Nonalcoholic fatty liver disease (NAFLD) is a significant complication of obesity and is recognized as the hepatic manifestation of the metabolic syndrome. The process occurs in adults and children and is characterized by the presence of increased amounts of fat in the liver (steatosis). With inflammation, cell death and scarring (fibrosis), the process may result in end-stage liver disease, or be a precursor for hepatocellular carcinoma. Excess hepatic fat is now recognized as an independent marker for increased cardiovascular risk. Even though imaging studies and laboratory-based tests are accurate at detecting significant steatosis and/or advanced fibrosis, respectively, the diagnosis and characterization of NAFLD ultimately depend on histopathologic evaluation, as the parenchymal alterations that comprise the spectrum of injury in NAFLD include patterns as well as specific lesions. Histologic findings in children may differ from those in adults. In this Review, the histologic features that are diagnostic and discriminatory between steatosis and steatohepatitis, the significance of the distinction between steatosis and steatohepatitis, the types and locations of fibrosis, and the histologic variances between adult and pediatric NAFLD are discussed. Clinical advantages as well as potential drawbacks of liver biopsy are presented. Current pathophysiologic concepts relevant to histologic findings are discussed.
The prevalence of nonalcoholic fatty liver disease (NAFLD) is estimated to be higher than that of other forms of liver disease, largely because it correlates with the ongoing worldwide obesity epidemic
Clinical tests, serologic studies, imaging and ultrasound methods for detecting steatosis and liver 'stiffness' are best at screening for extremes of disease, but have yet to replace liver biopsy
Evaluation of liver biopsy samples can be hampered by sampling differences and technical considerations, such as needle size and placement; pathologist expertise also has a role
The microscopic findings of NAFLD include not only the lesions of steatosis, lobular and portal inflammation and hepatocyte ballooning, but also the pattern or patterns of injury
In adults, the processes are most concentrated in the perivenular region; in children, the process may mimic that of adults, or may be concentrated in the periportal regions
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hossain, P., Kawar, B. & El Nahas, M. Obesity and diabetes in the developing world—a growing challenge. N. Engl. J. Med. 356, 213–215 (2007).
Lazo, M. & Clark, J. M. The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin. Liver Dis. 28, 339–350 (2008).
Centers for Disease Control and Prevention, National Center for Health Statistics, Obesity and Overweight [online], (2009).
World Health Organization, Obesity and Overweight, 2009 [online], (2009).
Brunt, E. M. & Tiniakos, D. G. in Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas (eds Odze, R. D. & Goldblum, J. R.) 1007–1014 (Elsevier, Philadelphia, 2009).
Argo, C. K. & Caldwell, S. H. Epidemiology and natural history of non-alcoholic steatohepatitis. Clin. Liver Dis. 13, 511–531 (2009).
McCullough, A. J. Update on nonalcoholic fatty liver disease. J. Clin. Gastroenterol. 34, 255–262 (2002).
Marra, F. & Bertolani, C. Adipokines in liver diseases. Hepatology 50, 957–969 (2009).
[No authors listed] Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 285, 2486–2497 (2001).
Marchesini, G. et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 50, 1844–1850 (2001).
Fabbrini, E. et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc. Natl Acad. Sci. USA 106, 15430–15435 (2009).
Targher, G. et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 30, 1212–1218 (2007).
Rafiq, N. et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin. Gastroenterol. Hepatol. 7, 234–238 (2009).
Gastaldelli, A. et al. Fatty liver is associated with insulin resistance, risk of coronary heart disease, and early atherosclerosis in a large European population. Hepatology 49, 1537–1544 (2009).
Kang, H. S. et al. Metabolic syndrome is associated with greater histologic severity, higher carbohydrate and lower fat diet in patients with NAFLD. Am. J. Gastroenterol. 101, 2247–2253 (2006).
Matteoni, C. A. et al. Nonalcoholic fatty liver disease: A spectrum of clinical and pathological severity. Gastroenterology 116, 1413–1419 (1999).
Adams, L. A. et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129, 113–121 (2005).
Younossi, Z. M., Gramlich, T., Matteoni, C. A., Boparai, N. & McCullough, A. J. Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clin. Gastroenterol. Hepatol. 2, 262–265 (2004).
Ekstedt, M. et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 44, 865–873 (2006).
Paradis, V. et al. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology 49, 851–859 (2009).
Guzman, G. et al. Does nonalcoholic fatty liver disease predispose patients to hepatocellular carcinoma in the absence of cirrhosis? Arch. Pathol. Lab. Med. 132, 1761–1766 (2008).
Weston, S. R. et al. Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease. Hepatology 41, 372–379 (2005).
Browning, J. D. et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40, 1387–1395 (2004).
Guerrero, R., Vega, G. L., Grundy, S. M. & Browning, J. D. Ethnic differences in hepatic steatosis: an insulin resistance paradox? Hepatology 49, 791–801 (2009).
Caldwell, S. H., Harris, D. M., Patrie, J. T. & Hespenheide, E. E. Is NASH underdiagnosed among African Americans? Am. J. Gastroenterol. 97, 1496–1500 (2002).
Giday, S. A., Shiny, Z., Naab, T., Smoot, D. & Banks, A. Frequency of nonalcoholic fatty liver disease and degree of hepatic steatosis in African-American patients. J. Natl Med. Assoc. 98, 1613–1615 (2006).
Kallwitz, E. R. et al. The histologic spectrum of liver disease in African-American, non-Hispanic white and Hispanic obesity surgery patients. Am. J. Gastroenterol. 104, 64–69 (2009).
Mohanty, S. R. et al. Influence of ethnicity on histological differences in nonalcoholic fatty liver disease. J. Hepatol. 50, 797–804 (2009).
Vos, M. B. & McClain, C. J. Nutrition and nonalcoholic fatty liver disease in children. Curr. Diab. Rep. 8, 399–406 (2008).
Wagenknecht, L. E. et al. Correlates and heritability of nonalcoholic fatty liver disease in a minority cohort. Obesity 17, 1240–1246 (2009).
Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461–1465 (2008).
Neuschwander-Tetri, B. A. Nonalcoholic steatohepatitis. Curr. Opin. Endocrinol. Diabetes 13, 119–126 (2006).
Kim, W. R., Flamm, S. L., Di Bisceglie, A. M. & Bodenheimer, H. C. Public Policy Committee of the American Association for the Study of Liver Disease Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease. Hepatology 47, 1363–1370 (2008).
Neuschwander-Tetri, B. A., Unalp, A., Creer, M. H. & NASH CRN Network. Influence of local reference populations on upper limits of normal for serum alanine aminotransferase levels. Arch. Intern. Med. 168, 663–666 (2008).
Mofrad, P. et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 37, 1286–1292 (2003).
Sorrentino, P. et al. Silent non-alcoholic fatty liver disease—a clinical-histological study. J. Hepatol. 41, 751–757 (2004).
Fracanzani, A. L. et al. Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase leves: a role for insulin resistance and diabetes. Hepatology 48, 792–798 (2008).
A-Kader, H. H., Henderson, J., Vanhoesen, K., Ghishan, F. & Bhattacharya, A. Nonalcoholic fatty liver disease in children: a single center experience. Clin. Gastroenterol. Hepatol. 6, 799–802 (2008).
Saadeh, S. & Younossi, Z. M. The spectrum of nonalcoholic fatty liver disease: from steatosis to nonalcoholic steatohepatitis. Cleve. Clin. J. Med. 67, 96–97 (2000).
Browning, J. D. New imaging techniques for non-alcoholic steatohepatitis. Clin. Liver Dis. 13, 607–619 (2009).
Fabbrini, E., Conte, C. & Magkos, F. Methods for assessing intrahepatic fat content and steatosis. Curr. Opin. Clin. Nutr. Metab. Care 12, 474–481 (2009).
Wieckowska, A. & Feldstein, A. E. Diagnosis of nonalcoholic fatty liver disease: invasive versus noninvasive. Semin. Liver Dis. 28, 386–395 (2008).
Shah, A. G. et al. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 7, 1104–1112 (2009).
Brown, K. E., Washington, K. & Brunt, E. M. in Comprehensive Clinical Hepatology (eds Bacon, B. R., O'Grady, J. G., Di Bisceglie, A. M. & Lake, J. R.) 101–121 (Elsevier Mosby, 2006).
Skelly, M. M., James, P. D. & Ryder, S. D. Findings on liver biopsy to investigate abnormal liver function tests in the absence of diagnostic serology. J. Hepatol. 35, 195–199 (2001).
Brunt, E. M. et al. Concurrence of histologic features of steatohepatitis with other forms of chronic liver disease. Mod. Pathol. 16, 49–56 (2003).
Sanyal, A. J. et al. Nonalcoholic fatty liver disease in patients with hepatitis C is associated with features of the metabolic syndrome. Am. J. Gastroenterol. 98, 2064–2071 (2003).
Koike, K. & Moriya, K. Metabolic aspects of hepatitis C viral infection: steatohepatitis resembling but distinct from NASH. J. Gastroenterol. 40, 329–336 (2005).
Milner, K.-L. et al. Chronic hepatitis C is associated with peripheral rather than hepatic insulin resistance. Gastroenterology doi:10.1053/j.gastro.2009.11.050.
Pillai, A. A. & Rinella, M. E. Nonalcoholic fatty liver disease: is bariatric surgery the answer? Clin. Liver Dis. 13, 689–710 (2009).
Teixeira, A. et al. The incapacity of the surgeon to identify NASH in bariatric surgery makes biopsy mandatory. Obes. Surg. 19, 1678–1684 (2009).
Dolce, C. J. et al. Does liver appearance predict histopathologic findings: prospective analysis of routine liver biopsies during bariatric surgery. Surg. Obes. Relat. Dis. 5, 323–328 (2009).
Dixon, J. B., Bhathal, P. S. & O'Brien, P. E. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 121, 91–100 (2001).
Campos, G. M. et al. A clinical scoring system for predicting nonalcoholic steatohepatitis in morbidly obese patients. Hepatology 47, 1916–1923 (2008).
Ratziu, V. et al. Liver fibrosis in overweight patients. Gastroenterology 118, 1117–1123 (2000).
Palekar, N. A., Naus, R., Larson, S. P., Ward, J. & Harrison, S. A. Clinical model for distinguishing nonalcoholic steatohepatitis from simple steatosis in patients with nonaloholic fatty liver disease. Liver Int. 26, 151–156 (2006).
Vizzutti, F. et al. Non-invasive assessment of fibrosis in non-alcoholic fatty liver disease. Ann. Hepatol. 8, 89–94 (2009).
Nobili, V. et al. Accuracy and reproducibility of transient elastography for the diagnosis of fibrosis in pediatric nonalcoholic steatohepatitis. Hepatology 48, 442–448 (2008).
Nobili, V. et al. Performance of ELF serum markers in predicting fibrosis stage in pediatric nonalcoholic fatty liver disease. Gastroenterology 136, 160–167 (2009).
Guha, I. N. et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology 47, 455–460 (2008).
Harrison, S. A., Oliver, D., Arnold, H. L., Gogia, S. & Neuschwander-Tetri, B. A. Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut 57, 1441–1447 (2008).
Angulo, P. et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 45, 846–854 (2007).
Pagadal, M., Zein, C. O. & McCullough, A. J. Predictors of steatohepatitis and advanced fibrosis in nonalcoholic fatty liver disease. Clin. Liver Dis. 13, 591–606 (2009).
Adams, L. A. & Angulo, P. Role of liver biopsy and serum markers of liver fibrosis in nonalcoholic fatty liver disease. Clin. Liver Dis. 11, 25–35 (2007).
Brunt, E. M., Janney, C. G., Di Bisceglie, A. M., Neuschwander-Tetri, B. A. & Bacon, B. R. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am. J. Gastroenterol. 94, 2467–2474 (1999).
Kleiner, D. E. et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41, 1313–1321 (2005).
Ratziu, V. et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 128, 1898–1906 (2005).
Merriman, R. B. et al. Histologic correlation of paired right lobe and left lobe liver biopsies in morbidly obese individuals with suspected nonalcoholic fatty liver disease. Hepatology 39, 232A (2003).
Larson, S. P. et al. Histopathologic variability between the right and left lobes of the liver in morbidly obese patients undergoing roux-en-Y bypass. Clin. Gastroenterol. Hepatol. 5, 1329–1332 (2007).
Vuppalanchi, R. et al. Effects of liver biopsy sample length and number of readings on histologic yield for nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 7, 481–486 (2009).
Rousselet, M.-C. et al. Sources of variability in histological scoring of chronic viral hepatitis. Hepatology 41, 257–264 (2005).
Colloredo, G., Guido, M., Sonzogni, A. & Leandro, G. Impact of liver biopsy size on histological evaluation of chronic viral hepatitis: the smaller the sample, the milder the disease. J. Hepatol. 39, 239–244 (2003).
Guido, M. & Rugge, M. Liver biopsy sampling in chronic viral hepatitis. Semin. Liver Dis. 24, 89–97 (2004).
Fukusato, T. et al. Interobserver variation in the histopathological assessment of nonalcoholic steatohepatitis. Hepatol. Res. 33, 122–127 (2005).
Younossi, Z. M. et al. Nonalcoholic fatty liver disease—assessment of variability in pathologic interpretations. Mod. Pathol. 11, 560–565 (1998).
Brunt, E. M. What's in a name? Hepatology 50, 663–667 (2009).
Yeh, M. et al. Acidophil body index may help diagnosing nonalcoholic steatohepatitis. Mod. Pathol. 22, 326A (2009).
Tiniakos, D. G., Vos, M. B. & Brunt, E. M. Nonalcoholic steatohepatitis: pathology and pathophysiology. Annu. Rev. Pathol. 5, 145–171 (2010).
Lackner, C. et al. Ballooned hepatocytes in steatohepatitis: The value of keratin immunohistochemistry for diagnosis. J. Hepatol. 48, 821–828 (2008).
Caldwell, S. H. et al. The ballooned hepatocyte in NAFLD: Denegerative or adaptive? J. Hepatol. 40 (Suppl. 1), 168A (2004).
Straub, B. K., Stoeffel, P., Heid, H., Zimbelmann, R. & Schirmacher, P. Differential pattern of lipid droplet-associated proteins and de novo perilipin expression in hepatocyte steatogenesis. Hepatology 47, 1936–1946 (2008).
Fuiji, H. et al. Expression of perilipin and adipophilin in nonalcoholic fatty liver disease; relevance to oxidative injury and hepatocyte ballooning. J. Atheroscler. Thromb. 16, 893–901 (2009).
Gregor, M. F. et al. Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss. Diabetes 58, 693–700 (2009).
Singh, R. et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135 (2009).
Lefkowitch, J. H., Haythe, J. & Regent, N. Kupffer cell aggregation and perivenular distribution in steatohepatitis. Mod. Pathol. 15, 699–704 (2002).
Valenti, L., Ludovica Fracanzani, A. & Fargion, S. The immunopathogenesis of alcoholic and nonalcoholic steatohepatitis: two triggers for one disease? Semin. Immunopathol. 31, 359–369 (2009).
Brunt, E. M. Alcoholic and nonalcoholic steatohepatitis. Clin. Liver Dis. 6, 399–420 (2002).
Feldstein, A. E. et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 125, 437–443 (2003).
Ribeiro, P. S. et al. Hepatocyte apoptosis, expression of death receptors, and activation of NF-kappaB in the liver of nonalcoholic and alcoholic steatohepatitis patients. Am. J. Gastroenterol. 99, 1708–1717 (2004).
Wieckowska, A. et al. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology 44, 27–33 (2006).
Bugianesi, E. et al. Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology 39, 179–187 (2004).
Fargion, S. Dysmetabolic iron overload syndrome. Hematologica 84, 97–98 (1999).
Brunt, E. M. & Clouston, A. D. in Nonalcoholic Steatohepatitis (NASH) (eds Bataller, R. & Caballeria, J.) 95–110 (Permanyer, Barcelona, 2007).
Brunt, E. M. et al. Portal chronic inflammation in nonalcoholic fatty liver disease (NAFLD): a histologic marker of advanced NAFLD-clinicopathologic correlations from the nonalcoholic steatohepatitis clinical research network. Hepatology 46, 809–820 (2009).
Jiao, J., Friedman, S. L. & Aloman, C. Hepatic fibrosis. Curr. Opin. Gastroenterol. 25, 223–229 (2009).
Richardson, M. M. et al. Progressive fibrosis in non-alcoholic steatohepatitis—altered regeneration and the ductular reaction. Gastroenterology 133, 80–90 (2007).
Syn, W.-K. et al. Hedgehog-mediated epithelial-to-mesenchymal transition and fibrogenic repair in nonalcoholic fatty liver disease. Gastroenterology 137, 1478–1488e8 (2009).
Sherman, M. Hepatocellular carcinoma: epidemiology, risk factors and screening. Semin. Liver Dis. 25, 143–154 (2005).
Bugianesi, E. et al. Expanding the natural history of non-alcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 123, 134–140 (2002).
Ratziu, V. et al. Survival, liver failure and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis. Hepatology 35, 1485–1493 (2002).
Farrell, G. C. & Larter, C. Z. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 43 (Suppl. 1), S99–S112 (2006).
Caldwell, S. H. et al. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 29, 664–669 (1999).
Poonawala, A., Nair, S. P. & Thuluvath, P. J. Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study. Hepatology 32, 689–692 (2000).
Struben, V. M., Hespenheide, E. E. & Caldwell, S. H. Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds. Am. J. Med. 108, 9–13 (2000).
Ong, J. P. et al. Cryptogenic cirrhosis and posttransplantation nonalcoholic fatty liver disease. Liver Transpl. 7, 797–801 (2001).
Abdelmalek, M., Ludwig, J. & Lindor, K. D. Two cases from the spectrum of nonalcoholic steatohepatitis. J. Clin. Gastroenterol. 20, 127–130 (1995).
Schwimmer, J. B., Pardee, P. E., Lavine, J. E., Blumkin, A. K. & Cook, S. Cardiovascular risk factors and the metabolic syndrome in pediatric nonalcoholic fatty liver disease. Circulation 118, 277–283 (2008).
Loomba, R., Sirlin, C. B., Schwimmer, J. B. & Lavine, J. E. Advances in pediatric nonalcoholic fatty liver disease. Hepatology 50, 1282–1293 (2009).
Schwimmer, J. B. et al. Prevalence of fatty liver in children and adolescents. Pediatrics 118, 1388–1393 (2006).
Pardee, P. E., Lavine, J. E. & Schwimmer, J. B. Diagnosis and treatment of pediatric nonalcoholic steatohepatitis and the implications for bariatric surgery. Semin. Pediatr. Surg. 18, 144–151 (2009).
Feldstein, A. E. et al. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut 58, 1538–1544 (2009).
Abdelmalek, M. F., Liu, C., Shuster, J., Nelson, D. R. & Asal, N. R. Familial aggregation of insulin resistance in first-degree relatives of patients with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 4, 1162–1169 (2006).
Schwimmer, J. B. et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology 42, 641–649 (2005).
Nobili, V. et al. NAFLD in children: a prospective clinical-pathological study and effect of lifestyle advice. Hepatology 44, 458–465 (2006).
Carter-Kent, C. A. et al. Nonalcoholic steatohepatitis in children: a multicenter clinicopathological study. Hepatology 48, 804A (2008).
Patton, H. M. et al. Clinical correlates of histopathology in pediatric nonalcoholic steatohepatitis. Gastroenterology 135, 1961–1971 (2008).
The author declares no competing financial interests.
About this article
Cite this article
Brunt, E. Pathology of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 7, 195–203 (2010). https://doi.org/10.1038/nrgastro.2010.21
Untargeted metabolomics as a diagnostic tool in NAFLD: discrimination of steatosis, steatohepatitis and cirrhosis
Val‐Val‐Tyr‐Pro protects against non‐alcoholic steatohepatitis in mice by modulating the gut microbiota and gut‐liver axis activation
Journal of Cellular and Molecular Medicine (2021)
Noninvasive stratification of nonalcoholic fatty liver disease by whole transcriptome cell-free mRNA characterization
American Journal of Physiology-Gastrointestinal and Liver Physiology (2021)
Berbamine induced activation of the SIRT1/LKB1/AMPK signaling axis attenuates the development of hepatic steatosis in high-fat diet-induced NAFLD rats
Food & Function (2021)
Frontiers in Endocrinology (2021)