The burden of non-alcoholic steatohepatitis: A systematic review of health-related quality of life and patient-reported outcomes

Background & Aims Non-alcoholic steatohepatitis (NASH) is associated with increased mortality and a high clinical burden. NASH adversely impacts patients’ health-related quality of life (HRQoL), but published data on the humanistic burden of disease are limited. This review aimed to summarise and critically evaluate studies reporting HRQoL or patient-reported outcomes (PROs) in populations with NASH and identify key gaps for further research. Methods Medline, EMBASE, the Cochrane Library and PsycINFO were searched for English-language publications published from 2010 to 2021 that reported HRQoL/PRO outcomes of a population or subpopulation with NASH. Results Twenty-five publications covering 23 unique studies were identified. Overall, the data showed a substantial impact of NASH on HRQoL, particularly in terms of physical functioning and fatigue, with deterioration of physical and mental health as NASH progresses. Prevalent symptoms, including fatigue, abdominal pain, anxiety/depression, cognition problems, and poor sleep quality, adversely impact patients’ ability to work and perform activities of daily living and the quality of relationships. However, some patients fail to attribute symptoms to their disease because of a lack of patient awareness and education. NASH is associated with high rates of comorbidities such as obesity and type 2 diabetes, which contribute to reduced HRQoL. Studies were heterogeneous in terms of diagnostic methods, population, outcomes, follow-up time, and measures of HRQoL/utility. Most studies were rated ‘moderate’ at quality assessment, and all evaluable studies had inadequate control of confounders. Conclusions NASH is associated with a significant HRQoL burden that begins early in the disease course and increases with disease progression. More robust studies are needed to better understand the humanistic burden of NASH, with adequate adjustment for confounders that could influence outcomes. Lay summary Non-alcoholic steatohepatitis (NASH) has a significant impact on quality of life, with individuals experiencing worse physical and mental health compared with the general population. NASH and its symptoms, which include tiredness, stomach pain, anxiety, depression, poor focus and memory, and impaired sleep, affect individuals’ relationships and ability to work and perform day-to-day tasks. However, not all patients are aware that their symptoms may be related to NASH. Patients would benefit from more education on their disease, and the importance of good social networks for patient health and well-being should be reinforced. More studies are needed to better understand the patient burden of NASH.

The burden of non-alcoholic steatohepatitis: A systematic review of health-related quality of life and patient-reported outcomes Introduction Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of related liver disorders. 1 It is defined by the presence of hepatic steatosis (accumulation of triglycerides in >5% of hepatocytes) in the absence of other causes of steatosis, including excess alcohol intake. [2][3][4] The earliest stage is termed simple steatosis or non-alcoholic fatty liver (NAFL), characterised by >5% hepatic steatosis without evidence of hepatocyte ballooning. 5 The global prevalence of NAFLD is currently estimated to be 25% 7,11 and is growing rapidly, fuelled by increasing rates of obesity and T2D. 4,11 A recent meta-analysis estimated the overall prevalence of NASH in the general population as between 1.50% and 6.45%, and overall mortality incidence rates were 25.56 (range 6.29-103.80) per 1,000 person-years for NASH and 11.77 (range 7.10-19.53) for NAFLD. 11 There are limited data on the impact of NASH on patients' health-related quality of life (HRQoL). Available evidence suggests that, in addition to its clinical burden, NASH is associated with a high patient burden and adverse effect on patients' HRQoL. [13][14][15] Understanding the impact of NASH and the effect of pharmacological treatments or lifestyle modification on HRQoL is important to inform future research on the development of patient-centred outcomes. The aim of this study was to summarise and critically evaluate studies that reported HRQoL or patient-reported outcomes (PROs) in populations with NASH and identify key evidence gaps.

Materials and methods
A systematic literature review was conducted using Medline, EMBASE, the Cochrane Library and PsycINFO via the Ovid platform using predefined search strategies (Table S1). Hand searching was also used to identify relevant studies not captured in the electronic database search. The review was conducted in line with Cochrane Collaboration methodology 16 and reported in line with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). 17 Further details on the review methodology are provided in the Supplementary methods.
The primary systematic review was undertaken on 17 February 2020 and an update performed on 6 January 2021. Eligible studies were full-text English-language publications published from 1 January 2010 to 6 January 2021 that reported HRQoL or PROs in populations with NASH or a subgroup with NASH within an NAFLD/NASH study, with or without comorbidities. NASH was defined based on individual study inclusion criteria. Full eligibility criteria are described in Table S2, and  Table S3 summarises key features of the HRQoL and PRO instruments used across the studies.
First-round screening of titles and abstracts was followed by second-round full-text screening of shortlisted articles and data extraction of articles meeting the eligibility criteria. First-and second-round screening were performed by 2 independent researchers, and the final inclusion was verified by the project lead. Disagreements regarding eligibility were referred to a third party. Data extraction was performed using predesigned data extraction tables by an analyst with a 100% independent quality check, and disagreements were referred to a third party. Data extracted from each study included, but were not limited to, country/region, study design, baseline characteristics (including age, sex, BMI, method of diagnosis, and comorbidities), type of intervention (including dose, duration, and frequency), and outcomes reported (as shown in Table S1). Hand-searching n = 2 Fig. 1. Flow diagram of publications included in and excluded from the systematic review. e1, excluded after screening title and abstract; e2, excluded after screening full text; i1, included to screen based on title and abstract; i2, included to screen full text; i3, total included studies after the full-text review stage for original report and 2021 search update.
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 (EPHPP), 18 which assesses the quality of 6 components (selection bias, design, confounders, blinding, data collection methods, and withdrawals/drop-outs) to assign a global rating for each study of 'strong' (no weak ratings for any of the listed criteria), 'moderate' (1 weak rating), or 'weak' (2 or more weak ratings).
Quality assessment (risk of bias) of randomised controlled trials (RCTs) was conducted using the 7-criteria checklist provided in Section 2.5.2 of the National Institute for Health and Care Excellence (NICE) single technology appraisal and highly specialised technologies evaluation user guide, 19 which assesses the quality of studies and likelihood of selection, performance, attrition, and detection bias.
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 7,261 citations, of which 2,600 were identified as duplicates and excluded. A further 4,459 were excluded based on title and abstract, and 179 during full-text screening, resulting in inclusion of 23 publications from the electronic database searches.  A further 2 studies meeting the eligibility criteria were identified from hand searching. 43,44 The study flow of included and excluded publications is shown in Fig. 1.
Overall, 25 publications covering 23 unique studies in several countries were included (Table 1). Four studies were US-based, and 2 each were derived from the UK, Iran, and Japan. One study each originated from Germany, Korea, and Spain, whereas 10 studies described multinational data (Table 1). Six studies were interventional, 11 were cross-sectional, 2 were qualitative online tools/interviews, 3 were prospective, and 1 was retrospective in nature. An overview of the disease focus and instruments used across the identified studies, including a summary of the validity of liver-and NASH-specific instruments, is included in the Supplementary materials.
Overall impact of NASH Key data summarising the overall impact of NASH on patients' HRQoL and an overview of reported symptoms of NASH and their impact are presented in Tables 2 and 3, respectively. Overall, patients with NASH had significantly reduced HRQoL (p <0.05) and health utility scores compared with the general population. 21,22,27,37,38,40 Patients with NASH also reported worse mental functioning compared with a matched population with T2D 21 and worse PRO scores related to physical domains vs. matched patients with chronic hepatitis C. 38 For example, in 1 study from Balp et al. 21 that assessed 184 multinational patients with NASH who participated in the National Health and Wellness Survey, patients with NASH had significantly worse HRQoL than a matched general population cohort, shown by lower (worse) Short Form-36 (SF-36) physical component summary (PCS) and mental component summary (MCS) scores, lower Short Form-6 Dimension (SF-6D) and EuroQol-5D (EQ-5D) utility scores (p <0.001 for all), and higher rates of absenteeism (p = 0.003), presenteeism (p = 0.006), overall work impairment (p <0.001), and activity impairment (p <0.001). Patients with NASH also reported lower SF-36 MCS  39 Younossi et al. 40 23 Younossi et al. 42 Global c 1/7 a Quantitative studies were assigned a global rating of strong, moderate, or weak based on the quality of 6 components (selection bias, design, confounders, blinding, data collection methods, and withdrawals/drop-outs), whereas randomised controlled trials were assessed based on achievement of 7 criteria that assessed study quality and likelihood of selection, performance, attrition and detection bias. b France, Germany, Italy, Spain, and the UK. c A total of 27 countries across Asia, Australia, Europe, New Zealand, North America, and South America.  (p = 0.003) and SF-6D scores (p = 0.002) than a matched T2D cohort, but no significant differences were seen in terms of SF-36 PCS, EQ-5D, or Work Productivity and Activity Impairment (WPAI) scores. Two studies, including a large database study that evaluated 1,338 patients with NASH, noted an adverse impact on physical but not mental function in patients with NASH compared with healthy individuals, 37,38 whereas other studies reported deterioration in both physical and mental PRO domains compared with the general population. 21,22,27,40 One study that assessed patients with NAFLD from 12 hospitals across Spain found an interaction between HRQoL and the level of social support received by patients with NASH from family, friends, their partner, or other significant persons. 27 A significant interaction between NASH and social support was found in terms of vitality, activity, anxiety, and denial (all p < − 0.05), with worse SF-36, Chronic Liver Disease Questionnaire (CLDQ)-NAFLD, Hospital Anxiety and Depression Scale, and Beck Depression Inventory-II scores among patients who perceived low levels of social support. Interestingly, the same was not true among patients with non-NASH NAFLD, for whom no differences in activity, anxiety, and denial were present between those with high and those with low perceived social support; only vitality was lower in patients with low perceived social support. 27

Impact of NASH symptoms
Several studies evaluated symptoms of NASH and their impact on patients' HRQoL (Table 3). 21,[23][24][25]28,41 Key symptoms reported across the studies in patients with NASH included fatigue/ tiredness (38-78%) and abdominal pain (13-61%). 23,25,28,41 Other reported symptoms included poor sleep quality, sleep apnoea, weakness/lethargy, anxiety/depression, weight gain, cognition problems (impaired memory and focus), abdominal bloating, pruritus, and jaundice. 21,[23][24][25]28,41 Patients reported that NASH and its associated symptoms impacted many aspects of their lives, including physical functioning, work performance, ability to perform daily living tasks, and the quality of family and personal relationships. 23,25 Two studies reported greater impairment of PRO scores (SF-36, CLDQ, CLDQ-NASH, WPAI: Specific Health Problem [WPAI:SHP], and health utility instruments) in symptomatic vs. non-symptomatic patients. 28,41 Notably, 2 studies reported that patients may not always directly associate their symptoms with NASH. 23,24 A multinational survey-based study of 166 patients with confirmed or suspected NASH asked participants to indicate whether the origin of certain symptoms could be attributed to NASH or a comorbid condition. 23 When asked about fatigue, for example, 14% of patients attributed this solely to other conditions, and a further 14% were unsure of what was causing their symptom. In another small study of 16 patients from the USA and UK, patients In both groups of patients with bridging fibrosis (n = 797) and  Patients were often unable to attribute their symptoms to NASH or other comorbid conditions The most common reported symptoms, not attributed to their liver condition, were fatigue/tiredness (71%), being obese/ overweight (62%), and abdominal pain (44%) When asked about fatigue, 14% were unsure which of their health conditions contributed to this symptom and a further 14% did not associate fatigue with being a symptom of their liver condition Geier et al.   did not spontaneously report any symptoms that they could directly associate with NASH; symptoms were acknowledged after probing but were not necessarily linked to NASH. 24 Impact of disease severity The impact of disease severity on HRQoL scores is summarised in Table 4 and below. Overall, populations with NASH reported worse HRQoL than patients with simple steatosis. 26,27,31 Among patients with NASH, more severe fibrosis and advanced stages of liver disease generally had a negative impact on patients' HRQoL and health utility scores. 27,31,35,38,40,42 For example, a study of over 300 patients from the European NAFLD Registry showed that patients with progressive NASH (indicated by higher steatosis histological score, more severe ballooning, and higher levels  patients with neither fatigue nor pruritus was between -5 and -37.5% of a PRO range size) CD, cognitive debriefing; CE, concept elicitation; CLDQ, Chronic Liver Disease Questionnaire; EQ-5D, EuroQol-5 Dimension; EQ-5D-5L, EQ-5D-5 level; F1-4, fibrosis stages 1-4; GfK, Growth from Knowledge; HRQoL, health-related quality of life; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; PRO, patient-reported outcome; RCT, randomised controlled trial; SF-36, 36-item Short Form Health Survey; SF-6D, Short Form-6 Dimension; T2D, type 2 diabetes; WPAI:SHP, Work Productivity and Activity Impairment: Specific Health Problem. a Representative sample of general population with varying health status. b Eight participants took part in both groups. c Data are presented in publication as a proportion of symptomatic patients. We have recalculated as a proportion of the full PRO cohort. d Bridging fibrosis (F3) or compensated cirrhosis (F4). e Presence of fatigue and pruritus were indicated by a score of 4 or less on the respective items of the CLDQ-NASH (scale range 1-7). of lobular inflammation) exhibited worse CLDQ scores than patients with less advanced disease (Fig. 2). 31 This was not consistent across all studies; for example, a single-centre study from the UK that assessed 224 patients with NAFLD did not find any significant difference in terms of difficulty with function (assessed using the Patient-Reported Outcome Measurement Information System Health Assessment Questionnaire [PHAQ]) between those who had pre-cirrhosis and those who had cirrhosis (p = 0.3), 26 and 1 post hoc analysis of a phase II RCT by Younossi et al. 37 did not show any differences in HRQoL between patients with NASH with F2 fibrosis (n = 25) and those with F3 (n = 47) fibrosis.
Links between non-invasive markers of disease severity and HRQoL were evaluated in 2 studies. 37,42 In a pooled analysis of over 2,000 patients who participated in 4 phase II/III clinical studies of simtuzumab or selonsertib vs. placebo, higher noninvasive test (NIT) scores (hepatic collagen > − 11.2%, FibroScan® > − 23.4 kPa, NAFLD activity score [NAS] > − 5, enhanced liver fibrosis score > − 10.43, NAFLD fibrosis score > − 1.802, and a FibroTest TM score of 0.54) were associated with impaired HRQoL. 42 During treatment, decreases in NIT scores (indicating improvement) were associated with improved PRO scores and increases (worsening) with worsened PRO scores (p <0.05; Fig. 3). 42 Similar findings were reported in a smaller analysis of 72 selonsertib-treated patients. 37 Only 1 study evaluated the impact of pharmacological intervention vs. placebo on HRQoL. In the 96-week phase III PIVENS study, change in quality of life, assessed by SF-36 PCS and MCS scores, did not differ significantly between placebo and vitamin E or pioglitazone (all p >0.05), despite a significantly higher rate of improvement with vitamin E vs. placebo, and a significant reduction in NASH histological features and NAS with both active treatments vs. placebo (Table 4). 43

Discussion
The findings of this study provide a detailed picture of the humanistic burden of NASH. Utilising 25 publications describing 23 unique studies, we show that there is a substantial impact of NASH/NAFLD on patients' HRQoL, especially in terms of physical functioning and fatigue. This high burden is associated with a considerable deterioration of physical and mental health that becomes more evident as NASH progresses. Nineteen studies reported data on populations with NASH exclusively, and 4 studies reported data on subgroups with NASH within populations with NASH/NAFLD. Although a broad search strategy and screening criteria were used, the included studies focussed on populations with NASH and NASH/NAFLD to answer the specific research question around the humanistic burden of NASH. The data related to patients with NASH were heterogenous with regard to NASH diagnostic methods, population, outcomes, follow-up time, and measures of HRQoL/utility. There was a mixed use of liver-or NASH-specific and generic HRQoL instruments among the studies, with some studies using both instruments to assess validity.

Research article
The generic SF-36 and liver-specific CLDQ instruments were used most frequently across the studies. Although criticisms exist regarding the use of non-disease-specific instruments for assessment of individuals with chronic diseases, SF-36 and CLDQ have been shown to be reliable in populations with NASH, and the studies identified in this review have provided useful information. In fact, the reliability and validity of the CLDQ when compared with those of SF-36 have been evaluated specifically in patients with NASH. 22 This study showed significant correlations between SF-36 and CLDQ, 22 and another study confirmed the correlation between SF-36 and most domains of CLDQ-NASH. 39 In the latter study, only the NASH-specific domains of 'abdominal' and 'worry' did not correlate with SF-36 domains. The authors note that CLDQ-NASH shares 29 of its 36 items with the original CLDQ, and the additional items that allow for more NASH-specific assessment will likely add to its reliability. 39 One qualitative study was undertaken to inform the development of a new NASH-specific instrument. 25 Doward et al. 25 used concept elicitation interviews and cognitive debriefing to develop and validate the pilot version of NASH-CHECK, a 31-item PRO tool. NASH-CHECK is not validated to the same extent as CLDQ-NASH, the most frequently used disease-specific tool, and full data for the psychometric characteristics of NASH-CHECK are not yet available. Once fully validated, NASH-CHECK may become relevant and acceptable to patients and clinicians. Primary endpoints in NASH clinical trials typically include measures of histological disease manifestations, but these do not capture the humanistic impact of NASH. Incorporation of validated PROs that capture the patient perspective can add value to clinical trial results and complement clinical endpoints. 25,45 PRO tools can also be of value to the field, and their inclusion into clinical trials could support their future validation.
Despite the evidence supporting the clinical burden of NASH, appreciation for the impact of NASH on patients' quality of life is quite limited. In fact, a frequent perception exists that NASH is an asymptomatic condition, particularly in its early stages. 25,31,38 The quantitative studies included in this systematic review dispel this misconception, showing that NASH is associated with significantly reduced HRQoL compared with the general population. 21,22,27,37,38,40 Some studies indicated that NASH predominately impacts patients' physical function, 37,38 although most showed significant impairments in HRQoL across the mental and physical domains of the SF-36 and CLDQ, as well as SF-6D and EQ-5D utility scores and WPAI scores. [21][22][23]27,40 NASH was also associated with worse HRQoL scores than those of matched participants with T2D (SF-36 MCS and health utility) and chronic hepatitis C (physical SF-36 domains and fatigue on CLDQ), 21,38 further supporting the significant burden of illness with NASH.
The most prevalent symptoms associated with NASH were fatigue, abdominal pain, anxiety/depression, cognition problems, and poor sleep quality. 21,[23][24][25]28,41 Symptoms of NASH were associated with worse HRQoL scores across several PROs, including SF-36, CLDQ, CLDQ-NASH, WPAI:SHP, and health utility instruments, 28,41 and were found to be detrimental to many aspects of patients' daily lives, including their ability to work and perform daily living tasks, and the quality of both family and intimate relationships. 24,25 Despite these varied symptoms and their consequences, 2 studies indicated that some patients do not attribute their symptoms to NASH, often attributing them to other comorbid conditions or feeling uncertain of their origin, 23,24 which may contribute to the misperception that chronic liver diseases such as NASH are asymptomatic. One study reported that NASH diagnoses were incidental in most of their patient population, largely because patients failed to associate their signs or symptoms with their liver condition. 24 It was shown that patients demonstrate a general lack of understanding of their disease, feel that other comorbid conditions are more concerning than NASH itself, and do not seem familiar with consequences of NASH in the long term. 24 Further, they felt a lack of adequate educational support from their physicians. Similar findings were reported in a recent systematic review that assessed quality of life in over 37,000 patients with chronic liver disease (including NASH), in which patients call for better education and information to understand and manage their disease. 46 Education of patients with NASH on their liver condition, diagnosis, and the progressive nature of the disease could lead to better disease management and improved patient outcomes.
The systematic review from Grønkjaer and Lauridsen 46 also found that patients with chronic liver diseases, including NASH, have inadequate support owing to limited knowledge of liver diseases in the general population, resulting in loneliness and social isolation. This adds weight to the finding that lower perceived social support from friends and relatives is associated with less activity and vitality, greater anxiety, and more denial among patients with NASH. 27 The importance of support networks in patient health has been demonstrated in a variety of conditions, including cancer, heart failure, multiple sclerosis, and liver transplant candidates. [47][48][49][50] Promotion of active coping skills and education of patients and their families on the importance of effective social networks and/or formal support sources may     Research article improve the overall health and well-being of patients with NASH. Unsurprisingly, patients with NASH had significantly more functional impairment than those with simple steatosis, 26,27,31 and patients with more progressive NASH generally exhibited worse HRQoL scores. 27,31,35,39,40,42 HRQoL by fibrosis stage was assessed in several studies. One showed worsening HRQoL with progression of fibrosis, 35 and another reported a trend toward worse HRQoL in patients with advanced fibrosis and compensated cirrhosis (F3/F4 vs. F0-2). 31 In contrast, a third study found no difference in HRQoL scores between patients with F2 fibrosis and those with F3 fibrosis. 37 Worse HRQoL was also evident in patients with more severe hepatic steatosis, ballooning, and lobular inflammation, the latter of which was a surprising finding since greater lobular inflammation does not independently correlate with overall or liver-specific mortality. 31 The authors note that improvement of steatosis, in particular lobular inflammation, may result in a measurable improvement in HRQoL, even independently of fibrosis improvement. This is an interesting finding as many economic evaluations tend to focus on change in fibrosis stage alone, so the value of changes in histological parameters such as steatosis, ballooning, and lobular inflammation is always captured. 51 As mentioned above, the recommended primary endpoints for clinical trials in patients with pre-cirrhotic NASH do include 'resolution of steatohepatitis and no worsening of fibrosis' and '> − 2-point reduction in NAS with > − 1-point reduction in either lobular ballooning or hepatocellular ballooning and no worsening of fibrosis', 52-54 but the absence of data linking histological parameters to long-term outcomes may prove a barrier to use in some studies. Indeed, fibrosis currently remains the only independent predictor of long-term outcomes such as mortality in NAFLD. [55][56][57][58] Change in non-invasive markers of NASH/fibrosis severity were shown to correlate with change in HRQoL in 2 interventional studies. 37,42 Similar findings were reported in 2 recent studies in the literature that examined the impact of treatment with obeticholic acid or resmetirom on quality of life. 59,60 Interim results from the REGENERATE study, which is assessing the safety and efficacy of obeticholic acid in patients with NASH, report greater improvement in some PRO domains in patients experiencing fibrosis improvement (total CLDQ-NASH score and fatigue and worry scores), decreased NAS (emotional and worry scores), or NASH resolution without worsening of fibrosis (worry score). 59 However, treatment with obeticholic acid itself was not associated with any HRQoL improvements vs. placebo after 18 months of treatment. In a phase II placebo-controlled study, resmetirom-treated patients experienced improvement of bodily pain and SF-6D scores at Week 12 and PCS improvement up to Week 36, with no improvement seen in the placebo group. 60 Adjusted analyses found that improvement in hepatic fat fraction was independently associated with greater HRQoL improvements, and improvement in NAS and fibrosis on serial liver biopsy was also linked to improvement in HRQoL components. Only 1 placebo-controlled study, the PIVENS study, was included in this systematic review, and in a surprising contrast to the aforementioned studies, no difference in the change in HRQoL was seen between placebo and vitamin E or pioglitazone, despite improvements in NASH histological features and NAS with both active treatments. 43 Understanding the impact of cirrhosis on HRQoL is important because there is a growing prevalence of NASH-related liver failure, as highlighted by US registry data for liver transplantation. 11,12 Although 1 single-centre study found no significant difference in function between patients with pre-cirrhotic and cirrhotic NAFLD, 26 the results overall suggest that the HRQoL burden is likely to be higher in patients with NASH who have progressed to cirrhosis, HCC, or liver failure. Similar findings were reported in a recent study in the literature, which showed that patients with NASH-cirrhosis have lower HRQoL and poorer physical health than patients with non-cirrhotic NASH. 61 Despite large variation in reported comorbidity rates across the studies, rates of obesity, diabetes, hypertension, hyperlipidaemia/ dyslipidaemia, and CVD were generally high, [20][21][22][23][24][25]28,29,31,33,[35][36][37][38][39]44 indicating a high disease and clinical management burden. Several studies reported worse HRQoL in patients with comorbidities than in those without comorbidities (such as T2D, obesity, and metabolic syndrome), 22,29,31,[38][39][40] although it is unclear what proportion of the NASH symptom burden should be attributed to the disease itself, or to patients' comorbidities, particularly in light of the weak rating for control of confounders noted in all quantitative studies. The impact of comorbidities on HRQoL is of relevance given the significant increase in obesity-related conditions across the world in recent decades and the accompanying increase in weight-related mortality. 62 Unfortunately, 1 study noted that patients can interpret physician recommendations for weight loss as relatively unimportant in relation to NASH, as this is routine guidance given regardless of their medical condition, 23 highlighting again the need for improved education on NASH, its management, disease progression, and impact of comorbidities, for both patients and healthcare providers.

Research article
Finally, it is important to note that the histologic endpoint of NASH may be increasingly replaced by NITs in future studies and practice. In 1 study, in which patients with NASH with liver biopsy and NITs were assessed using CLDQ-NASH and SF-36, 42 both histologic stage and NIT scores indicating high risk for advanced fibrosis were associated with poor PRO scores. 42 This study suggests the importance of associating PROs with NITs assessing hepatic fibrosis as well as with histologic endpoints.

Study and data limitations
This review was conducted as per systematic literature review guidelines with a robust methodology; however, there are certain inherent limitations with most literature reviews. This systematic literature review was limited to English language and restricted to those published since January 2010 to examine the most recent evidence. Most of the studies were conducted in Europe or North America, and almost half were cross-sectional in nature. The studies also included heterogenous patient populations and used varying definitions to diagnose NASH, limiting the comparability of the data. In addition, few studies that compared HRQoL in populations with NASH with that in other populations included matched populations adjusted for factors such as income, education, alcohol intake, and comorbidities.
Several studies using NASH-specific PRO instruments are underway, although studies using instruments other than CLDQ-NASH are limited, and further research utilising diseasespecific measures is justified to fully understand the humanistic burden of NASH. Although limited evidence is available, significant correlations between generic and liver disease-specific PRO instruments were reported, with both showing the high humanistic burden of NASH and greater impact among patients with more severe disease.
The quality assessment of the quantitative studies showed that all evaluable studies were rated as 'moderate' (n = 14) or 'weak' (n = 3), highlighting the need for more robust evidence on the HRQoL impact of NASH. Ratings are primarily attributable to the observational nature of most studies. Owing to the varied study designs, there is a possibility for comorbidities to confound HRQoL results, and notably, all quantitative studies scored weakly for control of confounders. This is particularly relevant given the high rates of comorbid conditions throughout the included studies, and the close links between NASH/NAFLD and T2D, obesity, and cardiovascular outcomes. As such, it is recommended that future studies consider comorbidities as important factors and use designs and methods to better control the potential of confounding caused by comorbidities and to promote our knowledge on the relationship between comorbidities and HRQoL in patients with NASH/NAFLD. 50

Conclusions
This systematic review identified a significant and often unrecognised HRQoL burden among individuals with NASH. This burden increases as the disease progresses, adversely impacting patients' family relationships and their ability to work and perform activities of daily living. These findings also highlighted a need for better quality studies examining the humanistic burden of NASH. In particular, HRQoL studies need to adjust for the presence of comorbidities that may influence outcomes.
Abbreviations and Nutrition; T2D, type 2 diabetes; VAS, visual analogue scale; WPAI, Work Productivity and Activity Impairment; WPAI:SHP, Work Productivity and Activity Impairment: Specific Health Problem.

Financial support
This study was funded by Novo Nordisk A/S, Søborg, Denmark. Novo Nordisk A/S was responsible for the study concept and design, data collection, and the decision to submit this article for publication. With the input of all authors, Novo Nordisk A/S was involved in the analysis and interpretation of data and writing of this report.

Conflicts of interest
IS, JF, PJ, and MA are employees of Novo Nordisk A/S or Novo Nordisk Denmark A/S. PJ, IS, and JF are also shareholders of Novo Nordisk A/S. ZY has received research funding and/or serves as a consultant to Abbott, AbbVie, Bristol Myers Squibb, Gilead Sciences, Intercept, Madrigal, Merck, Novartis, Novo Nordisk, Quest, Siemens, Terns, and Viking. The SLR was commissioned to DRG Abacus (Clarivate) by Novo Nordisk, and PA and SN are employees of DRG Abacus (Clarivate).
Please refer to the accompanying ICMJE disclosure forms for further details.