As discussed above, with wider diagnosis the recognised phenotype of PBC has changed from a universally severe disorder3,5 to a heterogeneous condition that is often asymptomatic when initially diagnosed. Six groups have subsequently reported their experience of asymptomatic PBC.9,11,13–19 These comprised between 13%16 and 70%15 of PBC patients in their case series.
Direct comparison between these series is difficult due to differences in patient populations (largely derived from tertiary referral centres and therefore possibly subject to Berkson’s bias)9,11,13–15 and varying definitions of the symptoms of PBC (and hence asymptomatic PBC). For example, Springer et al included 18 patients with persistent fatigue among 91 “asymptomatic” patients19 and Roll et al five patients with overt jaundice among 37 “asymptomatic” patients.16 Finally, these series were relatively small, ranging in size from 179 to 9119 asymptomatic patients.
This is the first report of strictly defined asymptomatic PBC in a cohort that was relatively free of selection and referral biases, and with a strict definition of the date of diagnosis. In this large group, slightly more than half (61%) of all patients were asymptomatic at the time that diagnosis was possible.
Three previous studies have compared the laboratory features at diagnosis of asymptomatic and symptomatic patients. Roll et al found that patients with asymptomatic PBC were more likely to have a lower AMA titre and less advanced histological fibrosis than symptomatic patients.16 Nyberg and Loof confirmed that asymptomatic PBC was associated with histologically less advanced disease.15 Uddenfeldt and Danielsson reported that asymptomatic patients had lower alkaline phosphatase, bilirubin, and transaminase levels.20 Our series confirmed all of these except the autoantibody differences.
Five surveys have previously reported on the survival of initially asymptomatic PBC but none of these studies accounted for the effect of prevalent cases on estimates of survival. Nyberg and Loof followed up 56 initially asymptomatic patients for a mean of 9.5 years.15 Median survival (12.7 years) was better than in symptomatic patients (8.0 years) but worse than expected for the general population, although it took 12 years for this to become statistically significant. The Yale liver unit reported the survival of 37 initially asymptomatic patients. These patients had better median survival than initially symptomatic patients (16 years v 7.5 years) but worse than the general population, which became apparent after 11 years of follow up.14,17 Balasubramaniam et al and Springer and colleagues11,19 reported that patients with asymptomatic PBC had decreased survival compared with the general population (median survival 9.5 and 14 years, respectively) although they did not compare this with survival in initially symptomatic PBC patients. In contrast, Uddenfeldt and Danielsson20 found that patients with asymptomatic PBC had similar survival to the normal population, which again was better than in symptomatic patients. However, all five studies were based on very few (all less than 18) patient deaths. (The total number of deaths in all five studies combined was just 47 compared with 248 in the present study.)
Thus until now the consensus has been that survival is better in initially asymptomatic than symptomatic patients. Our study reports survival over a longer period and with a very much larger number of patient deaths than previous series, and did not confirm this finding. We confirmed that asymptomatic PBC has a reduced survival compared with the general population (with an SMR over two and a half times as high as expected).11,13–15 We did not however find that initial symptom status affected subsequent survival, despite asymptomatic patients having lower median bilirubin and less cirrhosis on biopsy than symptomatic patients at diagnosis. Two possible reasons for this are firstly, that although the median bilirubin level was higher in symptomatic patients, relatively few patients had markedly elevated bilirubin levels. Secondly, any improvement in liver related survival in initially asymptomatic patients might have been outweighed by an excess of non-hepatic deaths, particularly in the asymptomatic group.
This is first study to examine non-liver related mortality in asymptomatic PBC. After excluding liver deaths, the mortality rate remained nearly twice that expected. There are several possible reasons for this excess. Firstly, asymptomatic PBC may have been diagnosed during investigation of unrelated conditions and the excess mortality was due to this comorbidity (surveillance bias). The excess of non-liver deaths early after diagnosis supports this possibility. Secondly, two case control studies have previously found an excess of smoking in patients with PBC24,25 and the excess mortality observed here may reflect non-hepatic smoking related adverse events. However, the rates of atheromatous disease and lung cancer, as recorded on death certificates, were broadly similar to those in the local population, suggesting that, if present, this effect is relatively small. Three previous studies have failed to find an excess of mortality due to coronary artery disease in patients with PBC.26–28 Thirdly, the excess mortality may reflect an association between PBC and other diseases. Patel et al found an excess of autoimmune disease in patients with PBC compared with their siblings and friends.25 PBC has been reported to be associated with an excess of non-hepatic malignancy.29–31 A previous study of this cohort followed for a median of 5.4 years found a small but statistically significant excess of non-hepatic cancers when the effect of increased surveillance was accounted for (standardised incidence ratio 1.7 (95% confidence limits 1.3–2.2)).32
Our study is the first to examine the effect of symptom development on patient survival in a time dependent manner. Symptom development did not significantly (p=0.34) affect patient survival. The lack of a marked effect of symptom development on survival is perhaps to be expected as, in contrast with the above studies, we did not find that survival was different in initially symptomatic and asymptomatic patients. Two previous studies suggested that initially asymptomatic disease had a better prognosis than symptomatic disease only until the development of symptoms.13,14 However, these studies reported on very small numbers of deaths in patients who developed symptoms (15 deaths and two deaths, respectively). Furthermore, they used analysis methods that did not account for the time delay between date of diagnosis and onset of symptoms.
This new perspective may also change attitudes as to when to introduce treatment for patients with asymptomatic PBC. As prognosis is broadly similar to symptomatic patients, it may be argued that, as in the case of asymptomatic systemic hypertension for example, treatment of patients with asymptomatic PBC should be started where possible at the date of diagnosis.
This is the first study to examine the time course of symptom development in initially asymptomatic patients. Previous studies have reported symptom development in 21 (60%) of 35,15 24 (67%) of 36,14 33 (36%) of 91, and 33 (89%) of 3711 initially asymptomatic patients followed for varying periods. However, none of these studies reported the time course of symptom progression. Kaplan-Meier analysis in our cohort clearly shows that the asymptomatic phase of PBC can be regarded as a temporary phenomenon. If patients survive for a long enough period, virtually all will develop one or more symptoms of PBC (95% after 20 years). However, we also found that many patients died before developing symptoms of PBC (45% of deaths occurred in patients who were still asymptomatic), reflecting the age of patients at diagnosis and variation in the progress of disease. The median age at diagnosis in this study (62 years) was 5–10 years higher than in most previous studies—perhaps reflecting referral patterns to tertiary referral centres. This greater age may also explain our higher proportion of non-liver deaths.
Only a small proportion of asymptomatic patients received therapy with UDCA prior to symptom development. The median UDCA dose (450 mg) used is now thought to be subtherapeutic,33 although it is controversial as to whether UDCA affects the prognosis of PBC.34,35 The pattern of UDCA usage may reflect the time period from which patients were drawn and varying prescribing habits among gastroenterologists in the study region.
In conclusion, 20% of initially asymptomatic patients died of liver disease or required transplantation. Furthermore, overall prognosis did not differ from patients presenting with symptoms. These findings contrast with the previous assumption that asymptomatic PBC represents a largely mild form of disease and may have profound implications in future considerations of treatment of disease.