Introduction

Quality of life is a construct that reflects the positive and negative aspects of an individual’s life. This construct is expanded upon by health-related quality of life (HRQL), which includes health risks and conditions, functional status, social support, and socioeconomic status on individuals’ well-being. Cirrhosis is the culmination of various pathways that can lead to the development of advanced hepatic fibrosis. These mechanisms include alcohol abuse, iron or copper overload, autoimmune liver diseases, biliary atresia, cystic fibrosis, and non-alcoholic fatty liver disease as well as chronic hepatitis B, chronic hepatitis C, and inborn errors of metabolism [1]. The most prevalent disease processes likely to result in cirrhosis in the United States include chronic hepatitis C virus (HCV), non-alcoholic fatty liver disease (NAFLD), and alcoholic liver disease (ALD) [1, 2].

The numbers of individuals progressing to cirrhosis is expected to increase until about 2030 [3]. These increases are due in part to the high prevalence of HCV in a cohort of individuals infected in the 1950s and 1960s. This high prevalence of HCV in the so-called “baby boomer” group has resulted in the recent recommendation by the Center for Disease Control to screen all US residents who are 40–64 years old [4•, 5•, 6]. The economic models have suggested that the new HCV Birth Cohort screening will be more cost effective than the “risk-based” screening. In fact, these data are supported by the disease burden estimates reported by Davis et al., which suggested that, while overall new infection rates of HCV have declined, the rates of HCV-infected individuals advancing to cirrhosis, decompensated cirrhosis, hepatocellular carcinoma (HCC), and liver-related death will continue to rise [3]. These dour projections focus solely on HCV-related liver problems and do not include the liver problems rising from increasing prevalence of obesity and its complications in the United States, i.e. NAFLD [7]. In fact, the recently published data suggest that, from 1988 to 2008, the prevalence rate for NAFLD continued to rise while the prevalence rates for other liver diseases remained stable [8]. This indicates that in the future the burden of liver disease will continue to increase, primarily fueled by an increasing prevalence of NAFLD.

Furthermore, the aging of populations with chronic liver disease is placing a greater number of individuals at risk for cirrhosis. The prevalence of cirrhosis is increasing and projected to continue to do so in part because of the aging of the population with chronic viral liver disease [9]. The elderly, who are aging with cirrhosis and other co morbidities, are likely to require more extensive medical intervention with decreased independence in activities of daily living and will face often deteriorating cognitive function [9].

Despite increasing knowledge of the pathogenesis of chronic liver disease (CLD), the pathophysiology of cirrhosis, and major advances in the treatment, there remains a paucity of information related to HRQL in patients with cirrhosis. Furthermore, the emotional and economic impact of cirrhosis on individual’s lives is rarely considered [10]. While the assessment of patient reported outcomes (PRO) has gained traction in clinical research and clinical trials, there has been a lag time for their acceptance and incorporation into clinical practice [11].

Definition of Quality of Life

In this review, we define HRQL as the impact of both physical and mental health on patients’ perceptions of their well-being. Systematic use of PRO allows researchers to examine symptom burden, disability, and HRQL difficulties that patients with cirrhosis endure. Measurement of symptom burden and HRQL inherently requires administration of various self-reported questionnaires, which aim to measure the impact of chronic diseases on 3 health domains: physical, psychological, and social [12, 13].

There are four generally accepted types of PRO measures; symptom scales, disease specific scales, general or generic health profiles, and health utilities. While many instruments are used in research settings, in this review, we discuss liver disease-specific scales [Chronic Liver Disease Questionnaire (CLDQ), Liver Disease Quality of Life 1.0 (LDQOL)] and the mostly commonly used general health profile [Short Form 36 Profile (SF-36)]. The measurement of HRQL has generated extensive research interest across the full spectrum of diseases as a means of examining disability, effects of treatment, and response to amelioration of disease [14].

Understanding the various factors that affect HRQL deepens our understanding of the multifaceted issues cirrhotics face and their effects on health status [15•, 16, 17]. It is critical that health care providers learn the impact of disease on individuals if treatments are not only to improve health but also function and unexpected treatment outcomes [18]. In this review, we will also examine recent literature describing what is known about quality of life of patients with cirrhosis and how to measure it.

Emotional, Social and Economic Aspects of Cirrhosis

Cirrhosis leads to physical complications that affect function and performance such as muscle cramps, wasting, hepatic encephalopathy and ascites, but these problems also influence patient sense of well-being and life satisfaction [9, 10]. It also has substantial impact on informal (family) caregivers [19]. The burden of physical complications and economic concerns and emotional struggles can and should be measured in clinical practice. Determining symptom burden for issues such as fatigue, ascites and hepatic encephalopathy in addition to emotional concerns of living with chronic viral hepatitis are important for the health care providers [15•, 16, 17].

There are many factors that influence outcome and HRQL in patients with cirrhosis, some which are related to the overall health of the individual, nature of their social support, and access to coordinated care. With this in mind, it cannot be forgotten that the extent of hepatic fibrosis and liver function clearly plays a major role affecting the HRQL of patients with cirrhosis. Patients with compensated cirrhosis face non-life-threatening symptoms, despite teetering on the edge between compensation and decompensation, which can determine overall survival and HRQL [20]. A patient clinically classified as having compensated cirrhosis may have reasonable liver function, yet can experience multiple symptoms that can negatively impact their level of function and their HRQL. Nausea, somnolence, “fuzzy-thinking”, weight loss, weakness, fatigue, itching, or osteoporosis are just a few of the common symptoms of cirrhosis that may interfere with a persons work, school, social activities, and sense of well being [21].

In addition to these symptoms, liver disease may have important social implications. In counseling sessions of patients with viral hepatitis (B and C), Alizadeh et al. found that infecting family members was the principal concern affecting 80.6 and 66.7 % of this cohort, respectively. Other significant concerns of patients were: disease progression to cirrhosis affecting 44.4 %, social stigma 36.1 %, and economic concerns surrounding medication and treatment 22.2 % [22]. Congruent findings focusing on HCV groups alone found that, while concerns of transmission remains the predominant worry, social stigma and disease progression also weigh heavily on the mind of patients [23]. Taken together, the literature suggests there is a high incidence of multifaceted psychological strains on patients with end-stage viral liver disease.

Finally, economic implications of cirrhosis can be tremendous. In fact, debilitating physical states requiring high cost treatments, often in low income patient populations, represents a vast burden on the health care system. In the United States alone, from 2005 to 2009, the inpatient charges patients with chronic liver disease has continued to increase [24]. In 2009, cirrhosis was implicated as the 12th leading cause of death in the United States, and in the same year over 190,000 patients were involved in short-stay hospital visits with nearly 30,000 patients dying due to cirrhosis-related issues [25]. Furthermore, in 2008, the costs associated with treating cirrhosis, including direct drug and hospitalization time and indirect costs, i.e. loss of work time, can be as high as US$2 billion [25, 26]. There are a number of contributors to the high cost of cirrhosis. In fact, cirrhotic patients with larger number of comorbidities [24] and those with more severe liver disease contribute more to the economic burden of cirrhosis [27]. Cirrhotic patients with high Model for End Stage Liver Disease (MELD) scores have been shown to have significantly higher medical expenses (R = .675, p = .0086) and are less likely to be working [27]. These concerns are bolstered when examining how few patients return to work post-transplant. While most cirrhotic patients with severe hepatic dysfunction (high MELD scores) have difficulty returning to work post-OLT, patients who undergo OLT for primary sclerosing cholangitis seem to do better [27, 28].

Patient Reported Outcomes, Symptoms and HRQL

In an effort to quantify the burden of cirrhosis and its complications on patients’ well-being, researchers have turned to a number of tools to assess PRO. While there are four general classes of self-reports, here we will define the scope of disease-specific and general health measures. Although a number of generic and disease-specific instrument have been used for patients with chronic liver disease (Table 1), we will focus on some of the most popular measurement instruments: disease specific instruments (CLDQ, LDQOL), and general health instruments (SF-36).

Table 1 Quality of life instruments used for patients with cirrhosis and its complications
Full size table

Disease-specific scales are designed to measure symptoms likely to occur in patients with a specific disease. They measure the impact of the symptoms of a particular disease on a patient’s well-being, responses to treatment, or burden of disease when compared to norms. They do not apply to other illnesses (asthma, rheumatoid arthritis, etc.) and are not typically designed to cover all aspects of health [29]. An optimal disease-specific HRQL questionnaire tracks with disease severity, i.e. Child−Pugh (CP), MELD score, and adequately reflects the influence of concomitant complications of cirrhosis (fatigue, ascites, hepatic encephalopathy, etc.) on a patient’s well-being. Two commonly used instruments designed for determining the burden of liver disease on a patient’s HRQL are the CLDQ and the LDQOL [30, 31]. The outcome measure for a disease-specific questionnaire sheds light on how particular aspects of cirrhosis negatively influence a patient’s health. While useful in examining the influence of disease status on a patient’s life, these scales may not capture other factors influencing a patient’s health and should not be considered a comprehensive view of quality of life. In fact, most experts recommend the use of disease-specific HRQL instruments in conjunction with a generic instrument. This approach will provide a better assessment of HRQL for patients with liver disease [18].

The CLDQ was developed in 1999 as a disease-specific instrument for patients with chronic liver disease. CLDQ was initially validated on 133 patients, 30 with cholestatic liver diseases and 103 with hepatocellular carcinoma, and of those, 46 repeated the questionnaire 6 months after initial administration to determine intraclass correlations for internal consistency [30]. The CLDQ has subsequently undergone worldwide validation in patients with HCV, Hepatitis B Virus (HBV) and NAFLD [32, 33•, 34–38]. The CLDQ is a 29-item self-reported questionnaire with patient response options ranging from “1 = all of the time” to “7 = none of the time” [30]. The CLDQ addresses the following domains when combined give a composite score that indicates overall HRQL: fatigue, activity, emotional function, abdominal pain, systemic symptoms, and worry [30]. Mean domain scores and an overall quality of life score can be calculated, with higher scores representing better outcome. As previously noted, CLDQ has been translated to a number of languages, including Greek, Bengali, Chinese, Spanish, and Thai, all showing high internal validity and reproducibility [32, 33•, 34–38]. Studies have shown how HRQL deteriorates from early cirrhosis (Child−Pugh A) to advanced cirrhosis (Child−Pugh B and C) [39]. The histological relationship to HRQL shows how longitudinal examination of HRQL data can aid in assessing the full impact of CLD and/or the outcomes of treatment.

In viral liver diseases, HRQL has been shown to increase with sustained viral response [18, 40, 41]. Furthermore, CLDQ differentiates between cirrhotic versus non-cirrhotic patients on all of its domains [30]. Studies examining the ability of the CLDQ to track with CP and MELD score have shown conflicting results [42, 43]. While CLDQ tracks well with CP score, it does not correlate well with MELD [44]. This is primarily due to the fact that MELD score measures disease severity and not HRQL. In addition to discriminating patients with early liver disease from those with advanced liver disease, CLDQ has been shown to perform well in clinical trials of patients with complications of cirrhosis. For example, in the clinical trials of regimens used to treat overt hepatic encephalopathy or minimal hepatic encephalopathy, HRQL improvement was seen in those patients with treatment-related improvement of their clinical outcomes [45•, 46].

It is also important to note that a hepatitis C-specific version of CLDQ (CLDQ-HCV) has also been developed and validated. This instrument has been used in clinical trials of anti-HCV regimens and seems to capture clinically important change [47–49]. CLDQ-HCV has undergone full validation and has been translated into over a dozen languages [47–50]

In addition to CLDQ, another disease-specific instrument which has been developed for patients with advanced cirrhosis is LDQOL [31]. Originally validated on 221 patients with cirrhosis (29 % CP A, 52 % CP B, 19 % CP C) of multiple etiologies, the LDQOL uses the SF-36 as a general core, supplemented with 12 additional multi-item scales, resulting in a 111-item self-report measure of general well-being with disease-specific supplementations [31]. The 12 items of the LDQOL are: liver disease-related symptoms, liver disease-related effects on daily living, memory, sexual functioning, concentration, sleep, loneliness, hopelessness, quality of social interaction, health distress, and perceived social stigma of liver disease [31]. These domains were incorporated into the questionnaire after being identified as significant concerns of patients with cirrhosis. The 111-item self-report is scored by averaging items within scales and transforming each scale linearly allowing for a possible range of 0–100, with higher scores corresponding to higher HRQL [31]. The LDQOL has consistently differentiated between the CP A, B, and C for the following domains; sexual problems, sexual functioning, and effects of liver disease [31].

There is some limited data using LDQOL primarily in patients awaiting liver transplantation [51–54]. Despite this, the LDQOL has been able to differentiate significant MELD classifications (≥15) in the following domains: memory (p < .001), social interaction (p < .008), loneliness (p < .001), stigma of disease (p < .004), sexual functioning (p < .01) and sexual problems (p < .012) [51]. Furthermore, the LDQOL has shown in multiple studies to track with severity of liver disease as determined by the CP score. The ability of the LDQOL to differentiate patients according to their CP scores and MELD classifications warrant larger studies. One of the issues related to LDQOL was the relatively long duration of time that is required to complete the questionnaire. Based on promising validation data for LDQOL, efforts have recently been made in creating a short version of LDQOL [54]. Finally, it is important to note that LDQOL was developed for patients with advanced cirrhosis, primarily those patients who were waiting for liver transplantation.

The other important category of HRQL instruments are the generic health profiles. The generic instruments measure the overall health of an individual, independent of a specific disease state such as cirrhosis. This approach uses the WHO’s definition of health, aiming to quantify a state of physical, mental, and social well-being allowing for the comparison of multiple populations to determine various factors contributing to quality of life burdens of diseased groups [55]. Furthermore, this allows for comparisons between two different diagnostic groups in order to compare the degree of disability in their daily lives. Arguably, the most extensively used general health instrument is the SF-36. The SF-36 measures a general HRQL and is disease-agnostic, as compared to either the CLDQ or the LDQOL. The CLDQ and the CLDQ-HCV have been widely validated with respect to the SF-36 [56]. The SF-36 subscales of physical functioning, physical limitations, emotional limitations, and social functioning, differentiate reliably and significantly among the CP classes. Combining items from an original questionnaire with generic measures should be approached cautiously. The validity of the measure has not been established for disease-specific components in all cases, and it may add a significant amount of time for administration.

The SF-36 is composed of 36 items which measure eight domains: physical functioning, role limitations due to physical problems, social functioning, bodily pain, role limitations due to emotional problems, vitality, and general health [57]. The eight domains can be interpreted as independent scores or two derived variables, the physical component score (PCS) and the mental component score (MCS). These scores are transformed to a 0–100 range with higher scores representing a higher quality of life. From the aforementioned SF-36 scaling, utility indices can be determined which are weighted scales that are used to calculate quality-adjusted life years which indicate benefits of medical intervention. The wealth of information available from the SF-36 speaks its acceptance in the research community.

In a large study assessing the HRQL of 1,103 patients with chronic liver disease, Afendy et al. found that patients with cirrhosis had lower HRQL in all scales of the SF-36 versus non-cirrhotic patients [58]. In this study, patients classified as CP class A scored higher than B and C groups on all subscales of the SF-36. Interestingly, beyond the A versus B and C comparisons, the SF-36 was not able to track with further disease severity (B vs. C). In addition, this study examined the role of disease etiology on HRQL and found that patients with cirrhosis due to NAFLD had the lowest HRQL as compared to ALD, viral hepatitis, and cholestatic liver disease [58].

Subscales of the SF-36 have been able to detect more prominent clinical manifestations of cirrhosis than the disease-specific questionnaires. Recent studies examining HRQL in decompensated cirrhosis found that patients with ascites had significantly lower scores in five out of the eight subscales [59–63]. Furthermore, patients with ascites had significantly lower PCS (38 ± 20 vs. 48 ± 21, p = .04) and MCS (40 ± 21 vs. 52 ± 20, p = .01), where a score of 50 on these two subscales represents the healthy population mean [59]. The negative impact of ascites on HRQL has been repeatedly shown [48, 49, 61, 62]. On the other hand, the negative impact of hepatic encephaolopathy on HRQL depends on the sub-category of this complication of cirrhosis [63]. Also, selecting the type of HRQL instrument will be important for assessing HRQL. In fact, SF-36 has reported inconclusive results for patients with minimal hepatic encephalopathy [60]. Rather than detecting these small changes, the SF-36 has been able to detect overt hepatic encephalopathy [45•, 46, 60, 63]. The studies examining HRQL in minimal hepatic encephalopathy highlight the limited sensitivity of generic health instruments. In these studies, disease-specific questionnaires may be a more appropriate measurement tool.

Future Directions in HRQL in Patients with Cirrhosis

As a clinician, one needs to make a choice in selection of the HRQL measures. Should one use multi-dimensional instruments, covering the three domains of physical, psychological and social function? This would be needed if the treatments were likely to encompass a broader aspect of health then those outcomes primarily focused around clinical outcomes. In our opinion, complex, chronic illnesses require multi-dimensional assessments that should include not only clinical outcomes but also all the important aspects of HRQL outcomes. In assessing HRQL, should a disease-specific measure or generic HRQL measure be chosen for a specific study? We believe that disease-specific and generic HRQL instruments measure different aspects of HRQL and their use should be complementary. What should you do with the HRQL data obtained as a part of clinical trial or natural history study of patients with cirrhosis? It is important to note that these data enable the clinicians to follow physical and emotional changes over time and in response to treatment, providing more accurate and comprehensive data for both natural history and treatment outcome measures. The CDC has established that evaluating these parameters is important for individual health, identifying unmet needs of patients and allocating resources to improve the nation’s health and well-being. Finally, it is important to note that, for certain types of patients, other disease-specific instruments are being developed. While CLDQ has been used for patients post-liver transplantation, it may not be able to capture issues related to the post-transplant setting. For these patients, a new Post-Transplant HRQL has been developed (pLTQ) [64]. This instrument should be further validated and, if fully valid, should be widely used for the patients.

In summary, HRQL assessment in patients with cirrhosis will capture a more complete impact of liver disease on patients’ health. Furthermore, including HRQL assessment as part of efficacy trials of regimens used to treat patients with cirrhosis will provide valuable data providing a more complete picture of the efficacy of a regimen on patients’ health and well-being.