1. Volume 144, Issue 3, Pages 560-569.e7 (March 2013)
Sex and Age Are Determinants of the Clinical Phenotype of Primary Biliary Cirrhosis and Response to Ursodeoxycholic Acid 
Marco Carbone, George F. Mells, Greta Pells, Muhammad F. Dawwas, Julia L. Newton, Michael A. Heneghan, James M. Neuberger, Darren B. Day, Samantha J. Ducker, Richard N. Sandford, Graeme J. Alexander, David E.J. Jones 
Gastroenterology 
Volume 144, Issue 3, Pages e7 (March 2013)
DOI: /j.gastro
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2. Figure 1
Clinical phenotypes in the UK-PBC patient cohorts. (A) Percentage of patients who have been on UDCA therapy for a minimum of 2 years at the time of enrolment in the study who met the Paris I criteria for response to UDCA, categorized according to their age at PBC diagnosis. Numbers of study subjects in each age group treated with UDCA for a minimum of two years are indicated. (B) Proportion of patients who did not meet the criteria for response to UDCA after a minimum of 2 years treatment because of the ALT/AST criterion (>2 × ULN) related to their age at diagnosis. (C) Severity of pruritus assessed using a visual analogue scale. (D) Severity of fatigue assessed using the PBC-40 fatigue domain at entry to the study in the whole study cohort (numbers of study subjects in each age group in the cohort are indicated). Younger age at presentation was associated with a significantly lower likelihood of being in a state of UDCA response, a greater likelihood that nonresponse was because they did not meet the ALT/AST response criterion, and higher average levels of itch and fatigue severity at the study time point. The clinical impact in terms of prognostic criteria and symptomatic impact appears to be increased in younger patients.
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3. Figure 2
Clinical associations of pruritus and fatigue. Relationship between (A–C) current pruritus severity assessed using a visual analogue scale (VAS) and (D–F) fatigue severity assessed using the PBC-40 fatigue domain with (A and D) alkaline phosphatase level expressed as the ratio of the individual to the upper limit of normal used in the center performing the measurement, (B and E) ALT/AST level, and (C and F) disease duration. Data are for the whole study cohort.
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4. Figure 3
Gender differences in the age-related likelihood of achieving UDCA response criteria. Proportions of male (triangles) and female (dots) patients treated with an adequate dose of UDCA for a minimum of 2 years in different presentation age groups. A weak age effect on likelihood of responding to UDCA was seen in male patients. In contrast, a strong age effect was seen for female patients with younger presenting patients significantly less likely to have met UDCA response criteria when treated for two years.
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5. Figure 4
Gender differences in the symptom profile of PBC in case-matched patients (n = 221 for both groups). (A) Fatigue severity (assessed using the PBC-40 fatigue domain). (B) autonomic symptom severity (assessed using the Orthostatic Grading Scale [OGS]). (C) daytime somnolence severity (assessed using the Epworth Sleepiness Scale [ESS]). (D) depression severity (assessed using the depression sub-scale of the Hospital Anxiety and Depression Scale [HADS-D]). Male patients experienced significantly lower levels of fatigue then female patients when matched for age and disease duration. This difference could not be accounted for by differences in daytime somnolence and depression (clinical features both associated with fatigue in PBC). In contrast, autonomic dysfunction was significantly lower in male patients. (E) Relationship between the difference in autonomic symptoms and the difference in fatigue severity for male and female patients. For matched male and female patients the differences within the subject pair for fatigue severity (the female fatigue severity score minus the score for the case-matched male patient) was directly proportional to the differences in autonomic symptoms. This finding suggests that the difference in fatigue severity between female and male patients is related directly to the difference in autonomic dysfunction.
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6. Supplementary Figure 1
Strong correlation between the age at presentation recorded in the patient records and the age at presentation self-reported by participants in the study. Based on these data, we were confident to use self-reported data for several analyses reported in the main text.
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7. Supplementary Figure 2
Duration of treatment calculated from case notes compared with the duration of treatment estimated from the self-reported age at diagnosis in the extended data patient subgroup. In this figure, the horizontal solid line indicates a calculated duration of therapy of 1 year. Points below this line represent subjects who have been taking UDCA for less than 1 year. The vertical dashed line represents an estimated duration of therapy of 1 year. Points to the right of this line represent subjects with an estimated duration of therapy longer than 1 year. Of note, there are many points that are right of the dashed vertical line but below the solid line. In these cases, the estimated duration of therapy has been overestimated and the actual duration of therapy is less than 1 year. The vertical dotted line represents an estimated duration of therapy of 2 years. There are comparatively few points to the right of the dotted line and below the solid line. For analysis of UDCA response in the whole patient cohort (for whom detailed data from the patient records are not available), we included subjects with an estimated duration of therapy of 2 or more years only.
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8. Supplementary Figure 3
Kaplan–Meier plots from time-to-event analysis in the extended data subgroup in which “failure” is defined as liver transplant (LT) for PBC; death from PBC-related liver failure, or (for surviving non-LT recipients) a serum bilirubin level of 100 μmol/L or greater. In the time-to-event analysis, the start point is the date of first presentation and the end point is the date of failure. Surviving, non-LT recipients with bilirubin levels less than 100 μmol/L were censored at the date of their most recent blood tests. The plots show survival curves for patients who met criteria for treatment response after 12 months of treatment with UDCA (blue) vs those who did not meet criteria for treatment response (red line). The Paris I criteria appear to best predict outcome. The Results box shows results from the log-rank test, confirming a significant difference in the survival curves for all criteria sets, and also confirming that Paris I criteria discriminate best between those with good or poor prognosis in our sample. Paris I criteria therefore were used for all subsequent analyses.
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9. Supplementary Figure 4
Impact of length of treatment with UDCA and likelihood of response in the whole cohort. The increase in apparent response between the 1- and 1.5-year and the 1.5- and 2-year duration groups may reflect the overestimation of duration of treatment identified in Supplementary Figure 2. There is no evidence that treatment beyond 2 years leads to any further increase in the likelihood of response.
Gastroenterology  , e7DOI: ( /j.gastro )
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