Keywords

In recent years, evaluating the impact of chronic liver disease and the success of its treatment has expanded beyond only measuring clinical outcomes. These assessments now include measuring patients’ perspective of their disease, and the effect treatment has on their quality of life [1–13]. In this context, health-related quality of life (HRQOL) has become a very important outcome for measuring patient’s perspective about their health and treatment.

HRQOL falls under the broader category of quality of life which accounts for many other aspects of a person’s life besides simply health, including the influence of environment, freedom, economy as well as aspects of their culture, values, and spirituality [2, 5, 6, 14, 17, 18, 19]. Therefore, HRQOL has been very succinctly defined as a broad multidimensional concept that includes self-reported measures of physical and mental health as well as the ability to be socially active (social well-being) [1–13].

Although HRQOL and patient-reported outcomes (PROs) can be interchangeable terms, PROs may include other outcomes reported by and important to patients. Alternative terms that are commonly used to define a patient’s perspective (self-report) of their physical, mental, and social functioning include health status and well-being [20–22]. In general, HRQOL tools or instruments are divided into general measures (generic instruments) and disease-specific instruments [1–24]. In the following paragraphs, we describe some of the most common generic and disease-specific instruments used to measure HRQOL in patients with cirrhosis.

Tools Used to Measure HRQOL (Tables 34.1 and 34.2)

Table 34.1 Health-related quality of life tools for patients with chronic hepatitis C virus
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Table 34.2 URLs for health-related quality of life tools used for patients infected with the hepatitis C virus (www.cldq.org)
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The Short Form -36 Version 2 (SF-36v2)

The Short Form -36 version 2 (SF-36v2) is a widely used instrument for HRQOL evaluation [6]. It assesses eight HRQOL scales (ranging 0–100 with higher values corresponding to a better health status): physical functioning (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE), and mental health (MH). The two summary scores summarize the physical and mental health components of the SF-36: the Physical Component Summary score (PCS) and Mental Component Summary score (MCS). The SF-36 scales and summary scores are calculated using the QualityMetric Health Outcomes Scoring Software 4.5 (Lincoln, RI, USA) and the 2009 US population norms [6].

Sickness Impact Profile (SIP)

The SIP is a generic health measurement tool that is used to investigate a change in behavior as a consequence of illness. It contains a 136 items divided by 12 categories covering activities of daily living (sleep and rest, eating, work, home management, recreation and pastimes, ambulation, mobility, body care and movement, social interaction, alertness behavior, emotional behavior, and communication). Items are scored on a numeric scale with higher scores reflecting greater dysfunction. In addition to individual category scores, an aggregate psychosocial score is derived from four categories, and an aggregate physical score is calculated from three categories [5, 12, 14].

Chronic Liver Disease Questionnaire (CLDQ)

The CLDQ is another widely used and validated HRQOL instrument developed specifically for assessment of HRQOL in chronic liver disease patients [7, 13, 14, 18]. It includes 29 items and 6 HRQOL scales: fatigue, activity, emotional function, abdominal symptoms, systemic symptoms, and worry. CLDQ has a summary score, CLDQ total score [7]. These scales are averaged to the total CLDQ score that ranges 1–7 with higher values representing better HRQOL [7, 17, 18]. In addition to CLDQ, a hepatitis C-specific version was also developed and validated (CLDQ-hepatitis C virus (HCV)). CLDQ-HCV consists of four scales that measure: activity/energy (AE), emotion (EM), worry (WO), and systemic (SY) as well as a CLDQ-HCV total score (CLDQ-HCV Tot) [25]. Both CLDQ and CLDQ-HCV are now widely used throughout the world to assess HRQOL for patients with liver disease and HCV [15, 20, 26–32].

Liver Disease Quality of Life (LDQOL)

The short form of liver disease quality of life instrument (SF-LDQOL) is a questionnaire that comprises 36 disease-targeted items representing nine domains, symptoms of liver disease, and the effects of liver disease. The SF-LDQOL has been shown to correlate highly with SF-36 scores, symptom severity, disability days, and global health [6, 14].

Post-Liver Transplant Quality of Life (pLTQ) Instrument

The pLTQ instrument is a relatively new measurement tool developed to measure health-related quality of life in posttransplant patients. After 12 liver experts and transplant recipients were interviewed, a thorough literature search was conducted, and factor analysis and testing in more than 200 liver transplant (LT) patients was performed, the pLTQ was formulated. The tool includes 32 items which covers eight domains (emotional function, worry, medications, physical function, health care, graft rejection concern, financial, and pain) and has been determined to be stable over time [35–39].

Hepatitis Quality of Life Questionnaire (HQLQv2)

The Hepatitis Quality of Life Questionnaire™ Version 2 (HQLQv2™) is a two-part survey designed to assess the functional health and well-being of patients with chronic hepatitis C . It includes the SF-36v2® Health Survey and 15 additional questions that measure other generic health concepts particularly relevant in assessing the impact of hepatitis (e.g., health distress, positive well-being), and disease-specific concepts (e.g., hepatitis-specific functional limitations, hepatitis-specific distress) [5, 14].

The HQLQv2 was developed to help patients and clinicians monitor the effects of hepatitis C and its treatment as well as screening and monitoring changes in disease impact. The HQLQv2 is available in a fixed form or interview (telephone/face-to-face) format. It can be administered in clinical settings, at home, or in other locations. The HQLQv2 is intended for adults 18 years of age and older, and is available in multiple language translations with a standard 4-week recall period [5, 14].

Liver Disease Symptom Index 2.0 (LDSI 2.0)

The Liver Disease Symptom Index 2.0 (LDSI) developed in a Dutch cohort of patients includes 18 items that measure symptom severity and symptom hindrance in the past week [5, 11, 14] Through convergent and divergent construct validity, the investigators determined that the information from the LDSI provided complementary information to the information gleaned from the SF-36 and the multidimensional fatigue inventory (MFI)-20 and it should be considered an additive tool when researching HRQOL in a population with liver disease [5, 11, 14].

Quality of Well-Being Scale (QWB)

The QWB-self-administered (SA) combines preference-weighted values for symptoms and functioning. Symptoms are assessed by questions that ask about the presence or absence of different symptoms or conditions. Functioning is assessed by a series of questions designed to record functional limitations over the previous 3 days, within three separate domains (mobility, physical activity, and social activity). The four domain scores are combined into a total score that provides a numerical point-in-time expression of well-being that ranges from zero (0) for death to one (1.0) for asymptomatic optimum functioning [5, 14].

Health Status/Utility Assessment (The Health Utilities Index (HUI), EuroQol-5D (EQ-5D), and the Short Form -6D (SF-6D))

One of the most important applications for quality of life assessment is in economic analysis. In fact, outcomes, such as life years gained or lost by an intervention, are usually qualified in terms of the quality-adjusted years of life gained or lost. Health utility assessment is the method used to obtain quality-of-life adjustments. The direct assessment of health utilities uses the technique of time trade-off or standard gamble, while the indirect assessment utilizes questionnaires designed to assess health status. Some of the important questionnaires that are available to assess health utilities are discussed below [5, 14].

To calculate the true value of a treatment, the scores from the SF-36v2® or the SF-12v2® Health Surveys can be converted into a utility index, called the SF-6D, which considers not only how many years a medical intervention can add to a patient’s life, but also the quality of that life. The SF-6D can then be used to obtain a better understanding of a patient’s real preference for a treatment, select the best course of action for a patient, compare two interventions based on quality-adjusted life years (QALYs) and cost, assess the cost-effectiveness of a medical product, procedure, or health and wellness program, and allocate health-care resources most efficiently [5, 6].

The approach most commonly used in the European community is the EQ-5D, which has been advanced by a collaborative group from Western Europe known as the EuroQol group. This group, originally formed in 1987, comprises a network of international, multidisciplinary researchers, originally from seven centers in England, Finland, the Netherlands, Norway, and Sweden. More recently, researchers from Spain as well as researchers from Germany, Greece, Canada, the USA, and Japan have joined the group. The intention of this effort is to develop a generic currency for health that could be used commonly across Europe. The original version of the EuroQol had 14 health states in six different domains. More current versions of the EuroQol, the EQ-5D, are now in use in a substantial number of clinical and population studies [5, 14].

HRQOL Findings in Patients with Chronic Liver Disease

Patients with chronic liver disease (CLD) report significant impairment of their HRQOL [1–22]. Although this impairment is applicable to most patients with CLD, patients with HCV , primary biliary cirrhosis (PBC) and non-alcoholic fatty liver disease (NAFLD) seem to have more impairment [1, 2]. In fact, several recent studies have reported that patients with HCV have a dramatically reduced HRQOL due to extreme fatigue and depression [2, 7, 18, 19, 25]. A number of studies of patients living with PBC report impairment of the physical health component related to fatigue. In fact, fatigue in PBC is so overwhelming that some have questioned whether it should be an indication for LT in this group of patients [39]. Carbone and group found that LT improved the HRQOL in patients with PBC; however, fatigue, though improved, persisted 2 years posttransplant calling into question the appropriateness of this symptom as an indication for transplant given the scarcity of donated organs [40]. Patients with cirrhosis have also demonstrated a significantly reduced HRQOL related to numerous clinical and demographic features in addition to suffering from depression and anxiety [1–25].

Specific Studies of HRQOL in Cirrhotics

In addition to etiology of CLD, severity of liver disease accounts for the majority of impairment in patients’ HRQOL . There are multiple publications suggesting that patients with compensated cirrhosis have more impairment than CLD patients without significant hepatic fibrosis. Worsening hepatic dysfunction in patients with cirrhosis, as documented by higher model for end-stage liver disease (MELD) scores, and the development of complications , such as ascites and hepatic encephalopathy, account for severe impairment of HRQOL [2, 3, 4, 9, 17, 20, 23, 30, 40–44].

When compared with the national norm for healthy subjects, HRQOL , as measured by SF-36 [6], shows severe impairment of HRQOL in patients with cirrhosis. In fact, this impairment occurs in every aspect of their well-being [17, 19, 45]. Marchesini and colleagues assessed HRQOL using 2 generic HRQOL tools (SF-36 and the Nottingham Health Profile) in a large cohort of Italian patients with cirrhosis and compared their results to norm-based results [46]. They found that the cirrhotic group had significantly lower HRQOL than the Italian population norms as a result of muscle cramps and pruritus associated with cirrhosis. It was noted that clinicians’ and patients’ perceptions of the importance of certain symptoms on well-being may differ [18]. Therefore, it is imperative that clinicians spend sufficient time to determine what is causing the most problems for patients so that an appropriate intervention plan will be developed [18].

Other investigators have explored the role of HRQOL in predicting mortality. Kenwal and associates administered the SF-LDQOL questionnaire to 156 patients who were awaiting LT [29, 47]. Using Cox proportional hazard modeling to measure the independent effect of baseline HRQOL on survival after adjusting for MELD scores and other covariates, they found that higher-baseline HRQOL predicted lower mortality (hazard ratio, 0.96; 95 % confidence interval, 0.94–0.99). Specifically, for each one-point increase in HRQOL, there was a 4 % decrease in mortality. These results did not change after adjusting for MELD scores, patient demographics, or psychosocial characteristics [47]. It was also interesting to note that the MELD score accounted for only 1 % of the variation in HRQOL scores (p = 0.18). Survival was most strongly predicted by activities of daily living, health distress, sleep disturbance, and perceived disease stigma. Based on these results, the authors concluded that measuring HRQOL may have a role in predicting survival of patients with advanced liver disease [47].

Sleep disturbances have long been associated with patients living with cirrhosis [48]. These changes are a multifactorial phenomenon [48]. Recently, Mostacci et al. evaluated daytime somnolence and sleep complaints in a group of 178 patients with cirrhosis compared to a control group using the Basic Nordic Sleep Questionnaire (BNSQ) and the Epworth Sleepiness Scale (ESS). Compared to controls, patients with cirrhosis complained of more daytime sleepiness (p < 0.005), sleeping badly at least three times a week (p < 0.005), difficulties falling asleep (p < 0.01) and frequent nocturnal awakening (p < 0.005). The study authors concluded that insomnia and daytime sleepiness are major complaints for this group of patients [48].

Studies assessing the feasibility and effectiveness of measuring HRQOL in daily clinical practice have been performed, generally showing positive results regarding the discussion of HRQOL-related topics, but mixed results regarding the added value to clinical practice of any actual improvement in HRQOL. In one study, which assessed the use of computerized measurement and feedback of HRQOL in the daily clinical practice of an outpatient hepatology department, results demonstrated that there was no improvement in HRQOL for the entire group of chronic liver patients. However, HRQOL showed an improvement in the mental subscale of older patients and male patients with CLD, which had an effect on patient management of this subgroup of patients [21]. Logistic and attitudinal barriers also seem to impede successful implementation of measuring HRQOL in clinical practice settings [22]. However, despite these, HRQOL remains important and relevant in helping to guide clinical decision making.

Cirrhosis Complications and HRQOL

Hepatic Encephalopathy and HRQOL

Hepatic encephalopathy (HE) impacts patients’ level of consciousness, intellect, personality, neuromuscular activity and survival, thus affecting their ability to carry out activities of daily living and so influencing their HRQOL [41–45, 49, 50]. Recent investigators have studied the impact on HRQOL of new cirrhosis treatments in patient suffering with HE. In one study, investigators reported the outcomes of a clinical trial where patients with HE were randomized to receive either rifaximin or a placebo twice daily for 6 months or until they had a breakthrough episode of HE [51]. Using the CLDQ, patients’ HRQOL was followed for the duration of the study. Taking rifaximin significantly improved patients’ HRQOL. However, within the group that had a breakthrough of HE, there was a decrease in scores prior to the appearance of HE. The authors concluded that a decrease in HRQOL in patients with a history of HE can signal the onset of a new episode of HE. Therefore, consideration should be given to using a quality of life tool to track a patients’ progress [51].

Other investigators have also found that the degree of HE was an independent predictor impacting a patients’ HRQOL—the more severe the HE, the lower the HRQOL scores. Results from some studies suggest that complete resolution of an episode of HE may not occur, so over time HRQOL will continue to decrease despite the normal functioning of the patient [41–45, 49–51]. HRQOL results have also helped investigators to determine resolution of the impact of clinically overt HE on a patient’s quality of life. Results have indicated that despite the patient appearing to function normally in all areas of daily activities, their HRQL scores have not returned to baseline. This may indicate that a number of these patients may suffer from covert HE, which may not completely resolve. However, further work is necessary to substantiate this finding [41–45, 49–51].

Ascites and HRQOL

Studies examining the impact of ascites caused by cirrhosis on patients’ HRQOL have noted similar findings to those found in patients suffering from HE. Sola and colleagues determined that having severe ascites, leg edema, and low serum sodium were all independent predictors for a low HRQOL [9]. Les et al. determined that several potentially treatable variables (ascites, hypoalbuminemia, minimal HE, and anemia) if corrected may positively alter a patients’ HRQOL [10].

In another study, Bhogal and Sanjay investigated the impact of using transjugular intrahepatic portosystemic shunts (TIPS) to correct cirrhosis induced complications [51]. Though the TIPS procedure carried potentially significant risks for HE, shunt induced hemolysis, and infection, its success in reducing portal hypertension was superior to paracentesis. However, in a meta-analysis, Albillos et al. found that better control of ascites by TIPS did not translate into improved survival and was associated with worsening of encephalopathy if present [52].

HCV-Related Cirrhosis and HRQOL

Work completed by Younossi et al. and Spiegel et al. suggest that patients infected with HCV have an already diminished quality of life even before reaching the stage of cirrhosis [18, 19, 20, 34, 35, 53]. In fact, Younossi et al. found that assessing HRQOL can be challenging as many of these patients suffer from the indirect effects of fatigue and psychological issues, namely depression and cognitive impairment, which are present early in the disease course [18, 19]. Another issue confounding the assessment of HRQOL is stigmatization resulting from the HCV diagnosis, creating the potential for a psychological disturbance, as well as acting as a barrier to treatment and eroding a patient’s social support network [54–56].

Speigel et al. found that achieving a sustained virologic response (SVR) with HCV treatment (i.e., being HCV RNA negative 6 months after completing therapy) was associated with an increase in HRQOL scores as well as a change of 4.2 points in the vitality score from the SF-36, representing a minimally important difference in HRQoL [53]. They also noted that HRQOL in patients with HCV was impaired regardless of the severity of the disease and attributed this impairment to extra hepatic manifestations related to HCV. Their results also confirmed previous observations that patients with HCV had impaired cognitive functioning as well as an increase in symptoms of their comorbid psychosocial issues after contracting HCV, making it difficult to assess the true of effects of cirrhosis alone [53].

The information gleaned from these studies has become invaluable as new treatments are developed for HCV. Recognizing the impact on patients beyond the biologic effects of the virus is now mandatory—therefore, obtaining a baseline HRQOL score prior to treatment is necessary to ensure any changes in the score will be associated with the correct variable(s), including treatment. Several recent studies on new treatment medications called direct acting antiviral agents (DAAs) have been completed [20, 33, 34]. Patients with HCV and cirrhosis who participated in recent phase III clinical trials using DAA’s demonstrated decreased scores in their PROs prior to the initiation of treatment. However, during treatment, the researchers found that interferon-free regimens were associated with minimal PRO decrements. On the other hand, PROs were substantially impacted in both cirrhotics and non-cirrhotics by the inclusion of interferon in sofosbuvir-based treatment regimens. The short duration of treatment (12 weeks) appeared to be advantageous, as the decrease in PROs during treatment disappeared and scores returned to baseline after termination of therapy. Finally, patients with cirrhosis who achieved an SVR 12 weeks after stopping treatment, especially with the interferon-free sofosbuvir-based regimens, enjoyed significant improvement in many areas of their PRO scores [20, 33, 34].

Cirrhosis and Liver Transplantation

Five-and ten-year patient survival after LT is now around 70 and 60 %, respectively. This improvement in life expectancy has shifted the emphasis on follow-up from simple clinical indicators to focusing on how patients cope with everyday life— physically, mentally, and socially [39]. Several studies have investigated the impact of LT on patients’ HRQOL [35–40].

Younossi and group determined that patients who underwent LT for complications of cirrhosis had significantly impaired HRQOL [35]. However, after transplantation, their mental health scores rose significantly and were the same or higher than the population norms, while their HRQOL physical component also rose significantly but did not surpass the population norms. They found that HRQOL was clearly associated with the amount of health-care resources expended during their transplant hospitalization such that the more expenses they were perceived to have used, the lower their HRQOL perhaps indicating that patients with a shorter length of stay were healthier [35].

Nutrition has also been found to play a role in patients HRQOL following transplantation. Urano and colleagues determined that after LT, it took at least 6 months for nutritional status, based on laboratory data and energy metabolism, to normalize [37]. Once these parameters normalized, the physical component HRQOL scores improved. They, therefore, concluded that long-term nutritional support is necessary for LT patients in order for them to obtain an optimal level of physical functioning [37]. Others who have studied HRQOL in LT recipients found that patients who were sicker, as noted by their MELD and quality-of-life scores pre-transplant, continued to have low HRQOL scores over time, although their scores improved from baseline [36].

Conclusions

The HRQOL in patients suffering from cirrhosis is significantly decreased when compared to patients without liver disease/cirrhosis. Many tools have been developed to measure the impact of cirrhosis on HRQOL. The most commonly used tools include the CLDQ, the SF-36, the LDQOL, and the EU 5D—for cost-effectiveness studies. HRQOL is influenced by the type of complications arising from cirrhosis. The net overall effect is lower scores, whether such scores are a result of mental impairment or a limitation that had been placed on patients’ ability to perform an activity of daily living. Collecting information on HRQOL is helpful in guiding and evaluating the impact of treatment on patients and will be particularly valuable as the management of cirrhosis continues to evolve. Measuring HRQOL in the clinical setting has never been more timely or important.