
==== Front
Clin Transl Gastroenterol
Clin Transl Gastroenterol
CLTG
CT9
Clinical and Translational Gastroenterology
2155-384X
Wolters Kluwer Philadelphia, PA

38738764
CTG-24-0039
10.14309/ctg.0000000000000709
00009
3
Article
Biliary
Validation of a Primary Biliary Cholangitis–Specific Version of Chronic Liver Disease Questionnaire: CLDQ-PBC
https://orcid.org/0000-0001-9313-577X
Younossi Zobair M. MD, MPH, FACG 12
Stepanova Maria PhD 2maria.stepanova@cldq.org

Younossi Issah MPH issah.younossi@cldq.org
2
Racila Andrei MS 2andrei.racila@cldq.org

1 Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, Virginia, USA;
2 Center for Outcomes Research in Liver Disease, Washington, District of Columbia, USA.
Correspondence: Zobair M. Younossi, MD, MPH, FACG. E-mail: zobair.younossi@cldq.org.
9 2024
13 5 2024
15 9 e130 1 2024
24 4 2024
© 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

INTRODUCTION:

Primary biliary cholangitis (PBC) is a chronic liver disease, leading to cirrhosis and impairment of patient-reported outcomes. We aimed to develop a PBC-specific version of the Chronic Liver Disease Questionnaire (CLDQ) instrument to assess health-related quality of life of patients with PBC.

METHODS:

From our Liver Database, we included patients with PBC who had CLDQ, clinicolaboratory data, and completed Short Form-36 and The Functional Assessment of Chronic Illness Therapy—Fatigue. The 29 items of CLDQ were subjected to item reduction, exploratory factor analysis, and fed into a standard instrument validation pipeline.

RESULTS:

Data were available for 108 patients with PBC: 57 ± 11 years, 7% male, 58% cirrhosis, and 24% decompensated cirrhosis (Child B and C). Of 29 CLDQ items, none met the exclusion criteria. Exploratory factor analysis (95% of variance) returned 7 factors. Based on evaluation of factor loadings and face validity, those factors yielded 7 domains (Diet, Emotion, Fatigue, Itch, Symptoms, Sleep, and Worry). Good to excellent internal consistency (Cronbach's α 0.85–0.93) was observed for 5/7 domains. For the remaining 2 domains (Diet and Itch), additional items obtained from patients, experts, and review of the literature were included. For 5 domains, known-group validity tests discriminated between patients with PBC with and without cirrhosis, advanced cirrhosis, and depression (P < 0.05 for 3–5 domains). The CLDQ-PBC domains were correlated with relevant domains of Short Form-36, CLDQ-PBC Fatigue correlated with Fatigue Scale of Functional Assessment of Chronic Illness Therapy—Fatigue (rho = +0.85), and CLDQ-PBC Worry domain negatively correlated with alkaline phosphatase (rho = −0.38, P = 0.0082).

DISCUSSION:

The CLDQ-PBC has been developed based on the original CLDQ. The new instrument has evidence for internal consistency and validity and is being fully validated using an external cohort.

KEYWORDS:

CLDQ
PBC
The Study was supported by funding from Center for Outcomes Research in Liver Disease. CLDQ and CLDQ-PBC were used in the study under permission granted by copyright holder of these instruments (LPRO LLC).NA OPEN-ACCESSTRUE
SDCT
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pmcINTRODUCTION

Primary biliary cholangitis (PBC) is a chronic immune-mediated liver disease with a prevalence of 25–40 cases per 100,000 adults and mostly affects women in their 40s–60s (1,2). The most common symptoms associated with PBC include fatigue, pruritus, sicca syndrome, and arthralgia (1–4). In fact, fatigue can affect more than half of patients with PBC (4,5). In turn, both fatigue and pruritus can have a significant negative impact on patients' health-related quality of life (HRQL) and other patient-reported outcomes (PROs) (5,6).

The HRQL is a part of PRO spectrum, which assesses the impact of a disease on patients' well-being and daily functioning. In this context, a PRO is a measurement based on what a patient reports about their health condition without any modification or interpretation by a clinician or anyone else (7). Because HRQL cannot be measured directly by observation, it must be estimated using specifically designed and validated HRQL instruments, which are generally subdivided into generic and disease-specific instruments. Using generic instruments, one may be able to compare different clinical populations such as liver disease and rheumatoid arthritis. By contrast, disease-specific instruments generally focus on impairment of HRQL associated with manifestations of a particular disease (7,8). Given that, for studies within clinical population, generic instruments may overlook or discount certain aspects of the disease and, therefore, are often not responsive or sensitive enough to capture clinically important changes in HRQL that may occur because of treatment or natural history of the disease (8–13). Because of this reason, the use of disease-specific instruments is preferred when changes in HRQL are among outcomes of interest, especially in clinical trials.

In the past 20 years, Chronic Liver Disease Questionnaire (CLDQ) has been used as a liver disease-specific HRQL instrument (14). In previous studies, CLDQ performed relatively well for subtypes of CLD including those with cholestatic liver disease (15–17). Although patients with different types of CLD share a large number of common issues affecting their HRQL, there are subtle differences between liver diseases of different etiologies. To address this, since development of the original CLDQ, a number of etiology-specific versions of CLDQ have been developed and validated, including those for patients with hepatitis C, hepatitis B (CLDQ-HBV), metabolic dysfunction-associated steatohepatitis (CLDQ-MASH), and PBC (CLDQ-PSC) (18–22). In these different versions of CLDQ, select CLD-related items from the original instrument were retained, whereas some etiology-specific items were added and irrelevant items were removed. Using this design, common items of different versions of CLDQ can be used to compare HRQL in patients with different CLD etiologies, whereas the etiology-specific items would allow assessing issues specifically related to the etiology with increased sensitivity to changes.

In this study, our aim was to validate a PBC-specific version of CLDQ (CLDQ-PBC) that can be used for clinical research and natural history of patients with PBC.

METHODS

Patient sample

We used data collected from subjects with an established diagnosis of PBC (age 18–80 years, of both genders, all ethnicities, with or without cirrhosis, and without any other potentially confounding comorbidities) who were seen in outpatient hepatology clinics. Patients' medical history along with several PRO questionnaires (the Short Form-36 version 2 [SF-36v2], the CLDQ, and the Functional Assessment of Chronic Illness—Fatigue [FACIT-F]) were available for this study. The study was designed and received IRB approval with exempt status to use historic deidentified data.

Description of the CLDQ instrument

The original CLDQ instrument includes 29 items each of which is scored on a Likert scale from 1 to 7, with higher scores indicating better health status. Its items belong to 6 nonoverlapping HRQL domains: Abdominal symptoms, Activity/energy, Emotional, Fatigue, Systemic symptoms, and Worry, which are calculated as an average of their constituent items; the total CLDQ score is an average of the 6 domains. The CLDQ has been widely used and extensively validated in both clinical trials and real-world settings since its development in 1999 (14,23–28). It also has been used as a base for developing other etiology-specific instruments such as CLDQ hepatitis C version, CLDQ-HBV, CLDQ-MASLD/MASH, and CLDQ-PSC (18–22). In this study, we aimed to validate the etiology-specific version of CLDQ for patients with PBC (CLDQ-PBC) using a similar methodology.

Selection of items for CLDQ-PBC

For identification of items that would be relevant specifically for patients with PBC, the proportions of patients with PBC who indicated that they never or rarely had a particular problem over the recall period of 2 weeks through choosing the highest scores of 6 or 7 for the respective question (worded as “none of the time” or “hardly any of the time” <have a problem/experience a symptom>) were calculated. Items that had been reported as never/rarely a problem by more than 65% of patients in the training set were removed as nonrelevant (item reduction).

Domains of CLDQ-PBC

To group the items into easily interpretable domains, exploratory factor analysis used the items that remained after the item reduction step. The number of factors was not predefined but rather determined from the proportion of variance accounted for by the factors (≥95% but <100%); items were presumed to be the most related to a factor with the greatest loading after varimax rotation. The resulting distribution of the items into domains was subjected to content validity assessment and checked for consistency with the original CLDQ. The same Likert scale ranging 1–7 was also supposed to be applied to the items of newly developed CLDQ-PBC.

Validation of the CLDQ-PBC instrument

A standard HRQL instrument validation pipeline was used for validation of CLDQ-PBC (18–22,29).

Internal consistency of CLDQ-PBC was assessed by calculation of Cronbach's α coefficients for its domains and by calculation of item-to-own-domain correlations after adjustment for overlap for all items. The distributions of the domain scores were also qualitatively evaluated for discriminatory power and skewness.

Known-group validity was assessed by evaluation of the association of CLDQ-PBC domain scores with available demographic and clinical parameters. The validation parameters were age, gender, severity of liver disease (the presence of cirrhosis and decompensated cirrhosis), and having depression as reported in medical history. The Wilcoxon nonparametric test was used to compare the CLDQ-PBC domain scores between the groups of patients listed above.

For the purpose of convergent validity assessment, correlations between domains of CLDQ-PBC and domains of SF-36 or FACIT-F were calculated; the correlations between the most related domains were expected to be the highest.

All analyses were in SAS 9.4 (SAS Institute, Cary, NC). The study was approved by the Western Institutional Review Board and was approved for a waiver of consent as all data were analyzed as deidentified data.

RESULTS

There were 108 patients with PBC used in this study: 57 ± 11 years old, 7% male, 77% enrolled in the United States, 58% with cirrhosis, 24% with advanced cirrhosis (CPT class B or C), 93% on ursodeoxycholic acid, and 23% with history of depression (Table 1).

Table 1. Demographics and clinical characteristics of patients with primary biliary cholangitis

Parameter	N (%) or mean ± SD	
N	108	
Enrolled in the United States	83 (76.9%)	
Age, yr	56.8 ± 10.8	
Age ≥55 yr	58 (55.8%)	
Male gender	8 (7.4%)	
BMI, kg/m2	27.2 ± 4.4	
Cirrhosis (CPT A–C)	60 (57.7%)	
Decompensated cirrhosis (CPT B or C)	19 (24.1%)	
On UDCA	25 (92.6%)	
History of anxiety	12 (48.0%)	
History of depression	6 (23.1%)	
Clinically overt fatigue	12 (48.0%)	
History of abdominal pain	4 (16.0%)	
Liver stiffness, kPa	15.8 ± 14.2	
ALT, U/L	57.5 ± 32.7	
AST, U/L	69.0 ± 68.7	
Platelet count, 1010/L	216.3 ± 94.0	
Total bilirubin, mg/dL	3.32 ± 5.44	
Alkaline phosphatase, U/L	289.6 ± 202.7	
Troubled by itching	44 (40.7%)	
SF-36 scores (range 0–100)		
 Physical functioning	59.6 ± 30.4	
 Role physical	44.8 ± 45.0	
 Bodily pain	60.3 ± 26.7	
 General health	45.6 ± 23.4	
 Vitality	40.8 ± 26.4	
 Social functioning	66.0 ± 31.4	
 Role emotional	57.0 ± 43.7	
 Mental health	65.1 ± 21.7	
 Physical component summary (PCS)	38.6 ± 11.8	
 Mental component summary (MCS)	44.4 ± 12.6	
FACIT-F scores (range)		
 Physical well-being (0–28)	24.1 ± 3.7	
 Emotional well-being (0–24)	17.7 ± 3.7	
 Social well-being (0–28)	20.1 ± 3.1	
 Functional well-being (0–28)	17.0 ± 3.8	
 Fatigue scale (0–52)	40.5 ± 10.2	
 Total FACIT-F (0–160)	119.4 ± 18.4	
ALT, alanine aminotransferase; AST, aspartate transferase; BMI, body mass index; CPT, Child-Pugh Turcotte; FACIT-F, Functional Assessment of Chronic Illness Therapy—Fatigue; SF-36, Short Form-36; UDCA, ursodeoxycholic acid.

Items of CLDQ-PBC

The 29 items of CLDQ were used for item reduction. As a result, none met the exclusion criteria (a problem or symptom is never or rarely experienced by at least 65% of patients with PBC) (Table 2), and therefore, all 29 items were included in the CLDQ-PBC.

Table 2. Description and factor analysis of items for the item reduction step

Item text (“How much has < this problem > bothered you over the past 2 wk?”)	Proportion with the highest possible scores (6 or 7), %	Mean (SD) item score	Factor loading	
Factor 1 (fatigue)				
 Item dealing with being tired or fatigued	22 (20.4%)	3.72 ± 1.86	0.76	
 Item dealing with feeling sleepy during the day	25 (23.6%)	4.08 ± 1.74	0.65	
 Item dealing with shortness of breath	55 (52.4%)	5.29 ± 1.68	0.61	
 Item dealing with having decreased strength	50 (46.3%)	4.60 ± 2.08	0.72	
 Item dealing with trouble lifting or carrying heavy objects	38 (35.2%)	4.02 ± 2.21	0.49	
 Item dealing with feeling a decreased level of energy	33 (30.6%)	4.11 ± 2.04	0.72	
 Item dealing with feeling drowsy	24 (22.2%)	4.11 ± 1.65	0.75	
Factor 2 (Worry)				
 Item dealing with being worried about the impact the liver disease has on the family	49 (45.4%)	4.77 ± 1.94	0.75	
 Item dealing with being worried that symptoms will develop into major problems	38 (35.2%)	4.45 ± 1.85	0.81	
 Item dealing with being worried about the condition getting worse	33 (30.6%)	4.27 ± 1.82	0.85	
 Item dealing with being worried about never feeling any better	40 (37.0%)	4.61 ± 1.84	0.72	
 Item dealing with being concerned about availability of a liver transplant	63 (58.3%)	5.41 ± 1.94	0.61	
Factor 4 (Emotional)				
 Item dealing with feeling anxious	38 (35.2%)	4.48 ± 1.68	0.60	
 Item dealing with feeling unhappy	40 (37.0%)	4.65 ± 1.46	0.70	
 Item dealing with being irritable	42 (39.3%)	4.75 ± 1.64	0.72	
 Item dealing with having mood swings	45 (41.7%)	4.94 ± 1.60	0.76	
 Item dealing with feeling depressed	46 (42.6%)	4.83 ± 1.69	0.70	
Factor 3 (Symptoms)				
 Item dealing with abdominal bloating	51 (47.2%)	4.79 ± 2.08	0.67	
 Item dealing with bodily pain	43 (40.2%)	4.68 ± 1.80	0.50	
 Item dealing with abdominal pain	64 (61.0%)	5.46 ± 1.64	0.73	
 Item dealing with feeling of abdominal discomfort	53 (49.1%)	4.95 ± 1.81	0.77	
 Item dealing with muscle cramps	53 (49.1%)	5.01 ± 1.74	0.42	
 Item dealing with dry mouth	43 (39.8%)	4.47 ± 1.96	0.49	
 Item dealing with having problems concentrating	49 (45.4%)	4.94 ± 1.73	0.42	
Factor 5 (Sleep)				
 Item dealing with having difficulty sleeping	33 (30.6%)	4.19 ± 1.83	0.76	
 Item dealing with unability to fall asleep at night	44 (40.7%)	4.58 ± 1.92	0.79	
Factor 6 (Diet)				
 Item dealing with not being able to eat as much as would like	52 (49.1%)	4.70 ± 2.23	0.59	
 Item dealing with being bothered by a limitation of the diet	53 (49.1%)	5.09 ± 1.95	0.49	
Factor 7 (Itch)				
Item dealing with being troubled by itching	44 (40.7%)	4.52 ± 1.99	0.52	
CLDQ, Chronic Liver Disease Questionnaire; PBC, primary biliary cholangitis.

Exploratory factor analysis of the 29 CLDQ-PBC items resulted in 95% of variance explained by 7 factors. Varimax rotation was used to calculate the resulting factor loadings for the items (Table 2). Three of 7 domains were found to be structured similarly to the CLDQ domains of Worry, Emotional, and Fatigue, with the exception of 2 items, which originally belonged to the CLDQ Systemic symptoms and Activity/energy domains but were found to be primarily loading onto the Fatigue factor for patients with PBC (asking about shortness of breath and trouble carrying or lifting heavy objects), and 3 items from the original CLDQ Emotional domain, which no longer belonged to the Emotional domain of CLDQ-PBC (asking about problems concentrating, difficulty sleeping at night, and being unable to fall asleep at night). In addition, all 3 items from the original CLDQ domain of Abdominal symptoms and 3 of 5 items of the CLDQ Systemic symptoms domain were found to be loading on the same factor along with one former Emotional domain item (asking about problems concentrating); that domain was named Symptoms. Two items (asking about having difficulty sleeping and being unable to fall asleep) originally from the CLDQ Emotional domain were found to be loading on the fifth factor for CLDQ-PBC; the domain was named Sleep. Another 2 items (asking about not being able to eat as much as one would like and being bothered by a limitation of one's diet) originally from the CLDQ Activity/energy domain were found to be loading on the sixth factor for CLDQ-PBC; the domain was named Diet. Finally, one item from the original CLDQ Systemic symptoms domain (asking about been troubled by itching) was loading on the seventh factor/domain, which was named Itch.

Therefore, the structure of CLDQ-PBC instrument initially included 29 items grouped into 7 domains: Diet, Emotional, Fatigue, Itch, Sleep, Systemic Symptoms, and Worry (Table 2).

Validation of CLDQ-PBC version 1

Good to excellent internal consistency was detected in 5 CLDQ-PBC domains (Emotional, Fatigue, Sleep, Symptoms, and Worry): all Cronbach's α >0.84 (Table 3). In addition, for those 5 domains, after sequential one-item exclusions, the resulting Cronbach's α did not change substantially; this indicates that the items are neither too correlated with, nor too different from other items belonging to the same domains. The item-to-own-dimension correlations for the internally consistent domains were >0.60 for 24/26 items, >0.67 for 21/26 items, and were the lowest in the Symptoms domain (Table 3). The distributions of the 5 CLDQ-PBC domain scores suggested minimal skewness toward higher values and limited ceiling effect (<20% had the highest values) (Figure 1). By contrast, internal consistency of the Diet domain was moderately good with α = 0.61 and could not be evaluated for the one-item Itch domain.

Table 3. Internal consistency of CLDQ-PBC

Domain	Cronbach's α	Item-to-own-dimension correlations	Cronbach's α with one item removed	
Diet	0.61	0.44	Not available	
Emotional	0.91	0.70 to 0.87	0.87 to 0.91	
Fatigue	0.93	0.68 to 0.89	0.91 to 0.93	
Itch	Not available	Not available	Not available	
Sleep	0.90	0.82	Not available	
Symptoms	0.85	0.43 to 0.74	0.80 to 0.85	
Worry	0.92	0.62 to 0.88	0.88 to 0.93	
CLDQ, Chronic Liver Disease Questionnaire; PBC, primary biliary cholangitis.

Figure 1. Distribution of scores for CLDQ-PBC domains. (a) Emotional, (b) Fatigue, (c) Sleep, (d) Symptoms, (e) Worry. CLDQ, Chronic Liver Disease Questionnaire; IQR, interquartile range; PBC, primary biliary cholangitis.

For the 5 consistent domains, known-group validity tests discriminated between patients with PBC with and without cirrhosis (P < 0.05 for 4 domains) or decompensation (P < 0.05 for all 5 domains) and with and without history of depression (P < 0.05 for Emotional, P < 0.10 for 3 domains) (Table 4). The highest correlated domains of SF-36 with those of CLDQ-PBC were Mental Health for Emotional (rho = +0.88), Physical Functioning and Vitality for Fatigue (both rho ≥ +0.83), Vitality and Social Functioning for Sleep (both rho ≥ +0.60), Vitality for Symptoms (rho = +0.74), and Social Functioning for Worry (rho = +0.73) (all P values <0.0001) (Table 5). Fatigue domain of CLDQ-PBC was also highly correlated with Fatigue Scale of FACIT-F (rho = +0.85) (Table 5), and Worry domain of CLDQ-PBC was negatively correlated with the level of alkaline phosphatase (rho = −0.38, P = 0.0082).

Table 4. Known groups validity and discriminatory power of CLDQ-PBC domains

Domain	Age ≥ 55 yr	Age < 55 yr	P	
N	58	46		
Emotional	4.89 ± 1.33	4.58 ± 1.45	0.27	
Fatigue	4.34 ± 1.59	4.29 ± 1.57	0.86	
Sleep	4.31 ± 1.79	4.53 ± 1.76	0.54	
Symptoms	4.94 ± 1.24	4.95 ± 1.36	0.89	
Worry	4.69 ± 1.57	4.84 ± 1.61	0.57	
Domain	Male	Female	P	
N	8	100		
Emotional	5.20 ± 1.54	4.69 ± 1.38	0.27	
Fatigue	4.52 ± 1.79	4.24 ± 1.59	0.59	
Sleep	5.00 ± 2.00	4.34 ± 1.77	0.30	
Symptoms	5.14 ± 1.57	4.88 ± 1.31	0.60	
Worry	4.75 ± 1.44	4.70 ± 1.65	0.99	
Domain	Cirrhosis	No cirrhosis	P	
N	60	44		
Emotional	4.60 ± 1.33	4.94 ± 1.46	0.16	
Fatigue	3.97 ± 1.62	4.72 ± 1.48	0.0206	
Sleep	4.09 ± 1.83	4.86 ± 1.64	0.0323	
Symptoms	4.64 ± 1.35	5.29 ± 1.23	0.0128	
Worry	4.48 ± 1.54	5.07 ± 1.68	0.0434	
Domain	Decompensated cirrhosis	No decompensated cirrhosis	P	
N	19	60		
Emotional	3.81 ± 1.19	4.98 ± 1.32	0.0013	
Fatigue	2.71 ± 1.10	4.66 ± 1.49	<0.0001	
Sleep	3.45 ± 1.76	4.74 ± 1.60	0.0060	
Symptoms	3.72 ± 1.12	5.15 ± 1.28	0.0001	
Worry	3.53 ± 1.42	5.26 ± 1.56	0.0001	
Domain	History of depression	No history of depression	P	
N	6	20		
Emotional	3.43 ± 0.90	5.40 ± 1.25	0.0041	
Fatigue	3.76 ± 1.35	5.02 ± 1.21	0.0673	
Sleep	3.58 ± 1.80	4.75 ± 1.93	0.18	
Symptoms	4.69 ± 1.11	5.57 ± 0.96	0.0719	
Worry	4.33 ± 0.87	4.63 ± 1.32	0.62	
CLDQ, Chronic Liver Disease Questionnaire; PBC, primary biliary cholangitis.

Table 5. Validity of CLDQ-PBC domains: correlations with domains of SF-36 and FACIT-F (Spearman's correlation ρ; all P < 0.05 for absolute ρ > 0.35)

SF-36 domain	Emotional	Fatigue	Sleep	Symptoms	Worry	
Physical functioning	0.60	0.83	0.52	0.67	0.67	
Role physical	0.61	0.76	0.55	0.68	0.64	
Bodily pain	0.57	0.71	0.54	0.68	0.60	
General health	0.57	0.61	0.37	0.46	0.52	
Vitality	0.69	0.85	0.60	0.74	0.64	
Social functioning	0.74	0.81	0.61	0.68	0.73	
Role emotional	0.56	0.60	0.51	0.50	0.57	
Mental health	0.88	0.63	0.53	0.51	0.64	
FACIT-F domain						
Physical well-being	0.59	0.72	−0.01	0.54	0.32	
Emotional well-being	0.74	0.40	0.11	0.70	0.73	
Social well-being	0.17	0.11	0.34	0.34	0.01	
Functional well-being	0.29	0.29	0.47	0.46	0.51	
Fatigue scale	0.55	0.85	0.25	0.61	0.25	
CLDQ, Chronic Liver Disease Questionnaire; FACIT-F, Functional Assessment of Chronic Illness Therapy—Fatigue; PBC, primary biliary cholangitis; SF-36, Short Form-36.

Given the limitation of the Itch and Diet domains of CLDQ0-PBC, 6 additional relevant items were selected from other instruments, review of the literature, and expert input. In this context, 4 additional items were added to the Itch domain and 2 items to the Diet domain. The final CLDQ-PBC v2 has 35 items in 7 domains (see Supplementary Table 1, http://links.lww.com/CTG/B124). The instrument is undergoing additional prospective validation using an external cohort.

DISCUSSION

Patients-reported outcomes and HRQL endpoints are increasingly being used in clinical trials of patients with CLD. The HRQL assessment is particularly important PRO for patients with PBC whose well-being can be negatively impacted by debilitating symptoms such as fatigue and pruritus (3–6). In fact, the impairment of HRQL caused by PBC can be severe and debilitating. In this context, drugs used for treatment of PBC should not only demonstrate efficacy using clinical endpoints but should also improve PROs including HRQL scores.

In a number of studies of PBC, generic instruments such as SF-36 or itch-specific visual analog scores have been used (30–32). Although useful to test some hypotheses, these assessments either could be too broad (SF-36) or limited to only one symptom (itch), which does not allow for assessment of other aspects of HRQL in patients with the spectrum of PBC complications. Another disease-specific PRO instrument (PBC-40) has been widely used in patients with PBC (30,33). Although its psychometric properties have been reported to be adequate (33–35), PBC-40 does not allow comparing HRQL scores to other CLD subpopulations such as primary sclerosing cholangitis (PSC), MASH, or viral hepatitis. In this context, an instrument from the CLDQ family of questionnaires, which have been used for thousands of patients with different CLDs over the past 2 decades, can provide more flexibility for comprehensive assessment of PROs in CLD patients both across and within etiologic subpopulations.

CLDQ-PBC contributes to the field of better assessment of HRQL impairment in patients with PBC. We used a standard pipeline to validate this disease-specific HRQL instrument. In contrast to some other CLD subpopulations (HBV and PSC (19,22)), patients with PBC seem to experience a substantial impairment in virtually all aspects of their HRQL and well-being that the original CLDQ covered. For this reason, at the item reduction step, we were able to retain all CLDQ items as relevant to PBC. However, the distribution of 29 items was optimally placed in 7 domains, 3 of which were similar to the original CLDQ, whereas 4 new domains were created for CLDQ-PBC. These domains are very relevant to PBC to include the domains of Sleep, Symptom, Diet, and Itch. Our factor analysis showed that 5 of 7 CLDQ-PBC domains demonstrated good to excellent internal consistency. However, the remaining 2 domains had limitations, so both domains had to be expanded with addition of relevant items from literature, patients' and experts' contributions. At the same time, the 5 internally consistent domains of CLDQ-PBC were found to discriminate well between known groups including those with or without cirrhosis and those with or without depression. Those 5 domains also showed good correlations with appropriate domains of SF-36 and FACIT-F, and there was a significant correlation of one domain with the level of alkaline phosphatase, which is an important surrogate of clinical outcomes in patients with PBC. Although CLDQ-PBC has good internal consistency, formal test–retest reproducibility is being currently performed.

The limitations of the study include the relatively small number of patients from tertiary care settings only as well as the limited number of clinical parameters, which would allow for extensive known-group validity assessments. To address these, CLDQ-PBC is being fully validated using a large global registry, which should provide better evidence for its assessment. However, the advantage of CLDQ-PBC is that it is a relatively short, easy-to-use HRQL instrument, which retains items from the original CLDQ for which very robust data are available from large numbers of CLD patients. Furthermore, because the symptom burden in PBC, to include fatigue and pruritus, has been strongly linked to the disease aggressiveness (36), the disease-specific HRQL impairment assessed by the CLDQ-PBC may contribute to evaluation of not only PROs but also clinical outcomes. In fact, approximately 50% of our patients did report significant fatigue and pruritus, which were strongly associated with more advanced liver disease. In addition to these symptoms, because multiple studies demonstrated the prognostic role of some serum autoantibodies such as anti-gp210 and anticentromere (37,38), the CLDQ-PBC in combination with an autoantibody profile can assist and improve the prognostic assessment of patients with PBC. This, in turn, might help in early identification of patients with PBC requiring a novel treatment approach to avoid liver disease progression.

In summary, we have validated an etiology-specific CLDQ, which is supposed to be used for patients with PBC. After revision of its domains to better represent the spectrum of HRQL impairment in PBC and further validation, CLDQ-PBC can become an important HRQL instrument for patients with PBC.

CONFLICTS OF INTEREST

Guarantor of the article: Zobair Younossi, MD, MPH, FACG.

Specific author contributions: Z.M.Y.: planning and conducting the study and drafting and editing the manuscript. He has approved the final draft submitted. M.S.: concept development, data analysis and interpretation, manuscript writing and editing, and has approved the final draft submitted. I.Y.: study administration and manuscript review and has approved the final draft submitted. A.R.: database administration and manuscript review and has approved the final draft submitted.

Financial support: The study was supported by funding from Center for Outcomes Research in Liver Disease. CLDQ and CLDQ-PBC were used in the study under permission granted by copyright holder of these instruments LPRO LLC.

Potential competing interests: Z.M.Y. has received research funding and/or served as consultant to Intercept, CymaBay, Boehringer Ingelheim, BMS, GSK, Novo Nordisk, Ipsen, AstraZeneca, Siemens, Madridgal, Merck, and Abbott.Study Highlights

WHAT IS KNOWN

✓ Health related quality of life (HRQL) is important for patients with PBC.

✓ A disease specific HRQL instrument is an important tool for measuring HRQL.

WHAT IS NEW HERE

✓ This study describe validation of CLDQ-PBC as an important disease specific HRQL instrument for patients with PBC.

Supplementary Material

SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/CTG/B124.
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