fibrosis, 15 (10%) had moderate fibrosis, 14 (10%) had bridging fibrosis, and 25 (17%) had cirrhosis. In multivariate analysis, older age (P = .001), obesity (P = .002), diabetes mellitus (P = .009), and aspartate transaminase/alanine transaminase (AST/ALT) ratio greater than 1 (P = .03) were significant predictors of severe liver fibrosis (bridging/cirrhosis). Body mass index (P = .003) was the only independent predictor of the degree of fat infiltration. Increased transferrin saturation correlated positively with the severity of fibrosis (P = .02) in univariate analysis, and there was a trend for more female patients among those with more advanced fibrosis (P = .09). However, iron studies or gender were not significant when controlled for age, obesity, diabetes, and AST/ALT ratio. In conclusion, older age, obesity, and presence of diabetes mellitus help identify those NASH patients who might have severe liver fibrosis. This is the subgroup of patients with NASH who would be expected to derive the most benefit from having a liver biopsy and considering investigational therapies.

[1]  J. Bargman,et al.  Subcapsular steatonecrosis in response to peritoneal insulin delivery: a clue to the pathogenesis of steatonecrosis in obesity. , 1989, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[2]  C. Day,et al.  Steatohepatitis: a tale of two "hits"? , 1998, Gastroenterology.

[3]  R. Komorowski,et al.  Hepatic Free Fatty Acids in Alcoholic Liver Disease and Morbid Obesity , 2007, Hepatology.

[4]  K. McColl,et al.  Rebound hypersecretion after omeprazole and its relation to on-treatment acid suppression and Helicobacter pylori status. , 1999, Gastroenterology.

[5]  R. Kuczmarski,et al.  Prevalence of overweight and weight gain in the United States. , 1992, The American journal of clinical nutrition.

[6]  I. Wanless,et al.  Fatty liver hepatitis (steatohepatitis) and obesity: An autopsy study with analysis of risk factors , 1990, Hepatology.

[7]  J. Witztum,et al.  Excess iron induces hepatic oxidative stress and transforming growth factor β1 in genetic hemochromatosis , 1997, Hepatology.

[8]  D. Pessayre,et al.  Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes. , 1998, Gastroenterology.

[9]  BOULIN,et al.  Classification and Diagnosis of Diabetes. , 2022, Primary care.

[10]  P. Ward,et al.  Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. , 1998, Gastroenterology.

[11]  Z. Younossi,et al.  Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. , 1999, Gastroenterology.

[12]  J. Ludwig,et al.  Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. , 1980, Mayo Clinic proceedings.

[13]  D. Pessayre,et al.  Acute and chronic hepatic steatosis lead to in vivo lipid peroxidation in mice. , 1996, Journal of hepatology.

[14]  E. Berry,et al.  Polymyxin B reduces cecal flora, TNF production and hepatic steatosis during total parenteral nutrition in the rat. , 1991, The Journal of surgical research.

[15]  K. Flegal Trends in body weight and overweight in the U.S. population. , 2009, Nutrition reviews.

[16]  F. Gordon,et al.  AST/ALT Ratio Predicts Cirrhosis in Patients With Chronic Hepatitis C Virus Infection , 1998, American Journal of Gastroenterology.

[17]  T. Peters,et al.  Raised hepatic free fatty acids in a patient with acute fatty liver after gastric surgery for morbid obesity. , 1986, Journal of clinical pathology.

[18]  J. Moorhouse,et al.  SEX DIFFERENCE IN SERUM-FREE FATTY ACID LEVELS IN DIABETIC SUBJECTS. , 1963, The Journal of clinical endocrinology and metabolism.

[19]  K. Ishak,et al.  Alcohollike liver disease in nonalcoholics. A clinical and histologic comparison with alcohol-induced liver injury. , 1988, Gastroenterology.

[20]  C. Gluud,et al.  Hepatic effects of dietary weight loss in morbidly obese subjects. , 1991, Journal of hepatology.

[21]  C. Trautwein,et al.  Stimulation of collagen α1(I) gene expression is associated with lipid peroxidation in hepatocellular injury: A link to tissue fibrosis? , 1994, Hepatology.

[22]  Randall G. Lee,et al.  Nonalcoholic steatohepatitis: a study of 49 patients. , 1989, Human pathology.

[23]  W. Vogel,et al.  Prognosis in nonalcoholic steatohepatitis. , 1995, Gastroenterology.

[24]  D F Williamson,et al.  Descriptive Epidemiology of Body Weight and Weight Change in U.S. Adults , 1993, Annals of Internal Medicine.

[25]  K. Ishak,et al.  Histopathology of Hepatitis C Virus Infection , 1995, Seminars in liver disease.

[26]  K. Flegal,et al.  Varying body mass index cutoff points to describe overweight prevalence among U.S. adults: NHANES III (1988 to 1994). , 1997, Obesity research.

[27]  M. Bennett,et al.  The natural history of nonalcoholic fatty liver: A follow‐up study , 1995, Hepatology.

[28]  B. Ruebner,et al.  Sequential acetaldehyde production, lipid peroxidation, and fibrogenesis in micropig model of alcohol‐induced liver disease , 1995, Hepatology.

[29]  K. S. Lee,et al.  Activation of hepatic stellate cells by TGF alpha and collagen type I is mediated by oxidative stress through c-myb expression. , 1995, The Journal of clinical investigation.

[30]  V. Paradis,et al.  In situ detection of lipid peroxidation in chronic hepatitis C: correlation with pathological features. , 1997, Journal of clinical pathology.

[31]  M. Lean,et al.  Pathophysiology of obesity , 2000, Proceedings of the Nutrition Society.

[32]  P. Vajro,et al.  Persistent hyperaminotransferasemia resolving after weight reduction in obese children. , 1994, The Journal of pediatrics.

[33]  A. Gentilini,et al.  Stimulation of lipid peroxidation or 4-hydroxynonenal treatment increases procollagen alpha 1 (I) gene expression in human liver fat-storing cells. , 1993, Biochemical and biophysical research communications.

[34]  R. Hanson,et al.  The natural history of nonalcoholic steatohepatitis: A follow‐up study of forty‐two patients for up to 21 years , 1990, Hepatology.

[35]  B. Bacon,et al.  Increased 4‐hydroxynonenal levels in experimental alcoholic liver disease: Association of lipid peroxidation with liver fibrogenesis , 1992, Hepatology.

[36]  B V Howard,et al.  Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects. , 1984, The Journal of clinical investigation.

[37]  A. Clouston,et al.  Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis , 1999, Hepatology.

[38]  K. Kawagoe,et al.  Comparison between nonalcoholic steatohepatitis and alcoholic hepatitis. , 1987, The American journal of gastroenterology.

[39]  M. Clemens,et al.  Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[40]  F. Schaffner,et al.  Fatty liver hepatitis and cirrhosis in obese patients. , 1979, The American journal of medicine.

[41]  J. Olefsky,et al.  Effects of Weight Loss on Mechanisms of Hyperglycemia in Obese Non-Insulin-Dependent Diabetes Mellitus , 1986, Diabetes.

[42]  B. Neuschwander‐Tetri,et al.  Nonalcoholic steatohepatitis: an expanded clinical entity. , 1994, Gastroenterology.

[43]  C. Degott,et al.  Liver in obesity. , 1985, Gut.

[44]  P. Baeuerle,et al.  Function and activation of NF-kappa B in the immune system. , 1994, Annual review of immunology.

[45]  D. Acosta,et al.  Injury produced by free fatty acids to lysosomes and mitochondria in cultured heart muscle and endothelial cells. , 1974, Atherosclerosis.