QJM Advance Access originally published online on April 8, 2005
QJM 2005 98(5):331-336; doi:10.1093/qjmed/hci058
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Review |
The natural history of asymptomatic primary biliary cirrhosis
From the 1Gastrointestinal and Liver Unit, The Prince of Wales Hospital and University of New South Wales, Sydney, Australia and 2Institute of Hepatology, University College London, London, UK
Address correspondence to A/Professor S.M. Riordan, Gastrointestinal and Liver Unit, The Prince of Wales Hospital, Barker Street, Randwick 2031, New South Wales, Australia. email: riordans{at}sesahs.nsw.gov.au
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Introduction |
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 Top Introduction PrevalenceNatural historyFactors influencing progressionSurvivalConclusionsReferences |
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Appreciation of the spectrum of clinical features of primary biliary cirrhosis (PBC) has evolved considerably over the past few decades. Although the substantial female predominance documented in early series remains true today, it has become clear that other so called ‘classical’ clinical features, such as symptoms of jaundice, pruritis and fatigue, and even biochemical markers of cholestasis, need not necessarily be present. Only a small minority of patients nowadays present with liver failure and most are even identified while asymptomatic, with up to 80% of patients in recently reported series having no PBC-related symptoms at the time of diagnosis, compared to only 4% some 30 years ago (Table 1).1–7 The diagnosis of PBC in asymptomatic patients is usually established after the chance finding of an abnormal physical sign, such as hepatomegaly, or, more often, an elevated serum alkaline phosphatase level during the course of an unrelated illness. Alternatively, patients may be diagnosed after biochemical or autoantibody, including anti-mitochondrial antibody (AMA), screening is carried out either as part of a routine health check or following the documentation of one of the many extrahepatic, predominantly autoimmune, disorders known to be associated with PBC. Crucial to the validity of diagnosing PBC on the basis of a positive AMA test in the latter circumstance is the finding that over 93% of AMA-positive yet asymptomatic patients with no biochemical evidence of cholestasis nonetheless have histological changes compatible with (or diagnostic of) PBC at liver biopsy.8
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Prevalence |
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TopIntroductionPrevalenceNatural historyFactors influencing progressionSurvivalConclusionsReferences |
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Recognition of the extended clinical spectrum of PBC has resulted in a substantial increase in its reported prevalence, at least in some areas. Far from the historical view of PBC as an uncommon condition,9 recent studies from the north-east of England and Olmstead County in the US indicate that PBC may affect up to 1:2500 people, including up to 1:1000 women aged >40 years.1,10 Reported prevalence rates in the north-east of England increased significantly during the period from the late 1980s to the mid-1990s,9,11 although whether this is a true phenomenon or a reflection of the application of more stringent case-finding methods and/or an increased general awareness of the disorder, is not clear.12 Nonetheless, substantial variability in prevalence rates in differing countries has been documented. For example, a prevalence rate of the order of 1:7000 was reported in a contemporary series from Norway,13 while a figure of approximately 1:50 000 was reported in Japan14 and Canada.15 Very few cases have been reported from the Indian subcontinent.16 To what extent these data reflect true geographical differences or rather differences in case-finding methods is currently uncertain. However, those studies which have incorporated the most rigorous case-finding strategies have, to date, generally documented the highest prevalence rates.12 A recent study using thorough case-finding methods to identify all cases of PBC in Victoria, Australia and to determine age-adjusted prevalence rates among different migrant groups found that prevalence in the three largest migrant groups (1:7000 for British migrants, 1:5000 for Italian migrants and 1:4800 for Greek migrants) was higher than that of Victoria as a whole (1:20 000). In women >40 years of age, the prevalence was approximately 1:3000 British-born immigrants compared to 1:6000 Australian-born women.17 These findings suggest that Victorians may be relatively protected from developing PBC, supporting the concept that environmental factors, as alluded to later, may be important in the aetiology of this disorder.
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Natural history |
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TopIntroductionPrevalenceNatural historyFactors influencing progressionSurvivalConclusionsReferences |
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It is well established that PBC, once symptomatic, is a progressive disorder in the majority of patients. Of considerable clinical importance, therefore, is the natural history of patients without PBC-related symptoms at diagnosis, given the increasing number of patients identified in this category. This issue is the subject of this review, which is based on a search of literature listed in Medline and PubMed databases, using ‘primary biliary cirrhosis’ as key words. Early comparative series, which were heavily weighted towards symptomatic rather than asymptomatic patients in terms of the number of enrolled patients, suggested that symptomatic PBC is generally a more advanced disorder than when detected at an asymptomatic stage. For example, Mahl et al.18 at Yale compared clinical and laboratory features at diagnosis in 243 patients with PBC-related symptoms, to those in only 36 asymptomatic PBC counterparts. The prevalences of abnormal physical signs including jaundice (59%), hyperpigmentation (42%), hepatomegaly (74%) and splenomegaly (47%) were each significantly higher in the symptomatic group than in patients without PBC-related symptoms (6%, 13%, 50% and 12%, respectively). Laboratory indices of cholestasis, including the serum bilirubin and cholesterol levels, were significantly higher in symptomatic patients, while the serum albumin concentration was significantly lower in this group, implying more advanced disease in those presenting with PBC-related symptoms. These findings are in keeping with the results of histological studies from centres in Sweden, the UK and the US, similarly biased in terms of numbers towards inclusion of symptomatic patients, which all indicated that a significantly higher proportion of symptomatic patients at diagnosis have stage III or IV disease than their asymptomatic counterparts.6,18,19 In a large population-based study of 469 initially asymptomatic patients and 301 symptomatic counterparts in the north-east of England, significantly higher serum levels of alkaline phosphatase, alanine transaminase and bilirubin were documented at diagnosis in the symptomatic group, and a significantly higher proportion of symptomatic than asymptomatic patients were cirrhotic at diagnosis (32% vs.16%, respectively).20
However, it would appear that most AMA-positive yet asymptomatic patients with normal liver biochemistry at diagnosis will develop biochemical evidence of cholestasis over time. Metcalf et al.21 in the UK followed 29 such patients for a median 17 years and found that 83% (24/29) developed cholestasis at a median 5.6 years after the first detection of a positive AMA titre. The proportion of initially asymptomatic patients that will subsequently develop PBC-related symptoms has also been investigated in series from centres in the UK, Sweden and the US.6,18,21–25 It must be stressed that these studies were retrospective in design and mostly enrolled only relatively small numbers of initially asymptomatic patients. Furthermore, a standardized definition of asymptomatic PBC is yet to be established, so the definition of symptomatic disease varied among the different authors. Within these constraints, data suggest progressive disease in a substantial proportion of initially asymptomatic patients, with between 36% and 89% of such patients becoming symptomatic during mean/median follow-up periods ranging from 4.5 to 17.8 years (Table 2). The median time from diagnosis to the development of symptoms was 2 years in a study from the north-east of England,21 and 4.2 years in a North American series.25 Notably, the onset of fatigue may pre-date the development of biochemical evidence of cholestasis, with 45% of cases in a series from the UK conforming to this trend.21 In keeping with the concept that initially asymptomatic PBC is a progressive disorder in the majority of cases, Prince et al.20 recently estimated (using Kaplan-Meier methods in a large series of 469 initially asymptomatic PBC patients followed for up to 28 years in the north-east of England) that the proportion of cases remaining asymptomatic after 5 years was 50%, and as little as 5% at 20 years.
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Factors influencing progression |
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TopIntroductionPrevalenceNatural historyFactors influencing progressionSurvivalConclusionsReferences |
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Whether the presence of various clinical and histological variables can be used to predict which patients will progress from asymptomatic to symptomatic disease over time has been the subject of considerable conjecture. A Swedish study of 56 initially asymptomatic patients suggested that the presence of hepatomegaly or advanced histological stage, but not associated autoimmune disorders, were strongly predictive of the subsequent development of PBC-related symptoms, including pruritis, jaundice, ascites, or variceal bleeding.6 In a Yale group of 37 patients with no PBC-related symptoms at diagnosis, the presence of associated autoimmune disorders was associated with decreased survival, while no other clinical or histological variable correlated with either survival or the development of PBC-related symptoms (defined as pruritis, malaise, jaundice, ascites, oedema or variceal bleeding).26 More recently, Springer et al.25 investigated 91 initially asymptomatic PBC patients in Toronto, and were unable to identify any prognostic variables that would distinguish those who would become symptomatic (including the development of pruritis, jaundice, hepatic encephalopathy, bleeding varices, oedema or ascites) from those who would remain symptom-free. In particular, neither associated autoimmune disorders, hepatomegaly nor histological stage predicted progression from asymptomatic to symptomatic disease.
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Survival |
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TopIntroductionPrevalenceNatural historyFactors influencing progressionSurvivalConclusionsReferences |
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The duration of survival in relation to the presence or absence of symptoms at diagnosis has been investigated in several studies (Table 3). In the relatively small numbers of symptomatic patients reported in the 1950s and 1960s, Foulk et al.27 and Sherlock28 reported median survival of 6 and 5 years, respectively. In 1983, Roll et al.29 at Yale reported that the estimated 10-year survival in 243 symptomatic patients was 50%, while that in 36 asymptomatic patients was >90%. Mahl et al.18 subsequently reported on an extended follow-up of the Yale patients. Symptomatic and asymptomatic patients were followed for a median time from diagnosis of 6.4 years (range 0.04–24.2 years) and 12.1 years (range 1.1–19.2 years), respectively. Despite similar ages at diagnosis, median survival in the asymptomatic group was more than twice as long as in symptomatic patients (16 years vs. 7.5 years, respectively). Springer et al.25 later reported an estimated 10-year survival of 70% in 91 initially asymptomatic patients in Toronto, while another contemporary series from the Mayo Clinic which included 46 patients, 80% of whom were asymptomatic at diagnosis, reported a 10-year survival rate of 57%.1 Several of these reports, based on only a relatively small number of patient deaths during the follow-up period, suggested that the survival of patients asymptomatic at diagnosis fell significantly below that of gender- and age-matched control groups after 6–12 years of follow-up.6,18,24,25 This was explained by the fact that a substantial proportion of patients asymptomatic at diagnosis ultimately become symptomatic, since, once this occurs, the survival rate of such patients becomes indistinguishable from that of patients who had been symptomatic from the outset.18,23,25 Median survival in the subgroup that remains persistently asymptomatic has been reported to be significantly longer than that in patients who develop symptoms, being comparable to that in healthy gender- and age-matched controls.18,25,30
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More recently, Prince et al.20 reported on the prognosis of initially asymptomatic PBC patients in their large geographically and temporally defined group in the north-east of England, a study which included 248 patient deaths compared to just 47 in all previous reports combined. The earlier observation that asymptomatic PBC carries a reduced survival compared with the general population was confirmed, with a standardized mortality ratio >2.6 times that expected. Twenty percent of initially asymptomatic patients died of liver failure or required liver transplantation during median follow-up of
7 years. Contrary to earlier reports, in smaller numbers of patients followed for a shorter period, the authors could not confirm the observation that survival is significantly better in initially asymptomatic than symptomatic patients, with comparable median survival of 9.6 years and 8.0 years, respectively, in the two groups. Similarly, symptom development did not significantly influence survival of initially asymptomatic patients when studied in a time-dependent manner. These latter observations may be at least partly explained by an excessive non-liver-related mortality rate in asymptomatic PBC patients of almost twice that expected. Whilst reasons for this excess in non-hepatic mortality in PBC patients without PBC-related symptoms remain speculative, factors such as alcohol intake and smoking habits may be important. Surveillance bias may have been at least contributory, as a substantial proportion of non-liver-related deaths occurred early after diagnosis.20 Nonetheless, a previous study of patients with PBC in this region suggested a modest yet statistically significant increase in non-hepatic malignancies, even after taking into account the effect of increased surveillance.31 |
Conclusions |
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TopIntroductionPrevalenceNatural historyFactors influencing progressionSurvivalConclusionsReferences |
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The greater recognition of asymptomatic PBC should serve to encourage liver units around the world to adopt stringent case-finding strategies, as proposed and adopted in the north-east of England,32 to better define the natural history of this disorder in larger groups than have generally been studied to date and in differing geographical locations. Comparative assessment of patient groups at various stages of disease evolution (such as those with and without cholestasis, those with and without symptoms, and those with and without liver failure) for evidence of environmental factors recently postulated to contribute to the pathogenesis of PBC, such as infection with retroviral and other microbial agents,33,34 along with any impact of anti-viral treatment,35 will further enhance current understanding of the natural history of initially asymptomatic PBC and the factors which may contribute to its progression. Rational approaches to early intervention in an attempt to prevent disease progression and improve long-term outcome need to be identified, especially if the findings from the north-east of England20 are confirmed in other centres: that virtually all initially asymptomatic PBC patients will become symptomatic if followed for long enough, and that survival of initially asymptomatic PBC patients, if untreated, is substantially reduced compared to that of the general population.
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References |
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TopIntroductionPrevalenceNatural historyFactors influencing progressionSurvivalConclusionsReferences |
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