Determinants of the Clinical Phenotype of PBC
Determinants of the Clinical Phenotype of PBC
Background, & Aims: Studies of primary biliary cirrhosis (PBC) phenotypes largely have been performed using small and selected populations. Study size has precluded investigation of important disease subgroups, such as men and young patients. We used a national patient cohort to obtain a better picture of PBC phenotypes.
Methods: We performed a cross-sectional study using the United Kingdom-PBC, patient cohort. Comprehensive data were collected for 2353 patients on diagnosis reports, response to therapy with ursodeoxycholic acid (UDCA), laboratory results, and symptom impact (assessed using the PBC-40 and other related measures).
Results: Seventy-nine percent of the patients reported current UDCA, therapy, with 80% meeting Paris response criteria. Men were significantly less likely to have responded to UDCA than women (72% vs 80% response rate; P < .05); male sex was an independent predictor of nonresponse on multivariate analysis. Age at diagnosis was associated strongly and independently with response to UDCA; response rates ranged from 90% among patients who presented with PBC when they were older than age 70, to less than 50% for those younger than age 30 (P < .0001). Patients who presented at younger ages also were significantly more likely not to respond to UDCA therapy, based on alanine aminotransferase and aspartate aminotransferase response criteria, and more likely to report fatigue and pruritus. Women had mean fatigue scores 32% higher than men's (P < .0001). The increase in fatigue severity in women was related strongly (r = 0.58; P < .0001) to higher levels of autonomic symptoms (P < .0001).
Conclusions: Among patients with PBC, response to UDCA, treatment and symptoms are related to sex and age at presentation, with the lowest response rates and highest levels of symptoms in women presenting at younger than age 50. Increased severity of fatigue in women is related to increased autonomic symptoms, making dysautonomia a plausible therapeutic target.
The autoimmune cholestatic liver disease primary biliary cirrhosis (PBC) is highly variable in terms of its impact on patients. One aspect of variability is the response to primary therapy with ursodeoxycholic acid (UDCA); a significant subgroup of patients have a suboptimal biochemical response. Increased awareness that a suboptimal response to UDCA, predicts poor outcome has driven the development of novel approaches to therapy that currently are undergoing clinical evaluation. Other studies highlight variability in the symptom phenotype of PBC. The condition affects individuals in different ways; a significant number of patients experience pruritus and fatigue, whereas others with apparently similar disease remain asymptomatic. Other aspects of PBC that have been little studied include the unusual gender distribution; most series suggest 10 affected women for every man. Whether the disease phenotype and disease implications are the same in men and women with PBC has been little studied, mainly because of the rarity of male patients and the difficulty in developing adequately powered cohorts. Those studies that have been published predate current concepts regarding disease phenotype and response to therapy.
Publications about PBC to date have typically reported small series, often of selected patients, because of the relative rarity of the disease, with a prevalence of 30 per 100,000. Much work on the UDCA response has been performed on selected subgroups followed up after the original clinical trials that showed UDCA benefit. Although valuable in understanding the response to UDCA, such approaches include an element of selection bias based on the initial recruitment to study cohorts. Studies of symptom phenotype have been criticized for their small cohort numbers and performance in specialist centers with an interest in complex phenotypes. This raises questions regarding the applicability of the findings across a broader spectrum of patients. Other studies of specific and rarer subgroups of patients, including men with PBC, have yet to be performed because of the difficulties in identifying large patient cohorts that allow adequately powered subgroup studies.
In the current study, we describe the clinical phenotype of the unique UK-PBC, patient cohort, recruited to participate in high-throughput genetic studies of PBC and definitive studies of disease impact and phenotype. This cohort, which includes patients from every hospital in the United Kingdom, represents approximately 25% of all UK PBC patients. The data derived on the demographics of PBC across the United Kingdom, the nature of response to UDCA, and the gender basis of PBC provide important insights and identify future clinical challenges. Long-term follow-up evaluation of the cohort will provide a unique opportunity to study the natural history, linking genetic susceptibility with clinical phenotype and outcome.
Abstract and Introduction
Abstract
Background, & Aims: Studies of primary biliary cirrhosis (PBC) phenotypes largely have been performed using small and selected populations. Study size has precluded investigation of important disease subgroups, such as men and young patients. We used a national patient cohort to obtain a better picture of PBC phenotypes.
Methods: We performed a cross-sectional study using the United Kingdom-PBC, patient cohort. Comprehensive data were collected for 2353 patients on diagnosis reports, response to therapy with ursodeoxycholic acid (UDCA), laboratory results, and symptom impact (assessed using the PBC-40 and other related measures).
Results: Seventy-nine percent of the patients reported current UDCA, therapy, with 80% meeting Paris response criteria. Men were significantly less likely to have responded to UDCA than women (72% vs 80% response rate; P < .05); male sex was an independent predictor of nonresponse on multivariate analysis. Age at diagnosis was associated strongly and independently with response to UDCA; response rates ranged from 90% among patients who presented with PBC when they were older than age 70, to less than 50% for those younger than age 30 (P < .0001). Patients who presented at younger ages also were significantly more likely not to respond to UDCA therapy, based on alanine aminotransferase and aspartate aminotransferase response criteria, and more likely to report fatigue and pruritus. Women had mean fatigue scores 32% higher than men's (P < .0001). The increase in fatigue severity in women was related strongly (r = 0.58; P < .0001) to higher levels of autonomic symptoms (P < .0001).
Conclusions: Among patients with PBC, response to UDCA, treatment and symptoms are related to sex and age at presentation, with the lowest response rates and highest levels of symptoms in women presenting at younger than age 50. Increased severity of fatigue in women is related to increased autonomic symptoms, making dysautonomia a plausible therapeutic target.
Introduction
The autoimmune cholestatic liver disease primary biliary cirrhosis (PBC) is highly variable in terms of its impact on patients. One aspect of variability is the response to primary therapy with ursodeoxycholic acid (UDCA); a significant subgroup of patients have a suboptimal biochemical response. Increased awareness that a suboptimal response to UDCA, predicts poor outcome has driven the development of novel approaches to therapy that currently are undergoing clinical evaluation. Other studies highlight variability in the symptom phenotype of PBC. The condition affects individuals in different ways; a significant number of patients experience pruritus and fatigue, whereas others with apparently similar disease remain asymptomatic. Other aspects of PBC that have been little studied include the unusual gender distribution; most series suggest 10 affected women for every man. Whether the disease phenotype and disease implications are the same in men and women with PBC has been little studied, mainly because of the rarity of male patients and the difficulty in developing adequately powered cohorts. Those studies that have been published predate current concepts regarding disease phenotype and response to therapy.
Publications about PBC to date have typically reported small series, often of selected patients, because of the relative rarity of the disease, with a prevalence of 30 per 100,000. Much work on the UDCA response has been performed on selected subgroups followed up after the original clinical trials that showed UDCA benefit. Although valuable in understanding the response to UDCA, such approaches include an element of selection bias based on the initial recruitment to study cohorts. Studies of symptom phenotype have been criticized for their small cohort numbers and performance in specialist centers with an interest in complex phenotypes. This raises questions regarding the applicability of the findings across a broader spectrum of patients. Other studies of specific and rarer subgroups of patients, including men with PBC, have yet to be performed because of the difficulties in identifying large patient cohorts that allow adequately powered subgroup studies.
In the current study, we describe the clinical phenotype of the unique UK-PBC, patient cohort, recruited to participate in high-throughput genetic studies of PBC and definitive studies of disease impact and phenotype. This cohort, which includes patients from every hospital in the United Kingdom, represents approximately 25% of all UK PBC patients. The data derived on the demographics of PBC across the United Kingdom, the nature of response to UDCA, and the gender basis of PBC provide important insights and identify future clinical challenges. Long-term follow-up evaluation of the cohort will provide a unique opportunity to study the natural history, linking genetic susceptibility with clinical phenotype and outcome.
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