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Recent Advances in the Epidemiology of Primary Biliary Cirrhosis
Clin Liver Dis 12 (2008) 289–303
Recent Advances in the Epidemiology of Primary Biliary Cirrhosis Rebekah G. Gross, MDa,*, Joseph A. Odin, MD, PhDb a
Division of Gastroenterology, The Mount Sinai School of Medicine, Box 1069, One Gustave L. Levy Place, New York, NY 10029, USA b Division of Liver Diseases, The Mount Sinai School of Medicine, Box 1123, One Gustave L. Levy Place, New York, NY 10029, USA
Primary biliary cirrhosis (PBC) is an uncommon chronic liver disease of unknown origin that occurs worldwide in an uneven geographic distribution. PBC most commonly afflicts middle-aged women in industrialized countries [1]. The pathogenesis, although incompletely understood, is known to involve progressive, nonsuppurative inflammatory destruction of intrahepatic bile ducts, leading to chronic cholestasis, which predisposes to cirrhosis [2]. Individuals who have PBC typically are identified at routine check-up with laboratory evidence of cholestasis, at a time when they are asymptomatic. The presence of antimitochondrial antibodies (AMA) in the serum is highly specific for PBC and it is diagnostic of the disease particularly in the presence of elevated serum alkaline phosphatase levels [2]. In some cases (certainly in those who test AMA negative), a liver biopsy may help confirm the diagnosis of PBC, but more often liver biopsy is used to determine disease stage for prognostic purposes. Despite an often asymptomatic presentation, PBC is an important cause of liver-related morbidity, with affected individuals making significant use of health care resources, including liver transplantation [3]. The Healthcare Cost and Utilization Project estimates the annual economic burden from this disease at $69 to $115 million for hospital charges alone [4]. There is concern that the economic impact of PBC could grow significantly in the future because of its increasing incidence and prevalence the world over (discussed later). Costs actually may decline in years to come, however, as a recent study suggests progressively fewer individuals diagnosed with PBC are transplanted, possibly because of improved treatment of PBC [5]. This update describes the changing epidemiology of PBC and examines * Corresponding author. E-mail address: [email protected] (R.G. Gross). 1089-3261/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.cld.2008.02.001 liver.theclinics.com
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the evidence supporting proposed genetic and environmental risk factors that may play a role in the etiopathogenesis of the disease.
Incidence and prevalence of primary biliary cirrhosis In the nearly 3.5 decades since Hamlyn and Sherlock [6] presented the first descriptive epidemiology study of PBC based on a review of mortality rates determined from United Kingdom death certification data, the literature on this topic has exploded. Although a large quantity of data has been amassed, sometimes the quality has been called into question. Most studies are limited to highly industrialized countries, and many, in particular those published before 1986, are marred by flawed methodology, use of small sample sizes, incomplete case ascertainment methods, and poorly defined diagnostic criteria to define PBC [3]. Perhaps in part because of these limitations, epidemiologic studies of PBC vary widely in their estimates of the frequency of PBC. Distinguishing true trends from artifactual differences stemming from variegated methodology across studies is challenging. As noted by Prince and James [3] in their excellent review of PBC published in 2003, however, individual studies that follow trends in a given population over time and those that report on the variation of PBC frequency within a given region have proved particularly useful. In reviewing these data, two broad observations emerge: (1) the incidence and prevalence of PBC are increasing over time and (2) geographic clustering of disease is evident, suggesting genetic and environmental influences on the etiopathogenesis of disease. Temporal changes in primary biliary cirrhosis incidence and prevalence Initial studies from Europe between 1970 and 1986 calculated the mean incidence of PBC at 0.6 to 13.7 cases per million population per year and the point prevalence at 11.1 to 128 cases per million population [6–13]. The majority of these studies focused on discrete geographically defined populations in the United Kingdom, Sweden, and Spain, although one surveyed a pan-European population, merging data from 10 European countries. Since 1986, additional studies with arguably more reliable and consistent methodologies have revealed higher incidence rates of 0.7 to 49 cases per million population per year and prevalence rates of 6.7 to 402 cases per million population [14–38]. These later studies also cast a wider net across the globe, looking at populations not only in Europe but also in North America, Australia, the Middle East, and Asia. Given that they focus on new geographic regions and their methods vary from older studies, these studies provide inconclusive evidence as to whether or not the prevalence and incidence of PBC are increasing. Analysis of specific geographic regions in the United Kingdom over time have attempted to address these concerns. Ray-Chadhuri and colleagues
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[32], updating data from an earlier epidemiologic study by Triger [9], observed an increase in annual incidence rates among residents of Sheffield, England, from 5.8 cases per million in the late 1970s to 20.5 cases per million in 1987. This incidence rate then was found to remain stable between 1987 and 1999. The prevalence of PBC, however, continued to rise during this period from 54 cases per million in 1977 to 57 cases per million in 1987 to 136 in 1993 and, finally, to 238 in 1999 [32]. Increased prevalence in the absence of increased incidence may reflect a combination of earlier diagnosis and improved care, including liver transplantation. Similarly, Steinke and colleagues [39], studying residents of Tayside, Scotland, over the decade spanning from 1986 to 1996, found an increase in annual incidence rate for PBC from 48 to 55 new cases per million. During the same period, the prevalence of PBC in this population was observed to rise from 186 to 379 cases per million. These rates represent a substantial increase over those documented in this same population by Stuart-Hislop and colleagues [8,40] in the late 1970s. At that time, the incidence of PBC was documented at 10.6 new cases per million and prevalence was calculated at 40.2 cases per million. Finally, sequential studies following residents of Northeast England documented an increase in incidence and prevalence of PBC in this region. Taken in conjunction, these studies show a rise in incidence from a mean of 11.3 cases per million in 1976 to18.8 cases per million in the years 1983 to 1987, 26.1 cases per million in the years 1987 to 1990, and 31.1 cases per million in the years 1991 to1994. The studies similarly show a rise in prevalence in the region over this time period, from 16 cases per million in 1976 to 250.8 cases per million in 1994 [17,29,30]. This point prevalence is among the highest documented in unselected populations worldwide, trumped only by the discoveries of a prevalence of 289 cases per million in Alaska [33], 379 cases per million in Scotland [39], and of 402 cases per million in Rochester, Minnesota [31]. The higher rates of incidence and prevalence of PBC in more contemporary studies and the increase in rates observed over time in specific geographic areas may reflect a true increase in frequency of the disease or simply an apparent increase due to a higher detection rate. Possible explanations for increased detection include more widespread availability of laboratory testing and changes in clinical practice patterns where screening tests are applied more commonly in the setting of mild or poorly-defined symptoms [3,41]. At least in part, this seems related to increased clinician and patient awareness of PBC and an improved ability to link a given clinical picture to the diagnosis of PBC. Room for improvement in clinician awareness remains even in the United Kingdom. James and colleagues [30] found that in patients in Northern England who underwent testing and had results consistent with PBC, in 37% the diagnosis neither was made nor considered by the consultant who had ordered the investigations.
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Geographic differences in primary biliary cirrhosis incidence and prevalence If the observed variation in incidence and prevalence of PBC reflects a true epidemiologic phenomenon, differing exposure to environmental risk factors may help to explain it. As discussed later, several environmental agents, potentially affecting women preferentially, already are implicated in the etiopathogenesis of PBC. Individual studies that document local geographic variation in the burden of PBC strengthen the case for environmental influences on the development and progression of this disease. In their extensive review of geographic variation in the prevalence of PBC, Prince and James [3] outlined 14 studies comparing the prevalence of this disease among subregions within Europe, Australia, and Canada. As the investigators point out, 11 of the 14 studies used aggregated data, outlining regions by administrative or political boundaries that may not be particularly meaningful from an epidemiologic perspective. All but 3 of the 14 studies found a differential distribution of PBC cases according to subregion. The most detailed data were extracted from large national studies performed in Estonia and Sweden. In the former, Remmel and colleagues [23] reported that the prevalence of PBC in the district of Viljandi was approximately 3 times greater than that in the rest of Estonia (P!.0001). In the latter, Danielsson and colleagues [18] found that the prevalence of PBC in Vaterbotten County was approximately half that seen in two other counties in Northern Sweden (P ¼ .004). Prince and colleagues’ [42] study of a cohort of 770 patients who had PBC in Northeast England used point process analysis to reveal marked clustering of PBC in several urban areas (up to 13 cases per km2). Although the investigators could find no obvious demographic or geographic features to explain the grouping, the results again seem to imply the presence of one or more environmental risk factors associated with PBC. North American studies have similarly localized clusters of PBC. Ala and colleagues [43] noted grouping of PBC cases in small geographic regions within New York City. In this study, a relationship was observed between the location of toxic waste sites and increased prevalence of PBC cases. A nationwide analysis to detect large-scale clusters of advanced PBC associated with high levels of air pollution (Odin and colleagues, unpublished data, 2007) identified two statistically significant clusters surrounding industrial cities located on the Great Lakes (one in Buffalo, New York, and a second in Gary, Indiana) and a cluster in Los Angeles (Fig. 1). The relative risk for PBC was 1.92-fold to 2.12-fold greater in these clusters after normalizing for age, race, and gender. United States Environmental Protection Agency monitoring sites within these clusters have recorded mean air pollutant levels among the top 10% nationally [44]. Other investigators who have noted geographic clustering of PBC include Abu-Mouch and colleagues [45], who found seven cases of PBC clustering in
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Fig. 1. Clusters of individuals listed for transplantation due to PBC. Using data for mean daily airborne pollutant concentrations obtained from the United States Environmental Protection Agency and data on individuals listed for liver transplantation from the Organ Procurement and Transplantation Network, three statistically significant (all P!.050) PBC clusters were identified using SaTScan software. The increased relative risk for PBC within each cluster ranged from 1.92 to 2.12.
a small town in Alaska and reported the case of a husband and wife who were diagnosed with PBC after growing up in the same city neighborhood. Likewise, Arbour and colleagues [46] have demonstrated that First Nations people of Vancouver, British Columbia, who comprise only 3.9% of the general population in the area, constitute 25% of patients referred for liver transplantation for PBC. PBC is the leading indication for liver transplantation referral in First Nations people, occurring at a rate 8 times higher than that of patients of other descent who have PBC (P ¼ .0001). Although genetic differences may contribute to the increased prevalence of PBC among First Nations people, a disproportionate number of cases were noted
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in patients who had this ethnic background living on Vancouver Island (48% of cases versus 18% expected, P!.05) [46]. Comparison of prevalence rates between immigrant and nonimmigrant groups living in the same area often is useful in assessing the relative roles of environment and genetics in the etiopathogenesis of disease. Data on patterns of PBC in immigrants seem to support the notion of interplay between genetic and environmental factors. A recent study from Victoria, Australia, where the overall prevalence of PBC is documented at 51 cases per million population, observed significantly higher rates of PBC in European immigrants (141 cases per million from Great Britain [a lower rate than that seen in British living in Great Britain], 200 cases per million from Italy, and 208 cases per million from Greece) [34]. Similarly, although the overall prevalence of PBC in southern Israel approximates that seen in some European countries, the rate is much higher among more recent immigrants to Israel, and it is higher in Jews than in Arabs. Delgado and colleagues [38] found that in women older than 40, the prevalence varied from 135 cases per million in those born in Israel to 450 cases per million in immigrants from Russia and Eastern Europe and 700 cases per million in immigrants from North Africa and Asia. Finally, Anand and colleagues [24] estimated that, although exceedingly rare in South Asia itself, the prevalence of PBC in South Asian migrants to Birmingham, United Kingdom, approached that seen in the host country, exceeding 14 cases per million. This number is striking given that PBC once was believed not to occur at all in India, although the disease more recently has been noted in reports and small series, presumably as a result of improved screening methods. The different prevalence of PBC among immigrants could be interpreted as an indication that local environment does not play a significant role in the etiopathogenesis of PBC. Given the long lag-time between loss of immune tolerance to mitochondrial autoantigens and the diagnosis of PBC, however, it is possible that local environmental factors affect the earlier stages of PBC. Also, environmental exposure by immigrants often does not entirely mimic that by nonimmigrants residing in the same region. Prevalence of primary ciliary cirrhosis in affected families Family members of patients who have PBC demonstrate an increased risk for developing the disease, such that cases occurring within a family are termed ‘‘familial PBC’’ [47]. The reported rate for familial PBC ranges from 1% to 6.4% in England, with higher rates found when more distant relatives are included in the analysis [7,17,47,48]. The rate is documented at 4.3% in the United States [49], 4.5% in Sweden [18], 3.8% in Italy [50], 5.1% in Japan [51], and 7.1% in Iceland [52], arguably a population that is unique from a genetic perspective. The prevalence rate of PBC in first-degree relatives ranges from 5% to 6% in various geographic areas [48,49,51], with the relative risk for a sibling of an affected individual diagnosed with
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the disease quoted as high as 10.5 [48]. Although the increased prevalence of PBC in relatives of PBC is significant, it is not great enough to account for geographic clustering of PBC. Most commonly, PBC is found among sisters and daughters who are younger at diagnosis than are index cases [51]. Additionally, serum AMA presence, which may be a harbinger of PBC, is found to aggregate in pedigrees of patients who have PBC. Lazaridis and colleagues, looking 145 families who had PBC, found that the prevalence of AMA in first-degree relatives of index cases versus controls was 13.1% versus 1%, with female family members affected predominantly [53]. Individuals who have PBC and their relatives may possess an increased frequency of immune-related gene polymorphisms [54] and autoimmume conditions. Patients who have PBC are known to exhibit an increased frequency of several extrahepatic autoimmune disorders. In one series, the risk of autoimmune disorders occurring among patients with PBC, including Sjogren’s syndrome and Raynaud’s syndrome, was found to be 3- to 14-fold higher than among controls [55]. Multivariate analysis suggests that Sjo¨gren’s syndrome and systemic lupus erythematosus are risk factors for PBC [4]. Although associations between PBC and other autoimmune diseases are noted, their true extent is not established. Looking at patterns of autoimmunity in the families of 160 index individuals who had PBC in the United Kingdom, Watt and colleagues [56] found that up to 14% of firstdegree relatives of the index cases had at least one autoimmune condition other than PBC, a rate over three times that for autoimmune disorders in the general population. In a much smaller study out of Brazil, however, where PBC is rare, Bittencourt and colleagues [37] found that the frequency and titers of autoantibodies and the prevalence of extrahepatic autoimmune disease in relatives of patients who had PBC were similar to those observed for the general population. Is familial PBC the result predominantly of genetic similarities or shared environmental exposures? The increased prevalence of certain genetic polymorphisms (eg, vitamin D receptor polymorphisms) in those who have PBC, including, in a variety of geographic areas supports an important role for genetics in the clustering of PBC within families [54]. Perhaps the most convincing evidence for a genetic influence in the development of PBC derives from twin studies. In autoimmune diseases other than PBC, concordance rates in monozygotic twins vary broadly, ranging from 12% to 15% in rheumatoid arthritis to 75% to 83% in celiac disease [57]. The rate averages less than 50% in most autoimmune diseases. Selmi and colleagues [57] studied concordance rates of 16 twin sets affected by PBC, the largest study of this kind in PBC to date. The investigators found the concordance rate for PBC registered 63% for eight genetically proved monozygotic twin sets (all female) whereas it was 0% for eight dizygotic twins sets (four female and four male-female pairs). Such a high concordance rate in monozygotic twins and the dramatic difference for dizygotic twins strongly suggests a genetic component to the etiopathogenesis of PBC. (Specific genetic risk
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factors associated with PBC are discussed in the article by Juran and Lazaridis elsewhere in this issue.)
Lifestyle or environmental risk factors associated with primary biliary cirrhosis As the twin data suggest, although genetic factors may increase susceptibility to PBC, they likely are not sufficient to cause disease in all cases. Recent epidemiologic research has sought to better define environmental factors that may play an adjunctive role in precipitating disease. Associations between PBC and various lifestyle choices, including smoking, toxin exposure, history of infection, and reproductive factors, have been explored (Table 1). Although the data can be conflicting, strengths of more recent studies include their case-control methodology and increased sample size over earlier reports. Lifestyle choices Epidemiologic studies consistently have found a positive association between smoking history and PBC (Table 2). In one British study, a history of past smoking was observed in 76% of patients who had PBC versus only 57% of unaffected controls. Furthermore, a longer smoking history was linked more often to PBC, with prevalence of the disease highest among those who had smoked more than 20 years (odds ratio [OR] 2.4 among all smokers; OR 3.5 among those who had greater than 20-year exposure). These data suggest a dose-response relationship between smoke exposure and disease development [58]. A subsequent survey study in the United Table 1 Proposed environmental risk factors for primary biliary cirrhosis Risk factor
Reproducibility
Cigarette smoking History of UTI History of other infectious exposure Chlamydia Human betaretrovirus Chemical exposure Toxic waste Cosmetics (eg, hair dye, nail polish) Prior surgery Frequency of pregnancy Hormone replacement therapy Pet ownership Alcohol consumption Stressful life events
High Medium
Abbreviation: na, no association found.
Very low Low Medium Low Low Low Low na na na
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Table 2 Smoking as a risk factor for primary biliary cirrhosis based on case-control studies Authors
Area Method of studied data collection
Number of cases enrolled Odds ratio
Howel UK et al, [57]
Postal self-completion questionnaire
Parikh-Patel et al, [54] Gershwin et al, [4] James et al, [58]a Corpechot et al, [59]b
Postal self-completion 199 questionnaire Telephone questionnaire 1032
a
US US UK
Postal self-completion questionnaire France Not documented
100
95% CI
2.4 (ever smoked) 3.5 (smoked R20 years) 2.04 (ever smoked)
1.1–3.8
1.6 (ever smoked)
1.3–1.9
2234 (Group1) 1.6 294 (Group 2) 1.8 210 3.12 (active and passive smoke exposure) 1.69 (active smoking)
1.4–4.1 1.9–6.3
1.4–1.8 1.3–2.3 2.0–5.0
1.1–2.6
Data published in abstract form, reporting on two separate groups of patients who had
PBC. b
Data published in abstract form; additional information derived from Joseph Odin and Raoul Poupon, personal communication, December 2007.
States found elevated odds of having smoke exposure in patients who had PBC compared with siblings and friends who did not have PBC [55]. Two additional questionnaire-based, case-control studies have confirmed that a history of smoking is significantly associated with an increased risk for PBC [4,59]. Results of a recent French study suggest a past history of active or passive smoking raises the risk for PBC at least threefold [60]. Smoking not only may predispose to disease but also may accelerate its progression. A recent retrospective assessment performed at three major teaching hospitals in the United States found that mean lifetime tobacco consumption was higher in PBC cases of advanced histologic disease at presentation than it was in cases of early disease [61]. Logistic regression demonstrated a significant association between lifetime tobacco consumption of greater than or equal to 10 pack-years and advanced histologic disease at presentation (OR 13.3). This association was independent of age, gender, and alcohol intake, other variables known to predict fibrosis. These results were corroborated by cross-validation using an independent set of 172 patients who had PBC for confirmation. The exact mechanism by which tobacco smoking affects the etiopathogenesis of PBC is unclear. It has been long been argued that the chemicals in cigarette smoke alter the balance of T-helper-1 to T-helper-2 lymphocytes, influencing cytokine production in the pattern that predominates in patients who have PBC [4]. Other lifestyle factors explored in PBC include pet ownership, alcohol consumption, and experience of stressful events. In a population-based, case-control study of PBC in the United Kingdom, none of these factors was found significantly associated with disease [58]. Additionally, in a survey
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study from the United States, intake of dietary fat was explored and found similar in PBC cases and controls [55]. Cosmetic compounds contain chemicals that have been evaluated for an association with PBC. A case-control study of 222 patients who had PBC from France found no association between the use of hair dye and PBC [60]. A study from the United States found a minimally increased OR of 1.002 for patients who had PBC over controls with each additional use of nail polish per year (P ¼ .0136) [4]. Toxin exposure Among the environmental factors considered potential risk factors for PBC, xenobiotics are at the forefront. Xenobiotics are chemical compounds that are not found naturally within living organisms. Strong linkage of PBC to specific xenobiotic exposure has not yet been reported, although halogenated hydrocarbons, aromatic hydrocarbons, and other additives in common commercial products and in industrial processes are implicated. In animal models, exposure to specific halogenated compounds induces AMA [62–64]. Halogenated hydrocarbons and aromatic hydrocarbons constitute the major toxins identified at toxic waste sites in New York City [65]. As described previously, Ala and colleagues noted an increased prevalence of PBC cases near toxic waste sites in New York City [43]. The open-air nature of the toxic sites associated with PBC and the lack of use of local ground water for drinking by area residents suggest airborne dissemination as a route of exposure. Given the volatile nature of organic compounds, widespread dispersion over many miles would involve their binding to aerosolized particulate matter. Detailed data are not available for airborne particulate matter concentrations throughout New York City. As discussed previously, however, nationwide geographic cluster analysis of PBC has revealed an association between PBC clusters and areas with high concentrations of airborne particulate matter (Joseph Odin and colleagues, unpublished data, 2007). Although these studies normalize for geographic differences in gender, age, and racial distribution, they do not adjust for other socioeconomic factors. Epidemiologic studies from the United Kingdom attempting to match geographic frequency of PBC to regional water supply in the past have been inconclusive. Triger [9] noted that 30 of 34 patients (88%) who had PBC living in Sheffield derived their drinking water from the Revelin reservoir. The relative risk for PBC associated with this water supply initially was calculated at 11.3 (95% CI, 3.9–31.9; P!.0001). Re-evaluation of this data in a much larger cohort did not confirm this finding, however [32]. Mayberry and colleagues [66] found clustering of a small number of PBC cases associated with the water supply in two areas within Nottingham. According to Prince and James [3], however, further unpublished analysis failed to confirm the original finding. An association between PBC clustering and air pollution was not evaluated in these studies.
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Past history of infection Many theorize that, as is the case with other autoimmune diseases, PBC develops as a result of ‘‘molecular mimicry,’’ with circulating antibodies developing normally in response to infection and then pathologically cross-reacting to self-antigens to cause disease [67]. In a controlled, interview-based study of more than 1000 patients who had PBC using a modified version of the United States National Health and Nutrition Examination Survey questionnaire (NHANES III), a history of urinary tract infection (UTI) was found with statistically significant increased frequency in PBC cases than controls (59% versus 52%; P ¼ .0003) [55]. In multivariable modeling, UTI was independently associated with PBC in this study. Similarly, an increased prevalence and frequency of vaginal infections was found in female patients in this PBC cohort. Neither UTI history nor vaginal infection history was confirmed by laboratory data in this study. Perhaps also relevant to the theory of an infectious trigger for loss of immune tolerance, a higher rate of tonsillitis was seen in affected patients in this study. One additional case-control study from the United States describes a similar significant association between history of UTI and PBC, as does a recent abstract describing case-control data from France [4,60]. A weak association was found in a case-control study from the United Kingdom [58]. Although a specific causative infectious agent for PBC has yet to be identified, research in this realm is ongoing. Chlamydial infection recently was ruled out as a risk factor for PBC [68], and a role for human betaretrovirus is being investigated. This virus is more prevalent among those who have PBC than those who do not have the disease [69]. Its importance in the etiopathogenesis of PBC, however, remains controversial. Reproductive factors It is postulated that persistence of immunocompetent fetal cells in maternal circulation may play a role in promoting PBC. A study from the United Kingdom found no greater association with PBC in nulliparous women than those who had incomplete pregnancies (as a result of abortion, miscarriage, or stillbirth), single pregnancies, or multiple pregnancies [58]. A study performed in the United States found that pregnancy, in particular multiparity, was positively associated with PBC [70]. A more recent, larger case-control study could not confirm these data but did suggest nulliparity might have a protective effect, with absence of pregnancy associated with a risk ratio for disease of 0.6 (95% CI, 0.45–0.83) [4]. French data looking at 222 patients who had PBC versus 509 controls found that although the mean number of pregnancies in the two groups was similar, the age at first pregnancy was significantly lower in the PBC group than it was in the control group (24.0 4.8 years versus 25.0 4.5 years; P ¼ .0096) [60]. Data on the effect of exogenous estrogen on PBC also are conflicting. A case-control study performed in the United States found that the current
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or prior use of hormone replacement therapy was observed at higher than expected rates in patients who had PBC as opposed to disease-free controls (60% versus 49%; P!.0001) [4]. The French data do not support these results, however, finding hormone replacement therapy use no more frequent in women who had PBC than controls [60]. According to this study, past oral contraceptive use is significantly associated with a decreased risk for the disease (adjusted OR 0.64; 95% CI, 0.43–0.95) [60]. Prospective studies are needed to clarify the role of reproductive hormones in disease pathogenesis.
Summary Since the first descriptive study of the epidemiology of PBC in 1974, significant variation in the incidence and prevalence of this disease has been noted worldwide, although an increased prevalence consistently is reported among family members of those who have PBC. At the same time, studies suggest environmental exposure to specific chemicals or infectious agents may be risk factors for PBC. The etiopathogenesis of PBC likely hinges on a complex interplay between genetic and environmental risk factors. The diagnosis of PBC long after the development of autoantibodies limits the ability to assign risk factors as disease triggers or accelerants. Sorting out the disease stage at which different risk factors are important will require large, multicenter, longitudinal studies. Successful research efforts ultimately will depend on the establishment of worldwide data systems and employment of more uniform methods of analysis.
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[34] Sood S, Gow PJ, Christie JM, et al. Epidemiology of primary biliary cirrhosis in Victoria, Australia: high prevalence in migrant populations. Gastroenterology 2004;127(2):470–5. [35] Chan CY, Lee SD, Huang YS, et al. Primary biliary cirrhosis in Taiwan. J Gastroenterol Hepatol 1990;5(5):560–5. [36] Yap I, Wee A, Tay HH, et al. Primary biliary cirrhosisdan uncommon disease in Singapore. Singapore Med J 1996;37(1):48–50. [37] Bittencourt PL, Farias AQ, Abrantes-Lemos CP, et al. Prevalence of immune disturbances and chronic liver disease in family members of patients with primary biliary cirrhosis. J Gastroenterol Hepatol 2004;19(8):873–8. [38] Delgado J, Sperber AD, Novack V, et al. The epidemiology of primary biliary cirrhosis in southern Israel. Isr Med Assoc J 2005;7(11):717–21. [39] Steinke D, Weston T, Morris A, et al. Incidence, prevalence and resource use of primary biliary cirrhosis in Tayside, Scotland. J Hepatol 2001;34(1):181. [40] Hislop WS, Main G, Robertson AJ. Primary biliary cirrhosis: experience in a non-referral centre. Lancet 1981;2(8238):144. [41] Lazaridis KN, Talwalkar JA. Clinical epidemiology of primary biliary cirrhosis: incidence, prevalence, and impact of therapy. J Clin Gastroenterol 2007;41(5):494–500. [42] Prince MI, Chetwynd A, Diggle P, et al. The geographical distribution of primary biliary cirrhosis in a well-defined cohort. Hepatology 2001;34(6):1083–8. [43] Ala A, Stanca CM, Bu-Ghanim M, et al. Increased prevalence of primary biliary cirrhosis near Superfund toxic waste sites. Hepatology 2006;43(3):525–31. [44] United States Environmental Protection Agency. AirData: access to air pollution data. Avialable at: http://www.epa.gov/air/data/index.html. Accessed May 10, 2007. [45] Abu-Mouch S, Selmi C, Benson GD, et al. Geographic clusters of primary biliary cirrhosis. Clin Dev Immunol 2003;10(2–4):127–31. [46] Arbour L, Field L, Ross P, et al. The mystery of primary biliary cirrhosis in British Columbia’s First Nations people. Int J Circumpolar Health 2004;63(Suppl 2):185–8. [47] Brind AM, Bray GP, Portmann BC, et al. Prevalence and pattern of familial disease in primary biliary cirrhosis. Gut 1995;36(4):615–7. [48] Jones DE, Watt FE, Metcalf JV, et al. Familial primary biliary cirrhosis reassessed: a geographically-based population study. J Hepatol 1999;30(3):402–7. [49] Bach N, Schaffner F. Familial primary biliary cirrhosis. J Hepatol 1994;20(6):698–701. [50] Floreani A, Naccarato R, Chiaramonte M. Prevalence of familial disease in primary biliary cirrhosis in Italy. J Hepatol 1997;26(3):737–8. [51] Tsuji K, Watanabe Y, Van De Water J, et al. Familial primary biliary cirrhosis in Hiroshima. J Autoimmun 1999;13(1):171–8. [52] Olafsson S, Gudjonsson H, Selmi C, et al. Antimitochondrial antibodies and reactivity to N. aromaticivorans proteins in Icelandic patients with primary biliary cirrhosis and their relatives. Am J Gastroenterol 2004;99(11):2143–6. [53] Lazaridis KN, Juran BD, Boe GM, et al. Increased prevalence of antimitochondrial antibodies in first-degree relatives of patients with primary biliary cirrhosis. Hepatology 2007;46(3):785–92. [54] Selmi C, Invernizzi P, Zuin M, et al. Genetics and geoepidemiology of primary biliary cirrhosis: following the footprints to disease etiology. Semin Liver Dis 2005;25(3):265–80. [55] Parikh-Patel A, Gold EB, Worman H, et al. Risk factors for primary biliary cirrhosis in a cohort of patients from the united states. Hepatology 2001;33(1):16–21. [56] Watt FE, James OF, Jones DE. Patterns of autoimmunity in primary biliary cirrhosis patients and their families: a population-based cohort study. Q J Med 2004;97(7): 397–406. [57] Selmi C, Mayo MJ, Bach N, et al. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology 2004;127(2):485–92. [58] Howel D, Fischbacher CM, Bhopal RS, et al. An exploratory population-based case-control study of primary biliary cirrhosis. Hepatology 2000;31(5):1055–60.
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[59] James O, Ducker S, Prince M. Case control studies support the association of environmental and genetic risk factors with primary biliary cirrhosis. Hepatology 2005;42(Suppl): 209A. [60] Corpechot C, Chretien Y, Chazouilleres O. Results of the French study of risk factors for primary biliary cirrhosis. Hepatology 2007;46(Suppl 4):547A. [61] Zein CO, Beatty K, Post AB, et al. Smoking and increased severity of hepatic fibrosis in primary biliary cirrhosis: a cross validated retrospective assessment. Hepatology 2006; 44(6):1564–71. [62] 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):2956–63. [63] Leung PS, Quan C, Park O. Immunization with a xenobiotic 6-bromohexanoate bovine serum albumin conjugate induces antimitochondrial antibodies. J Immunol 2003;170: 5326–32. [64] Leung PS, Park O, Tsuneyama K. Induction of primary biliary cirrhosis in guinea pigs using chemical xenobiotic immunization: implications for tolerance and the etiology of human PBC. Hepatology 2007;46(Suppl):543A. [65] Annual Report of the Inactive Hazardous Waste Disposal Sites in New York. New York State Department of Environmental Conservation, Division of Environmental Remediation, 2002. [66] Mayberry J, Giggs J, Smart H. Urban clustering of primary biliary cirrhosis. Gut 1986;27: 1265A. [67] Selmi C, Ichiki Y, Invernizzi P, et al. The enigma of primary biliary cirrhosis. Clin Rev Allergy Immunol 2005;28(2):73–81. [68] Montano-Loza A, Vazquez-Ballesteros E, Meza-Junco J, et al. (Seropositivity for Chlamydia pneumoniae in patients with primary biliary cirrhosis). Gastroenterol Hepatol 2006;29(3): 113–7 [in Spanish]. [69] Xu L, Sakalian M, Shen Z, et al. Cloning the human betaretrovirus proviral genome from patients with primary biliary cirrhosis. Hepatology 2004;39(1):151–6. [70] Parikh-Patel A, Gold E, Utts J, et al. The association between gravidity and primary biliary cirrhosis. Ann Epidemiol 2002;12(4):264–72.
Recent Advances in the Epidemiology of Primary Biliary Cirrhosis Rebekah G. Gross, MDa,*, Joseph A. Odin, MD, PhDb a
Division of Gastroenterology, The Mount Sinai School of Medicine, Box 1069, One Gustave L. Levy Place, New York, NY 10029, USA b Division of Liver Diseases, The Mount Sinai School of Medicine, Box 1123, One Gustave L. Levy Place, New York, NY 10029, USA
Primary biliary cirrhosis (PBC) is an uncommon chronic liver disease of unknown origin that occurs worldwide in an uneven geographic distribution. PBC most commonly afflicts middle-aged women in industrialized countries [1]. The pathogenesis, although incompletely understood, is known to involve progressive, nonsuppurative inflammatory destruction of intrahepatic bile ducts, leading to chronic cholestasis, which predisposes to cirrhosis [2]. Individuals who have PBC typically are identified at routine check-up with laboratory evidence of cholestasis, at a time when they are asymptomatic. The presence of antimitochondrial antibodies (AMA) in the serum is highly specific for PBC and it is diagnostic of the disease particularly in the presence of elevated serum alkaline phosphatase levels [2]. In some cases (certainly in those who test AMA negative), a liver biopsy may help confirm the diagnosis of PBC, but more often liver biopsy is used to determine disease stage for prognostic purposes. Despite an often asymptomatic presentation, PBC is an important cause of liver-related morbidity, with affected individuals making significant use of health care resources, including liver transplantation [3]. The Healthcare Cost and Utilization Project estimates the annual economic burden from this disease at $69 to $115 million for hospital charges alone [4]. There is concern that the economic impact of PBC could grow significantly in the future because of its increasing incidence and prevalence the world over (discussed later). Costs actually may decline in years to come, however, as a recent study suggests progressively fewer individuals diagnosed with PBC are transplanted, possibly because of improved treatment of PBC [5]. This update describes the changing epidemiology of PBC and examines * Corresponding author. E-mail address: [email protected] (R.G. Gross). 1089-3261/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.cld.2008.02.001 liver.theclinics.com
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the evidence supporting proposed genetic and environmental risk factors that may play a role in the etiopathogenesis of the disease.
Incidence and prevalence of primary biliary cirrhosis In the nearly 3.5 decades since Hamlyn and Sherlock [6] presented the first descriptive epidemiology study of PBC based on a review of mortality rates determined from United Kingdom death certification data, the literature on this topic has exploded. Although a large quantity of data has been amassed, sometimes the quality has been called into question. Most studies are limited to highly industrialized countries, and many, in particular those published before 1986, are marred by flawed methodology, use of small sample sizes, incomplete case ascertainment methods, and poorly defined diagnostic criteria to define PBC [3]. Perhaps in part because of these limitations, epidemiologic studies of PBC vary widely in their estimates of the frequency of PBC. Distinguishing true trends from artifactual differences stemming from variegated methodology across studies is challenging. As noted by Prince and James [3] in their excellent review of PBC published in 2003, however, individual studies that follow trends in a given population over time and those that report on the variation of PBC frequency within a given region have proved particularly useful. In reviewing these data, two broad observations emerge: (1) the incidence and prevalence of PBC are increasing over time and (2) geographic clustering of disease is evident, suggesting genetic and environmental influences on the etiopathogenesis of disease. Temporal changes in primary biliary cirrhosis incidence and prevalence Initial studies from Europe between 1970 and 1986 calculated the mean incidence of PBC at 0.6 to 13.7 cases per million population per year and the point prevalence at 11.1 to 128 cases per million population [6–13]. The majority of these studies focused on discrete geographically defined populations in the United Kingdom, Sweden, and Spain, although one surveyed a pan-European population, merging data from 10 European countries. Since 1986, additional studies with arguably more reliable and consistent methodologies have revealed higher incidence rates of 0.7 to 49 cases per million population per year and prevalence rates of 6.7 to 402 cases per million population [14–38]. These later studies also cast a wider net across the globe, looking at populations not only in Europe but also in North America, Australia, the Middle East, and Asia. Given that they focus on new geographic regions and their methods vary from older studies, these studies provide inconclusive evidence as to whether or not the prevalence and incidence of PBC are increasing. Analysis of specific geographic regions in the United Kingdom over time have attempted to address these concerns. Ray-Chadhuri and colleagues
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[32], updating data from an earlier epidemiologic study by Triger [9], observed an increase in annual incidence rates among residents of Sheffield, England, from 5.8 cases per million in the late 1970s to 20.5 cases per million in 1987. This incidence rate then was found to remain stable between 1987 and 1999. The prevalence of PBC, however, continued to rise during this period from 54 cases per million in 1977 to 57 cases per million in 1987 to 136 in 1993 and, finally, to 238 in 1999 [32]. Increased prevalence in the absence of increased incidence may reflect a combination of earlier diagnosis and improved care, including liver transplantation. Similarly, Steinke and colleagues [39], studying residents of Tayside, Scotland, over the decade spanning from 1986 to 1996, found an increase in annual incidence rate for PBC from 48 to 55 new cases per million. During the same period, the prevalence of PBC in this population was observed to rise from 186 to 379 cases per million. These rates represent a substantial increase over those documented in this same population by Stuart-Hislop and colleagues [8,40] in the late 1970s. At that time, the incidence of PBC was documented at 10.6 new cases per million and prevalence was calculated at 40.2 cases per million. Finally, sequential studies following residents of Northeast England documented an increase in incidence and prevalence of PBC in this region. Taken in conjunction, these studies show a rise in incidence from a mean of 11.3 cases per million in 1976 to18.8 cases per million in the years 1983 to 1987, 26.1 cases per million in the years 1987 to 1990, and 31.1 cases per million in the years 1991 to1994. The studies similarly show a rise in prevalence in the region over this time period, from 16 cases per million in 1976 to 250.8 cases per million in 1994 [17,29,30]. This point prevalence is among the highest documented in unselected populations worldwide, trumped only by the discoveries of a prevalence of 289 cases per million in Alaska [33], 379 cases per million in Scotland [39], and of 402 cases per million in Rochester, Minnesota [31]. The higher rates of incidence and prevalence of PBC in more contemporary studies and the increase in rates observed over time in specific geographic areas may reflect a true increase in frequency of the disease or simply an apparent increase due to a higher detection rate. Possible explanations for increased detection include more widespread availability of laboratory testing and changes in clinical practice patterns where screening tests are applied more commonly in the setting of mild or poorly-defined symptoms [3,41]. At least in part, this seems related to increased clinician and patient awareness of PBC and an improved ability to link a given clinical picture to the diagnosis of PBC. Room for improvement in clinician awareness remains even in the United Kingdom. James and colleagues [30] found that in patients in Northern England who underwent testing and had results consistent with PBC, in 37% the diagnosis neither was made nor considered by the consultant who had ordered the investigations.
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Geographic differences in primary biliary cirrhosis incidence and prevalence If the observed variation in incidence and prevalence of PBC reflects a true epidemiologic phenomenon, differing exposure to environmental risk factors may help to explain it. As discussed later, several environmental agents, potentially affecting women preferentially, already are implicated in the etiopathogenesis of PBC. Individual studies that document local geographic variation in the burden of PBC strengthen the case for environmental influences on the development and progression of this disease. In their extensive review of geographic variation in the prevalence of PBC, Prince and James [3] outlined 14 studies comparing the prevalence of this disease among subregions within Europe, Australia, and Canada. As the investigators point out, 11 of the 14 studies used aggregated data, outlining regions by administrative or political boundaries that may not be particularly meaningful from an epidemiologic perspective. All but 3 of the 14 studies found a differential distribution of PBC cases according to subregion. The most detailed data were extracted from large national studies performed in Estonia and Sweden. In the former, Remmel and colleagues [23] reported that the prevalence of PBC in the district of Viljandi was approximately 3 times greater than that in the rest of Estonia (P!.0001). In the latter, Danielsson and colleagues [18] found that the prevalence of PBC in Vaterbotten County was approximately half that seen in two other counties in Northern Sweden (P ¼ .004). Prince and colleagues’ [42] study of a cohort of 770 patients who had PBC in Northeast England used point process analysis to reveal marked clustering of PBC in several urban areas (up to 13 cases per km2). Although the investigators could find no obvious demographic or geographic features to explain the grouping, the results again seem to imply the presence of one or more environmental risk factors associated with PBC. North American studies have similarly localized clusters of PBC. Ala and colleagues [43] noted grouping of PBC cases in small geographic regions within New York City. In this study, a relationship was observed between the location of toxic waste sites and increased prevalence of PBC cases. A nationwide analysis to detect large-scale clusters of advanced PBC associated with high levels of air pollution (Odin and colleagues, unpublished data, 2007) identified two statistically significant clusters surrounding industrial cities located on the Great Lakes (one in Buffalo, New York, and a second in Gary, Indiana) and a cluster in Los Angeles (Fig. 1). The relative risk for PBC was 1.92-fold to 2.12-fold greater in these clusters after normalizing for age, race, and gender. United States Environmental Protection Agency monitoring sites within these clusters have recorded mean air pollutant levels among the top 10% nationally [44]. Other investigators who have noted geographic clustering of PBC include Abu-Mouch and colleagues [45], who found seven cases of PBC clustering in
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Fig. 1. Clusters of individuals listed for transplantation due to PBC. Using data for mean daily airborne pollutant concentrations obtained from the United States Environmental Protection Agency and data on individuals listed for liver transplantation from the Organ Procurement and Transplantation Network, three statistically significant (all P!.050) PBC clusters were identified using SaTScan software. The increased relative risk for PBC within each cluster ranged from 1.92 to 2.12.
a small town in Alaska and reported the case of a husband and wife who were diagnosed with PBC after growing up in the same city neighborhood. Likewise, Arbour and colleagues [46] have demonstrated that First Nations people of Vancouver, British Columbia, who comprise only 3.9% of the general population in the area, constitute 25% of patients referred for liver transplantation for PBC. PBC is the leading indication for liver transplantation referral in First Nations people, occurring at a rate 8 times higher than that of patients of other descent who have PBC (P ¼ .0001). Although genetic differences may contribute to the increased prevalence of PBC among First Nations people, a disproportionate number of cases were noted
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in patients who had this ethnic background living on Vancouver Island (48% of cases versus 18% expected, P!.05) [46]. Comparison of prevalence rates between immigrant and nonimmigrant groups living in the same area often is useful in assessing the relative roles of environment and genetics in the etiopathogenesis of disease. Data on patterns of PBC in immigrants seem to support the notion of interplay between genetic and environmental factors. A recent study from Victoria, Australia, where the overall prevalence of PBC is documented at 51 cases per million population, observed significantly higher rates of PBC in European immigrants (141 cases per million from Great Britain [a lower rate than that seen in British living in Great Britain], 200 cases per million from Italy, and 208 cases per million from Greece) [34]. Similarly, although the overall prevalence of PBC in southern Israel approximates that seen in some European countries, the rate is much higher among more recent immigrants to Israel, and it is higher in Jews than in Arabs. Delgado and colleagues [38] found that in women older than 40, the prevalence varied from 135 cases per million in those born in Israel to 450 cases per million in immigrants from Russia and Eastern Europe and 700 cases per million in immigrants from North Africa and Asia. Finally, Anand and colleagues [24] estimated that, although exceedingly rare in South Asia itself, the prevalence of PBC in South Asian migrants to Birmingham, United Kingdom, approached that seen in the host country, exceeding 14 cases per million. This number is striking given that PBC once was believed not to occur at all in India, although the disease more recently has been noted in reports and small series, presumably as a result of improved screening methods. The different prevalence of PBC among immigrants could be interpreted as an indication that local environment does not play a significant role in the etiopathogenesis of PBC. Given the long lag-time between loss of immune tolerance to mitochondrial autoantigens and the diagnosis of PBC, however, it is possible that local environmental factors affect the earlier stages of PBC. Also, environmental exposure by immigrants often does not entirely mimic that by nonimmigrants residing in the same region. Prevalence of primary ciliary cirrhosis in affected families Family members of patients who have PBC demonstrate an increased risk for developing the disease, such that cases occurring within a family are termed ‘‘familial PBC’’ [47]. The reported rate for familial PBC ranges from 1% to 6.4% in England, with higher rates found when more distant relatives are included in the analysis [7,17,47,48]. The rate is documented at 4.3% in the United States [49], 4.5% in Sweden [18], 3.8% in Italy [50], 5.1% in Japan [51], and 7.1% in Iceland [52], arguably a population that is unique from a genetic perspective. The prevalence rate of PBC in first-degree relatives ranges from 5% to 6% in various geographic areas [48,49,51], with the relative risk for a sibling of an affected individual diagnosed with
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the disease quoted as high as 10.5 [48]. Although the increased prevalence of PBC in relatives of PBC is significant, it is not great enough to account for geographic clustering of PBC. Most commonly, PBC is found among sisters and daughters who are younger at diagnosis than are index cases [51]. Additionally, serum AMA presence, which may be a harbinger of PBC, is found to aggregate in pedigrees of patients who have PBC. Lazaridis and colleagues, looking 145 families who had PBC, found that the prevalence of AMA in first-degree relatives of index cases versus controls was 13.1% versus 1%, with female family members affected predominantly [53]. Individuals who have PBC and their relatives may possess an increased frequency of immune-related gene polymorphisms [54] and autoimmume conditions. Patients who have PBC are known to exhibit an increased frequency of several extrahepatic autoimmune disorders. In one series, the risk of autoimmune disorders occurring among patients with PBC, including Sjogren’s syndrome and Raynaud’s syndrome, was found to be 3- to 14-fold higher than among controls [55]. Multivariate analysis suggests that Sjo¨gren’s syndrome and systemic lupus erythematosus are risk factors for PBC [4]. Although associations between PBC and other autoimmune diseases are noted, their true extent is not established. Looking at patterns of autoimmunity in the families of 160 index individuals who had PBC in the United Kingdom, Watt and colleagues [56] found that up to 14% of firstdegree relatives of the index cases had at least one autoimmune condition other than PBC, a rate over three times that for autoimmune disorders in the general population. In a much smaller study out of Brazil, however, where PBC is rare, Bittencourt and colleagues [37] found that the frequency and titers of autoantibodies and the prevalence of extrahepatic autoimmune disease in relatives of patients who had PBC were similar to those observed for the general population. Is familial PBC the result predominantly of genetic similarities or shared environmental exposures? The increased prevalence of certain genetic polymorphisms (eg, vitamin D receptor polymorphisms) in those who have PBC, including, in a variety of geographic areas supports an important role for genetics in the clustering of PBC within families [54]. Perhaps the most convincing evidence for a genetic influence in the development of PBC derives from twin studies. In autoimmune diseases other than PBC, concordance rates in monozygotic twins vary broadly, ranging from 12% to 15% in rheumatoid arthritis to 75% to 83% in celiac disease [57]. The rate averages less than 50% in most autoimmune diseases. Selmi and colleagues [57] studied concordance rates of 16 twin sets affected by PBC, the largest study of this kind in PBC to date. The investigators found the concordance rate for PBC registered 63% for eight genetically proved monozygotic twin sets (all female) whereas it was 0% for eight dizygotic twins sets (four female and four male-female pairs). Such a high concordance rate in monozygotic twins and the dramatic difference for dizygotic twins strongly suggests a genetic component to the etiopathogenesis of PBC. (Specific genetic risk
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factors associated with PBC are discussed in the article by Juran and Lazaridis elsewhere in this issue.)
Lifestyle or environmental risk factors associated with primary biliary cirrhosis As the twin data suggest, although genetic factors may increase susceptibility to PBC, they likely are not sufficient to cause disease in all cases. Recent epidemiologic research has sought to better define environmental factors that may play an adjunctive role in precipitating disease. Associations between PBC and various lifestyle choices, including smoking, toxin exposure, history of infection, and reproductive factors, have been explored (Table 1). Although the data can be conflicting, strengths of more recent studies include their case-control methodology and increased sample size over earlier reports. Lifestyle choices Epidemiologic studies consistently have found a positive association between smoking history and PBC (Table 2). In one British study, a history of past smoking was observed in 76% of patients who had PBC versus only 57% of unaffected controls. Furthermore, a longer smoking history was linked more often to PBC, with prevalence of the disease highest among those who had smoked more than 20 years (odds ratio [OR] 2.4 among all smokers; OR 3.5 among those who had greater than 20-year exposure). These data suggest a dose-response relationship between smoke exposure and disease development [58]. A subsequent survey study in the United Table 1 Proposed environmental risk factors for primary biliary cirrhosis Risk factor
Reproducibility
Cigarette smoking History of UTI History of other infectious exposure Chlamydia Human betaretrovirus Chemical exposure Toxic waste Cosmetics (eg, hair dye, nail polish) Prior surgery Frequency of pregnancy Hormone replacement therapy Pet ownership Alcohol consumption Stressful life events
High Medium
Abbreviation: na, no association found.
Very low Low Medium Low Low Low Low na na na
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Table 2 Smoking as a risk factor for primary biliary cirrhosis based on case-control studies Authors
Area Method of studied data collection
Number of cases enrolled Odds ratio
Howel UK et al, [57]
Postal self-completion questionnaire
Parikh-Patel et al, [54] Gershwin et al, [4] James et al, [58]a Corpechot et al, [59]b
Postal self-completion 199 questionnaire Telephone questionnaire 1032
a
US US UK
Postal self-completion questionnaire France Not documented
100
95% CI
2.4 (ever smoked) 3.5 (smoked R20 years) 2.04 (ever smoked)
1.1–3.8
1.6 (ever smoked)
1.3–1.9
2234 (Group1) 1.6 294 (Group 2) 1.8 210 3.12 (active and passive smoke exposure) 1.69 (active smoking)
1.4–4.1 1.9–6.3
1.4–1.8 1.3–2.3 2.0–5.0
1.1–2.6
Data published in abstract form, reporting on two separate groups of patients who had
PBC. b
Data published in abstract form; additional information derived from Joseph Odin and Raoul Poupon, personal communication, December 2007.
States found elevated odds of having smoke exposure in patients who had PBC compared with siblings and friends who did not have PBC [55]. Two additional questionnaire-based, case-control studies have confirmed that a history of smoking is significantly associated with an increased risk for PBC [4,59]. Results of a recent French study suggest a past history of active or passive smoking raises the risk for PBC at least threefold [60]. Smoking not only may predispose to disease but also may accelerate its progression. A recent retrospective assessment performed at three major teaching hospitals in the United States found that mean lifetime tobacco consumption was higher in PBC cases of advanced histologic disease at presentation than it was in cases of early disease [61]. Logistic regression demonstrated a significant association between lifetime tobacco consumption of greater than or equal to 10 pack-years and advanced histologic disease at presentation (OR 13.3). This association was independent of age, gender, and alcohol intake, other variables known to predict fibrosis. These results were corroborated by cross-validation using an independent set of 172 patients who had PBC for confirmation. The exact mechanism by which tobacco smoking affects the etiopathogenesis of PBC is unclear. It has been long been argued that the chemicals in cigarette smoke alter the balance of T-helper-1 to T-helper-2 lymphocytes, influencing cytokine production in the pattern that predominates in patients who have PBC [4]. Other lifestyle factors explored in PBC include pet ownership, alcohol consumption, and experience of stressful events. In a population-based, case-control study of PBC in the United Kingdom, none of these factors was found significantly associated with disease [58]. Additionally, in a survey
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study from the United States, intake of dietary fat was explored and found similar in PBC cases and controls [55]. Cosmetic compounds contain chemicals that have been evaluated for an association with PBC. A case-control study of 222 patients who had PBC from France found no association between the use of hair dye and PBC [60]. A study from the United States found a minimally increased OR of 1.002 for patients who had PBC over controls with each additional use of nail polish per year (P ¼ .0136) [4]. Toxin exposure Among the environmental factors considered potential risk factors for PBC, xenobiotics are at the forefront. Xenobiotics are chemical compounds that are not found naturally within living organisms. Strong linkage of PBC to specific xenobiotic exposure has not yet been reported, although halogenated hydrocarbons, aromatic hydrocarbons, and other additives in common commercial products and in industrial processes are implicated. In animal models, exposure to specific halogenated compounds induces AMA [62–64]. Halogenated hydrocarbons and aromatic hydrocarbons constitute the major toxins identified at toxic waste sites in New York City [65]. As described previously, Ala and colleagues noted an increased prevalence of PBC cases near toxic waste sites in New York City [43]. The open-air nature of the toxic sites associated with PBC and the lack of use of local ground water for drinking by area residents suggest airborne dissemination as a route of exposure. Given the volatile nature of organic compounds, widespread dispersion over many miles would involve their binding to aerosolized particulate matter. Detailed data are not available for airborne particulate matter concentrations throughout New York City. As discussed previously, however, nationwide geographic cluster analysis of PBC has revealed an association between PBC clusters and areas with high concentrations of airborne particulate matter (Joseph Odin and colleagues, unpublished data, 2007). Although these studies normalize for geographic differences in gender, age, and racial distribution, they do not adjust for other socioeconomic factors. Epidemiologic studies from the United Kingdom attempting to match geographic frequency of PBC to regional water supply in the past have been inconclusive. Triger [9] noted that 30 of 34 patients (88%) who had PBC living in Sheffield derived their drinking water from the Revelin reservoir. The relative risk for PBC associated with this water supply initially was calculated at 11.3 (95% CI, 3.9–31.9; P!.0001). Re-evaluation of this data in a much larger cohort did not confirm this finding, however [32]. Mayberry and colleagues [66] found clustering of a small number of PBC cases associated with the water supply in two areas within Nottingham. According to Prince and James [3], however, further unpublished analysis failed to confirm the original finding. An association between PBC clustering and air pollution was not evaluated in these studies.
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Past history of infection Many theorize that, as is the case with other autoimmune diseases, PBC develops as a result of ‘‘molecular mimicry,’’ with circulating antibodies developing normally in response to infection and then pathologically cross-reacting to self-antigens to cause disease [67]. In a controlled, interview-based study of more than 1000 patients who had PBC using a modified version of the United States National Health and Nutrition Examination Survey questionnaire (NHANES III), a history of urinary tract infection (UTI) was found with statistically significant increased frequency in PBC cases than controls (59% versus 52%; P ¼ .0003) [55]. In multivariable modeling, UTI was independently associated with PBC in this study. Similarly, an increased prevalence and frequency of vaginal infections was found in female patients in this PBC cohort. Neither UTI history nor vaginal infection history was confirmed by laboratory data in this study. Perhaps also relevant to the theory of an infectious trigger for loss of immune tolerance, a higher rate of tonsillitis was seen in affected patients in this study. One additional case-control study from the United States describes a similar significant association between history of UTI and PBC, as does a recent abstract describing case-control data from France [4,60]. A weak association was found in a case-control study from the United Kingdom [58]. Although a specific causative infectious agent for PBC has yet to be identified, research in this realm is ongoing. Chlamydial infection recently was ruled out as a risk factor for PBC [68], and a role for human betaretrovirus is being investigated. This virus is more prevalent among those who have PBC than those who do not have the disease [69]. Its importance in the etiopathogenesis of PBC, however, remains controversial. Reproductive factors It is postulated that persistence of immunocompetent fetal cells in maternal circulation may play a role in promoting PBC. A study from the United Kingdom found no greater association with PBC in nulliparous women than those who had incomplete pregnancies (as a result of abortion, miscarriage, or stillbirth), single pregnancies, or multiple pregnancies [58]. A study performed in the United States found that pregnancy, in particular multiparity, was positively associated with PBC [70]. A more recent, larger case-control study could not confirm these data but did suggest nulliparity might have a protective effect, with absence of pregnancy associated with a risk ratio for disease of 0.6 (95% CI, 0.45–0.83) [4]. French data looking at 222 patients who had PBC versus 509 controls found that although the mean number of pregnancies in the two groups was similar, the age at first pregnancy was significantly lower in the PBC group than it was in the control group (24.0 4.8 years versus 25.0 4.5 years; P ¼ .0096) [60]. Data on the effect of exogenous estrogen on PBC also are conflicting. A case-control study performed in the United States found that the current
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or prior use of hormone replacement therapy was observed at higher than expected rates in patients who had PBC as opposed to disease-free controls (60% versus 49%; P!.0001) [4]. The French data do not support these results, however, finding hormone replacement therapy use no more frequent in women who had PBC than controls [60]. According to this study, past oral contraceptive use is significantly associated with a decreased risk for the disease (adjusted OR 0.64; 95% CI, 0.43–0.95) [60]. Prospective studies are needed to clarify the role of reproductive hormones in disease pathogenesis.
Summary Since the first descriptive study of the epidemiology of PBC in 1974, significant variation in the incidence and prevalence of this disease has been noted worldwide, although an increased prevalence consistently is reported among family members of those who have PBC. At the same time, studies suggest environmental exposure to specific chemicals or infectious agents may be risk factors for PBC. The etiopathogenesis of PBC likely hinges on a complex interplay between genetic and environmental risk factors. The diagnosis of PBC long after the development of autoantibodies limits the ability to assign risk factors as disease triggers or accelerants. Sorting out the disease stage at which different risk factors are important will require large, multicenter, longitudinal studies. Successful research efforts ultimately will depend on the establishment of worldwide data systems and employment of more uniform methods of analysis.
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