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Quality of life among patients suffering from cholestatic liver disease-induced pruritus: A systematic review
Journal of the Formosan Medical Association (2016) 115, 689e702
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.jfma-online.com
REVIEW ARTICLE
Quality of life among patients suffering from cholestatic liver disease-induced pruritus: A systematic review Xin Yee Jin, Tahir Mehmood Khan* School of Pharmacy, Monash University, Bandar Sunway, 45700, Selangor, Malaysia Received 7 December 2015; received in revised form 31 March 2016; accepted 5 May 2016
KEYWORDS cholestatic liver disease; pruritus; quality of life
A systematic assessment of literature was done to estimate the impact of pruritus on healthrelated quality of life among patients with cholestatic liver disease (CLD). All the articles were reviewed manually for study design, population, outcomes, and study quality. A qualitative approach was used to analyze and extract data from included studies. A total of eight studies were retrieved, of which one was a cohort study and the other seven were cross-sectional studies. Overall, it appears that the incidence of pruritus was a common complication reported by most of the studies. Among patients with CLD incidence of pruritus was 29%. Pruritus was found to have a substantial impact on patients’ health-related quality of life. Greater health-related quality of life impairment was observed with increased severity of pruritus. Pruritus was found to have a significant association (p < 0.05) in quality-of-life instrument domains such as role limitationephysical, role limitationeemotional, bodily pain, vitality, energy, and physical mobility. Evidence suggests that pruritus has a substantial impact on health-related quality of life among patients with CLD. More research is required to support the evidence. Copyright ª 2016, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).
Introduction
Conflict of interest: The authors have no conflicts of interest relevant to this article. * Corresponding author. School of Pharmacy, Monash University, Bandar Sunway, 45700, Selangor, Malaysia. E-mail address: [email protected] (T.M. Khan).
Pruritus is defined as an irritating and unpleasant sensation that provokes the desire to scratch.1 Despite being a common symptom in many dermatological conditions, pruritus can also be caused by systemic diseases such as cancer, chronic renal failure, cholestasis, hyperthyroidism, diabetes mellitus, and iron-deficiency anemia (hematologic).1 Pruritus is a common symptom in patients with cholestatic
http://dx.doi.org/10.1016/j.jfma.2016.05.006 0929-6646/Copyright ª 2016, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
690 liver disease (CLD) such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC).2 Among the patients with liver diseases, 80e100% with cholestasis suffer from chronic pruritus.3 Often pruritus is refractory and it has shown substantial negative impact on health-related quality of life (HRQL) by impairing both physical and mental health. Pruritus can also be the sole indication for orthotopic liver transplantation even though hepatic decompensation is absent. Quality of life (QOL) is a patient-reported measure comprised of physical well-being, emotional well-being, and social functioning. It reflects on the perception of an individual regarding their health status. HRQL focuses on the effects of a disease on every dimension of an individual’s life including physical, social, psychological, emotional, and cognitive functioning.4 HRQL assessment has become a key component in the evaluation of therapeutic intervention. Patients are more attentive to morbidity and quality than longevity, especially those with chronic illnesses. The goal of intervention is also mainly centralized in maintaining community-living and symptomfree patients.5 There are only limited data available regarding the impact of pruritus on HRQL among patients with CLD. No study has ever specifically assessed the relationship between pruritus and HRQL among these patients. Most of the studies focused only on the impact of general symptoms, such as fatigue and muscle cramps that are closely associated with CLD, on HRQL. Besides, previous findings on the incidence and severity of pruritus in CLD are scarce. Pruritus only receives minor attention from both patients and doctors because it is often not considered to be a condition worth assessing or treating.6 Pruritus is also not visible and it is hard to identify the intensity of pruritus based on symptoms. Thus, a systematic review is appealing to provide information regarding the impact of pruritus on quality of life in order to fulfill the gap of knowledge in the community. In addition, this review regarding the epidemiology of pruritus as a whole may also reveal a massive burden of disease in the community. In this systematic review, we reviewed both randomized controlled trials and observational studies that assessed QOL among patients suffering from liver disease induced pruritus, particularly in CLD (PBC and PSC). Patient HRQL was compared with those of a healthy population in order to indicate the extent of impairment in HRQL.
Method Literature search To identify studies that evaluate the HRQL among patients suffering from CLD induced pruritus, online journal articles indexed were searched in the following databases PubMed, CINAHL plus, Cochrane library, Medline, Embase, and Scopus. The search was done from inception of databases till 31st August 2015. Research articles published in English language were considered for further assessment. Titles and abstracts were searched by using OR and AND Boolean to combine free texts and MeSH terms including “quality of life” or “life quality” and pruritus or pruritic or pruritis or
X.Y. Jin, T.M. Khan itch* and cholestasis or cholestases or cholangitis or cholangitides or cirrhosis or cirrhosis (Table 1). The references of retrieved articles were reviewed for other articles that may be relevant to the research aim in order to complement the search. All titles and abstracts were screened for relevance and full texts were obtained if appropriate.
Study selection An article was included in our systematic review if it met each of the following criteria: (1) the study assesses the QOL among patients with CLDs, including PBC or PSC; (2) impact of pruritus or itch on QOL must be assessed and sufficient data must be provided in the study; (3) the study was reported in an original article; and (4) the study design was a randomized controlled trial, cross-sectional study, or cohort study.
Data extraction and quality assessment Abstracts with relevant content were selected for full texts review. Data were extracted using standardized data collection forms onto a Microsoft Excel spreadsheet. The form included title, year of publication, journal title, objective, study design, study population, number of respondents, method, summary of findings, and study limitations. The methodological quality of each article selected was assessed by using quality assessment tool devised by National Institutes of Health.7 This is a standard quality checklist that specifically tailored to assess the quality of observational cohort and cross-sectional studies.7 For each item, a similar grading scale was applied (yes Z U Z 1 and no Z ✗ Z 0). If the criteria were not applicable to the study, NA is indicated and the item rated as 1. If the criteria were not reported in the study, NR was indicated and the item rated as 0. All areas were summed and the quality of the included studies were rated as good (total > 10), fair (5 < total < 11), or poor (total < 6).
Results Study selection and characteristics From the literature search of electronic database, 633 studies were identified. Two additional studies were found from other sources. After removal of duplications, 217 articles remained. There were 94 full-text articles selected based on title and abstract, following by assessment for
Table 1
Number of records found in each database.
Databases
Number of records
PubMed CINAHL plus Cochrane Library Medline Embase Scopus
55 13 1 93 203 268
QOL in cholestatic liver disease-induced pruritus
691
eligibility. Only eight studies were included in our systematic review. A flow diagram is presented in Figure 1. Included studies were published over a period of 17 years, from 1999 to 2015. Of the studies that met our research criteria, seven were cross-sectional study and one was a cohort study. Our review included a total of 1548 participants who suffered from PBC or PSC or both.2,5,8e13 Of the eight eligible studies, one study investigated the QOL before and after liver transplantation among patients with CLD.8 Another study assessed the impact of fatigue in QOL among patients with PBC.9 Although these two studies had titles that appear irrelevant to our research aim, data regarding the impact of pruritus on QOL were reported. The remaining six studies were included as they investigated the impact of pruritus on QOL among patients with CLD, which perfectly fulfilled our inclusion criteria.2,5,10e13 The study details are shown in Table 2.
HRQL instruments
Identification
In our systematic review, there were six different HRQL instruments were used in the eight studies (Table 3). Among them, two were generic, two were PBC-specific, and two were liver disease-specific. The most frequently used HRQL tools were SF-36. Five out of the eight studies used SF-36 to measure HRQL.2,5,10,11,13 Two studies used Chronic Liver Disease Questionnaire (CLDQ), two used Nottingham Health Profile Questionnaire (NHPQ), two used National Institute of
Records identified through database search (n = 633)
Diabetes and Digestive and Kidney DiseaseseQuality of Life: Adults, and one study used both PBC-40 and PBC-27 to measure HRQL among the patients.2,5,8e12 Three studies used both generic and disease-specific HRQL tools to assess HRQL.2,10,11 All the HRQL assessment tools are reliable and validated for assessing HRQL in patients with CLD except for PBC-40 and PBC-27.14e20 Raszeja et al11 was the first study to evaluate the reliability of PBC-40 and PBC-27 in assessing HRQL among PSC patients. This study concluded that both questionnaires could be of future use for HRQL assessment in PSC patients. Nevertheless, they must be used with caution by taking into consideration of different characteristics between PSC and PBC.11 Details of HRQL instruments are shown in Table 3.
HRQL among cholestatic patients Six of the studies reported greater HRQL impairment in patients with CLD compared to healthy controls.2,5,8,10e12 Comparison of HRQL between patients with CLD and a normal population was not reported by Stanca et al9 or Gotthardt et al.13 This was because the main focus of Stanca et al9 was on the correlation between liver disease symptoms and QOL, and Gotthardt et al13 identifies the factors associated with QOL in patients with PSC. Gotthardt et al stated that comparable high values for SF-36 indicating good HRQL in PSC patients.13 However, the validity of this statement is questionable as there is no comparison
Additional records identified through other sources (n = 2)
Screening
Records after duplicates removed (n = 217)
Records screened (n = 217)
Eligibility
Full-text articles assessed for eligibility (n = 94)
Included
Studies included in qualitative synthesis (n = 8)
Records excluded (n = 123)
Full-text articles excluded, with reasons (n = 86) Review, case report, conference paper, letter: 77 Other language: 1 Insufficient data: 4 No full texts: 2 Unfulfilled inclusion criteria: 2
Studies included in quantitative synthesis (meta-analysis) (n = 0)
Figure 1
PRISMA flow diagram of study selection.
692
Table 2
Characteristics of included studies. Objective
Gross, 19998
Describe the Crosshealth sectional status and study QOL in patients with CLD before and after liver transplantation.
Younossi, 20002
Measure HRQL in patients with chronic CLD. Determine factors associated with more severe impairment.
CrossPatients with diagnosis sectional of study PBC or PSC. Exclusion criteria: other major active medical or psychiatric disorder requiring treatment; malignancy; liver transplantation; unable to consent. n Z 104 (75 PBC; 29 PSC)
Marchesini, 20015
Study QOL in patients
CrossPatients with sectional cirrhosis from
Study design
Study population Intervention group
Comparison group
HRQL measures (method)
Patients who received liver transplantations for PBC or PSC between April 1990 and January 1995 at Baylor University Medical Center or Mayo Clinic. n Z 157 (95 Mayo; 62 BUMC)
NIDDK LTD-QOL Comparison of QOL was made in between patients with PBC or PSC before and 1 y after liver transplantation. Healthy SF-36, CLDQ individuals Patient’s (n Z 52); same HRQL was period from compared 2 primary care with healthy physicians at population, Cleveland Clinic patients Foundation. with Patients with congestive variety of heart failure, progressive COPD and chronic diabetes. conditions.
Normal population
SF-36, NHPQ
Summary of findings
Study limitations
No significant differences of QOL between patients with PBC and PSC. The 3 most bothersome symptoms before LT were fatigue, sleeplessness and skin itching. Pruritus showed the greatest improvement after LT, from moderate distress to almost not at all.
History of encephalopathy was found more common in nonrespondent which may impair the QOL of patients. In addition, in depth information on health status and QOL is not obtainable. Moreover, the bilirubin level was significantly higher, this may have adversely affected their QOL before LT.
PBC: For both SF-36 and CLDQ, PBC patients had greater HRQL impairment compared to healthy population. Increased severity, increased HRQL impairment (CLDQ and PCS in SF-36; not MCS). PSC: More HRQL impairment than healthy population (in all aspects). PSC did not show gradual decline in HRQL with disease severity. PSC had less impairment compared to other chronic conditions. No significant difference between PSC and PBC HRQL. Cholestatic patients had less impairment in physical health but more impairment in mental health compared to other chronic conditions. Patients with pruritus had more HRQL impairment. All domains of HRQL (except pain) were altered in cirrhosis.
Small sample size. Limit ability to further describe the relationship between progression of CLD and HRQL. (CLDQ shows no difference on progression and HRQL). Selection bias: inclusion of more symptomatic and advanced patients.
Bias when checking questionnaires
X.Y. Jin, T.M. Khan
First author, yearref
study
3 centers. Exclusion criteria: overt encephalopathy, preventing correct filling of questionnaires, proven or suspected hepatocellular carcinoma. n Z 544
randomly selected via registry offices (independent of health status). Adjustment of questionnaires was made to represent normal Italian population.
HRQL data of patients was compared with age and gender adjusted values of 2 random samples of Italian population (> 2000 participants).
Individualize the impact of PBC on QOL. Identify the associations between NHP scores and main characteristic of PBC.
CrossUnselected sectional patients with study PBC regardless of the duration or severity of the disease. Exclusion criteria: presence of associated disorders threatening life expectancy, previous liver transplantation, inclusion on waiting list for liver transplantation. n Z 276
Subjects randomly selected from a large prospective cohort (n Z 173), in which only workers younger than 65 y were included. Volunteers over age 65 y (n Z 103) are either nonaffected relatives of PBC patients or relatives of medical staff.
NHPQ
and further instruction given to complete missing items. Higher rate of missing data was expected and observed (potential representative bias). Unselected population, comorbidities may lead to poor perceived health status.
Clinical relevance of the results of NHP could not be compared with other generic QOL instruments as SF-36 French version was not available when the study was done. Some PBC and controls could also have other comorbid conditions such as diabetes, arthritis, and heart diseases, which may lead to poor perceived health status.
(continued on next page)
693
In SF-36, all domains scored significantly lower in cirrhosis. Largest differences: role-limitation physical, general health, emotional. Bodily pain was minimally affected. Same for NHP; largest difference: energy, physical mobility; pain no difference. Younger patients (< 55 y) showed more marked impairment especially in physical health, not in mental health. Muscle cramps were the factors most closely associated with poor health status perception. Self-rating of disease progression was associated with ascites and pruritus. PBC patients showed a strong statistically significant difference in worse scores for energy and emotional reactions compared to controls. Social isolation was also affected to a lesser extent. A worse overall QOL, expressed as the percentage of positive answers, was associated with pruritus, jaundice, fatigue, splenomegaly, and osteopenia. Fatigue was the finding most often associated with the subscores dimensions. There was no finding on impact of pruritus on QOL but the energy subscore was diminished with pruritus when the impact of pruritus was tested independently on each domain.
QOL in cholestatic liver disease-induced pruritus
Poupon, 200412
with cirrhosis and factors associated with a poor perceived health status.
694
Table 2 (continued ) First author, yearref
Objective
Stanca, 20059
Examines the extent of fatigue and its effect on quality of life in US PBC patients.
Benito de Valle, 201210
Study design
Study population Intervention group
Summary of findings
Study limitations
Nonliver disease controls (n Z 21). Women aged 27e77 y.
NIDDK-QA
From the 70 patients, fatigue was reported by 50 patients, depression by 34 and pruritus by 31. FIS and QOL scores in those with or without fatigue and depression significant difference, but not in those with or without pruritus. Neither FIS nor QOL scores correlate with age.
Not mentioned.
General population
SF-36, CLDQ
PSC patients had significant lower scores in all SF-36 domains, except the physical functioning and bodily pain. Patients who underwent liver transplant showed no difference to controls, except general health. Age showed negative impact on SF-36 PCS; positive impact on MCS. Serum alkaline phosphatase showed negative impacts in all SF-36 domains. Large duct PSC showed lower SF-36 vitality and MCS.
Clinical data were obtained retrospectively after scrutinizing medical records. Previous studies have reported impaired quality of life among patients with IBD. 79% of PSC patients had concomitant IBD in this cohort. Possibility of IBD confounding the results cannot be excluded.
Comparison group
X.Y. Jin, T.M. Khan
CrossPatients with sectional antimitochondrial study antibody positive PBC were recruited within the Division of Liver Diseases at the Mount Sinai School of Medicine, New York. Exclusion criteria: history of ascites, spontaneous bacterial peritonitis, variceal bleeding or encephalopathy. n Z 70 Evaluate HRQL Cohort All patients and its study with PSC potential residing in determinants Vastra Gotaland, in 2 Sweden and populationin Oxfordshire, based cohorts England. of patients Exclusion with PSC. criteria: patients Study the whose prevalence of permanent fatigue among address was these patients. not within the chosen places, unable to understand Swedish
HRQL measures (method)
Gotthardt, 201413
Identify Crossfactors sectional associated with study QOL in patients with PSC.
Not mentioned.
SF-36
Caucasians with PSC who received their medical care in this institution. Mean age: 36 12 y. Exclusion criteria: other
53 matched healthy controls
SF-36, PBC-40, PBC-27
Method for patient selection was not clear as there was no description regarding exclusion criteria and missing patients. Patients with other severe comorbidities may lead to more impaired QOL. There was no comparison group established in this study.
Not mentioned.
(continued on next page)
695
Evaluate the CrossRaszejasectional Wyszomirska, applicability of PBC-40 study 201511 and PBC-27 to PSC patients for HRQL assessment by comparing to generic
Patients with confirmed PSC treated in endoscopy facility/unit/ department at University Hospital of Heidelberg, Germany during 2008e2009 were recruited. Exclusion criteria: Patients who had undergone liver transplantation. n Z 113
CLDQ appeared similar to SF-36. Fatigue and psychological distress showed no difference between patients and controls. Pruritus was identified as an independent predictor of SF-36 bodily pain and role functioning domains. General systemic symptoms and pruritus are more related to reduction of HRQL compared to disease severity. Older age was associated with reduced physical function in SF-36. Women appeared to have lower score for all items in SF-36 compared to men, where statistically significant differences were observed in physical function and role limitations because of emotional problems. QOL decreased with increased pruritus intensity in terms of physical and social functioning, general and mental health, bodily pain, vitality, and roles. Patients with pruritus also had significantly higher PHQ-9 (depression) scores depending on severity. SF-36: Most SF-36 domains were significantly lower in PSCs than controls. Physical Functioning and Mental Component Summary scores were significantly lower in female patients and correlated negatively with age but not with concurrent inflammatory bowel disease.
QOL in cholestatic liver disease-induced pruritus
and English. n Z 182
696
Table 2 (continued ) First author, yearref
Objective
SF-36. To systematically evaluate the impact of PSC on patients’ HRQL.
Study design
Study population Intervention group severe comorbidities which could influence HRQL such as malignancy, decompensated diabetes mellitus, renal impairment (dialysis), heart failure NYHA II, rheumatoid arthritis or pulmonary disease. n Z 102 (73 males; 29 females)
Comparison group
HRQL measures (method)
Summary of findings
Study limitations
Cirrhosis was associated with lower Physical Functioning, Role Physical, General Health, Vitality and Physical Component Summary. PBC-40 and PBC-27: Both tools showed similar HRQL impairment scoring. Fatigue and cognitive were impaired in female patients. Several correlations existed between HRQL and laboratory parameters, including cholestatic tests and itch. Cirrhosis correlated with Other symptoms and Fatigue PBC-40. PBC-40 vs. PBC-27: Strong correlations among most domains of both questionnaires were seen, as well as between SF-36 and PBC-40 or SF-36 and PBC-27.
CLD Z cholestatic liver disease; CLDQ Z Chronic Liver Disease Questionnaire; COPD Z chronic obstructive pulmonary disease; FIS Z Fisk Fatigue Impact score; HRQL Z health-related quality of life; HRQL Z health-related quality of life; IBD Z inflammatory bowel disease; LT Z liver transplant; MCS Z mental component summary; NHPQ Z Nottingham Health Profile Questionnaires; NIDDK LTD-QOL / NIDDK-QA Z National Institute of Diabetes and Digestive and Kidney Disease Liver Transplant Database e Quality of Life: Adults; NYHA II Z New York Heart Association class II; PBC Z primary biliary cirrhosis; PBC-27 Z primary biliary cirrhosis-27; PBC-40 Z primary biliary cirrhosis-40; PCS Z physical component summary; PHQ9 Z patient health questionnaire; PSC Z primary sclerosing cholangitis; QOL Z quality of life; SF-36 Z Short Form-36.
X.Y. Jin, T.M. Khan
QOL in cholestatic liver disease-induced pruritus group available to show the extent of HRQL impairment from baseline HRQL. Two studies showed that there was no significant difference in HRQL between PSC and PBC patients.2,8 Four studies also showed that HRQL among patients with CLD were further affected by worsening disease severity.2,5,10,11
697
Quality assessment In terms of study quality, only one study was rated as good quality and the remaining seven studies were rated as fair,2,5,8e13 although they met either nine or 10 quality criteria. This indicates that they were close to good quality. Overall, the quality of the findings that contributed to this study is fair (Table 4).
Incidence and severity of pruritus among cholestatic patients
Discussion
Five of the studies2,5,9,10,12 revealed the number of patients who disclosed pruritus as one of the disease characteristics of CLD. There were 336 out of 1153 (29%) patients with CLD found to have pruritus in the five studies.2,5,9,10,12 Two studies showed that HRQL impairment was greater in patients with pruritus compared to patients without pruritus.2,13 Five studies reported that patients with pruritus had significant association with some domains in different HRQL assessment tools used in the studies.5,10e13
This is the first systematic review to assess the impact of pruritus on HRQL among patients with CLD. Although pruritus is a frequent symptom in liver disease, surprisingly few studies have investigated the incidence and severity of pruritus in CLD, as well as the impact of pruritus on HRQL among the patients. HRQL assessment tools used to assess the impact of pruritus also lack uniformity and transparency. The findings of this review suggest that the frequency of pruritus is high among the patients with CLD. Although the
Table 3
HRQL instruments used in eligible studies.
Instrument
Type
Goals
Domains/subscales
National Institute of Diabetes and Digestive and Kidney Diseases-Quality of Life: Adults (NIDDK-QA) Short Form-36 (SF-36)
Liver disease-specific
Assess the impact of liver disease on quality of life from the patients’ perspective.
4 domains: liver disease symptoms, physical functioning, health satisfaction and overall well-being.16
Generic
Assess health functioning; often used as a general measure of HRQL
Chronic Liver Disease Questionnaire (CLDQ)
Liver disease-specific
Nottingham Health Profile Questionnaire (NHPQ)
Generic
Assess the HRQL of patients with liver diseases. Measure patients’ perceived emotional, social and physical health problems (present distress).
Primary Biliary Cirrhosis-40 (PBC-40)
Primary biliary cirrhosis-specific
Primary Biliary Cirrhosis-27 (PBC-27)
Primary biliary cirrhosis-specific
8 subscales: physical functioning, vitality, social functioning, general health, bodily pain, physical role, emotional role and mental health. 2 component summary scales: physical and mental component summary scales (PCS and MCS).13,15 6 domains: fatigue, emotional function, worry, activity, abdominal symptoms and systemic symptoms.17 Part I: 6 domains including energy, sleep, pain, emotional reactions, social isolation, physical mobility. Part II: effects of disease on relevant daily activities: occupation, jobs around the home, social life, home life, sex life, hobbies and holidays.18 6 domains: cognitive, itch, fatigue, social, emotional and other symptoms (5-point scale).19 7 domains: symptoms, dryness, itch, fatigue, cognitive, emotional and social.20
Assess the impact of PBC on patient’s well being Simplified version of PBC-40. Assess the impact of PBC on patient’s well being
698 Table 4
X.Y. Jin, T.M. Khan Quality assessment for included studies by using quality assessment tool devised by National Institute of Health (NIH). Studies (first author, yearref)
Criteria
1. Was the research question or objective in this paper clearly stated? 2. Was the study population clearly specified and defined? 3. Was the participation rate of eligible persons at least 50%? 4. Were all the participants selected or recruited from the same or similar populations (including the same time period)? Were inclusion and exclusion criteria for being in the study prespecified and applied uniformly to all participants? 5. Was a sample size justification, power description, or variance and effect estimates provided? 6. For the analyses in this paper, were the exposure(s) of interest measured prior to the outcome(s) being measured? 7. Was the timeframe sufficient so that one could reasonably expect to see an association between exposure and outcome if it existed?
Gross, Younossi, 19998 20002
Marchesini, 20015
Poupon, 200412
Stanca, 20059
Benito de Gotthardt, Valle, 201210 201413
RaszejaWyszomirska, 201511
U
U
U
U
U
U
U
U
U
✗ (location not reported)
✗ (location not reported)
✗ (time period not reported)
U
U
✗ (time period not reported)
U
NR
U
✗ (location and time period not reported) NR
NR
✗
U
NR
U
U (for U (for U (for U (for U (for U (for U (for intervention intervention intervention intervention intervention intervention intervention group only) group only) group only) group only) group only) group only) group only)
✗
✗
✗
✗
✗
✗
✗
✗
U
U
U
U
U
U
U
U
U
✗
✗
✗
✗
✗
✗
✗
QOL in cholestatic liver disease-induced pruritus
699
Table 4 (continued ) Studies (first author, yearref)
Criteria
8. For exposures that can vary in amount or level, did the study examine different levels of the exposure as related to the outcome (e.g., categories of exposure, or exposure measured as continuous variable)? 9. Were the exposure measures (independent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? 10. Was the exposure(s) assessed more than once over time? 11. Were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? 12. Were the outcome assessors blinded to the exposure status of participants? 13. Was loss to follow-up after baseline 20% or less? 14. Were key potential confounding variables
Gross, Younossi, 19998 20002
Marchesini, 20015
Poupon, 200412
Stanca, 20059
Benito de Gotthardt, Valle, 201210 201413
RaszejaWyszomirska, 201511
NA
NA
NA
NA
NA
NA
NA
U
U (for U (for U (for U (for U (for U (for U (for intervention intervention intervention intervention intervention intervention intervention group only) group only) group only) group only) group only) group only) group only)
✗
✗
✗
✗
✗
✗
✗
✗
U
U
U
U
U
U
U
U
NA
NA
NA
NA
NA
NA
NA
NA
✗ (73%)
NA
NA
NA
NA
NA
NA
NA
U
U
U
U
U
U
U
U
NA
(continued on next page)
700
X.Y. Jin, T.M. Khan
Table 4 (continued ) Studies (first author, yearref)
Criteria Gross, Younossi, 19998 20002 measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)? Quality rating (good, Good fair, poor)
Fair
Marchesini, 20015
Poupon, 200412
Stanca, 20059
Benito de Gotthardt, Valle, 201210 201413
RaszejaWyszomirska, 201511
Fair
Fair
Fair
Fair
Fair
frequency of pruritus may not appear substantially high, the impacts of pruritus on HRQL among the patients cannot be neglected. Gross et al stated that pruritus was one of the most bothersome symptoms experienced by patients with CLD before liver transplantation.8 This may imply that patients with CLD often experience skin itching to a degree that it has critically affect their daily lives. Relatively few studies have investigated the incidence of pruritus as the reviewed studies focused mainly on HRQL among patients with CLD. Thus, the incidence of pruritus among the patients may be underestimated from the results observed. Greater HRQL impairment was found with increased severity of pruritus among patients with CLD. Younossi et al2 and Gotthardt et al13 were the only studies that assessed the relationship between severity of pruritus and HRQL among patients with CLD. Patients with CLD were classified into four subgroups: no pruritus (), mild pruritus (þ), moderate pruritus (þþ) and severe pruritus (þþþ). Result had shown that HRQL impairment was greater in patients with pruritus compared to patients without pruritus. All the domains in both SF-36 and CLDQ declined with increased severity of pruritus. Rishe et al,21 a study that was not included in the review, found that “itch was described as a sensation of bugs crawling and a deep itch, which, at times, was relentless and made those with this sensation want to tear their skin off or scratch until they bled.” This suggests that patients with CLD perceive pruritus as a severe and irritating symptom. The reasons for not including Rishe et al were that it is a clinical report and it does not utilize any validated QOL assessment tool to measure HRQL of the patients. However, the questionnaires generated by the author allowed PBC patients to describe their experiences of living with itch. This study was able to reflect the true feeling of patients on how they perceived itch in their lives as well as support the findings of this review.21 In terms of the impact of pruritus on HRQL, several studies have shown that pruritus is significantly correlates with certain domains in different QOL instruments. In Marchesini et al,5 patients with pruritus were found to have significant association with role limitationephysical, bodily pain, general health, vitality, and role limitationeemotional domains in SF-36. However, significant association
Fair
between pruritus and NHPQ domains were shown in energy, sleep, and physical mobility subscores.5 In Benito De Valle et al, pruritus was identified as an independent predictor of SF-36 bodily pain and role functioning domains.10 RaszejaWyszomirska et al also reported that itch domains in PBC40 and PBC-27 significantly correlate with vitality, social functioning, and role limitationeemotional domains in SF36.11 In Gotthardt et al, the presence of pruritus was significantly associated with several domains in SF-36 such as impairment in physical functioning, general health, vitality, mental health, bodily pain, and role limitations because of physical health.13 Patients with pruritus also had significantly higher PHQ-9 scores, indicating that degree of depression increased with increased pruritus intensity or frequency.13 There was no significant impact of pruritus on HRQL found by Poupon et al,12 who, nevertheless, found that the energy subscore in NHPQ was significantly diminished by the presence of pruritus when each domain was independently tested.12 Stanca et al is the only study that showed no significant difference of HRQL between patients with pruritus and patients without pruritus.9 This may be due to small sample size which is unable to detect the significant effects of pruritus on HRQL; further, data were not shown in the study.9 To summarize, pruritus was described as an independent predictor of impaired HRQL in patients with CLD, as well as a more important determinants of HRQL than markers of liver disease severity.2,5,10,13 Pruritus also appears to have substantial impact on patients’ physical health (role limitationephysical, physical mobility, energy), vitality, body pain, and mental health (role limitationeemotional). Other than CLDs, high incidence of pruritus is also seen in other diseases such as hematologic disease, end-stage renal disease and HIV.22e24 Studies have found that systemic etiology was observed in 30% to 40% of patients with pruritus and absence of itching dermatosis.25e27 Although frequency of pruritus in patients with CLD is lower than other systemic disease, not unexpectedly, presence of pruritus has made the HRQL worse, regardless of any underlying systemic disease the patient may have. Moreover, the results of Kini et al show that there is no significant difference between the impact of pruritus and chronic pain on HRQL.28 Unlike pruritus, chronic pain is a famous topic
QOL in cholestatic liver disease-induced pruritus among healthcare researchers that has been well studied consistently for centuries. The findings from Kini et al support that pruritus has a great impact on patients’ QOL, given that the extent of the QOL impacts of chronic pain and pruritus are the same.28 Therefore, pruritus should be deemed equally important as pain in order to obtain better understanding in terms of disease complexity and development of novel treatments through conducting more research. In contrast to CLD, higher incidence and prevalence of pruritus were found in dermatological conditions such as psoriasis and atopic dermatitis.29e32 Undeniably, there is more research into the impact of pruritus on HRQL among patients with dermatological diseases compared to systemic diseases. Impact of pruritus was found to be more pronounced among patients with skin disease as most of the studies utilized skin-specific instruments to assess patients’ HRQL.29e32 Skin-specific instruments provide more comprehensive assessment of characteristics and severity of pruritus among the patients compared to generic instruments.4 In psoriasis patients, pruritus intensity was found to have significant correlations with patients’ QOL, feeling of stigmatization, mental distress and depressive symptoms.30,31,33 Moreover, pruritus also showed negative impacts on mood, concentration, work ability, sleep, and appetite.29,31,34 Results regarding the impact of pruritus on QOL among patients with psoriasis are similar to the results of the review, especially in terms of mental health impairment (role limitationeemotional domains in SF-36). Among these, stigmatization plays a very important role in affecting emotional wellness of patients. Generally, social stigma is not common in pruritus, as pruritus is a subjective invisible sensation. Increases in stigmatization may be explained by scratching behavior induced by itching which will then draw attention from other people.31,35 Patients’ feelings of shame and guilt increase when they are constantly stared at by other people.35 Excessive scratching may also lead to unpleasant skin appearance such as bleeding and excoriations, which results in increased stigmatization, as well as increased risk of infection.35 Increased stigmatization will compromise patients’ selfesteem, which in turns lead to poor working performance, social withdrawal behavior, and interpersonal relationship impairment. Altunay et al also found that pruritus had comparable negative effects with psoriasis on HRQL.35 This shows that pruritus is capable of inducing both self-stigma and social stigma, even though it is not a visible skin condition. However, treatment options for pruritus appeared to be lack of consistency and effectivity.21,35 According to the participants in Rishe et al’s study, their physicians did not commence any treatments or management for their itch even though they reported that the itch was very troublesome.21 Thus, it is ultimately important to arouse awareness among physicians and researchers in order to formulate consistent and effective therapeutic guidelines for pruritus management. Several limitations must be considered. This review may have missed some relevant papers published in non-English journals. The overall level of evidence among the included studies is low.36 Only observational cohort and crosssectional studies were recruited in the review. Nevertheless, quality of every included study was assessed to
701 minimize potential risk of bias. Besides, most of the studies used very small sample sizes and none of the studies reported effect sizes. Other unreported comorbidities and life controversies in both patients and healthy population may also lead to poor perceived health status, which in turn exaggerates the impact of pruritus on HRQL. Furthermore, data available from the included studies are limited. Data regarding incidence of pruritus and correlation between pruritus and HRQL were not documented well in several studies as most focused mainly on HRQL of patients with CLD. Moreover, all the eight studies used different tools to assess the QOL among the selected patients. Therefore, it will be challenging to quantify the overall effect of pruritus on QOL due to heterogenicity among the results. Therefore, to avoid the chance of heterogenicity, the results are only summarized and no quantitative analysis is performed. Future research is encouraged to focus on assessing impact of pruritus on HRQL and epidemiology of pruritus among patients with CLD. To measure HRQL of the patients, skin-specific instruments, such as Dermatology Life Quality Index and Skindex, can be used in order to study the characteristics and severity of pruritus extensively.37e39 Development of more transparent and consistent pruritusspecific instruments for HRQL measures would also appear as a useful area for upcoming research. Studies with larger scales and sample sizes regarding impact of pruritus on HRQL among patients with CLD alongside with longitudinal follow-up studies are required in order to support the existing data further.
Conclusion In conclusion, HRQL among patients with CLD is significantly impaired by pruritus. Pruritus is a common chronic condition that was found in 29% of patients with CLD. Although pruritus was found to be less common among patients with CLD, data available on assessing the prevalence of pruritus were scarce and insufficient. Thus, more high-quality research and studies are required to provide more reliable data regarding the burden of pruritus among patients with CLD. Among healthcare providers, pruritus should be treated as important as the other symptoms in chronic liver diseases as it can also be a sole indication for end-stage liver disease.2,40 Physicians should also be more aware of pruritic symptoms when treating patients with CLD as scratching may impair patients’ QOL and lead to other medical complications such as secondary infection.
Acknowledgements The authors would like to thank Mr Tengku Mohd Suhaimi Raja Abdullah, for assistance in literature search and the document delivery librarian from Library and Learning Commons, Monash University Malaysia. In addition, we are grateful for Ms. Wenli’s assistance in compiling the EndNote file for the paper.
702
References 1. Butler DF. Pruritus and Systemic Disease. 2014 [cited August 21, 2015]; Available from:http://emedicine.medscape.com/ article/1098029-overview#showall. 2. Younossi ZM, Kiwi ML, Boparai N, Price LL, Guyatt G. Cholestatic liver diseases and health-related quality of life. Am J Gastroenterol 2000;95:497e502. 3. Bergasa NV, Mehlman JK, Jones EA. Pruritus and fatigue in primary biliary cirrhosis. Baillieres Best Pract Res Clin Gastroenterol 2000;14:643e55. 4. Leader B, Carr C, Chen S. Pruritus epidemiology and quality of life. In: Cowan A, Yosipovitch G, editors. Pharmacology of itch. Heidelberg: Springer Berlin; 2015. p. 15e38. 5. Marchesini G, Bianchi G, Amodio P, Salerno F, Merli M, Panella C, et al. Factors associated with poor health-related quality of life of patients with cirrhosis. Gastroenterology 2001;120:170e8. 6. Elke W, Uwe M. Epidemiology of itch. In: Itch. Boca Raton: CRC Press; 2014. p. 9e18. 7. Quality Assessment Tool for Observational Cohort and CrossSectional Studies. 2014 Mar [cited 2015 Oct 01]; Available from: https://www.nhlbi.nih.gov/health-pro/guidelines/indevelop/cardiovascular-risk-reduction/tools/cohort. 8. Gross CR, Malinchoc M, Kim WR, Evans RW, Wiesner RH, Petz JL, et al. Quality of life before and after liver transplantation for cholestatic liver disease. Hepatology 1999;29:356e64. 9. Stanca CM, Bach N, Krause C, Tandon N, Freni MA, Gutierrez JA, et al. Evaluation of fatigue in U.S. patients with primary biliary cirrhosis. Am J Gastroenterol 2005;100:1104e9. 10. Benito de Valle M, Rahman M, Lindkvist B, Bjo ¨rnsson E, Chapman R, Kalaitzakis E. Factors that reduce health-related quality of life in patients with primary sclerosing cholangitis. Clin Gastroenterol Hepatol 2012;10. 769e75.e2. 11. Raszeja-Wyszomirska J, Wunsch E, Krawczyk M, Rigopoulou EI, Bogdanos D, Milkiewicz P. Prospective evaluation of PBCspecific health-related quality of life questionnaires in patients with primary sclerosing cholangitis. Liver Int 2015;35: 1764e71. 12. Poupon RE, Chre ´tien Y, Chazouille `res O, Poupon R, Chwalow J. Quality of life in patients with primary biliary cirrhosis. Hepatology 2004;40:489e94. 13. Gotthardt DN, Rupp C, Bruhin M, Schellberg D, Weiss KH, Stefan R, et al. Pruritus is associated with severely impaired quality of life in patients with primary sclerosing cholangitis. Eur J Gastroenterol Hepatol 2014;26:1374e9. 14. Jay CL, Butt Z, Ladner DP, Skaro AI, Abecassis MM. A review of quality of life instruments used in liver transplantation. J Hepatol 2009;51:949e59. 15. A1 Mutebi, Brazier JE, Walters SJ. A comparison of the discriminative and evaluative properties of the SF-36 and the SF-6D index. Qual Life Res 2011;20:1477e86. 16. Kim WR, Lindor KD, Malinchoc M, Petz JL, Jorgensen R, Dickson ER. Reliability and validity of the NIDDK-QA instrument in the assessment of quality of life in ambulatory patients with cholestatic liver disease. Hepatology 2000;32:924e9. 17. Younossi ZM, Guyatt G, Kiwi M, Boparai N, King D. Development of a disease specific questionnaire to measure health related quality of life in patients with chronic liver disease. Gut 1999; 45:295e300. 18. Jenkinson C, Fitzpatrick R, Argyle M. The Nottingham health profile: An analysis of its sensitivity in differentiating illness groups. Soc Sci Med 1988;7:1411e4. 19. Jacoby A, Rannard A, Buck D, Bhala N, Newton JL, James OF, et al. Development, validation, and evaluation of the PBC-40, a disease specific health related quality of life measure for primary biliary cirrhosis. Gut 2005;54:1622e9.
X.Y. Jin, T.M. Khan 20. Montali L, Tanaka A, Riva P, Takahashi H, Cocchi C, Ueno Y, et al. A short version of a HRQoL questionnaire for Italian and Japanese patients with primary biliary cirrhosis. Dig Liver Dis 2010;42:718e23. 21. Rishe E, Azarm A, Bergasa NV. Itch in primary biliary cirrhosis: a patients’ perspective. Acta Derm Venereol 2008;88:34e7. 22. Zucker I, Yosipovitch G, David M, Gafter U, Boner G. Prevalence and characterization of uremic pruritus in patients undergoing hemodialysis: uremic pruritus is still a major problem for patients with end-stage renal disease. J Am Acad Dermatol 2003;49:842e6. 23. Saini KS, Patnaik MM, Tefferi A. Polycythemia vera-associated pruritus and its management. Eur J Clin Invest 2010;40:828e34. 24. Pruritus in HIV-infected patients in the era of highly active antiretroviral therapy. J Am Acad Dermatol 2009;60(3, Supplement 1):AB119. 25. Kantor GR, Lookingbill DP. Generalized pruritus and systemic disease. J Am Acad Dermatol 1983;9:375e82. 26. Weisshaar E, Apfelbacher C, Ja ¨ger G, Zimmermann E, Bruckner T, Diepgen TL, et al. Pruritus as a leading symptom: clinical characteristics and quality of life in German and Ugandan patients. Br J Dermatol 2006;155:957e64. 27. Y1 Afifi, Aubin F, Puzenat E, Degouy A, Aubrion D, Hassam B, et al. Pruritus sine materia: a prospective study of 95 patients. Rev Med Interne 2004;25:490e3 [Article in French]. 28. Kini SP, DeLong LK, Veledar E, McKenzie-Brown AM, Schaufele M, Chen SC. The impact of pruritus on quality of life: the skin equivalent of pain. Arch Dermatol 2011;147:1153e6. 29. Yosipovitch G, Goon A, Wee J, Chan YH, Goh CL. The prevalence and clinical characteristics of pruritus among patients with extensive psoriasis. Br J Dermatol 2000;143:969e73. 30. Hrehoro ´w E, Salomon J, Matusiak L, Reich A, Szepietowski JC. Patients with psoriasis feel stigmatized. Acta Derm Venereol 2012;92:67e72. 31. Reich A, Hrehoro ´w E, Szepietowski JC. Pruritus is an important factor negatively influencing the well-being of psoriatic patients. Acta Derm Venereol 2010;90:257e63. 32. Weber MB, Fontes Neto Pde T, Prati C, Soirefman M, Mazzotti NG, Barzenski B, et al. Improvement of pruritus and quality of life of children with atopic dermatitis and their families after joining support groups. J Eur Acad Dermatol Venereol 2008;22:992e7. 33. Halvorsen JA, Dalgard F, Thoresen M, Thoresen M, Bjertness E, Lien L. Itch and mental distress: a cross-sectional study among late adolescents. Acta Derm Venereol 2009;89:39e44. 34. Amatya B, Wennersten G, Nordlind K. Patients’ perspective of pruritus in chronic plaque psoriasis: a questionnaire-based study. J Eur Acad Dermatol Venereol 2008;22:822e6. 35. Altunay IK, Atis G, Esen K, Kucukunal A. Impact of functional pruritus compared with mild psoriasis on quality of life: a cross-sectional questionnaire study in Turkey. Am J Clin Dermatol 2014;15:365e70. 36. Burns PB, Rohrich RJ, Chung KC. The levels of evidence and their role in evidence-based medicine. Plast Reconstr Surg 2011;128:305e10. 37. Abeni D, Picardi A, Pasquini P, Melchi CF, Chren MM. Further evidence of the validity and reliability of the Skindex-29: an Italian study on 2,242 dermatological outpatients. Dermatology 2002;204:43e9. 38. Chren MM, Lasek RJ, Sahay AP, Sands LP. Measurement properties of Skindex-16: a brief quality-of-life measure for patients with skin diseases. J Cutan Med Surg 2001;5:105e10. 39. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)da simple practical measure for routine clinical use. Clin Exp Dermatol 1994;19:210e6. 40. Champion RH. Generalised pruritus. Br Med J (Clin Res Ed) 1984;289:751e3.
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REVIEW ARTICLE
Quality of life among patients suffering from cholestatic liver disease-induced pruritus: A systematic review Xin Yee Jin, Tahir Mehmood Khan* School of Pharmacy, Monash University, Bandar Sunway, 45700, Selangor, Malaysia Received 7 December 2015; received in revised form 31 March 2016; accepted 5 May 2016
KEYWORDS cholestatic liver disease; pruritus; quality of life
A systematic assessment of literature was done to estimate the impact of pruritus on healthrelated quality of life among patients with cholestatic liver disease (CLD). All the articles were reviewed manually for study design, population, outcomes, and study quality. A qualitative approach was used to analyze and extract data from included studies. A total of eight studies were retrieved, of which one was a cohort study and the other seven were cross-sectional studies. Overall, it appears that the incidence of pruritus was a common complication reported by most of the studies. Among patients with CLD incidence of pruritus was 29%. Pruritus was found to have a substantial impact on patients’ health-related quality of life. Greater health-related quality of life impairment was observed with increased severity of pruritus. Pruritus was found to have a significant association (p < 0.05) in quality-of-life instrument domains such as role limitationephysical, role limitationeemotional, bodily pain, vitality, energy, and physical mobility. Evidence suggests that pruritus has a substantial impact on health-related quality of life among patients with CLD. More research is required to support the evidence. Copyright ª 2016, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).
Introduction
Conflict of interest: The authors have no conflicts of interest relevant to this article. * Corresponding author. School of Pharmacy, Monash University, Bandar Sunway, 45700, Selangor, Malaysia. E-mail address: [email protected] (T.M. Khan).
Pruritus is defined as an irritating and unpleasant sensation that provokes the desire to scratch.1 Despite being a common symptom in many dermatological conditions, pruritus can also be caused by systemic diseases such as cancer, chronic renal failure, cholestasis, hyperthyroidism, diabetes mellitus, and iron-deficiency anemia (hematologic).1 Pruritus is a common symptom in patients with cholestatic
http://dx.doi.org/10.1016/j.jfma.2016.05.006 0929-6646/Copyright ª 2016, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
690 liver disease (CLD) such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC).2 Among the patients with liver diseases, 80e100% with cholestasis suffer from chronic pruritus.3 Often pruritus is refractory and it has shown substantial negative impact on health-related quality of life (HRQL) by impairing both physical and mental health. Pruritus can also be the sole indication for orthotopic liver transplantation even though hepatic decompensation is absent. Quality of life (QOL) is a patient-reported measure comprised of physical well-being, emotional well-being, and social functioning. It reflects on the perception of an individual regarding their health status. HRQL focuses on the effects of a disease on every dimension of an individual’s life including physical, social, psychological, emotional, and cognitive functioning.4 HRQL assessment has become a key component in the evaluation of therapeutic intervention. Patients are more attentive to morbidity and quality than longevity, especially those with chronic illnesses. The goal of intervention is also mainly centralized in maintaining community-living and symptomfree patients.5 There are only limited data available regarding the impact of pruritus on HRQL among patients with CLD. No study has ever specifically assessed the relationship between pruritus and HRQL among these patients. Most of the studies focused only on the impact of general symptoms, such as fatigue and muscle cramps that are closely associated with CLD, on HRQL. Besides, previous findings on the incidence and severity of pruritus in CLD are scarce. Pruritus only receives minor attention from both patients and doctors because it is often not considered to be a condition worth assessing or treating.6 Pruritus is also not visible and it is hard to identify the intensity of pruritus based on symptoms. Thus, a systematic review is appealing to provide information regarding the impact of pruritus on quality of life in order to fulfill the gap of knowledge in the community. In addition, this review regarding the epidemiology of pruritus as a whole may also reveal a massive burden of disease in the community. In this systematic review, we reviewed both randomized controlled trials and observational studies that assessed QOL among patients suffering from liver disease induced pruritus, particularly in CLD (PBC and PSC). Patient HRQL was compared with those of a healthy population in order to indicate the extent of impairment in HRQL.
Method Literature search To identify studies that evaluate the HRQL among patients suffering from CLD induced pruritus, online journal articles indexed were searched in the following databases PubMed, CINAHL plus, Cochrane library, Medline, Embase, and Scopus. The search was done from inception of databases till 31st August 2015. Research articles published in English language were considered for further assessment. Titles and abstracts were searched by using OR and AND Boolean to combine free texts and MeSH terms including “quality of life” or “life quality” and pruritus or pruritic or pruritis or
X.Y. Jin, T.M. Khan itch* and cholestasis or cholestases or cholangitis or cholangitides or cirrhosis or cirrhosis (Table 1). The references of retrieved articles were reviewed for other articles that may be relevant to the research aim in order to complement the search. All titles and abstracts were screened for relevance and full texts were obtained if appropriate.
Study selection An article was included in our systematic review if it met each of the following criteria: (1) the study assesses the QOL among patients with CLDs, including PBC or PSC; (2) impact of pruritus or itch on QOL must be assessed and sufficient data must be provided in the study; (3) the study was reported in an original article; and (4) the study design was a randomized controlled trial, cross-sectional study, or cohort study.
Data extraction and quality assessment Abstracts with relevant content were selected for full texts review. Data were extracted using standardized data collection forms onto a Microsoft Excel spreadsheet. The form included title, year of publication, journal title, objective, study design, study population, number of respondents, method, summary of findings, and study limitations. The methodological quality of each article selected was assessed by using quality assessment tool devised by National Institutes of Health.7 This is a standard quality checklist that specifically tailored to assess the quality of observational cohort and cross-sectional studies.7 For each item, a similar grading scale was applied (yes Z U Z 1 and no Z ✗ Z 0). If the criteria were not applicable to the study, NA is indicated and the item rated as 1. If the criteria were not reported in the study, NR was indicated and the item rated as 0. All areas were summed and the quality of the included studies were rated as good (total > 10), fair (5 < total < 11), or poor (total < 6).
Results Study selection and characteristics From the literature search of electronic database, 633 studies were identified. Two additional studies were found from other sources. After removal of duplications, 217 articles remained. There were 94 full-text articles selected based on title and abstract, following by assessment for
Table 1
Number of records found in each database.
Databases
Number of records
PubMed CINAHL plus Cochrane Library Medline Embase Scopus
55 13 1 93 203 268
QOL in cholestatic liver disease-induced pruritus
691
eligibility. Only eight studies were included in our systematic review. A flow diagram is presented in Figure 1. Included studies were published over a period of 17 years, from 1999 to 2015. Of the studies that met our research criteria, seven were cross-sectional study and one was a cohort study. Our review included a total of 1548 participants who suffered from PBC or PSC or both.2,5,8e13 Of the eight eligible studies, one study investigated the QOL before and after liver transplantation among patients with CLD.8 Another study assessed the impact of fatigue in QOL among patients with PBC.9 Although these two studies had titles that appear irrelevant to our research aim, data regarding the impact of pruritus on QOL were reported. The remaining six studies were included as they investigated the impact of pruritus on QOL among patients with CLD, which perfectly fulfilled our inclusion criteria.2,5,10e13 The study details are shown in Table 2.
HRQL instruments
Identification
In our systematic review, there were six different HRQL instruments were used in the eight studies (Table 3). Among them, two were generic, two were PBC-specific, and two were liver disease-specific. The most frequently used HRQL tools were SF-36. Five out of the eight studies used SF-36 to measure HRQL.2,5,10,11,13 Two studies used Chronic Liver Disease Questionnaire (CLDQ), two used Nottingham Health Profile Questionnaire (NHPQ), two used National Institute of
Records identified through database search (n = 633)
Diabetes and Digestive and Kidney DiseaseseQuality of Life: Adults, and one study used both PBC-40 and PBC-27 to measure HRQL among the patients.2,5,8e12 Three studies used both generic and disease-specific HRQL tools to assess HRQL.2,10,11 All the HRQL assessment tools are reliable and validated for assessing HRQL in patients with CLD except for PBC-40 and PBC-27.14e20 Raszeja et al11 was the first study to evaluate the reliability of PBC-40 and PBC-27 in assessing HRQL among PSC patients. This study concluded that both questionnaires could be of future use for HRQL assessment in PSC patients. Nevertheless, they must be used with caution by taking into consideration of different characteristics between PSC and PBC.11 Details of HRQL instruments are shown in Table 3.
HRQL among cholestatic patients Six of the studies reported greater HRQL impairment in patients with CLD compared to healthy controls.2,5,8,10e12 Comparison of HRQL between patients with CLD and a normal population was not reported by Stanca et al9 or Gotthardt et al.13 This was because the main focus of Stanca et al9 was on the correlation between liver disease symptoms and QOL, and Gotthardt et al13 identifies the factors associated with QOL in patients with PSC. Gotthardt et al stated that comparable high values for SF-36 indicating good HRQL in PSC patients.13 However, the validity of this statement is questionable as there is no comparison
Additional records identified through other sources (n = 2)
Screening
Records after duplicates removed (n = 217)
Records screened (n = 217)
Eligibility
Full-text articles assessed for eligibility (n = 94)
Included
Studies included in qualitative synthesis (n = 8)
Records excluded (n = 123)
Full-text articles excluded, with reasons (n = 86) Review, case report, conference paper, letter: 77 Other language: 1 Insufficient data: 4 No full texts: 2 Unfulfilled inclusion criteria: 2
Studies included in quantitative synthesis (meta-analysis) (n = 0)
Figure 1
PRISMA flow diagram of study selection.
692
Table 2
Characteristics of included studies. Objective
Gross, 19998
Describe the Crosshealth sectional status and study QOL in patients with CLD before and after liver transplantation.
Younossi, 20002
Measure HRQL in patients with chronic CLD. Determine factors associated with more severe impairment.
CrossPatients with diagnosis sectional of study PBC or PSC. Exclusion criteria: other major active medical or psychiatric disorder requiring treatment; malignancy; liver transplantation; unable to consent. n Z 104 (75 PBC; 29 PSC)
Marchesini, 20015
Study QOL in patients
CrossPatients with sectional cirrhosis from
Study design
Study population Intervention group
Comparison group
HRQL measures (method)
Patients who received liver transplantations for PBC or PSC between April 1990 and January 1995 at Baylor University Medical Center or Mayo Clinic. n Z 157 (95 Mayo; 62 BUMC)
NIDDK LTD-QOL Comparison of QOL was made in between patients with PBC or PSC before and 1 y after liver transplantation. Healthy SF-36, CLDQ individuals Patient’s (n Z 52); same HRQL was period from compared 2 primary care with healthy physicians at population, Cleveland Clinic patients Foundation. with Patients with congestive variety of heart failure, progressive COPD and chronic diabetes. conditions.
Normal population
SF-36, NHPQ
Summary of findings
Study limitations
No significant differences of QOL between patients with PBC and PSC. The 3 most bothersome symptoms before LT were fatigue, sleeplessness and skin itching. Pruritus showed the greatest improvement after LT, from moderate distress to almost not at all.
History of encephalopathy was found more common in nonrespondent which may impair the QOL of patients. In addition, in depth information on health status and QOL is not obtainable. Moreover, the bilirubin level was significantly higher, this may have adversely affected their QOL before LT.
PBC: For both SF-36 and CLDQ, PBC patients had greater HRQL impairment compared to healthy population. Increased severity, increased HRQL impairment (CLDQ and PCS in SF-36; not MCS). PSC: More HRQL impairment than healthy population (in all aspects). PSC did not show gradual decline in HRQL with disease severity. PSC had less impairment compared to other chronic conditions. No significant difference between PSC and PBC HRQL. Cholestatic patients had less impairment in physical health but more impairment in mental health compared to other chronic conditions. Patients with pruritus had more HRQL impairment. All domains of HRQL (except pain) were altered in cirrhosis.
Small sample size. Limit ability to further describe the relationship between progression of CLD and HRQL. (CLDQ shows no difference on progression and HRQL). Selection bias: inclusion of more symptomatic and advanced patients.
Bias when checking questionnaires
X.Y. Jin, T.M. Khan
First author, yearref
study
3 centers. Exclusion criteria: overt encephalopathy, preventing correct filling of questionnaires, proven or suspected hepatocellular carcinoma. n Z 544
randomly selected via registry offices (independent of health status). Adjustment of questionnaires was made to represent normal Italian population.
HRQL data of patients was compared with age and gender adjusted values of 2 random samples of Italian population (> 2000 participants).
Individualize the impact of PBC on QOL. Identify the associations between NHP scores and main characteristic of PBC.
CrossUnselected sectional patients with study PBC regardless of the duration or severity of the disease. Exclusion criteria: presence of associated disorders threatening life expectancy, previous liver transplantation, inclusion on waiting list for liver transplantation. n Z 276
Subjects randomly selected from a large prospective cohort (n Z 173), in which only workers younger than 65 y were included. Volunteers over age 65 y (n Z 103) are either nonaffected relatives of PBC patients or relatives of medical staff.
NHPQ
and further instruction given to complete missing items. Higher rate of missing data was expected and observed (potential representative bias). Unselected population, comorbidities may lead to poor perceived health status.
Clinical relevance of the results of NHP could not be compared with other generic QOL instruments as SF-36 French version was not available when the study was done. Some PBC and controls could also have other comorbid conditions such as diabetes, arthritis, and heart diseases, which may lead to poor perceived health status.
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693
In SF-36, all domains scored significantly lower in cirrhosis. Largest differences: role-limitation physical, general health, emotional. Bodily pain was minimally affected. Same for NHP; largest difference: energy, physical mobility; pain no difference. Younger patients (< 55 y) showed more marked impairment especially in physical health, not in mental health. Muscle cramps were the factors most closely associated with poor health status perception. Self-rating of disease progression was associated with ascites and pruritus. PBC patients showed a strong statistically significant difference in worse scores for energy and emotional reactions compared to controls. Social isolation was also affected to a lesser extent. A worse overall QOL, expressed as the percentage of positive answers, was associated with pruritus, jaundice, fatigue, splenomegaly, and osteopenia. Fatigue was the finding most often associated with the subscores dimensions. There was no finding on impact of pruritus on QOL but the energy subscore was diminished with pruritus when the impact of pruritus was tested independently on each domain.
QOL in cholestatic liver disease-induced pruritus
Poupon, 200412
with cirrhosis and factors associated with a poor perceived health status.
694
Table 2 (continued ) First author, yearref
Objective
Stanca, 20059
Examines the extent of fatigue and its effect on quality of life in US PBC patients.
Benito de Valle, 201210
Study design
Study population Intervention group
Summary of findings
Study limitations
Nonliver disease controls (n Z 21). Women aged 27e77 y.
NIDDK-QA
From the 70 patients, fatigue was reported by 50 patients, depression by 34 and pruritus by 31. FIS and QOL scores in those with or without fatigue and depression significant difference, but not in those with or without pruritus. Neither FIS nor QOL scores correlate with age.
Not mentioned.
General population
SF-36, CLDQ
PSC patients had significant lower scores in all SF-36 domains, except the physical functioning and bodily pain. Patients who underwent liver transplant showed no difference to controls, except general health. Age showed negative impact on SF-36 PCS; positive impact on MCS. Serum alkaline phosphatase showed negative impacts in all SF-36 domains. Large duct PSC showed lower SF-36 vitality and MCS.
Clinical data were obtained retrospectively after scrutinizing medical records. Previous studies have reported impaired quality of life among patients with IBD. 79% of PSC patients had concomitant IBD in this cohort. Possibility of IBD confounding the results cannot be excluded.
Comparison group
X.Y. Jin, T.M. Khan
CrossPatients with sectional antimitochondrial study antibody positive PBC were recruited within the Division of Liver Diseases at the Mount Sinai School of Medicine, New York. Exclusion criteria: history of ascites, spontaneous bacterial peritonitis, variceal bleeding or encephalopathy. n Z 70 Evaluate HRQL Cohort All patients and its study with PSC potential residing in determinants Vastra Gotaland, in 2 Sweden and populationin Oxfordshire, based cohorts England. of patients Exclusion with PSC. criteria: patients Study the whose prevalence of permanent fatigue among address was these patients. not within the chosen places, unable to understand Swedish
HRQL measures (method)
Gotthardt, 201413
Identify Crossfactors sectional associated with study QOL in patients with PSC.
Not mentioned.
SF-36
Caucasians with PSC who received their medical care in this institution. Mean age: 36 12 y. Exclusion criteria: other
53 matched healthy controls
SF-36, PBC-40, PBC-27
Method for patient selection was not clear as there was no description regarding exclusion criteria and missing patients. Patients with other severe comorbidities may lead to more impaired QOL. There was no comparison group established in this study.
Not mentioned.
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695
Evaluate the CrossRaszejasectional Wyszomirska, applicability of PBC-40 study 201511 and PBC-27 to PSC patients for HRQL assessment by comparing to generic
Patients with confirmed PSC treated in endoscopy facility/unit/ department at University Hospital of Heidelberg, Germany during 2008e2009 were recruited. Exclusion criteria: Patients who had undergone liver transplantation. n Z 113
CLDQ appeared similar to SF-36. Fatigue and psychological distress showed no difference between patients and controls. Pruritus was identified as an independent predictor of SF-36 bodily pain and role functioning domains. General systemic symptoms and pruritus are more related to reduction of HRQL compared to disease severity. Older age was associated with reduced physical function in SF-36. Women appeared to have lower score for all items in SF-36 compared to men, where statistically significant differences were observed in physical function and role limitations because of emotional problems. QOL decreased with increased pruritus intensity in terms of physical and social functioning, general and mental health, bodily pain, vitality, and roles. Patients with pruritus also had significantly higher PHQ-9 (depression) scores depending on severity. SF-36: Most SF-36 domains were significantly lower in PSCs than controls. Physical Functioning and Mental Component Summary scores were significantly lower in female patients and correlated negatively with age but not with concurrent inflammatory bowel disease.
QOL in cholestatic liver disease-induced pruritus
and English. n Z 182
696
Table 2 (continued ) First author, yearref
Objective
SF-36. To systematically evaluate the impact of PSC on patients’ HRQL.
Study design
Study population Intervention group severe comorbidities which could influence HRQL such as malignancy, decompensated diabetes mellitus, renal impairment (dialysis), heart failure NYHA II, rheumatoid arthritis or pulmonary disease. n Z 102 (73 males; 29 females)
Comparison group
HRQL measures (method)
Summary of findings
Study limitations
Cirrhosis was associated with lower Physical Functioning, Role Physical, General Health, Vitality and Physical Component Summary. PBC-40 and PBC-27: Both tools showed similar HRQL impairment scoring. Fatigue and cognitive were impaired in female patients. Several correlations existed between HRQL and laboratory parameters, including cholestatic tests and itch. Cirrhosis correlated with Other symptoms and Fatigue PBC-40. PBC-40 vs. PBC-27: Strong correlations among most domains of both questionnaires were seen, as well as between SF-36 and PBC-40 or SF-36 and PBC-27.
CLD Z cholestatic liver disease; CLDQ Z Chronic Liver Disease Questionnaire; COPD Z chronic obstructive pulmonary disease; FIS Z Fisk Fatigue Impact score; HRQL Z health-related quality of life; HRQL Z health-related quality of life; IBD Z inflammatory bowel disease; LT Z liver transplant; MCS Z mental component summary; NHPQ Z Nottingham Health Profile Questionnaires; NIDDK LTD-QOL / NIDDK-QA Z National Institute of Diabetes and Digestive and Kidney Disease Liver Transplant Database e Quality of Life: Adults; NYHA II Z New York Heart Association class II; PBC Z primary biliary cirrhosis; PBC-27 Z primary biliary cirrhosis-27; PBC-40 Z primary biliary cirrhosis-40; PCS Z physical component summary; PHQ9 Z patient health questionnaire; PSC Z primary sclerosing cholangitis; QOL Z quality of life; SF-36 Z Short Form-36.
X.Y. Jin, T.M. Khan
QOL in cholestatic liver disease-induced pruritus group available to show the extent of HRQL impairment from baseline HRQL. Two studies showed that there was no significant difference in HRQL between PSC and PBC patients.2,8 Four studies also showed that HRQL among patients with CLD were further affected by worsening disease severity.2,5,10,11
697
Quality assessment In terms of study quality, only one study was rated as good quality and the remaining seven studies were rated as fair,2,5,8e13 although they met either nine or 10 quality criteria. This indicates that they were close to good quality. Overall, the quality of the findings that contributed to this study is fair (Table 4).
Incidence and severity of pruritus among cholestatic patients
Discussion
Five of the studies2,5,9,10,12 revealed the number of patients who disclosed pruritus as one of the disease characteristics of CLD. There were 336 out of 1153 (29%) patients with CLD found to have pruritus in the five studies.2,5,9,10,12 Two studies showed that HRQL impairment was greater in patients with pruritus compared to patients without pruritus.2,13 Five studies reported that patients with pruritus had significant association with some domains in different HRQL assessment tools used in the studies.5,10e13
This is the first systematic review to assess the impact of pruritus on HRQL among patients with CLD. Although pruritus is a frequent symptom in liver disease, surprisingly few studies have investigated the incidence and severity of pruritus in CLD, as well as the impact of pruritus on HRQL among the patients. HRQL assessment tools used to assess the impact of pruritus also lack uniformity and transparency. The findings of this review suggest that the frequency of pruritus is high among the patients with CLD. Although the
Table 3
HRQL instruments used in eligible studies.
Instrument
Type
Goals
Domains/subscales
National Institute of Diabetes and Digestive and Kidney Diseases-Quality of Life: Adults (NIDDK-QA) Short Form-36 (SF-36)
Liver disease-specific
Assess the impact of liver disease on quality of life from the patients’ perspective.
4 domains: liver disease symptoms, physical functioning, health satisfaction and overall well-being.16
Generic
Assess health functioning; often used as a general measure of HRQL
Chronic Liver Disease Questionnaire (CLDQ)
Liver disease-specific
Nottingham Health Profile Questionnaire (NHPQ)
Generic
Assess the HRQL of patients with liver diseases. Measure patients’ perceived emotional, social and physical health problems (present distress).
Primary Biliary Cirrhosis-40 (PBC-40)
Primary biliary cirrhosis-specific
Primary Biliary Cirrhosis-27 (PBC-27)
Primary biliary cirrhosis-specific
8 subscales: physical functioning, vitality, social functioning, general health, bodily pain, physical role, emotional role and mental health. 2 component summary scales: physical and mental component summary scales (PCS and MCS).13,15 6 domains: fatigue, emotional function, worry, activity, abdominal symptoms and systemic symptoms.17 Part I: 6 domains including energy, sleep, pain, emotional reactions, social isolation, physical mobility. Part II: effects of disease on relevant daily activities: occupation, jobs around the home, social life, home life, sex life, hobbies and holidays.18 6 domains: cognitive, itch, fatigue, social, emotional and other symptoms (5-point scale).19 7 domains: symptoms, dryness, itch, fatigue, cognitive, emotional and social.20
Assess the impact of PBC on patient’s well being Simplified version of PBC-40. Assess the impact of PBC on patient’s well being
698 Table 4
X.Y. Jin, T.M. Khan Quality assessment for included studies by using quality assessment tool devised by National Institute of Health (NIH). Studies (first author, yearref)
Criteria
1. Was the research question or objective in this paper clearly stated? 2. Was the study population clearly specified and defined? 3. Was the participation rate of eligible persons at least 50%? 4. Were all the participants selected or recruited from the same or similar populations (including the same time period)? Were inclusion and exclusion criteria for being in the study prespecified and applied uniformly to all participants? 5. Was a sample size justification, power description, or variance and effect estimates provided? 6. For the analyses in this paper, were the exposure(s) of interest measured prior to the outcome(s) being measured? 7. Was the timeframe sufficient so that one could reasonably expect to see an association between exposure and outcome if it existed?
Gross, Younossi, 19998 20002
Marchesini, 20015
Poupon, 200412
Stanca, 20059
Benito de Gotthardt, Valle, 201210 201413
RaszejaWyszomirska, 201511
U
U
U
U
U
U
U
U
U
✗ (location not reported)
✗ (location not reported)
✗ (time period not reported)
U
U
✗ (time period not reported)
U
NR
U
✗ (location and time period not reported) NR
NR
✗
U
NR
U
U (for U (for U (for U (for U (for U (for U (for intervention intervention intervention intervention intervention intervention intervention group only) group only) group only) group only) group only) group only) group only)
✗
✗
✗
✗
✗
✗
✗
✗
U
U
U
U
U
U
U
U
U
✗
✗
✗
✗
✗
✗
✗
QOL in cholestatic liver disease-induced pruritus
699
Table 4 (continued ) Studies (first author, yearref)
Criteria
8. For exposures that can vary in amount or level, did the study examine different levels of the exposure as related to the outcome (e.g., categories of exposure, or exposure measured as continuous variable)? 9. Were the exposure measures (independent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? 10. Was the exposure(s) assessed more than once over time? 11. Were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? 12. Were the outcome assessors blinded to the exposure status of participants? 13. Was loss to follow-up after baseline 20% or less? 14. Were key potential confounding variables
Gross, Younossi, 19998 20002
Marchesini, 20015
Poupon, 200412
Stanca, 20059
Benito de Gotthardt, Valle, 201210 201413
RaszejaWyszomirska, 201511
NA
NA
NA
NA
NA
NA
NA
U
U (for U (for U (for U (for U (for U (for U (for intervention intervention intervention intervention intervention intervention intervention group only) group only) group only) group only) group only) group only) group only)
✗
✗
✗
✗
✗
✗
✗
✗
U
U
U
U
U
U
U
U
NA
NA
NA
NA
NA
NA
NA
NA
✗ (73%)
NA
NA
NA
NA
NA
NA
NA
U
U
U
U
U
U
U
U
NA
(continued on next page)
700
X.Y. Jin, T.M. Khan
Table 4 (continued ) Studies (first author, yearref)
Criteria Gross, Younossi, 19998 20002 measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)? Quality rating (good, Good fair, poor)
Fair
Marchesini, 20015
Poupon, 200412
Stanca, 20059
Benito de Gotthardt, Valle, 201210 201413
RaszejaWyszomirska, 201511
Fair
Fair
Fair
Fair
Fair
frequency of pruritus may not appear substantially high, the impacts of pruritus on HRQL among the patients cannot be neglected. Gross et al stated that pruritus was one of the most bothersome symptoms experienced by patients with CLD before liver transplantation.8 This may imply that patients with CLD often experience skin itching to a degree that it has critically affect their daily lives. Relatively few studies have investigated the incidence of pruritus as the reviewed studies focused mainly on HRQL among patients with CLD. Thus, the incidence of pruritus among the patients may be underestimated from the results observed. Greater HRQL impairment was found with increased severity of pruritus among patients with CLD. Younossi et al2 and Gotthardt et al13 were the only studies that assessed the relationship between severity of pruritus and HRQL among patients with CLD. Patients with CLD were classified into four subgroups: no pruritus (), mild pruritus (þ), moderate pruritus (þþ) and severe pruritus (þþþ). Result had shown that HRQL impairment was greater in patients with pruritus compared to patients without pruritus. All the domains in both SF-36 and CLDQ declined with increased severity of pruritus. Rishe et al,21 a study that was not included in the review, found that “itch was described as a sensation of bugs crawling and a deep itch, which, at times, was relentless and made those with this sensation want to tear their skin off or scratch until they bled.” This suggests that patients with CLD perceive pruritus as a severe and irritating symptom. The reasons for not including Rishe et al were that it is a clinical report and it does not utilize any validated QOL assessment tool to measure HRQL of the patients. However, the questionnaires generated by the author allowed PBC patients to describe their experiences of living with itch. This study was able to reflect the true feeling of patients on how they perceived itch in their lives as well as support the findings of this review.21 In terms of the impact of pruritus on HRQL, several studies have shown that pruritus is significantly correlates with certain domains in different QOL instruments. In Marchesini et al,5 patients with pruritus were found to have significant association with role limitationephysical, bodily pain, general health, vitality, and role limitationeemotional domains in SF-36. However, significant association
Fair
between pruritus and NHPQ domains were shown in energy, sleep, and physical mobility subscores.5 In Benito De Valle et al, pruritus was identified as an independent predictor of SF-36 bodily pain and role functioning domains.10 RaszejaWyszomirska et al also reported that itch domains in PBC40 and PBC-27 significantly correlate with vitality, social functioning, and role limitationeemotional domains in SF36.11 In Gotthardt et al, the presence of pruritus was significantly associated with several domains in SF-36 such as impairment in physical functioning, general health, vitality, mental health, bodily pain, and role limitations because of physical health.13 Patients with pruritus also had significantly higher PHQ-9 scores, indicating that degree of depression increased with increased pruritus intensity or frequency.13 There was no significant impact of pruritus on HRQL found by Poupon et al,12 who, nevertheless, found that the energy subscore in NHPQ was significantly diminished by the presence of pruritus when each domain was independently tested.12 Stanca et al is the only study that showed no significant difference of HRQL between patients with pruritus and patients without pruritus.9 This may be due to small sample size which is unable to detect the significant effects of pruritus on HRQL; further, data were not shown in the study.9 To summarize, pruritus was described as an independent predictor of impaired HRQL in patients with CLD, as well as a more important determinants of HRQL than markers of liver disease severity.2,5,10,13 Pruritus also appears to have substantial impact on patients’ physical health (role limitationephysical, physical mobility, energy), vitality, body pain, and mental health (role limitationeemotional). Other than CLDs, high incidence of pruritus is also seen in other diseases such as hematologic disease, end-stage renal disease and HIV.22e24 Studies have found that systemic etiology was observed in 30% to 40% of patients with pruritus and absence of itching dermatosis.25e27 Although frequency of pruritus in patients with CLD is lower than other systemic disease, not unexpectedly, presence of pruritus has made the HRQL worse, regardless of any underlying systemic disease the patient may have. Moreover, the results of Kini et al show that there is no significant difference between the impact of pruritus and chronic pain on HRQL.28 Unlike pruritus, chronic pain is a famous topic
QOL in cholestatic liver disease-induced pruritus among healthcare researchers that has been well studied consistently for centuries. The findings from Kini et al support that pruritus has a great impact on patients’ QOL, given that the extent of the QOL impacts of chronic pain and pruritus are the same.28 Therefore, pruritus should be deemed equally important as pain in order to obtain better understanding in terms of disease complexity and development of novel treatments through conducting more research. In contrast to CLD, higher incidence and prevalence of pruritus were found in dermatological conditions such as psoriasis and atopic dermatitis.29e32 Undeniably, there is more research into the impact of pruritus on HRQL among patients with dermatological diseases compared to systemic diseases. Impact of pruritus was found to be more pronounced among patients with skin disease as most of the studies utilized skin-specific instruments to assess patients’ HRQL.29e32 Skin-specific instruments provide more comprehensive assessment of characteristics and severity of pruritus among the patients compared to generic instruments.4 In psoriasis patients, pruritus intensity was found to have significant correlations with patients’ QOL, feeling of stigmatization, mental distress and depressive symptoms.30,31,33 Moreover, pruritus also showed negative impacts on mood, concentration, work ability, sleep, and appetite.29,31,34 Results regarding the impact of pruritus on QOL among patients with psoriasis are similar to the results of the review, especially in terms of mental health impairment (role limitationeemotional domains in SF-36). Among these, stigmatization plays a very important role in affecting emotional wellness of patients. Generally, social stigma is not common in pruritus, as pruritus is a subjective invisible sensation. Increases in stigmatization may be explained by scratching behavior induced by itching which will then draw attention from other people.31,35 Patients’ feelings of shame and guilt increase when they are constantly stared at by other people.35 Excessive scratching may also lead to unpleasant skin appearance such as bleeding and excoriations, which results in increased stigmatization, as well as increased risk of infection.35 Increased stigmatization will compromise patients’ selfesteem, which in turns lead to poor working performance, social withdrawal behavior, and interpersonal relationship impairment. Altunay et al also found that pruritus had comparable negative effects with psoriasis on HRQL.35 This shows that pruritus is capable of inducing both self-stigma and social stigma, even though it is not a visible skin condition. However, treatment options for pruritus appeared to be lack of consistency and effectivity.21,35 According to the participants in Rishe et al’s study, their physicians did not commence any treatments or management for their itch even though they reported that the itch was very troublesome.21 Thus, it is ultimately important to arouse awareness among physicians and researchers in order to formulate consistent and effective therapeutic guidelines for pruritus management. Several limitations must be considered. This review may have missed some relevant papers published in non-English journals. The overall level of evidence among the included studies is low.36 Only observational cohort and crosssectional studies were recruited in the review. Nevertheless, quality of every included study was assessed to
701 minimize potential risk of bias. Besides, most of the studies used very small sample sizes and none of the studies reported effect sizes. Other unreported comorbidities and life controversies in both patients and healthy population may also lead to poor perceived health status, which in turn exaggerates the impact of pruritus on HRQL. Furthermore, data available from the included studies are limited. Data regarding incidence of pruritus and correlation between pruritus and HRQL were not documented well in several studies as most focused mainly on HRQL of patients with CLD. Moreover, all the eight studies used different tools to assess the QOL among the selected patients. Therefore, it will be challenging to quantify the overall effect of pruritus on QOL due to heterogenicity among the results. Therefore, to avoid the chance of heterogenicity, the results are only summarized and no quantitative analysis is performed. Future research is encouraged to focus on assessing impact of pruritus on HRQL and epidemiology of pruritus among patients with CLD. To measure HRQL of the patients, skin-specific instruments, such as Dermatology Life Quality Index and Skindex, can be used in order to study the characteristics and severity of pruritus extensively.37e39 Development of more transparent and consistent pruritusspecific instruments for HRQL measures would also appear as a useful area for upcoming research. Studies with larger scales and sample sizes regarding impact of pruritus on HRQL among patients with CLD alongside with longitudinal follow-up studies are required in order to support the existing data further.
Conclusion In conclusion, HRQL among patients with CLD is significantly impaired by pruritus. Pruritus is a common chronic condition that was found in 29% of patients with CLD. Although pruritus was found to be less common among patients with CLD, data available on assessing the prevalence of pruritus were scarce and insufficient. Thus, more high-quality research and studies are required to provide more reliable data regarding the burden of pruritus among patients with CLD. Among healthcare providers, pruritus should be treated as important as the other symptoms in chronic liver diseases as it can also be a sole indication for end-stage liver disease.2,40 Physicians should also be more aware of pruritic symptoms when treating patients with CLD as scratching may impair patients’ QOL and lead to other medical complications such as secondary infection.
Acknowledgements The authors would like to thank Mr Tengku Mohd Suhaimi Raja Abdullah, for assistance in literature search and the document delivery librarian from Library and Learning Commons, Monash University Malaysia. In addition, we are grateful for Ms. Wenli’s assistance in compiling the EndNote file for the paper.
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