Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Roadmap
  • Published:

A roadmap for clinical trials in MASH-related compensated cirrhosis

Nature Reviews Gastroenterology & Hepatology (2024)Cite this article

Subjects

An Author Correction to this article was published on 05 August 2024

This article has been updated

Abstract

Although metabolic dysfunction-associated steatohepatitis (MASH) is rapidly becoming a leading cause of cirrhosis worldwide, therapeutic options are limited and the number of clinical trials in MASH-related compensated cirrhosis is low as compared to those conducted in earlier disease stages. Moreover, designing clinical trials in MASH cirrhosis presents a series of challenges regarding the understanding and conceptualization of the natural history, regulatory considerations, inclusion criteria, recruitment, end points and trial duration, among others. The first international workshop on the state of the art and future direction of clinical trials in MASH-related compensated cirrhosis was held in April 2023 at Vall d’Hebron University Hospital in Barcelona (Spain) and was attended by a group of international experts on clinical trials from academia, regulatory agencies and industry, encompassing expertise in MASH, cirrhosis, portal hypertension, and regulatory affairs. The presented Roadmap summarizes important content of the workshop on current status, regulatory requirements and end points in MASH-related compensated cirrhosis clinical trials, exploring alternative study designs and highlighting the challenges that should be considered for upcoming studies on MASH cirrhosis.

Key points

  • MASH-related compensated cirrhosis is a broad entity encompassing persons with differing drivers of disease and differing risks of clinical outcomes.

  • Identification of persons at risk of clinical outcomes using existing non-invasive tests (NITs) and prognostic models will enrich clinical trial samples.

  • A combination of NITs evaluating fibrosis and measures of portal pressure might be used to guide drug development in phase II clinical trials.

  • A core outcome set of NITs and clinical outcomes needs to be developed for implementation and reporting in all clinical trials.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Main stages and pathophysiological mechanisms in the natural history of MASLD.
Fig. 2: Effect of metabolic drivers on different levels of MASLD natural history.
Fig. 3: Summary of the pathophysiology, natural history and treatment modalities of MASH cirrhosis.
Fig. 4: Oesophageal varices as ordinal outcomes in patients with cirrhosis.

Similar content being viewed by others

Data availability

Calculations for the illustrative scenarios shown in Table 2 and Fig. 4 are based on published data (refs. 24,25,112,114,164 and 165,166, respectively). The Excel sheets with the data used and the calculations will be provided upon request.

Change history

References

  1. Rinella, M. E. et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. J. Hepatol. 79, 1542–1556 (2023).

    Article  CAS  PubMed  Google Scholar 

  2. Younossi, Z. et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol. 15, 11–20 (2018).

    Article  PubMed  Google Scholar 

  3. Brown, G. T. & Kleiner, D. E. Histopathology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Metabolism 65, 1080–1086 (2016).

    Article  CAS  PubMed  Google Scholar 

  4. Anstee, Q. M., Reeves, H. L., Kotsiliti, E., Govaere, O. & Heikenwalder, M. From NASH to HCC: current concepts and future challenges. Nat. Rev. Gastroenterol. Hepatol. 16, 411–428 (2019).

    Article  PubMed  Google Scholar 

  5. Estes, C., Razavi, H., Loomba, R., Younossi, Z. & Sanyal, A. J. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology 67, 123–133 (2018).

    Article  CAS  PubMed  Google Scholar 

  6. Estes, C. et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030. J. Hepatol. 69, 896–904 (2018).

    Article  PubMed  Google Scholar 

  7. Younossi, Z. M. et al. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology 77, 1335–1347 (2023).

    Article  PubMed  Google Scholar 

  8. Huang, D. Q. et al. Global epidemiology of cirrhosis — aetiology, trends and predictions. Nat. Rev. Gastroenterol. Hepatol. 20, 388–398 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Huang, D. Q., El-Serag, H. B. & Loomba, R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol. 18, 223–238 (2021).

    Article  PubMed  Google Scholar 

  10. Francque, S. et al. Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors. Nat. Rev. Gastroenterol. Hepatol. 18, 24–39 (2021).

    Article  PubMed  Google Scholar 

  11. Haas, J. T., Francque, S. & Staels, B. Pathophysiology and mechanisms of nonalcoholic fatty liver disease. Annu. Rev. Physiol. 78, 181–205 (2016).

    Article  CAS  PubMed  Google Scholar 

  12. Francque, S. & Vonghia, L. Pharmacological treatment for non-alcoholic fatty liver disease. Adv. Ther. 36, 1052–1107 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lefere, S. & Tacke, F. Macrophages in obesity and non-alcoholic fatty liver disease: crosstalk with metabolism. JHEP Rep. 1, 30–43 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Gastaldelli, A. & Cusi, K. From NASH to diabetes and from diabetes to NASH: mechanisms and treatment options. JHEP Rep. 1, 312–328 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Wree, A., Broderick, L., Canbay, A., Hoffman, H. M. & Feldstein, A. E. From NAFLD to NASH to cirrhosis-new insights into disease mechanisms. Nat. Rev. Gastroenterol. Hepatol. 10, 627–636 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. Cheung, A. et al. Defining improvement in nonalcoholic steatohepatitis for treatment trial endpoints: recommendations from the liver forum. Hepatology 70, 1841–1855 (2019).

    Article  PubMed  Google Scholar 

  17. Rinella, M. E., Tacke, F., Sanyal, A. J. & Anstee, Q. M. Report on the AASLD/EASL joint workshop on clinical trial endpoints in NAFLD. J. Hepatol. 71, 823–833 (2019).

    Article  PubMed  Google Scholar 

  18. Ratziu, V., Francque, S. & Sanyal, A. Breakthroughs in therapies for NASH and remaining challenges. J. Hepatol. 76, 1263–1278 (2022).

    Article  CAS  PubMed  Google Scholar 

  19. Harrison, S. A. et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N. Engl. J. Med. 390, 497–509 (2024).

    Article  PubMed  Google Scholar 

  20. FDA. FDA Approves First Treatment for Patients with Liver Scarring due to Fatty Liver Disease, March 14 2024 https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-liver-scarring-due-fatty-liver-disease (2024).

  21. Francque, S. & Ratziu, V. Future treatment options and regimens for nonalcoholic fatty liver disease. Clin. Liver Dis. 27, 429–444 (2023).

    Article  PubMed  Google Scholar 

  22. Cusi, K. et al. American Association of Clinical Endocrinology clinical practice guideline for the diagnosis and management of nonalcoholic fatty liver disease in primary care and endocrinology clinical settings: co-sponsored by the American Association for the Study of Liver Diseases (AASLD). Endocr. Pract. 28, 528–562 (2022).

    Article  PubMed  Google Scholar 

  23. Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M. & Sanyal, A. J. Mechanisms of NAFLD development and therapeutic strategies. Nat. Med. 24, 908–922 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sanyal, A. J. et al. Prospective study of outcomes in adults with nonalcoholic fatty liver disease. N. Engl. J. Med. 385, 1559–1569 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Allen, A. M. et al. Clinical course of non-alcoholic fatty liver disease and the implications for clinical trial design. J. Hepatol. 77, 1237–1245 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rinella, M. E. et al. AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology 77, 1797–1835 (2023).

    Article  PubMed  Google Scholar 

  27. Younossi, Z. M., Zelber-Sagi, S., Henry, L. & Gerber, L. H. Lifestyle interventions in nonalcoholic fatty liver disease. Nat. Rev. Gastroenterol. Hepatol. 20, 708–722 (2023).

    Article  CAS  PubMed  Google Scholar 

  28. Tacke, F. et al. Updated S2k clinical practice guideline on non-alcoholic fatty liver disease (NAFLD) issued by the German Society of Gastroenterology, digestive and metabolic diseases (DGVS). Z. Gastroenterol. 60, E733–E801 (2022).

    Article  Google Scholar 

  29. Fayad, L. et al. Endoscopic sleeve gastroplasty versus laparoscopic sleeve gastrectomy: a case-matched study. Gastrointest. Endosc. 89, 782–788 (2019).

    Article  PubMed  Google Scholar 

  30. Aminian, A. et al. Association of bariatric surgery with major adverse liver and cardiovascular outcomes in patients with biopsy-proven nonalcoholic steatohepatitis. JAMA 326, 2031–2042 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Wilding, J. P. H. et al. Once-weekly semaglutide in adults with overweight or obesity. N. Engl. J. Med. 384, 989–1002 (2021).

    Article  CAS  PubMed  Google Scholar 

  32. Jastreboff, A. M. et al. Tirzepatide once weekly for the treatment of obesity. N. Engl. J. Med. 387, 205–216 (2022).

    Article  CAS  PubMed  Google Scholar 

  33. Loomba, R. et al. Semaglutide 2.4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. Lancet Gastroenterol. Hepatol. 8, 511–522 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Verrastro, O. et al. Bariatric-metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES): a multicentre, open-label, randomised trial. Lancet 401, 1786–1797 (2023).

    Article  PubMed  Google Scholar 

  35. Younossi, Z. M. et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 394, 2184–2196 (2019).

    Article  CAS  PubMed  Google Scholar 

  36. Sanyal, A. J. et al. Topline results from a new analysis of the regenerate trial of obeticholic acid for the treatment of nonalcoholic steatohepatitis. Abstract 5008. The Liver Meeting 2022: American Association for the Study of Liver Diseases (AASLD), Washington, D.C., USA (2022).

  37. Harrison, S. A. et al. Primary data analyses of MAESTRO-NAFLD-1 a 52 week double blind placebo-controlled phase 3 clinical trial of resmetirom in patients with NAFLD. EASL LB005. J. Hepatol. 77 (2023).

  38. Lefere, S. et al. Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages. J. Hepatol. 73, 757–770 (2020).

    Article  CAS  PubMed  Google Scholar 

  39. Tacke, F., Puengel, T., Loomba, R. & Friedman, S. L. An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH. J. Hepatol. 79, 552–566 (2023).

    Article  CAS  PubMed  Google Scholar 

  40. Francque, S. M. et al. A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH. N. Engl. J. Med. 385, 1547–1558 (2021).

    Article  CAS  PubMed  Google Scholar 

  41. Harrison, S. A. et al. Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial. Nat. Med. 27, 1262–1271 (2021).

    Article  CAS  PubMed  Google Scholar 

  42. Harrison, S. A. et al. A randomized, double-blind, placebo-controlled phase IIa trial of efruxifermin for patients with compensated NASH cirrhosis. JHEP Rep. 5, 100563 (2023).

    Article  PubMed  Google Scholar 

  43. US National Library of Medicine. ClinicalTrials.gov https://classic.clinicaltrials.gov/ct2/show/NCT04767529 (2023).

  44. Puengel, T. et al. Combined therapy with a CCR2/CCR5 antagonist and FGF21 analogue synergizes in ameliorating steatohepatitis and fibrosis. Int. J. Mol. Sci. 23, 6696 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Alkhouri, N. et al. Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: a randomised, open-label phase II trial. J. Hepatol. 77, 607–618 (2022).

    Article  CAS  PubMed  Google Scholar 

  46. US National Library of Medicine. ClinicalTrials.gov https://classic.clinicaltrials.gov/ct2/show/NCT03439254 (2023).

  47. US National Library of Medicine. ClinicalTrials.gov https://classic.clinicaltrials.gov/ct2/show/NCT03053063 (2019).

  48. US National Library of Medicine. ClinicalTrials.gov https://classic.clinicaltrials.gov/ct2/show/NCT04365868 (2019).

  49. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04849728?cond=steatohepatitis&intr=lanifibranor (2021).

  50. Boyer-Diaz, Z. et al. Pan-PPAR agonist lanifibranor improves portal hypertension and hepatic fibrosis in experimental advanced chronic liver disease. J. Hepatol. 74, 1188–1199 (2021).

    Article  CAS  PubMed  Google Scholar 

  51. US National Library of Medicine. ClinicalTrials.gov https://classic.clinicaltrials.gov/ct2/show/NCT04210245 (2019).

  52. US National Library of Medicine. ClinicalTrials.gov https://classic.clinicaltrials.gov/ct2/show/NCT04971785 (2021).

  53. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04197479 (2019).

  54. US National Library of Medicine. ClinicalTrials.gov https://classic.clinicaltrials.gov/ct2/show/NCT05500222 (2022).

  55. U.S. Food and Drug Administration. Nonalcoholic Steatohepatitis with Compensated Cirrhosis: Developing Drugs for Treatment Guidance For Industry https://www.fda.gov/media/127738/download (2023).

  56. Vilar-Gomez, E. et al. Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study. Gastroenterology 155, 443–457 (2018).

    Article  PubMed  Google Scholar 

  57. Bassegoda, O. et al. High frequency of acute decompensation and cancer in patients with compensated cirrhosis due to nonalcoholic fatty liver disease: a retrospective cohort study. Hepatol. Commun. 6, 3212–3222 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. The European Medicines Agency - EMA EMA/CHMP/299976/2018. Reflection paper on regulatory requirements for the development of medicinal products for chronic non-infectious liver diseases (PBC, PSC, NASH). https://www.ema.europa.eu/en/documents/scientific-guideline/draft-reflection-paper-regulatory-requirements-development-medicinal-products-chronic-non-infectious-liver-diseases-pbc-psc-nash_en.pdf (2018).

  59. U.S. Food and Drug Administration. Regulatory Perspectives for Development of Drugs for Treatment of NASH https://www.fda.gov/drugs/news-events-human-drugs/regulatory-perspectives-development-drugs-treatment-nash-01292021-01292021 (2021).

  60. Vilar-Gomez, E. et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 149, 365–367 (2015).

    Article  Google Scholar 

  61. Promrat, K. et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 51, 121–129 (2010).

    Article  CAS  PubMed  Google Scholar 

  62. Harrison, S. A., Fecht, W., Brunt, E. M. & Neuschwander-Tetri, B. A. Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial. Hepatology 49, 80–86 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Wong, V. W. et al. Community-based lifestyle modification programme for non-alcoholic fatty liver disease: a randomized controlled trial. J. Hepatol. 59, 536–542 (2013).

    Article  PubMed  Google Scholar 

  64. Berzigotti, A. et al. Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis. Gastroenterology 144, 102–111 (2013).

    Article  PubMed  Google Scholar 

  65. Berzigotti, A. et al. Effects of an intensive lifestyle intervention program on portal hypertension in patients with cirrhosis and obesity: the SportDiet study. Hepatology 65, 1293–1305 (2017).

    Article  PubMed  Google Scholar 

  66. Bunchorntavakul, C. Sarcopenia and frailty in cirrhosis: assessment and management. Med. Clin. North Am. 107, 589–604 (2023).

    Article  PubMed  Google Scholar 

  67. Eisenberg, D. et al. American Society for Metabolic and Bariatric Surgery (ASMBS) and International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO): indications for metabolic and bariatric surgery. Surg. Obes. Relat. Dis. 18, 1345–1356 (2022).

    Article  PubMed  Google Scholar 

  68. Newsome, P. N. et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N. Engl. J. Med. 384, 1113–1124 (2020).

    Article  PubMed  Google Scholar 

  69. Armstrong, M. J. et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 387, 679–690 (2016).

    Article  CAS  PubMed  Google Scholar 

  70. Gastaldelli, A. et al. Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol. 10, 393–406 (2022).

    Article  CAS  PubMed  Google Scholar 

  71. US National Library of Medicine. ClinicalTrials.gov https://classic.clinicaltrials.gov/ct2/show/NCT04166773 (2019).

  72. Hope, D. C. D., Vincent, M. L. & Tan, T. M. M. Striking the balance: GLP-1/glucagon co-agonism as a treatment strategy for obesity. Front. Endocrinol. 12, 735019 (2021).

    Article  Google Scholar 

  73. Boland, M. L. et al. Resolution of NASH and hepatic fibrosis by the GLP-1R/GcgR dual-agonist Cotadutide via modulating mitochondrial function and lipogenesis. Nat. Metab. 2, 413–431 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lewis, K. H., Sloan, C. E., Bessesen, D. H. & Arterburn, D. Effectiveness and safety of drugs for obesity. BMJ 384, e072686 (2024).

    Article  PubMed  Google Scholar 

  75. Casimiro, I., Sam, S. & Brady, M. J. Endocrine implications of bariatric surgery: a review on the intersection between incretins, bone, and sex hormones. Physiol. Rep. 7, e14111 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Lassailly, G. et al. Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis. Gastroenterology 159, 1290–1301 (2020).

    Article  PubMed  Google Scholar 

  77. Thereaux, J. et al. Long-term adverse events after sleeve gastrectomy or gastric bypass: a 7-year nationwide, observational, population-based, cohort study. Lancet Diabetes Endocrinol. 7, 786–795 (2019).

    Article  PubMed  Google Scholar 

  78. Backman, O., Stockeld, D., Rasmussen, F., Näslund, E. & Marsk, R. Alcohol and substance abuse, depression and suicide attempts after Roux-en-Y gastric bypass surgery. Br. J. Surg. 103, 1336–1342 (2016).

    Article  CAS  PubMed  Google Scholar 

  79. Lee, Y. et al. Complete resolution of nonalcoholic fatty liver disease after bariatric surgery: a systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 17, 1040–1060.e11 (2019).

    Article  PubMed  Google Scholar 

  80. Zhou, H. et al. Bariatric surgery improves nonalcoholic fatty liver disease: systematic review and meta-analysis. Obes. Surg. 32, 1872–1883 (2022).

    Article  PubMed  Google Scholar 

  81. Wang, G. et al. Impacts of bariatric surgery on adverse liver outcomes: a systematic review and meta-analysis. Surg. Obes. Relat. Dis. 19, 717–726 (2023).

    Article  PubMed  Google Scholar 

  82. Mendoza, Y. P. et al. Malnutrition and alcohol in patients presenting with severe complications of cirrhosis after laparoscopic bariatric surgery. Obes. Surg. 31, 2817–2822 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Jan, A., Narwaria, M. & Mahawar, K. K. A systematic review of bariatric surgery in patients with liver cirrhosis. Obes. Surg. 25, 1518–1526 (2015).

    Article  PubMed  Google Scholar 

  84. Nor Hanipah, Z. et al. Efficacy of adjuvant weight loss medication after bariatric surgery. Surg. Obes. Relat. Dis. 14, 93–98 (2018).

    Article  PubMed  Google Scholar 

  85. Ahmed, S. et al. Outcomes of bariatric surgery in patients with liver cirrhosis: a systematic review. Obes. Surg. 31, 2255–2267 (2021).

    Article  PubMed  Google Scholar 

  86. Safwan, M., Collins, K. M., Abouljoud, M. S. & Salgia, R. Outcome of liver transplantation in patients with prior bariatric surgery. Liver Transpl. 23, 1415–1421 (2017).

    Article  PubMed  Google Scholar 

  87. Kleiner, D. E. et al. Association of histologic disease activity with progression of nonalcoholic fatty liver disease. JAMA Netw. Open 2, e1912565–e1912565 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Sanyal, A. J. et al. Cirrhosis regression is associated with improved clinical outcomes in patients with nonalcoholic steatohepatitis. Hepatology 75, 1235–1246 (2022).

    Article  CAS  PubMed  Google Scholar 

  89. Brunt, E. M. et al. Complexity of ballooned hepatocyte feature recognition: defining a training atlas for artificial intelligence-based imaging in NAFLD. J. Hepatol. 76, 1030–1041 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Davison, B. A. et al. Suboptimal reliability of liver biopsy evaluation has implications for randomized clinical trials. J. Hepatol. 73, 1322–1332 (2020).

    Article  CAS  PubMed  Google Scholar 

  91. Rowe, I. A. & Parker, R. The placebo response in randomized trials in nonalcoholic steatohepatitis simply explained. Clin. Gastroenterol. Hepatol. 20, e564–e572 (2022).

    Article  CAS  PubMed  Google Scholar 

  92. Sanyal, A. J., Prakash, J. & Kleiner, D. E. Digital pathology for nonalcoholic steatohepatitis assessment. Nat. Rev. Gastroenterol. Hepatol. 21, 57–69 (2023).

    Article  PubMed  Google Scholar 

  93. Cunningham, R. P. & Porat-Shliom, N. Liver zonation — revisiting old questions with new technologies. Front. Physiol. 12, 732929 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Steinman, J. B., Salomao, M. A. & Pajvani, U. B. Zonation in NASH — a key paradigm for understanding pathophysiology and clinical outcomes. Liver Int. 41, 2534–2546 (2021).

    Article  CAS  PubMed  Google Scholar 

  95. Dhingra, S., Mahadik, J. D., Tarabishy, Y., May, S. B. & Vierling, J. M. Prevalence and clinical significance of portal inflammation, portal plasma cells, interface hepatitis and biliary injury in liver biopsies from patients with non-alcoholic steatohepatitis. Pathology 54, 686–693 (2022).

    Article  CAS  PubMed  Google Scholar 

  96. Mitten, E. K. & Baffy, G. Mechanotransduction in the pathogenesis of non-alcoholic fatty liver disease. J. Hepatol. 77, 1642–1656 (2022).

    Article  CAS  PubMed  Google Scholar 

  97. Angelini, G. et al. Accurate liquid biopsy for the diagnosis of non-alcoholic steatohepatitis and liver fibrosis. Gut 72, 392–403 (2023).

    Article  CAS  PubMed  Google Scholar 

  98. Aghigh, A. et al. Second harmonic generation microscopy: a powerful tool for bio-imaging. Biophys. Rev. 15, 43–70 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Liu, F. et al. qFIBS: an automated technique for quantitative evaluation of fibrosis, inflammation, ballooning, and steatosis in patients with nonalcoholic steatohepatitis. Hepatology 71, 1953–1966 (2020).

    Article  CAS  PubMed  Google Scholar 

  100. Forlano, R. et al. High-throughput, machine learning-based quantification of steatosis, inflammation, ballooning, and fibrosis in biopsies from patients with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 18, 2081–2090.e9 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Taylor-Weiner, A. et al. A machine learning approach enables quantitative measurement of liver histology and disease monitoring in NASH. Hepatology 74, 133–147 (2021).

    Article  PubMed  Google Scholar 

  102. Ripoll, C. et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology 133, 481–488 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. D’Amico, G. et al. Clinical states of cirrhosis and competing risks. J. Hepatol. 68, 563–576 (2018).

    Article  PubMed  Google Scholar 

  104. Silva-Junior, G. et al. The prognostic value of hepatic venous pressure gradient in patients with cirrhosis is highly dependent on the accuracy of the technique. Hepatology 62, 1584–1592 (2015).

    Article  PubMed  Google Scholar 

  105. Hernández-Gea, V. et al. Development of ascites in compensated cirrhosis with severe portal hypertension treated with β-blockers. Am. J. Gastroenterol. 107, 418–427 (2012).

    Article  PubMed  Google Scholar 

  106. Villanueva, C. et al. β-Blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 393, 1597–1608 (2019).

    Article  CAS  PubMed  Google Scholar 

  107. Abraldes, J. G. et al. Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis. Hepatology 37, 902–908 (2003).

    Article  PubMed  Google Scholar 

  108. Silva-Junior, G. et al. Timing affects measurement of portal pressure gradient after placement of transjugular intrahepatic portosystemic shunts in patients with portal hypertension. Gastroenterology 152, 1358–1365 (2017).

    Article  PubMed  Google Scholar 

  109. Sebastiani, G. et al. Prognostic value of non-invasive fibrosis and steatosis tools, hepatic venous pressure gradient (HVPG) and histology in nonalcoholic steatohepatitis. PLoS One 10, e0128774 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Rodrigues, S. G. et al. Patients with signs of advanced liver disease and clinically significant portal hypertension do not necessarily have cirrhosis. Clin. Gastroenterol. Hepatol. 17, 2101–2109.e1 (2019).

    Article  PubMed  Google Scholar 

  111. Chalasani, N. et al. Effects of belapectin, an inhibitor of galectin-3, in patients with nonalcoholic steatohepatitis with cirrhosis and portal hypertension. Gastroenterology 158, 1334–1345 (2020).

    Article  CAS  PubMed  Google Scholar 

  112. Harrison, S. A. et al. Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis. Gastroenterology 155, 1140–1153 (2018).

    Article  CAS  PubMed  Google Scholar 

  113. Sanyal, A. J. et al. The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials. Hepatology 70, 1913–1927 (2019).

    Article  CAS  PubMed  Google Scholar 

  114. Paternostro, R. et al. Natural history of patients with NAFLD-associated compensated advanced chronic liver disease stratified according to severity of portal hypertension. Z. Gastroenterol. 61, e195 (2023).

    Google Scholar 

  115. Bassegoda, O. et al. Decompensation in advanced nonalcoholic fatty liver disease may occur at lower hepatic venous pressure gradient levels than in patients with viral disease. Clin. Gastroenterol. Hepatol. 20, 2276–2286.e6 (2022).

    Article  CAS  PubMed  Google Scholar 

  116. Ferrusquía-Acosta, J. et al. Agreement between wedged hepatic venous pressure and portal pressure in non-alcoholic steatohepatitis-related cirrhosis. J. Hepatol. 74, 811–818 (2021).

    Article  PubMed  Google Scholar 

  117. Paternostro, R. et al. The prognostic value of HVPG-response to non-selective beta-blockers in patients with NASH cirrhosis and varices. Dig. Liver Dis. 54, 500–508 (2022).

    Article  CAS  PubMed  Google Scholar 

  118. FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource (FDA & NIH, 2016).

  119. U.S. Food and Drug Administration. Considerations for Discussion of a New Surrogate Endpoint(s) at a Type C PDUFA Meeting Request https://www.fda.gov/media/115120/download (2023).

  120. Anstee, Q. M. et al. Noninvasive tests accurately identify advanced fibrosis due to NASH: baseline data from the STELLAR trials. Hepatology 70, 1521–1530 (2019).

    Article  PubMed  Google Scholar 

  121. Vali, Y. et al. Biomarkers for staging fibrosis and non-alcoholic steatohepatitis in non-alcoholic fatty liver disease (the LITMUS project): a comparative diagnostic accuracy study. Lancet Gastroenterol. Hepatol. 8, 714–725 (2023).

    Article  PubMed  Google Scholar 

  122. Dyson, J. K., McPherson, S. & Anstee, Q. M. Non-alcoholic fatty liver disease: non-invasive investigation and risk stratification. J. Clin. Pathol. 66, 1033–1045 (2013).

    Article  CAS  PubMed  Google Scholar 

  123. 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).

    Article  CAS  PubMed  Google Scholar 

  124. Wai, C. T. et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 38, 518–526 (2003).

    Article  PubMed  Google Scholar 

  125. Angulo, P. et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 45, 846–854 (2007).

    Article  CAS  PubMed  Google Scholar 

  126. Sterling, R. K. et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 43, 1317–1325 (2006).

    Article  CAS  PubMed  Google Scholar 

  127. Hagström, H., Talbäck, M., Andreasson, A., Walldius, G. & Hammar, N. Repeated FIB-4 measurements can help identify individuals at risk of severe liver disease. J. Hepatol. 73, 1023–1029 (2020).

    Article  PubMed  Google Scholar 

  128. Boyle, M. et al. Performance of the PRO-C3 collagen neo-epitope biomarker in non-alcoholic fatty liver disease. JHEP Rep. 1, 188–198 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Daniels, S. J. et al. ADAPT: an algorithm incorporating PRO-C3 accurately identifies patients with NAFLD and advanced fibrosis. Hepatology 69, 1075–1086 (2019).

    Article  CAS  PubMed  Google Scholar 

  130. Karsdal, M. A. et al. Novel insights into the function and dynamics of extracellular matrix in liver fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 308, G807–G830 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Angulo, P. et al. Simple noninvasive systems predict long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 145, 782–789 (2013).

    Article  PubMed  Google Scholar 

  132. Anstee, Q. M. et al. Non-invasive fibrosis scores as prognostic biomarkers of liver events, cardiovascular events and all-cause mortality in people with obesity and/or type 2 diabetes in the UK: a longitudinal cohort study. EASL OS025. J. Hepatol. 77 (2022).

  133. Mózes, F. E. et al. Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis. Lancet Gastroenterol. Hepatol. 8, 704–713 (2023).

    Article  PubMed  Google Scholar 

  134. Vali, Y. et al. Enhanced liver fibrosis test for the non-invasive diagnosis of fibrosis in patients with NAFLD: a systematic review and meta-analysis. J. Hepatol. 73, 252–262 (2020).

    Article  PubMed  Google Scholar 

  135. Anstee, Q. M. et al. Change in fibrosis-4 index (FIB4) over time is associated with subsequent risk of liver events, cardiovascular events, and all-cause mortality in patients with obesity and/or type 2. The Liver Meeting 2022: American Association for the Study of Liver Diseases (AASLD). Abstract 5049 (2022).

  136. Gidener, T. et al. Change in serial liver stiffness measurement by magnetic resonance elastography and outcomes in NAFLD. Hepatology 77, 268–274 (2023).

    Article  PubMed  Google Scholar 

  137. Sanyal, A. J. et al. Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology 43, 682–689 (2006).

    Article  PubMed  Google Scholar 

  138. Anstee, Q. M. et al. Longitudinal variability of noninvasive tests of fibrosis: implications for treatment response monitoring in patients with NASH. International Liver Congress, 23-26 June 2021, Abstract PO-1568 (2021).

  139. Fowler, K. et al. Repeatability of MRI biomarkers in nonalcoholic fatty liver disease: the NIMBLE consortium. Radiology 309, e231092 (2023).

    Article  PubMed  Google Scholar 

  140. Rasmussen, D. N. et al. Prognostic performance of 7 biomarkers compared to liver biopsy in early alcohol-related liver disease. J. Hepatol. 75, 1017–1025 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Rasmussen, D. G. K. et al. NAFLD and NASH biomarker qualification in the LITMUS consortium — lessons learned. J. Hepatol. 78, 852–865 (2023).

    Article  CAS  PubMed  Google Scholar 

  142. de Franchis, R. et al. Renewing consensus in portal hypertension. J. Hepatol. 76, 959–974 (2022).

    Article  PubMed  Google Scholar 

  143. Pennisi, G. et al. AGILE 3+ score for the diagnosis of advanced fibrosis and for predicting liver-related events in NAFLD. Clin. Gastroenterol. Hepatol. 21, 1293–1302.e5 (2023).

    Article  PubMed  Google Scholar 

  144. Sanyal, A. J. et al. Enhanced diagnosis of advanced fibrosis and cirrhosis in individuals with NAFLD using FibroScan-based Agile scores. J. Hepatol. 78, 247–259 (2023).

    Article  CAS  PubMed  Google Scholar 

  145. Calzadilla-Bertot, L. et al. ABIDE: an accurate predictive model of liver decompensation in patients with nonalcoholic fatty liver-related cirrhosis. Hepatology 73, 2238–2250 (2021).

    Article  CAS  PubMed  Google Scholar 

  146. Abraldes, J. G. et al. Noninvasive tools and risk of clinically significant portal hypertension and varices in compensated cirrhosis: the “Anticipate” study. Hepatology 64, 2173–2184 (2016).

    Article  CAS  PubMed  Google Scholar 

  147. Pons, M. et al. Noninvasive diagnosis of portal hypertension in patients with compensated advanced chronic liver disease. Am. J. Gastroenterol. 116, 723–732 (2021).

    Article  PubMed  Google Scholar 

  148. Pons, M. et al. Point-of-care noninvasive prediction of liver-related events in patients with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. https://doi.org/10.1016/j.cgh.2023.08.004 (2023).

    Article  PubMed  Google Scholar 

  149. Bath, P. M. W. et al. Statistical analysis of the primary outcome in acute stroke trials. Stroke 43, 1171–1178 (2012).

    Article  PubMed  Google Scholar 

  150. Groszmann, R. J. et al. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology 99, 1401–1407 (1990).

    Article  CAS  PubMed  Google Scholar 

  151. Vorobioff, J. et al. Prognostic value of hepatic venous pressure gradient measurements in alcoholic cirrhosis: a 10-year prospective study. Gastroenterology 111, 701–709 (1996).

    Article  CAS  PubMed  Google Scholar 

  152. Bendtsen, F., Skovgaard, L. T., Sørensen, T. I. & Matzen, P. Agreement among multiple observers on endoscopic diagnosis of esophageal varices before bleeding. Hepatology 11, 341–347 (1990).

    Article  CAS  PubMed  Google Scholar 

  153. Groszmann, R. J. et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N. Engl. J. Med. 353, 2254–2261 (2005).

    Article  CAS  PubMed  Google Scholar 

  154. Rowe, I. A. & Parker, R. The diagnosis of nonalcoholic fatty liver disease should carry important prognostic information. Nat. Rev. Gastroenterol. Hepatol. 16, 449–450 (2019).

    Article  PubMed  Google Scholar 

  155. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344, 1383–1389 (1994).

    Google Scholar 

  156. Pericàs, J. M. et al. Platform trials to overcome major shortcomings of traditional clinical trials in non-alcoholic steatohepatitis? Pros and cons. J. Hepatol. 78, 442–447 (2023).

    Article  PubMed  Google Scholar 

  157. Filozof, C. et al. Clinical endpoints and adaptive clinical trials in precirrhotic nonalcoholic steatohepatitis: facilitating development approaches for an emerging epidemic. Hepatol. Commun. 1, 577–585 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Bedossa, P., Dargère, D. & Paradis, V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 38, 1449–145 (2003).

    Article  PubMed  Google Scholar 

  159. Shearer, J. E., Jones, R., Parker, R., Ferguson, J. & Rowe, I. A. The natural history of advanced chronic liver disease defined by transient elastography. Clin. Gastroenterol. Hepatol. 21, 694–703.e8 (2023).

    Article  PubMed  Google Scholar 

  160. Shearer, J. E. et al. Systematic review: development of a consensus code set to identify cirrhosis in electronic health records. Aliment. Pharmacol. Ther. 55, 645–657 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Mallet, V. et al. Burden of liver disease progression in hospitalized patients with type 2 diabetes mellitus. J. Hepatol. 76, 265–274 (2022).

    Article  CAS  PubMed  Google Scholar 

  162. Staufer, K. et al. Ethyl glucuronide in hair detects a high rate of harmful alcohol consumption in presumed non-alcoholic fatty liver disease. J. Hepatol. 77, 918–993 (2022).

    Article  CAS  PubMed  Google Scholar 

  163. Hagström, H. et al. Administrative coding in electronic health care record-based research of NAFLD: an expert panel consensus statement. Hepatology 74, 474–482 (2021).

    Article  PubMed  Google Scholar 

  164. Harrison, S. A. et al. Design of the phase 3 MAESTRO clinical program to evaluate resmetirom for the treatment of nonalcoholic steatohepatitis. Aliment. Pharmacol. Ther. 59, 51–63 (2024).

    Article  CAS  PubMed  Google Scholar 

  165. D’Amico, G., Abraldes, J. G., Rebora, P., Valsecchi, M. G. & Garcia-Tsao, G. Ordinal outcomes are superior to binary outcomes for designing and evaluating clinical trials in compensated cirrhosis. Hepatology 72, 1029–1042 (2020).

    Article  PubMed  Google Scholar 

  166. Pennisi, G. et al. Oesophageal varices predict complications in compensated advanced non-alcoholic fatty liver disease. JHEP Rep. 5, 100809 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Harrison, S. A. et al. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized phase III STELLAR trials. J. Hepatol. 73, 26–39 (2020).

    Article  CAS  PubMed  Google Scholar 

  168. Frenette, C. et al. Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis. J. Hepatol. 74, 274–282 (2021).

    Article  CAS  PubMed  Google Scholar 

  169. Garcia-Tsao, G. et al. Randomized placebo-controlled trial of emricasan for non-alcoholic steatohepatitis-related cirrhosis with severe portal hypertension. J. Hepatol. 72, 885–895 (2020).

    Article  CAS  PubMed  Google Scholar 

  170. Loomba, R. et al. Combination therapies including cilofexor and firsocostat for bridging fibrosis and cirrhosis attributable to NASH. Hepatology 73, 625–643 (2021).

    Article  CAS  PubMed  Google Scholar 

  171. Abdelmalek, M. F. et al. Pegbelfermin in patients with nonalcoholic steatohepatitis and compensated cirrhosis (FALCON 2): a randomized phase 2b study. Clin. Gastroenterol. Hepatol. 22, 113–123.e9 (2023).

    Article  PubMed  Google Scholar 

  172. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04267393 (2021).

  173. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05282121 (2022).

  174. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05039450 (2023).

  175. Harrell Jr, F. Harrell miscellaneous. R package version 5.1-1 https://cran.r-project.org/web/packages/Hmisc/Hmisc.pdf (2023).

Download references

Acknowledgements

The authors thank J. Bosch, A. Albillos, J. Luis Calleja, R. Bañares, A. Trylesinski, C. de Oliveira, V. Vargas, R. Basuroy and L. Boyette for their involvement in the workshop as moderators; M. Romero for the preparation and writing of this manuscript; M. Jesus Rivas for their assistance in managing the event, and C. Adame for their role in setting up the meeting as well as the website https://www.bcn-liverhuvh.com/bcn-nash. Moreover, we acknowledge the scientific support of the European Association for the Study of the Liver (EASL), the British Association for the Study of the Liver (BASL), the Asociación Latinoamericana para el Estudio del Hígado (ALEH), the Spanish Networks of Biomedical Research Centers in Digestive and Liver Diseases (CIBERehd), the Associazione Italiana per lo Studio del Fegato (AISF), and the Spanish Association for the Study of the Liver (AEEH), also for their dissemination activities of the workshop.

Author information

Authors and Affiliations

  1. Liver Unit, Division of Digestive Diseases, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Research (VHIR), Vall d’Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain

    Juan M. Pericàs, Mònica Pons & Joan Genescà

  2. Centros de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain

    Juan M. Pericàs, Virginia Hernández-Gea & Joan Genescà

  3. Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

    Quentin M. Anstee

  4. Newcastle NIHR Biomedical Research Center, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK

    Quentin M. Anstee

  5. Boehringer Ingelheim International GmbH, Ingelheim, Germany

    Salvador Augustin

  6. Liver Unit, Hospital Clinic Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat Barcelona, Barcelona, Spain

    Ramón Bataller & Virginia Hernández-Gea

  7. Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

    Annalisa Berzigotti

  8. Endocrinology and Nutrition Department, Morbid Obesity Unit Coordinator, Vall d’Hebron University Hospital, Barcelona, Spain

    Andreea Ciudin

  9. Centros de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas asociadas (CIBERdem), Instituto de Salud Carlos III, Madrid, Spain

    Andreea Ciudin

  10. Department of Gastroenterology and Hepatology, Antwerp University Hospital, InflaMed Centre of Excellence, Laboratory for Experimental Medicine and Paediatrics, Translational Sciences in Inflammation and Immunology, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium

    Sven Francque

  11. Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Canada

    Juan G. Abraldes

  12. Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria

    Thomas Reiberger

  13. Leeds Institute for Medical Research, University of Leeds, Leeds, UK

    Ian A. Rowe

  14. Medical Department, Madrigal Pharmaceuticals, West Conshohocken, PA, USA

    Peter Rydqvist

  15. Federal Institute for Drugs and Medical Devices, Bonn, Germany

    Elmer Schabel

  16. Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany

    Frank Tacke

  17. UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, UK

    Emmanuel A. Tsochatzis

Authors
  1. Juan M. Pericàs
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Quentin M. Anstee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Salvador Augustin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ramón Bataller
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Annalisa Berzigotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andreea Ciudin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sven Francque
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Juan G. Abraldes
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Virginia Hernández-Gea
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mònica Pons
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Thomas Reiberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ian A. Rowe
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Peter Rydqvist
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Elmer Schabel
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Frank Tacke
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Emmanuel A. Tsochatzis
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Joan Genescà
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched data for the article. J.M.P., Q.M.A., S.A., R.B., A.B., A.C., S.F., J.G.A., V.H.-G., M.P., T.R., I.A.R., P.R., E.S., F.T., E.A.T. and J.G. contributed substantially to discussion of the content. J.M.P., Q.M.A., S.A., R.B., A.B., S.F., J.G.A., V.H.-G., I.A.R., F.T. and J.G. wrote the article. All authors reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Juan M. Pericàs.

Peer review

Peer review information

Nature Reviews Gastroenterology & Hepatology thanks Aleksander Krag, Daniel Huang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Competing interests

J.M.P. reports having received consulting fees from Boehringer Ingelheim and Novo Nordisk. He has received speaking fees from Gilead, and travel expenses from Gilead, Rubió, Pfizer, Astellas, MSD, CUBICIN, and Novo Nordisk. He has received educational and research support from Gilead, Pfizer, Astellas, Accelerate, Novartis, Abbvie, ViiV and MSD. Q.M.A. is coordinator of the EU IMI2 LITMUS consortium, which is funded by the EU Horizon 2020 programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA). This multistakeholder consortium includes industry partners. He has received research grant funding from Astra Zeneca, Boehringer Ingelheim, and Intercept Pharmaceuticals, Inc. and has served as a consultant on behalf of Newcastle University for Alimentiv, Akero, Astra Zeneca, Axcella, 89bio, Boehringer Ingelheim, Bristol Myers Squibb, Galmed, Genfit, Genentech, Gilead, GSK, Hanmi, HistoIndex, Intercept Pharmaceuticals, Inc., Inventiva, Ionis, IQVIA, Janssen, Madrigal, Medpace, Merck, NGM Bio, Novartis, Novo Nordisk, PathAI, Pfizer, Poxel, Resolution Therapeutics, Roche, Ridgeline Therapeutics, RTI, Shionogi, and Terns. He has served as a speaker for Fishawack, Integritas Communications, Kenes, Novo Nordisk, Madrigal, Medscape, and Springer Healthcare, and receives royalties from Elsevier Ltd. S.A. works for Boehringer Ingelheim. S.F. has acted as consultant for Abbvie, Actelion, Aelin Therapeutics, AgomAb, Aligos Therapeutics, Allergan, Alnylam, Astellas, Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol-Meyers Squibb, CSL Behring, Coherus, Echosens, Dr. Falk Pharma, Eisai, Enyo, Galapagos, Galmed, Genetech, Genfit, Genflow Biosciences, Gilead Sciences, Intercept, Inventiva, Janssens Pharmaceutica, PRO.MED.CS Praha, Julius Clinical, Madrigal, Medimmune, Merck Sharp & Dome, Mursla Bio, NGM Bio, Novartis, Novo Nordisk, Promethera, Roche, and Siemens Healthineers. He has been a lecturer for Abbvie, Allergan, Bayer, Eisai, Genfit, Gilead Sciences, Janssens Cilag, Intercept, Inventiva, Merck Sharp & Dome, Novo Nordisk, Promethera and Siemens. His institution has received grants from Astellas, Falk Pharma, Genfit, Gilead Sciences, GlympsBio, Janssens Pharmaceutica, Inventiva, Merck Sharp & Dome, Pfizer, and Roche. P.R. works for Madrigal Pharmaceuticals. E.S. contributions do not represent the official position of the Federal Institute for Drugs and Medical Devices (BfArM) or EMA/Committee for Medicinal Products for Human Use. I.R. has received honoraria for consulting from Boehringer Ingelheim and Roche, fees for educational material from Norgine, and fees for adjudication committees for Astra Zeneca and Novo Nordisk. The F.T. lab has received research funding from Allergan, Bristol Myers Squibb, Gilead and Inventiva. F.T. has received honoraria for consulting or lectures from Astra Zeneca, Gilead, AbbVie, Boehringer, Madrigal, Intercept, Falk, Inventiva, Merz, Pfizer, Alnylam, NGM, CSL Behring, Novo Nordisk and Novartis. J.G. has received consulting fees from Boehringer Ingelheim, speaking fees from Echosens, and travel expenses from Gilead and Abbie. J.M.P. received funds from European Commission/EFPIA IMI2 853966-2, IMI2 777377, H2020 847989, HLTH-101136299, ISCIII PI19/01898 and PI22/01770, Barcelona City Council-“La Caixa” Foundation 22S07286-001 and SR20-00386, and Next Generation EU-IBEC Q6922. Q.M.A. is an NIHR Senior Investigator supported by the Newcastle NIHR Biomedical Research Center and the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) project, which received funding from the Innovative Medicines Initiative 2 Joint Undertaking, under grant agreement No. 777377. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA. S.F. holds a senior clinical investigator fellowship from the Research Foundation Flanders (FWO) (1802154N). F.T. is supported by the German Research Foundation (DFG Ta434/8-1, SFB/TRR 296 and CRC1382, Project-ID 403224013). J.G. was partially funded by grant PI21/00691 from Instituto de Salud Carlos III and co-funded by the European Union (ERDF/ESF, “Investing in your future”). The Spanish Networks of Biomedical Research Centers in Digestive and Liver Diseases (CIBERehd) is supported by Instituto de Salud Carlos III.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pericàs, J.M., Anstee, Q.M., Augustin, S. et al. A roadmap for clinical trials in MASH-related compensated cirrhosis. Nat Rev Gastroenterol Hepatol (2024). https://doi.org/10.1038/s41575-024-00955-8

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41575-024-00955-8

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing