Cholestatic liver diseases are heterogeneous diseases that involve dysfunction of bile production or bile flow, leading to the buildup of bile acids and other substances that can damage the liver.[1] Chronic cholestasis may result in chronic inflammation, fibrosis, cirrhosis, and eventually liver failure.[2] Primary biliary cholangitis (PBC) is one of the important chronic autoimmune cholestatic diseases, which mainly occurs in middle-aged women.[3] Patients often have symptoms that are debilitating such as fatigue and itching, that can occur even if biochemical markers of liver disease are controlled.[4] Pruritus is especially problematic because it can interfere with sleep, daily activities, psychological well-being, and overall health-related quality of life.[5]

Pruritus is one of the most troublesome extrahepatic problems in cholestatic liver disease, and prevalence rates have been reported to be widely different based on the population and how it is measured.[6] About 60–70% of patients with PBC may have itching at some point in the disease.[7] In a real-world study involving 211 patients with PBC, 81% of patients had symptoms of pruritus and about 30% of patients had clinically significant symptoms.[8] Importantly, there were worse results on a number of domains of the PBC-40 questionnaire in patients with clinically significant pruritus.[7]

Ursodeoxycholic acid (UDCA) is the accepted first-line drug for PBC and is used at a dose of 13-15 mg/kg/day.[9] Its therapeutic effects are: alteration of bile composition, activation of bile flow, and protection of cholangiocytes from bile acid-mediated injury.[10] UDCA has demonstrated benefits in improving biochemical parameters and delaying disease progression, although its effects on pruritus are inconsistent.[11] In patients who have not responded biochemically or tolerate UDCA, other therapeutic strategies might be needed. In the case of PBC, a powerful Farnesoid X receptor agonist, obeticholic acid (OCA) was introduced as a second-line therapy for selected individuals.[12] OCA regulates the production and transport of bile acids, which in turn leads to better biochemical markers of cholestasis such as alkaline phosphatase.[13] However, pruritus is a recognised adverse effect of OCA treatment and may negatively influence treatment tolerability and patients' quality of life.

The role of UDCA and OCA in pharmacological treatment of PBC has been established, but their comparative associations with patient-centered outcomes need to be investigated. The present study is designed to compare the effects of ursodeoxycholic acid and obeticholic acid on pruritus severity and health-related quality of life (HRQoL) in patients with cholestatic liver disease. Specifically, it seeks to determine whether patients receiving these medications differ in the intensity of itching and its impact on daily functioning, sleep, emotional well-being, and overall quality of life. This study aims to offer clinically meaningful evidence which includes patient-reported outcomes and may contribute to the decision-making process for treatment, better symptom monitoring and more tailored approaches to management in cholestatic liver disease.

A comparative analytical cross-sectional study was conducted at the Department of Gastroenterology, Ayub Teaching Hospital, Abbottabad, Khyber Pakhtunkhwa (KPK), Pakistan. The hospital was a tertiary-care referral center and was able to recruit patients who had chronic cholestatic liver conditions and were managed by a specialist in medicine. This study was carried out from 1st December 2025 to 30th May 2026 for a period of six months. The sample size was calculated using the OpenEpi online sample size calculator under the Sample Size for a Proportion option. The anticipated prevalence of pruritus was taken as 81%, based on the previous study by Mayo et al. (2023), which reported pruritus in 170 out of 211 patients (81%) with primary biliary cholangitis.[14] A 95% confidence level and 8% absolute precision were used, and the design effect =1. The minimum sample size calculated was 93 participants. After accounting for a 10% potential non-response or incomplete-data rate, the final required sample size was increased to 104 participants. Patients were recruited using a non-probability consecutive sampling technique during the study period. Patients presenting to the gastroenterology OPD or admitted to the hospital and meeting the pre-defined eligibility criteria were consecutively evaluated. Participants were recruited until a total of 104 were reached or until the time limit for the study. Patients were divided into two groups (UDCA group and OCA group). Treatment allocation was based on the treating physician's clinical decision and was not influenced by the study investigators. Patients were aged 18 years or older and had a confirmed diagnosis of cholestatic liver disease. The patients enrolled in the study had been treated with either UDCA or OCA for at least 8 weeks. Eligible patients were those who were clinically stable, who could provide informed consent and complete the study questionnaires. There were no gender differences, so both genders were included. Acute liver failure patients and patients with end stage liver disease and liver transplantation were excluded. Other exclusion criteria included dermatological diseases, chronic kidney disease, and other non-hepatic diseases that independently contribute to pruritus. Those with acute allergic reactions, skin infections, or other recognized causes of itching were excluded. Patients receiving UDCA and OCA at the same time were also excluded, as were those who had recently changed their treatment regimen or those who could not complete the assessment questionnaires. After obtaining written informed consent, a structured data collection proforma was used to collect data. Relevant demographic and clinical information, including age, gender, body mass index, underlying liver disease, duration of illness, comorbidities, medication history, and duration of treatment, was recorded. Laboratory parameters, including serum bilirubin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and albumin, were obtained from patients' medical records or available laboratory investigations. Information regarding UDCA and OCA treatment, including prescribed dosage, duration, and concomitant medications, was also documented. Pruritus severity was assessed using the Worst Itch Numerical Rating Scale (WI-NRS), in which patients rated their worst itching intensity on a scale ranging from 0 (no itching) to 10 (worst imaginable itching).[15] The 5-D Itch Scale was also employed to evaluate the multidimensional response to itching, including its duration, intensity, direction, disability, and distribution.[16] Health-related quality of life was measured using the Chronic Liver Disease Questionnaire (CLDQ), which measured the physical, emotional, and functional impact of liver disease.[17] The higher the pruritus score, the more serious the symptoms, while quality of life scores were based on the instructions for scoring those instruments. These patient-reported assessment methods have been used in prior investigations of the symptom of itching and its effects on quality of life (QOL) associated with cholestatic itching. IBM SPSS Statistics 27 was used for the analysis of data collected. For quantitative variables, such as age, disease duration, laboratory parameters, and questionnaire scores, the mean and standard deviation or median and interquartile range were reported. Categorical variables such as gender, underlying liver disease, and treatment category were presented as frequencies and percentages. The normality of continuous variables was assessed using the Shapiro–Wilk test. The independent-samples t-test was used to compare normally distributed continuous variables between the UDCA and OCA groups, whereas the Mann–Whitney U test was applied to non-normally distributed variables. The chi-square test was used to compare differences in categorical variables as appropriate. Associations between pruritus severity and quality-of-life scores were examined using Pearson's coefficients, depending on data distribution. Multivariable linear regression analysis was performed to assess the independent association between treatment category and pruritus and quality-of-life scores after adjustment for potential confounding variables, including age, gender, disease duration, baseline disease severity, and relevant biochemical parameters. The two-sided significance value was set at <0.05.

A total of 104 patients were included in the study, comprising 72 patients receiving ursodeoxycholic acid (UDCA) and 32 receiving obeticholic acid (OCA). Demographic and clinical parameters such as age, gender distribution, BMI, underlying liver disease, and disease duration and comorbidities were similar in the two treatment groups. There were no significant differences between the groups for these baseline characteristics (p > 0.05). (Table 1)In biochemical parameters, patients with OCA had relatively low mean ALP, ALT, and AST values compared to those with UDCA; total bilirubin values were higher, and serum albumin values were slightly lower in the OCA group. The differences were not statistically significant, however (p > 0.05). (Table 2)Assessment of pruritus showed a significant difference in symptom severity between patients receiving OCA. The OCA group was found to have higher scores on the WI-NRS and 5-D Itch Scale than the UDCA group. In addition, those receiving OCA were more likely to experience moderate-to-severe itching, while UDCA recipients were more likely to experience no or mild itching. (Table 3)Health-related quality of life was assessed, and patients receiving OCA had relatively poor scores. There were lower scores on all areas of the CLDQ, especially on the systemic symptoms domain and the emotional function and overall quality of life domains. The OCA group had statistically significant differences in systemic symptoms, emotional function, and CLDQ scores, suggesting a higher burden of quality-of-life in this group. (Table 4)

The results of the correlation analysis showed strong negative relationships between the severity of pruritus and the health-related quality of life. There were negative correlations between higher WI-NRS and 5-D Itch Scale and CLDQ. There were also negative correlations with severity of itching and the Fatigue, Emotional Function, and Activity domains. (Table 5)Multivariable linear regression analysis showed that after adjusting for selected demographic and clinical factors, OCA use was independently correlated with increasing severity of pruritus. Increased duration of disease was also a significant predictor of worsening pruritus. Age, gender, cirrhosis, total bilirubin, and ALP, however, were not associated with WI-NRS scores in the adjusted model. (Table 6)

Table 1. Demographic and clinical characteristics of participants

Table 2. Biochemical and laboratory characteristics

Table 3. Comparison of pruritus severity between treatment groups

Table 4. Health-related quality-of-life scores by treatment group

Table 5. Correlation of pruritus severity with quality-of-life outcomes

Table 6. Multivariable linear regression analysis of factors associated with pruritus severity

The present study demonstrated that patients receiving obeticholic acid (OCA) had greater pruritus severity and comparatively poorer health-related quality of life than those receiving ursodeoxycholic acid (UDCA). Higher WI-NRS and 5-D Itch Scale scores were observed in the OCA group, suggesting a greater burden of itching among these patients. The results were congruent with those of Mayo et al. (2023), who found that 81% of PBC patients had pruritus, and itching in those with clinically significant itching was linked with decreased quality of life and increased fatigue.[8] In a similar claims-based analysis in the United States, Gungabissoon et al. (2022) found that patients with PBC-associated pruritus had higher rates of fatigue, depression, anxiety, and sleep complaints.[18] The results of this study show the need to measure itching as a clinically relevant parameter, and not just liver biochemical markers. The higher pruritus scores observed among OCA recipients were also consistent with evidence regarding the tolerability of this medication. Ng et al. (2023) performed a pooled analysis of 1,878 patients and found that OCA was associated with a significant increase in the risk of pruritus compared to placebo (RR 1.75; 95% CI 1.43–2.15).[19] Furthermore, De Vincentis et al. (2022), in a cohort of 100 patients with PBC and cirrhosis, reported that pruritus contributed to treatment discontinuation in 10 patients.[20] Abreu et al. (2025), conducting a systematic review and meta-analysis of 1,285 patients, found that pruritus was the most common adverse event associated with OCA, leading to a significant number of treatment interruptions.[21] These results corroborate the association between OCA use and more itchy skin that we found in the current study, but the variability in treatment choice and disease severity must be taken into account. The poorer quality-of-life scores observed among OCA recipients, particularly in systemic symptoms, emotional functioning, and overall CLDQ scores, were consistent with previous patient-reported outcome research. In the GLIMMER study of 147 PBC patients, Smith et al. (2025) reported that patients with severe pruritus had significantly lower EQ-5D-5L scores and more sleep disturbances.[22] Similarly, Levy et al. (2025) found a significantly worse quality of life in patients with moderate-to-severe pruritus than in those who did not report any pruritus or mild pruritus in the ITCH-E study.[7] Gungabissoon et al. (2024) also found that patient-reported itching was linked to lower quality of life and was significantly under-reported in routine medical records.[18] The results of the present study corroborate these observations, namely the lower emotional and systemic quality-of-life scores for patients with higher itching scores. The relationship between pruritus and impaired daily functioning was further supported by the strong inverse correlations between the severity of pruritus and quality-of-life scores. In a longitudinal cohort study of patients with chronic liver diseases, Gungabissoon et al. (2025) discovered that higher severity of pruritus was linked to poorer health-related quality of life (HRQoL), with emotional well-being, concentration and intimate relationships being most affected.[23] Likewise, the systematic review and network meta-analysis conducted by Giannini et al. (2024) showed a higher risk of new onset pruritus in OCA than in the placebo group.[24] Kowdley et al. (2024) also reported the clinical outcomes of OCA treatment in PBC, though the trial was mainly focused on clinical events related to the disease and not on patient-reported itching.[25] These studies collectively underscore the need to account for patient-centred outcomes as well as treatment tolerability when assessing second-line treatment. Finally, the multivariable analysis in the current study showed that OCA use and longer disease duration were independent factors associated with higher pruritus severity. The results should be taken with a grain of salt, as OCA is typically used in patients who have either been unresponsive or intolerant to UDCA, which may represent confounding by treatment indication. Long-term POISE extension reported by Bowlus et al. (2026) also showed pruritus as an uncommon side effect of prolonged treatment with OCA.[26] OCA has been shown to have biochemical benefits, but is a significant factor to consider during clinical management with respect to itching. In summary, the present results support the importance of assessing individual patients for treatment, frequent evaluation of itchiness, and attention to quality of life in patients with cholestatic liver disease. LIMITATIONS This study was not without limitations. First, the relatively small number of patients and the single-center nature of the study may limit the generalizability of findings to other populations. Secondly, the duration of the study (6 months) limited the assessment of long-term treatment responses and severity of itching. Third, the study was conducted as an observational study, which could not definitively determine the cause-and-effect relationship between medications and itching severity. Other factors, such as disease severity at baseline and indication for treatment, could have affected the results. In addition, relying on patient-reported questionnaires could have led to recall and reporting bias. Further multicentre prospective studies with extended follow-up are recommended to confirm these results.

The current study showed that obeticholic acid-treated patients had more severe itching and lower quality of life scores than ursodeoxycholic acid-treated patients. The severity of itching was also significantly correlated with the decline of QOL scores in the systemic and emotional domains. The severity of pruritus was independently increased with OCA use and longer disease duration. These findings emphasize that, in patients with cholestatic liver disease, biochemical and symptom burden responses should be taken into account when choosing treatment, as well as quality of life. Individualized treatment decisions and regular assessment of pruritus may help improve patient-centered care.

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