The age and sex of the patient at the onset of primary biliary cirrhosis predict the severity of disease and the likelihood of response to treatment with ursodeoxycholic acid, Dr. Marco Carbone and his associates reported in Gastroenterology.
In what they described as the first study large enough to permit examination of meaningful numbers of patient subgroups, the researchers found that among women, older age at diagnosis correlated with a better chance of responding to UDCA and with a less severe disease phenotype. These findings are reassuring because women with primary biliary cirrhosis outnumber men by approximately 10 to 1, and most are older than 50 years at disease onset.
Source: American Gastroenterological Association
But the other side of the coin is that the minority of patients who do present at an earlier age, or are men, are more likely to have a severe disease phenotype and less likely to respond to therapy.
"Collectively our findings highlight that primary biliary cirrhosis is not a uniform disease with uniform risks and impact, but one with high- and low-risk patients," said Dr. Carbone of the department of hepatology, Cambridge (England) University Hospitals National Health Service Foundation Trust, and his associates (doi:10.1053/j.gastro.2012.12.005).
The researchers analyzed data from the United Kingdom–Primary Biliary Cirrhosis cohort, an ongoing national genetic study of the disease that enrolled patients from every hospital in the country during a recent 3-year period. This patient population represents 25% of all primary biliary cirrhosis patients in the United Kingdom.
Dr. Carbone and his colleagues assessed the records of 2,353 participants in the UK-PBC, including a subgroup of 1,379 who supplied extra detailed clinical information. The cohort included 221 men.
More than 80% of the study subjects were managed outside of specialist liver transplant centers. These patients were just as likely as were those managed at specialty centers to be offered therapy with UDCA.
Women who presented at age 50 or older were significantly more likely than were younger women or men to have less severe disease and to respond to UDCA. In particular, women aged 70 and older at presentation had a greater than 90% chance of responding.
One possible explanation for this finding is that hormones, particularly high estrogen levels, may raise resistance to treatment. "There certainly are plausible biologic mechanisms for such an endocrine effect, as female sex hormones modulate immune regulation and biliary epithelial cell turnover. Furthermore, case reports show that tamoxifen, an antiestrogen, improves liver biochemistry in primary biliary cirrhosis," the investigators said.
This finding suggests that a clinical trial of antiestrogens as adjunctive therapy should be considered for high-risk patients who don’t respond to UDCA, they noted.
Men typically presented at an older age but with more severe disease, as evidenced by their reduced platelet counts and higher frequency of splenomegaly.
"This is likely to represent delayed diagnosis resulting from the misperception that primary biliary cirrhosis is ‘a female disease,’ with the presence of features such as elevated [liver enzymes] being falsely ascribed to conditions or etiologies that are common in the male population, such as increased alcohol consumption," Dr. Carbone and his associates said.
Men were just as likely as were women to be offered UDCA therapy, but were significantly less likely to respond adequately.
Autonomic symptoms were more marked among women than men. In a substudy in which male subjects were matched with female subjects, the difference in autonomic symptoms closely correlated with differences in fatigue severity, "raising the obvious question as to whether reduction in autonomic dysfunction might reduce fatigue," the investigators said.
One possible reason that men have fewer autonomic symptoms may be that they tend to have higher underlying blood pressure than women, they added.
Overall, it appears that most patients with primary biliary cirrhosis present at an older age, have few symptoms, and respond well to UDCA – a "benign picture" that should guide planning and delivery of care.
In contrast, younger patients tend to have a more complex course, with more symptoms that interfere with daily life and a higher risk of treatment failure. "Such patients should be the focus for novel therapy to improve outcomes."
Men have a lower chance of responding to therapy, but fortunately they have a lower symptom burden and their age at disease onset doesn’t affect prognosis.
No financial conflicts were reported.