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The Burden of Nonalcoholic Steatohepatitis: A Systematic Review of Epidemiology Studies

Open AccessPublished:July 18, 2022DOI:https://doi.org/10.1016/j.gastha.2022.06.016

      Background and Aims

      Nonalcoholic steatohepatitis (NASH) is associated with increased mortality and risk of complications but is often asymptomatic and under-recognized. A systematic review of NASH epidemiology was conducted to provide information on the burden of NASH and highlight important evidence gaps for future research.

      Methods

      Medline, EMBASE, and Cochrane Library databases were searched for English-language publications published from 2010 to January 2022 that reported on natural history, risk factors, comorbidities, and complications of a NASH population or subpopulation.

      Results

      Overall, 173 publications were included. NASH was shown to have a variable disease course and high prevalence of comorbid disease. Although many patients progressed to cirrhosis and end-stage liver disease, disease regression or resolution was reported in up to half of patients in some studies. Reported risk factors for disease progression or resolution included levels of (or changes in) serum fibrosis markers, liver enzymes, and platelets. The presence of NASH increased the risk of liver cirrhosis and other serious diseases such as hepatocellular carcinoma, colorectal cancer, chronic kidney disease, and cardiovascular disease. In 2017, NASH was responsible for ∼118,000 cirrhosis deaths globally, and an increasing proportion of patients are receiving liver transplantation for NASH in Europe and the United States. Consolidation of data was hampered by heterogeneity across the studies in terms of patient populations, follow-up time, and outcomes measured.

      Conclusion

      NASH is associated with significant morbidity and mortality, an increased risk of comorbidities, and imposes an increasing burden among liver transplantation recipients. Longer studies with harmonized study criteria are required to better understand the impact of NASH on patient outcomes.

      Keywords

      Abbreviations used in this paper:

      α-SMA (alpha-smooth muscle actin), AC (alcoholic cirrhosis), ACE2 (angiotensin-converting enzyme 2), AF (atrial fibrillation), AHC (autoimmune hepatic cirrhosis), AIH (autoimmune hepatitis), ALD (alcoholic liver disease), ALT (alanine aminotransferase), APRI (AST-to-platelet ratio index), ASCVD (atherosclerotic cardiovascular disease), ASH (alcoholic steatohepatitis), AST (aspartate aminotransferase), AUC (area under the curve), BMI (body mass index), C (cilofexor), CAD (coronary artery disease), CC (cryptogenic cirrhosis), CF (cilofexor + firsocostat), CI (confidence interval), CKD (chronic kidney disease), CLD (chronic liver disease), CRN (Clinical Research Network), CS (cilofexor + selonsertib), CV (cardiovascular), CVD (cardiovascular disease), DDLT (deceased donor liver transplant), E/e’ (ratio of early diastolic mitral inflow velocity to early diastolic mitral annulus velocity), ECG (echocardiogram), eGFR (estimated glomerular filtration rate), ELF (enhanced liver fibrosis), ELTR (European Liver Transplant Registry), EMR (electronic medical record), EOT (end of treatment), F (firsocostat), FGF21 (fibroblast growth factor 21), FIB-4 (fibrosis-4), FLINT (Farnesoid x Receptor Ligand Obeticholic Acid in NASH Treatment), GA (glycated albumin), GBD (Global Burden of Disease), GGT (gamma-glutamyl transferase), HbA1c (glycated hemoglobin), HBV (hepatitis B virus), HCC (hepatocellular carcinoma), HCUP (Healthcare Cost and Utilization Project), HCV (hepatitis C virus), HDL (high-density lipoprotein), HDL-C (HDL-cholesterol), HOMA-IR (homeostasis model assessment of insulin resistance), HR (hazard ratio), hs-CRP (high-sensitivity C-reactive protein), HVPG (hepatic venous pressure gradient), INR (international normalized ratio), LDL (low-density lipoprotein), LDL-MI (LDL-migration index), LOXL2 (lysyl oxidase like 2), LT (liver transplantation), MACE (major adverse cardiovascular events), MELD (Model for End-Stage Liver Disease), MetS (metabolic syndrome), MetS-Z (MetS severity Z-score), MTF (metformin), N/A (not applicable), NAC (N-acetylcysteine), NAFL (nonalcoholic fatty liver), NAFLD (nonalcoholic fatty liver disease), NAS (NAFLD activity score), NASH (nonalcoholic steatohepatitis), NFS (NAFLD fibrosis score), NIS (National Inpatient Sample), NMEDW (Northwestern Medicine Enterprise Database Warehouse), NR (not recorded), NS (not significant), OPTN (Organ Procurement and Transplantation Network), OR (odds ratio), PBO (placebo), PIVENS (Pioglitazone vs Vitamin E vs Placebo for the Treatment of Non-Diabetic Patients with Nonalcoholic Steatohepatitis), PUFA (polyunsaturated fatty acid), RCT (randomized controlled trial), r (correlation coefficient), re-LT (re-transplantation), SAF-A, Steatosis, Activity (and Fibrosis-Activity), SRTR (Scientific Registry of Transplant Recipients), STI (Thomas E. Starzl Transplantation Institute), TACE (transarterial chemoembolization), T2D (type 2 diabetes), TC (total cholesterol), TG (triglyceride), UAB (University of Alabama at Birmingham), UDCA (ursodeoxycholic acid), UHC (University HealthSystem Consortium), UNOS (United Network for Organ Sharing), UoC (University of Chicago), VCAM-1 (vascular cell adhesion molecule-1), WHVP (wedge hepatic venous pressure)

      Introduction

      Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide, with an estimated global prevalence of 25%.
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • et al.
      Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes.
      NAFLD represents a spectrum of liver disease ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), which can then progress to cirrhosis.
      • Moon A.M.
      • Singal A.G.
      • Tapper E.B.
      Contemporary epidemiology of chronic liver disease and cirrhosis.
      NASH, the most severe form of NAFLD, occurs when excess fat has accumulated in the liver, and lobular inflammation and hepatocellular ballooning are present.
      European Association for the Study of the Liver (EASL)European Association for the Study of Diabetes (EASD)European Association for the Study of Obesity (EASO)
      EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease.
      Despite this, NASH is often perceived as asymptomatic or unrecognized and may not be diagnosed until late stages.
      • Cook N.
      • Geier A.
      • Schmid A.
      • et al.
      The patient perspectives on future therapeutic options in NASH and patient needs.
      ,
      • LaBrecque D.
      • Abbas Z.
      • Anania F.
      • et al.
      World Gastroenterology Organisation global guidelines. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.
      NASH occurs in almost one-quarter of patients with NAFLD.
      • Wong V.W.
      • Wong G.L.
      • Choi P.C.
      • et al.
      Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years.
      It has an estimated prevalence of 1.50%–6.45% in the general population,
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • et al.
      Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes.
      although disease prevalence and incidence estimates vary considerably due to differing patient populations and disease criteria.
      • Moon A.M.
      • Singal A.G.
      • Tapper E.B.
      Contemporary epidemiology of chronic liver disease and cirrhosis.
      NASH is associated with obesity and type 2 diabetes (T2D), hepatic complications including cirrhosis, hepatocellular carcinoma (HCC), and extrahepatic conditions including cardiovascular disease (CVD) and cancer.
      European Association for the Study of the Liver (EASL)European Association for the Study of Diabetes (EASD)European Association for the Study of Obesity (EASO)
      EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease.
      ,
      • Allen A.M.
      • Hicks S.B.
      • Mara K.C.
      • et al.
      The risk of incident extrahepatic cancers is higher in non-alcoholic fatty liver disease than obesity - a longitudinal cohort study.
      NASH cirrhosis is predicted to become the leading cause of liver transplantation (LT) in the United States between 2020 and 2025.
      • Charlton M.R.
      • Burns J.M.
      • Pedersen R.A.
      • et al.
      Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States.
      This study aimed to summarize and critically appraise studies on the natural history of NASH, risk factors for NASH, hepatic and extrahepatic complications associated with NASH, related comorbidities, and LT outcomes, and to highlight important evidence gaps for future research.

      Methods

      A systematic literature review was conducted using Medline, EMBASE, and Cochrane Library databases via the Ovid platform using predefined search strategies (Table A1). The review was conducted in line with Cochrane guidelines
      and is reported in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • et al.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      The primary systematic literature review was conducted in February 2020, with updates in January 2021 and January 2022 (last searches ran on January 17, 2022). Relevant conference proceedings from 2017 to February 10, 2020, were handsearched for unpublished studies (repeated on January 6, 2021, and January 17–18, 2022), and submission documents from Health Technology Assessment agencies were reviewed for relevant data (Table A2). Conference abstracts were identified and screened, but data were not extracted as it was anticipated that the large number of full-text publications would provide an adequate evidence base of relevant information. Eligible publications were full-text English-language epidemiology studies that included outcomes in NASH populations (with or without comorbidities), or a NASH subgroup within a NAFLD study, published from 2010 to January 2022. Data from NAFLD or heterogeneous NAFLD/NASH populations were excluded. Full eligibility criteria are described in Table A3.
      First-round screening of titles and abstracts was followed by second-round full-text screening of short-listed articles and data extraction from articles meeting the eligibility criteria. Both first- and second-round screenings were performed by 2 independent researchers, and final inclusion was verified by the project lead. Data extraction was performed using predesigned data extraction tables in Microsoft Excel by an analyst with a 100% quality check by an independent senior analyst. Data extracted from each study included, but were not limited to, reference, country, study design, publication and study characteristics, baseline characteristics, intervention(s), and outcomes reported. Disputes regarding eligibility or data extraction were referred to a third party.
      The quality of included observational studies was assessed using the Quality Assessment Tool for Quantitative Studies produced as part of the Effective Public Health Practice Project.
      Effective Public Health Practice Project
      Quality assessment tool for quantitative studies.
      This assesses the quality of 6 components to assign a global rating for each study of “strong” (no weak ratings for any of the listed criteria), “moderate” (one weak rating), or “weak” (2 or more weak ratings). The components are selection bias (likelihood of representativeness of target population and percentage participation), design (study type), confounders (percentage of relevant confounders controlled for), blinding (of outcome assessors and study participants), data collection methods (validity and reliability), and withdrawals and dropouts. Any component that did not apply to the study was marked “not applicable.” Quality assessment (risk of bias) of randomized controlled trials was conducted using the 7-criteria checklist provided in Section 4.6 of the UK National Institute for Health and Care Excellence single technology appraisal user guide to assess the likelihood of selection, performance, attrition, and detection bias.
      National Institute for Health and Care Excellence
      Single technology appraisal and highly specialised technologies evaluation: user guide for company evidence submission template.
      Quality assessments were not used to exclude studies. Two reviewers independently assessed the likelihood of bias, and any disagreements were resolved by discussion and/or additional referees.

      Results

      The electronic database searches identified 12,105 citations, of which 2022 were identified as duplicates and excluded. A further 9926 were excluded after screening by title and abstract or full-text screening. Sixteen studies that met the eligibility criteria were identified from handsearching, resulting in inclusion of 173 publications covering 167 unique studies (Figure A1 and Table A4). An overview of the study and patient characteristics across the identified studies is included in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7 and Tables A5–A7.

      Disease Trajectory

      Only 6 studies reported on aspects of disease progression or regression that occurred naturally over time without pharmacological intervention (Table 1). Study populations and outcomes measured were heterogeneous, and it was therefore not possible to make direct comparisons across studies. Generally, further disease progression was common among patients with advanced disease at baseline.
      • O'Leary J.G.
      • Landaverde C.
      • Jennings L.
      • et al.
      Patients with NASH and cryptogenic cirrhosis are less likely than those with hepatitis C to receive liver transplants.
      ,
      • Henson J.B.
      • Wilder J.M.
      • Kappus M.R.
      • et al.
      Transplant outcomes in older patients with nonalcoholic steatohepatitis compared to alcohol-related liver disease and hepatitis C.
      • Sanyal A.J.
      • Harrison S.A.
      • Ratziu V.
      • et al.
      The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.
      • Ampuero J.
      • Aller R.
      • Gallego-Durán R.
      • et al.
      Definite and indeterminate nonalcoholic steatohepatitis share similar clinical features and prognosis: a longitudinal study of 1893 biopsy-proven nonalcoholic fatty liver disease subjects.
      Rates of progression to cirrhosis were shown to increase with increasing fibrosis severity in a Spanish database analysis,
      • Ampuero J.
      • Aller R.
      • Gallego-Durán R.
      • et al.
      Definite and indeterminate nonalcoholic steatohepatitis share similar clinical features and prognosis: a longitudinal study of 1893 biopsy-proven nonalcoholic fatty liver disease subjects.
      and a 22% rate of progression from F3 fibrosis to cirrhosis over a median 29 months was reported in a pooled analysis of the phase 2b simtuzumab trials (in which simtuzumab is assumed to have no biological activity).
      • Sanyal A.J.
      • Harrison S.A.
      • Ratziu V.
      • et al.
      The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.
      Interestingly, patient age was linked to disease progression, but not regression, in a study of first-time adult LT registrants; in this study, removal from the LT wait list because of death or being too sick increased with increasing age, whereas removal from the LT wait list due to condition improving was similar regardless of patient age.
      • Henson J.B.
      • Wilder J.M.
      • Kappus M.R.
      • et al.
      Transplant outcomes in older patients with nonalcoholic steatohepatitis compared to alcohol-related liver disease and hepatitis C.
      Table 1Progression or Regression of NASH and Fibrosis Over Time
      ReferenceCountry/regionData source/populationStudy typeNDisease progression
      O'Leary et al
      • O'Leary J.G.
      • Landaverde C.
      • Jennings L.
      • et al.
      Patients with NASH and cryptogenic cirrhosis are less likely than those with hepatitis C to receive liver transplants.
      USANASH/CC or HCV patients listed for an orthotopic LT (single center, 2002–2008)Observational cohort studyNASH/CC: 217

      HCV: 645
      • Median baseline MELD score of 14
      • 5-y follow-up
      • In patients with MELD score ≤15, median rate of progression of 1.3 MELD points per year
      • Rate of progression could not be calculated in patients with MELD score >15 as generally received LT within 1 y
      Ajmera et al
      • Ajmera V.
      • Belt P.
      • Wilson L.A.
      • et al.
      Among patients with nonalcoholic fatty liver disease, modest alcohol use is associated with less improvement in histologic steatosis and steatohepatitis.
      USANASH CRN participants ≥21 y with biopsy-confirmed NAFLD and alcohol use history within 2 y of initial biopsy
      Participants were drawn from 3 groups: (1) the adult NAFLD Database study, (2) adults on placebo in the Pioglitazone vs Vitamin E vs Placebo for the Treatment of Non-Diabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial, and (3) adults on placebo in the Farnesoid × Receptor Ligand Obeticholic Acid in NASH Treatment (FLINT) trial.
      Observational cohort studyNASH: 182

      Borderline NASH: 49

      NAFL: 54
      • Mean 47 (±26) mo between paired biopsies for mixed population
      • Among patients with definite NASH, consistent nondrinkers
        Nondrinkers were defined as current “never” drinkers who have not, over the course of their lifetime, had ≥1 alcoholic drink/month during a 12-month period or had ≥3 drinks per day for ≥3 consecutive days, whereas modest drinkers were defined as those drinking ≤2 drinks on a typical day, in the absence of monthly (or more frequent) heavy drinking.
        were most likely to have NASH resolution:
        • Consistent nondrinkers: 22%
        • Modest drinker to nondrinker: 17%
        • Nondrinker to modest drinker: 13%
        • Consistent modest drinker: 11%
      • In logistic regression models adjusted for sex, age, race, and smoking history, consistent modest drinkers were significantly less likely to have NASH resolution than consistent nondrinkers (adjusted OR 0.32, 95% CI 0.11–0.92, P = .04)
      Reddy et al
      • Reddy Y.K.
      • Marella H.K.
      • Jiang Y.
      • et al.
      Natural history of non-alcoholic fatty liver disease: a study with paired liver biopsies.
      USAElectronic medical records of patients with biopsy-proven NAFLD with ≥2 liver biopsies ≥1 y apart (2006–2016)Observational chart review studyNASH: 10

      NAFL: 26
      • Median 3.8 y between paired biopsies for mixed population
      • At follow-up, 7 patients with NAFL progressed to NASH and 5 patients with NASH no longer met NASH criteria (NAS ≥5)
      • There was a 50% fibrosis progression in patients with NASH:
        • At baseline, 80% of patients had a fibrosis score of ≤2, and 20% had a fibrosis score of 3/4
        • On follow-up, 58% of patients had a fibrosis score of ≤2, and 42% had a fibrosis score of 3/4
      Henson et al
      • Henson J.B.
      • Wilder J.M.
      • Kappus M.R.
      • et al.
      Transplant outcomes in older patients with nonalcoholic steatohepatitis compared to alcohol-related liver disease and hepatitis C.
      USAFirst-time adult LT registrants (UNOS database, 2004–2017)Retrospective database analysisNASH: 14,197

      ALD: 27,053

      HCV: 24,827
      • In NASH patients, removal from the LT wait list because of death or being too sick increased with increasing age:
        • 18.8%, 22.5%, 26.3%, 27.3%, 31.4%, and 36.1% in 18–49, 50–54, 55–59, 60–64, 65–69, and ≥70 y, respectively
      • Removal from the LT wait list due to condition improving was similar regardless of patient age:
        • 5.0%, 3.1%, 2.6%, 2.8%, 3.6%, and 4.1% in 18–49, 50–54, 55–59, 60–64, 65–69, and ≥70 y, respectively
      Sanyal et al
      • Sanyal A.J.
      • Harrison S.A.
      • Ratziu V.
      • et al.
      The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.
      GlobalPatients with biopsy-confirmed NASH and bridging fibrosis (F3) or compensated cirrhosis (F4)
      Simtuzumab- and placebo-treated patients were pooled based on the assumption that simtuzumab has no biological activity, supported by its failure to improve liver histology, portal pressure, liver biochemistry, and serum fibrosis markers in RCTs.
      Interventional study (Phase 2b RCTs
      NCT01672866 and NCT01672879.
      )
      NASH with F3 fibrosis: 217

      NASH with compensated cirrhosis: 258
      • After a median follow-up of 29.0 mo (range 0.3–46.3), progression to cirrhosis occurred in 22% of patients with F3 fibrosis
      Ampuero et al
      • Ampuero J.
      • Aller R.
      • Gallego-Durán R.
      • et al.
      Definite and indeterminate nonalcoholic steatohepatitis share similar clinical features and prognosis: a longitudinal study of 1893 biopsy-proven nonalcoholic fatty liver disease subjects.
      SpainPatients with biopsy-proven NAFLD (HepaMet registry)Retrospective database studySurvival analysis:

      NAFL: 281

      Indeterminate NASH: 355

      NASH: 598
      • Mean 4.7 ± 3.8 y follow-up for full NAFLD cohort
        Excluding patients who underwent liver biopsy during bariatric surgery (n = 539) or were enrolled in clinical trials (n = 120).
      • Despite having more patients with advanced liver disease, survival and rate of first cirrhosis decompensation were similar for patients with NASH vs indeterminate NASH or NAFL, respectively:
        • Survival: 2.7% vs 1.4% vs 4.6%
        • Rate of first cirrhosis decompensation: 2% vs 1.7% vs 2.1%
      • Progression to cirrhosis was significantly higher for NASH and indeterminate NASH vs NAFL (9.5% vs 7.9% vs 5%, respectively); this translated to a higher annual incidence of progression to cirrhosis with NASH and indeterminate NASH vs NAFL
      • Annual incidence of progression to cirrhosis increased with increasing fibrosis severity
      ALD, alcoholic liver disease; CC, cryptogenic cirrhosis; CI, confidence interval; CRN, Clinical Research Network; HCV, hepatitis C virus; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; NAFL, nonalcoholic fatty liver; NAFLD, nonalcoholic fatty liver disease; NAS, NAFLD Activity Score; NASH, nonalcoholic steatohepatitis; OR, odds ratio; RCT, randomized controlled trial; UNOS, United Network for Organ Sharing.
      a Participants were drawn from 3 groups: (1) the adult NAFLD Database study, (2) adults on placebo in the Pioglitazone vs Vitamin E vs Placebo for the Treatment of Non-Diabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial, and (3) adults on placebo in the Farnesoid × Receptor Ligand Obeticholic Acid in NASH Treatment (FLINT) trial.
      b Nondrinkers were defined as current “never” drinkers who have not, over the course of their lifetime, had ≥1 alcoholic drink/month during a 12-month period or had ≥3 drinks per day for ≥3 consecutive days, whereas modest drinkers were defined as those drinking ≤2 drinks on a typical day, in the absence of monthly (or more frequent) heavy drinking.
      c Simtuzumab- and placebo-treated patients were pooled based on the assumption that simtuzumab has no biological activity, supported by its failure to improve liver histology, portal pressure, liver biochemistry, and serum fibrosis markers in RCTs.
      d NCT01672866 and NCT01672879.
      e Excluding patients who underwent liver biopsy during bariatric surgery (n = 539) or were enrolled in clinical trials (n = 120).
      Nineteen interventional studies (over 21 publications) reported on the reversibility of histologic changes associated with NASH and fibrosis stage in response to therapy, lifestyle intervention, or placebo (summarized in Table 2). Histologic improvement in NASH (NAFLD Activity Score [NAS] improvement of ≥1 or ≥2 stages or improvement in Steatosis, Activity, and Fibrosis score) were reported in up to 92% of patients receiving pharmacologic therapies, with the highest rates of improvement seen with efruxifermin and semaglutide.
      • Harrison S.A.
      • Ruane P.J.
      • Freilich B.L.
      • et al.
      Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial.
      ,
      • Newsome P.N.
      • Buchholtz K.
      • Cusi K.
      • et al.
      A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.
      Histologic improvement was also seen in 47%–61% of patients receiving lifestyle intervention,
      • Promrat K.
      • Kleiner D.E.
      • Niemeier H.M.
      • et al.
      Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.
      ,
      • Vilar-Gomez E.
      • Martinez-Perez Y.
      • Calzadilla-Bertot L.
      • et al.
      Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis.
      whereas improvement in placebo or control arms generally occurred in one-third or fewer participants.
      • Promrat K.
      • Kleiner D.E.
      • Niemeier H.M.
      • et al.
      Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.
      ,
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ,
      • Cusi K.
      • Orsak B.
      • Bril F.
      • et al.
      Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial.
      • Francque S.M.
      • Bedossa P.
      • Ratziu V.
      • et al.
      A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH.
      • Friedman S.L.
      • Ratziu V.
      • Harrison S.A.
      • et al.
      A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis.
      ,
      • Harrison S.A.
      • Neff G.
      • Guy C.D.
      • et al.
      Efficacy and safety of aldafermin, an engineered FGF19 analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis.
      ,
      • Harrison S.A.
      • Ruane P.J.
      • Freilich B.L.
      • et al.
      Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial.
      ,
      • Loomba R.
      • Noureddin M.
      • Kowdley K.V.
      • et al.
      Combination therapies including cilofexor and firsocostat for bridging fibrosis and cirrhosis attributable to NASH.
      • Newsome P.N.
      • Buchholtz K.
      • Cusi K.
      • et al.
      A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.
      • Okanoue T.
      • Sakamoto M.
      • Harada K.
      • et al.
      Efficacy and safety of apararenone (MT-3995) in patients with nonalcoholic steatohepatitis: a randomized controlled study.
      • Ratziu V.
      • de Guevara L.
      • Safadi R.
      • et al.
      Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial.
      Significantly greater proportions of patients achieving resolution of NASH (or resolution of NASH without worsening of fibrosis) compared with placebo were reported for few pharmacologic interventions. These included vitamin E (36% vs 21%, P = .05), pioglitazone (47% vs 21%, P < .001 and 51% vs 19%, P < .001), elafibranor (19% vs 12%, P = .045), and semaglutide 0.4 mg (59% vs 17%, P < .001).
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ,
      • Cusi K.
      • Orsak B.
      • Bril F.
      • et al.
      Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial.
      ,
      • Newsome P.N.
      • Buchholtz K.
      • Cusi K.
      • et al.
      A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.
      ,
      • Ratziu V.
      • Harrison S.A.
      • Francque S.
      • et al.
      Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening.
      NASH resolution was seen in up to 22% of patients receiving placebo or control.
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ,
      • Cusi K.
      • Orsak B.
      • Bril F.
      • et al.
      Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial.
      • Francque S.M.
      • Bedossa P.
      • Ratziu V.
      • et al.
      A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH.
      • Friedman S.L.
      • Ratziu V.
      • Harrison S.A.
      • et al.
      A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis.
      ,
      • Harrison S.A.
      • Neff G.
      • Guy C.D.
      • et al.
      Efficacy and safety of aldafermin, an engineered FGF19 analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis.
      ,
      • Huang J.F.
      • Dai C.Y.
      • Huang C.F.
      • et al.
      First-in-Asian double-blind randomized trial to assess the efficacy and safety of insulin sensitizer in nonalcoholic steatohepatitis patients.
      ,
      • Loomba R.
      • Noureddin M.
      • Kowdley K.V.
      • et al.
      Combination therapies including cilofexor and firsocostat for bridging fibrosis and cirrhosis attributable to NASH.
      ,
      • Newsome P.N.
      • Buchholtz K.
      • Cusi K.
      • et al.
      A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.
      ,
      • Ratziu V.
      • de Guevara L.
      • Safadi R.
      • et al.
      Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial.
      Bariatric surgery was the most effective intervention in terms of NASH improvement, with NASH disappearing in 85% of recipients.
      • Lassailly G.
      • Caiazzo R.
      • Buob D.
      • et al.
      Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients.
      In some studies, improvements in NASH were accompanied by improvements in fibrosis,
      • Lassailly G.
      • Caiazzo R.
      • Buob D.
      • et al.
      Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients.
      ,
      • Li Y.H.
      • Yang L.H.
      • Sha K.H.
      • et al.
      Efficacy of poly-unsaturated fatty acid therapy on patients with nonalcoholic steatohepatitis.
      ,
      • Francque S.M.
      • Bedossa P.
      • Ratziu V.
      • et al.
      A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH.
      ,
      • Harrison S.A.
      • Ruane P.J.
      • Freilich B.L.
      • et al.
      Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial.
      but improvements in NASH without substantial improvement in fibrosis were also reported in several studies,
      • Kimura Y.
      • Hyogo H.
      • Yamagishi S.
      • et al.
      Atorvastatin decreases serum levels of advanced glycation endproducts (AGEs) in nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: clinical usefulness of AGEs as a biomarker for the attenuation of NASH.
      • Promrat K.
      • Kleiner D.E.
      • Niemeier H.M.
      • et al.
      Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ,
      • Huang J.F.
      • Dai C.Y.
      • Huang C.F.
      • et al.
      First-in-Asian double-blind randomized trial to assess the efficacy and safety of insulin sensitizer in nonalcoholic steatohepatitis patients.
      ,
      • Newsome P.N.
      • Buchholtz K.
      • Cusi K.
      • et al.
      A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.
      and one study reported improvements in fibrosis without improvements in NAS.
      • Friedman S.L.
      • Ratziu V.
      • Harrison S.A.
      • et al.
      A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis.
      Table 2Changes in NASH and Fibrosis in Response to Interventions
      ReferenceCountryData source/populationStudy typeNInterventionDurationEffects on NASHEffects on fibrosis
      Kimura et al
      • Kimura Y.
      • Hyogo H.
      • Yamagishi S.
      • et al.
      Atorvastatin decreases serum levels of advanced glycation endproducts (AGEs) in nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: clinical usefulness of AGEs as a biomarker for the attenuation of NASH.
      JapanPatients with biopsy-proven NASH and dyslipidemiaSingle-arm open-label cohort study43Atorvastatin1 yNAS improved: 68%

      No change: 27%

      Exacerbated: 5%
      Improved: 9%

      No change: 59%

      Exacerbated: 32%
      Promrat et al
      • Promrat K.
      • Kleiner D.E.
      • Niemeier H.M.
      • et al.
      Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.
      USAPhysician-recruited patients with biopsy-confirmed NASH from Rhode Island areaInterventional study (RCT)31Lifestyle vs control (basic education)48 wkMean change in NAS score:

      Lifestyle vs control: −2.4 vs −1.4, P = .05

      NAS improvement ≥3 points:

      Lifestyle vs control: 61% vs 20%, P = .04
      Mean change in fibrosis score:

      Lifestyle vs control: 0.0 vs −0.3, P = .62
      Sanyal et al
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      USANondiabetic patients with biopsy-confirmed NASH (PIVENS; NCT00063622)Interventional study (RCT)247Vitamin E 800 IU vs pioglitazone 30 mg vs PBO96 wkHistologic improvement in NASH:
      Improvement by ≥1 point in hepatocellular ballooning score; no increase in the fibrosis score; and either a decrease in the activity score for NAFLD to ≤3 or a ≥2-point decrease in the activity score, with a ≥1-point decrease in either the lobular inflammation or steatosis score.


      Vitamin E vs PBO: 43% vs 19%, P = .001

      Pioglitazone vs PBO: 34% vs 19%, P = .04

      Mean change in NAS:

      Vitamin E vs PBO: −1.9 vs −0.5, P < .001

      Pioglitazone vs PBO: −1.9 vs −0.5, P < .001

      Resolution of definite NASH:

      Vitamin E vs PBO: 36% vs 21%, P = .05

      Pioglitazone vs PBO: 47% vs 21%, P < .001
      Fibrosis improvement:

      Vitamin E vs PBO: 41% vs 31%, P = .24

      Pioglitazone vs PBO: 44% vs 31%, P = .12

      Mean change in fibrosis score:

      Vitamin E vs PBO: −0.3 vs −0.1, P = .19

      Pioglitazone vs PBO: −0.4 vs −0.1, P = .10
      Hoofnagle et al
      • Hoofnagle J.H.
      • Van Natta M.L.
      • Kleiner D.E.
      • et al.
      Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis.
      USANondiabetic patients with biopsy-confirmed NASH (PIVENS; NCT00063622)Interventional study (RCT)139Vitamin E 800 IU vs PBO96 wkMean change in NAS:

      Vitamin E – ALT responders vs nonresponders:
      ALT response was defined as a decrease to ≤40 U/L and by ≥30% of baseline.
      −3.0 vs −0.8, P < .001

      PBO – ALT responders vs nonresponders: −1.6 vs −0.4, P = .03

      ≥2-point reduction in NAS:

      Vitamin E – ALT responders vs nonresponders: 82% vs 32%, P < .001

      PBO – ALT responders vs nonresponders: 55% vs 25%, P = .07
      Mean change in fibrosis score:

      Vitamin E – ALT responders vs nonresponders: −0.5 vs −0.2, P = .34

      PBO – ALT responders vs nonresponders: −0.8 vs 0, P = .04
      Lassailly et al
      • Lassailly G.
      • Caiazzo R.
      • Buob D.
      • et al.
      Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients.
      FranceMorbidly obese patients with biopsy-proven NASH (Lille Bariatric Cohort, 1994–2013)Prospective observational cohort study109Bariatric surgery1 y1-y postsurgery:
      • NASH disappeared from 85% (95% CI 75.8–92.2) of patients
      • Steatosis detected in 10% of tissue (vs 60% presurgery; P < .0001)
      • Mean NAS reduced from 5 (presurgery) to 1 (P < .0001)
      • Hepatocyte ballooning and lobular inflammation reduced in 84.2% and 67.1% of samples, respectively
      1-y postsurgery:
      • Significant improvement in fibrosis observed based on Metavir (P < .003) and Kleiner (P < .0001) scores
      • Fibrosis according to Metavir score was reduced in 33.8% (95% CI 23.6–45.2) of patients overall and 46.6% (95% CI 33.3–60.1) of patients with a fibrosis score ≥1 at baseline
        • Baseline score (0/1/2/3/4), n: 22/32/17/6/3
        • 1-y, n: 35/26/11/6/2
      • Fibrosis according to Kleiner score was reduced in 46.3% (95% CI 35.8–55.8) of patients overall and 51.4% (95% CI 39.3–63.4) of patients with a fibrosis score ≥1 at baseline
        • Baseline score (0/1a/1b/1c/2/3/4), n: 8/10/6/9/26/19/3
        • 1-y, n: 26/7/4/13/15/14/2
      Li et al
      • Li Y.H.
      • Yang L.H.
      • Sha K.H.
      • et al.
      Efficacy of poly-unsaturated fatty acid therapy on patients with nonalcoholic steatohepatitis.
      ChinaPatients with pathologically diagnosed NASHInterventional study (RCT)78PUFA vs saline6 moSignificant reduction in steatosis grade, necroinflammatory grade, and ballooning score vs controlSignificant reduction in fibrosis stage vs control: 1.6 vs 1.1, P = .02
      Vilar-Gomez et al
      • Vilar-Gomez E.
      • Martinez-Perez Y.
      • Calzadilla-Bertot L.
      • et al.
      Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis.
      CubaPatients with biopsy-proven NASH (single center, 2009–2013)Prospective cohort study293Lifestyle1 yNAS improvement ≥2 points: 47%

      NAS change from baseline:

      −1.58 ± 0.27
      Regression:
      Change by ≥1 point.
      19%

      Stable: 65%

      Progression:
      Change by ≥1 point.
      16%

      Change from baseline: −0.01 ± 0.02
      Cusi et al
      • Cusi K.
      • Orsak B.
      • Bril F.
      • et al.
      Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial.
      USAPatients with prediabetes or T2D and biopsy-proven NASH (NCT00994682)Interventional study (RCT)101Pioglitazone vs PBO18 mo>2-point reduction in NAS without worsening of fibrosis:

      58% vs 17%, P < .001

      Resolution of NASH:

      51% vs 19%, P < .001
      >1-point improvement: 39% vs 25%, P = .130

      Mean change in score: –0.5 vs 0, P = .039
      Ratziu et al
      • Ratziu V.
      • Harrison S.A.
      • Francque S.
      • et al.
      Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening.
      USA and EuropePatients with NASH without cirrhosis (NCT01694849)Interventional study (RCT)183Elafibranor 120 mg vs PBO52 wkNASH resolved
      Resolution of NASH as disappearance of ballooning (score 0), together with either disappearance of lobular inflammation or the persistence of mild lobular inflammation only (score 0 or 1), and resulting in an overall pathologic diagnosis of either steatosis alone or steatosis with mild inflammation.
      with no worsening of fibrosis:

      19% vs 12%; OR 2.31, P < .045
      Patients with NASH resolution after receiving elafibranor 120 mg had reduced liver fibrosis stages compared with those without NASH resolution: mean reduction of 0.65 ± 0.61 in responders vs an increase of 0.10 ± 0.98 in nonresponders; P < .001
      Friedman et al
      • Friedman S.L.
      • Ratziu V.
      • Harrison S.A.
      • et al.
      A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis.
      GlobalPatients with biopsy-proven NASH, NAS ≥4 with ≥1 in each component, and NASH CRN stage 1–3 liver fibrosis (CENTAUR; NCT02217475)Interventional study (RCT)289Cenicriviroc
      The cencricriviroc program has been canceled after early termination of AURORA (NCT03028740) due to lack of efficacy.
      vs PBO
      1 y≥2-point NAS improvement with no worsening of fibrosis:

      15.9% vs 18.8%, P = .52

      Complete resolution of steatohepatitis and no worsening of fibrosis stage:

      8% vs 6%, P = .49
      Improvement in fibrosis by ≥1 stage with no worsening of steatohepatitis:

      20.0% vs 10.4%, P = .0234
      Oliveira et al
      • Oliveira C.P.
      • Cotrim H.P.
      • Stefano J.T.
      • et al.
      N-acetylcysteine and/or ursodeoxycholic acid associated with metformin in non-alcoholic steatohepatitis: an open-label multicenter randomized controlled trial.
      BrazilPatients with biopsy-confirmed NASHInterventional study (RCT)53MTF + NAC + UDCA vs MTF + UDCA vs MTF + NAC48 wkStatistically significant improvements from baseline in steatosis degree, ballooning, and in NAS for only the NAC + MTF groupNo progression of fibrosis and inflammation in any group
      Francque et al
      • Francque S.M.
      • Bedossa P.
      • Ratziu V.
      • et al.
      A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH.
      USA, Australia, Canada, Mauritius, and Europe (12 countries)Patients with noncirrhotic, highly active NASH (NATIVE; NCT03008070)Interventional study (RCT)247Lanifibranor (1200 mg or 800 mg) vs PBO24 wk≥2-point SAF-A
      The activity part of the SAF scoring system that incorporates scores for ballooning and inflammation.
      improvement with no worsening of fibrosis:

      1200 mg: 55% vs 33%, P = .007

      800 mg: 48% vs 33%, P = .07

      Resolution of NASH with no worsening of fibrosis:

      1200 mg: 49% vs 22%

      800 mg: 39% vs 22%

      Resolution of NASH and ≥1-stage fibrosis improvement:

      1200 mg: 35% vs 9%

      800 mg: 25% vs 9%
      ≥1-stage fibrosis improvement with no worsening of NASH:

      1200 mg: 48% vs 29%

      800 mg: 34% vs 29%
      Gurka et al
      • Harrison S.A.
      • Neff G.
      • Guy C.D.
      • et al.
      Efficacy and safety of aldafermin, an engineered FGF19 analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis.
      USAPatients with biopsy-confirmed NASH (PIVENS; NCT00063622)Interventional study (RCT)201Vitamin E vs pioglitazone vs PBO96 wkSignificant decrease in MetS-Z at 48 and 96 wk with pioglitazone
      Harrison et al
      • Harrison S.A.
      • Neff G.
      • Guy C.D.
      • et al.
      Efficacy and safety of aldafermin, an engineered FGF19 analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis.
      USAPatients with biopsy-confirmed NASH (NCT02443116)Interventional study (RCT)78Aldafermin vs PBO24 wkResolution of NASH with no worsening of fibrosis:

      24% vs 9%, P = .20

      Resolution of NASH and ≥1-stage fibrosis improvement:

      22% vs 0%, P = .015

      ≥2-point improvement in NAS and no worsening of fibrosis:

      62% vs 9%, P < .001
      ≥1-stage fibrosis improvement with no worsening of NASH:

      38% vs 18%, P = .10
      Harrison et al
      • Harrison S.A.
      • Ruane P.J.
      • Freilich B.L.
      • et al.
      Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial.
      USAPatients with biopsy-confirmed NASH, F1–3 fibrosis (BALANCED; NCT03976401)Interventional study (RCT)80Efruxifermin (28 mg, 50 mg, or 70 mg) or PBO16 wkResolution of NASH with no worsening of fibrosis:
      Only 2 patients receiving placebo were included in the biopsy-evaluable set; therefore, meaningful comparison with placebo is not possible.


      28 mg, 46%; 50 mg, 54%; 70 mg, 43%; PBO, 50%

      Resolution of NASH and ≥1-stage fibrosis improvement:
      Only 2 patients receiving placebo were included in the biopsy-evaluable set; therefore, meaningful comparison with placebo is not possible.


      28 mg, 31%; 50 mg, 39%; 70 mg, 14%; PBO, 0%

      ≥2-point improvement in NAS:
      Only 2 patients receiving placebo were included in the biopsy-evaluable set; therefore, meaningful comparison with placebo is not possible.


      28 mg, 92%; 50 mg, 77%; 70 mg, 86%; PBO, 50%

      ≥2-point improvement in NAS with no worsening of fibrosis:
      Only 2 patients receiving placebo were included in the biopsy-evaluable set; therefore, meaningful comparison with placebo is not possible.


      28 mg, 77%; 50 mg, 77%; 70 mg, 79%; PBO, 50%
      ≥1-stage fibrosis improvement:
      Only 2 patients receiving placebo were included in the biopsy-evaluable set; therefore, meaningful comparison with placebo is not possible.


      28 mg, 54%; 50 mg, 77%; 70 mg, 36%; PBO, 0%

      ≥2-stage fibrosis improvement:
      Only 2 patients receiving placebo were included in the biopsy-evaluable set; therefore, meaningful comparison with placebo is not possible.


      28 mg, 31%; 50 mg, 39%; 70 mg, 14%; PBO, 0%

      ≥1-stage fibrosis improvement with no worsening of NASH:
      Only 2 patients receiving placebo were included in the biopsy-evaluable set; therefore, meaningful comparison with placebo is not possible.


      28 mg, 46%; 50 mg, 62%; 70 mg, 36%; PBO, 0%

      ≥2-stage fibrosis improvement with no worsening of NASH:
      Only 2 patients receiving placebo were included in the biopsy-evaluable set; therefore, meaningful comparison with placebo is not possible.


      28 mg, 23%; 50 mg, 31%; 70 mg, 14%; PBO, 0%
      Huang et al
      • Huang J.F.
      • Dai C.Y.
      • Huang C.F.
      • et al.
      First-in-Asian double-blind randomized trial to assess the efficacy and safety of insulin sensitizer in nonalcoholic steatohepatitis patients.
      TaiwanTreatment-naive Taiwanese patients with biopsy-confirmed NASH (NCT01068444)Interventional study (RCT)90Pioglitazone vs PBO24 wkNASH improvement with no worsening of fibrosis:

      46.7% vs 11.1%, P = .002

      Resolution of NASH:

      26.7% vs 11.1%, P = .103

      Other:

      Statistically significant improvements from baseline in steatosis degree, lobular inflammation, and NAS for pioglitazone group only
      Fibrosis:

      No significant change with pioglitazone; significant increase in PBO arm (P = .007)
      Kedarisetty et al
      • Kedarisetty C.K.
      • Bhardwaj A.
      • Kumar G.
      • et al.
      Efficacy of combining pentoxiphylline and vitamin E versus vitamin E alone in non-alcoholic steatohepatitis– a randomized pilot study.
      IndiaConsecutive patients with biopsy-confirmed NASH (NCT01384578)Interventional study (RCT)69Pentoxiphylline + vitamin E vs vitamin E alone52 wkNo difference in reduction in NAS score between treatment groups (significant reduction in both groups, both P = .03)Significantly greater reduction in fibrosis score with combination vs vitamin E alone at 1 y (P = .004)

      Significant reduction in liver stiffness by FibroScan seen in both groups (both P < .05)
      Loomba et al
      • Loomba R.
      • Noureddin M.
      • Kowdley K.V.
      • et al.
      Combination therapies including cilofexor and firsocostat for bridging fibrosis and cirrhosis attributable to NASH.
      USA, Canada, Australia, New Zealand, and Hong KongPatients with biopsy-confirmed NASH and bridging fibrosis or compensated cirrhosis (F3–F4) (ATLAS; NCT03449446)Interventional study (RCT)392Selonsertib or cilofexor or firsocostat or cilofexor + selonsertib or firsocostat + selonsertib or cilofexor + firsocostat vs PBO48 wkNASH resolution with no worsening of fibrosis:

      F vs PBO: 2.9% vs 0%, P = .65

      C vs PBO: 0% vs 0%, P = 1.00

      FS vs PBO: 1.4% vs 0%, P = .74

      CS vs PBO: 1.5% vs 0%, P = .76

      CF vs PBO: 4.5% vs 0%, P = .35

      ≥2-point improvement in NAS:

      F vs PBO: 29% vs 11%, P = NS

      C vs PBO: 18% vs 11%, P = NS

      FS vs PBO: 14% vs 11%, P = NS

      CS vs PBO: 9% vs 11%, P = NS

      CF vs PBO: 35% vs 11%, P ≤ .05
      ≥1-stage fibrosis improvement with no worsening of NASH:

      F vs PBO: 12% vs 11%, P = .94

      C vs PBO: 12% vs 11%, P = .96

      FS vs PBO: 15% vs 11%, P = .62

      CS vs PBO: 19% vs 11%, P = .26

      CF vs PBO: 21% vs 11%, P = .17
      Newsome et al
      • Newsome P.N.
      • Buchholtz K.
      • Cusi K.
      • et al.
      A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.
      USA, Canada, Australia, Japan, Russian Federation, and Europe (11 countries)Patients with biopsy-confirmed NASH and BMI ≥25 kg/m2 ± T2D (NCT02970942)Interventional study (RCT)320Semaglutide (0.4 mg, 0.2 mg, or 0.1 mg) vs PBO72 wkNASH resolution with no worsening of fibrosis:

      0.4 mg: 59% vs 17%, P < .001

      0.2 mg: 36% vs 17%

      0.1 mg: 40% vs 17%

      NASH resolution and improvement in fibrosis:

      0.4 mg: 37% vs 15%

      ≥1-point improvement in NAS:

      0.4 mg, 83%; 0.2 mg, 80%; 0.1 mg, 71%; PBO, 44%
      ≥1-stage fibrosis improvement with no worsening of NASH:

      0.4 mg: 43% vs 33%, P = .48

      0.2 mg: 32% vs 33%

      0.1 mg: 49% vs 33%

      ≥2-stage fibrosis improvement with no worsening of NASH:

      0.4 mg, 20%; 0.2 mg, 19%; 0.1 mg, 25%; PBO, 17%
      Okanoue et al
      • Okanoue T.
      • Sakamoto M.
      • Harada K.
      • et al.
      Efficacy and safety of apararenone (MT-3995) in patients with nonalcoholic steatohepatitis: a randomized controlled study.
      JapanPatients with biopsy-confirmed NASHInterventional study (RCT)48Apararenone vs PBO72 wk≥2-point improvement in NAS without worsening of fibrosis:

      20.8% vs 26.1%, P = .736
      ≥1-stage fibrosis improvement with no worsening of NAS:

      41.7% vs 26.1%, P = .203

      ≥1-stage fibrosis improvement:

      45.8% vs 30.4%, P = .291
      Ratziu et al
      • Ratziu V.
      • de Guevara L.
      • Safadi R.
      • et al.
      Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial.
      USA, Mexico, Israel, Chile, Georgia, Hong Kong, and Europe (5 countries)Patients with biopsy-confirmed NASH, BMI ≥25–40 kg/m2 and T2D or prediabetes (ARREST; NCT02279524)Interventional study (RCT)247Aramchol (600 mg or 400 mg) vs PBO52 wkNASH resolution with no worsening of fibrosis:

      600 mg: 16.7% vs 5%, P = .051

      400 mg: 7.5% vs 5%, P = .50

      ≥2-point improvement in NAS
      Contributed to by at least 2 of: steatosis, inflammation, ballooning.
      with no worsening of fibrosis

      600 mg: 25.6% vs 17.5%, P = .31

      400 mg: 20.0% vs 17.5%, P = .56

      ≥2-point improvement in SAF-A with no worsening of fibrosis:

      600 mg: 35.9% vs 25.0%, P = .16

      400 mg: 25.0% vs 25.0%, P = .86
      ≥1-stage fibrosis improvement with no worsening of NAS:

      600 mg: 29.5% vs 17.5%, P = .21

      400 mg: 21.3% vs 17.5%, P = .84
      Bold text denotes clinical endpoints.
      ALT, alanine aminotransferase; BMI, body mass index; C, cilofexor; CF, cilofexor + firsocostat; CI, confidence interval; CRN, Clinical Research Network; CS, cilofexor + selonsertib; F, firsocostat; FS, firsocostat + selonsertib; MetS-Z, metabolic syndrome severity Z-score; MTF, metformin; NAC, N-acetylcysteine; NAFLD, nonalcoholic fatty liver disease; NAS, NAFLD Activity Score; NASH, nonalcoholic steatohepatitis; NS, not significant; OR, odds ratio; PBO, placebo; PIVENS, Pioglitazone vs Vitamin E vs Placebo for the Treatment of Non-Diabetic Patients with Nonalcoholic Steatohepatitis; PUFA, polyunsaturated fatty acid; RCT, randomized controlled trial; SAF-A, Steatosis, Activity, and Fibrosis-Activity; T2D, type 2 diabetes; UDCA, ursodeoxycholic acid.
      a Improvement by ≥1 point in hepatocellular ballooning score; no increase in the fibrosis score; and either a decrease in the activity score for NAFLD to ≤3 or a ≥2-point decrease in the activity score, with a ≥1-point decrease in either the lobular inflammation or steatosis score.
      b ALT response was defined as a decrease to ≤40 U/L and by ≥30% of baseline.
      c Change by ≥1 point.
      d Resolution of NASH as disappearance of ballooning (score 0), together with either disappearance of lobular inflammation or the persistence of mild lobular inflammation only (score 0 or 1), and resulting in an overall pathologic diagnosis of either steatosis alone or steatosis with mild inflammation.
      e The cencricriviroc program has been canceled after early termination of AURORA (NCT03028740) due to lack of efficacy.
      f The activity part of the SAF scoring system that incorporates scores for ballooning and inflammation.
      g Only 2 patients receiving placebo were included in the biopsy-evaluable set; therefore, meaningful comparison with placebo is not possible.
      h Contributed to by at least 2 of: steatosis, inflammation, ballooning.
      Resolution of NASH may result in improvement in metabolic parameters. Two post-hoc analyses of the Pioglitazone vs Vitamin E vs Placebo for the Treatment of Non-Diabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) study, which pooled data from patients receiving pioglitazone, vitamin E, and placebo in nondiabetic patients with NASH, found that NASH resolution was associated with favorable changes in triglycerides, high-density lipoprotein levels, and lipoprotein fractions, compared with patients without NASH resolution.
      • Corey K.E.
      • Vuppalanchi R.
      • Wilson L.A.
      • et al.
      NASH resolution is associated with improvements in HDL and triglyceride levels but not improvement in LDL or non-HDL-C levels.
      ,
      • Corey K.E.
      • Wilson L.A.
      • Altinbas A.
      • et al.
      Relationship between resolution of non-alcoholic steatohepatitis and changes in lipoprotein sub-fractions: a post-hoc analysis of the PIVENS trial.

      Risk Factors for Progression or Resolution of NASH and/or Fibrosis

      Five publications reported on factors associated with regression or resolution of NASH or fibrosis (Table 3).
      • Ajmera V.
      • Belt P.
      • Wilson L.A.
      • et al.
      Among patients with nonalcoholic fatty liver disease, modest alcohol use is associated with less improvement in histologic steatosis and steatohepatitis.
      ,
      • Sanyal A.J.
      • Harrison S.A.
      • Ratziu V.
      • et al.
      The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.
      ,
      • Gurka M.J.
      • Mack J.A.
      • Chi X.
      • et al.
      Use of metabolic syndrome severity to assess treatment with vitamin E and pioglitazone for non-alcoholic steatohepatitis.
      ,
      • Okanoue T.
      • Sakamoto M.
      • Harada K.
      • et al.
      Efficacy and safety of apararenone (MT-3995) in patients with nonalcoholic steatohepatitis: a randomized controlled study.
      ,
      • Vilar-Gomez E.
      • Calzadilla-Bertot L.
      • Friedman S.L.
      • et al.
      Serum biomarkers can predict a change in liver fibrosis 1 year after lifestyle intervention for biopsy-proven NASH.
      In the PIVENS trial, factors associated with higher odds of NASH resolution included reductions in alanine aminotransferase (ALT) and aspartate aminotransferase (AST; vitamin E and pioglitazone arms), lower baseline metabolic syndrome (MetS) severity Z-score (MetS-Z; vitamin E and pioglitazone arms), and reductions in MetS-Z (placebo arm).
      • Gurka M.J.
      • Mack J.A.
      • Chi X.
      • et al.
      Use of metabolic syndrome severity to assess treatment with vitamin E and pioglitazone for non-alcoholic steatohepatitis.
      In patients not receiving pharmacologic intervention, lower odds of NASH resolution were also reported in consistent moderate drinkers compared with consistent nondrinkers.
      • Ajmera V.
      • Belt P.
      • Wilson L.A.
      • et al.
      Among patients with nonalcoholic fatty liver disease, modest alcohol use is associated with less improvement in histologic steatosis and steatohepatitis.
      Factors that predicted fibrosis regression included higher baseline fibrosis stage, lower baseline levels of fibrosis markers, and reduced/normal liver enzyme levels.
      • Sanyal A.J.
      • Harrison S.A.
      • Ratziu V.
      • et al.
      The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.
      ,
      • Okanoue T.
      • Sakamoto M.
      • Harada K.
      • et al.
      Efficacy and safety of apararenone (MT-3995) in patients with nonalcoholic steatohepatitis: a randomized controlled study.
      Table 3Predictors of NASH/Fibrosis Progression or Resolution
      ReferenceCountryData source/populationStudy typeNPredictive factors
      Markers of disease regression/resolution
       Vilar-Gomez et al
      • Vilar-Gomez E.
      • Calzadilla-Bertot L.
      • Friedman S.L.
      • et al.
      Serum biomarkers can predict a change in liver fibrosis 1 year after lifestyle intervention for biopsy-proven NASH.
      CubaPatients with biopsy-proven NASH who underwent 12 mo lifestyle modification (single center, 2009–2013)Observational cohort study261
      • Factors predicting improvement in liver fibrosis (≥1 stage) 1 y after lifestyle intervention were:
        • Age at baseline (OR 0.94; P = .04)
        • Normal levels of ALT at EOT (<19 U/L for women and <30 U/L for men; OR 9.7; P < .01)
        • Change in HbA1c (OR 0.39; P < .01), HOMA-IR (OR 0.88; P = .01), platelets count (OR 1.22; P < .01), NFS (OR 0.27; P < .01)
      • Change in liver enzymes (ALT, AST) and other fibrosis models (APRI, FIB-4) were not associated with fibrosis improvement even after adjustments by improvements in other histologic outcomes
       Ajmera et al
      • Ajmera V.
      • Belt P.
      • Wilson L.A.
      • et al.
      Among patients with nonalcoholic fatty liver disease, modest alcohol use is associated with less improvement in histologic steatosis and steatohepatitis.
      USANASH CRN participants ≥21 y with biopsy-confirmed NAFLD who did not receive specific pharmacologic therapy for NASH and had alcohol use history within 2 y of initial biopsy
      Participants were drawn from 3 groups: (1) the adult NAFLD Database study, (2) adults on placebo in the Pioglitazone vs Vitamin E vs Placebo for the Treatment of Non-Diabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial, and (3) adults on placebo in the Farnesoid × Receptor Ligand Obeticholic Acid in NASH Treatment (FLINT) trial.
      Observational cohort studyNASH: 182

      Borderline NASH: 49

      NAFL: 54
      • In patients with confirmed NASH, consistent modest drinkers had significantly lower odds of NASH resolution vs consistent nondrinkers (22% vs 11%; adjusted OR 0.32, 95% CI 0.11–0.92; P = .04)
        Nondrinkers were defined as current “never” drinkers who had not, over the course of their lifetime, had ≥1 alcoholic drink per month during a 12-month period or had ≥3 drinks per day for ≥3 consecutive days, whereas modest drinkers were defined as those drinking ≤2 drinks on a typical day in the absence of monthly (or more frequent) heavy drinking. Consistent drinkers and nondrinkers were those whose drinking status did not change between baseline and follow-up.
        ,
        Adjusted for age at biopsy, sex, race, and ever smoker.
      • Modest drinkers who reported nondrinking at follow-up had the second highest proportion with NASH resolution (17%)
      • Changes in lobular inflammation, hepatocyte ballooning, portal inflammation, fibrosis stage, and NAS were not significantly different between consistent drinkers and nondrinkers
       Sanyal et al
      • Sanyal A.J.
      • Harrison S.A.
      • Ratziu V.
      • et al.
      The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.
      GlobalPatients with biopsy-confirmed NASH and bridging fibrosis (F3) or compensated cirrhosis (F4)
      Simtuzumab- and placebo-treated patients were pooled based on the assumption that simtuzumab has no biological activity, supported by its failure to improve liver histology, portal pressure, liver biochemistry, and serum fibrosis markers in RCTs.
      Interventional study (Phase 2b RCTs
      NCT01672866 and NCT01672879.
      )
      NASH with F3 fibrosis: 217

      NASH with compensated cirrhosis: 258
      • In patients with bridging fibrosis at baseline, fibrosis regression was associated with:
        • Baseline Ishak fibrosis stage (4 vs 3; P = .040)
        • Lower baseline hepatic collagen content (P = .044)
        • Greater reduction in hepatic collagen over time (P < .0001)
        • Lower α-SMA expression at baseline (P = .007)
        • α-SMA reduction at wk 96 (P < .001)
        • Lower baseline ELF, NFS, FIB-4, and APRI (all P ≤ .013)
        • Smaller increase in LOXL2 over time (P = .001)
      • In patients with compensated cirrhosis at baseline, cirrhosis regression was associated with:
        • Baseline Ishak fibrosis stage (6 vs 5; P = .034)
        • Lower levels of α-SMA expression at baseline (P = .029)
        • Smaller increases in α-SMA expression or hepatic collagen content over time (both P < .001)
        • Lower baseline ELF, NFS, FIB-4, and APRI (all P ≤ .021)
      • Baseline levels of serum LOXL2, FibroSure/FibroTest, NAS, and severity of steatosis, lobular inflammation, and ballooning were not associated with fibrosis improvement in either group, nor were changes in serum fibrosis markers over time (apart from LOXL2 in patients with bridging fibrosis at baseline)
       Gurka et al
      • Gurka M.J.
      • Mack J.A.
      • Chi X.
      • et al.
      Use of metabolic syndrome severity to assess treatment with vitamin E and pioglitazone for non-alcoholic steatohepatitis.
      USAPatients with biopsy-confirmed NASH (PIVENS; NCT00063622)Interventional study (RCT)201
      • Inverse association between baseline MetS-Z and NASH resolution during treatment with pioglitazone (OR 0.38, 95% CI 0.15–0.96) and vitamin E (OR 0.41, 95% CI 0.19–0.90), but not placebo
      • Week 48 reductions in MetS-Z were associated with NASH resolution in the placebo group (OR 0.36, 95% CI 0.16–0.82), but not in the vitamin E and pioglitazone groups
      • Week 48 reductions in AST and ALT were associated with higher odds of NASH resolution in vitamin E and pioglitazone groups
       Okanoue et al
      • Okanoue T.
      • Sakamoto M.
      • Harada K.
      • et al.
      Efficacy and safety of apararenone (MT-3995) in patients with nonalcoholic steatohepatitis: a randomized controlled study.
      JapanPatients with biopsy-confirmed NASHInterventional study (RCT)47
      • Multivariate analysis showed that improvement in the FIB-4 index was significantly influenced by total bilirubin (P < .0001), GGT (P < .0001), ELF score (P < .0001), HDL-C (P = .0207), soluble VCAM-1 (P = .0215), and baseline Kleiner fibrosis staging (P = .0408)
      Markers of disease progression and/or more advanced disease
       Sorrentino et al
      • Sorrentino P.
      • Terracciano L.
      • D'Angelo S.
      • et al.
      Predicting fibrosis worsening in obese patients with NASH through parenchymal fibronectin, HOMA-IR, and hypertension.
      ItalyObese (BMI >30 kg/m2) patients with NAFLD (single center, 1993–2003)Observational cohort studyTotal patients: 132

      NASH: 83

      Baseline fibrosis score (Brunt): 0, 85; 1, 30; 2, 15; 3, 2; 4, 0
      • In the overall NAFLD population, independent predictors worsening fibrosis from baseline to follow-up were:
        • Intralobular fibronectin >1 (OR 14.1; P < .001)
        • Hypertension (OR 4.8; P = .028)
        • HOMA-IR score >10 (OR 1.9; P = .004)
      • These factors also correlated with more advanced fibrosis at baseline
       Kruger et al
      • Kruger F.C.
      • Daniels C.R.
      • Kidd M.
      • et al.
      APRI: a simple bedside marker for advanced fibrosis that can avoid liver biopsy in patients with NAFLD/NASH.
      South AfricaPatients with biopsy-proven NAFLD recruited at 3 South African centersObservational cohort studyTotal patients: 111

      NASH: 41%

      Advanced fibrosis: 17%
      • In the overall NAFLD population, APRI score increased with fibrosis stage (no/mild fibrosis: 0.7; advanced fibrosis: 1.54
      • Lower NFS was also associated with more advanced fibrosis (P < .01), but AST:ALT ratio was not significantly associated with fibrosis stage (P = .06)
      • APRI was superior to AST:ALT ratio and comparable to NFS for predicting advanced fibrosis
       Bando et al
      • Bando Y.
      • Kanehara H.
      • Aoki K.
      • et al.
      The glycated albumin to glycated haemoglobin ratio increases along with the fibrosis stage in non-alcoholic steatohepatitis.
      JapanPatients with biopsy-proven NASH treated at 2 Japanese centersObservational cohort-analytic study36
      • Serum ALT, platelet count, and hemoglobin level decreased with progression of fibrosis (P = .026, P = .001, and P = .001, respectively)
      • Histologic progression of fibrosis was also associated with increasing GA (P = .004) and GA/HbA1c ratio (P = .003)
      • Significant inverse correlation was seen between GA/HbA1c ratio with serum ALT (r = −0.572, P < .001) and platelet count (r = −0.663, P < .0001)
       Jung et al
      • Jung K.Y.
      • Cho S.Y.
      • Kim H.J.
      • et al.
      Nonalcoholic steatohepatitis associated with metabolic syndrome: relationship to insulin resistance and liver histology.
      South KoreaBiopsy-proven and nonbiopsy-proven NASH patients (single center, 2003–2012)Observational cohort studyTotal patients: 94

      Biopsy-proven NASH: 41

      Brunt fibrosis stage (biopsy-proven NASH): S1, 15; S2, 21; S3, 4; S4, 1
      • In patients with biopsy-proven NASH, serum AST:ALT ratio significantly increased with fibrosis stage:
        • S1, 0.4 ± 0.2; S2, 0.6 ± 0.3; S3, 1.3 ± 0.5; S4, 2.1 (P = .029)
      • Serum HDL-C (mg/dL) significantly decreased with fibrosis stage:
        • S1, 45 ± 15; S2, 39 ± 8; S3, 38 ± 10; S4, 8 (P = .034)
      • No significant correlation was seen between fibrosis stage and BMI, triglycerides, AST, ALT, fasting blood sugar, or HOMA-IR
       Cengiz et al
      • Cengiz M.
      • Ozenirler S.
      • Yılmaz G.
      • et al.
      Impact of hepatic immunoreactivity of angiotensin-converting enzyme 2 on liver fibrosis due to non-alcoholic steatohepatitis.
      TurkeyConsecutive patients with biopsy-proven NASH (single center, 2009–2013)Observational cohort-analytic study108 (F1/2: 94; F3/4: 14)
      • Hepatic ACE2 immunoreactivity was seen in 65.9% of patients with mild (F1/2) fibrosis vs 28.5% of those with advanced fibrosis
      • Presence of ACE2 immunoreactivity was inversely correlated with fibrosis score (r = −0.337, P < .001) and was an independent predicting factor for liver fibrosis by univariate analysis (OR 0.194, 95% CI 0.042–0.897)
      • There were no correlations between ACE2 immunoreactivity and other histopathological features of NASH such as steatosis, inflammation, and ballooning (P > .05)
       Huang et al
      • Huang J.F.
      • Yeh M.L.
      • Yu M.L.
      • et al.
      Hyperuricemia inversely correlates with disease severity in Taiwanese nonalcoholic steatohepatitis patients.
      TaiwanBaseline data of RCT participants with biopsy-proven NASH (NCT01068444)Observational cohort study130
      • There was a significant inverse correlation between fibrosis stages with:
        • Uric acid levels: F0, 7.2 mg/dL; F1, 6.5 mg/dL; F2, 6.3 mg/dL; F3/4, 6.0 mg/dL (P = .04)
        • Presence of hyperuricemia:
          Presence of hyperuricemia defined as ≥7 mg/dL for men and ≥6 mg/dL for women.
          F0/1, 48.4%; F2, 33.3%; F3/4, 9.1% (P = .01)
      • Multivariate logistic regression showed that decreased serum albumin (<3.5 g/dL; OR 40.0, 95% CI 4.5–300, P = .001) and absence of hyperuricemia (OR 5.6, 95% CI 1.5–21.7, P = .01) were significantly associated with advanced fibrosis
       Sebastiani et al
      • Sebastiani G.
      • Alshaalan R.
      • Wong P.
      • et al.
      Prognostic value of non-invasive fibrosis and steatosis tools, hepatic venous pressure gradient (HVPG) and histology in nonalcoholic steatohepatitis.
      CanadaConsecutive patients with transjugular biopsy-proven NASH (single center, 2004–2013)Observational cohort study148
      • After adjustment for age, sex, and diabetes, incidence of clinical outcomes
        Clinical outcomes were death, liver transplantation, and end-stage hepatic complications (HCC, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, de novo varices, or significant worsening of varices).
        was significantly greater (HR, 95% CI) in patients with:
        • HVPG >10 mm Hg (9.60, 3.07–30.12)
        • Histologic fibrosis stage (F3-F4; 3.14, 1.41–6.95)
        • APRI >1.5 (5.02, 1.6–15.7)
        • FIB-4 >3.25 (6.33, 1.98–20.2)
        • NFS >0.676 (11.9, 3.79–37.4)
      • Prognostic values of associated factors were (AUC, 95% CI): histologic fibrosis stage (0.85, 0.76–0.93), HVPG (0.81, 0.70–0.91), APRI (0.89, 0.82–0.96), FIB-4 (0.89, 0.83–0.95), NFS (0.79, 0.69–0.91), transient elastography (0.87, 0.77–0.97)
      • Neither histologic steatosis nor noninvasive steatosis methods predicted outcomes (AUC <0.50)
       Seko et al
      • Seko Y.
      • Sumida Y.
      • Tanaka S.
      • et al.
      Serum alanine aminotransferase predicts the histological course of non-alcoholic steatohepatitis in Japanese patients.
      JapanPatients with biopsy-confirmed NASH (single center, 1999–2014)Observational cohort study52
      • Multivariate analysis identified ALT nonresponse
        ALT response was defined as a decrease of 30% or more from baseline.
        as a significant and independent predictor of:
        • Deterioration of NAS: HR 5.85; P = .031
        • Progression of liver fibrosis: HR 4.50; P = .029
       Sourianarayanane et al
      • Sourianarayanane A.
      • Talluri J.
      • Humar A.
      • et al.
      Stage of fibrosis and portal pressure correlation in nonalcoholic steatohepatitis.
      USALiver disease patients who underwent transjugular biopsy with pressure measurements (single center, 2001–2013)Observational cohort studyTotal patients: 142

      NASH: 35

      Fibrosis stage (NASH): S0, 0; S1, 9; S2, 6; S3, 8; S4, 12
      • Strong correlations were reported between increasing HVPG (r = 0.64; P < .039) and WHVP (r = 0.63; P < .0001) and increasing fibrosis stage in NASH patients
      • Correlation was seen in all fibrosis stages, including noncirrhotic patients
      • At each stage of fibrosis, HVPG and WHVP measurements were lower in NASH vs HCV patients, indicating potential for underestimation of pressures or fibrosis in NASH patients
       Vilar-Gomez et al
      • Vilar-Gomez E.
      • Calzadilla-Bertot L.
      • Friedman S.L.
      • et al.
      Serum biomarkers can predict a change in liver fibrosis 1 year after lifestyle intervention for biopsy-proven NASH.
      CubaPatients with biopsy-proven NASH undertaking 12 mo lifestyle modification (single center, 2009–2013)Observational cohort study261
      • Predictors of fibrosis progression (≥1 stage) 1 y after lifestyle intervention were:
        • High baseline BMI (OR 1.09; P = .01)
        • T2D at baseline (OR 2.40; P = .02)
        • ALT normalization (<19 U/L for women and <30 U/L for men; OR 0.21; P < .01)
        • Change in platelets count (OR 0.96; P < .01), NFS (OR 1.81; P < .01)
       Mahamid et al
      • Mahamid M.
      • Mahroum N.
      • Bragazzi N.L.
      • et al.
      Folate and B12 levels correlate with histological severity in NASH patients.
      IsraelPatients with biopsy-proven NASH (single center, 2015–2017)Observational cohort study83

      Fibrosis stage: F0, 11; F1, 20; F2, 42; F3, 7; F4, 3
      • Lower folate levels were significantly correlated with increasing fibrosis stage (P < .01).
      • Low B12 levels were significantly associated with a higher fibrosis grade and NASH activity (P < .001 and P < .05, respectively)
       Barb et al
      • Barb D.
      • Bril F.
      • Kalavalapalli S.
      • et al.
      Plasma fibroblast growth factor 21 is associated with severity of nonalcoholic steatohepatitis in patients with obesity and type 2 diabetes.
      USAIndividuals with BMI >25 kg/m2 recruited from the general population (single center)Cross-sectional studyNASH: 94

      NAFL or borderline NASH: 52

      No NAFLD: 41
      • In patients with confirmed NASH, increasing plasma FGF21 level correlated with worsening fibrosis stage (β-coefficient 83 ± 20, 95% CI 44–121, P < .001)
      • FGF21 levels were not significantly changed with worsening grades of steatosis (P = .6) but were higher with greater necroinflammation scores (sum of ballooning and inflammation scores; P = .02)
       Sanyal et al
      • Sanyal A.J.
      • Harrison S.A.
      • Ratziu V.
      • et al.
      The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.
      GlobalPatients with biopsy-confirmed NASH and bridging fibrosis (F3) or compensated cirrhosis (F4)
      Simtuzumab- and placebo-treated patients were pooled based on the assumption that simtuzumab has no biological activity, supported by its failure to improve liver histology, portal pressure, liver biochemistry, and serum fibrosis markers in RCTs.
      Interventional study (Phase 2b RCTs
      NCT01672866 and NCT01672879.
      )
      NASH with F3 fibrosis: 217

      NASH with compensated cirrhosis: 258
      • In patients with bridging fibrosis at baseline, factors associated with progression to cirrhosis included:
        • Higher baseline hepatic collagen content (P = .013)
        • Greater increase in hepatic collagen over time (P < .001)
        • Higher baseline α-SMA expression (P < .001)
        • Greater increase in α-SMA change at week 96 (P < .001)
        • Higher baseline ELF, NFS, FIB-4, FibroSure/FibroTest, and APRI (all P < .001), and LOXL2 (P = .010)
        • Greater increase in ELF (P < .001), APRI (P = .029), and LOXL2 (P < .001) over time
        • Lower platelets at baseline (P < .001)
        • Higher INR at baseline (P = .026)
        • Severe hepatic ballooning at baseline (grade 2 vs 0; P = .010)
      • Ishak fibrosis stage was not associated with progression to cirrhosis (P = .46)
      • In patients with compensated cirrhosis at baseline, factors associated with liver-related clinical events
        Liver-related clinical events included ascites, hepatic encephalopathy, newly diagnosed varices, esophageal variceal bleed, ≥2-point increase in Child-Pugh score and/or MELD ≥15, and death.
        included:
        • Lack of improvement in Ishak fibrosis score (P = .027)
        • Higher baseline hepatic collagen content (P = .018)
        • Higher baseline ELF, NFS, FIB-4, APRI, LOXL2 (all P ≤ .001), and FibroSure/FibroTest (P = .006)
        • Higher baseline bilirubin, INR, and MELD (all P ≤ .007)
        • Greater increases in bilirubin, MELD, hepatic collagen, FIB-4 (all P ≤ .040), and LOXL2 (P < .001) over time
        • Lower platelets at baseline (P < .002)
        • Clinically significant portal hypertension at baseline (HVPG ≥10 mm Hg; P = .007)
        • Higher baseline HVPG and greater change over time (both P < .001)
      • • Failure to achieve ≥20% decrease in HVPG, and failure to achieve HVPG <10 mm Hg and/or a ≥20% decrease (both P = .005)
       Reddy et al
      • Reddy Y.K.
      • Marella H.K.
      • Jiang Y.
      • et al.
      Natural history of non-alcoholic fatty liver disease: a study with paired liver biopsies.
      USAElectronic medical records of patients with biopsy-proven NAFLD with ≥2 biopsies ≥1 y apart (2006–2016)Observational chart review studyNAFL: 26

      NASH: 10
      • In the overall population, baseline FIB-4 score, NFS, and AST:ALT ratio were all significantly higher in patients with fibrosis progression vs no progression of fibrosis, respectively:
        • FIB-4: 1.95 ± 0.96 vs 1.24 ± 0.73, P = .02
        • NFS: −0.29 ± 1.24 vs −1.61 ± 1.56, P = .019
        • AST:ALT ratio: 1.05 ± 0.25 vs 0.91 ± 0.72, P = .018
      • After a median 3.8 y follow-up, FIB-4 score, NFS, and AST:ALT remained significantly higher in patients whose fibrosis had progressed
      • Significantly more patients with fibrosis progression had T2D at follow-up vs those without progression (30.5% vs 25.0%, P = .04)
       Ruiz-Cassas et al
      • Ruiz-Casas L.
      • Pedra G.
      • Shaikh A.
      • et al.
      Clinical and sociodemographic determinants of disease progression in patients with nonalcoholic steatohepatitis in the United States.
      USAPatients with histologically or phenotypically confirmed NASH (GAIN study [O’Hara et al.
      • O'Hara J.
      • Finnegan A.
      • Dhillon H.
      • et al.
      Cost of non-alcoholic steatohepatitis in Europe and the USA: the GAIN study.
      • Doycheva I.
      • Zhang T.
      • Amjad W.
      • et al.
      Diabetes and hepatocellular carcinoma: incidence trends and impact of liver disease etiology.
      ] US cohort)
      Retrospective cross-sectional studyNASH: 989
      • By multivariate analysis,
        The final multivariable model included age, years since diagnosis, sex, employment status, smoking status, obesity, fibrosis stage, diagnostic biopsy, vitamin E, and liver transplant proposed at diagnosis.
        the odds of fibrosis progression were:
        • 17% higher with each year since NASH diagnosis (P < .001)
        • 41% lower for women than men (P = .016)
        • 131% higher for smokers vs nonsmokers (P = .004)
        • 89% higher for those with obesity (P = .002)
        • 395% higher when a liver transplant was proposed at diagnosis vs not proposed (P = .002)
      • Compared with those in full-time employment, the odds of fibrosis progression were:
        • 75% higher for those with part-time employment (P = .046)
        • 106% higher for patients who were retired (P = .045)
        • 108% higher for those who are unemployed (P = .039)
        • 2563% higher for those who are physically unable to work due to NASH or related complications (P = .002)
          Only 6 patients reported inability to work due to NASH; this OR should be interpreted with caution.
       Vieira Barbosa et al
      • Vieira Barbosa J.
      • Milligan S.
      • Frick A.
      • et al.
      Fibrosis-4 index as an independent predictor of mortality and liver-related outcomes in NAFLD.
      USAPatients with NAFLD/NASH from the TriNetX global federated research networkObservational cohort studyNASH: 914
      • Patients with baseline FIB-4 ≥2.67 experienced a substantial increase in all-cause mortality compared with those with FIB-4 <2.67 (P < .001)
      α-SMA, alpha-smooth muscle actin; ACE2, angiotensin-converting enzyme 2; ALT, alanine aminotransferase; APRI, AST-to-platelet ratio index; AST, aspartate aminotransferase; AUC, area under the curve; BMI, body mass index; CI, confidence interval; CRN, Clinical Research Network; ELF, enhanced liver fibrosis; EOT, end of treatment; FGF21, fibroblast growth factor 21; FIB-4, fibrosis-4; GA, glycated albumin; GGT, gamma-glutamyl transferase; HbA1c, glycated hemoglobin; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; HR, hazard ratio; HVPG, hepatic venous pressure gradient; INR, international normalized ratio; LOXL2, lysyl oxidase like 2; MELD, Model for End-Stage Liver Disease; MetS-Z, metabolic syndrome severity Z-score; NAFL, nonalcoholic fatty liver; NAFLD, nonalcoholic fatty liver disease; NAS, NAFLD Activity Score; NASH, nonalcoholic steatohepatitis; NFS, NASH fibrosis score; OR, odds ratio; PIVENS, Pioglitazone vs Vitamin E vs Placebo for the Treatment of Non-Diabetic Patients with Nonalcoholic Steatohepatitis; r, correlation coefficient; RCT, randomized controlled trial; T2D, type 2 diabetes; VCAM-1, vascular cell adhesion molecule-1; WHVP, wedge hepatic venous pressure.
      a Participants were drawn from 3 groups: (1) the adult NAFLD Database study, (2) adults on placebo in the Pioglitazone vs Vitamin E vs Placebo for the Treatment of Non-Diabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial, and (3) adults on placebo in the Farnesoid × Receptor Ligand Obeticholic Acid in NASH Treatment (FLINT) trial.
      b Nondrinkers were defined as current “never” drinkers who had not, over the course of their lifetime, had ≥1 alcoholic drink per month during a 12-month period or had ≥3 drinks per day for ≥3 consecutive days, whereas modest drinkers were defined as those drinking ≤2 drinks on a typical day in the absence of monthly (or more frequent) heavy drinking. Consistent drinkers and nondrinkers were those whose drinking status did not change between baseline and follow-up.
      c Adjusted for age at biopsy, sex, race, and ever smoker.
      d Simtuzumab- and placebo-treated patients were pooled based on the assumption that simtuzumab has no biological activity, supported by its failure to improve liver histology, portal pressure, liver biochemistry, and serum fibrosis markers in RCTs.
      e NCT01672866 and NCT01672879.
      f Presence of hyperuricemia defined as ≥7 mg/dL for men and ≥6 mg/dL for women.
      g Clinical outcomes were death, liver transplantation, and end-stage hepatic complications (HCC, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, de novo varices, or significant worsening of varices).
      h ALT response was defined as a decrease of 30% or more from baseline.
      i Liver-related clinical events included ascites, hepatic encephalopathy, newly diagnosed varices, esophageal variceal bleed, ≥2-point increase in Child-Pugh score and/or MELD ≥15, and death.
      j The final multivariable model included age, years since diagnosis, sex, employment status, smoking status, obesity, fibrosis stage, diagnostic biopsy, vitamin E, and liver transplant proposed at diagnosis.
      k Only 6 patients reported inability to work due to NASH; this OR should be interpreted with caution.
      Several publications reported on factors associated with disease progression or more advanced disease; these were predominantly cross-sectional studies that evaluated markers in patients with different stages of fibrosis (Table 3). One study in Japanese patients reported that absence of ALT response to pharmacologic treatment was associated with worsening NAS or fibrosis.
      • Seko Y.
      • Sumida Y.
      • Tanaka S.
      • et al.
      Serum alanine aminotransferase predicts the histological course of non-alcoholic steatohepatitis in Japanese patients.
      Two studies noted factors associated with liver-related clinical events in patients with compensated cirrhosis
      • Sanyal A.J.
      • Harrison S.A.
      • Ratziu V.
      • et al.
      The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.
      or NASH
      • Sebastiani G.
      • Alshaalan R.
      • Wong P.
      • et al.
      Prognostic value of non-invasive fibrosis and steatosis tools, hepatic venous pressure gradient (HVPG) and histology in nonalcoholic steatohepatitis.
      ; these included baseline (or lack of improvement in) fibrosis stage; higher baseline levels of hepatic collagen, lysyl oxidase like 2, bilirubin, international normalized ratio, and Model for End-Stage Liver Disease; lower baseline platelets; higher noninvasive tests (enhanced liver fibrosis, NAFLD fibrosis score [NFS], fibrosis-4, AST-to-platelet ratio index, FibroSure/FibroTest); and higher (or worsening/lack of improvement in) hepatic venous pressure gradient. The most prevalent factors associated with fibrosis progression or advanced fibrosis stage across the studies were higher NFS/change in NFS,
      • Reddy Y.K.
      • Marella H.K.
      • Jiang Y.
      • et al.
      Natural history of non-alcoholic fatty liver disease: a study with paired liver biopsies.
      ,
      • Sanyal A.J.
      • Harrison S.A.
      • Ratziu V.
      • et al.
      The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.
      ,
      • Vilar-Gomez E.
      • Calzadilla-Bertot L.
      • Friedman S.L.
      • et al.
      Serum biomarkers can predict a change in liver fibrosis 1 year after lifestyle intervention for biopsy-proven NASH.
      ,
      • Kruger F.C.
      • Daniels C.R.
      • Kidd M.
      • et al.
      APRI: a simple bedside marker for advanced fibrosis that can avoid liver biopsy in patients with NAFLD/NASH.
      higher AST:ALT ratio,
      • Reddy Y.K.
      • Marella H.K.
      • Jiang Y.
      • et al.
      Natural history of non-alcoholic fatty liver disease: a study with paired liver biopsies.
      ,
      • Jung K.Y.
      • Cho S.Y.
      • Kim H.J.
      • et al.
      Nonalcoholic steatohepatitis associated with metabolic syndrome: relationship to insulin resistance and liver histology.
      ALT normalization/nonresponse,
      • Vilar-Gomez E.
      • Calzadilla-Bertot L.
      • Friedman S.L.
      • et al.
      Serum biomarkers can predict a change in liver fibrosis 1 year after lifestyle intervention for biopsy-proven NASH.
      ,
      • Seko Y.
      • Sumida Y.
      • Tanaka S.
      • et al.
      Serum alanine aminotransferase predicts the histological course of non-alcoholic steatohepatitis in Japanese patients.
      higher AST-to-platelet ratio index,
      • Sanyal A.J.
      • Harrison S.A.
      • Ratziu V.
      • et al.
      The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.
      ,
      • Kruger F.C.
      • Daniels C.R.
      • Kidd M.
      • et al.
      APRI: a simple bedside marker for advanced fibrosis that can avoid liver biopsy in patients with NAFLD/NASH.
      higher fibrosis-4,
      • Reddy Y.K.
      • Marella H.K.
      • Jiang Y.
      • et al.
      Natural history of non-alcoholic fatty liver disease: a study with paired liver biopsies.
      ,
      • Sanyal A.J.
      • Harrison S.A.
      • Ratziu V.
      • et al.
      The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.
      lower platelets/change in platelet count,
      • Sanyal A.J.
      • Harrison S.A.
      • Ratziu V.
      • et al.
      The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.
      ,
      • Vilar-Gomez E.
      • Calzadilla-Bertot L.
      • Friedman S.L.
      • et al.
      Serum biomarkers can predict a change in liver fibrosis 1 year after lifestyle intervention for biopsy-proven NASH.
      ,
      • Bando Y.
      • Kanehara H.
      • Aoki K.
      • et al.
      The glycated albumin to glycated haemoglobin ratio increases along with the fibrosis stage in non-alcoholic steatohepatitis.
      and T2D.
      • Reddy Y.K.
      • Marella H.K.
      • Jiang Y.
      • et al.
      Natural history of non-alcoholic fatty liver disease: a study with paired liver biopsies.
      ,
      • Vilar-Gomez E.
      • Calzadilla-Bertot L.
      • Friedman S.L.
      • et al.
      Serum biomarkers can predict a change in liver fibrosis 1 year after lifestyle intervention for biopsy-proven NASH.
      The predictive value of some factors was not consistent. Serum ALT level and AST:ALT ratio, for example, were each reported in one study as not being significantly associated with patients’ fibrosis stage.
      • Kruger F.C.
      • Daniels C.R.
      • Kidd M.
      • et al.
      APRI: a simple bedside marker for advanced fibrosis that can avoid liver biopsy in patients with NAFLD/NASH.
      ,
      • Jung K.Y.
      • Cho S.Y.
      • Kim H.J.
      • et al.
      Nonalcoholic steatohepatitis associated with metabolic syndrome: relationship to insulin resistance and liver histology.
      Clinical and sociodemographic predictors of fibrosis progression included longer time since NASH diagnosis, male sex, current smoking, obesity, and lack of full-time employment.
      • Ruiz-Casas L.
      • Pedra G.
      • Shaikh A.
      • et al.
      Clinical and sociodemographic determinants of disease progression in patients with nonalcoholic steatohepatitis in the United States.

      Hepatic Complications of NASH

      One study reporting data from the US National Inpatient Sample found that NASH accounted for 9.3% of all cirrhosis-related hospitalizations from 2006 to 2014, with the proportion of hospital admissions due to NASH-related cirrhosis doubling from 2006–2008 to 2012–2014.
      • Axley P.
      • Ahmed Z.
      • Arora S.
      • et al.
      NASH is the most rapidly growing etiology for acute-on-chronic liver failure-related hospitalization and disease burden in the United States: a population-based study.
      Twelve studies reported the incidence (or an increased risk) of HCC in individuals with NASH, and 6 studies reported on the prevalence of NASH in HCC (Table 4 and Table A5). A study in diabetic patients with NASH and bridging fibrosis or cryptogenic cirrhosis reported that 14.7% of the study population developed HCC over the study period (2004–2016).
      • Vilar-Gomez E.
      • Vuppalanchi R.
      • Desai A.P.
      • et al.
      Long-term metformin use may improve clinical outcomes in diabetic patients with non-alcoholic steatohepatitis and bridging fibrosis or compensated cirrhosis.
      Studies in patients with NASH and cirrhosis reported development of HCC in 13% and 15% of patients, after a median 5.1 years and mean 6.8 years follow-up, respectively,
      • Amarapurkar D.N.
      • Dharod M.
      • Gautam S.
      • et al.
      Risk of development of hepatocellular carcinoma in patients with NASH-related cirrhosis.
      ,
      • Vilar-Gomez E.
      • Calzadilla-Bertot L.
      • Wong V.W.
      • et al.
      Type 2 diabetes and metformin use associate with outcomes of patients with nonalcoholic steatohepatitis-related, child-pugh A cirrhosis.
      and in LT wait list patients with NASH cirrhosis, the annual incidence of HCC was 2.7%.
      • O'Leary J.G.
      • Landaverde C.
      • Jennings L.
      • et al.
      Patients with NASH and cryptogenic cirrhosis are less likely than those with hepatitis C to receive liver transplants.
      HCC prevalence in LT recipients with NASH ranged from 16.7% to 54%.
      • Hernandez-Alejandro R.
      • Croome K.P.
      • Drage M.
      • et al.
      A comparison of survival and pathologic features of non-alcoholic steatohepatitis and hepatitis C virus patients with hepatocellular carcinoma.
      ,
      • Kern B.
      • Feurstein B.
      • Fritz J.
      • et al.
      High incidence of hepatocellular carcinoma and postoperative complications in patients with nonalcoholic steatohepatitis as a primary indication for deceased liver transplantation.
      • Zarrinpar A.
      • Faltermeier C.M.
      • Agopian V.G.
      • et al.
      Metabolic factors affecting hepatocellular carcinoma in steatohepatitis.
      • Jothimani D.
      • Danielraj S.
      • Narasimhan G.
      • et al.
      Nonalcoholic steatohepatitis: a rapidly increasing indication for liver transplantation in India.
      HCC was more common in patients with advanced (stage 3/4) fibrosis compared with early-stage (0–2) fibrosis
      • Zarrinpar A.
      • Faltermeier C.M.
      • Agopian V.G.
      • et al.
      Metabolic factors affecting hepatocellular carcinoma in steatohepatitis.
      ,
      • Hirose S.
      • Matsumoto K.
      • Tatemichi M.
      • et al.
      Nineteen-year prognosis in Japanese patients with biopsy-proven nonalcoholic fatty liver disease: lean versus overweight patients.
      and in patients with diabetes vs without.
      • Cho Y.
      • Lim S.K.
      • Joo S.K.
      • et al.
      Nonalcoholic steatohepatitis is associated with a higher risk of advanced colorectal neoplasm.
      In studies that assessed the prevalence of NASH in HCC, NASH was reported in 4%–20% of HCC patients. Generally, there were no significant differences in survival outcomes between patients with NASH-HCC and non-NASH-HCC.
      • Holzner M.L.
      • Florman S.
      • Schwartz M.E.
      • et al.
      Outcomes of liver transplantation for nonalcoholic steatohepatitis-associated hepatocellular carcinoma.
      ,
      • Young S.
      • Sanghvi T.
      • Rubin N.
      • et al.
      Transarterial chemoembolization of hepatocellular carcinoma: propensity score matching study comparing survival and complications in patients with nonalcoholic steatohepatitis versus other causes cirrhosis.
      ,
      • Billeter A.T.
      • Müller P.C.
      • Albrecht T.
      • et al.
      Impact of type 2 diabetes on oncologic outcomes of hepatocellular carcinomas in non-cirrhotic, non-alcoholic steatohepatitis: a matched-pair analysis.
      Table 4Incidence of HCC in Patients With NASH
      ReferenceCountryData source/populationStudy typeNASH participants (N)Proportion of patients with/developing HCC
      LT recipients
       Hernandez-Alejandro et al
      • Hernandez-Alejandro R.
      • Croome K.P.
      • Drage M.
      • et al.
      A comparison of survival and pathologic features of non-alcoholic steatohepatitis and hepatitis C virus patients with hepatocellular carcinoma.
      CanadaPatients undergoing LT for NASH or HCV (single center, 2000–2011)Retrospective database reviewNASH: 10216.7% (vs 22.6% for HCV LT recipients [n = 283])
       Doycheva et al
      • Doycheva I.
      • Zhang T.
      • Amjad W.
      • et al.
      Diabetes and hepatocellular carcinoma: incidence trends and impact of liver disease etiology.
      USAPatients receiving LT for HCC (UNOS database, 2002–2017)Retrospective database reviewNASH with T2D: 1193

      NASH without T2D: 732
      Adjusted risk of HCC, OR (95% CI):

      NASH with T2D vs NASH without T2D: 1.50 (1.35–1.66)

      NASH with T2D vs other etiologies with T2D (n = 4577): 0.60 (0.56–0.65)

      NASH without T2D vs other etiologies without T2D (n = 17,639): 0.49 (0.45–0.53)
       Kern et al
      • Kern B.
      • Feurstein B.
      • Fritz J.
      • et al.
      High incidence of hepatocellular carcinoma and postoperative complications in patients with nonalcoholic steatohepatitis as a primary indication for deceased liver transplantation.
      AustriaPatients undergoing primary deceased-donor LT (single center, 2002–2012)Observational cohort studyNASH cirrhosis: 6553.7% (vs 31.2% ALD [n = 183] and 47.7% for HCV [n = 116] LT recipients)
       Zarrinpar et al
      • Zarrinpar A.
      • Faltermeier C.M.
      • Agopian V.G.
      • et al.
      Metabolic factors affecting hepatocellular carcinoma in steatohepatitis.
      USAPatients undergoing LT for steatohepatitis (single center, 2002–2012)Observational cohort studyNASH: 13524%
      All patients with NASH-HCC had advanced fibrosis (stage 3: 3%; stage 4: 97%).
      (vs 26% for ALD LT recipients [n = 182])
       Jothimani et al
      • Jothimani D.
      • Danielraj S.
      • Narasimhan G.
      • et al.
      Nonalcoholic steatohepatitis: a rapidly increasing indication for liver transplantation in India.
      IndiaPatients undergoing LT (single center, 2009–2019)Observational cohort studyNASH (2009–2014): 85

      NASH (2015–2019): 311
      2009–2014: 21.2%

      2015–2019: 19.9%
      Fibrosis
       Vilar-Gomez et al
      • Vilar-Gomez E.
      • Vuppalanchi R.
      • Desai A.P.
      • et al.
      Long-term metformin use may improve clinical outcomes in diabetic patients with non-alcoholic steatohepatitis and bridging fibrosis or compensated cirrhosis.
      USADiabetic patients with NASH and bridging fibrosis or compensated cirrhosis (single center, 2004–2016)Observational cohort studyNASH: 191 (metformin users: 110; metformin never-users: 81)Overall: 14.7% (over study period) (Metformin users vs never-users: 6.4% vs 25.9%)

      10-y incidence: Metformin, 12%; no metformin, 40%
       Hirose et al
      • Hirose S.
      • Matsumoto K.
      • Tatemichi M.
      • et al.
      Nineteen-year prognosis in Japanese patients with biopsy-proven nonalcoholic fatty liver disease: lean versus overweight patients.
      JapanPatients with biopsy-proven NAFLD (single center, 1975–2012)Observational cohort studyNASH: 167n = 6
      Ninety patients (40.4%) were lost to follow-up.


      HCC incidence by fibrosis stage (per 1000 person-years of follow-up):

      0–2: 0.77 (95% CI 0.26–2.25)

      3–4: 9.88 (95% CI 3.36–29.1)
      Cirrhosis
       Amarapurkar et al
      • Amarapurkar D.N.
      • Dharod M.
      • Gautam S.
      • et al.
      Risk of development of hepatocellular carcinoma in patients with NASH-related cirrhosis.
      IndiaPatients with liver cirrhosis (single center, 2010–2011)Observational cohort studyNASH cirrhosis: 4115% (mean follow-up 6.8 ± 1.2 y)

      Annual incidence: 0.46%
       O'Leary et al
      • O'Leary J.G.
      • Landaverde C.
      • Jennings L.
      • et al.
      Patients with NASH and cryptogenic cirrhosis are less likely than those with hepatitis C to receive liver transplants.
      USANASH/CC or HCV patients listed for an orthotopic LT (single center, 2002–2008)Observational cohort studyNASH/CC: 217

      HCV: 646
      Annual incidence: 2.7% (NASH/CC patients) and 4.7% (HCV)
       Vilar-Gomez et al
      • Vilar-Gomez E.
      • Calzadilla-Bertot L.
      • Wong V.W.
      • et al.
      Type 2 diabetes and metformin use associate with outcomes of patients with nonalcoholic steatohepatitis-related, child-pugh A cirrhosis.
      Spain, Australia, Hong Kong, and CubaPatients with biopsy-proven NASH and compensated cirrhosis (multicenter, 1995–2016)Retrospective database analysisNASH + compensated cirrhosis: 299n = 39 (13.0%; median follow-up 5.1 y, range 0.5–10 y)

      10-y incidence with diabetes:

      25% (95% CI 18–30) vs without diabetes: 7% (95% CI 3–13; P < .01)
       Tan et al
      • Tan H.K.
      • Teng M.L.P.
      • Soh A.Y.S.
      • et al.
      Poor outcomes of cirrhosis due to nonalcoholic steatohepatitis compared with hepatitis B after decompensation with ascites.
      SingaporePatients with NASH/HBV cirrhosis who were admitted to hospital for first-onset ascites (multicenter, 2004–2015)Observational cohort studyNASH cirrhosis: 90Baseline prevalence: 16.7%
      Other
       Vieira Barbosa et al
      • Vieira Barbosa J.
      • Milligan S.
      • Frick A.
      • et al.
      Fibrosis-4 index as an independent predictor of mortality and liver-related outcomes in NAFLD.
      USAPatients with NAFLD/NASH from the TriNetX global federated research networkObservational cohort studyNASH: 914Baseline prevalence: 2.3%
      ALD, alcoholic liver disease; CC, cryptogenic cirrhosis; CI, confidence interval; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LT, liver transplantation; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; OR, odds ratio; T2D, type 2 diabetes; UNOS, United Network for Organ Sharing.
      a All patients with NASH-HCC had advanced fibrosis (stage 3: 3%; stage 4: 97%).
      b Ninety patients (40.4%) were lost to follow-up.

      Extrahepatic Comorbidities and Complications

      This review identified 16 studies reporting extrahepatic complications of NASH and 21 studies reporting CV complications. Key findings are summarized below, with further details in Table 5.
      Table 5NASH Comorbidity Outcomes
      ReferenceCountryData source/populationStudy typeNOutcomes
      Colorectal cancer
       Wong et al
      • Wong V.W.
      • Wong G.L.
      • Tsang S.W.
      • et al.
      High prevalence of colorectal neoplasm in patients with non-alcoholic steatohepatitis.
      Hong KongCohort 1: Community-recruited subjects with NAFLD (n = 64) and healthy controls
      Diagnosis based on proton magnetic resonance spectroscopy.


      Cohort 2: Consecutive patients with biopsy-proven NASH from 2 hepatology clinics in Hong Kong (n = 135)
      Cross-sectional studyNAFL: 199

      NASH: 49

      Healthy controls: 181
      • In patients with biopsy-proven NAFLD, patients with NASH had a higher prevalence of adenomas (51.0% vs 25.6%; P = .005) and advanced neoplasms (34.7% vs 14.0%; P = .011) than those with NAFL
      • After adjusting for demographic and metabolic factors, NASH remained associated with adenomas (OR 4.89, 95% CI 2.04–11.70) and advanced neoplasms (OR 5.34, 95% CI 1.92–14.84)
      • Prevalence of adenomas and advanced neoplasms was similar between patients with NAFL and control subjects
       Mahamid et al
      • Mahamid M.
      • Yassin T.
      • Abu Elheja O.
      • et al.
      Association between fatty liver disease and hyperplastic colonic polyp.
      IsraelPatients with biopsy-proven NASH or patients without NASH who underwent screening colonoscopy (single center, 2013–2015)Observational cohort studyNASH: 123

      Non-NASH community subjects: 100
      • Colonic adenomas occurred in 11% of NASH patients and 16% in the control group (P = .9)
      • NASH was significantly associated with an increased frequency of colonic hyperplastic polyps vs control group (22.7% vs 8%; P < .05)
      • Presence of NASH was associated with increased risk for colonic hyperplastic polyps (OR 1.69, P < .01)
       Cho et al
      • Cho Y.
      • Lim S.K.
      • Joo S.K.
      • et al.
      Nonalcoholic steatohepatitis is associated with a higher risk of advanced colorectal neoplasm.
      KoreaPatients who underwent screening colonoscopy within a prospective biopsy-evaluated NAFLD cohort (single center, 2013–2018)Observational cohort studyTotal patients: 476

      Disease state following confirmatory liver biopsy:

      No NAFLD: 97

      NAFLD: 194

      NASH: 185
      • Advanced colorectal neoplasms seen in 12% and 13% of individuals with NAFL and NASH, respectively, vs 5% of non-NAFLD patients
      • Low-grade tubular adenomas were seen in 50%, 35%, and 15% of NAFL, NASH, and non-NAFLD patients, respectively
      • NASH independently associated with a 2.8-fold increased risk for developing advanced colorectal neoplasm compared with individuals without any histologic finding of NAFLD (P = .049)
      CKD
       Targher et al
      • Targher G.
      • Bertolini L.
      • Rodella S.
      • et al.
      Relationship between kidney function and liver histology in subjects with nonalcoholic steatohepatitis.
      ItalyOverweight subjects with biopsy-proven NASH and nonsteatotic controls matched for age, gender, and BMIObservational case-control studyNASH: 80

      Controls: 80
      • NASH patients vs control subjects had:
        • Significantly lower eGFR (75.3 vs 87.5 mL/min per 1.73 m2, P < .001)
        • Greater frequency of abnormal albuminuria (14% vs 2.5%, P < .01)
        • Greater frequency of CKD (25% vs 3.7%, P < .001)
      • NASH strongly associated with increased prevalence of CKD (OR 8.31, 95% CI 2.4–16.8, P < .001)
      • Histologic severity of NASH was strongly associated with either decreasing eGFR or increasing albuminuria (P ≤ .01), independent of other potential confounding factors
       Yasui et al
      • Yasui K.
      • Sumida Y.
      • Mori Y.
      • et al.
      Nonalcoholic steatohepatitis and increased risk of chronic kidney disease.
      JapanPatients with biopsy-proven NAFLD from 2 Japanese hospitals (2001–2009)Cross-sectional studyNon-NASH NAFLD: 82

      NASH: 92
      • Prevalence of CKD was significantly higher in patients with NASH vs non-NASH NAFLD (21% vs 6%, P = .007)
      • Patients with NASH tended to have a more advanced stage of CKD than patients with non-NASH NAFLD
       Fussner et al
      • Fussner L.A.
      • Charlton M.R.
      • Heimbach J.K.
      • et al.
      The impact of gender and NASH on chronic kidney disease before and after liver transplantation.
      USAConsecutive primary solitary LT recipients (single center, 1998–2004)Observational cohort studyTotal patients: 455

      NASH: 47
      • NASH was independently predictive of stage ≥3 CKD at 5 y post-LT (OR 2.95, P = .039)
       Nagai et al
      • Nagai S.
      • Safwan M.
      • Kitajima T.
      • et al.
      Disease-specific waitlist outcomes in liver transplantation – a retrospective study.
      USAPatients with liver diseases on LT wait list (OPTN/UNOS database, 2016–2018)Retrospective database studyTotal patients: 13,016

      NASH: 3848
      • Presence of CKD stage 3 or 4/5 significantly increased risk of 1-y wait list mortality in NASH patients
        • Stage 3: HR 1.58, 95% CI 1.21–2.07, P < .001
        • Stage 4/5: HR 1.16, 95% CI 1.03–1.31, P = .01
      CVD
       Alkhouri et al
      • Alkhouri N.
      • Tamimi T.A.
      • Yerian L.
      • et al.
      The inflamed liver and atherosclerosis: a link between histologic severity of nonalcoholic fatty liver disease and increased cardiovascular risk.
      USAConsecutive patients undergoing liver biopsy for clinical suspicion of NAFLD (single center)Observational cohort studyTotal patients: 83

      Normal: 11

      NAFL: 36

      NASH: 36
      • Histologic severity of liver injury and inflammation strongly associated with increased cardiovascular risk and atherogenic lipid profile
      • Stepwise significant increase in lipid ratios with increasing histologic severity (normal biopsies vs NAFL vs NASH):
        • TG/HDL: 1.5 vs 3.2 vs 4.5
        • TC/HDL: 3.0 vs 4.3 vs 4.8
        • LDL/HDL: 1.6 vs 2.5 vs 2.8
       Domanski et al
      • Domanski J.P.
      • Park S.J.
      • Harrison S.A.
      Cardiovascular disease and nonalcoholic fatty liver disease: does histologic severity matter?.
      USAPatients with biopsy-confirmed NAFLD (single center, 2003–2009)Observational chart review studyNASH: 219

      Non-NASH NAFLD: 158
      • Similar prevalence of CVD in NASH vs NAFLD (6.8% vs 6.3%)
      • Trend to higher incidence with NASH vs NAFLD of unstable angina (3.2% vs 1.3%), myocardial infarction (3.2% vs 1.3%), and revascularization (4.6% vs 2.5%), respectively
       Imajo et al
      • Imajo K.
      • Hyogo H.
      • Yoneda M.
      • et al.
      LDL-migration index (LDL-MI), an indicator of small dense low-density lipoprotein (sdLDL), is higher in non-alcoholic steatohepatitis than in non-alcoholic fatty liver: a multicenter cross-sectional study.
      JapanPatients with biopsy-diagnosed NAFLD from 4 Japanese medical centersCross-sectional study
      NAFLD patients with dislipidemia in the primary cohort (43.4% and 58.3% of patients with NAFL and NASH, respectively) were prospectively treated in a single-arm, open-label trial, with lipid-lowering medications, including 21 patients treated with 10 mg/kg/d ezetimibe, 15 treated with 10 mg/kg/d atorvastatin, and 19 treated with 400 mg/kg/d fibrate for 12 weeks.
      Primary cohort:
      • NASH: 103
      • NAFL: 53
      Validation cohort:
      • NASH: 44
      • NAFL: 25
      • No differences in prevalence of T2D, hypertension, dyslipidemia, and obesity between NAFL and NASH
      • No differences in mean serum lipid levels (TC, TG, LDL, HDL, non-HDL-C, LDL/HDL ratio) between NAFL and NASH
      • Significantly elevated LDL-MI in patients with NASH vs NAFL, indicating risk of CVD may be higher in patients with NASH vs NAFL or healthy subjects
      • Nonuse of lipid-lowering medications and NASH were independently associated with higher LDL-MI in patients with NAFLD
       VanWagner et al
      • VanWagner L.B.
      • Serper M.
      • Kang R.
      • et al.
      Factors associated with major adverse cardiovascular events after liver transplantation among a national sample.
      USAPatients who underwent first LT or simultaneous liver-kidney transplant from 2002 to 2011 (OPTN and UHC databases)Retrospective database analysisTotal patients: 32,810

      NASH as primary indication for LT: 9.7%
      • NASH is an independent risk factor for MACE after LT (incidence rate ratio 1.6; 95% CI 1.1–2.24)
       Patel et al
      • Patel S.S.
      • Nabi E.
      • Guzman L.
      • et al.
      Coronary artery disease in decompensated patients undergoing liver transplantation evaluation.
      USAPatients who had coronary angiography as part of LT evaluation (single center, 2011–2014)Observational cohort studyTotal patients: 228

      NASH: 53
      • Significantly more patients with NASH vs HCV or alcoholic liver disease had CAD before undergoing LT (53% vs 39% vs 20%; P = .004)
      • After adjusting for age, sex, BMI, smoking, and family history, NASH was associated with a 3.12-fold increased risk of significant CAD (P = .005)
      • Other independent predictors of significant CAD were diabetes (OR 2.36; P = .01), dyslipidemia (OR 2.09; P = .04), and current or prior history of hypertension (OR 2.2; P = .02)
       Whitsett et al
      • Whitsett M.
      • Wilcox J.
      • Yang A.
      • et al.
      Atrial fibrillation is highly prevalent yet undertreated in patients with biopsy-proven nonalcoholic steatohepatitis.
      USAPatients with biopsy-proven NASH (NMEDW database, 2002–2015)Retrospective database study215
      • Overall prevalence of AF in NASH cohort: 4.6%
      • Higher prevalence of AF in <65-y-old patients with NASH (4.0%) vs non-NASH/NAFLD tertiary care cohort (2.7%) and general population
        Prevalence in general population determined from previously published literature.
        (2.0%)
      • Increased incidence of CVD in NASH patients with AF vs NASH without AF:
        • Heart failure: 54.5% vs 8.8%, P < .001
        • Cerebrovascular disease: 27.3% vs 2.0%, P < .001
        • Vascular disease: 54.5% vs 13.2%, P = .002
        • Hypertension: 81.8% vs 43.6%, P = .03
        • T2D: 81.8% vs 45.4%, P = .03
      • NASH and AF associated with more hospital visits (4.3 vs 2.0, P = .006) and longer hospital stays (11.1 vs 4.5 d, P = .002) vs NASH alone
       Lee et al
      • Lee H.H.
      • Cho Y.
      • Choi Y.J.
      • et al.
      Non-alcoholic steatohepatitis and progression of carotid atherosclerosis in patients with type 2 diabetes: a Korean cohort study.
      KoreaPatients with T2D who underwent repeat carotid artery ultrasonography for 6–8 y and evaluations for hepatic steatosis or fibrosis at baseline (single center, 1997–2016)Observational cohort studyTotal patients: 1120

      Hepatic steatosis: 636

      Hepatic steatosis with significant fibrosis: 222
      • Atherosclerosis progression after 6–8 y (P = .001 for difference):
        • No hepatic steatosis: 34.3%
        • Hepatic steatosis: 37.9%
        • Hepatic steatosis with fibrosis: 48.6%
      • Hepatic steatosis was significantly associated with atherosclerosis progression: adjusted OR 1.370, 95% CI 1.025–1.832 (P < .05)
        • Among patients with hepatic steatosis, only individuals with fibrosis showed significant association with atherosclerosis: adjusted OR 1.615, 95% CI 1.005–2.598 (P < .05)
       Vilar-Gomez et al
      • Vilar-Gomez E.
      • Calzadilla-Bertot L.
      • Wong V.W.
      • et al.
      Type 2 diabetes and metformin use associate with outcomes of patients with nonalcoholic steatohepatitis-related, child-pugh A cirrhosis.
      Spain, Australia, Hong Kong, and CubaPatients with biopsy-proven NASH and compensated cirrhosis (multicenter, 1995–2016)Observational cohort studyNASH + compensated cirrhosis: 299
      • Higher annualized incidence rate of total major vascular events
        Major vascular events included cardiovascular, cerebrovascular, and arterial peripheral diseases.
        for NASH patients with T2D (0.45, 95% CI 0.18–1.07) vs without T2D (0.28, 95% CI 0.02–1.42)
       Aminian et al
      • Aminian A.
      • Al-Kurd A.
      • Wilson R.
      • et al.
      Association of bariatric surgery with major adverse liver and cardiovascular outcomes in patients with biopsy-proven nonalcoholic steatohepatitis.
      USAPatients with biopsy-confirmed fibrotic NASH and obesity, without cirrhosis (single center, 2004–2016)Retrospective cohort studyBariatric surgery patients: 650

      Medically managed patients: 508
      • Higher baseline incidence of CVD in bariatric surgery candidates vs nonsurgical patients:
        • Hypertension: 83.0% vs 46.9%
        • Dyslipidemia: 73.9% vs 46.3%
        • T2D: 40.6% vs 40.6%
        • Heart failure: 6.1% vs 1.7%
        • CAD: 6.1% vs 4.2%
        • Cerebrovascular disease: 1.9% vs 1.4%
       Johnson et al
      • Johnson P.C.
      • Cochet A.A.
      • Gore R.S.
      • et al.
      Early cardiac dysfunction in biopsy-proven nonalcoholic fatty liver disease.
      USAPatients with biopsy-confirmed NAFLD with transthoracic ECG within 1 y of biopsy (single center tissue and serum repository, 2011–2016)Retrospective cohort studyNAFL: 17

      NASH: 16
      • Patients with NASH had higher rates of T2D, CAD, and hypertension vs NAFL
      • The E/e’ ratio, a marker of left ventricular diastolic dysfunction, was significantly higher in:
        • NASH vs NAFL (P = .004)
        • Advanced-stage NASH vs nonadvanced NAFLD (P = .021)
        • High-grade NASH vs lower-grade NAFLD (P = .00)
      • The E/e’ ratio was not significantly higher with NASH vs NAFL in patients with comorbid T2D (P = .31)
       Jothimani et al
      • Jothimani D.
      • Danielraj S.
      • Narasimhan G.
      • et al.
      Nonalcoholic steatohepatitis: a rapidly increasing indication for liver transplantation in India.
      IndiaPatients receiving LT (single center, 2009–2019)Retrospective observational studyTotal: 1017

      NASH: 396
      • Strong association between CAD and NASH (HR 1.963, 95% CI 1.19–3.32; P = .00)
      • High-risk CAD
        High-risk CAD patients underwent percutaneous balloon angioplasty along with coronary artery stent insertion before LT.
        was more prevalent in NASH vs non-NASH groups (7.3% vs 4.1%; P = .000)
       Park et al
      • Park J.H.
      • Koo B.K.
      • Kim W.
      • et al.
      Histological severity of nonalcoholic fatty liver disease is associated with 10-year risk for atherosclerotic cardiovascular disease.
      South KoreaKorean subjects with biopsy-proven NAFLDCross-sectional studyNAFL: 216

      NASH: 182
      • Prevalence of NASH was greater in patients with ≥10% 10-y ASCVD risk vs <10% (50.0% vs 29.3%, P < .001)
      • Histologic severity of NAFLD predicted the 10-y ASCVD risk. Adjusted OR
        Adjusted for age, sex, BMI, systolic and diastolic blood pressure, LDL cholesterol, TGs, AST, ALT, hs-CRP, and HOMA-IR.
        (95% CI) for NASH and NAFLD vs no NAFLD:
        • NASH: 4.07 (1.40–11.88)
        • NAFLD: 1.46 (0.55–3.88)
        • P = .014 for trend
      • Fibrosis severity was also a significant risk factor for ASCVD
       Ruiz-Casas et al
      • Ruiz-Casas L.
      • Pedra G.
      • Shaikh A.
      • et al.
      Clinical and sociodemographic determinants of disease progression in patients with nonalcoholic steatohepatitis in the United States.
      USAPatients with histologically or phenotypically confirmed NASH (GAIN study [O’Hara et al
      • Doycheva I.
      • Zhang T.
      • Amjad W.
      • et al.
      Diabetes and hepatocellular carcinoma: incidence trends and impact of liver disease etiology.
      ] US cohort)
      Retrospective cross-sectional studyNASH: 989
      • Participants with fibrosis progression appear to have higher baseline rates of CVD (6% vs 3%), hypertension (38% vs 28%), and dyslipidemia (40% vs 30%), and similar T2D (28% vs 24%) compared with those without fibrosis progression
       Tan et al
      • Tan H.K.
      • Teng M.L.P.
      • Soh A.Y.S.
      • et al.
      Poor outcomes of cirrhosis due to nonalcoholic steatohepatitis compared with hepatitis B after decompensation with ascites.
      SingaporePatients with NASH/HBV cirrhosis who were admitted to hospital for first-onset ascites (multicenter, 2004–2015)Observational cohort studyNASH: 90
      • CVD and metabolic conditions were more prevalent at baseline in patients with NASH cirrhosis compared with HBV cirrhosis:
        • CVD: 35.6% vs 3.6%
        • T2D: 93.3% vs 30.0%
        • Hypertension: 93.3% vs 29.1%
        • Dyslipidemia: 100% vs 9.1%
       Vieira Barbosa et al
      • Vieira Barbosa J.
      • Milligan S.
      • Frick A.
      • et al.
      Fibrosis-4 index as an independent predictor of mortality and liver-related outcomes in NAFLD.
      USAPatients with NAFLD/NASH from the TriNetX global federated research networkObservational cohort studyNASH: 914

      NAFLD: 17,582

      RISK:
      RISK includes patients with risk profile of NASH using the following formula: age >50 years, ALT >30 U/L, and (BMI >30 kg/m2 or T2D).
      62,612
      • Baseline prevalence of CVD and metabolic conditions appeared generally similar in the NASH group compared with NAFLD or those at risk of NASH, respectively:
        • MetS: 13.2% vs 15.3% vs 15.0%
        • T2D: 46.2% vs 28.7% vs 35.6%
        • Hyperlipidemia: 54.7% vs 58.0% vs 66.3%
        • Hypertension: 58.8% vs 52.7% vs 57.8%
        • CVD: 68.1% vs 60.4% vs 62.5%
        • MACE: 12.9% vs 14.9% vs 17.7%
      AF, atrial fibrillation; ALT, alanine aminotransferase; ASCVD, atherosclerotic cardiovascular disease; AST, aspartate aminotransferase; BMI, body mass index; CAD, coronary artery disease; CI, confidence interval; CKD, chronic kidney disease; CVD, cardiovascular disease; E/e’, ratio of early diastolic mitral inflow velocity to early diastolic mitral annulus velocity; ECG, echocardiogram; eGFR, estimated glomerular filtration rate; HBV, hepatitis B virus; HCV, hepatitis C virus; HDL, high-density lipoprotein; HDL-C, HDL cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; HR, hazard ratio; hs-CRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; LDL-MI, LDL-migration index; LT, liver transplantation; MACE, major adverse cardiovascular events; MetS, metabolic syndrome; NAFL, nonalcoholic fatty liver; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NMEDW, Northwestern Medicine Enterprise Database Warehouse; OPTN, Organ Procurement and Transplantation Network; OR, odds ratio; T2D, type 2 diabetes; TC, total cholesterol; TG, triglyceride; UHC, University HealthSystem Consortium; UNOS, United Network for Organ Sharing.
      a Diagnosis based on proton magnetic resonance spectroscopy.
      b NAFLD patients with dislipidemia in the primary cohort (43.4% and 58.3% of patients with NAFL and NASH, respectively) were prospectively treated in a single-arm, open-label trial, with lipid-lowering medications, including 21 patients treated with 10 mg/kg/d ezetimibe, 15 treated with 10 mg/kg/d atorvastatin, and 19 treated with 400 mg/kg/d fibrate for 12 weeks.
      c Prevalence in general population determined from previously published literature.
      d Major vascular events included cardiovascular, cerebrovascular, and arterial peripheral diseases.
      e High-risk CAD patients underwent percutaneous balloon angioplasty along with coronary artery stent insertion before LT.
      f Adjusted for age, sex, BMI, systolic and diastolic blood pressure, LDL cholesterol, TGs, AST, ALT, hs-CRP, and HOMA-IR.
      g RISK includes patients with risk profile of NASH using the following formula: age >50 years, ALT >30 U/L, and (BMI >30 kg/m2 or T2D).
      Three studies have reported an increased risk of developing colorectal cancer in patients with NASH/NAFLD (Table 5)
      • Wong V.W.
      • Wong G.L.
      • Tsang S.W.
      • et al.
      High prevalence of colorectal neoplasm in patients with non-alcoholic steatohepatitis.
      • Mahamid M.
      • Yassin T.
      • Abu Elheja O.
      • et al.
      Association between fatty liver disease and hyperplastic colonic polyp.
      • Cho Y.
      • Lim S.K.
      • Joo S.K.
      • et al.
      Nonalcoholic steatohepatitis is associated with a higher risk of advanced colorectal neoplasm.
      ; these suggest that NAFLD or NASH approximately doubles the risk of developing colorectal neoplasms. Three studies reported that NASH is an independent risk factor for chronic kidney disease (CKD) or is associated with an increased risk for severe CKD post-LT (Table 5). When compared against nonsteatotic controls matched for age, gender, and body mass index (BMI), NASH was associated with an 8.3-fold increased risk of CKD.
      • Targher G.
      • Bertolini L.
      • Rodella S.
      • et al.
      Relationship between kidney function and liver histology in subjects with nonalcoholic steatohepatitis.
      In individuals undergoing LT, the increased risk was approximately 3-fold higher in those with NASH vs those without
      • Fussner L.A.
      • Charlton M.R.
      • Heimbach J.K.
      • et al.
      The impact of gender and NASH on chronic kidney disease before and after liver transplantation.
      and 3.5-fold higher in patients with NASH vs non-NASH NAFLD.
      • Yasui K.
      • Sumida Y.
      • Mori Y.
      • et al.
      Nonalcoholic steatohepatitis and increased risk of chronic kidney disease.
      The presence of severe CKD (stage 3 or 4/5) in patients with NASH was associated with significantly increased risk of 1-year LT wait list mortality.
      • Nagai S.
      • Safwan M.
      • Kitajima T.
      • et al.
      Disease-specific waitlist outcomes in liver transplantation – a retrospective study.
      Associations between NASH and CVD were investigated in 15 studies (Table 5). Several studies reported increased risk of CV conditions with NASH compared with nonalcoholic fatty liver,
      • Domanski J.P.
      • Park S.J.
      • Harrison S.A.
      Cardiovascular disease and nonalcoholic fatty liver disease: does histologic severity matter?.
      ,
      • Whitsett M.
      • Wilcox J.
      • Yang A.
      • et al.
      Atrial fibrillation is highly prevalent yet undertreated in patients with biopsy-proven nonalcoholic steatohepatitis.
      ,
      • Lee H.H.
      • Cho Y.
      • Choi Y.J.
      • et al.
      Non-alcoholic steatohepatitis and progression of carotid atherosclerosis in patients with type 2 diabetes: a Korean cohort study.
      ,
      • Johnson P.C.
      • Cochet A.A.
      • Gore R.S.
      • et al.
      Early cardiac dysfunction in biopsy-proven nonalcoholic fatty liver disease.
      ,
      • Park J.H.
      • Koo B.K.
      • Kim W.
      • et al.
      Histological severity of nonalcoholic fatty liver disease is associated with 10-year risk for atherosclerotic cardiovascular disease.
      and accordingly, NASH patients were found to have a more atherogenic lipid profile in NASH compared with non-NASH populations.
      • Alkhouri N.
      • Tamimi T.A.
      • Yerian L.
      • et al.
      The inflamed liver and atherosclerosis: a link between histologic severity of nonalcoholic fatty liver disease and increased cardiovascular risk.
      One database study of more than 9000 patients with NASH/NAFLD reported a higher prevalence of atrial fibrillation in individuals aged <65 years with biopsy-proven NASH (4.0%) vs a non-NASH/NAFLD tertiary care cohort (2.7%) and vs a general population estimate from published literature (2.0%).
      • Whitsett M.
      • Wilcox J.
      • Yang A.
      • et al.
      Atrial fibrillation is highly prevalent yet undertreated in patients with biopsy-proven nonalcoholic steatohepatitis.
      Furthermore, the presence of atrial fibrillation increased the risk of other cardiovascular complications, and led to more frequent and longer hospitalizations, compared with NASH patients without atrial fibrillation.
      • Whitsett M.
      • Wilcox J.
      • Yang A.
      • et al.
      Atrial fibrillation is highly prevalent yet undertreated in patients with biopsy-proven nonalcoholic steatohepatitis.
      Coronary artery disease was shown to occur more frequently in patients with NASH compared with hepatitis C virus (HCV) and alcoholic liver disease, and NASH is a significant risk factor for both coronary artery disease and major adverse cardiovascular events.
      • VanWagner L.B.
      • Serper M.
      • Kang R.
      • et al.
      Factors associated with major adverse cardiovascular events after liver transplantation among a national sample.
      In addition, one study found that hepatic steatosis with fibrosis is independently associated with the progression of carotid atherosclerosis in patients with T2D.
      • Lee H.H.
      • Cho Y.
      • Choi Y.J.
      • et al.
      Non-alcoholic steatohepatitis and progression of carotid atherosclerosis in patients with type 2 diabetes: a Korean cohort study.
      Comorbid conditions such as T2D, obesity, and hepatitis increase the risk of NASH/NAFLD and/or are associated with worse outcomes. In a single-center Belgian study, NASH was one of the most frequently reported comorbidities, occurring in 72% of participants.
      • Hermans M.P.
      • Dath N.
      Prevalence and co-prevalence of comorbidities in Belgian patients with type 2 diabetes mellitus: a transversal, descriptive study.
      Another study of 1069 patients with NAFLD, 30% of whom had diabetes, showed that family history of diabetes is strongly associated with risk of NASH, fibrosis, and advanced fibrosis.
      • Loomba R.
      • Abraham M.
      • Unalp A.
      • et al.
      Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis.
      T2D in NASH patients is associated with poor outcomes; in an international cohort of 299 patients with NASH, the presence of T2D was associated with a 4.59-fold increased risk of mortality, 2.46-fold increased risk of hepatic decompensation, and 4.2-fold increased risk of HCC vs patients without T2D.
      • Vilar-Gomez E.
      • Calzadilla-Bertot L.
      • Wong V.W.
      • et al.
      Type 2 diabetes and metformin use associate with outcomes of patients with nonalcoholic steatohepatitis-related, child-pugh A cirrhosis.
      Obesity and overweight are established significant risk factors for NASH and fibrosis, including risk of NASH post-LT.
      • Kim G.
      • Lee Y.H.
      • Park Y.M.
      • et al.
      Use of a diabetes self-assessment score to predict nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.
      • Thuluvath P.J.
      • Kantsevoy S.
      • Thuluvath A.J.
      • et al.
      Is cryptogenic cirrhosis different from NASH cirrhosis?.
      • Eshraghian A.
      • Nikeghbalian S.
      • Dehghani M.
      • et al.
      Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in Iranian patients.
      • Pirvulescu I.
      • Gheorghe L.
      • Csiki I.
      • et al.
      Noninvasive clinical model for the diagnosis of nonalcoholic steatohepatitis in overweight and morbidly obese patients undergoing bariatric surgery.
      • Wang D.
      • Wang L.
      • Wang Z.
      • et al.
      Higher non-HDL-cholesterol to HDL-cholesterol ratio linked with increased nonalcoholic steatohepatitis.
      • Patel Y.A.
      • Gifford E.J.
      • Glass L.M.
      • et al.
      Risk factors for biopsy-proven advanced non-alcoholic fatty liver disease in the Veterans Health Administration.
      However, individuals with NAFLD without obesity may also be at risk of progression to NASH. One Italian study of patients with biopsy-proven NAFLD showed that increasing waist circumference was associated with increasing prevalence of severe hepatosteatosis and NASH (but not fibrosis), but in a multivariate analysis, neither NASH nor fibrosis were significantly associated with waist circumference, implying that patients with a normal waist circumference may also be at risk of NASH and fibrosis.
      • Fracanzani A.L.
      • Valenti L.
      • Bugianesi E.
      • et al.
      Risk of nonalcoholic steatohepatitis and fibrosis in patients with nonalcoholic fatty liver disease and low visceral adiposity.
      Another study showed that the presence of NASH in patients with hepatitis was associated with significantly worse long-term outcomes, including reduced event-free survival, increased risk of HCC, HCC-free survival, transplant-free survival, and LT/death (all P < .01).
      • Choi H.S.J.
      • Brouwer W.P.
      • Zanjir W.M.R.
      • et al.
      Nonalcoholic steatohepatitis is associated with liver-related outcomes and all-cause mortality in chronic hepatitis B.

      LT and Post-transplant Outcomes

      As NASH progresses, many patients require LT, and consequently, NASH is one of the main indications for LT in many countries. The results from studies comparing the proportion of patients with different etiologies for LT suggest that in 2016, NASH accounted for ∼15%–20% of LTs in the United States and 8.4% in Europe.
      • Cholankeril G.
      • Wong R.J.
      • Hu M.
      • et al.
      Liver transplantation for nonalcoholic steatohepatitis in the US: temporal trends and outcomes.
      ,
      • Haldar D.
      • Kern B.
      • Hodson J.
      • et al.
      Outcomes of liver transplantation for non-alcoholic steatohepatitis: a European Liver Transplant Registry study.
      ,
      • Younossi Z.
      • Stepanova M.
      • Ong J.P.
      • et al.
      Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates.
      ,
      • Thuluvath P.J.
      • Hanish S.
      • Savva Y.
      Waiting list mortality and transplant rates for NASH cirrhosis when compared with cryptogenic, alcoholic, or AIH cirrhosis.
      ,
      • Golabi P.
      • Bush H.
      • Stepanova M.
      • et al.
      Liver transplantation (LT) for cryptogenic cirrhosis (CC) and nonalcoholic steatohepatitis (NASH) cirrhosis: data from the Scientific Registry of Transplant Recipients (SRTR): 1994 to 2016.
      Both US and European studies have shown that NASH patients as a proportion of all patients undergoing LT have increased over time.
      • Haldar D.
      • Kern B.
      • Hodson J.
      • et al.
      Outcomes of liver transplantation for non-alcoholic steatohepatitis: a European Liver Transplant Registry study.
      ,
      • Thuluvath P.J.
      • Hanish S.
      • Savva Y.
      Waiting list mortality and transplant rates for NASH cirrhosis when compared with cryptogenic, alcoholic, or AIH cirrhosis.
      In 2 large US studies, NASH was the second most common indication for LT.
      • Cholankeril G.
      • Wong R.J.
      • Hu M.
      • et al.
      Liver transplantation for nonalcoholic steatohepatitis in the US: temporal trends and outcomes.
      ,
      • Younossi Z.
      • Stepanova M.
      • Ong J.P.
      • et al.
      Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates.
      Additional detail on the proportion of NASH patients undergoing LT across the studies is provided in Table A6.
      Studies assessing recurrence of NASH post-LT suggested that up to 50% of patients develop recurrent NASH post-LT, which progresses to fibrosis in a minority of patients.
      • El Atrache M.M.
      • Abouljoud M.S.
      • Divine G.
      • et al.
      Recurrence of non-alcoholic steatohepatitis and cryptogenic cirrhosis following orthotopic liver transplantation in the context of the metabolic syndrome.
      ,
      • Kakar S.
      • Dugum M.
      • Cabello R.
      • et al.
      Incidence of recurrent NASH-related allograft cirrhosis.
      ,
      • Tokodai K.
      • Karadagi A.
      • Kjaernet F.
      • et al.
      Characteristics and risk factors for recurrence of nonalcoholic steatohepatitis following liver transplantation.
      ,
      • Holzner M.L.
      • Florman S.
      • Schwartz M.E.
      • et al.
      Outcomes of liver transplantation for nonalcoholic steatohepatitis-associated hepatocellular carcinoma.
      ,
      • Sourianarayanane A.
      • Arikapudi S.
      • McCullough A.J.
      • et al.
      Nonalcoholic steatohepatitis recurrence and rate of fibrosis progression following liver transplantation.
      However, very few patients (<2%) develop cirrhosis.
      • Kakar S.
      • Dugum M.
      • Cabello R.
      • et al.
      Incidence of recurrent NASH-related allograft cirrhosis.
      ,
      • Sourianarayanane A.
      • Arikapudi S.
      • McCullough A.J.
      • et al.
      Nonalcoholic steatohepatitis recurrence and rate of fibrosis progression following liver transplantation.
      Factors associated with recurrence included higher BMI (pre- and post-LT) and presence of diabetes/insulin use, metabolic syndrome, and hypertension,
      • El Atrache M.M.
      • Abouljoud M.S.
      • Divine G.
      • et al.
      Recurrence of non-alcoholic steatohepatitis and cryptogenic cirrhosis following orthotopic liver transplantation in the context of the metabolic syndrome.
      ,
      • Kakar S.
      • Dugum M.
      • Cabello R.
      • et al.
      Incidence of recurrent NASH-related allograft cirrhosis.
      ,
      • Tokodai K.
      • Karadagi A.
      • Kjaernet F.
      • et al.
      Characteristics and risk factors for recurrence of nonalcoholic steatohepatitis following liver transplantation.
      although one study found no association between recurrence post-LT with diabetes or hypertension.
      • Kakar S.
      • Dugum M.
      • Cabello R.
      • et al.
      Incidence of recurrent NASH-related allograft cirrhosis.
      Twenty-four studies measured survival post-LT (key data presented in Table 6). Considering the large database analyses, 1-year survival was 84%–90.4% (6 studies), 3-year survival was 76.5%–85.4% (6 studies), and 5-year survival was 68.6%–84.1% (6 studies). Supporting data from smaller single-center studies are in broad agreement with the larger studies.
      Table 6Overall Survival in Patients With NASH Undergoing Transplantation
      ReferenceCountry/regionData source/populationStudy typeNOverall survival in NASH patients, %
      1 y3 y5 y10 y
      Liver transplant
       Charlton et al
      • Charlton M.R.
      • Burns J.M.
      • Pedersen R.A.
      • et al.
      Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States.
      USALT recipients in the USA from 2001 to 2009 (SRTR database)Retrospective database analysisTotal patients: 35,781

      NASH: 1959
      Population includes patients for whom NASH is primary (n = 1840) and secondary (n = 119) indication for LT.
      8478NRNR
       El Atrache et al
      • El Atrache M.M.
      • Abouljoud M.S.
      • Divine G.
      • et al.
      Recurrence of non-alcoholic steatohepatitis and cryptogenic cirrhosis following orthotopic liver transplantation in the context of the metabolic syndrome.
      USAEMRs of hospital patients undergoing orthotopic LT for NASH or CC at Henry Ford Hospital (1996–2008)Retrospective chart review studyTotal patients: 83

      NASH: 46
      NRNRNASH + MetS: 52
      Survival data were pooled for patients with NASH (n = 46) and CC (diagnosis based on exclusion of all other forms of liver disease; n = 37).


      NASH – MetS: 90

      NASH + hypertension: 61

      NASH – hypertension: 86

      NASH + insulin use: 58

      NASH – insulin use: 88
      NR
       Heuer et al
      • Heuer M.
      • Kaiser G.M.
      • Kahraman A.
      • et al.
      Liver transplantation in nonalcoholic steatohepatitis is associated with high mortality and post-transplant complications: a single-center experience.
      GermanyPatients undergoing LT due to NASH-induced cirrhosis (single center, 2007–2011)Observational cohort study40NROverall survival at final follow-up:
      Final follow-up was January 2011, approximately 4 years after study initiation.
      65
      NRNR
       Kennedy et al
      • Kennedy C.
      • Redden D.
      • Gray S.
      • et al.
      Equivalent survival following liver transplantation in patients with non-alcoholic steatohepatitis compared with patients with other liver diseases.
      USAPatients who received deceased-donor LT from 1999 to 2009 (UAB internal transplant database)Observational chart review study129908885NR
       Reddy et al
      • Reddy S.K.
      • Steel J.L.
      • Chen H.W.
      • et al.
      Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease.
      USAPatients undergoing curative therapy for HCC at University of Pittsburgh STI (2000–2010)Observational cohort studyTotal patients: 214

      Transplanted HCC + NASH: 20
      NRTransplanted HCC + NASH: 83.3NRNR
       VanWagner et al
      • VanWagner L.B.
      • Bhave M.
      • Te H.S.
      • et al.
      Patients transplanted for nonalcoholic steatohepatitis are at increased risk for postoperative cardiovascular events.
      USAEMRs of patients undergoing LT for NASH or AC at Northwestern Memorial Hospital and UoC (1993–2010)Retrospective chart review studyTotal patients: 242

      NASH: 115
      81.373.360.3NR
       Singal et al
      • Singal A.K.
      • Guturu P.
      • Hmoud B.
      • et al.
      Evolving frequency and outcomes of liver transplantation based on etiology of liver disease.
      USAPatients receiving first LT from 1994 to 2009 (UNOS database)Retrospective database analysisTotal patients: 54,687

      NASH: 1368
      88.885.484.183.9
       Wong et al
      • Wong R.J.
      • Chou C.
      • Bonham C.A.
      • et al.
      Improved survival outcomes in patients with non-alcoholic steatohepatitis and alcoholic liver disease following liver transplantation: an analysis of 2002–2012 United Network for Organ Sharing data.
      USAPatients receiving LT for HCV, NASH, ALD, and HCC from 2002 to 2012 (UNOS database)Retrospective database analysisTotal patients: 41,289

      NASH: 7100
      89.382.575.5NR
       VanWagner et al
      • VanWagner L.B.
      • Lapin B.
      • Skaro A.I.
      • et al.
      Impact of renal impairment on cardiovascular disease mortality after liver transplantation for nonalcoholic steatohepatitis cirrhosis.
      USAPatients undergoing first LT from 2002 to 2012 (OPTN database)Retrospective database analysisTotal patients: 48,360

      NASH: 5057
      Survival data were pooled for patients with NASH (n = 2705) and patients with probable NASH, defined as a diagnosis of CC with ≥1 component of MetS (n = 2352).
      NROverall survival at median 3.2 y follow-up: 73.9NRNR
       Piazza et al
      • Piazza N.A.
      • Singal A.K.
      Frequency of cardiovascular events and effect on survival in liver transplant recipients for cirrhosis due to alcoholic or nonalcoholic steatohepatitis.
      USAPatients undergoing deceased-donor LT for steatohepatitis-related cirrhosis (single center, 2005–2010)Observational cohort studyTotal patients: 143

      NASH: 78
      NRNASH + CV event: 70

      NASH – CV event: 90.1
      NRNR
       Cholankeril et al
      • Cholankeril G.
      • Wong R.J.
      • Hu M.
      • et al.
      Liver transplantation for nonalcoholic steatohepatitis in the US: temporal trends and outcomes.
      USAPatients undergoing LT in the USA from 2003 to 2014 (UNOS database)Retrospective database analysisTotal patients: 63,061

      NASH: 8262
      89.583.177.8NR
       Thuluvath et al
      • Thuluvath P.J.
      • Hanish S.
      • Savva Y.
      Liver transplantation in cryptogenic cirrhosis: Outcome comparisons between NASH, alcoholic, and AIH cirrhosis.
      USAPatients receiving first LT for NASH, CC, AC, or AIH (excluding multiorgan LT and HCC) 2002–2016 (UNOS database)Retrospective database analysisTotal patients: 16,602

      NASH: 4089
      NASH cirrhosis alive: 2314 (at 2 y)

      NASH cirrhosis survival probability: 0.89
      NASH cirrhosis alive: NR

      NASH cirrhosis survival probability: 0.83
      NASH cirrhosis alive: 1535 (at 4 y)

      NASH cirrhosis survival probability: 0.77
      NASH cirrhosis alive: 213

      NASH cirrhosis survival probability: 0.63
       Haldar et al
      • Haldar D.
      • Kern B.
      • Hodson J.
      • et al.
      Outcomes of liver transplantation for non-alcoholic steatohepatitis: a European Liver Transplant Registry study.
      EuropePatients undergoing primary LT for CLD from 2002 to 2016 (ELTR database)Retrospective database analysisTotal patients: 68,950

      NASH – HCC: 1667

      NASH + HCC: 1073
      NASH – HCC: 84.1

      NASH + HCC: 89.1
      Data at 2.5 y

      NASH – HCC: 80.2

      NASH + HCC: 76.5
      NASH – HCC: 73.4

      NASH + HCC: 68.6
      NASH – HCC: 62.1

      NASH + HCC: 46.9
       Kakar et al
      • Kakar S.
      • Dugum M.
      • Cabello R.
      • et al.
      Incidence of recurrent NASH-related allograft cirrhosis.
      USAPatients undergoing LT for NASH cirrhosis (single center, 2000–2015)Observational cohort study22682NR7362
       Kern et al
      • Kern B.
      • Feurstein B.
      • Fritz J.
      • et al.
      High incidence of hepatocellular carcinoma and postoperative complications in patients with nonalcoholic steatohepatitis as a primary indication for deceased liver transplantation.
      AustriaPatients undergoing primary deceased-donor LT (single center, 2002–2012)Observational cohort studyTotal patients: 513

      NASH cirrhosis: 65
      93.278.572.1NR
       Nagai et al
      • Nagai S.
      • Collins K.
      • Chau L.C.
      • et al.
      Increased risk of death in first year after liver transplantation among patients with nonalcoholic steatohepatitis vs liver disease of other etiologies.
      USALT patients who had NASH, HCV, or ALD from 2008 to 2017 (UNOS database)Retrospective database analysisTotal patients: 32,660

      NASH: 6344
      2008–2010: 90.3

      2011–2013: 90.6

      2014–2015: 90.4

      2016–2017: 90.4
      NRNRNR
       Tokodai et al
      • Tokodai K.
      • Karadagi A.
      • Kjaernet F.
      • et al.
      Characteristics and risk factors for recurrence of nonalcoholic steatohepatitis following liver transplantation.
      SwedenPatients undergoing LT for NASH or ALD (single center, 2007–2017)Observational cohort studyTotal patients: 95

      NASH: 27
      89NRNRNR
       Younossi et al
      • Younossi Z.
      • Stepanova M.
      • Ong J.P.
      • et al.
      Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates.
      USALT candidates with HCC listing diagnosis from 2002 to 2017 (SRTR database)Retrospective database analysisTotal patients: 28,935

      NASH + HCC: 2690 (post-transplant data available: 1631)
      Post-transplant mortality, %

      NASH + HCC: 10.6
      Post-transplant mortality, %

      NASH + HCC: 19.7
      Post-transplant mortality, %

      NASH + HCC: 28.2
      NR
       Zarrinpar et al
      • Zarrinpar A.
      • Faltermeier C.M.
      • Agopian V.G.
      • et al.
      Metabolic factors affecting hepatocellular carcinoma in steatohepatitis.
      USAPatients undergoing LT for steatohepatitis (single center, 2002–2012)Observational cohort studyTotal patients: 317

      NASH + HCC: 33

      NASH – HCC: 102
      NRNRNASH + HCC:

      Overall: 62

      Recurrence free: 50
      NR
       Holzner et al
      • Holzner M.L.
      • Florman S.
      • Schwartz M.E.
      • et al.
      Outcomes of liver transplantation for nonalcoholic steatohepatitis-associated hepatocellular carcinoma.
      USAPatients undergoing LT for HCC (single center, 2001–2017)Observational cohort studyNASH-HCC: 51NASH-HCC: 92NASH-HCC: 86NASH-HCC: 80NR
       Jothimani et al
      • Jothimani D.
      • Danielraj S.
      • Narasimhan G.
      • et al.
      Nonalcoholic steatohepatitis: a rapidly increasing indication for liver transplantation in India.
      IndiaPatients undergoing LT (single center, 2009–2019)Observational cohort studyTotal patients: 1017

      NASH: 396
      86.681.875.9NR
       Karnam et al
      • Karnam R.S.
      • Mitsakakis N.
      • Saracino G.
      • et al.
      Predicting long-term survival after liver transplantation in patients with NASH cirrhosis.
      USAPatients undergoing DDLT for NASH cirrhosis (SRTR database, 2002–2019)Retrospective database analysis6515NRNR79NR
      Simultaneous liver and kidney transplant
       Singal et al
      • Singal A.K.
      • Salameh H.
      • Kuo Y.F.
      • et al.
      Evolving frequency and outcomes of simultaneous liver kidney transplants based on liver disease etiology.
      USASimultaneous liver-kidney transplant recipients from 2002 to 2011 (UNOS database)Retrospective database analysisTotal patients: 2606

      NASH: 221
      NRNR74NR
      Patients undergoing retransplantation
       Thuluvath et al
      • Thuluvath A.J.
      • Chen P.H.
      • Thuluvath P.J.
      • et al.
      Poor survival after retransplantation in NASH cirrhosis.
      USAPatients receiving re-LT for NASH, CC, AC, or AHC (excluding multiorgan re-LT and HCC) from 2002 to 2016 (UNOS database)Retrospective database analysisTotal patients: 735

      NASH: 128
      655952NR
      AC, alcoholic cirrhosis; AHC, autoimmune hepatic cirrhosis; AIH, autoimmune hepatitis; ALD, alcoholic liver disease; CC, cryptogenic cirrhosis; CLD, chronic liver disease; CV, cardiovascular; DDLT, deceased donor liver transplant; ELTR, European Liver Transplant Registry; EMR, electronic medical record; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LT, liver transplantation; MetS, metabolic syndrome; NASH, nonalcoholic steatohepatitis; NR, not recorded; OPTN, Organ Procurement and Transplantation Network; re-LT, re-transplantation; SRTR, Scientific Registry of Transplant Recipients; STI, Thomas E. Starzl Transplantation Institute; UAB, University of Alabama at Birmingham; UNOS, United Network for Organ Sharing; UoC, University of Chicago.
      a Population includes patients for whom NASH is primary (n = 1840) and secondary (n = 119) indication for LT.
      b Survival data were pooled for patients with NASH (n = 46) and CC (diagnosis based on exclusion of all other forms of liver disease; n = 37).
      c Final follow-up was January 2011, approximately 4 years after study initiation.
      d Survival data were pooled for patients with NASH (n = 2705) and patients with probable NASH, defined as a diagnosis of CC with ≥1 component of MetS (n = 2352).

      Mortality

      Key non-LT mortality data is presented in Table 7, including the Global Burden of Disease, Injuries, and Risk Factors study.
      Table 7NASH Mortality Outcomes in Non-LT Patients
      ReferenceCountryData source/populationStudy typeNSurvival outcomes
      Hashizume et al
      • Hashizume H.
      • Sato K.
      • Yamazaki Y.
      • et al.
      A prospective study of long-term outcomes in female patients with nonalcoholic steatohepatitis using age- and body mass index-matched cohorts.
      JapanConsecutive female patients with NASH or chronic HCV (single center)Observational cohort studyAdvanced fibrosis/NASH: 20

      Mild fibrosis/NASH: 19
      • After 85.6 mo follow-up, advanced NASH associated with shorter liver-related complication-free survival and HCC-free survival vs mild NASH, but no significant difference in overall survival
      Angulo et al
      • Angulo P.
      • Kleiner D.E.
      • Dam-Larsen S.
      • et al.
      Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.
      MultinationalUntreated patients with biopsy-proven NAFLD (multicenter, 1975–2005)Observational cohort studyTotal patients: 619

      Definitive NASH: 179

      Borderline NASH: 105
      • Median 12.6 y follow-up
      • Survival free of LT was similar for definitive NASH (63.1%) and borderline NASH (60.0%), but lower than non-NASH (74.6%; P < .001)
      • In the NASH group (borderline plus definitive), survival free of LT was significantly lower in patients with fibrosis (60.2%) vs those without fibrosis (72.1%; P = .018)
      Hirose et al
      • Hirose S.
      • Matsumoto K.
      • Tatemichi M.
      • et al.
      Nineteen-year prognosis in Japanese patients with biopsy-proven nonalcoholic fatty liver disease: lean versus overweight patients.
      JapanPatients with biopsy-proven NAFLD (single center, 1975–2012)Observational cohort studyTotal patients: 223

      NASH: 167
      • Median 19.5 y follow-up
      • All-cause mortality was significantly higher in NASH patients than in NAFL patients (P = .041)
      • In multivariate analysis, older age (HR 1.09, 95% CI 1.05–1.14, P < .001) and T2D (HR 2.87, 95% CI [1.12–7.04], P = .021) were significantly associated with all-cause mortality
      Renno et al
      • Renno A.
      • Abdel-Aziz Y.
      • Alastal Y.
      • et al.
      The association between obstructive sleep apnea and non-alcoholic steatohepatitis: a retrospective nationwide inpatient sample analysis.
      USAHospitalized patients with NASH (HCUP-NIS, 2016)Retrospective database analysisNASH: 10,950

      Matched non-NASH controls: 43,810
      • Risk of in-hospital mortality was greater in NASH (3.8%) vs non-NASH patients (2%; OR 1.34, 95% CI 1.22–1.48, P < .0001)
      Kidney failure outcomes
       Reja et al
      • Reja M.
      • Patel R.
      • Pioppo L.
      • et al.
      Renal failure is associated with increased mortality and hospital utilization in patients admitted with nonalcoholic steatohepatitis.
      USAHospitalized patients with NASH and comorbid kidney failure (NIS, 2016)Observational cohort studyNASH + kidney failure: 598

      Matched controls (NASH without kidney failure): 598
      • Renal failure was significantly associated with higher in-hospital mortality (3.0% vs 0.2%)
        • Adjusted OR 28.72, 95% CI 8.99–91.71, P < .0001
      Cirrhosis outcomes
       Axley et al
      • Axley P.
      • Ahmed Z.
      • Arora S.
      • et al.
      NASH is the most rapidly growing etiology for acute-on-chronic liver failure-related hospitalization and disease burden in the United States: a population-based study.
      USANASH cirrhosis-related hospitalizations from US NIS (2006–2014)Retrospective database analysis179,104
      • 3.7% inpatient mortality among hospitalizations for NASH cirrhosis
       Vilar-Gomez et al
      • Vilar-Gomez E.
      • Vuppalanchi R.
      • Desai A.P.
      • et al.
      Long-term metformin use may improve clinical outcomes in diabetic patients with non-alcoholic steatohepatitis and bridging fibrosis or compensated cirrhosis.
      USADiabetic patients with NASH and bridging fibrosis or compensated cirrhosis (single center, 2004–2016)Observational cohort study191
      • Overall 2-, 4-, 6-, 8-, and 10-y cumulative mortality or liver transplant crude rates were 98%, 93%, 86%, 72%, and 52%, respectively
      • Cumulative 10-y transplant-free survival rate significantly lower in metformin nonusers vs users (35% vs 65%; unadjusted HR 0.42, 95% CI 0.24–0.74; P = .003)
       GBD 2017 Cirrhosis Collaborators
      • Kim G.
      • Lee Y.H.
      • Park Y.M.
      • et al.
      Use of a diabetes self-assessment score to predict nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.
      USAGlobal Burden of Diseases, Injuries, and Risk Factors Study 2017Retrospective database analysisN/A• Cirrhosis responsible for 1.32 million (2.4%) of global deaths in 2017, with NASH responsible for ∼118,000 of them
       Vilar-Gomez et al
      • Vilar-Gomez E.
      • Vuppalanchi R.
      • Gawrieh S.
      • et al.
      Vitamin E improves transplant-free survival and hepatic decompensation among patients with nonalcoholic steatohepatitis and advanced fibrosis.
      USAPatients with biopsy-proven NASH and bridging fibrosis or compensated cirrhosis (single center, 2004–2016)Observational cohort study236• Vitamin E use associated with:
      • Lower overall mortality and transplant rates vs propensity score-matched nonusers (10% vs 33%, P < .001)
      • Higher 10-y time-dependent, adjusted, transplant-free survival rate (78% vs 49%, P < .01)
       Vilar-Gomez et al
      • Vilar-Gomez E.
      • Vuppalanchi R.
      • Desai A.P.
      • et al.
      Long-term metformin use may improve clinical outcomes in diabetic patients with non-alcoholic steatohepatitis and bridging fibrosis or compensated cirrhosis.
      Spain, Australia, Hong Kong, and CubaPatients with biopsy-proven NASH and compensated cirrhosis (multicenter, 1995–2016)Observational cohort studyNASH + compensated cirrhosis: 299
      • 87% of all deaths were liver related
      • 10-y survival without LT was lower in diabetic patients (38%, 95% CI 31–45) vs nondiabetic patients (81%, 95% CI 75–88)
      • Annualized mortality or transplant rates were 4.9 and 3.0 per 100 person-years in diabetic and nondiabetic patients, respectively (Cox-adjusted P < .01)
      • T2D increased risk of all-cause mortality or transplant 4.59-fold (95% CI 2.23–9.43) compared with no T2D
      • This remained significant when analyzing T2D as a time-dependent variable (adjusted HR 4.23, 95% CI 1.93–9.29, P < .001)
      LT wait list outcomes
       Thuluvath et al
      • Thuluvath P.J.
      • Hanish S.
      • Savva Y.
      Waiting list mortality and transplant rates for NASH cirrhosis when compared with cryptogenic, alcoholic, or AIH cirrhosis.
      USAPatients listed for LT with primary diagnosis of NASH, CC, AC, or AIH (excluding HCC and multiple-organ transplants) from 2002 to 2016 (UNOS LT registry)Retrospective database analysisTotal patients: 33,566

      NASH: 7935
      • Cumulative incidence of LT wait list death or deterioration by 3 y was 29% NASH, 28% CC and AC, 24% AIH
       Kaswala et al
      • Kaswala D.H.
      • Zhang J.
      • Liu A.
      • et al.
      A comprehensive analysis of liver transplantation outcomes among ethnic minorities in the United States.
      USAPatients listed for LT for NASH, HCV, ALD, or HCV/ALD from 2005 to 2016 (UNOS LT registry)Retrospective database analysisTotal patients: 88,542

      NASH: 22.3%
      • Adjusted risk of LT wait list death lower in Hispanics and Asians vs non-Hispanic whites
      Ascites-related hospitalization outcomes
       Sourianarayanane et al
      • Sourianarayanane A.
      • O'Shea R.S.
      • Barnes D.S.
      • et al.
      High prevalence of normal serum albumin in NASH patients with ascites: a retrospective analysis.
      USAPatients with ascites who underwent transjugular procedures (single center, 2005–2009)Observational cohort studyTotal patients: 138

      NASH: 41
      • NASH patients had a 1-y mortality of 38.0%
      • Overall unadjusted mortality was no different between NASH and non-NASH patients (48.8% vs 55.7%; P = .46)
       Tan et al
      • Tan H.K.
      • Teng M.L.P.
      • Soh A.Y.S.
      • et al.
      Poor outcomes of cirrhosis due to nonalcoholic steatohepatitis compared with hepatitis B after decompensation with ascites.
      SingaporePatients with NASH/HBV cirrhosis who were admitted to hospital for first-onset ascites (multicenter, 2004–2015)Observational cohort studyNASH cirrhosis: 90

      HBV cirrhosis: 110
      • Median survival of patients with NASH cirrhosis was shorter than those with HBV cirrhosis (34.6 mo vs 72.7 mo, P = .001)
      • The 12- and 60-mo transplant-free survival was significantly shorter with NASH cirrhosis vs HBV cirrhosis
        • 12-mo: P = .038
        • 60-mo: 27.2% vs 56.6%, P = .003
      • Cumulative incidence of cirrhosis-related deaths and LT was greater for NASH cirrhosis vs HBV cirrhosis patients (65.7% vs 42.5%, P = .008)
      HCC outcomes
       Weinmann et al
      • Weinmann A.
      • Alt Y.
      • Koch S.
      • et al.
      Treatment and survival of non-alcoholic steatohepatitis associated hepatocellular carcinoma.
      GermanyPatients with NASH-associated and non-NASH-HCC (single center, 2000–2010)Observational cohort studyTotal patients: 1119

      NASH-HCC: 45
      • Median overall survival was 11.3 mo vs 15.5 mo for NASH-HCC and non-NASH-HCC, respectively (P = .287)
       Kumar et al
      • Kumar R.
      • Goh B.G.
      • Kam J.W.
      • et al.
      Comparisons between non-alcoholic steatohepatitis and alcohol-related hepatocellular carcinoma.
      SingaporePatients with NASH-HCC or ASH-HCC (single center HCC database, 2000–2013)Retrospective database analysisNASH-HCC: 54

      ASH-HCC: 45
      • Median overall survival was 13 ± 2.5 vs 7 ± 1.6 mo for NASH-HCC and ASH-HCC groups, respectively (P = .12)
      • Liver-related mortality was significantly better for NASH-HCC vs ASH-HCC groups (median survival 19 ± 10.3 vs 8 ± 1.3 mo, P = .047)
      • Child-Pugh score and tumor stage were significant determinants of all-cause and liver-related mortality
       Young et al
      • Young S.
      • Sanghvi T.
      • Rubin N.
      • et al.
      Transarterial chemoembolization of hepatocellular carcinoma: propensity score matching study comparing survival and complications in patients with nonalcoholic steatohepatitis versus other causes cirrhosis.
      USAPatients undergoing TACE for HCC (single center, 2011–2016)Observational cohort studyTotal: 220

      NASH: 30
      • No significant difference in overall survival in NASH-HCC vs non-NASH-HCC patients (853 vs 706 d, P = .48)
       Billeter et al
      • Billeter A.T.
      • Müller P.C.
      • Albrecht T.
      • et al.
      Impact of type 2 diabetes on oncologic outcomes of hepatocellular carcinomas in non-cirrhotic, non-alcoholic steatohepatitis: a matched-pair analysis.
      GermanyPatients operated on for noncirrhotic HCC (single center, 2001–2017)Observational cohort studyNASH-HCC ± T2D: 34

      Hepatitis-HCC ± T2D: 26

      ALD-HCC ± T2D: 28
      • There was no difference in overall survival among NASH-HCC (1-, 3-, and 5-y overall survival of 82.8%, 75.7%, and 71.3%), hepatitis-HCC (95.7%, 77.6%, and 60.4%), and ALD-HCC (92.0%, 79.9%, and 79.9%), P = .952
      • NASH-HCC was associated with longer disease-specific survival than hepatitis-HCC (1-, 3-, and 5-y survival of 93%, 93%, and 87.5% vs 95.7%, 81.9%, and 63.7%, P = .048)
      • Recurrence-free survival was comparable between NASH-HCC, hepatitis-HCC, and ALD-HCC
      • Presence of T2D had no impact on outcomes in either liver disease
       Holzner et al
      • Holzner M.L.
      • Florman S.
      • Schwartz M.E.
      • et al.
      Outcomes of liver transplantation for nonalcoholic steatohepatitis-associated hepatocellular carcinoma.
      USAPatients receiving LT for HCC (single center, 2001–2017)Observational cohort studyNASH: 51

      Non-NASH: 584
      • There was no significant difference in overall survival between NASH-HCC and non-NASH-HCC
      AC, alcoholic cirrhosis; AIH, autoimmune hepatitis; ALD, alcoholic liver disease; ASH, alcoholic steatohepatitis; CC, cryptogenic cirrhosis; CI, confidence interval; GBD, Global Burden of Disease; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCUP, Healthcare Cost and Utilization Project; HCV, hepatitis C virus; HR, hazard ratio; LT, liver transplantation; N/A, not applicable; NAFL, nonalcoholic fatty liver; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NIS, National Inpatient Sample; OR, odds ratio; T2D, type 2 diabetes; TACE, transarterial chemoembolization; UNOS, United Network for Organ Sharing.
      Consolidating mortality data is challenging because of the variety of patient populations and outcomes measured; however, in general, the studies demonstrate a high mortality burden that is further exacerbated by older age or the presence of fibrosis or comorbidities such as T2D.
      • Hirose S.
      • Matsumoto K.
      • Tatemichi M.
      • et al.
      Nineteen-year prognosis in Japanese patients with biopsy-proven nonalcoholic fatty liver disease: lean versus overweight patients.
      ,
      • Vilar-Gomez E.
      • Calzadilla-Bertot L.
      • Wong V.W.
      • et al.
      Type 2 diabetes and metformin use associate with outcomes of patients with nonalcoholic steatohepatitis-related, child-pugh A cirrhosis.
      ,
      • Angulo P.
      • Kleiner D.E.
      • Dam-Larsen S.
      • et al.
      Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.
      • Renno A.
      • Abdel-Aziz Y.
      • Alastal Y.
      • et al.
      The association between obstructive sleep apnea and non-alcoholic steatohepatitis: a retrospective nationwide inpatient sample analysis.
      • Reja M.
      • Patel R.
      • Pioppo L.
      • et al.
      Renal failure is associated with increased mortality and hospital utilization in patients admitted with nonalcoholic steatohepatitis.
      Individual studies reported that NASH-related cirrhosis was responsible for ∼118,000 deaths globally in 2017,
      GBD 2017 Cirrhosis Collaborators
      The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017.
      and there was a 3.7% inpatient mortality rate among patients hospitalized for cirrhosis in the United States between 2006 and 2014.
      • Axley P.
      • Ahmed Z.
      • Arora S.
      • et al.
      NASH is the most rapidly growing etiology for acute-on-chronic liver failure-related hospitalization and disease burden in the United States: a population-based study.
      There was no consistent position on the impact of NASH etiology (vs other underlying etiologies) on mortality in HCC populations.
      • Weinmann A.
      • Alt Y.
      • Koch S.
      • et al.
      Treatment and survival of non-alcoholic steatohepatitis associated hepatocellular carcinoma.
      • Kumar R.
      • Goh B.G.
      • Kam J.W.
      • et al.
      Comparisons between non-alcoholic steatohepatitis and alcohol-related hepatocellular carcinoma.
      • Young S.
      • Sanghvi T.
      • Rubin N.
      • et al.
      Transarterial chemoembolization of hepatocellular carcinoma: propensity score matching study comparing survival and complications in patients with nonalcoholic steatohepatitis versus other causes cirrhosis.
      • Billeter A.T.
      • Müller P.C.
      • Albrecht T.
      • et al.
      Impact of type 2 diabetes on oncologic outcomes of hepatocellular carcinomas in non-cirrhotic, non-alcoholic steatohepatitis: a matched-pair analysis.

      Quality of Included Studies

      Information on the quality assessment of included studies is provided in Supplementary Materials.

      Discussion

      The findings of this study provide a detailed picture of the course of NASH and the associated complications, as well as risk factors for the development of NASH and worsening fibrosis. Overall, 173 publications were included in this review, but considerable heterogeneity in study designs and methodologies, population sizes, study duration, outcomes, and study quality meant that direct comparison across studies was challenging.
      Few studies evaluated the natural history of NASH in the absence of pharmacologic or bariatric surgery intervention, and no firm conclusions could be drawn due to study heterogeneity. Generally, findings showed that NASH progresses over time for many patients, with an increasing risk of liver-related complications such as cirrhosis and HCC with increasing fibrosis.
      • O'Leary J.G.
      • Landaverde C.
      • Jennings L.
      • et al.
      Patients with NASH and cryptogenic cirrhosis are less likely than those with hepatitis C to receive liver transplants.
      • Ajmera V.
      • Belt P.
      • Wilson L.A.
      • et al.
      Among patients with nonalcoholic fatty liver disease, modest alcohol use is associated with less improvement in histologic steatosis and steatohepatitis.
      • Reddy Y.K.
      • Marella H.K.
      • Jiang Y.
      • et al.
      Natural history of non-alcoholic fatty liver disease: a study with paired liver biopsies.
      • Henson J.B.
      • Wilder J.M.
      • Kappus M.R.
      • et al.
      Transplant outcomes in older patients with nonalcoholic steatohepatitis compared to alcohol-related liver disease and hepatitis C.
      • Sanyal A.J.
      • Harrison S.A.
      • Ratziu V.
      • et al.
      The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.
      ,
      • Seko Y.
      • Sumida Y.
      • Tanaka S.
      • et al.
      Serum alanine aminotransferase predicts the histological course of non-alcoholic steatohepatitis in Japanese patients.
      ,
      • Hernandez-Alejandro R.
      • Croome K.P.
      • Drage M.
      • et al.
      A comparison of survival and pathologic features of non-alcoholic steatohepatitis and hepatitis C virus patients with hepatocellular carcinoma.
      • Doycheva I.
      • Zhang T.
      • Amjad W.
      • et al.
      Diabetes and hepatocellular carcinoma: incidence trends and impact of liver disease etiology.
      • Kern B.
      • Feurstein B.
      • Fritz J.
      • et al.
      High incidence of hepatocellular carcinoma and postoperative complications in patients with nonalcoholic steatohepatitis as a primary indication for deceased liver transplantation.
      • Zarrinpar A.
      • Faltermeier C.M.
      • Agopian V.G.
      • et al.
      Metabolic factors affecting hepatocellular carcinoma in steatohepatitis.
      ,
      • Vilar-Gomez E.
      • Vuppalanchi R.
      • Desai A.P.
      • et al.
      Long-term metformin use may improve clinical outcomes in diabetic patients with non-alcoholic steatohepatitis and bridging fibrosis or compensated cirrhosis.
      • Hirose S.
      • Matsumoto K.
      • Tatemichi M.
      • et al.
      Nineteen-year prognosis in Japanese patients with biopsy-proven nonalcoholic fatty liver disease: lean versus overweight patients.
      • Amarapurkar D.N.
      • Dharod M.
      • Gautam S.
      • et al.
      Risk of development of hepatocellular carcinoma in patients with NASH-related cirrhosis.
      ,
      • Wong V.W.
      • Wong G.L.
      • Tsang S.W.
      • et al.
      High prevalence of colorectal neoplasm in patients with non-alcoholic steatohepatitis.
      ,
      • Cholankeril G.
      • Wong R.J.
      • Hu M.
      • et al.
      Liver transplantation for nonalcoholic steatohepatitis in the US: temporal trends and outcomes.
      ,
      • Haldar D.
      • Kern B.
      • Hodson J.
      • et al.
      Outcomes of liver transplantation for non-alcoholic steatohepatitis: a European Liver Transplant Registry study.
      ,
      • Younossi Z.
      • Stepanova M.
      • Ong J.P.
      • et al.
      Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates.
      ,
      • Thuluvath P.J.
      • Hanish S.
      • Savva Y.
      Waiting list mortality and transplant rates for NASH cirrhosis when compared with cryptogenic, alcoholic, or AIH cirrhosis.
      ,
      • Golabi P.
      • Bush H.
      • Stepanova M.
      • et al.
      Liver transplantation (LT) for cryptogenic cirrhosis (CC) and nonalcoholic steatohepatitis (NASH) cirrhosis: data from the Scientific Registry of Transplant Recipients (SRTR): 1994 to 2016.
      Despite this, some studies report spontaneous NASH regression or resolution in patients not receiving pharmacologic treatment (including in placebo arms of randomized control trials), albeit in a smaller proportion than among patients receiving interventions.
      • Promrat K.
      • Kleiner D.E.
      • Niemeier H.M.
      • et al.
      Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      • Hoofnagle J.H.
      • Van Natta M.L.
      • Kleiner D.E.
      • et al.
      Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis.
      ,
      • Li Y.H.
      • Yang L.H.
      • Sha K.H.
      • et al.
      Efficacy of poly-unsaturated fatty acid therapy on patients with nonalcoholic steatohepatitis.
      • Vilar-Gomez E.
      • Martinez-Perez Y.
      • Calzadilla-Bertot L.
      • et al.
      Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis.
      • Cusi K.
      • Orsak B.
      • Bril F.
      • et al.
      Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial.
      • Francque S.M.
      • Bedossa P.
      • Ratziu V.
      • et al.
      A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH.
      The reasons for these spontaneous regressions are not clear, and although variance within the limitations of histologic assessments may play a role, they likely reflect behavioral changes. Interestingly, although previous studies have indicated that NASH resolution is linked to fibrosis regression,
      • Kleiner D.E.
      • Brunt E.M.
      • Wilson L.A.
      • et al.
      Association of histologic disease activity with progression of nonalcoholic fatty liver disease.
      ,
      • Brunt E.M.
      • Kleiner D.E.
      • Wilson L.A.
      • et al.
      Improvements in histologic features and diagnosis associated with improvement in fibrosis in nonalcoholic steatohepatitis: results from the Nonalcoholic Steatohepatitis Clinical Research Network treatment trials.
      several interventional studies reported improvements in NASH histologic features without significant improvements in fibrosis stage.
      • Kimura Y.
      • Hyogo H.
      • Yamagishi S.
      • et al.
      Atorvastatin decreases serum levels of advanced glycation endproducts (AGEs) in nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: clinical usefulness of AGEs as a biomarker for the attenuation of NASH.
      • Promrat K.
      • Kleiner D.E.
      • Niemeier H.M.
      • et al.
      Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ,
      • Huang J.F.
      • Dai C.Y.
      • Huang C.F.
      • et al.
      First-in-Asian double-blind randomized trial to assess the efficacy and safety of insulin sensitizer in nonalcoholic steatohepatitis patients.
      ,
      • Newsome P.N.
      • Buchholtz K.
      • Cusi K.
      • et al.
      A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.
      The reasons for this discordancy are unclear but could include differences between studies in patient baseline characteristics (eg, fibrosis stage, BMI) or study design (eg, dosing, treatment duration).
      • Huang J.F.
      • Dai C.Y.
      • Huang C.F.
      • et al.
      First-in-Asian double-blind randomized trial to assess the efficacy and safety of insulin sensitizer in nonalcoholic steatohepatitis patients.
      It is also possible that assessment of fibrosis using continuous variables, such as the degree of liver stiffness, may have shown improvements that could not be detected using categorical outcome measures.
      • Newsome P.N.
      • Buchholtz K.
      • Cusi K.
      • et al.
      A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.
      Overall, the balance of disease trajectory data suggests that development of steatohepatitis and fibrosis are mostly reversible changes that may respond to pharmacologic interventions but also to changes in lifestyle (ie, diet and physical activity) mediated largely by weight loss. In the absence of long-term follow-up for many of the identified studies, the durability and impact of these regressions or resolutions remain unclear.
      Liver biopsy remains the only validated tool for NASH diagnosis and staging, and as such, repetitive biopsies are a typical regulatory requirement for interventional studies.
      European Medicines Agency
      Draft eflection paper on regulatory requirements for the development of medicinal products for chronic non-infectious liver diseases (PBC, PSC, NASH).
      ,
      U.S. Food & Drug Administration
      Noncirrhotic nonalcoholic steatohepatitis with liver fibrosis: developing drugs for treatment. Guidance for industry [draft guidance].
      However, liver biopsies are inherently invasive, can be a burden to patients, and present logistical challenges for use in clinical trials (eg, costs, availability of sufficiently experienced pathologists).
      European Medicines Agency
      Draft eflection paper on regulatory requirements for the development of medicinal products for chronic non-infectious liver diseases (PBC, PSC, NASH).
      ,
      U.S. Food & Drug Administration
      Noncirrhotic nonalcoholic steatohepatitis with liver fibrosis: developing drugs for treatment. Guidance for industry [draft guidance].
      Therefore, development of noninvasive markers, such as blood-based biomarkers, is an active area of research,
      • Povsic M.
      • Wong O.Y.
      • Perry R.
      • et al.
      A structured literature review of the epidemiology and disease burden of non-alcoholic steatohepatitis (NASH).
      ,
      • Francque S.
      • Vonghia L.
      The future of diagnosing NASH - could a simple blood test be the key?.
      and indeed, both the U.S. Food and Drug Administration and the European Medicines Agency encourage their development to potentially replace liver biopsy in future clinical trials.
      European Medicines Agency
      Draft eflection paper on regulatory requirements for the development of medicinal products for chronic non-infectious liver diseases (PBC, PSC, NASH).
      ,
      U.S. Food & Drug Administration
      Noncirrhotic nonalcoholic steatohepatitis with liver fibrosis: developing drugs for treatment. Guidance for industry [draft guidance].
      The present review includes several studies that identified blood-based risk factors for NASH disease progression or regression; however, many risk factors were identified by single studies only, and the more frequently occurring factors were not always consistent across studies. Further research is needed to test and validate such biomarkers to determine their reliability and potential for use in clinical practice.
      • Povsic M.
      • Wong O.Y.
      • Perry R.
      • et al.
      A structured literature review of the epidemiology and disease burden of non-alcoholic steatohepatitis (NASH).
      ,
      • Francque S.
      • Vonghia L.
      The future of diagnosing NASH - could a simple blood test be the key?.
      The burden of NASH in terms of comorbidities and complications is high and growing. More than 80% of patients with NASH are estimated to have one or more comorbidity, with notably high global prevalence rates for obesity (82%), hyperlipidemia/dyslipidemia (72%), MetS (71%), hypertension (68%), and diabetes (44%).
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • et al.
      Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes.
      Furthermore, increasing incidence rates of NAFLD-related cirrhosis, NAFLD cirrhosis-related mortality, and NAFLD-related liver cancer have been reported.
      • Paik J.M.
      • Golabi P.
      • Younossi Y.
      • et al.
      Changes in the global burden of chronic liver diseases from 2012 to 2017: the growing impact of NAFLD.
      The present review confirms a high burden in terms of both hepatic complications (eg, cirrhosis and HCC) and extrahepatic manifestations (comorbid CVD and metabolic conditions; increased risk of CKD and colorectal cancer).
      • Vilar-Gomez E.
      • Calzadilla-Bertot L.
      • Wong V.W.
      • et al.
      Type 2 diabetes and metformin use associate with outcomes of patients with nonalcoholic steatohepatitis-related, child-pugh A cirrhosis.
      ,
      • Wong V.W.
      • Wong G.L.
      • Tsang S.W.
      • et al.
      High prevalence of colorectal neoplasm in patients with non-alcoholic steatohepatitis.
      ,
      • Cho Y.
      • Lim S.K.
      • Joo S.K.
      • et al.
      Nonalcoholic steatohepatitis is associated with a higher risk of advanced colorectal neoplasm.
      • Targher G.
      • Bertolini L.
      • Rodella S.
      • et al.
      Relationship between kidney function and liver histology in subjects with nonalcoholic steatohepatitis.
      • Yasui K.
      • Sumida Y.
      • Mori Y.
      • et al.
      Nonalcoholic steatohepatitis and increased risk of chronic kidney disease.
      • Fussner L.A.
      • Charlton M.R.
      • Heimbach J.K.
      • et al.
      The impact of gender and NASH on chronic kidney disease before and after liver transplantation.
      ,
      • VanWagner L.B.
      • Serper M.
      • Kang R.
      • et al.
      Factors associated with major adverse cardiovascular events after liver transplantation among a national sample.
      • Patel S.S.
      • Nabi E.
      • Guzman L.
      • et al.
      Coronary artery disease in decompensated patients undergoing liver transplantation evaluation.
      • Whitsett M.
      • Wilcox J.
      • Yang A.
      • et al.
      Atrial fibrillation is highly prevalent yet undertreated in patients with biopsy-proven nonalcoholic steatohepatitis.
      • Lee H.H.
      • Cho Y.
      • Choi Y.J.
      • et al.
      Non-alcoholic steatohepatitis and progression of carotid atherosclerosis in patients with type 2 diabetes: a Korean cohort study.
      Surprisingly, no studies were identified in this review that reported an association between NASH with other solid tumor types. This may arise from the constraints of this study’s eligibility criteria to include outcomes reported in NASH populations or subpopulations only because associations between mixed severity NAFLD populations with other extrahepatic tumor types have been reported.
      • Allen A.M.
      • Hicks S.B.
      • Mara K.C.
      • et al.
      The risk of incident extrahepatic cancers is higher in non-alcoholic fatty liver disease than obesity - a longitudinal cohort study.
      ,
      • Sanna C.
      • Rosso C.
      • Marietti M.
      • et al.
      Non-alcoholic fatty liver disease and extra-hepatic cancers.
      For example, a large longitudinal cohort study in patients with NAFLD, including patients with NASH and nonalcohol-related cirrhosis, has reported increased risk of uterine, stomach, and pancreatic cancers in addition to liver and colorectal cancer.
      • Allen A.M.
      • Hicks S.B.
      • Mara K.C.
      • et al.
      The risk of incident extrahepatic cancers is higher in non-alcoholic fatty liver disease than obesity - a longitudinal cohort study.
      Lack of universal noninvasive diagnostic methods and unreliability of liver enzymes as serum biomarkers makes it difficult to attribute cancer risk to NASH vs simple steatosis in large population-based studies,
      • Allen A.M.
      • Hicks S.B.
      • Mara K.C.
      • et al.
      The risk of incident extrahepatic cancers is higher in non-alcoholic fatty liver disease than obesity - a longitudinal cohort study.
      which may contribute to the limited reports identified in this NASH-specific review.
      Alongside the rising prevalence of NASH and its adverse complications, the proportion of LTs resulting from NASH has increased over time in the United States, Europe, Australia, and New Zealand.
      • Haldar D.
      • Kern B.
      • Hodson J.
      • et al.
      Outcomes of liver transplantation for non-alcoholic steatohepatitis: a European Liver Transplant Registry study.
      ,
      • Thuluvath P.J.
      • Hanish S.
      • Savva Y.
      Waiting list mortality and transplant rates for NASH cirrhosis when compared with cryptogenic, alcoholic, or AIH cirrhosis.
      ,
      • Calzadilla-Bertot L.
      • Jeffrey G.P.
      • Jacques B.
      • et al.
      Increasing incidence of nonalcoholic steatohepatitis as an indication for liver transplantation in Australia and New Zealand.
      Although NASH is not yet one of the most common causes of LT in Europe,
      • Haldar D.
      • Kern B.
      • Hodson J.
      • et al.
      Outcomes of liver transplantation for non-alcoholic steatohepatitis: a European Liver Transplant Registry study.
      it was reported to be the second most common cause for LT in 2 large US studies, behind HCV.
      • Cholankeril G.
      • Wong R.J.
      • Hu M.
      • et al.
      Liver transplantation for nonalcoholic steatohepatitis in the US: temporal trends and outcomes.
      ,
      • Younossi Z.
      • Stepanova M.
      • Ong J.P.
      • et al.
      Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates.
      The magnitude of the impact of NASH on LT in the United States may serve as an indication of the future burden in Europe, considering the projected rise in obesity across the continent.
      • Haldar D.
      • Kern B.
      • Hodson J.
      • et al.
      Outcomes of liver transplantation for non-alcoholic steatohepatitis: a European Liver Transplant Registry study.
      In addition, HCV is likely to decline as a cause of LT in coming years considering improvements in pharmacologic treatment options, and transplantation for NASH will therefore increase in both relative and absolute terms.
      • VanWagner L.B.
      • Serper M.
      • Kang R.
      • et al.
      Factors associated with major adverse cardiovascular events after liver transplantation among a national sample.
      Crucially, LT for NASH can be precluded by the presence of comorbidities. For example, the cause of death in individuals with NASH or cryptogenic cirrhosis is often CVD-related (whereas HCV patients are more likely to die of liver-related complications). Indicators of comorbid conditions (eg, diabetes, obesity, lipid disorders, and hypertension) should be treated aggressively to limit the risk of conditions that may be fatal or make patients ineligible for transplant.
      • O'Leary J.G.
      • Landaverde C.
      • Jennings L.
      • et al.
      Patients with NASH and cryptogenic cirrhosis are less likely than those with hepatitis C to receive liver transplants.

      Strengths and Limitations

      This review synthesized a large body of evidence (173 publications), with most (116/151) of the quantitative studies rated as “strong” or “moderate” quality to provide a comprehensive picture of the available data.
      However, we acknowledge several limitations. First, the search criteria for the present study focused on patients with NASH, and although NAFLD was included in the search strategy, publications were not included if outcome data for a NASH subgroup was absent. As NASH is the progressive phenotype of NAFLD, it is likely that some NAFLD publications lacking explicit mention of NASH were excluded. However, as all publications that described NASH in their title/abstract were included, it is unlikely that excluded publications would have focused on NASH, and they may not have presented any discrete results outside of the overall NAFLD population. Second, although the review identified an extensive body of evidence regarding the course of NASH and common complications, the evidence may not address differences in the characteristics or course of disease in different ethnic groups or different geographic regions. Furthermore, more than half of the publications reported data from the United States (88/173), and consequently, most of the evidence, especially relating to LT, is based on studies performed in the United States. Third, there was considerable heterogeneity across the included publications with regard to the sample size, study design, follow-up time, and outcomes. Furthermore, conference abstracts were excluded from any further analysis, and only full-text publications were included. Finally, despite most publications receiving “strong” or “moderate” ratings in the quality assessment, 35 publications were rated as “weak,” primarily because of missing data regarding withdrawals and dropouts, as most of these studies were observational, and inadequate controlling of confounders.

      Evidence Gaps and Recommendations

      This systematic literature review included studies from 2010 to 2022, and almost half of the publications (n = 78) were published in 2019–2021. Although this shows a growing interest in research on the NASH population, data on NASH incidence and prevalence are limited and extremely variable.
      • Moon A.M.
      • Singal A.G.
      • Tapper E.B.
      Contemporary epidemiology of chronic liver disease and cirrhosis.
      There is also a paucity of studies evaluating the natural history of NASH in the absence of pharmacologic or surgical intervention.
      Evidence identified by this review clearly demonstrates that a significant number of interventional trials have measured histologic improvement and regression of NASH after pharmacological treatment; however, the durability and impact of regression are unclear in studies with only a few years’ follow-up. Longitudinal studies demonstrate effectively how a slowly progressing disease such as NASH occurs, but their follow-up is also not always sufficient to accurately capture NASH progression or regression. For example, Sanyal et al
      • Sanyal A.J.
      • Harrison S.A.
      • Ratziu V.
      • et al.
      The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.
      noted that their follow-up of 2 years is short for a slowly progressing disease such as NASH, and Ampuero et al
      • Ampuero J.
      • Aller R.
      • Gallego-Durán R.
      • et al.
      Definite and indeterminate nonalcoholic steatohepatitis share similar clinical features and prognosis: a longitudinal study of 1893 biopsy-proven nonalcoholic fatty liver disease subjects.
      commented that a mean follow-up time of 4.7 years may not be enough to observe a high number of prognostic outcomes (eg, HCC), whereas Hirose et al
      • Hirose S.
      • Matsumoto K.
      • Tatemichi M.
      • et al.
      Nineteen-year prognosis in Japanese patients with biopsy-proven nonalcoholic fatty liver disease: lean versus overweight patients.
      lost ∼40% of participants to follow-up over a median of 19.5 years. More longitudinal studies or real-world evidence studies over longer time frames are needed to accurately assess NASH progression/regression, especially given the expected increase in future prevalence and impact of NASH with the obesity epidemic. Harmonized study durations and patient populations and appropriate control of confounders are also needed to fully assess the prevalence and impact of NASH, which in turn could support an evidence-based focused approach to its disease burden.
      Despite a wealth of studies assessing risk factors for progression of NASH and/or fibrosis, validated noninvasive biomarkers that predict patients’ disease trajectory or response to interventions are lacking. Testing and validation of such biomarkers should be prioritized, both for use in clinical practice and clinical trials, and to support our future understanding of NASH epidemiology and disease progression. Future studies should also focus on improving our understanding of NASH progression and its association with comorbidities, morbidity, and mortality, as well as associated risk factors. Except for colorectal cancer, there are limited data on the increased risk of solid tumors specifically in NASH populations. It would be beneficial for studies assessing the risk of solid tumors to stratify patients by the degree of steatohepatitis to determine if increased risks are incurred once patients’ disease progresses from nonalcoholic fatty liver to NASH.

      Conclusions

      NASH is associated with significant morbidity and mortality, an increased risk of comorbidities that include HCC, CKD, and CVD, and imposes an increasing burden among LT patients. Although it is difficult to predict, NASH/NAFLD prevalence is expected to increase in parallel with the obesity and diabetes epidemics, exacerbated by a lack of general awareness, pharmacologic treatments, or a clear care pathway. Longitudinal studies with longer follow-up are required to truly understand the impact of NASH on patient outcomes.

      Authors’ Contributions:

      Elliot B. Tapper: Validation; Visualization; Writing – review and editing; Charlotte Fleming: Data curation; Formal analysis; Investigation; Resources; Validation; Visualization; Writing – review and editing; Adriana Rendon: Validation; Visualization; Writing – review and editing; João Fernandes: Methodology; Validation; Visualization; Writing – review and editing; Pierre Johansen: Conceptualization; Methodology; Supervision; Validation; Visualization; Writing – review and editing; Margarida Augusto: Validation; Visualization; Writing – review and editing; Sunita Nair: Data curation; Formal analysis; Investigation; Resources; Validation; Visualization; Writing – review and editing.

      Supplementary Materials

      References

        • Younossi Z.M.
        • Koenig A.B.
        • Abdelatif D.
        • et al.
        Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes.
        Hepatology. 2016; 64: 73-84
        • Moon A.M.
        • Singal A.G.
        • Tapper E.B.
        Contemporary epidemiology of chronic liver disease and cirrhosis.
        Clin Gastroenterol Hepatol. 2020; 18: 2650-2666
        • European Association for the Study of the Liver (EASL)
        • European Association for the Study of Diabetes (EASD)
        • European Association for the Study of Obesity (EASO)
        EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease.
        J Hepatol. 2016; 64: 1388-1402
        • Cook N.
        • Geier A.
        • Schmid A.
        • et al.
        The patient perspectives on future therapeutic options in NASH and patient needs.
        Front Med (Lausanne). 2019; 6: 61
        • LaBrecque D.
        • Abbas Z.
        • Anania F.
        • et al.
        World Gastroenterology Organisation global guidelines. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.
        (Available at:)
        • Wong V.W.
        • Wong G.L.
        • Choi P.C.
        • et al.
        Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years.
        Gut. 2010; 59: 969-974
        • Allen A.M.
        • Hicks S.B.
        • Mara K.C.
        • et al.
        The risk of incident extrahepatic cancers is higher in non-alcoholic fatty liver disease than obesity - a longitudinal cohort study.
        J Hepatol. 2019; 71: 1229-1236
        • Charlton M.R.
        • Burns J.M.
        • Pedersen R.A.
        • et al.
        Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States.
        Gastroenterology. 2011; 141: 1249-1253
      1. Higgins J.P.T. Thomas J. Chandler J. Cochrane handbook for systematic reviews of interventions version 6.0, 2019. 2019 (Available at:)
        https://training.cochrane.org/handbook
        Date accessed: February 11, 2020
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • et al.
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        PLoS Med. 2009; 6e1000097
        • Effective Public Health Practice Project
        Quality assessment tool for quantitative studies.
        (Available at:)
        • National Institute for Health and Care Excellence
        Single technology appraisal and highly specialised technologies evaluation: user guide for company evidence submission template.
        (Available at:)
        • O'Leary J.G.
        • Landaverde C.
        • Jennings L.
        • et al.
        Patients with NASH and cryptogenic cirrhosis are less likely than those with hepatitis C to receive liver transplants.
        Clin Gastroenterol Hepatol. 2011; 9: 700-704.e1
        • Ajmera V.
        • Belt P.
        • Wilson L.A.
        • et al.
        Among patients with nonalcoholic fatty liver disease, modest alcohol use is associated with less improvement in histologic steatosis and steatohepatitis.
        Clin Gastroenterol Hepatol. 2018; 16: 1511-1520.e5
        • Reddy Y.K.
        • Marella H.K.
        • Jiang Y.
        • et al.
        Natural history of non-alcoholic fatty liver disease: a study with paired liver biopsies.
        J Clin Exp Hepatol. 2020; 10: 245-254
        • Henson J.B.
        • Wilder J.M.
        • Kappus M.R.
        • et al.
        Transplant outcomes in older patients with nonalcoholic steatohepatitis compared to alcohol-related liver disease and hepatitis C.
        Transplantation. 2020; 104: e164-e173
        • Sanyal A.J.
        • Harrison S.A.
        • Ratziu V.
        • et al.
        The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.
        Hepatology. 2019; 70: 1913-1927
        • Ampuero J.
        • Aller R.
        • Gallego-Durán R.
        • et al.
        Definite and indeterminate nonalcoholic steatohepatitis share similar clinical features and prognosis: a longitudinal study of 1893 biopsy-proven nonalcoholic fatty liver disease subjects.
        Liver Int. 2021; 41: 2076-2086
        • Kimura Y.
        • Hyogo H.
        • Yamagishi S.
        • et al.
        Atorvastatin decreases serum levels of advanced glycation endproducts (AGEs) in nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: clinical usefulness of AGEs as a biomarker for the attenuation of NASH.
        J Gastroenterol. 2010; 45: 750-757
        • Promrat K.
        • Kleiner D.E.
        • Niemeier H.M.
        • et al.
        Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.
        Hepatology. 2010; 51: 121-129
        • Sanyal A.J.
        • Chalasani N.
        • Kowdley K.V.
        • et al.
        Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
        N Engl J Med. 2010; 362: 1675-1685
        • Hoofnagle J.H.
        • Van Natta M.L.
        • Kleiner D.E.
        • et al.
        Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis.
        Aliment Pharmacol Ther. 2013; 38: 134-143
        • Lassailly G.
        • Caiazzo R.
        • Buob D.
        • et al.
        Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients.
        Gastroenterology. 2015; 149: 379-388
        • Li Y.H.
        • Yang L.H.
        • Sha K.H.
        • et al.
        Efficacy of poly-unsaturated fatty acid therapy on patients with nonalcoholic steatohepatitis.
        World J Gastroenterol. 2015; 21: 7008-7013
        • Vilar-Gomez E.
        • Martinez-Perez Y.
        • Calzadilla-Bertot L.
        • et al.
        Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis.
        Gastroenterology. 2015; 149: 367-378.e5
        • Cusi K.
        • Orsak B.
        • Bril F.
        • et al.
        Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial.
        Ann Intern Med. 2016; 165: 305-315
        • Francque S.M.
        • Bedossa P.
        • Ratziu V.
        • et al.
        A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH.
        N Eng J Med. 2021; 385: 1547-1558
        • Friedman S.L.
        • Ratziu V.
        • Harrison S.A.
        • et al.
        A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis.
        Hepatology. 2018; 67: 1754-1767
        • Oliveira C.P.
        • Cotrim H.P.
        • Stefano J.T.
        • et al.
        N-acetylcysteine and/or ursodeoxycholic acid associated with metformin in non-alcoholic steatohepatitis: an open-label multicenter randomized controlled trial.
        Arq Gastroenterol. 2019; 56: 184-190
        • Gurka M.J.
        • Mack J.A.
        • Chi X.
        • et al.
        Use of metabolic syndrome severity to assess treatment with vitamin E and pioglitazone for non-alcoholic steatohepatitis.
        J Gastroenterol Hepatol. 2021; 36: 249-256
        • Harrison S.A.
        • Neff G.
        • Guy C.D.
        • et al.
        Efficacy and safety of aldafermin, an engineered FGF19 analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis.
        Gastroenterology. 2021; 160: 219-231.e1
        • Harrison S.A.
        • Ruane P.J.
        • Freilich B.L.
        • et al.
        Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial.
        Nat Med. 2021; 27: 1262-1271
        • Huang J.F.
        • Dai C.Y.
        • Huang C.F.
        • et al.
        First-in-Asian double-blind randomized trial to assess the efficacy and safety of insulin sensitizer in nonalcoholic steatohepatitis patients.
        Hepatol Int. 2021; 15: 1136-1147
        • Kedarisetty C.K.
        • Bhardwaj A.
        • Kumar G.
        • et al.
        Efficacy of combining pentoxiphylline and vitamin E versus vitamin E alone in non-alcoholic steatohepatitis– a randomized pilot study.
        Indian J Gastroenterol. 2021; 40: 41-49
        • Loomba R.
        • Noureddin M.
        • Kowdley K.V.
        • et al.
        Combination therapies including cilofexor and firsocostat for bridging fibrosis and cirrhosis attributable to NASH.
        Hepatology. 2021; 73: 625-643
        • Newsome P.N.
        • Buchholtz K.
        • Cusi K.
        • et al.
        A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.
        N Engl J Med. 2021; 384: 1113-1124
        • Okanoue T.
        • Sakamoto M.
        • Harada K.
        • et al.
        Efficacy and safety of apararenone (MT-3995) in patients with nonalcoholic steatohepatitis: a randomized controlled study.
        Hepatol Res. 2021; 51: 943-956
        • Ratziu V.
        • de Guevara L.
        • Safadi R.
        • et al.
        Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial.
        Nat Med. 2021; 27: 1825-1835
        • Vilar-Gomez E.
        • Calzadilla-Bertot L.
        • Friedman S.L.
        • et al.
        Serum biomarkers can predict a change in liver fibrosis 1 year after lifestyle intervention for biopsy-proven NASH.
        Liver Int. 2017; 37: 1887-1896
        • Sorrentino P.
        • Terracciano L.
        • D'Angelo S.
        • et al.
        Predicting fibrosis worsening in obese patients with NASH through parenchymal fibronectin, HOMA-IR, and hypertension.
        Am J Gastroenterol. 2010; 105: 336-344
        • Kruger F.C.
        • Daniels C.R.
        • Kidd M.
        • et al.
        APRI: a simple bedside marker for advanced fibrosis that can avoid liver biopsy in patients with NAFLD/NASH.
        S Afr Med J. 2011; 101: 477-480
        • Bando Y.
        • Kanehara H.
        • Aoki K.
        • et al.
        The glycated albumin to glycated haemoglobin ratio increases along with the fibrosis stage in non-alcoholic steatohepatitis.
        Ann Clin Biochem. 2012; 49: 387-390