Quality of life in patients with nonalcoholic fatty liver disease: A systematic review

Journal of Psychosomatic Research 112 (2018) 73–80

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Journal of Psychosomatic Research journal homepage: www.elsevier.com/locate/jpsychores

Review article

Quality of life in patients with nonalcoholic fatty liver disease: A systematic review

T

Konstantinos Assimakopoulosa, Katerina Karaivazogloua, Evangelia-Eirini Tsermpinib, ⁎ Georgia Diamantopoulouc, Christos Triantosc, a

Department of Psychiatry, School of Medicine, University of Patras, Rion Patras, Greece Department of Pharmacy, Laboratory of Molecular Biology and Immunology, School of Health Science, University of Patras, Rion Patras, Greece c Department of Gastroenterology, School of Medicine, University of Patras, Rion Patras, Greece b

A R T I C LE I N FO

A B S T R A C T

Keywords: Nonalcoholic fatty liver disease Quality of life Systematic review

Objective: Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent medical condition, which may lead to severe complications including cirrhosis and hepatocellular carcinoma. Its chronic course and its association with obesity and diabetes mellitus augment the long-term impact of NAFLD on patients' health and quality of life (QoL) and put great strain on healthcare systems worldwide. Research is growingly focusing on NAFLD patients' QoL in an attempt to describe the full spectrum of disease burden and tackle its future consequences. Relevant studies are characterized by sample heterogeneity and provide conflicting findings which should be interpreted with the use of a systematic and integrative approach. In this context, our aim was to conduct a systematic literature review on the topic of NAFLD patients' QoL. Methods: We performed a systematic search of PubMed, ScienceDirect and GoogleScholar databases according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) protocol. Results: Our search yielded 14 suitable articles reporting data from almost 5000 patients. All authors agree that NAFLD patients' QoL is impaired especially in the physical sub-domain. In addition, several demographic, clinical and histopathological parameters have emerged as major determinants of patients' QoL. However, future studies are needed to further clarify these issues. Conclusions: NAFLD patients report poor physical QoL. QoL impairment is associated with a variety of diseaserelated parameters, mostly the presence of fatigue and cirrhosis.

1. Introduction The term non-alcoholic fatty liver disease (NAFLD) is used to define a spectrum of chronic liver diseases, ranging from simple steatosis to steatohepatitis, advanced fibrosis and cirrhosis, in the absence of excessive alcohol consumption or other causes of steatosis [1]. NAFLD's prevalence is sharply rising, reaching almost 25% of the adult population worldwide [2–5] and this epidemic-like rise could be, at least in part, attributed to modern dietary habits and sedentary lifestyle along with recent technological advances in diagnostic methods. Its strong associations with obesity and diabetes mellitus type II and its even stronger links with the metabolic syndrome render NAFLD a major public health issue which merits clinicians' and researchers' attention [2–8]. In this context, there have been several studies on the pathophysiology, risk factors, co-morbidity, complications and management of

⁎

the disease, which expand clinicians' understanding and their ability to cope with its consequences [5,7,9]. Moreover, there has been an increasing interest in its impact on individuals' quality of life (QoL) and in the burden it imposes on societal and financial resources [7–10]. QoL outcomes are considered end-points of great clinical and scientific value in an attempt not only to treat chronic diseases' symptoms and reduce their complications but also to address patients' self-perceived physical, psychological, social, sexual and spiritual needs thus improving their quality of living [11]. In this respect, researchers are growingly focusing on NAFLD patients' QoL, and their findings provide useful information to healthcare providers. However, the analysis of these findings requires careful interpretation, given that there is great variability in the sub-populations studied [9]. NAFLD diagnosis is currently challenging and vulnerable to referral or methodological bias, due to the fact that it is mainly asymptomatic and it requires the exclusion of other causes of liver disease [1,8]. In

Corresponding author at: Department of Gastroenterology, University Hospital of Patras, Rion, Greece. E-mail address: [email protected] (C. Triantos).

https://doi.org/10.1016/j.jpsychores.2018.07.004 Received 11 March 2018; Received in revised form 10 July 2018; Accepted 11 July 2018 0022-3999/ © 2018 Published by Elsevier Inc.

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Fig. 1. Depicts a flow chart analytically describing the process of article selection.

end of September 2017. PubMed search was performed using the following terms: (quality of life OR well-being OR patient-reported outcomes) AND (non alcoholic fatty liver disease OR non-alcoholic steatohepatitis OR non-alcoholic steatosis). GoogleScholar search was conducted using the following terms: “quality of life” and “non alcoholic fatty liver disease” or “non-alcoholic steatohepatitis”, while ScienceDirect search was performed with the terms “quality of life and nonalcoholic fatty liver disease”. Our search focused exclusively on full papers that encompassed a detailed description of their methodology and findings. Four reviewers (K.A., K.K., E.T. and G.D.) independently reviewed all titles and abstracts retrieved from the search according to specific inclusion criteria. At the next step of the search, all reviewers met to discuss each article's eligibility in order to reach a consensus, which was achieved at a rate of almost 90%. In the remaining cases of unresolved disagreement between the reviewers, a senior reviewer (CT), blind to the other reviewers' suggestions, made the final decision.

addition, it seems that although all patients with hepatic steatosis fall under the broad category of NAFLD, there is a distinct group of patients whose steatosis progresses to non-alcoholic steatohepatitis (NASH) and their prognosis is significantly worse [12,13]. This heterogeneity in sample recruitment among relevant studies might convey confusion and should be addressed by thoroughly analyzing and qualitatively assessing the reported findings. In this context, we have conducted a systematic review on the impact of NAFLD on patients' QoL. Our primary aim was to integrate existing findings into a comprehensive set of evidence-based knowledge. Furthermore, we sought to detect areas of scientific ambiguity and define directions for future research. 2. Materials and methods A systematic literature search was conducted from 3 biomedical databases, namely PubMed, ScienceDirect and Google Scholar, according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) protocol [14]. In addition, we have performed a manual search using all references of the selected articles in order to detect any additional relevant literature. No chronological restriction was applied. Last search was performed at the

2.1. Inclusion and exclusion criteria All original studies written in English assessing QoL in adult patients with non-alcoholic fatty liver disease, using validated instruments or Likert-type scales were included in the current review. We excluded 74

75

[9]

[25]

[24]

David

Newton

Dan

2007

2008

2009

2009

2010

2012

2014

2015

2016

2015

2016

2016

2017

2017

Year of publication

USA

UK

USA

USA/Italy

USA

Italy/ Romania

Greece

USA

UK

Australia

USA

USA

USA

USA

Country

36 NAFLD and 36 controls 106 NAFLD 75 HCV, 56HBV

67 NAFLD in a sample of 1103 patients with CLD 713 patients with NAFLD

247 NASH patients

180 NAFLD (91 on RA vs 88 on placebo for 12 months)

15 NAFLD patients

79 NASH patients

23 patients vs 22 controls

34 NAFLD patients

3333 NAFLD patients 89 NAFLD patients

104 NAFLD patients

151 NAFLD patients

No of participants

26% DMII

63% obese

Validation study, CS

Liver biopsy or imaging SF36 CLDQNAFLD

Age (mean): 55 Males (%): 50 Age (mean): 46.4 Males (%): 30.2

Age (mean): 48 Males (%): 38

Age (mean): 57.4 Males (%): 37

Age (mean): 46.3 Males (%): 40

Age (mean): 47.9 Males (%): 86.7 Age (mean): 40.8–44.2 (NAFLD patients), 46.9–50.9 (NAFLD +HCV patients) Males (%): 83.3 (NAFLD patients), 40 (NAFLD + HCV patients)

Males (%): 35

Age (mean): 46

Age (mean): 51 Males (%): 59.6

Age (mean): 50.4–53.1 Males (%): 59.5

50% NASH 15% compensated cirrhosis Age (mean): 51.3 Males (%): 57.8 Age (mean): 49.1 (non-cirrhotics), 54.1 (cirrhotics) Males (%): 37.3 (non-cirrhotics), 56.7 (cirrhotics)

Age (mean): 57.2 Males (%): 35

Age (mean): 51.5 Males (%): 60

Demographic characteristics

BMI (mean): 34.3 27% DMII 81% definite or borderline NASH 28% bridging fibrosis or cirrhosis BMI (mean): 32 53% DMII 14.1% cirrhosis 26.5% DMII 75.5% obese

100% NASH No cirrhosis BMI (mean): 31.4 19% DMII 37% hypertension BMI (mean): 32.7 20% DMII BMI (mean): 29.3–29.9 (NAFLD patients), 27.6–27.8 (NAFLD + HCV patients) BMI (mean): 34

BMI (mean): 33.66 20.75% DMII 45.8% DMII 13.8% CVD 33.7% cirrhosis BMI (mean): 31.1–31.8 17.6% DMII 27% hypertension No cirrhosis 44.2% DMII

30% DMII 21% advanced fibrosis or cirrhosis 63% obese 26% DMII 50% NASH 15% compensated cirrhosis

Clinical characteristics

CS, controlled

CS controlled

CS

Randomized, prospective, placebocontrolled Retrospective

Non-randomized, open label prospective Randomized, prospective, placebocontrolled

Multicentre, doubleblinded, randomized, placebo-controlled trial CS

Prospective, randomized, controlled

Retrospective

CS, controlled

Validation study, CS

Prospective cohort

Design

NAFLD: Nonalcoholic Fatty Liver Disease; NASH: Nonalcoholic Steatohepatitis, QoL: Quality of life; DM: Diabetes mellitus; CVD: Cardiovascular disease; BMI: Body Mass Index CLDQ: Chronic Liver Disease Questionnaire; SF36: Short Form-36, Health Survey CS: Cross-sectional

[26]

[12]

Chawla

Afendy

[19]

Armstrong

[23]

[22]

Adams

Sanyal

[8]

Sayiner

[20]

[10]

Golabi

Loguercio

[17]

Younossi

[21]

[18]

Tapper

Mazokopakis

Reference

Author

Table 1 Studies reporting data on NAFLD patients' QoL.

Liver biopsy or imaging

Liver biopsy

Liver biopsy

Unspecified

CLDQ

CLDQ

SF36

SF36

SF36

SF36

Liver biopsy

Liver biopsy

CLDQ

SF36 CLDQ

SF36 PCS and MCS

SF36

NHANES HRQOL-4 SF36 SF6D

SF36 CLDQ-NAFLD

CLDQ

QoL assessment

Imaging

Liver biospy

Liver biopsy

Imaging

Liver biopsy

Imaging

Liver biopsy or imaging

Liver biopsy

NAFLD diagnosis

K. Assimakopoulos et al.

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3.2. QoL impairment in NAFLD patients

studies whose methodology was based on other patient reported outcomes (PRO), such as functional ability, fatigue, cognitive impairment, psychological and sexual functioning, but not quality of life (QoL) as this latter construct is explicitly defined and measured according to the World Health Organization's initial description [15]. We have also excluded studies of pediatric NAFLD, given that the emergence of liver steatosis and steatohepatitis among pediatric populations constitutes an issue of growing concern which should be the focus of a separate review [16]. Finally, we have excluded studies whose sample included NAFLD patients but the authors failed to provide adequate demographic and clinical data for this sub-group of participants. We have used a data collection report to extract data for each study, including name of first author, year of study and publication, country of origin, number and demographic data of participants, method of NAFLD diagnosis, psychometric tools used to assess QoL and major outcomes.

Table 2 summarizes major outcomes reported by eligible studies. In all relevant studies, NAFLD patients reported poorer QoL compared to healthy controls or the general population. More specifically, in a recent, large, cross-sectional study [10], NAFLD patients reported poorer overall QoL and poorer physical health compared to healthy controls, even after adjustment for age, gender, race and, BMI. In contrast, no significant differences were observed between NAFLD patients and healthy controls in mental health. In an earlier study, another research group [9] assessed QoL in biopsy-proven NAFLD patients with the use of a generic instrument (SF36) and found that they report worse physical and mental health compared to the general population, with the greatest impairment being observed in general health, vitality and physical functioning sub-domains. Likewise, a series of small-scale studies have detected significant impairment in QoL, especially in the physical health sub-domains, including role limitations due to physical problems, vitality and the component score of physical health [8,12]. NAFLD patients' QoL has also been compared to other chronic liver disease patients' QoL in several studies [10,24,26] including HCV, HBV, alcoholic liver disease, autoimmune hepatitis and primary biliary cirrhosis. In an earlier study on this topic, Dan et al. compared NAFLD patients with chronic hepatitis C and B patients using a disease-specific QoL instrument, the Chronic Liver Disease Questionnaire [24]. Their analysis revealed that NAFLD patients score lower in all sub-domains of the questionnaire except for the worry sub-scale compared to HBV patients and in the sub-domains of systemic symptoms and emotional functioning compared to HCV patients. The authors emphasize that even after controlling for the effect of gender, BMI, ALT levels and the presence of cirrhosis or co-morbidity, the diagnosis of NAFLD was independently associated with increased burden of systemic symptoms, impaired activity and disturbed emotional functioning [24]. These findings were further corroborated by another study which found that NAFLD patients without cirrhosis report poorer physical functioning compared to chronic viral hepatitis patient [26]. In the subgroup of patients with cirrhosis, NAFLD patients scored significantly lower in physical functioning, role limitations due to physical problems, bodily pain and vitality compared to chronic viral hepatitis and alcoholic liver disease patients and in physical functioning and role limitations due to emotional problems compared to patients suffering from cholestatic liver disease. In further regression analysis, the diagnosis of NAFLD emerged as an independent factor that could predict lower physical and mental component scores of the SF36 [26]. More recently, Golabi et al. showed that although NAFLD patients suffer from physical QoL impairment compared to healthy controls, their QoL scores are generally higher than HCV patients' scores, especially in the domain of mental health [10].

3. Results The initial automated search of the databases yielded 4118 titles from PubMed, 7990 titles from GoogleScholar and 3978 titles from ScienceDirect. After thoroughly reviewing all abstracts, we concluded that 25 PubMed, 106 GoogleScholar and 13 ScienceDirect articles were of relevance. Among the 144 identified articles, 15 were indexed in more than one database, leaving thus 129 studies to be candidates for inclusion in the present review. In addition, we searched all references lists from these 129 articles to detect any unidentified literature and we detected 4 additional articles, raising the total number of potentially eligible manuscripts to 133. At the next step of the selection procedure, the full-texts of all 133 articles were retrieved and carefully assessed according to the review's inclusion criteria. This process led to the selection of 14 studies which fulfilled inclusion criteria and entered the review. Fig. 1 3.1. General characteristics of the included studies Table 1 provides all studies reporting data on NAFLD patients' QoL. 10 studies were published during the present decade [8,10,12,17–23]. Eight (8) studies originated from the USA [8,9,10,12,17,18,23,24], 3 from Europe [19,21,25], 1 from Australia [22] and 2 studies [20,26] were conducted within a setting of international collaboration, 1 with the participation of Italy and Romania [20] and 1 with the participation of Italy and USA [26]. Six (6) studies [18–23] were prospective 4 with sample randomization [19,20,22,23], 6 were cross-sectional [9,10,12,17,24,25] (3 with a control group [10,24,25]) and 2 were retrospective [8,26]. In 6 articles [18–23], the authors prospectively investigated the effect of several therapeutic interventions on patients' QoL, either weight loss (1 study [18]), venesection (1 study [22]) or medications (4 studies [19–21,23]). Thirteen (13) studies [8,9,10,17–26] recruited patients with NAFLD, while 1 study [12] enrolled exclusively patients with nonalcoholic steatohepatitis (NASH). In eight (8) studies [8,9,12,18,19,20,23,25] all participants had undergone liver biopsy to establish NAFLD diagnosis, in two (2) studies [17,24] the diagnosis was based on either radiological or histopathological evidence and in the remaining 3 studies [10,21,22], participants were diagnosed based on non-invasive imaging techniques. In 1 article the authors do not provide adequate information regarding the method of NAFLD diagnosis [26]. QoL was assessed with a validated psychometric tool in 11 studies, either the Short Form 36 Health Survey (SF36) in 7 studies [8,9,19,20,22,23,26] or the Chronic Liver Disease Questionnaire (CLDQ) in 4 studies [18, 21, 274 25], while in 2 investigations [12,17] the research team used both instruments (the NAFLD-specific form in 1 study [17]). In addition, one research group has used the NHANES HRQOL-4 Questionnaire [10]. In total, in this review we analyzed data derived from 4952 NAFLD patients (2497 males).

3.3. Determinants of NAFLD patients' QoL 3.3.1. Demographic variables and QoL In a study of patients with non-alcoholic steatohepatitis (NASH) and no cirrhosis neither age nor gender correlated with QoL as measured by SF36 and CLDQ [12]. However, other researchers have shown that older age was independently associated with lower QoL scores, especially in the physical sub-domains [9,26], while in a validation study of the disease-specific CLDQ-NAFLD, older patients reported lower activity levels but also fewer abdominal symptoms and better emotional functioning compared to younger patients [17]. Likewise, in these studies, female gender appeared to be associated with lower activity levels [17], lower overall CLDQ score [18] and worse physical and mental QoL [9,26]. In this latter study of a large sample of NAFLD patients, multivariate analysis revealed that lower income correlated with lower physical and mental health scores, while lower educational level independently predicted poor mental QoL [9]. 76

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Table 2 Major outcomes reported by studies on NAFLD patients' QoL. Author

Reference

Major outcomes

Tapper

[18]

Younossi

[17]

Golabi

[10]

Sayiner

[8]

Adams

[22]

Armstrong Chawla

[19] [12]

Mazokopakis Loguercio Sanyal

[21] [20] [23]

Afendy

[26]

David

[9]

Newton Dan

[25] [24]

5% Weight loss led to overall QoL, abdominal symptoms, fatigue, activity and worry improvement. More improved patients with NASH, without advanced fibrosis (F0–2) or DM Older patients reported more abdominal symptoms, less activity levels and worse emotional functioning Females reported less activity levels Obesity was associated with less activity, more pronounced fatigue, more systemic symptoms and lower total CLDQ score Diabetes mellitus and metabolic syndrome were associated with lower activity levels, while diabetic patients also had lower total CLDQ score. NAFLD patients reported poorer health compared to controls Physical health was more impaired than mental health Less pronounced impairment compared to HCV patients, particularly in mental health All sub-domains of SF36 and health utilities scores were lower than the general population. Cirrhotic patients reported poorer QoL. Only cirrhosis and not DM, BMI or CVD predicted QoL At baseline, all NAFLD participants had the lowest scores in VT and GH sub-scales. Venesection did not improve QoL. Both groups reported significantly better general health at 6 months compared to baseline Liraglutide 48-week treatment is associated with significant improvement in PCS of QoL score compared to placebo NASH patients reported worse QoL (all domains) than the general population. Only DM associated with poor QoL (physical component). Age, sex, fibrosis and obesity did not correlate with QoL Spirulina improves overall CLDQ score QoL did not change from baseline No significant differences in QoL scores post-treatment between pioglitazone-, vitamin E- and placebo-treated patients. Post-treatment scores did not change significantly In non-cirrhotics NAFLD worse PF than VH. In cirrhotics NAFLD worse in PF and PCS than VH, ALD,CholLD, worse in RP, BP and VT than ALD and VH and worse in RE than CholLD. PCS and MCS scores were predicted by NAFLD diagnosis Lower physical and mental QoL than the general population Lowest scores in general health, vitality and physical functioning Patients with definite NASH worse physical QoL than NAFLD (GH, BP,VT,RP) Worse physical QoL in > 40, females, DM, lower income, BMI > 40 and unmarried High scores in all domains of the CLDQ. Strong negative associations between fatigue and QoL scores NAFLD vs HBV worse QoL in all domains except Worry NAFLD vs HCV worse in Systemic and Emotion Domain After controlling for gender, cirrhosis, BMI, ALT, and co-morbidity NAFLD independently predicts Emotions, Systemic and Activity domains

NAFLD: Nonalcoholic Fatty Liver Disease; NASH: Nonalcoholic Steatohepatitis, QoL: Quality of life; DM: Diabetes mellitus; CVD: Cardiovascular disease; BMI: Body Mass Index; ALD: Alcoholic Liver Disease; CholLD: Cholestatic Liver Disease; VH:Viral Hepatitis; HCV: Hepatitis C Virus; HBV: Hepatitis B Virus; ALT: Alaninotransferase CLDQ: Chronic Liver Disease Questionnaire; SF36: Short Form-36, Health Survey; PCS: Physical Component Score; MCS: Mental Component Score; PF: Physical functioning; RP: Role limitations due to physical problems; BP: Bodily pain; GH: General health; VT: Vitality; SF: Social functioning; RE: Role limitations due to emotional problems; MH: Mental health

patients' QoL. Fatigue is a highly prevalent symptom among NAFLD patients and its severity negatively correlates with all aspects of their QoL [12,17,18,25].

3.3.2. Clinical parameters and QoL The impact of clinical parameters on NAFLD patients' QoL has been addressed by several researchers, given that the vast majority of fatty liver disease patients suffer from co-morbid conditions, which may independently contribute to QoL impairment [7]. Obesity represents the most frequent co-morbidity in NAFLD patients with prevalence rates reaching 80% [27] and obese individuals commonly report poor mental and physical health [28]. Surprisingly, several studies failed to detect significant independent associations between BMI and QoL scores [8,12,18]. In contrast, David et al. reported that BMI > 40 independently predicted poorer physical QoL [9]. In line with these findings, obese patients have been shown to report lower activity, more fatigue, more pronounced systemic symptoms and lower total score of the CLDQ-NAFLD [17,24]. However, in this latter study, the authors determined QoL's correlates in the whole sample of chronic liver disease patients and not exclusively in the sub-group of NAFLD patients [24]. As far as the impact of diabetes mellitus on NAFLD patients' QoL is concerned, several authors agree that NAFLD patients with diabetes are equally impaired in terms of QoL compared to patients without diabetes [8,18,24]. However, in two recent studies, the presence of diabetes mellitus was significantly associated with worse physical QoL [12,17], while according to an earlier study, diabetes mellitus emerges as a significant predictor of deterioration in both components of NAFLD patients' QoL [9]. In a similar vein, in the broader group of chronic liver disease patients, the presence of metabolic syndrome did not correlate with QoL impairment [24], while in a sample of NAFLD patients, the metabolic syndrome was associated only with lower activity levels [17]. Despite these discrepancies between research findings, there seems to be an agreement among researchers regarding the role of fatigue in NAFLD

3.3.3. Biochemical and histopathological indices and QoL According to two relevant studies, biochemical indices of liver functioning including AP, ALT, AST, albumin and total protein levels did not correlate with NAFLD patients' QoL [12,24]. In contrast, according to two well-designed studies of biopsy-proven NAFLD patients, fibrosis stage and the presence of cirrhosis were found to independently predict impairment in the physical component of QoL [8,9], a finding which corroborated early results obtained from chronic liver disease patients [24,26]. However, as far as the mental component of QoL is concerned, data appear rather ambiguous. Sayiner et al. reported that NAFLD patients with cirrhosis suffer from greater impairment in all QoL sub-domains apart from mental health compared to patients without cirrhosis [8], while the two earlier studies of chronic liver disease patients revealed that cirrhosis is associated with increased health worries which is a component of mental QoL [24] and with lower scores in the mental component of the SF36, although these associations appear less strong than those observed between cirrhosis and the physical component of QoL [26]. Among studies which included a well-defined sub-group of NASH patients, Tapper et al. (2016) found that the presence of nonalcoholic steatohepatitis does not correlate with QoL scores [18], while an earlier study showed that NASH patients report lower scores in vitality, general health, bodily pain and role limitations due to physical problems, however these associations vanished at multivariate analyses suggesting that they reflected the effect of other factors and not the impact of NASH [9]. 77

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significantly influence QoL outcomes. Our main finding is that NAFLD patients suffer from poor QoL compared to healthy controls, mostly in the domain of physical health. In addition, compared to other chronic liver disease patients, NAFLD patients report worse physical health and more role limitations due to health issues compared to chronic hepatitis B patients, alcoholic liver disease patients and cholestatic liver disease patients. In the case of QoL comparisons between NAFLD and chronic hepatitis C patients, findings are rather conflicting with some authors reporting greater burden in NAFLD patients [24], while others report that HCV patients are more impaired especially in the domain of mental health [10]. It is noteworthy, that studies with a large sample size which allowed the performance of multivariate comparisons suggest that the diagnosis of NAFLD independently predicts mental and physical QoL after controlling for demographic variables and co-morbid conditions that might also disturb patients' well-being [10,24]. Nevertheless, a crucial point of caution when interpreting the above findings is the fact that the vast majority of patients in these studies are clinical populations already referred to specialist departments. Among all included studies, only 1 analyzed data derived from the general population and not from clinically referred subjects [10]. It is therefore possible that they represent a group of patients with more advanced liver fatty disease and the aforementioned findings reflect the QoL burden of more severe NAFLD cases. NAFLD is largely asymptomatic or characterized by subtle, non-specific symptoms and for this reason many cases go undetected or do not reach medical services until the emergence of serious complications. To draw solid conclusions regarding the medical and societal burden of the disease and its impact on patients' lives, researchers should also study non-clinical samples derived from the general population. Another important issue in QoL research is the detection of parameters which contribute to the observed deficits. Our search yielded conflicting evidence regarding the role of demographic variables on NAFLD patients' QoL, however, the study by David et al. (2009) provides strong evidence that older age, female gender, lower educational level and lower socio-financial level strongly correlate with QoL scores [10]. Clarifying these associations would give clinicians the opportunity to detect vulnerable populations and provide proper care. In addition, several studies [8,9,12,17,18,25] have attempted to describe the contribution of clinical co-morbidities, including diabetes mellitus, obesity and metabolic syndrome, to patients' QoL providing inconclusive results. These discrepancies may be due to sample differences between studies and provide support to the notion that there are different clinical sub-types of NAFLD. Although the majority of NAFLD patients are overweight or obese, there is a sub-group of patients who are lean and their liver steatosis probably represents a distinct nosological entity [32]. Determining QoL levels and their correlates in these patients might provide useful information for the role of obesity and metabolism abnormalities in physical and mental health. Another important finding of the current review was that fatigue is commonly reported by NAFLD patients and it is strongly associated with worse QoL [12,17,18,25]. The central role of fatigue has already been demonstrated in other chronic liver disease patients including HCV and primary biliary cirrhosis patients and has been linked to neuroinflammation and disrupted neurophysiological processes [33,34]. Although fatigue is a non-specific, subjective symptom, it merits clinicians' and researchers' attention due to the negative impact is has on NAFLD patients' well-being. The presence of advanced fibrosis or cirrhosis leads to greater deficits in the physical component of QoL, while the association between cirrhosis and the mental component of QoL appears less strong [8,9,24,26]. Liver disease progression has been repeatedly linked to greater physical health impairment in patients with chronic viral hepatitis and chronic liver disease in general. The finding that NAFLDrelated cirrhosis is associated with greater physical health burden while NASH is not [9,18], probably indicates that the negative impact of

3.4. The effect of treatment on NAFLD patients' QoL Six studies [18–23] prospectively investigated the effect of several treatment modalities on NAFLD patients' QoL, however only in 2 of these studies, QoL was a primary outcome [18,20]. In addition, statistical data provided by the authors were not sufficient to calculate effect sizes for any of these studies. A recent double-blind randomized placebo-controlled study [19] assessed the efficacy and safety of a liraglutide regimen administered for a 48-week interval to biopsy-proven NASH patients. Statistical analysis revealed that liraglutide leads to significant improvement of the physical component of QoL compared to placebo. Despite the small sample size of this study, its solid methodological design adds reliability to its findings. In contrast, the administration of pioglitazone or vitamin E for 96 weeks in a large sample of NASH patients without diabetes mellitus was not associated with any QoL improvement [23]. Similarly, Loguercio et al. studied prospectively 138 NAFLD patients randomized to receive either a combination of silybin, phosphatidylcholine and vitamin E acetate or placebo for 12 months and observed no significant changes in QoL scores from baseline during the treatment period [20]. Another pharmaceutical regimen that has been used in NAFLD treatment is spirulina and its efficacy was evaluated by Mazokopakis et al. (2014) in an open-label, non-randomized, prospective study [21]. In this study, 15 NAFLD patients received a daily dose of spirulina for 6 months and they reported significantly higher total CLDQ scores post-treatment, however the authors did not include a control group in their methodology [21]. Weight loss through exercise and/or dietary interventions remains the treatment of choice for most cases of NAFLD, and a recent systematic review of articles addressing NAFLD treatment issues has clearly shown that weight loss may be accompanied by significant QoL gains [29]. Our search retrieved only one methodologically adequate study which assessed the effect of weight loss on QoL by prospectively recruiting 151 NAFLD patients including patients with diabetes mellitus and advanced fibrosis. According to this investigation, a 5% weight loss was associated with significant increase in total CLDQ score and improvement in the fatigue, abdominal symptoms, activity and worry subdomains [18]. In addition, sub-group analysis revealed that patients with active NASH in the absence of diabetes mellitus or advanced fibrosis experienced the greatest QoL benefits through weight loss. Finally, other researchers evaluated the effect of venesection on QoL by studying 34 NAFLD patients randomized to receive either regular phlebotomy combined with lifestyle advice or lifestyle advice alone for a period of 6 months. Their analysis revealed that both groups of patients presented with similar changes in QoL scores during the 6-month period [22]. 4. Discussion To our knowledge, this the first systematic review focussing exclusively on the issue of QoL in NAFLD patients, given that all previous reviews [6,7,29–31] focused on broader NAFLD-related clinical issues and their reference in QoL studies was rather limited, not employed in a systematic methodological design and lacking further in depth analysis of the retrieved findings. In agreement with our findings, all previous reviews emphasize the negative impact of NAFLD on patients' wellbeing. However our systematic approach to the topic allowed us to classify research findings in distinct thematic categories and more importantly to detect areas of scientific vagueness which require more rigorous future research. All included studies were characterized by homogeneity regarding the method of QoL assessment given that most researchers used either the generic SF36 or the disease-specific CLDQ, which are valid psychometric instruments and their sub-domains scores are highly correlated. Nevertheless, we detected great heterogeneity in sample selection, mainly due to differences in the percentage of patients with cirrhosis, NASH and medical co-morbidities and this variability might 78

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NAFLD on patients' well-being is mostly mediated by its severe complications and is largely growing due to fact that diagnosis is frequently established at later stages of the disease, there is no definite treatment and a significant number of patients eventually progress to cirrhosis. In this context, the impact of treatment on patients' symptoms and QoL is gaining greater clinical importance. Although, there have been numerous studies on the effect of several treatments on liver enzymes and histology [29], our search found only 6 studies which included QoL assessment in their analysis [18–23]. This lack of QoL studies should be addressed by carefully designing prospective investigations on the impact of already existing and novel NAFLD treatments on patients' wellbeing. As in the case of most chronic diseases, any therapeutic intervention, apart from improving biomedical outcomes, should provide solid evidence regarding its benefits on patients' lives and everyday functioning. Among the limited data we retrieved, weight loss and liraglitude were associated with significant improvement in patients' physical health and with reduction in fatigue, abdominal symptoms and health-related worries [18,19]. No other treatment provided strong, convincing evidence for QoL benefits. In conclusion, NAFLD patients suffer from significant impairment in the physical sub-domains of QoL compared to healthy individuals and other chronic liver disease patients, while their mental health appears less affected. A variety of demographic, clinical and laboratory factors have been linked to this impairment with the greatest contribution being attributed to fatigue and the presence of cirrhosis. The current review revealed the scarcity of available QoL data for this group of patients and underlined the need for larger, well-designed studies focussing mainly on further determining QoL correlates, investigating the clinical and QoL profile of distinct NAFLD sub-types and evaluating in a randomized, controlled manner the impact of treatment interventions.

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Competing interest statement All authors have completed the Unified Competing Interest form at. http://www.icmje.org/coi_disclosure.pdf and declare that. (1) No author received support for the submitted work. (2) Triantos Christos has received fees for serving as a speaker and/ or advisory board member for MSD, Roche, Abbvie, Bristol-Myers Squibb και Gilead Sciences in the past three years that could be perceived to constitute a conflict of interest. (3) No spouses, partners, or children of any of the authors have financial relationships that may be relevant to the submitted work. (4) No author has any non-financial interests that may be relevant to the submitted work. Conflict of interest Triantos Christos has received fees for serving as a speaker and/or advisory board member for MSD, Roche, Abbvie, Bristol-Myers Squibb και Gilead Sciences. All remaining authors declare no potential conflict of interest. Financial support No financial support was provided for the completion of this review. References [1] Y. Fazel, A.B. Koenig, M. Sayiner, Z.D. Goodman, Z.M. Younossi, Epidemiology and Nat. Hist. of non-alcoholic fatty Liver disease, Metabolism 65 (2016) 1017–1025, https://doi.org/10.1016/j.metabol.2016.01.012 [PMID: 26997539] [Internet], [cited 2017 Oct 24];Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 26997539. [2] Z.M. Younossi, A.B. Koenig, D. Abdelatif, Y. Fazel, L. Henry, M. Wymer, Global epidemiology of non alcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence and outcomes, Hepatology 64 (2016) 73–84.

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