Diagnostic Considerations and Clinical End Points for Nonalcoholic Steatohepatitis

  • Arun J. SanyalEmail author


Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease seen in clinical practice. It is associated with an increased risk of liver-, cardiac-, and cancer-related mortality. Nonalcoholic steatohepatitis (NASH) is the phenotype that typically progresses to cirrhosis and is associated with increased cardiac events. The presence of NAFLD can be suspected from elevated liver enzymes without an obvious cause or from imaging studies that demonstrate the presence of hepatic steatosis. A key question in the assessment of NAFLD is to estimate the risk of development of clinically meaningful outcomes. These include an assessment of cardiovascular risk, cancer risk, and the risk of progression to cirrhosis. Elevated ALT, multiple features of the metabolic syndrome, and histological evidence of inflammation and ballooning and some degree of fibrosis are all risk factors for progression. Those who have these features should be considered for treatment. The therapeutics for NASH include both lifestyle modification to include a healthy diet, optimizing body weight via diet and exercise, and pharmacological treatment for those with aggressive NASH. Currently, a liver biopsy is the best way to assess histological response to treatment. However, there is an intense effort to evaluate response to treatment using noninvasive measures. The best end points for those with early-stage disease are histological regression of steatohepatitis, while those with advanced disease should have a decreased risk of outcomes. This chapter summarizes the diagnostic approach to NASH and the best ways to assess outcomes of treatment for NASH.


Nonalcoholic steatohepatitis Nonalcoholic fatty liver Nonalcoholic fatty liver disease Cirrhosis Model for End-Stage Liver Disease Hepatic venous pressure gradient Quantitative liver function tests Biomarkers Type 2 diabetes mellitus Metabolic syndrome 



Nonalcoholic fatty liver disease


Nonalcoholic steatohepatitis


Nonalcoholic fatty liver


Hepatic venous pressure gradient


Model for End-Stage Liver Disease


Type 2 diabetes mellitus


Metabolic syndrome


Food and Drug Administration


American Association for the Study of Liver Disease


Grant Support

This work was supported in part by a grant from the National Institutes of Health to Dr. Sanyal DK 81410 and T32 DK007150.

Conflicts of Interest

Dr. Sanyal serves as a consultant to Abbvie, Bristol Myers-Squibb, Genfit, Exhalenz, Islet Pharmaceuticals, Nimbus, Nitto-Denko, and Tobira. His institution receives research funding from Gilead, Galectin, Novartis, Salix, Cumberland, and Intercept Pharmaceuticals. He has also served as a non-remunerated consultant to Immuron and Echosens.


  1. 1.
    Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol. 2013;10:686–90.CrossRefPubMedGoogle Scholar
  2. 2.
    Ahmed MH, Abu EO, Byrne CD. Non-Alcoholic Fatty Liver Disease (NAFLD): new challenge for general practitioners and important burden for health authorities? Prim Care Diabetes. 2010;4:129–37.CrossRefPubMedGoogle Scholar
  3. 3.
    Neuschwander-Tetri BA, Clark JM, Bass NM, Van Natta ML, Unalp-Arida A, Tonascia J, Zein CO, et al. Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology. 2010;52:913–24.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40:1387–95.CrossRefPubMedGoogle Scholar
  5. 5.
    Patton HM, Sirlin C, Behling C, Middleton M, Schwimmer JB, Lavine JE. Pediatric nonalcoholic fatty liver disease: a critical appraisal of current data and implications for future research. J Pediatr Gastroenterol Nutr. 2006;43:413–27.CrossRefPubMedGoogle Scholar
  6. 6.
    Denzer C, Thiere D, Muche R, Koenig W, Mayer H, Kratzer W, Wabitsch M. Gender-specific prevalences of fatty liver in obese children and adolescents: roles of body fat distribution, sex steroids, and insulin resistance. J Clin Endocrinol Metab. 2009;94:3872–81.CrossRefPubMedGoogle Scholar
  7. 7.
    Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology. 1990;12:1106–10.CrossRefPubMedGoogle Scholar
  8. 8.
    Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129:113–21.CrossRefPubMedGoogle Scholar
  9. 9.
    Rafiq N, Bai C, Fang Y, Srishord M, McCullough A, Gramlich T, Younossi ZM. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol. 2009;7:234–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Treeprasertsuk S, Leverage S, Adams LA, Lindor KD, St Sauver J, Angulo P. The Framingham risk score and heart disease in nonalcoholic fatty liver disease. Liver Int. 2012;32:945–50.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Adams LA, Harmsen S, St Sauver JL, Charatcharoenwitthaya P, Enders FB, Therneau T, Angulo P. Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: a community-based cohort study. Am J Gastroenterol. 2010;105:1567–73.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Koebnick C, Getahun D, Reynolds K, Coleman KJ, Porter AH, Lawrence JM, Punyanitya M, et al. Trends in nonalcoholic fatty liver disease-related hospitalizations in US children, adolescents, and young adults. J Pediatr Gastroenterol Nutr. 2009;48:597–603.CrossRefPubMedGoogle Scholar
  13. 13.
    Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology. 2011;141:1249–53.CrossRefPubMedGoogle Scholar
  14. 14.
    Stewart K, Haller D, Sargeant C, Levenson J, Puri P, Sanyal AJ. Readiness for behavior change in non-alcoholic fatty liver disease: implications for multidisciplinary care models. Liver Int. 2015;35(3):936–43.CrossRefPubMedGoogle Scholar
  15. 15.
    Ramesh S, Sanyal AJ. Evaluation and management of non-alcoholic steatohepatitis. J Hepatol. 2005;42(Suppl):S2–12.CrossRefPubMedGoogle Scholar
  16. 16.
    Caldwell SH, Hespenheide EE. Subacute liver failure in obese women. Am J Gastroenterol. 2002;97:2058–62.CrossRefPubMedGoogle Scholar
  17. 17.
    Berrut C, Curati W, de Gautard R, Widmann JJ, Godin N, Loizeau E. The role of ultrasonography in the diagnosis of diffuse liver disease. Schweiz Med Wochenschr. 1986;116:215–8.PubMedGoogle Scholar
  18. 18.
    Mishra P, Younossi ZM. Abdominal ultrasound for diagnosis of nonalcoholic fatty liver disease (NAFLD). Am J Gastroenterol. 2007;102:2716–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Estep JM, Birerdinc A, Younossi Z. Non-invasive diagnostic tests for non-alcoholic fatty liver disease. Curr Mol Med. 2010;10:166–72.CrossRefPubMedGoogle Scholar
  20. 20.
    Yajima Y, Narui T, Ishii M, Abe R, Ohtsuki M, Goto Y, Endo S, et al. Computed tomography in the diagnosis of fatty liver: total lipid content and computed tomography number. Tohoku J Exp Med. 1982;136:337–42.CrossRefPubMedGoogle Scholar
  21. 21.
    Saadeh S, Younossi ZM, Remer EM, Gramlich T, Ong JP, Hurley M, Mullen KD, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology. 2002;123:745–50.CrossRefPubMedGoogle Scholar
  22. 22.
    Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S, Hobbs HH, et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab. 2005;288:E462–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Tang A, Desai A, Hamilton G, Wolfson T, Gamst A, Lam J, Clark L, et al. Accuracy of MR Imaging-estimated Proton Density Fat Fraction for Classification of Dichotomized Histologic Steatosis Grades in Nonalcoholic Fatty Liver Disease. Radiology. 2015;274:416–25.CrossRefPubMedGoogle Scholar
  24. 24.
    Shah AG, Lydecker A, Murray K, Tetri BN, Contos MJ, Sanyal AJ. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2009;7:1104–12.PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, Enders F, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:846–54.CrossRefPubMedGoogle Scholar
  26. 26.
    Kim D, Kim WR, Kim HJ, Therneau TM. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology. 2013;57:1357–65.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Crespo G, Fernandez-Varo G, Marino Z, Casals G, Miquel R, Martinez SM, Gilabert R, et al. ARFI, FibroScan, ELF, and their combinations in the assessment of liver fibrosis: a prospective study. J Hepatol. 2012;57:281–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Castera L. Use of elastometry (FibroScan) for the non-invasive staging of liver fibrosis. Gastroenterol Clin Biol. 2007;31:524–30. quiz 500, 531–22.CrossRefPubMedGoogle Scholar
  29. 29.
    Sanchez-Conde M, Miralles P, Bellon JM, Rincon D, Ramirez M, Gutierrez I, Ripoll C, et al. Use of transient elastography (FibroScan(R)) for the noninvasive assessment of portal hypertension in HIV/HCV-coinfected patients. J Viral Hepat. 2011;18:685–91.CrossRefPubMedGoogle Scholar
  30. 30.
    de Ledinghen V, Vergniol J, Foucher J, Merrouche W, le Bail B. Non-invasive diagnosis of liver steatosis using controlled attenuation parameter (CAP) and transient elastography. Liver Int. 2012;32:911–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Brunt EM, Kleiner D, Wilson L, Belt P, Neuschwander-Tetri BL, NASH CRN. The NAS and the histopathologic diagnosis of NASH: distinct clinicopathologic meanings. Hepatology. 2011;53(3):810-20.Google Scholar
  32. 32.
    Younossi ZM, Stepanova M, Rafiq N, Makhlouf H, Younoszai Z, Agrawal R, Goodman Z. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology. 2011;53:1874–82.CrossRefPubMedGoogle Scholar
  33. 33.
    Kistler KD, Molleston J, Unalp A, Abrams SH, Behling C, Schwimmer JB. Symptoms and quality of life in obese children and adolescents with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2010;31:396–406.PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    David K, Kowdley KV, Unalp A, Kanwal F, Brunt EM, Schwimmer JB. Quality of life in adults with nonalcoholic fatty liver disease: baseline data from the nonalcoholic steatohepatitis clinical research network. Hepatology. 2009;49:1904–12.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Dan AA, Kallman JB, Wheeler A, Younoszai Z, Collantes R, Bondini S, Gerber L, et al. Health-related quality of life in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2007;26:815–20.CrossRefPubMedGoogle Scholar
  36. 36.
    Elwing JE, Lustman PJ, Wang HL, Clouse RE. Depression, anxiety, and nonalcoholic steatohepatitis. Psychosom Med. 2006;68:563–9.CrossRefPubMedGoogle Scholar
  37. 37.
    Bajaj JS, Wade JB, Gibson DP, Heuman DM, Thacker LR, Sterling RK, Stravitz RT, et al. The multi-dimensional burden of cirrhosis and hepatic encephalopathy on patients and caregivers. Am J Gastroenterol. 2011;106:1646–53.PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Loria A, Escheik C, Gerber NL, Younossi ZM. Quality of life in cirrhosis. Curr Gastroenterol Rep. 2013;15:301.CrossRefPubMedGoogle Scholar
  39. 39.
    Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, Kechagias S. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44:865–73.CrossRefPubMedGoogle Scholar
  40. 40.
    Bhala N, Angulo P, van der Poorten D, Lee E, Hui JM, Saracco G, Adams LA, et al. The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study. Hepatology. 2011;54:1208–16.PubMedCentralCrossRefPubMedGoogle Scholar
  41. 41.
    Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–9.CrossRefPubMedGoogle Scholar
  42. 42.
    Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;51:1972–8.CrossRefPubMedGoogle Scholar
  43. 43.
    Sanyal AJ, Banas C, Sargeant C, Luketic VA, Sterling RK, Stravitz RT, Shiffman ML, et al. Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology. 2006;43:682–9.CrossRefPubMedGoogle Scholar
  44. 44.
    Gines P, Quintero E, Arroyo V, Teres J, Bruguera M, Rimola A, Caballeria J, et al. Compensated cirrhosis: natural history and prognostic factors. Hepatology. 1987;7:122–8.CrossRefPubMedGoogle Scholar
  45. 45.
    D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44:217–31.CrossRefPubMedGoogle Scholar
  46. 46.
    Child CG, Turcotte J. The liver and portal hypertension. In: Child CG, editor. Surgery and portal hypertension. Philadelphia: Saunders; 1964. p. 50–8.Google Scholar
  47. 47.
    Durand F, Valla D. Assessment of prognosis of cirrhosis. Semin Liver Dis. 2008;28:110–22.CrossRefPubMedGoogle Scholar
  48. 48.
    Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM, Kosberg CL, D’Amico G, et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;33:464–70.CrossRefPubMedGoogle Scholar
  49. 49.
    Wiesner R, Edwards E, Freeman R, Harper A, Kim R, Kamath P, Kremers W, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology. 2003;124:91–6.CrossRefPubMedGoogle Scholar
  50. 50.
    Merion RM. When is a patient too well and when is a patient too sick for a liver transplant? Liver Transpl. 2004;10:S69–73.CrossRefPubMedGoogle Scholar
  51. 51.
    Habib S, Berk B, Chang CC, Demetris AJ, Fontes P, Dvorchik I, Eghtesad B, et al. MELD and prediction of post-liver transplantation survival. Liver Transpl. 2006;12:440–7.CrossRefPubMedGoogle Scholar
  52. 52.
    Atterbury CE, Groszmann RJ. Portal venous pressure measurement and its clinical significance. Lab Res Methods Biol Med. 1983;7:567–85.PubMedGoogle Scholar
  53. 53.
    Zipprich A, Garcia-Tsao G, Rogowski S, Fleig WE, Seufferlein T, Dollinger MM. Prognostic indicators of survival in patients with compensated and decompensated cirrhosis. Liver Int. 2012;32:1407–14.PubMedCentralCrossRefPubMedGoogle Scholar
  54. 54.
    Groszmann RJ, Wongcharatrawee S. The hepatic venous pressure gradient: anything worth doing should be done right. Hepatology. 2004;39:280–2.CrossRefPubMedGoogle Scholar
  55. 55.
    Ripoll C, Groszmann R, Garcia-Tsao G, Grace N, Burroughs A, Planas R, Escorsell A, et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology. 2007;133:481–8.CrossRefPubMedGoogle Scholar
  56. 56.
    Ripoll C, Banares R, Rincon D, Catalina MV, Lo Iacono O, Salcedo M, Clemente G, et al. Influence of hepatic venous pressure gradient on the prediction of survival of patients with cirrhosis in the MELD Era. Hepatology. 2005;42:793–801.CrossRefPubMedGoogle Scholar
  57. 57.
    Everson GT, Shiffman ML, Hoefs JC, Morgan TR, Sterling RK, Wagner DA, Lauriski S, et al. Quantitative liver function tests improve the prediction of clinical outcomes in chronic hepatitis C: results from the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis Trial. Hepatology. 2012;55:1019–29.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Division of Gastroenterology, Hepatology and Nutrition, Department of Internal MedicineVirginia Commonwealth University School of MedicineRichmondUSA

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