REVIEW

A Structured Literature Review of the Epidemiologyand Disease Burden of Non-Alcoholic Steatohepatitis(NASH)

Manca Povsic . On Yee Wong . Richard Perry . Juliana Bottomley

Received: March 12, 2019 / Published online: May 7, 2019� The Author(s) 2019

ABSTRACT

Introduction: Non-Alcoholic Steatohepatitis(NASH) is a chronic, progressive disease charac-terized by fatty liver and liver cell injury,advancing to fibrosis, cirrhosis and hepatocellu-lar carcinoma (HCC). Diagnosis involves liverbiopsy; however, as a result of its high cost andinvasiveness, NASH remains underdiagnosed,and accurate burden of disease (BoD) data arelacking. Our aim was to understand the epi-demiological and BoD landscape in NASH andidentify knowledge gaps.Methods: The Ovid search engine was used toconduct a structured review, following qualitysystematic principles. It included publicationsthat reported on epidemiology, quality of life(QoL) and BoD outcomes in NASH adults.Searches were limited to English languagestudies published between January 2007 and

September 2017. Additional grey literaturesearches were conducted. A total of 53 refer-ences were selected; 38 were peer-reviewed and15 were grey literature sources.Results: NASH is estimated to affect 3–5% ofthe global population, most suffering fromseveral comorbidities. Advancing fibrosis drivesclinical outcomes, with approximately 20% ofpatients developing cirrhosis and/or HCC, thelatter being a leading cause of death in NASH. Arecent model predicted the 15-year survival ofadvanced fibrosis patients at F3 and F4 as 51.0%and 28.4%, respectively. The limited data con-sistently show that NASH patients experiencesignificantly poorer QoL and higher costs com-pared to non-NASH patients.Conclusion: This first broad-ranging examina-tion of NASH literature revealed a paucity ofevidence,with poor-quality, small studies found.The overwhelming impact of NASH and itspatient andhealthcare burden is evident. Furtherevidence is needed to improve our understand-ing ofNASH, especially as fibrosis stages advance.Funding: Gilead Science Inc.

Keywords: Burden of disease; Epidemiology;NASH; Non-alcoholic steatohepatitis

INTRODUCTION

Non-alcoholic steatohepatitis (NASH) is achronic and progressive liver disease

Enhanced Digital Features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.7992944.

Electronic supplementary material The onlineversion of this article (https://doi.org/10.1007/s12325-019-00960-3) contains supplementary material, which isavailable to authorized users.

M. Povsic (&) � O. Y. Wong � R. PerryAdelphi Values, Bollington, Cheshire, UKe-mail: manca.povsic@adelphivalues.com

J. BottomleyGilead Sciences Inc., Uxbridge, Middlesex, UK

Adv Ther (2019) 36:1574–1594

https://doi.org/10.1007/s12325-019-00960-3

characterized by the accumulation of fat in theliver (steatosis), as well inflammation [1, 2].NASH is a progression of non-alcoholic fattyliver disease (NAFLD), an umbrella term todescribe excess fat in the liver of patients whodrink little to no alcohol [1]. The exact cause ofNAFLD to NASH progression is unknown and islikely due to a complex interplay of environ-mental and genetic factors; however, certainhealth conditions, such as obesity, high bloodpressure and diabetes, increase the risk of itdeveloping [3, 4]. Numerous genetic, epigeneticand environmental contributors have recentlybeen proposed as the cause of NAFLD andNASH, including smoking and altered copperbioavailability [5–7].

NASH is often inaccurately described as anasymptomatic disease [8]—it presents with non-specific symptoms, such as tiredness or devel-oping pain in the upper right side of the abdo-men, therefore the disease can progressundetected [3]. This makes the exact burdendifficult to establish. However, NASH burden isincreasing, parallelled by the rise of obesity andNAFLD, with an estimated one-third of NAFLDpatients progressing into NASH [1]. In the UKalone, this represents approximately 5% of thepopulation [9, 10]. NASH can lead to liverfibrosis, with approximately 20% of all NASHpatients suffering from advanced fibrosis—namely bridging fibrosis (F3) or cirrhosis (F4)[1, 11]. Advanced fibrosis increases the diseaseburden in NASH significantly, leading to end-stage liver disease, hepatocellular cancer (HCC),liver transplantation and death [12]. Theunderlying fibrosis stage is key in determiningclinical outcomes and mortality, with advancedfibrosis being an independent predictor ofoverall and disease-specific mortality [13].

Despite its growing burden, there is a lack ofeffective non-invasive diagnosis tests for NASH[14]. Liver biopsy is often considered the currentgold standard for diagnosis in spite of chal-lenges associated with its accuracy, patientacceptance, safety and cost. In addition to itscomplex nature and difficulties in diagnosing,there are currently no approved therapies forNASH [14–16]. Understanding the epidemiol-ogy and burden of NASH is vital in establishing

clear guidelines for early detection and effectivetherapies [17].

The current evidence base for the epidemi-ology and burden of disease (BoD) of NASH isvery limited, with few systematic literaturereviews (SLRs) available and NASH frequentlyreported as part of the wider NAFLD burden. Tounderstand the unmet need in NASH, thisstructured literature review aimed to examinethe current knowledge on NASH epidemiologyand BoD, focusing on the prevalence, comor-bidities, disease progression, mortality, qualityof life (QoL) and economic burden. The primaryobjective was to understand the NASH epi-demiology landscape, encompassing the broadoverarching societal and economic impacts onboth the individual and the healthcare system,and to identify key gaps in current knowledgeto inform future research.

METHODOLOGY

A structured literature review was performedaccording to an agreed search protocol follow-ing the systematic principles of the Cochranehandbook for systematic reviews [18]. The fol-lowing electronic databases were searched uti-lizing the Ovid search engine: Embase, Medline,PsycINFO and EconLit. Two independent liter-ature searches were conducted to identify pub-lications relating to the epidemiology and BoDof NASH. The search terms used in the searchstrategy utilized a combination of free-textsearching and ‘subject headings’ to ensure thatthe most relevant literature was identified forreview. The full search strategy is presented inAppendix A. Searches were limited to Englishlanguage publications between January 2007and September 2017.

Publications were included in the full-textreview if they reported on disease burden, dis-ease progression, epidemiology, humanisticburden, healthcare utilization or economicburden in adults with NASH only. As a result ofthe breadth of our overarching objectives tocritique and understand epidemiological andBoD aspects of NASH, the specific detail ofindividual therapy and management optionswas not a consideration for inclusion criteria

Adv Ther (2019) 36:1574–1594 1575

and evaluation in this review. In addition toNASH-focused publications, data from NAFLD-focused publications were included in thisreview if the reported patient population wasstratified into discrete NASH and NAFLD popu-lations, and results were reported in sufficientdetail that the NASH results could be inferred orcalculated.

An internet-based search using a combina-tion of keywords was also conducted to ensurethat the latest relevant abstracts and publica-tions were captured. The search included bothnon-peer-reviewed publicly available informa-tion and peer-reviewed publications that maynot yet be indexed in databases such asPUBMED or Embase, because of their recentpublication date, or because they were pub-lished in journals that are not indexed withinthese databases. A grey literature search was alsocarried out, reviewing conference proceedingsfrom International Society for Pharmacoeco-nomics and Outcomes Research (ISPOR),American Association for the Study of LiverDiseases (AASLD), European Association for theStudy of Diabetes (EASD), European Associationfor the Study of the Liver (EASL), Paris Hepa-tology Conference (PHC) and 3rd Paris NASHSymposium.

This article is based on previously conductedstudies and does not contain any studies withhuman participants or animals performed byany of the authors.

RESULTS

During the title and abstract screening, 1229 of the1273 retrieved abstractswere excludedon thebasisof defined inclusion criteria presented in the pre-ceding section. The full text of 44 potentially rele-vant records was assessed and six records wereexcluded. The grey literature search identified 15conferenceabstracts/postersandguidelines,whichwere deemed relevant for inclusion. In total, 53publications (38 full-text and 15 grey literaturesources)were included into the evidence base usedto develop this review. A full Preferred ReportingItems for Systematic Reviews and Meta-Analyses(PRISMA) diagram is presented in Fig. 1. The pub-lications were categorized on the basis of the typeof BoD data reported as follows:• NASH prevalence and incidence• Comorbidities associated with NASH• Disease progression and mortality in NASH

patients• NASH QoL• NASH economic burden

Fig. 1 PRISMA diagram of included and excluded publications

1576 Adv Ther (2019) 36:1574–1594

The majority of the 53 included publicationswere small cohort studies and narrative reviews.Several SLRs and economic models and evalua-tions were also reported (Fig. 2). The full list ofcaptured publications is presented in AppendixB.

NASH Prevalence and Incidence

The overall NASH prevalence was reported in 13publications [19–31]. NASH was estimated toaffect between 3% and 5% of the global popu-lation, with minor variation at the country-specific level; prevalence data were captured forthe Chinese, Japanese, UK and USA populations(Fig. 3).

Over half of the publications primarilyfocused on the NAFLD population andemployed a narrative review approach. Theresearch focus varied across publications anddifferent methodologies were used to determineNASH epidemiology; therefore, direct compar-ison of prevalence data was difficult. Of note,only four of the 13 prevalence publicationsspecified the exact methodology. One popula-tion-based study used a validated histological‘NASH’ score to estimate the NASH prevalence.The remaining three publications used data

from annual health checks, national healthsurveys and autopsy results to estimate theprevalence of NASH [24, 26, 28, 29].

The epidemiology of NASH was reported inan SLR and meta-analysis which collated datafrom the USA, UK, France, Germany and Italy[19]. By computing the incidence, mortality anddisease transition probability parameters in aseries of interlinked Markov chains, it reportedthat the majority of NASH patients exhibitNASH without fibrosis (approximately 67%),while up to 25% and 11% had fibrosis and cir-rhosis, respectively [19]. These were also mostcommon in the 65? age group, highlighting theprogressive increase in disease burden in NASH[19].

Although NASH prevalence was reportedfrequently in the captured publications, noincidence data for NASH were found, high-lighting a data gap.

The NAFLD/NASH ContinuumWhile several NAFLD-focused publicationsreported NASH prevalence in the general pop-ulation, one publication reported on NAFLD-specific NASH prevalence [19]. In this SLR andmeta-analysis, approximately 60% of biopsiedNAFLD patients (95% confidence interval (CI)

Fig. 2 Publications captured in the literature review by study type. PRO patient-reported outcomes, RCT randomizedcontrolled trial, SLR systematic literature review

Adv Ther (2019) 36:1574–1594 1577

47.55–69.73) progressed to NASH [19]. How-ever, the authors acknowledged there may be aselection and ascertainment bias in this esti-mate since indication for biopsy is typicallyconducted in NAFLD patients with a high risk ofprogressing to NASH. Further stratification ofNASH prevalence was available for NAFLDpatients with and without an indication forbiopsy across Asia, Europe (EU) and NorthAmerica. Although NASH prevalence was simi-lar across regions (ranging from 63% to 69%),NASH was over four times more prevalent inNAFLD patients without indication for biopsyin North America (29.85%; 95% CI22.72–38.12) compared to Asia (6.67%; 95% CI2.17–18.73) [19].

Comorbidities Associated with NASH

Comorbidity data were the most frequentlyreported, with 18 publications describing obe-sity, diabetes and cardiovascular comorbidities

in NASH patients (Table 1) [19, 21, 22,24, 28–30, 32–42].

Overall, the prevalence of comorbiditiesassociated with NASH was high, indicating ahigh disease burden and the burden of clinicalmanagement [19]. There was huge variability inthe focus of the publications: some publicationsdescribed the overall NASH population, whilstothers focused on specific sub-populations, suchas obese, diabetic, liver transplant (LT) andbariatric surgery patients. Consequently, find-ings were described as either a comorbidityprevalence in NASH or NASH prevalence in thecomorbid sub-populations and, as such, a broadrange of prevalence was reported. Variations instudy methodologies meant that it was notpossible to establish the correlation betweenthese two types of prevalence reported; there-fore, both are presented here (Table 1).

Risk factors for developing NASH were alsoreported, with female gender, over 50 years ofage, diabetes, obesity, hyperlipidaemia/dyslipi-daemia, hypertriglyceridaemia, metabolic syn-drome and hypertension being reported as

Fig. 3 Overall NASH prevalence in the general population. NASH non-alcoholic steatohepatitis, UK United Kingdom,USA United States. aValues rounded to 1 decimal point

1578 Adv Ther (2019) 36:1574–1594

Table 1 NASH and comorbidities prevalence

References Type Country Totalstudy size(n)

Adult population Prevalence(%)

NASH prevalence

Lall et al. [28] Narrative review USA Not

reported

NASH in obese patients 15–30

Mummadi et al. [33] Meta-analysis USA 766 NASH in obese patients 18.5

NASH in morbidly obese

patients

33

Estep et al. [43] Cohort study abstract Not

reported

44 NASH in obese bariatric

surgery patients

75

Hyysalo et al. [24] Population-based

prevalence study

Finland 676 NASH in obese bariatric

surgery patients aged 45–74

14.5

NASH in diabetic bariatric

surgery patients aged 45–74

17

Athyros et al. [21] Narrative review Global Not

reported

NASH in morbidly obese

patients

37

Losekann et al. [32] Retrospective cohort study Brazil 250 NASH in morbidly obese

patients

70.4

Sanyal et al. [30] SLR abstract Global Not

reported

NASH in obese bariatric

surgery patients

34–94

Sayiner et al. [29] Narrative review Global Not

reported

NASH in obese bariatric

surgery patients

33.6–37

Joshi et al. [41] Retrospective study

abstract

USA 1920 NASH in type 2 diabetic

patients

38

Institute for Clinical

and Economic

Review [42]

Evidence review and

comparative clinical

effectiveness analysis

USA Not

reported

NASH in type 2 diabetic

patients

63–87

Obesity prevalence

Younossi et al. [19] SLR and meta-analysis Global 8,515,431 Obesity in NASH patients 81.8a

EU Obesity in NASH patients 89.2a

Oceania Obesity in NASH patients 95.2a

South

America

Obesity in NASH patients 45.5a

North

America

Obesity in NASH patients

without indication for

biopsy

80

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Table 1 continued

References Type Country Totalstudy size(n)

Adult population Prevalence(%)

Sanyal et al. [30] SLR abstract Global Not

reported

Obesity in NASH patients 31–89

Type 2 diabetes prevalence

Promrat et al. [40] RCT USA 31 Type 2 diabetes in NASH 48

Simons et al. [39] Cohort study abstract USA 324 Type 2 diabetes in NASH LT

patients

77

VanWagner et al.

[38]

Cohort study abstract USA 6932 Type 2 diabetes in NASH LT

patients

46.2

Estep et al. [43] Cohort study abstract Not

reported

44 Type 2 diabetes in obese

NASH bariatric surgery

patients

20.3b

McPherson et al.

[35]

Cohort study UK 448 Type 2 diabetes in NASH 56

VanWagner et al.

[37]

Database analysis USA 5057 Type 2 diabetes in NASH LT

patients

57.1

Losekann et al. [32] Retrospective cohort study Brazil 250 Type 2 diabetes in morbidly

obese diabetic NASH

patients

9c

Younossi et al. [19] SLR and meta-analysis Global 8,515,431 Type 2 diabetes in NASH 43.6a

Mantry et al. [36] Retrospective study

abstract

USA 650 Type 2 diabetes in NASH 45

Sanyal et al. [30] SLR abstract USA Not

reported

Type 2 diabetes in NASH 5.3–73.1

CVD prevalence

Vilar-Gomez et al.

[34]

Prospective cohort study Cuba Not

reported

CVD in NASH patients 2

Barritt et al. [44] Observational study USA 1441 CVD in NASH patients 9.4d

Hyperlipidaemia prevalence

Estep et al. [43] Cohort study abstract Not

reported

44 Hyperlipidaemia in obese

NASH bariatric surgery

patients

23.3e

Vilar-Gomez et al.

[34]

Prospective cohort study Cuba Not

reported

Hyperlipidaemia in NASH

patients

52

Younossi et al. [19] SLR and meta-analysis Global 8,515,431 Hyperlipidaemia in NASH

patients

72.1a

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Table 1 continued

References Type Country Totalstudy size(n)

Adult population Prevalence(%)

Sanyal et al. [30] SLR abstract USA Not

reported

Hyperlipidaemia in NASH

patients

16.9–86.2

Hypertension prevalence

Estep et al. [43] Cohort study abstract Not

reported

44 Hypertension in obese NASH

bariatric surgery patients

28.5f

VanWagner et al.

[37]

Database analysis USA 5057 Hypertension in NASH LT

patients

35.7

Younossi et al. [19] SLR and meta-analysis Global 8,515,431 Hypertension in NASH

patients

68a

Sanyal et al. [30] SLR abstract USA Not

reported

Hypertension in NASH

patients

20.2–85.7

Metabolic syndrome prevalence

Hyysalo et al. [24] Population-based

prevalence study

Finland 676 Metabolic syndrome in

NASH bariatric surgery

patients aged 45–74

3.4g

Merola et al. [22] Clinical review USA Not

reported

Metabolic syndrome in

NASH LT patients

40–60

Younossi et al. [19] SLR and meta-analysis Global 8,515,431 Metabolic syndrome in

NASH patients

70.7a

Sanyal et al. [30] SLR abstract USA Not

reported

Metabolic syndrome in

NASH patients

7.5–92.7

Hypercholesterolaemia prevalence

Sanyal et al. [30] SLR abstract USA Not

reported

Hypercholesterolaemia in

NASH patients

90.2

Hypertriglyceridaemia prevalence

Younossi et al. [19] SLR and meta-analysis Global 8,515,431 Hypercholesterolaemia in

NASH patients

40.7a

CVD cardiovascular disease, EU Europe, LT liver transplant, NASH non-alcoholic steatohepatitis, RCT randomizedcontrolled trial, SLR systematic literature review, UK United Kingdom, USA United Statesa Values rounded to 1 decimal pointb Calculated 27 9 0.75 = 20.3%, based on 75% of the population being NASH obese patients with bariatric surgeryc Calculated 12.8 9 0.704 = 9%, based on 70.4% of the population being NASH morbidly obese patientsd Calculated 20 9 0.47 = 9.4%, based on 47% of the population being diagnosed with NASHe Calculated 31 9 0.75 = 23.3%, based on 75% of the population being NASH obese patients with bariatric surgeryf Calculated 38 9 0.75 = 28.5%, based on 75% of the population being NASH obese patients with bariatric surgeryg Calculated 57 9 0.06 = 3.4, based on 6% of the population being diagnosed with NASH

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specific factors increasing the risk of NASH[19, 22, 26, 29, 35].

ObesityThe obesity prevalence in the NASH populationwas reported in two publications, ranging from31% to 95% (Table 1) [19, 30]. An SLR with ameta-analysis estimated that 82% of NASHpatients suffer from obesity, with another SLRin broad agreement (estimated prevalence wasbetween 31% and 89%); however, the authorscautioned that this range is likely influenced bythe variable case definitions and methods usedin individual studies examined in this review[19, 30]. Obesity prevalence in NASH was alsoreported in different geographical regions, withobesity being twice as prevalent in NASHpatients in the EU (89.19%, 95% CI74.51–95.88) and Oceania (95.24%, 95% CI82.86–98.81) compared to South America(45.45%, 95% CI 26.47–65.86) [19].

NASH prevalence in the obese populationwas reported in seven publications and wasmore fragmented compared to obesity preva-lence in NASH, largely due to the differentpopulations of focus in the relevant publica-tions (such as morbidly obese, obese, or bar-iatric surgery patients) [21, 24, 28–30, 32, 33].NASH prevalence ranged from 15% to 94%,depending on the population examined(Table 1), with prevalence in obese and mor-bidly obese patients reported as 15–30% and

33–70%, respectively [21, 28, 33]. NASH preva-lence in the obese population with bariatricsurgery was between 34% and 94% [29, 30].Obese prevalence data were frequently reportedfor the global or USA populations, with onepublication each focusing on Finnish andBrazilian NASH populations [24, 32].

Type 2 DiabetesType 2 diabetes prevalence in NASH was repor-ted in ten publications [19, 30, 32, 35–40, 43].An SLR and meta-analysis estimated the globaldiabetes prevalence among NASH patients to be43.6% (Table 1) [19]. Similar results were pre-sented in cohort studies (ranging between 33%and 56%) [34–36]. Another SLR reported abroader estimate of between 5% and 73%;however, similarly to the obese population, theauthors cautioned that the variable methodsused in the captured studies have likely influ-enced these results [30]. The prevalence of dia-betes was also reported in NASH LT patients andranged between 46% and 77%, suggesting anincreased burden of diabetes LT patients[37–39].

NASH prevalence in the diabetic populationwas reported in three publications, rangingfrom 18% to 87% [24, 41, 42]. Although theNASH prevalence was higher in diabetics alonecompared to diabetic bariatric surgery patients,the research focus of the captured publicationsvaried substantially in terms of the geography,

Fig. 4 NASH disease progression. F0/4 fibrosis stage 0/4, HCC hepatocellular carcinoma, NASH non-alcoholicsteatohepatitis. Data adapted from Traussnigg et al. [44]

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with two publications focusing on the USA andone on Finland, and the type of population,such as NASH diabetic and NASH diabetic bar-iatric surgery patients, therefore making furthermeaningful comparisons impossible.

Cardiovascular DiseaseEight publications reported the prevalence ofcardiovascular comorbidities in NASH patients,specifically focusing on hypercholesterolaemia,

hyperlipidaemia, hypertension and metabolicsyndrome (Table 1) [19, 22, 24, 30, 34, 37, 43,44]. Only two publications reported the overallcardiovascular disease (CVD) prevalence amongNASH patients, which ranged from 2% to 20%[34, 44]. A large SLR and meta-analysis reportedthe overall pooled prevalence for cardiovascularcomorbidities among NASH patients as 72% forhyperlipidaemia/dyslipidaemia, 41% for hyper-triglyceridaemia, 68% for hypertension and

Table 2 NASH progression to fibrosis

References Type Country Total studysize (n)

NASH stage Progression (%)

Progression from NASH to fibrosis

Argo et al.

[46]

SLR USA 221 All NASH patients to stage 3/4

fibrosis

15.8% over 3.7 years

(mean interval)

NASH fibrosis patients who

progressed to stage 3/4 fibrosis

42.1% over 3.7 years

(mean interval)

Musso et al.

[49]

Meta-analysis Not

reported

Not

reported

NASH to progressive fibrosis 25–30% over 4 years

50% over 6 years

Sporea et al.

[54]

Retrospective

cohort study

Romania 478 NASH to severe fibrosis 18.5%a

NASH to no severe fibrosis 70.8%a

Satapathy

et al. [23]

Narrative

review

USA Not

reported

NASH to fibrosis 37%a

NASH to F3 fibrosis 22%a

NASH to progressive fibrosis 34.5%a

Younossi

et al. [19]

SLR USA 8,515,431 NASH to fibrosis 41%a

Shouhed

et al. [53]

Narrative

review

USA Not

reported

NASH to fibrosis 26–57%a

Progression from F1/F2 fibrosis onwards

Musso et al.

[49]

Meta-analysis Sweden Not

reported

F1/2 fibrosis to cirrhosis 13%a

Progression from F3 fibrosis onwards

Musso et al.

[49]

Meta-analysis Sweden Not

reported

F3 fibrosis to cirrhosis and end stage

liver disease

25%a

Shouhed

et al. [53]

Narrative

review

USA Not

reported

Fibrosis to cirrhosis 9–17%a

F1/2/3/4 fibrosis stage 1/2/3/4, NASH non-alcoholic steatohepatitis, SLR systematic literature review, USA United Statesa Time frame not reported

Adv Ther (2019) 36:1574–1594 1583

71% for metabolic syndrome [19]. This was inbroad agreement with the wide range of preva-lence (from 7.5% to 92.7%) reported in anotherSLR [30]. Other publications reported a range ofprevalence estimates, in line with the varyingmethodologies and population focus of thepublications [22, 24, 34, 37, 43]. Small cohortstudies and narrative reviews reported lowerprevalence, specifically in sub-populations,such as NASH LT patients and NASH bariatricsurgery patients [22, 24, 34, 37, 43]. As a resultof fragmentation of the data and the less robustmethodologies employed by these studies, nofurther conclusions could reliably be drawn.

Disease Progression and Mortalityin NASH Patients

Disease progression and mortality was reportedin 24 publications; fibrosis data were the mostfrequently reported, followed by cirrhosis andHCC [19–23, 26–28, 35, 37, 45–58]. Half of thepublications were narrative reviews, while theother half ranged from small cohort studies toSLRs, highlighting a substantial range in therobustness of the data reported.

Disease Progression in NASHAs a result of a lack of effective diagnostic toolsand nonspecific symptoms, NASH progressionwas difficult to establish. The majority of thepublications did not specify the methodologiesused to confirm disease progression; only a fewutilized liver biopsies [19, 28, 46, 47].

The captured literature reported that up to44% of patients with steatosis progress to NASH[23, 35]. While early stages of NASH can bebidirectional (i.e. progression and regressioncan occur), the majority of patients (93%) didnot regress back to earlier stages of fibrosis(Fig. 4) [35].

Fibrosis Progression in NASH Several studiesexamining liver biopsy reported that approxi-mately 40% of NASH patients progress tofibrosis globally [19, 28, 46, 47]. Global averageannual progression of NASH to fibrosis wastwice as fast as non-alcoholic fatty liver (NAFL)progression, corresponding to an average

progression by one stage over 7.1 years versus14.3 years, and highlighting the increase in thepatient burden of NASH compared to NAFLD[23, 47].

An SLR of risk factors for fibrosis progressionhighlighted that the rate of progression increa-ses in fibrosis patients compared to the overallNASH cohort, from 0.03 stages/year to0.41 stages/year, respectively [46]. Inflamma-tion on initial biopsy had a strongly significantpredictive value for development of advancedfibrosis (p\0.0001), with median time to pro-gression to advanced fibrosis in patients withinflammation being 4.2 years versus 13.4 yearsin patients without inflammation [46].

In long-term follow-up over 5.3 years, mostpatients experienced no change in NASHseverity; however, of the patients who did pro-gress, approximately 70% advanced one stageand approximately 32% progressed two or morestages [46]. The authors concluded that between5% and 10% of patients with NASH diagnosedon their initial biopsy will present with clini-cally significant fibrosis at this initial biopsy,and an additional 15–20% will progress toadvanced fibrosis in less than a decade,emphasizing the progressive burden of NASHadvanced fibrosis [46].

Progression between NASH fibrosis stageswas also described in the evidence base. Pro-gression between any fibrosis stages was repor-ted in 16–71% of NASH patients, progressionfrom F1/F2 onwards in 9–13%, and from F3onwards in 9–25% of patients (Table 2)[19, 23, 46, 49, 53, 54]. It is important tohighlight that the publications reporting fibro-sis stage progression utilized different stage ter-minology, e.g. F0–F4, stage 1/4, progressivefibrosis, advanced fibrosis, severe fibrosis, etc.The definitions for these stages were not alwaysclarified; therefore, the comparability of theseresults was limited.

Cirrhosis and HCC Progression in NASH Cir-rhosis and HCC progression were reported inten publications [19, 20, 22, 23, 26, 27, 45, 50,51, 55]. In the captured publications, up to 25%of NASH patients progressed to liver cirrhosisand HCC [20, 22, 27, 45].

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The prevalence of cirrhosis progression wasreported as significantly higher in NASHpatients compared to NAFL patients (10.8%versus 0.7%, respectively) [50]. A model ofsimulated NASH patient life course examinedthe average time of progression to decompen-sated cirrhosis and HCC for every NASH fibrosisstage, and the simulated average time to pro-gress from early stage fibrosis (F1/F2) was longer(approximately 16 years) than the time to pro-gress from advanced fibrosis (approximately10 years) [55]. This highlighted the long-termclinical outcomes and increased mortality riskrelated to NASH progression [55].

HCC incidence was reported in three publi-cations; however, this was reported as threedistinct types of incidence: global cumulativeincidence (2.4% over 7 years and 12.8% over3 years), global annual incidence [5.29 per1000 patient years (95% CI 0.75–37.56)] andincidence in Japan (between 5% and 25% dur-ing approximately 7 years) [23, 26]. As theincidence type varied between publications, norobust comparisons could be made across thesedata.

An increased burden of NASH progressionwas acknowledged, highlighting that the rate ofHCC progression is expected to increase fasterthan other hepatic diseases, such as hepatitis Bor C. Consequently there are important impli-cations for resource utilization, given that HCChas emerged as the sixth most common cancerand second leading etiology of cancer-relateddeaths worldwide [19]. A healthcare utilizationmodel was in accord with this, predicting adisproportionate increase in NASH by 2030: theprevalences of compensated and decompen-sated cirrhosis cases were projected to increase180% and 200% from 2015 to 2030, respectively[51]. The number of NASH-related HCC caseswas also projected to reach 12,220 cases in 2030,an increase of approximately 140% compared to2015 [51].

Mortality in NASHFifteen publications reported mortality out-comes in NASH patients [20–23, 26, 28, 37,46, 48–50, 55–58]. Several publications outlinedan increased risk of death in NASH compared tothe general population and patients with NAFL,

and decreased survival compared to NAFLDpatients [20, 28, 48, 49].

The overall mortality rate in NASH was 25.56per 1000 patient years, with the liver-specificmortality rate reported as 11.77 per 1000 pa-tient years [20]. An SLR and meta-analysisreported liver disease as the main cause of deathin NASH, with a liver-related mortality rate of11–17.5% compared to 1.7–2.7% of NAFLD(pooled odds ratio (OR) 5.71; 95% CI2.31–14.13; p = 0.0002) [49]. However, this wasdisputed in several narrative reviews, whichreported CVD and malignancies as the maincause of death in NASH patients [20, 23, 57].These publications reported the cause of deathusing several different measurements and acrossdifferent populations; therefore, a selection biasmay have been present.

NASH Fibrosis Mortality There was a signifi-cant worsening of mortality outcomes reportedwith advanced fibrosis (F3/F4) in NASH. Fibrosisprogression was linked to a 70% increase intotal mortality, compared with patients withoutfibrosis [21]. NASH patients with moderate-to-severe fibrosis at baseline also showed a worsesurvival rate compared to patients with mildfibrosis or no fibrosis (adjusted hazard ratio (HR)2.09, p = 0.01) [21].

In addition, a model on the life course ofNASH patients predicted that the long-termliver-related mortality and survival in NASH isworsened with fibrosis progression over 15 years[55]. This aligned with a previously conductedSLR and meta-analysis, which showed thatadvanced fibrosis increases liver-related mortal-ity almost fivefold compared to mild fibrosis[49].

NASH Cirrhosis and HCC Mortality Anincreased mortality burden was also reportedwith NASH cirrhosis. NASH cirrhosis patient lifeexpectancy was lower than non-cirrhotic NASHpatients, with cirrhotic patients’ survival rang-ing from 59% to 84% of the life expectancy ofthose without cirrhosis [26, 46, 50]. Mediansurvival in NASH cirrhosis patients wasapproximately 6 years; they had a similar liver-related mortality compared to viral cirrhosisand a higher CVD-related mortality was

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observed [49]. Annual mortality rates forpatients with compensated cirrhosis anddecompensated cirrhosis specifically were 2%and 13%, respectively, demonstrating a highermortality burden with progressive worsening ofcirrhosis [58].

There was a paucity of HCC mortality data,reported in only two publications [26, 50]. The5-year survival of NASH HCC was reported as44.8%, with HCC being one of the leadingcauses of death in NASH patients (47% ofdeaths), representing an independent risk factorfor liver-related mortality (HR 7.96) [26, 50].

NASH QoL

There was a paucity of data reporting on QoL,specifically on patient-reported outcomes(PRO), with only three publications identified[59–61]. The following experiences were cap-tured in the search: only one generic PROinstrument, the Short Form-36 (SF-36) healthsurvey and one liver-specific questionnaire, theChronic Liver Disease Questionnaire (CLDQ)reported BoD data [59–61].

Two publications reported on NASH patientsexperiencing poorer physical and mental healthcompared to non-NASH patients according tothe SF-36 scale, with significantly poorer scoresin NASH patients compared to non-NASHpatients in mental health, physical functioning,role limitations due to emotional health andsocial function (p\0.05 for all) [59, 60]. Thesefindings were confirmed via the CLDQ instru-ment, which revealed additional impairmentsin all domains (abdominal symptoms, fatigue,systemic symptoms, activity, emotional func-tion, worry) associated with a reduced overallCLDQ score (p\ 0.0001 for all) [60, 62]. Thepresence of diabetes [p = 0.04 for PhysicalComponent Score (PCS)] was the only demo-graphic/clinical variable reported that wasassociated with impaired health-related qualityof life (HRQoL) amongst NASH patients [60].The authors concluded that CLDQ was a reliableand valid measurement tool of disease-specificHRQoL in adults with NASH.

NASH Economic Burden

NASH economic burden was reported in 12publications [30, 42, 58, 63–70].

The majority of the publications were healtheconomic evaluations, with the cost-effective-ness of NASH screening methods and treat-ments the most reported-on economicoutcome. However, there was a paucity of dataon the societal costs or the healthcare burden ofNASH with only one meta-analysis reporting onthe direct costs of NASH [63].

Advanced fibrosis progression was associatedwith significant increases in costs [63]. In allstages of NASH, direct medical costs werereported to be high using prevalence-basedsimulation modelling techniques: in 2016 thetotal burden was estimated to be $103 billionper year in the USA versus €27.7 billion inFrance, Germany and Italy together and £5.24billion in the UK [63]. NASH patients withcompensated cirrhosis presented the highestdirect cost burden compared to patients inother stages of NASH, highlighting the costburden of advanced NASH progression.

Direct medical costs were also examined perage group, with total costs highest in patientsaged 45–65, mirroring the disease prevalence[63]. However, per patient costs were reported ashighest in the 65? age group, reflecting thehigher proportion of patients in advancedfibrosis and HCC, and the increased burden ofcomorbidities [63]. A USA SLR and model con-firmed the high economic burden of NASH,reporting that the total cost of NASH-relatedcare in North America will amount to $593billion between 2013 and 2033 [30].

Lastly, a USA database analysis reported onhigh costs of NASH hospitalizations, with hos-pitalizations related to CVD incurring a longerstay and higher associated financial cost com-pared to NAFLD hospitalizations unrelated toCVD (length of stay was 6.5 versus 5.3 days,p\0.001; hospitalization cost was $57,534versus $44,007, p\0.001) [52, 70].

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DISCUSSION

To the authors’ knowledge, this structured lit-erature review is the first broad-ranging exami-nation of the NASH epidemiology, BoDliterature, QoL and economic burden literature.In total, 53 publications were included in thisreview, with a significant paucity of dataobserved across all aspects of NASH epidemiol-ogy. The publications presented varying studydesigns and methodologies; the majority of thepublications were small cohort studies (samplesizes of less than or equal to 100) and narrativereviews with undefined methodologies, whileonly a few publications employed a robust sys-tematic approach. As a result, comparison of theresults was difficult. Eight SLRs were captured inthis review; however, only two examined theBoD in NASH [19, 25, 30, 31, 33, 46, 47, 49]. Thehigh impact BoD SLR and meta-analysis studyby Younossi et al. was underpinned by a modelforecasting NASH prevalence and incidence[19]. The other BoD SLR by Sanyal et al. pre-sented limited information on NASH preva-lence, comorbidities and economic burden asthe study was only available in abstract form[30]. Compared to the available literature iden-tified, the current structured literature reviewprovides a robust methodology and a morerecent examination of data, with a broaderscope, including NASH QoL and diseaseprogression.

NASH was estimated to account for 3–5% ofthe global population, and approximately 60%of biopsied NAFLD patients [19–29]. Prevalencedata are essential in understanding the size ofcurrent and future NASH populations; however,the captured publications presented a range ofprevalence data, likely due to the varying pub-lication focus and robustness of the method-ologies used. Over half of the capturedpublications employed a narrative reviewapproach and most did not specify themethodology used, reflecting the poor qualityof these publications.

As a result of the unreliability of liver biopsyin diagnosing NASH and its association withhigh costs and invasive nature, especially in thegeneral population, NASH prevalence data

cannot be retrieved accurately and were fre-quently estimated [14]. Validated ‘histological’NASH score, data from annual health checks,national health surveys, and autopsy resultswere used in the identified publications to esti-mate the prevalence of NASH; however, thesedata can be fragmented and subject to selectionbias, specifically in higher burden population,who likely also have one or more comorbidconditions, e.g. advanced fibrosis patients willlikely have a higher instance of obesity andCVD compared to mild fibrosis patients. Toensure that accurate prevalence data areobtained not only from patients but also fromthe general public, an accurate, non-invasiveand cost-effective screening tool is needed. Forinstance, ultrasound screening has emerged as apromising screening technique that is non-in-vasive, accurate and widely available[31, 67–69, 71]. Blood-based biomarkers havealso emerged as a promising diagnostic alter-native in NASH as they are non-invasive, haverapid turnaround times and pose limited risks topatients [72]. More research on biomarkers inNASH is needed to determine if these markersaccurately reflect disease progression in NASHand can be implemented in clinical practice[72].

The global burden of NASH is high, withclinical consequences extending beyond theliver. Approximately 80% of NASH patientssuffer from at least one comorbidity, with obe-sity, diabetes and CVD being the most common[19]. While it is unclear to what extent NASHdevelopment is linked to these conditions, it isclear that NASH association with these comor-bidities increases both the patient and health-care burden [19, 21, 22, 24, 28–30, 32–42].Despite this, the specific prevalence of comor-bidities in NASH remains unclear with sub-stantial discrepancies in the literature,specifically in sub-populations, such as in obese,morbidly obese, or bariatric surgery patients.For instance, NASH prevalence in a diabeticpopulation was 14.5% in one study, andbetween 63% and 87% in a different study onthe diabetic population [41, 42]. This can be dueto several reasons, e.g. different baseline popu-lations, or different definitions of how NASH isestimated/measured. Specifically, the varied

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focus of the publications was a key factor in thediscrepancies noted, and a selection bias couldhave affected these results. This was furthercompounded by the robustness of the method-ologies used, as the majority of the publicationsconsisted of small cohort or observationalstudies.

On the basis of the current evidence base, itis unclear whether the BoD in NASH stems pri-marily from comorbidities or from NASHdirectly. For example, when comparing the QoLin patients with NASH, of which 27% havediabetes and 28% had bridging fibrosis or cir-rhosis, to diabetic patients alone, the SF-36 PCSscores of patients with NASH and diabetes(mean 44.5) are lower than those with diabetes(mean 49.8), suggesting that the disease severityis worse in NASH and that comorbidities add tothe overall burden of disease [59, 73]. However,when comparing the QoL in patients withNASH, of which 19% had diabetes and 37% hadhypertension, to heart failure patients alone,the SF-36 PCS scores (mean 44.2) are higherthan for those with heart failure (mean 36.5),suggesting that the burden of NASH is mostlydependent on the comorbidities [60, 74]. As aresult of the limited QoL data in NASH patientsand the different patient populations described,the true role of comorbidities in NASH BoDremains unclear. Further research is required toclarify the relationship between NASH and itscomorbidities before firm conclusions can bedrawn.

Despite the limited conclusions gatheredfrom the literature on comorbidities in NASH,data on NASH progression were numerous[19–23, 26–28, 35, 37, 45–58]. The results clearlyshowed that NASH with advanced fibrosis sig-nificantly increases the likelihood of furtherprogression to cirrhosis and HCC, with one infive NASH patients developing cirrhosis and/orHCC. While mild fibrosis (F1/F2) frequentlypresents with nonspecific symptoms and lowdisease burden, advanced fibrosis (F3/F4) expo-nentially reduces survival and increases liver-related mortality, with an approximately sev-enfold increase in mortality rate in NASHcompared to NAFLD [50, 55]. NASH, specificallyNASH with advancing fibrosis, therefore pre-sents itself as a clear target for future

pharmacological therapies aiming at reducingthe burden of NAFLD and its complications.Despite this, not all published literature is inagreement that NASH should be the main targetof NAFLD therapy: a recent retrospective studyof 60 NAFLD patient biopsies by Hagstrom et al.reported that baseline steatohepatitis was notassociated with an increased risk for fibrosisprogression in NAFLD and that fibrosis pro-gression can occur in NAFLD patients withoutsteatohepatitis [75]. In contrast, a multinationalprospective study of 458 NAFLD patients byVilar-Gomez et al. reported that steatosis is sig-nificantly associated with a higher risk of deathand liver-related complications, which alignswith the findings of this review, showcasingthat NASH is associated with a significant bur-den and poor long-term prognosis [76]. It isimportant to note that because the exact causeof NAFLD and NASH is not yet understood, it isdifficult to accurately assess the underlyingfactors for progression [5–7]. Therefore, furtherresearch into the cause of this disease is rec-ommended to improve our understanding ofdisease progression and the key factors at play.

Understanding of disease progression inNASH was impeded by the lack of consistencyin fibrosis and cirrhosis stage terminologyreported. Several terminologies were used inNASH staging, which were frequently unex-plained in the publications and some appearedsubjective, e.g. advanced cirrhosis, severe fibro-sis and progressive fibrosis. Therefore, to ensurethat the progression of NASH to a highly bur-densome advanced fibrosis stage is clearlyunderstood, a consensus on staging terminol-ogy is required. Correct terminology will allowfor a clear quantification of the true diseaseburden of each step of this progressive diseaseand supports the development of effectivetherapies, specifically in advancing fibrosis,which has presented itself as a key determinantof disease progression and mortality [46].

There was a significant lack of NASH QoLdata, with only three publications reporting onPROs in NASH [59–61]. NASH patients reportedsignificantly poorer physical and mental health,impacting the quality of their daily lives[59, 60]. Only the SF-36 health survey andCLDQ were reported, with standardized liver

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disease PROs, such as CLDQ, considered mostappropriate. In order to truly understand theburden of this disease, however, patient-rele-vant outcomes, as well as clinical outcomes,must be further researched.

NASH-specific economic burden data, andespecially in relation to direct costs of NASH,were lacking in the literature [30, 63, 70]. Themost prevalent economic data described NASHscreening and treatment strategies, indicatingan interest in new diagnostic tools and appro-priate therapies, but a lack of research into theirexact costs. The publications that investigateddirect costs of NASH reported that, despite pre-senting with little or no symptoms, NASHassociation with comorbidities and its progres-sive nature significantly impacts healthcaresystems in terms of costs. One meta-analysisreported that disease progression to cirrhosisand beyond was associated with significantincreases in costs [63]. Additionally, NASH cir-rhosis patients exhibited significantly higherrates of hospitalizations compared with othercirrhosis etiologies. While several publicationsbriefly reported on the economic burden ofNASH specifically, few reported explicit costs.When costs were reported, they were notdefined, e.g. ‘‘direct costs’’ were used but noclarification of what these costs included wasprovided. This is likely because there are littlepatient-level data available and cost databasesfrequently do not report NASH diagnosis, ratherreporting liver disease or NAFLD with fibrosis orcirrhosis. This makes any information on NASHcosts difficult to establish or compare; thus, theexact economic burden of NASH remainsunclear.

Therapy options in NASH were not a focus ofthis review, and very few papers specificallylooking at the economic impact of managementoptions were retrieved. This is likely a reflectionof no licensed drugs currently being availablefor NASH. At present, NASH management isvaried and many off-label treatment options arebeing utilised in routine practice [77–81]. Cur-rent treatment focuses primarily on lifestylemodification and disease management, includ-ing weight loss, dietary modifications, exerciseand managing comorbidities [79–81]. Manyinvestigational treatments are being researched

with more than 150 interventional studies cur-rently ongoing (as described by clinicaltrials.-gov) [82]. Although advanced fibrosis isassociated with the highest morbidity andmortality burden in NASH, there is a lack oftreatments targeting NASH patients withadvanced fibrosis with only two current thera-pies showing improvements in this population[81]. Further investigational therapies are nee-ded for NASH with advanced fibrosis, given thatthe majority of the available and upcomingNASH therapies are primarily focused onpatients with mild-to-moderate fibrosis [81].

Limitations

A number of limitations were noted during thecourse of this structured literature review. Thefocus of this review was the NASH population,and as such the NAFLD population was notexplicitly included in the search strategy. AsNASH is the progressive phenotype of NAFLD, itis likely that some NAFLD publications withNASH information were excluded on the basisof this criterion. However, as publicationsreporting on NASH by name (even as part of thelarger NAFLD population) were included,excluded publications would have likely notfocused on NASH and may not have presentedany discrete results other than for the overallNAFLD population.

Another limitation was the restriction of thisstructured review to English language publica-tions. Despite a third of the included publica-tions reporting data on non-English speakingcountries, it is possible that some eligible pub-lications were not captured because of thisexclusion.

Additionally, a sparse evidence base wasfound across all stages of NASH, with severallimitations identified in the captured literature.The publications consisted of generally poor-quality small studies, with short follow-uptimes, lack of consistency in describing NASHstaging, variations in individual study aims,highly selective populations or differinggeographies. As NASH is frequently reported aspart of the wider NAFLD burden and is oftennot clearly distinguished from NAFLD, this may

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explain the small amount of studies focusing onNASH specifically and the poor quality of theliterature identified in this review.

CONCLUSION

This first broad-ranging structured examinationof the NASH literature revealed a paucity ofevidence, which likely reflects the absence ofapproved therapies. As a result of its nonspecificsymptoms and progressive nature, NASHremains underdiagnosed and poorly understooddespite its high patient burden. Fibrosis is thekey prognostic factor in NASH, with a worseprognosis observed in advanced fibrosis. Theoverwhelming impact of advanced fibrosis onpatients and healthcare systems is evident.There is a clear need for early detection inNASH, particularly among symptomaticpatients, along with the need for lifestylemodifications alongside new therapies. Impor-tant knowledge gaps remain in the literature,including a clear understanding of NASH pro-gression and its association with comorbidities,NASH patient QoL and NASH-specific economicburden. Further robust quality evidence,specifically real-world and clinical trial data, isneeded to improve our understanding of NASH,especially as fibrosis stages advance and NASHburden increases. This will inform the develop-ment of effective therapies in NASH andimprove the management of this highly bur-densome disease.

ACKNOWLEDGEMENTS

Funding. This study was funded by GileadScience Inc and was conducted by AdelphiValues Limited. All authors were involved indrafting the article and revising it critically forimportant intellectual content, and all authorsapproved the final version to be published. Thesponsor also funded the article processingcharges and Open Access fee for this article.

Authorship. All named authors meet theInternational Committee of Medical Journal

Editors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Juliana Bottomley is a consul-tant to Gilead Sciences Inc and received con-sultancy payment for her contract. AdelphiValues Limited received budgetary compensa-tion for involvement in the conduct of the lit-erature review and manuscript development.Richard Perry is an employee of Adelphi ValuesLimited. Manca Povsic is an employee of Adel-phi Values Limited. On Yee Wong is anemployee of Adelphi Values Limited.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

Data Availability. Data sharing is notapplicable to this article as no databases weregenerated or analysed during the current study.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercialuse, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

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