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Diagnosis of metabolic dysfunction-associated steatohepatitis (MASH) - Review, Part 1

Hans-Holger Bleß / Dr. rer. nat. Ines Witte

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is a growing healthcare challenge, closely linked to metabolic syndrome. It manifests in a range of forms, from simple steatosis to steatohepatitis (MASH), fibrosis, and cirrhosis. The revised nomenclature better reflects the role of metabolic disorders. The pathophysiology is complex, characterized by metabolic risk factors, lipotoxicity, and inflammatory processes. Advances in research emphasize the importance of mitochondrial function and immune responses. Noninvasive diagnostic methods are prioritized to minimize risks and costs. Imaging techniques and serum-based scores support the assessment of fibrosis stages. Treatment focuses on lifestyle changes, particularly weight reduction and physical activity. Pharmacological interventions are still being investigated, with promising approaches in clinical trials. The high prevalence of MASLD in diabetes patients and its association with severe complications underscore the urgency of effective diagnostic and treatment strategies. Future research and innovative therapies are crucial to improving the prognosis for those affected and reducing the burden of disease.

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First publication date: 02.04.2024
Hans-Holger BleßHans-Holger BleßDr. rer. nat. Ines WitteDr. rer. nat. Ines Witte

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http://doi.org/10.24945/MVF.02.24.1866-0533.2597

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Abstract: Diagnostik der Metabolischen Dysfunktion-assoziierten Steatohepatitis (MASH) - Übersichtsarbeit, Teil 1

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is a growing healthcare challenge, closely linked to metabolic syndrome. It manifests in a range of forms, from simple steatosis to steatohepatitis (MASH), fibrosis, and cirrhosis. The revised nomenclature better reflects the role of metabolic disorders. The pathophysiology is complex, characterized by metabolic risk factors, lipotoxicity, and inflammatory processes. Advances in research emphasize the importance of mitochondrial function and immune responses. Noninvasive diagnostic methods are prioritized to minimize risks and costs. Imaging techniques and serum-based scores support the assessment of fibrosis stages. Treatment focuses on lifestyle changes, particularly weight reduction and physical activity. Pharmacological interventions are still being investigated, with promising approaches in clinical trials. The high prevalence of MASLD in diabetes patients and its association with severe complications underscore the urgency of effective diagnostic and treatment strategies. Future research and innovative therapies are crucial to improving the prognosis for those affected and reducing the burden of disease.

Abstract: Diagnosis of metabolic dysfunction-associated steatohepatitis (MASH) – a Review, Part 1

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a growing public health challenge closely associated with metabolic syndrome. It manifests itself from simple steatosis to steatohepatitis (MASH), fibrosis and cirrhosis. The revised nomenclature better reflects the role of metabolic disorders. The pathophysiology is complex, characterized by metabolic risk factors, lipotoxicity and inflammatory processes. Advances in research emphasizes the importance of mitochondrial functions and immune responses. In diagnostics, non-invasive methods have priority in order to minimize risks and costs. Imaging techniques and serum-based scores support the assessment of fibrosis stages. Treatment focuses on lifestyle changes, especially weight reduction and physical activity. Pharmacological interventions are still under investigation, with promising approaches in clinical trials. The high prevalence of MASLD in diabetic patients and its association with severe complications emphasizes the urgency of effective diagnostic and treatment strategies. Future research and innovative therapies are crucial to improve the prognosis for affected individuals and reduce the burden of disease.

Keywords (German)

Treatment, Diagnosis, fatty liver, Fibrosis staging, Steatohepatitis

Keywords (English)

diagnostics, Fatty liver, Fibrosis staging, Fibrosis treatment, Steatohepatitis

Literature

1. Weiß J, Rau M, Geier A. Non-alcoholic fatty liver disease: epidemiology, clinical course, investigation, and treatment. Dtsch Arztebl Int 2014; 111(26):447–52. doi: 10.3238/arztebl.2014.0447. 2. Roeb E, Canbay A, Bantel H, Bojunga J, Laffolie J de, Demir M et al. Updated S2k guideline for non-alcoholic fatty liver disease of the German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS) – April 2022 – AWMF registry number: 021–025. Z Gastroenterol 2022; 60(9):1346–421. doi: 10.1055/a-1880-2283. 3. Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol 2023; 79(6):1542–56. doi: 10.1016/j.jhep.2023.06.003. 4. Israelsen M, Torp N, Johansen S, Thiele M, Krag A. MetALD: new opportunities to understand the role of alcohol in steatotic liver disease. Lancet Gastroenterol Hepatol 2023; 8(10):866–8. doi: 10.1016/S2468-1253(23)00206-6. 5. Åberg F, Byrne CD, Pirola CJ, Männistö V, Sookoian S. Alcohol consumption and metabolic syndrome: Clinical and epidemiological impact on liver disease. J Hepatol 2023; 78(1):191–206. doi: 10.1016/j.jhep.2022.08.030. 6. Lee BP, Dodge JL, Terrault NA. National prevalence estimates for steatotic liver disease and subclassifications using consensus nomenclature. Hepatology 2023. doi: 10.1097/HEP.0000000000000604. 7. Hagström H, Vessby J, Ekstedt M, Shang Y. 99% of patients with NAFLD meet MASLD criteria and natural history is therefore identical. J Hepatol 2023. doi: 10.1016/j.jhep.2023.08.026. 8. Li M, Zhang W, Li X, Liang S, Zhang Y, Mo Y et al. Metabolic and Risk Profiles of Lean and Non-Lean Hepatic Steatosis among US Adults. Nutrients 2023; 15(13). doi: 10.3390/nu15132856. 9. Sookoian S, Pirola CJ. Systematic review with meta-analysis: risk factors for non-alcoholic fatty liver disease suggest a shared altered metabolic and cardiovascular profile between lean and obese patients. Aliment Pharmacol Ther 2017; 46(2):85–95. doi: 10.1111/apt.14112. 10. Arrese M, Cabrera D, Kalergis AM, Feldstein AE. Innate Immunity and Inflammation in NAFLD/NASH. Dig Dis Sci 2016; 61(5):1294–303. doi: 10.1007/s10620-016-4049-x. 11. Day CP, James OF. Steatohepatitis: a tale of two hits? Gastroenterology 1998; 114(4):842–5. doi: 10.1016/s0016-5085(98)70599-2. 12. Mehta R, Jeiran K, Koenig AB, Otgonsuren M, Goodman Z, Baranova A et al. The role of mitochondrial genomics in patients with non-alcoholic steatohepatitis (NASH). BMC Med Genet 2016; 17(1):63. doi: 10.1186/s12881-016-0324-0. 13. Chow MD, Lee YH, Guo GL. The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Mol Aspects Med 2017; 56:34-44. doi: 10.1016/j.mam.2017.04.004. 14. Tilg H, Adolph TE, Moschen AR. Multiple Parallel Hits Hypothesis in Nonalcoholic Fatty Liver Disease: Revisited After a Decade. Hepatology 2021; 73(2):833–42. doi: 10.1002/hep.31518. 15. Bedossa P, Poitou C, Veyrie N, Bouillot JL, Basdevant A, Paradis V et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology 2012; 56(5):1751–9. doi: 10.1002/hep.25889. 16. Kleiner DE, Brunt EM, van Natta M, Behling C, Contos MJ, Cummings OW et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41(6):1313–21. doi: 10.1002/hep.20701. 17. Bellentani S. The epidemiology of non-alcoholic fatty liver disease. Liver Int 2017; 37 Suppl 1:81–4. doi: 10.1111/liv.13299. 18. Bataller R, Rombouts K, Altamirano J, Marra F. Fibrosis in alcoholic and nonalcoholic steatohepatitis. Best Pract Res Clin Gastroenterol 2011; 25(2):231–44. doi: 10.1016/j.bpg.2011.02.010. 19. Burra P, Becchetti C, Germani G. NAFLD and liver transplantation: Disease burden, current management and future challenges. JHEP Rep 2020; 2(6):100192. doi: 10.1016/j.jhepr.2020.100192. 20. Fuchs A, Janssens U, Mayet WJ, Mertens P, Müller OA, Pfeifer M et al., eds. Rational diagnostics and therapy in internal medicine: Chapter 7.3: Non-alcoholic fatty liver disease (NAFLD). Munich: Elsevier GmbH; 2022. 21. Fuchs A, Janssens U, Mayet WJ, Mertens P, Müller OA, Pfeifer M et al., eds. Rational diagnostics and therapy in internal medicine: Chapter 7.2: Alcoholic liver diseases. Munich: Elsevier GmbH; 2022. 22. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994; 19(6):1513–20. 23. Ishak K, Baptista A, Bianchi L, Callea F, Groote J de, Gudat F et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22(6):696–9. doi: 10.1016/0168-8278(95)80226-6. 24. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 1996; 24(2):289–93. doi: 10.1002/hep.510240201. 25. Younossi ZM, Golabi P, Avila L de, Paik JM, Srishord M, Fukui N et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. J Hepatol 2019; 71(4):793–801. doi: 10.1016/j.jhep.2019.06.021. 26. Castera L, Laouenan C, Vallet-Pichard A, Vidal-Trécan T, Manchon P, Paradis V et al. High Prevalence of NASH and Advanced Fibrosis in Type 2 Diabetes: A Prospective Study of 330 Outpatients Undergoing Liver Biopsies for Elevated ALT, Using a Low Threshold. Diabetes Care 2023; 46(7):1354–62. doi: 10.2337/dc22-2048. 27. Castera L, Laouenan C, Vallet-Pichard A, Vidal-Trécan T, Manchon P, Paradis V et al. High Prevalence of NASH and Advanced Fibrosis in Type 2 Diabetes: A Prospective Study of 330 Outpatients Undergoing Liver Biopsies for Elevated ALT, Using a Low Threshold. Diabetes Care 2023; 46(7):1354–62. doi: 10.2337/dc22-2048. 28. Harrison SA, Ratziu V, Anstee QM, Noureddin M, Sanyal AJ, Schattenberg JM et al. Design of the phase 3 MAESTRO clinical program to evaluate resmetirom for the treatment of nonalcoholic steatohepatitis. Aliment Pharmacol Ther 2024; 59(1):51–63. doi: 10.1111/apt.17734. 29. Demir M, Lang S, Nierhoff D, Drebber U, Hardt A, Wedemeyer I et al. Stepwise combination of simple noninvasive fibrosis scoring systems increases diagnostic accuracy in nonalcoholic fatty liver disease. J Clin Gastroenterol 2013; 47(8):719–26. doi: 10.1097/MCG.0b013e3182819a89. 30. Petta S, Wong VW-S, Cammà C, Hiriart JB, Wong GL-H, Vergniol J et al. Serial combination of non-invasive tools improves the diagnostic accuracy of severe liver fibrosis in patients with NAFLD. Aliment Pharmacol Ther 2017; 46(6):617–27. doi: 10.1111/apt.14219. 31. Boursier J, Vergniol J, Guillet A, Hiriart JB, Lannes A, Le Bail B et al. Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by FibroScan in non-alcoholic fatty liver disease. J Hepatol 2016; 65(3):570–8. doi: 10.1016/j.jhep.2016.04.023. 32. Labenz C, Huber Y, Kalliga E, Nagel M, Ruckes C, Straub BK et al. Predictors of advanced fibrosis in non-cirrhotic non-alcoholic fatty liver disease in Germany. Aliment Pharmacol Ther 2018; 48(10):1109–16. doi: 10.1111/apt.14976. 33. Wong VW-S, Vergniol J, Wong GL-H, Foucher J, Chan HL-Y, Le Bail B et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology 2010; 51(2):454–62. doi: 10.1002/hep.23312. 1. Weiß J, Rau M, Geier A. Non-alcoholic fatty liver disease: epidemiology, clinical course, investigation, and treatment. Dtsch Ärztebl Int 2014; 111(26):447–52. doi: 10.3238/arztebl.2014.0447. 2. Roeb E, Canbay A, Bantel H, Bojunga J, Laffoil J de, Demir M et al. Updated S2k guideline for non-alcoholic fatty liver disease of the German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS) – April 2022 – AWMF registry number: 021–025. Z Gastroenterol 2022; 60(9):1346–421. doi: 10.1055/a-1880-2283. 3. Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol 2023; 79(6):1542–56. doi: 10.1016/j.jhep.2023.06.003. 4. Israelsen M, Torp N, Johansen S, Thiele M, Krag A. MetALD: new opportunities to understand the role of alcohol in steatotic liver disease. Lancet Gastroenterol Hepatol 2023; 8(10):866–8. doi: 10.1016/S2468-1253(23)00206-6. 5. Åberg F, Byrne CD, Pirola CJ, Männistö V, Sookoian S. Alcohol consumption and metabolic syndrome: Clinical and epidemiological impact on liver disease. J Hepatol 2023; 78(1):191–206. doi: 10.1016/j.jhep.2022.08.030. 6. Lee BP, Dodge JL, Terrault NA. National prevalence estimates for steatotic liver disease and subclassifications using consensus nomenclature. Hepatology 2023. doi: 10.1097/HEP.0000000000000604. 7. Hagström H, Vessby J, Ekstedt M, Shang Y. 99% of patients with NAFLD meet MASLD criteria and natural history is therefore identical. J Hepatol 2023. doi: 10.1016/j.jhep.2023.08.026. 8. Li M, Zhang W, Li X, Liang S, Zhang Y, Mo Y et al. Metabolic and Risk Profiles of Lean and Non-Lean Hepatic Steatosis among US Adults. Nutrients 2023; 15(13). doi: 10.3390/nu15132856. 9. Sookoian S, Pirola CJ. Systematic review with meta-analysis: risk factors for non-alcoholic fatty liver disease suggest a shared altered metabolic and cardiovascular profile between lean and obese patients. Aliment Pharmacol Ther 2017; 46(2):85–95. doi: 10.1111/apt.14112. 10. Arrese M, Cabrera D, Kalergis AM, Feldstein AE. Innate Immunity and Inflammation in NAFLD/NASH. Dig Dis Sci 2016; 61(5):1294–303. doi: 10.1007/s10620-016-4049-x. 11. Day CP, James OF. Steatohepatitis: a tale of two hits? Gastroenterology 1998; 114(4):842–5. doi: 10.1016/s0016-5085(98)70599-2. 12. Mehta R, Jeiran K, Koenig AB, Otgonsuren M, Goodman Z, Baranova A et al. The role of mitochondrial genomics in patients with non-alcoholic steatohepatitis (NASH). BMC Med Genet 2016; 17(1):63. doi: 10.1186/s12881-016-0324-0. 13. Chow MD, Lee YH, Guo GL. The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Mol Aspects Med 2017; 56:34-44. doi: 10.1016/j.mam.2017.04.004. 14. Tilg H, Adolph TE, Moschen AR. Multiple Parallel Hits Hypothesis in Nonalcoholic Fatty Liver Disease: Revisited After a Decade. Hepatology 2021; 73(2):833–42. doi: 10.1002/hep.31518. 15. Bedossa P, Poitou C, Veyrie N, Bouillot JL, Basdevant A, Paradis V et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology 2012; 56(5):1751–9. doi: 10.1002/hep.25889. 16. Kleiner DE, Brunt EM, van Natta M, Behling C, Contos MJ, Cummings OW et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41(6):1313–21. doi: 10.1002/hep.20701. 17. Bellentani S. The epidemiology of non-alcoholic fatty liver disease. Liver Int 2017; 37 Suppl 1:81–4. doi: 10.1111/liv.13299. 18. Bataller R, Rombouts K, Altamirano J, Marra F. Fibrosis in alcoholic and nonalcoholic steatohepatitis. Best Pract Res Clin Gastroenterol 2011; 25(2):231–44. doi: 10.1016/j.bpg.2011.02.010. 19. Burra P, Becchetti C, Germani G. NAFLD and liver transplantation: Disease burden, current management and future challenges. JHEP Rep 2020; 2(6):100192. doi: 10.1016/j.jhepr.2020.100192. 20. Fuchs A, Janssens U, Mayet WJ, Mertens P, Müller OA, Pfeifer M et al., eds. Rational diagnostics and therapy in internal medicine: Chapter 7.3: Non-alcoholic fatty liver disease (NAFLD). Munich: Elsevier GmbH; 2022. 21. Fuchs A, Janssens U, Mayet WJ, Mertens P, Müller OA, Pfeifer M et al., eds. Rational diagnostics and therapy in internal medicine: Chapter 7.2: Alcoholic liver diseases. Munich: Elsevier GmbH; 2022. 22. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994; 19(6):1513–20. 23. Ishak K, Baptista A, Bianchi L, Callea F, Groote J de, Gudat F et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22(6):696–9. doi: 10.1016/0168-8278(95)80226-6. 24. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 1996; 24(2):289–93. doi: 10.1002/hep.510240201. 25. Younossi ZM, Golabi P, Avila L de, Paik JM, Srishord M, Fukui N et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. J Hepatol 2019; 71(4):793–801. doi: 10.1016/j.jhep.2019.06.021. 26. Castera L, Laouenan C, Vallet-Pichard A, Vidal-Trécan T, Manchon P, Paradis V et al. High Prevalence of NASH and Advanced Fibrosis in Type 2 Diabetes: A Prospective Study of 330 Outpatients Undergoing Liver Biopsies for Elevated ALT, Using a Low Threshold. Diabetes Care 2023; 46(7):1354–62. doi: 10.2337/dc22-2048. 27. Castera L, Laouenan C, Vallet-Pichard A, Vidal-Trécan T, Manchon P, Paradis V et al. High Prevalence of NASH and Advanced Fibrosis in Type 2 Diabetes: A Prospective Study of 330 Outpatients Undergoing Liver Biopsies for Elevated ALT, Using a Low Threshold. Diabetes Care 2023; 46(7):1354–62. doi: 10.2337/dc22-2048. 28. Harrison SA, Ratziu V, Anstee QM, Noureddin M, Sanyal AJ, Schattenberg JM et al. Design of the phase 3 MAESTRO clinical program to evaluate resmetirom for the treatment of nonalcoholic steatohepatitis. Aliment Pharmacol Ther 2024; 59(1):51–63. doi: 10.1111/apt.17734. 29. Demir M, Lang S, Nierhoff D, Drebber U, Hardt A, Wedemeyer I et al. Stepwise combination of simple noninvasive fibrosis scoring systems increases diagnostic accuracy in nonalcoholic fatty liver disease. J Clin Gastroenterol 2013; 47(8):719–26. doi: 10.1097/MCG.0b013e3182819a89. 30. Petta S, Wong VW-S, Cammà C, Hiriart JB, Wong GL-H, Vergniol J et al. Serial combination of non-invasive tools improves the diagnostic accuracy of severe liver fibrosis in patients with NAFLD. Aliment Pharmacol Ther 2017; 46(6):617–27. doi: 10.1111/apt.14219. 31. Boursier J, Vergniol J, Guillet A, Hiriart JB, Lannes A, Le Bail B et al. Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by FibroScan in non-alcoholic fatty liver disease. J Hepatol 2016; 65(3):570–8. doi: 10.1016/j.jhep.2016.04.023. 32. Labenz C, Huber Y, Kalliga E, Nagel M, Ruckes C, Straub BK et al. Predictors of advanced fibrosis in non-cirrhotic non-alcoholic fatty liver disease in Germany. Aliment Pharmacol Ther 2018; 48(10):1109–16. doi: 10.1111/apt.14976. 33. Wong VW-S, Vergniol J, Wong GL-H, Foucher J, Chan HL-Y, Le Bail B et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology 2010; 51(2):454–62. doi: 10.1002/hep.23312. 1. Weiß J, Rau M, Geier A. Non-alcoholic fatty liver disease: epidemiology, clinical course, investigation, and treatment. Dtsch Ärztebl Int 2014; 111(26):447–52. doi: 10.3238/arztebl.2014.0447. 2. Roeb E, Canbay A, Bantel H, Bojunga J, Laffolie J de, Demir M et al. Updated S2k guideline for non-alcoholic fatty liver disease of the German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS) – April 2022 – AWMF registry number: 021–025. Z Gastroenterol 2022; 60(9):1346–421. doi: 10.1055/a-1880-2283. 3. Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol 2023; 79(6):1542–56. doi: 10.1016/j.jhep.2023.06.003. 4. Israelsen M, Torp N, Johansen S, Thiele M, Krag A. MetALD: new opportunities to understand the role of alcohol in steatotic liver disease. Lancet Gastroenterol Hepatol 2023; 8(10):866–8. doi: 10.1016/S2468-1253(23)00206-6. 5. Åberg F, Byrne CD, Pirola CJ, Männistö V, Sookoian S. Alcohol consumption and metabolic syndrome: Clinical and epidemiological impact on liver disease. J Hepatol 2023; 78(1):191–206. doi: 10.1016/j.jhep.2022.08.030. 6. Lee BP, Dodge JL, Terrault NA. National prevalence estimates for steatotic liver disease and subclassifications using consensus nomenclature. Hepatology 2023. doi: 10.1097/HEP.0000000000000604. 7. Hagström H, Vessby J, Ekstedt M, Shang Y. 99% of patients with NAFLD meet MASLD criteria and natural history is therefore identical. J Hepatol 2023. doi: 10.1016/j.jhep.2023.08.026. 8. Li M, Zhang W, Li X, Liang S, Zhang Y, Mo Y et al. Metabolic and Risk Profiles of Lean and Non-Lean Hepatic Steatosis among US Adults. Nutrients 2023; 15(13). doi: 10.3390/nu15132856. 9. Sookoian S, Pirola CJ. Systematic review with meta-analysis: risk factors for non-alcoholic fatty liver disease suggest a shared altered metabolic and cardiovascular profile between lean and obese patients. Aliment Pharmacol Ther 2017; 46(2):85–95. doi: 10.1111/apt.14112. 10. Arrese M, Cabrera D, Kalergis AM, Feldstein AE. Innate Immunity and Inflammation in NAFLD/NASH. Dig Dis Sci 2016; 61(5):1294–303. doi: 10.1007/s10620-016-4049-x. 11. Day CP, James OF. Steatohepatitis: a tale of two hits? Gastroenterology 1998; 114(4):842–5. doi: 10.1016/s0016-5085(98)70599-2. 12. Mehta R, Jeiran K, Koenig AB, Otgonsuren M, Goodman Z, Baranova A et al. The role of mitochondrial genomics in patients with non-alcoholic steatohepatitis (NASH). BMC Med Genet 2016; 17(1):63. doi: 10.1186/s12881-016-0324-0. 13. Chow MD, Lee YH, Guo GL. The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Mol Aspects Med 2017; 56:34-44. doi: 10.1016/j.mam.2017.04.004. 14. Tilg H, Adolph TE, Moschen AR. Multiple Parallel Hits Hypothesis in Nonalcoholic Fatty Liver Disease: Revisited After a Decade. Hepatology 2021; 73(2):833–42. doi: 10.1002/hep.31518. 15. Bedossa P, Poitou C, Veyrie N, Bouillot JL, Basdevant A, Paradis V et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology 2012; 56(5):1751–9. doi: 10.1002/hep.25889. 16. Kleiner DE, Brunt EM, van Natta M, Behling C, Contos MJ, Cummings OW et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41(6):1313–21. doi: 10.1002/hep.20701. 17. Bellentani S. The epidemiology of non-alcoholic fatty liver disease. Liver Int 2017; 37 Suppl 1:81–4. doi: 10.1111/liv.13299. 18. Bataller R, Rombouts K, Altamirano J, Marra F. Fibrosis in alcoholic and nonalcoholic steatohepatitis. Best Pract Res Clin Gastroenterol 2011; 25(2):231–44. doi: 10.1016/j.bpg.2011.02.010. 19. Burra P, Becchetti C, Germani G. NAFLD and liver transplantation: Disease burden, current management and future challenges. JHEP Rep 2020; 2(6):100192. doi: 10.1016/j.jhepr.2020.100192. 20. Fuchs A, Janssens U, Mayet WJ, Mertens P, Müller OA, Pfeifer M et al., eds. Rational diagnostics and therapy in internal medicine: Chapter 7.3: Non-alcoholic fatty liver disease (NAFLD). Munich: Elsevier GmbH; 2022. 21. Fuchs A, Janssens U, Mayet WJ, Mertens P, Müller OA, Pfeifer M et al., eds. Rational diagnostics and therapy in internal medicine: Chapter 7.2: Alcoholic liver diseases. Munich: Elsevier GmbH; 2022. 22. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994; 19(6):1513–20. 23. Ishak K, Baptista A, Bianchi L, Callea F, Groote J de, Gudat F et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22(6):696–9. doi: 10.1016/0168-8278(95)80226-6. 24. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 1996; 24(2):289–93. doi: 10.1002/hep.510240201. 25. Younossi ZM, Golabi P, Avila L de, Paik JM, Srishord M, Fukui N et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. J Hepatol 2019; 71(4):793–801. doi: 10.1016/j.jhep.2019.06.021. 26. Castera L, Laouenan C, Vallet-Pichard A, Vidal-Trécan T, Manchon P, Paradis V et al. High Prevalence of NASH and Advanced Fibrosis in Type 2 Diabetes: A Prospective Study of 330 Outpatients Undergoing Liver Biopsies for Elevated ALT, Using a Low Threshold. Diabetes Care 2023; 46(7):1354–62. doi: 10.2337/dc22-2048. 27. Castera L, Laouenan C, Vallet-Pichard A, Vidal-Trécan T, Manchon P, Paradis V et al. 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Additional Information

Citation: Bleß, H., Witte, I.: "Diagnosis of Metabolic Dysfunction-Associated Steatohepatitis (MASH) – Review, Part 1" (02/24), pp. 76–83. http://doi.org/10.24945/MVF.02.24.1866-0533.2597

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Diagnosis of metabolic dysfunction-associated steatohepatitis (MASH) - Review, Part 1

As the central metabolic organ, the liver plays a key role in human physiological processes, particularly the metabolism of almost all nutrients. Changes in liver cells due to fatty degeneration impair the liver's physiological processes. While hepatocellular fat deposits of up to 5% are considered normal, fatty liver disease is defined as more than 5–10% of liver cells being fatty (1). Depending on the degree of fatty degeneration, mild (< 33%, 33–66%, ... The most important distinction between steatotic liver diseases, according to the newly established nomenclature, is based on their triggers. This distinguishes between metabolic dysfunction (defined by components of the metabolic syndrome), primary alcoholic liver steatosis (defined by very high alcohol consumption), and mixed etiology. Under the auspices of the American Association for the Study of Liver Disease (AASLD) and the European Association for the Study of the Liver (EASL), changes to the nomenclature and diagnostic criteria for fatty liver disease were developed in June 2023 following a multi-stage modified Delphi process to address key pathophysiological aspects and perceived patient stigma (3).

>> The entity previously known as non-alcoholic fatty liver disease (NAFLD) is now called metabolic dysfunction-associated steatotic liver disease (MASLD). Non-alcoholic steatohepatitis (NASH) is being renamed metabolic dysfunction-associated steatohepatitis (MASH).
These terms reflect the close pathophysiological connection with metabolic syndrome, in which obesity plays a central role as a trigger. This disease must be distinguished from alcoholic liver disease (ALD), which is primarily induced by increased alcohol consumption, and from alcoholic liver disease (ALD), which is characterized by metabolic factors and relevant alcohol consumption.
MetALD (metabolic and alcoholic liver disease).
The AASLD/EASL nomenclature defines a limit of 140 g/week for alcohol consumption for women and 210 g/week for men, respectively. In contrast, the guideline of the German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS) specifies a lower limit of 70 g/week and 140 g/week, respectively (2). The acronym MetALD was chosen to designate a separate group of patients with MASLD who consume 140–350 g/week for women and 210–420 g/week for men, but who also have metabolic risk factors (see Table 1). The synergistic effect of alcohol consumption and metabolic syndrome on the progression of liver fibrosis and the occurrence of decompensation events has recently been clearly demonstrated again in light of this expert consensus (4, 5). Furthermore, these steatoses are distinguished from those that are caused by secondary factors such as drug influence or genetic metabolic abnormalities.
Various analyses by the European LITMUS consortium of the North American NHANES cohort and the Swedish National Registry showed that 98 to 99% of the existing registry cohorts of patients with NAFLD would meet the new criteria for MASLD (3, 6, 7). This high level of agreement allows the terms NAFLD and MASLD to be used synonymously in clinical practice. The change in nomenclature in favor of cardiometabolic risk factors also allows a rational reclassification of most cases previously referred to as "lean NASH" into the regular MASLD category, provided the defining metabolic risk factors are present. The prevalence of diabetes, hypertension, and dyslipidemia in this group is almost comparable to the overweight patient population, and most patients classified as "lean" exhibit at least one criterion of the metabolic syndrome (8, 9).
The new nomenclature is used below.
Etiology and pathophysiology
The etiology and pathophysiology of MASLD remain largely unclear and are the subject of ongoing discussions and research projects. Of particular importance is the frequent association of MASLD with visceral obesity, insulin resistance, or hyperlipidemia, which suggests a close connection with the metabolic syndrome (1). Models for the pathophysiology of MASLD
and MASH have changed significantly in recent years due to new research findings. In older literature, the term "two-hit model" is often used to describe the pathogenesis of MASH. The first event is the increased accumulation of triglycerides in hepatocytes. This corresponds to the histopathological picture of MASLD. The second event is lipotoxicity. This influences inflammation, cell death, and fibrosis of the hepatocytes. Hepatocyte cell death is described as a key process in the development and progression of MASH. The progression of this process can lead to a chronic inflammatory reaction with scarring, fibrosis (10, 11).
Later studies point to the importance of mitochondrial genetics and its influence on the modulation of oxidative stress and the efficiency of oxidative phosphorylation (12). Other research focuses on innate immune activation or the influence of bile acid as triggers for the development of MASH and the progression to fibrosis, cirrhosis, or carcinogenesis (10, 13). A complex interplay of various organ systems with adipose tissue inflammation (adipositis) and shifts in the intestinal microbiome (dysbiosis) are now recognized as further relevant pathophysiological events (14). The "two-hit model" has thus evolved into a "multiple parallel hit model," for which new research efforts are increasingly identifying more influencing factors and pathophysiological processes.
Symptoms and course of the disease

ALD, MetALD, and MASLD are very similar in their symptoms and progression. In all cases, patients are often asymptomatic or exhibit nonspecific general symptoms such as fatigue, lethargy, or abdominal pain. In addition, MetALD and MASLD are associated with metabolic risk factors, resulting in elevated values in at least one of the criteria: weight, blood glucose, blood pressure, and blood lipid levels (see Table 1).
Patients with steatohepatitis, an inflammatory stage of the disease, typically do not manifest any classic, externally recognizable symptoms. Therefore, the diagnosis of this disease is primarily based on the presence of various histologically identifiable features. These features include steatosis, an inflammatory infiltration of hepatocytes, and liver cell damage, which classically becomes visible in the form of so-called ballooning (swelling due to the formation of an intracellular fluid collection) of the hepatocytes (15, 16). MASH is defined according to the SAF classification (steatosis, activity, fibrosis) by the simultaneous histological detection of steatosis, ballooning, and inflammatory infiltration (15). The NASH classification developed by the Clinical Research Network (CRN)
CRN classification allows a quantification of inflammatory activity with the NASH Activity Score (NAS), which serves less to identify MASH, but rather to quantitatively record the aforementioned histological criteria for the purposes of clinical studies (16).
Both ALD, MetALD, and MASLD can remain limited to the stage of simple steatosis, but can also progress to inflammatory steatohepatitis. Metabolic dysfunction-associated steatohepatitis (MASH), in particular, represents the inflammatory and progressive manifestation of MASLD, as shown in Figure 1.
The progression of MASLD is characterized by a gradual loss of hepatocyte function due to liver fibrosis. This process can progress through the development of liver cirrhosis as the terminal stage and ultimately to hepatocellular carcinoma (HCC) as the most serious complication (17).
It is estimated that 5–20% of MASLD patients develop MASH. Of these patients, 10–20% progress to fibrosis, a condition characterized by increased scar tissue formation (1, 17). This development of fibrosis and the associated complex remodeling processes in the liver are considered a critical phase in the course of MASH (18). Complete reversibility of fibrosis is often no longer possible, especially when tissue changes are far advanced. In fewer than 5% of cases with fibrosis, liver cirrhosis develops, which can progress to decompensation and significantly increases the risk/probability of developing HCC (see Fig. 1) (17).
MASLD, and especially its progressive form, MASH, are the fastest-growing indications for liver transplantation in Western countries. Furthermore, diabetes, obesity, and cardiovascular disease are often co-existing. Immunosuppression after transplantation can further increase the risk of cardiovascular events and metabolic complications. MASH patients are prone to early post-transplant complications and long-term health problems, which are associated with increased mortality (19).
Various scoring systems exist to assess the severity of fibrosis. The Desmet/Scheuer staging system is the most commonly used approach and is defined in Table 2 (22). Other commonly used systems include the Ishak score, which provides a grading from 0 to 6 (23), or the Metavir score, which considers both the degree of fibrosis and histological activity (15, 24).
Treatment
Therapeutic interventions for MASLD and MASH are currently primarily focused on lifestyle-modification approaches. A central aspect is weight reduction in the mostly overweight or obese patients. This primarily aims to improve steatosis and inflammation. To reduce hepatic steatosis, a weight reduction of at least 5% is targeted. To improve existing fibrosis, a weight reduction of at least 10% is targeted. In addition, physical exercise is also recommended to reduce fatty liver disease (2).
Currently, no drugs are approved for the treatment of MASLD or MASH. However, several promising drugs are in various phases of clinical trials. A significant focus is currently being placed on glucagon-like peptide-1 (GLP-1) agonists, which are already established for the treatment of diabetes mellitus and obesity. Their efficacy in MASH is being further investigated in various studies, but application outside of clinical trials is currently not possible.
According to the current S2k guideline, until specific MASH medications are approved, inclusion in clinical trials should be considered for patients with advanced fibrosis (F3) and/or other special risk constellations (e.g., high MASH activity with F2 fibrosis, cardiometabolic comorbidities). Furthermore, for patients with comorbidities such as type 2 diabetes, dyslipidemia, and obesity, the choice of medications with beneficial effects on MASH is recommended.
The prevalence of MASLD in patients with diabetes mellitus is very high and, according to a 2019 meta-analysis by Younossi et al., is 55.5% worldwide, and even 68% in Europe (25). In the same analysis, MASH was present in 37.3% of diabetes mellitus patients worldwide. This is particularly important due to the high prevalence of advanced fibrosis in patients with MASH and diabetes. In 2019, it was 17% and, based on current model studies on the prevalence of MASH, has likely continued to rise (25, 26). A recent study from 2023 by Castera et al. showed that even very slight elevations in ALT levels in diabetes mellitus patients can lead to
(> 20 IU/L in women and > 30 IU/L in men) revealed significantly higher prevalence rates for MASH (58%) and advanced fibrosis (38%). Thus, in the future, diagnostic workup for MASH and advanced fibrosis may be advisable even in cases of mild liver function test elevations in this patient population (27).
In addition to GLP-1 agonists, which have a very promising study base, developments in other drug classes, such as pan-peroxisome proliferator-activated receptor (PPAR) agonists and fibroblast growth factor (FGF)-2, also reflect the ongoing efforts of the global research community to develop effective therapies for MASH. The thyroid hormone receptor beta (ThRß) agonist resmetirom is the first drug to date to demonstrate a significant positive effect on both the reduction of NASH activity and fibrosis regression in a phase 3 study (MAESTRO-NASH) (28). In view of the expected approvals of specific medications in the near future, calculations of the expected economic burden of MASLD/MASH for the healthcare system are of particular relevance, which will be described in more detail later and further emphasize the urgency of developing new, effective treatment methods for MASLD/MASH.
Diagnosis
Non-invasive diagnostics
Non-invasive diagnostic procedures play a key role in the care of patients with MASH. The current S2k guideline for steatotic liver disease1 lists non-invasive procedures for both screening and further specialist diagnostics to determine the stage of the disease. They form the basis for the decision-making process regarding liver biopsy, which is the current gold standard for definitive diagnosis of MASH (2). In general, non-invasive procedures are preferable to invasive liver biopsy due to their generally lower costs and lack of invasive risk.

Fibrosis scores
Using laboratory-based scores, liver tissue fibrosis can be assessed non-invasively. These scores form the foundation of MASH fibrosis screening: They are easy to use and are based on common laboratory values as well as routinely collected data in a general medical setting. They can therefore be collected and evaluated with minimal additional effort. The laboratory-based, simple, or indirect, fibrosis scores exhibit a high negative predictive value (NPV) and are therefore particularly suitable for identifying low-risk patients who do not require further, specialized diagnostics and treatment.
The two currently central scores for fibrosis risk assessment in MASLD care in Germany, and also recommended by the current guidelines, are the NAFLD Fibrosis Score (NFS) and the Fibrosis (FIB)-4 Index. Both scores have been evaluated for the diagnosis of advanced fibrosis in MASLD, in contrast to other available scores such as the AST-to-Platelet Ratio Index (APRI) and the BMI-AST/ALT Ratio-Diabetes (BARD) score. In two studies, one multicenter with 741 MASLD patients and one monocenter with 323 MASLD patients, FIB-4 and NFS were superior to the BARD score (both studies) and the APRI (in the second study) (29, 30).
In comparative studies with transient elastography (see below), all scores were inferior (30–33). Therefore, the diagnostic algorithm of the S2k guideline always recommends performing elastography in addition to laboratory-based scores. Free online calculators are available for both the NFS and the FIB-4 index (see Table 3).
The diagnostic and prognostic value of the three non-invasive test procedures recommended in the DGVS guideline algorithm, FIB-4, NFS and transient elastometry (Fibroscan), has since been confirmed in a large patient cohort in the European LITMUS consortium (36, 37).
Sonographic diagnostics
Sonography is of central importance in the diagnosis of MASLD, both as a screening method of first choice alongside laboratory tests and the calculation of the Fatty Liver Index (FLI) and in further specialist fibrosis diagnostics with elastography as a novel sonographic procedure for determining the stiffness of the liver tissue.
Due to the non-invasive nature of the procedure and the widespread availability of ultrasound devices in general medical practices, sonography has the potential to be widely used as a screening procedure. However, many elastography procedures require specialized software components and probes that are only applicable to modern ultrasound or elastography devices and are therefore less readily available for patient care. In some cases, elastography procedures are not available as software components, but only on devices sold by the manufacturer.

Elastography (sonographic)
Elastography measures liver tissue stiffness. This can be done using sonographic methods or magnetic resonance imaging (MRI-guided). Elastography is performed by a specialist in the relevant field, not by a general practitioner, as is the case with MASLD screening. Sonographic methods are particularly important for healthcare provision in Germany, as they are widely available, at least in university outpatient clinics and specialized practice centers. MRI elastography is used only in a few centers, primarily for research purposes (see the section on radiological diagnostics).
There are two predominantly used measurement techniques for sonographic elastography: transient elastography, which includes vibration-controlled transient elastography (VCTE), which is of great importance in the proposed screening algorithm in the guideline, and shear wave-based methods (SWE) such as point-SWE (pSWE) and 2D-SWE. High-quality, histologically controlled studies are available for both measurement techniques (38–41).
According to current studies, shear wave-based methods are more suitable for severe obesity. In morbid obesity (BMI ≥ 40 kg/m²), a study using the VCTE method found valid values in only 60% of cases (42, 43). However, a general superiority of shear wave-based methods compared to the more widely available VCTE has not been established in current studies (44).
Both procedures require an experienced physician to perform the measurement, as various technical and patient-related factors must be considered during the measurement. These include, among others, increased liver capsule tension due to cardiac congestion or acute hepatitis, which can lead to falsely high values. Furthermore, it is important to ensure that the measurement is taken sufficiently long after the patient's last meal (at least three hours), with shallow, normal breathing, and with the patient in a standardized lying position (2).

Radiological diagnostics
The radiological diagnostic methods of computed tomography (CT) and MRI are generally of secondary importance for the diagnosis of MASLD and, according to the S2k guideline, should not be used as a screening method for steatotic liver disease. However, if a CT or MRI examination is performed for another indication, it can be used to diagnose liver steatosis.
The subordinate position of CT and MRI diagnostics of MASLD
The lack of suitable methods for diagnosing liver steatosis in the S2k guideline is not due to the lack of suitability of the methods for diagnosing liver steatosis. For example, MR-based quantification of liver fat content using proton density fat fraction (PDFF) is now recognized as the best method according to the guideline due to its exceptionally high accuracy (2, 45). The limited availability and complexity of the necessary hardware and software, as well as the required expertise, are the primary reasons for the subordinate position of radiological diagnostics in the care of MASLD patients.
In several studies, MR-enhanced elastography (MRE) has demonstrated slightly higher diagnostic accuracy and a high positive predictive value (PPV) in combination with serum markers compared to sonographic examination methods (44, 46, 47). However, in the current care of MASLD patients, MRE plays a minor role due to its high application costs and its availability, which is generally limited to university hospitals and research centers.

Liver fat quantification
Liver fat quantification based on an MRI examination is of secondary importance in the diagnosis due to the factors mentioned in the previous section. Liver fat quantification using ultrasound-based techniques, such as Controlled Attenuation Parameter (CAP) technology, can be used according to the guidelines for liver fat quantification, but is currently only available in conjunction with VCTE-based liver stiffness measurement (2). Accurate determination of liver fatty infiltration in the lower limit range of 5–20% steatosis is not possible with CAP technology, and especially in cases of severe obesity, the findings must be critically reviewed and interpreted due to the large skin-liver capsule distance (2).

Biomarkers
Various serum markers are used to calculate fibrosis scores and are therefore of great importance for screening potential MASH patients (see the chapter on fibrosis scores). In addition to the routinely available indirect fibrosis markers, there are also more cost-intensive so-called direct fibrosis markers, which generally demonstrate superior test performance. Among them, the Enhanced Liver Fibrosis (ELF) test, which has been approved by the FDA for this test indication and is used in the Anglo-American region, deserves mention. However, there are currently no individual, high-quality serum markers for the diagnosis of MASH that have been evaluated in a sufficient number of studies.
The currently most widely evaluated single biomarker is keratin-18. As an apoptosis marker, it correlates with histologically detectable inflammation and hepatocellular ballooning, which is a key criterion for a histologically confirmed diagnosis of MASH. However, multiple studies using various cutoff values have failed to achieve sufficient sensitivity, specificity, and diagnostic value (AUC) for routine use (48–51). Thus, biomarkers cannot be used for the definitive diagnosis of MASH. However, in combination with other serum markers, they play a central role in the care pathway during the screening process prior to diagnosis.

Invasive diagnostics
Invasive histological diagnostics are particularly relevant for the definitive diagnosis of MASH, which, according to the criteria defined in the guideline, should only be performed in the presence of certain constellations of findings that indicate an increased risk of advanced fibrosis. The indication criteria listed in the recommended algorithm, potential complications of the method, and the core histological criteria for the definitive diagnosis of MASH are presented in the following section. According to the guideline, the indication for a liver biopsy should be made by a specialist in the relevant field.

Liver biopsy
Liver biopsy remains the gold standard for diagnosing MASH. A biopsy can histologically demonstrate lobular inflammation and ballooned hepatocytes, which differentiate MASH from steatosis hepatis/simple steatosis. These three factors (steatosis hepatis/ballooned hepatocytes/lobular inflammation) are the diagnostic criteria for MASH and can currently only be detected histologically.
According to the S2k guideline, a liver biopsy should be considered primarily in two patient groups to determine the exact stage of the disease: in patients in whom the determined liver stiffness lies between the low and high limit (8–12 kPa) and who therefore have a medium risk for the presence of advanced fibrosis and therefore require further clarification, and in patients with a high liver stiffness of > 12 kPa, if there is no already clear evidence of liver cirrhosis through laboratory measurements, clinical symptoms or further imaging.
A liver biopsy is associated with potential complications such as bleeding and injury to the lungs, gallbladder, or pleura. Furthermore, the inflammatory changes in the liver, especially in MASH, are not evenly distributed throughout the liver, meaning that a liver biopsy also carries a risk of sampling error, further justifying the need to establish and validate other diagnostic procedures. For these reasons, the indication should be made strictly according to the criteria defined in the guideline. Due to the potential complications of liver biopsy, many patients refuse this procedure, significantly reducing the number of histologically confirmed, definitive MASH diagnoses. This has various consequences for MASH care, which are discussed in the care aspects in Part 2 of the review (MVF 03/24).

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