The New Epidemiology of Primary Biliary Cirrhosis Laura Griffiths, MBChB1

Jessica K. Dyson, MBBS2

1 Institute of Cellular Medicine, Medical School, Newcastle University,

Newcastle-upon-Tyne, United Kingdom 2 Liver Unit, Freeman Hospital, Newcastle-upon-Tyne, United Kingdom

David E.J. Jones, MD, PhD1 Address for correspondence David Jones, MD, PhD, Institute of Cellular Medicine, Medical School, Framlington Place, Newcastle-uponTyne, NE2 4HH, United Kingdom (e-mail: [email protected]).



► primary biliary cirrhosis ► epidemiology

Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease. Susceptibility to PBC probably arises from a combination of genetic and environmental factors. The prevalence of PBC varies both on an international and a regional level. This can be explained, in part, by differences in clinical practice and case-finding activity. It is likely, however, that substantive geographical differences exist both in terms of genetic susceptibility and environmental factors that potentially trigger the disease in genetically susceptible individuals. The study of the epidemiology of PBC has strongly supported the concept of an environmental triggering factor, but as yet no specific agent has been identified. Ongoing work to discover the environmental agent, as well as the mechanism that causes the disease will answer key questions as to the epidemiology of this complex autoimmune disease as well as providing useful information for other autoimmune conditions.

The epidemiology of primary biliary cirrhosis (PBC) represents a story that has evolved constantly over the past 60 years. Study of the epidemiology of PBC has assisted in our understanding of the disease itself, its causes, and its population impacts. Primary biliary cirrhosis is, however, also an important exemplar for complex autoimmune disease in general, resulting in part from of its simple, accurate. and widely available diagnostic tests. This gives the study of epidemiology in PBC a broad potential relevance. Our views of the epidemiology of PBC have evolved constantly since its first modern description by Ahrens in the 1940s. This pattern continues to this day, with rapidly evolving areas such as the detailed geoepidemiology, molecular epidemiology, and the epidemiology of disease phenotype. These areas of study have been facilitated by the advent of large-scale national and international patient cohorts, providing novel insights into the disease, its causes, and approaches to its systematic management. The aim of this review is to integrate established and new thinking regarding the epidemiology of disease and to provide a vision of the future for this everevolving disease.

Issue Theme Primary Biliary Cirrhosis; Guest Editor, Pietro Invernizzi, MD, PhD

Population Epidemiology of Primary Biliary Cirrhosis Primary biliary cirrhosis is a rare disease that predominantly affects women, with a ratio of 10 females to 1 male.1 The median age of disease onset is around 50 years.2 Individual susceptibility is likely to be due to a combination of gender, genetic (largely immunogenetic) factors, and environmental factors. The diagnosis of PBC is conventionally made using the combination of abnormal serum liver tests (elevation of serum alkaline phosphatase [AP] of liver origin for at least 6 months), the presence of antimitochondrial antibodies (AMAs) or PBC-specific antinuclear antibodies (titer 1:40) in serum and diagnostic or compatible liver biopsy (showing the characteristic florid bile duct lesion).3 In widely used clinical and epidemiological criteria the presence of all three features is interpreted as “definite” PBC and the presence of two as “probable” PBC. Antimitochondrial antibodies at a titer of > 1:40 in the context of cholestatic liver biochemistry are over 95% sensitive and specific for the diagnosis4 and the accuracy of the combination of serology and biochemistry in

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DOI http://dx.doi.org/ 10.1055/s-0034-1383730. ISSN 0272-8087.

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Semin Liver Dis 2014;34:318–328.

The New Epidemiology of Primary Biliary Cirrhosis

Regional Variation in the Prevalence of Primary Biliary Cirrhosis The published literature on disease prevalence in PBC has identified significant interstudy variation. This variation in prevalence of disease seems to be, at least in part, geographically determined, with an apparent “north-south” divide with countries in Northern Europe having a much higher rate of disease (►Table 1). Studies in the United Kingdom have shown a disease prevalence of 200 per million in southern Wales5 and 240 to 251 per million in northern England.6,7 The prevalence of PBC in Scandinavian countries is high with 180 per million population in Finland in 19998 and 128 to 151 per million in Sweden.9,10 The United States of America also has a high prevalence of PBC with 400.2 per million population being affected in a study from Olmsted County, Minnesota, in 2000.11 These findings stand in contrast to those suggesting much lower disease prevalence in Asia and Africa, although good epidemiological studies are lacking from these areas.12–16 Prevalence rates in Japan are reported as between 27 and 54 per million population.17,18 Interestingly, a recent study from southern China found the point prevalence rate of PBC was 492 cases per million population and 1,558 per million in women over 40 years.19 Due to the very high prevalence of hepatitis B in China, which is responsible for the majority of

liver disease in this area, the diagnosis of PBC is likely to have been previously underreported. The prevalence of PBC in Australia is also low at 19 per million population.20 A more recent study in Victoria, Australia, showed a higher disease prevalence, but this is strongly influenced by immigrant populations from European countries.21

Is the Prevalence of Primary Biliary Cirrhosis Increasing Over Time? There has been some suggestion that the prevalence of PBC is increasing over time. A case-finding study in northern England found an increase in the prevalence of PBC from 201.9 per million adult population in 1987 to 334.6 in 1994. The authors acknowledge that this apparent increase may be due to a true increase in disease prevalence, or improved casefinding and increased disease awareness.6 A Canadian study also found an increase from 100 per million adult population in 1996 to 227 per million in 2002 (p < 0.0005).22 However, data from Olmsted County, Minnesota, suggest a stable incidence rate over the past 25 years.11 The reporting of prevalence varies significantly even in the same geographical areas. In Canada, for example, the reported prevalence ranges from 22.39 to 100 per million population in similar time periods.22,23 This variation may be attributable to differences in study populations and methods of identifying cases. The study that showed a lower prevalence relied on clinicians identifying patients with PBC. The later study, showing a higher prevalence, used population-based administrative databases and a diagnostic coding algorithm to identify patients, which is likely to be more accurate in identifying the majority of affected patients. Over the past 60 years, the pathway to the diagnosis of PBC has changed significantly. In earliest descriptions of the

Table 1 Prevalence of primary biliary cirrhosis in national cohort studies Study


Prevalence per 100,000

United States

65.4 (Women) 12.1 (Men) 40.2 (Overall)




24 (Overall) 90 (Women  40 y)






18 (Overall) 29 (Women)

Lofgren et al, 198510



Danielsson et al, 19909










1.9 (Overall) 5.1 (Women > 24 y)

Kim et al, 2000


Witt-Sullivan et al, 199023 Metcalf et al, 1997


Kingham & Parker, 19985 James et al, 1999


Rautiainen et al, 2007

Inoue et al, 1995 Mori et al, 1997 Liu et al, 2010




Watson et al, 199520



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the diagnosis has led to much reduced use of biopsy for PBC diagnosis in recent years. The reliability of PBC diagnostic criteria, the use of widely available cheap tests, and their uniform adoption in the field have all contributed to the very robust epidemiological science that has been undertaken in PBC, with a significant number of epidemiological studies performed in several geographical locations over many years.

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disease,24,25 PBC was typically diagnosed following the onset of jaundice or other manifestations of advanced disease. Such late presentation is now very much the exception, with the majority of cases coming to light following investigation of abnormal liver serum biochemistry found on screening or of unexplained symptoms. This raises important questions as to whether there is a significant additional pool of similar “silent” patients who have not come to light because they have not happened to have their blood biochemistry checked. Were this to be the case, and given the advances in treatment in recent years, a case could be made for enhanced screening approaches to identify population cases of early (and treatment amenable) disease. Population-level screening for clinically significant levels of PBC autoantibodies has been relatively limited. When such studies have been undertaken, however, they do not identify a prevalence of such antibodies, which is significantly greater than the predicted prevalence of PBC in the population. Within their limitations, these studies suggest that the reported prevalence of PBC is probably close to the true population prevalence.

Primary Biliary Cirrhosis as a Rare Disease Despite the variation in disease prevalence, PBC remains a rare disease as defined by the European Commission for Public Health (diseases affecting less than 50 per 100,000 population). Even in high prevalence areas such as northern Europe, PBC affects 20 to 25 per 100,000 population in the United Kingdom5–7 and 12 to 18 per 100,000 in Scandinavian countries.8–10 The definition of PBC as a rare disease has advantages in terms of drug licensing, with the European Medicines Agency (EMA) and Food and Drug Administration (FDA) classifying PBC as an “orphan disease.” Pharmaceutical companies benefit from incentives from the European Union and other bodies to develop medicines for rare diseases, such as reduced fees and protection from competition once on the market. This has potential benefits in the development of therapeutics for PBC, the impact of which we will see in the near future.

Positive Antimitochondrial Antibodies with Normal Liver Function Tests It is important to consider the growing number of patients being identified with positive AMA (or other PBC-specific autoantibodies), but normal liver function tests. These patients cannot be diagnosed with PBC according to current diagnostic criteria in the absence of biopsy (which is typically contraindicated in patients with normal liver biochemistry). These patients are classified as “possible” PBC and would not be considered to have PBC in epidemiological terms. When biopsy of these patients was performed in the only study yet undertaken that has addressed the nature of histological change in individuals with AMA and normal liver biochemistry, a high incidence of mild, PBC-like histological features was reported. Furthermore, these patients were then shown to have a high risk of developing overt clinical PBC during followup (although the risk of developing advanced disease appeared low).26 It is unclear what determines the progression to clinically apparent disease, although ongoing studies are Seminars in Liver Disease

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exploring the genetic contribution to risk of disease progression. Current advice is not to treat this group with conventional first-line therapy (ursodeoxycholic acid [UDCA]) until serum liver biochemical abnormality is seen. It is recommended, however, that these patients undergo regular monitoring.

Geoepidemiology of Primary Biliary Cirrhosis Our understanding of the etiology of autoimmune diseases is increasing rapidly, both in terms of a detailed understanding of the factors conferring genetic susceptibility and an increased awareness of the potential role of environmental triggers for disease. It has long been suggested that exposure to an environmental agent may lead to a breakdown in immune tolerance in a genetically susceptible individual in PBC. Environmental risk factors have been postulated to be in the form of transient agents that could be either infectious or toxic in nature. Although there have been significant recent advances in our understanding of the genetic basis of susceptibility to PBC, there have only been a limited number of studies that have looked specifically at the question of environmental triggers. Although many candidate agents have been investigated and suggestive results obtained, it is still not clear as to the nature of the agent or agents involved. Here we will discuss the evidence suggesting that an environmental agent is involved in the pathogenesis of PBC and review the studies that have attempted to describe potential environmental risk factors. Two broad approaches have been used, the geoepidemiology approach exploring localized geographical variation in disease prevalence and the case control approach study of risk exposure to the level of the individual.

Geography Spatial Variation As outlined earlier, geographical variation in the prevalence of PBC is seen worldwide with a high prevalence in northern European countries. Critically, prevalence variation also seems to exist even within relatively small geographical areas. The authors’ group conducted an epidemiological study that described the spatial distribution of cases of PBC within a welldefined area over an 8-year period. They found that within the northeast of England there is uneven spatial variation of PBC patients, with clusters of cases being identified in the urban areas of Gateshead and Newcastle, which cannot be obviously accounted for by location of hospitals, referral bias, or any obvious geographical variation (►Figs. 1 and 2). Even within urban areas, and to a lesser degree the rural areas, there was uneven spatial variation. The spatial variation in the distribution of PBC is highly suggestive that exposure to an environmental agent is key in the pathogenesis of disease, with increased prevalence areas reflecting increased exposure risk or exposure levels. Prince et al, who made the observation, were able to identify spatial clustering, but were not able to hypothesize based on their data, as to whether the putative

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Fig. 1 Map of spatial variation in risk across the whole study region (solid line outlining areas of significantly higher risk and dashed line outlining areas of reduced risk at a 5% probability). Reproduced with permission of the publisher.27

trigger was an infectious or noninfectious agent, or whether it was a transient agent.27 The Prince et al study provided good evidence of geographical clustering, however, a subsequent follow-up study was able to use space–time clustering to give additional information as to whether the environmental agent is transient, which may be more suggestive of an infectious agent.

Fig. 2 Spatial variation in risk across the predominantly urban subregion of Tyneside and Wearside (solid line outlining areas of significantly higher risk and dashed line outlining areas of reduced risk at a 5% probability). Reproduced with permission of the publisher. 27

Space–time clustering occurs when an excess of cases occurs within a limited geographical area over a limited period. A study in the northeast of England reviewed over a thousand PBC patients in a well-defined geographical region, fully independent of the original Prince et al clustering study cohort, and found evidence of both geographical clustering, confirming the original Prince et al finding in a new patient cohort, and space–time clustering. The authors analyzed the data using both geographical and nearest neighbor thresholds and found evidence of clustering using both, minimizing the possibility that differences in population density could account for the results. The analysis used the concept of “close proximity,” which is defined as date of diagnosis and residential address at the time of diagnosis as being close. They identified the number of pairs of PBC cases in close proximity and the number of pairs of cases expected to be in close proximity and used this to look for evidence of space–time clustering.28 The finding of space–time clustering provides evidence for a transient environmental agent in the pathogenesis of PBC and more specifically the possibility of an infectious agent.

Toxic Waste Thyroid disease, another autoimmune condition, has been found to be more prevalent in women living in close proximity to Superfund toxic waste sites (SFS) in New York. A study was performed to see if the same might be true for PBC, given the longstanding hypothesis that PBC might be triggered by an environmental toxin. This study set out to investigate whether the prevalence of PBC was higher in areas within close proximity of a SFS. It found that PBC patients on the transplant waiting list were significantly more prevalent in zip codes that contained or were adjacent to a SFS. When they performed a global clustering analysis that would identify clusters of PBC patients independent of the SFS sites, they found five clusters of PBC patients on the transplant waiting list. These clusters were not statistically significant, but interestingly, four of the five clusters had an SFS within their border. When they did global clustering for PBC patients not on the transplant waiting list, there were three statistically significant clusters. One of these clusters was in close proximity to a transplant center and therefore might be accounted for by referral bias. The other two clusters were not and were in very close proximity to two large toxic waste sites, one with high levels of benzene, volatile organic compounds, and trichloroethylene, and the other with benzene alone. There was a statistically significant overlap of the clusters of PBC patients on the transplant list and PBC patients not on the transplant list at a site near to one particular SFS (►Fig. 3). Limitations of this study are that within these clusters near toxic waste sites there may be explanations other than the waste site itself such as socioeconomic status, smoking, or other unrecognized factors.29

Water An epidemiological study in Sheffield in the late 1970s reviewed the cases of PBC within the city and found a Seminars in Liver Disease

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Space–Time Clustering

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Fig. 3 Identification of individual clusters of PBC patients using the SaTScan software. Clusters of PBC-OLT cases and PBC-MSSM cases are denoted by solid and dashed circles, respectively. Focused analysis (i.e., the location of Superfund sites was included) identified a statistically significant cluster in Staten Island, New York (p ¼ .039). PBC, primary biliary cirrhosis; PBC-OLT, PBC patients listed for liver transplantation; PBC-MSSM, PBC patients followed at Mount Sinai School of Medicine, New York. Reproduced with permission of the publisher. 29

prevalence of 54 per million population. As well as determining the prevalence, it was noted that there appeared to be clustering of cases in certain areas of the city. On further investigation, it was found that 30 of the 34 cases of PBC received their water supply from one reservoir, the Rivelin reservoir. The clustering could not be accounted for by differences in socioeconomic status, familial cases, or differences in clinicians reporting of cases. The prevalence of PBC in the area supplied by this one reservoir was more than 10 times that in the areas supplied by other reservoirs. Following these findings, the water was analyzed and although the fluoride content in the Rivelin water was lower than that in other reservoirs, no other differences could be found. However, there may be differences that had not been identified or potentially there was contamination between the reservoir and the patient’s home.30

Case-Control Studies The case-control approach takes the geoepidemiology concept and extends it to the level of the individual patient and environmental risk exposure. There have been three large, Seminars in Liver Disease

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well-designed case-control studies to investigate the risk factors associated with PBC (►Table 2). A large American study enrolled over 1,000 PBC patients from multiple centers. They conducted telephone interviews to obtain data about lifestyle, personal, family, and reproductive history. Unsurprisingly, they found having a first-degree relative with PBC was a risk factor for developing the condition, as well as the presence of several other autoimmune conditions. Primary biliary cirrhosis was associated with a history of urinary infections as has been the finding in other epidemiological studies. Patients with PBC were significantly more likely to have a history of smoking compared with controls; however, interestingly more controls were current smokers. Nail varnish use was more common in PBC cases, but in that they did not find any association with use of hair dye as other groups have found.31 There have been two case-control studies in the northeast of England, which used postal questionnaires to investigate possible environmental triggers for PBC. The first published in 2000 identified PBC cases and controls in a defined geographical area and reported an association with smoking, psoriasis, and eczema.32 The second case-control

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Table 2 Summary of the findings of disease associations in primary biliary cirrhosis case control studies (bold denotes associations reported as significant in more than one case control study) Risk factor

Howel et al, 200032 OR 95% CI

Gershwin et al, 200531 (multivariate analysis) AOR 95%CI

Prince et al 201033 (OR compared with epidemiological cases) OR 95% CI


Medical / family history Family history of PBC
















Urinary infections







Ever smoked







Alcohol consumption





Hair dye



Hair perm



Nail varnish



Abbreviations: AOR, adjusted odds ratio; CI, confidence interval; OR, odds ratio; PBC, primary biliary cirrhosis.

study recruited three cohorts of patients; PBC cases in the northeast of England, cases identified through the national patient support group and controls. They also identified several risk factors associated with PBC including family history of PBC, history of urinary infections, smoking, use of hair dye, and history of psoriasis and shingles.33 In conclusion, despite there being relatively few studies to investigate the presence of environmental risk factors in the etiology PBC the literature to date suggests that an environmental agent is likely to be involved. Geographical variation and clustering of cases of PBC has been identified in several well-designed case control studies. Some of the geographical variation may be accounted for by the differences in the methodology of the studies conducted or genetic variations in the population, but current thinking is that there is likely to be one or more environmental agents responsible for this variation. The finding of space–time clustering provides further evidence of the likelihood of an environmental risk factor as this not only shows geographical clustering, but also a relationship in time with cases diagnosed. This suggests the presence of a transient environmental agent. The studies that attempted to identify specific risk factors have varied in their findings with some common risk factors such as family history of PBC, smoking, and a history of urinary tract infections, but have also shown conflicting results. The large American study investigating whether proximity to toxic waste sites could be a risk factor for PBC had limitations and although it did show clustering around the waste sites was unable to prove that it was toxins from the waste sites themselves that were linked with the PBC rather than other factors associated with living near a toxic waste site. Both the Sheffield reservoir study and the New York toxic waste site study showed convincing clustering around certain areas, but have not identified specific agents that may be responsible. There are many challenges in identifying environmental risk

factors in PBC, which include the period between exposure and onset of disease, as well as the latent period between onset and diagnosis making epidemiological studies more difficult. There may well be multiple environmental triggers involved, which makes it even more of a challenge to try and identify these agents. More work is needed in this area to identify environmental risk factors before it is going to be of clinical relevance.

The “New” Epidemiology of Primary Biliary Cirrhosis Epidemiology of Disease Phenotype in Primary Biliary Cirrhosis The advent of national and international-scale patient cohorts, exemplified by the International PBC Group and UKPBC (datasets and cohorts of up to 6,000 independent patients) have provided an important opportunity to explore not only the population level epidemiology of PBC per se, but to explore, for the first time, the epidemiology of disease variants.34–36 This approach, which has in the last year identified startling variations in disease phenotype amongst epidemiological groups, will underpin the emerging science of stratified therapy in PBC (►Table 3). There are key findings relating to both disease severity and response to primary therapy and to symptom impact.

The Epidemiology of Response to Ursodeoxycholic Acid The concept that response to primary therapy with UDCA is variable across the population is now firmly established and entering routine clinical practice.37–39 Until recently, however, there were few data to inform our understanding of the population level risk of nonresponse. That such nonresponse is clinically significant is indicated both by the studies in which UDCA response-criteria were developed, and more Seminars in Liver Disease

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The New Epidemiology of Primary Biliary Cirrhosis

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Table 3 The epidemiology of disease phenotype in primary biliary cirrhosis. Clinical phenotypes in the UK-PBC cohort split by gender.34 Data represent cohorts matched for age (bold denotes associations reported as significant in more than one case control study). Male


P value

Age at diagnosis y (range)

60 (34–81)

55 (16–86)

< 0.0001

UCDA use %




Response to UDCA (Paris 1) %



< 0.05

Itch severity (VAS)

1.7 (1.3–2.4)

2.5 (2.4–2.6)

< 0.0005

General symptoms (PBC-40 symptom domain)

13.4 (12.1–14.2)

16.4 (15.8–16.5)

< 0.0001

Fatigue (PBC-40 fatigue domain)

26.1 (2.2–27.4)

30.4 (29.2–32.2)

< 0.0001

Cognitive symptoms (PBC-40 cognitive domain)

11.9 (11.1–12.8)

13.3 (13.0–13.5)

< 0.005

Social dysfunction (PBC-40 social domain)

22.4 (21.0–23.7)

24.3 (23.9–24.8)

< 0.01

Emotional dysfunction (PBC40–emotional domain)

6.6 (6.1–7.1)

7.8 (7.7–8.0)

< 0.0001

Sleep disturbance (ESS)

8.3 (7.6–9.0)

7.7 (6.9–8.4)


Autonomic symptoms (OGS)

2.1 (1.7–2.5)

3.5 (3.0–4.0)

< 0.0001

Anxiety (HADS-A)

5.1 (4.5–5.6)

7.2 (7.0–7.4)

< 0.0001

Depression (HADS-D)

4.3 (3.7–4.8)

5.1 (3.7–4.8)


Abbreviations: ESS, Epsworth Sleepiness Scale; HADS, Hospital Anxiety and Depression Scale; Ns, nonsignificant; OGS, Orthostatic Grading Scale; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid.

recently, the population level validation studies, which have confirmed that a failure to meet response criteria to UDCA given at adequate dose is associated with a significantly increased risk of death or need for transplant in PBC.34 The deriving studies suggested that there are serological factors associated with UDCA nonresponse, including PBC-type antinuclear antibody reactivity.38 Both the International PBC Group cohort study, utilizing the historical record of patients from across the world with a large number of disease outcome events, and the UK-PBC prospective study recruiting patients into a long-term follow-up cohort have validated the response criteria and have underpinned the current therapeutics activity around agents that may improve outcomes in patients showing inadequate response to UDCA. The nature of the UK-PBC cohort, with its prospectively collected, extended clinical dataset has, for the first time, allowed exploration of the epidemiological factors associated with UDCA nonresponse. These studies have identified both a gender and an age effect in terms of UDCA nonresponse.34 Male patients with PBC are significantly less likely to respond to UDCA. Although this is potentially associated with delayed disease recognition in men (mean age at commencement of therapy is significantly older) the effect remains even when this factor is corrected for. Within the female, but not male patient population age also plays a significant effect on response to UDCA with younger presenting patients at substantially increased risk of nonresponse. Elderly patients with PBC are highly responsive to therapy with over 90% of patients presenting above the age 70 reaching UDCA response criteria. In patients presenting below the age of 40 this falls to below 50%. In the UK-PBC cohort, among patients presenting below the age of 50 across the UK over 50% of those presenting below the age of 50 have already been transplanted or are in a state of UDCA nonresponse and at high risk of needing Seminars in Liver Disease

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transplantation. These observations identify epidemiological groups in PBC with a high degree of unmet clinical need and will inform future therapeutic intervention approaches. At present these phenomena remain unexplained, although the potential for endocrine factors to be associated with responsivity to UDCA is clear. It may be that these are at level of regulation of the immune response, but it is also important to note that the biliary epithelial cells (BEC), the target cells for autoimmune injury in PBC, express estrogen receptors.40 Furthermore, there are anecdotal reports that tamoxifen is effective at augmenting the response to UDCA.41 The demographic data associated with the UDCA response, together with the overall strong association between female gender and PBC all point to further exploration of the nature of female sexual hormone effects in PBC as an area of priority for research and potential therapeutic development. In addition to future benefits in terms of disease understanding and novel therapies, our current understanding of the epidemiology of disease response to therapy allows us to explore how we can optimally configure clinical services in the future. The authors believe that the evidence regarding UDCA response are strong enough to warrant this information entering routine clinical practice, with integrated approaches to care delivery based around the nature of formal response to UDCA being at the heart of the approach.42 It is the authors’ current practice that younger-presenting patients, male patients and all patients who are unresponsive to UDCA after a year of therapy at adequate dose are monitored in an enhanced fashion, with increased surveillance for complication development and fast-tracking into clinical trials of novel agents. Increased understanding of low risk in PBC, exemplified by older-presenting female patients and patients in all demographic groups who show a full response to UDCA, also allows evolution in how we configure clinical

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The New Epidemiology of Primary Biliary Cirrhosis

The Epidemiology of Symptoms In addition to the risks associated with progression of PBC to end-stage liver disease and death or need for liver transplantation, there is now clear evidence to suggest that there is substantial symptomatic burden in PBC, and that this is associated with significant impairment of quality of life. The population-level studies again allow us to explore the epidemiology of symptom impact. The UK-PBC dataset has demonstrated clearly that as with UDCA nonresponse, both fatigue (the symptom in PBC with the greatest overall impact on life quality) and pruritus (the archetypal symptom of PBC) are age-related with young age of diagnosis being strongly associated with worse fatigue severity.34 Strikingly, this effect is independent of UDCA response, with no differences in fatigue severity between UDCA-responders and UDCA nonresponders. This lack of association with UDCA response status also applied to all other symptom domains assessed using the disease-standard quality of life measure the PBC-40, with the exception of current pruritus, which was marginally worse among UDCA nonresponders. Among the other symptom domains associated with PBC relating to orthostatic intolerance, daytime somnolence, depression, and anxiety, only depression showed an UDCA-response association, with depression scores being significantly higher in UDCA nonresponders. With regard to gender, again as with response to UDCA, a gender effect was seen for some, but not all PBC symptoms, with fatigue being significantly worse in female patients than age-matched male patients. Of the major associated factors for fatigue,44 daytime somnolence was no different between genders nor was depression. Interestingly, autonomic dysfunction was also significantly lower in male patients than in female patients, and across matched pairs the differences between male and female patients for fatigue severity correlated directly with autonomic dysfunction difference.34 This would suggest that males are relatively protected from fatigue in PBC because they lack the tendency toward hypotension as a manifestation of autonomic dysfunction experienced by females. It may be that this simply reflects difference in base-line blood pressure between male and female populations. In addition to the obvious implications for the management of symptoms in male and female patients, this observation presents direct evidence for a role in autonomic dysfunction in the pathogenesis of fatigue and justifies targeting of this phenomenon (as well as daytime somnolence and depression where pres-


ent) with a goal of improving fatigue. This observation demonstrates the ways in which epidemiology can potentially reach out from being a science directed at understanding disease, to one that is focused on improving life quality for patients through enhanced therapy.

Molecular Epidemiology of Primary Biliary Cirrhosis The combination of large-scale genetic consortium work and study of the geoepidemiology of PBC has combined to create enormous opportunity in the area of the molecular epidemiology of complex disease. This science looks to combine genetic and toxicological modalities of working with conventional epidemiological techniques. At present, the field is in its infant stages in PBC, but the approach offers considerable promise. In terms of the genetic basis of PBC, the striking observation from the emerging large-scale GWASs and iCHIP studies is that, with the exception of Japanese populations where genetic associations appear distinctive, PBC is associated in differing European and North American populations with highly consistent single nucleotide polymorphism (SNP) associations.45–48 These are principally around HLA and genes encoding cytokines receptors and signaling molecules in the interleukin-12 (IL-12) pathway, together with SNPs in genes associated with antigen presentation and T-cell activation. Differences between individual GWAS studies are largely related to study power in terms of cohort size, with the key index observations showing a high level of replication. It is striking that all genome-wide significant associations in PBC to date relate to immunoregulation with, as yet, no significant associations related to bile acid biology or the biochemistry of the autoantigens in PBC. The consistency of genetic associations across different Western populations would argue for homogeneity of PBC as a disease—a finding that has potential implications for homogeneity in therapeutic approach.49 The significance of genetic association differences between Japanese and non-Japanese populations remain, as yet, unexplored. In terms of the environmental triggers that are potentially involved in disease pathogenesis there has been no work, to date, to link the highly suggestive geoepidemiology patterns for the disease with mechanistic studies demonstrating how molecular pathways might be subverted in PBC (in particular, around the biology are pyruvate dehydrogenase the key mitochondrial antigen and the potential for subversion of the critical lipolylation pathway by xenobiotics).50,51 This has generated important questions as to whether some of the putative xenobiotics that can trigger PBC-like lesions and suggestive serology in experimental animals52–55 actually are present in the environment, and associated with geographical locations where disease incidence is at its highest. Ongoing projects will begin to bridge the gap between geoepidemiology and mechanistic studies. Future approaches will also begin to link genetic with environmental trigger studies. It may well be, however, given the nature of the genetic associations in PBC, that the genetic environment in patients is merely permissive, with the actual triggering event being a specifically environmental one in inherently susceptible individuals. Seminars in Liver Disease

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delivery with such patients being safe for management in the primary care setting. A risk-based approach to management based on a robust understanding of the epidemiology of response to therapy will allow us to streamline PBC management in clinical practice, to target patients to the most appropriate follow-up setting, and potentially to generate funds through the reduction in the overmanagement of lowrisk patients sufficient to enable introduction into reimbursed clinical practice of the new generation of secondline therapies, which are showing significant promise in terms of therapeutic response in high risk and nonresponsive patients.43

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A key ultimate question will be the extent to which molecular epidemiology will have any direct impact on patients. Approaches to utilizing genetic information in terms of identifying putative therapies are at their infant stage, but as yet have been unproductive in PBC. How environmental factors may be avoided in the disease to reduce risk is an area that is highly speculative. It is likely that the advent of the large-scale molecular epidemiology projects on the back of large-scale consortium work will address these questions over the next few years.

Conclusions and Future Perspectives Clear conclusions can now be drawn regarding the epidemiology of PBC, while emerging themes identify new questions and future challenges. 1. Although the prevalence of PBC depends on geography to a degree, and on case- finding methodologies, there is a broad consensus for northern European and related populations of a prevalence of 30/100,000 of the population. This makes PBC a “rare disease” in terms of drug-licensing jurisdictions. This has advantages in terms of the potential therapeutic pipeline in PBC. Primary biliary cirrhosis is, however, by the definition of rare disease (prevalence < 50/100,000) common, meaning that in a country the size of the UK there are 20,000 patients, presenting an appreciable challenge for the delivery of optimal management. The scale of PBC therefore makes it a paradigm for rare disease, and solutions to care configuration based on its epidemiology may have a relevance to other disease areas beyond the liver. 2. There is convincing evidence that PBC has a geographical distribution even within national areas. There are evidence strands that would support a chemical environmental factor in disease pathogenesis, with other strands pointing to a potential infectious agent. Geographical distribution within areas where longitudinal studies have been performed seems stable, pointing to the possibility of deep-seated environmental factors in triggering disease. The geoepidemiology of the disease potentially links to mechanistic studies, implicating both infectious agents and xenobiotics as disease triggers. As yet, no direct link has been made, however, between an identified environmental factor and a disease-triggering mechanism. 3. In terms of the molecular epidemiology of PBC the genetic basis of the disease appears remarkably consistent across European and European-related populations where the largest-scale studies have been performed, large-scale GWASs across northern America and Europe having identified remarkably consistent genetic associations. There is evidence that genetic susceptibility in Japan may be based on different factors. The advent of large population cohorts, the well-established genetic dataset in PBC, and the emerging concepts regarding geoepidemiology and potential mechanisms for environmental factors triggering the disease make PBC extremely well placed as a unique

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disease opportunity in which to explore the interaction between genetic and environmental factors in the triggering of complex disease. Primary biliary cirrhosis may, therefore, also be a paradigm for understanding the link between epidemiology and mechanism in chronic disease. 4. The advent of large-scale population cohorts clearly points to an epidemiology of disease phenotypes. Primary biliary cirrhosis appears not to be a consistent disease, with younger patients seemingly having a more aggressive disease course and lower levels of response to therapy with UDCA. Symptom impact also varies across population groups with younger patients experiencing more severe fatigue and other related symptoms. Phenotype also appears to be related to gender in PBC, with male patients having a more aggressive disease course (although one that is consistent across age groups) and lower levels of symptom impact than female patients. The highest risk population subgroup in PBC both in terms of symptoms and in terms of disease risk/nonresponse to therapy are, however, young females. An awareness of this epidemiology of phenotype will naturally lead on to stratification approaches in which we target different risk groups for enhanced monitoring and therapy based on the clear understanding of their risk. This may be the ultimate expression of epidemiology in PBC reaching the clinic. In conclusion, over the past 50 years the study of the epidemiology of PBC has provided important insights into this disease. This work has generated hypotheses and helped address key questions. It is likely to continue to evolve to answer the fundamental questions over the next decade as to how the disease arises, and most importantly, how we can optimally treat the disease while matching patient risk with therapy.

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The New Epidemiology of Primary Biliary Cirrhosis

The New Epidemiology of Primary Biliary Cirrhosis

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antibodies by ab initio quantum chemistry. Hepatology 2001; 34:341A 53 Long SA, Quan C, Van de Water J, et al. Immunoreactivity of organic mimeotopes of the E2 component of pyruvate dehydrogenase: connecting xenobiotics with primary biliary cirrhosis. J Immunol 2001;167(5):2956–2963

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The new epidemiology of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease. Susceptibility to PBC probably arises from a combination of genetic and en...
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