Review JOURNAL OF HEPATOLOGY Determinants of fibrosis progression and regression in NASH ⇑ Detlef Schuppan1,2, , Rambabu Surabattula1, Xiao Yu Wang1 Summary Keywords: Cirrhosis; Collagen; Cirrhosis has become the major liver-related clinical endpoint in non-alcoholic steatohepatitis (NASH). Fibroblast; Fibrosis; Integrin; However, progression to cirrhosis is less predictable in NASH than in other chronic liver diseases. This is Lipoapoptosis; Liver; Macro- phage; Myofibroblast; due to the complex and multifactorial aetiology of NASH, which is determined by lifestyle and nutrition, Progenitor cell; Stellate cell; multiple genetic and epigenetic factors, and a prominent role of hepatic and extrahepatic comorbidities. Therapy. Thus, modest changes in these cofactors can also induce fibrosis regression, at least in patients with pre- cirrhotic liver disease. Fibrogenesis in NASH correlates with, but is indirectly coupled to, classical inflam- Received 20 October 2017; mation, since fibrosis progression is driven by repetitive periods of repair. While hepatocyte received in revised form 2 November 2017; accepted 9 lipoapoptosis is a key driving force of fibrosis progression, activated hepatic stellate cells, myofibrob- November 2017 lasts, cholangiocytes, macrophages and components of the pathological extracellular matrix are major fibrogenic effectors and thus pharmacological targets for therapies aimed at inhibition of fibrosis pro- gression or induction of fibrosis reversal. The advent of novel, highly sensitive and specific serum biomarkers and imaging methods to assess the dynamics of liver fibrosis in NASH will improve detec- tion, stratification and follow-up of patients with progressive NASH . These non-invasive tools will also promote the clinical development of antifibrotic drugs, by permitting the design of lean proof-of- concept studies, and enabling development of a personalised antifibrotic therapy for patients with rapid fibrosis progression or advanced disease. Ó 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Relevance of liver fibrosis in NASH 1Institute of Translational NASH is distinct from other liver diseases, because mortality increase in patients with stage 1 fibro- Immunology and Research Center it is tightly associated with comorbidities of the sis.5 Notably, all-cause mortality, which is domi- for Immunotherapy, University of metabolic syndrome, such as insulin resistance nated by cardiovascular complications in early Mainz Medical Center, Mainz, Germany; and type 2 diabetes, and cardiovascular complica- stages, was increased to a similar level, i.e. 2–3- 2Division of Gastroenterology, tions linked to hypertension and dyslipidaemia. fold, both in early stages and advanced stage 3–4 Beth Israel Deaconess Medical These comorbidities already exist in mere NAFLD, fibrosis. A large single retrospective study Center, Harvard Medical School, Boston, USA which is defined by the absence of fibrosis and included 619 US patients with biopsy confirmed major liver inflammation.1–4 These non-hepatic NASH who were followed up for an average of companion diseases represent the major comor- 12.6 years.6 A total of 33.2% reached the hard end- bidities and causes of mortality in NAFLD and points of all-cause mortality or liver transplanta- the early stages of fibrotic NASH, up to stage 2 tion. Fibrosis of any stage vs. no fibrosis was fibrosis. Liver-related morbidity and mortality associated with a hazard ratio (HR) for these end- only increase significantly beyond stage 1 fibrosis, points of 1.86, increasing to 3.8 and 10.9 for stage especially with the emergence of cirrhosis. Thus, 3 and 4 fibrosis, while the HR for liver-related hard prevention and therapy must address two largely endpoints rose to 14.2 and 51.5, respectively. The independent targets: the metabolic complications only other relevant predictors were age (HR which are treatable with a range of medications, 1.07), type 2 diabetes (HR 1.62) and smoking (HR and moderate to advanced fibrosis (stage 2–4) 2.62). Interestingly, statin use decreased the risk for which no approved drugs exist. To prevent of mortality or transplantation significantly (HR liver-related mortality, the primary goal is to 0.32). The relevance of advanced fibrosis as the reverse advanced fibrosis, or prevent progression primary hepatic endpoint in clinical studies has to cirrhosis in patients that can be identified as now been recognised by the regulatory authorities rapid progressors. Whereas antifibrotic treatment and drug developers. Advanced fibrosis has of NASH patients with stage 1 fibrosis is less become a central focus in the ongoing phase III meaningful, as mild fibrosis may not progress and in most phase II studies,7 with an increasing and can even regress with minor lifestyle changes demand to include compensated cirrhotics in cur- or pharmacological treatment of the metabolic rent clinical trials.8 syndrome. Stratifying patients with NASH into Key point those with mild vs. advanced fibrosis is supported Prevention and therapy of by several smaller studies and a recent meta- Epidemiology and natural history of liver NAFLD must address two analysis that demonstrated a 9.57-, 16.69- and fibrosis in NASH largely independent tar- 42.3-fold increase in liver-related mortality, in There is no doubt that the epidemic of NAFLD and gets: the metabolic com- subjects with stage 2, 3 and 4 fibrosis vs. subjects plications, and moderate to NASH is mainly caused by overnutrition, advanced fibrosis. with no (stage 0) fibrosis, with only a 1.41-fold unhealthy food constituents and a sedentary Journal of Hepatology 2017 vol. xxx j xxx–xxx Please cite this article in press as: Schuppan D et al. Determinants of fibrosis progression and regression in NASH. J Hepatol (2017), https://doi.org/10.1016/j.jhep.2017.11.012 Review lifestyle, which have steadily and inconspicuously Overweight and type 2 diabetes as key infiltrated our daily lives. From 1994–2015, obe- determinants of fibrosis progression and sity, as defined by a body mass index (BMI) >30 regression in Western and >28 in far Eastern countries, has A recent extensive meta-analysis has assessed the increased roughly twofold in the US. This is per- global burden of NAFLD and NASH, and disease fectly paralleled by the prevalence of type 2 dia- outcome, demonstrating a prevalence of NAFLD betes, which reaches 10% or more in some between 15% and 30% in most affluent and 9,10 Southern and Midwestern states of the US developing countries.22 To clearly identify and in more affluent North African and Middle individuals with NAFLD that have significant liver 11 Eastern countries. The reported national and inflammation and fibrosis would completely regional prevalence of NAFLD and the overall overwhelm any healthcare system, since we do prevalence of NASH-related cirrhosis largely paral- not currently have a simple and cheap non- lel these developments in adults, as well as in chil- invasive tool with sufficient sensitivity and 12–15 dren and adolescents. specificity. This problem is further potentiated by While reliable data on obesity and type 2 dia- expected increases in NAFLD disease burden in betes can be obtained on a nationwide scale, the the next few years.23 clear diagnosis of NAFLD and especially the differ- Notably, the natural history of NASH is much entiation between NAFLD and NASH in large rep- less predictable than that of other chronic liver resentative cohorts is difficult. This is because diseases, such as viral hepatitis B or C, where pro- the only accepted diagnostic criterion is liver gression is tightly linked to the underlying cause, biopsy, with specified criteria for significant hep- and where causal treatment like efficient viral atic steatosis, hepatocyte ballooning and inflam- suppression or elimination halts fibrosis progres- 16,17 mation (NAS score >4 or >5). sion and even causes reversal.24,25 The important Studies based on follow-up biopsies in patients role of lifestyle changes, especially weight reduc- Key point with non-inflammatory fatty liver (NAFL) and tion, but also physical exercise, and a healthier, The natural history of NASH revealed interesting characteristics of fibro- yet ill-defined, nutrient composition on inflamma- NASH is less predictable sis progression vs. regression in patients under tion and fibrosis in NASH is highlighted in a than for other chronic liver standard follow-up. In a study from Newcastle Cuban-US study. It demonstrated that an intensive diseases, but the important that included 108 patients who were followed up role of lifestyle changes, weight loss programme in 293 patients with including weight reduc- for an average of 6.6 years with a second biopsy, NASH, 261 of whom were biopsied after 52 weeks, tion, physical exercise and 42% progressed, 40% remained stable, and 18% led to resolution of NASH (NAS score below 3) in 18 nutrient composition is regressed. Interestingly, 10 of the 27 NAFL 25%, reduced the NAS score in 47% and reduced becoming clear. patients with stage 0 fibrosis progressed, six of fibrosis in 19%. In those patients who lost ≥10% whom developed stage 3 fibrosis. The best expla- of body weight, NASH resolved in 90% and fibrosis nation for spontaneous fibrosis regression, besides improved in 45%.26 Based on these data, the biopsy sampling variability, may be favourable authors developed an index, based on age, pre- lifestyle changes. Another study from France fol- intervention type 2 diabetes and NAS score ≥5, lowed up 70 patients with untreated NAFLD using weight loss and ALT normalisation, with a high a second biopsy after a mean of 3.7 years. A total predictive value for NASH resolution (area under of 25 patients had NAFL and 45 had NASH and/or receiver operator curve <5).27 Moreover, follow- advanced fibrosis. Of the patients with NAFL, 16 up studies on morbidly obese patients that under- developed NASH, eight with ballooning and six went bariatric surgery have demonstrated that the with bridging fibrosis (stage 3) on follow-up.