Q J Med 2004; 97: 397-406
QJM vol. 97 no. 7 © Association of Physicians 2004; all rights reserved.
Patterns of autoimmunity in primary biliary cirrhosis patients and their families: a population-based cohort study
From the Centre for Liver Research, University of Newcastle, Newcastle-upon-Tyne, UK
Received 28 November 2003 and in revised form 4 March 2004
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Summary |
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Background: Primary biliary cirrhosis (PBC) is a chronic liver disease with autoimmune features but uncertain aetiology. Increased risk of PBC among relatives of patients may reflect common environmental factors, or inherited immunogenetic susceptibility. Associations between PBC and other autoimmune diseases have been reported, but their true extent and pattern is unknown.
Aim: To examine the prevalence and association patterns of autoimmune disease in a representative group of PBC patients.
Design: Clinical cohort study.
Methods: We clinically assessed members of a geographically-based PBC patient cohort (n = 160) for the presence of additional autoimmune disease, using established specific diagnostic criteria.
Results: Some 53% of patients had at least one additional autoimmune condition, and 63% had serum autoantibodies other than AMA or ANA. AMA+ patients had a significantly lower prevalence of additional autoimmunity than AMA– patients (49% vs. 79%; p < 0.01). The greatest relative increase in disease prevalence was for scleroderma (8% of patients). Autoimmune disease was present in 14% of first-degree relatives.
Discussion: PBC patients and their families have a wide susceptibility to autoimmunity. This observation supports an autoimmune aetiology and suggests that the genetic basis of PBC is likely to be expressed, at least in part, through factors controlling immune tolerance in general.
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Introduction |
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Primary biliary cirrhosis (PBC) is a chronic liver disease characterized by damage to, and destruction of, the biliary epithelial cells lining small intra-hepatic bile ducts.1 PBC exhibits a number of autoimmune features, including the almost universal presence of auto-antibodies reactive with highly conserved mitochondrial antigens (anti-mitochondrial antibodies, AMA). The almost universal presence of such autoimmune features in PBC has led to the conventional view that the disease has an autoimmune pathogenesis.2 More recently this view has been challenged, and an alternative aetiological model invoking retroviral infection proposed.3 One observation invoked to support an infectious aetiology is the well-described clustering of the disease seen within affected families,4 the suggestion being that family members share exposure to an aetiological agent. An alternative explanation would be, of course, that such familial clustering reflects a sharing of genetic susceptibility factors (although progress in identifying any such loci has been limited5). The observations regarding familial disease susceptibility do not, therefore, help to distinguish between an infectious and an autoimmune aetiology for PBC.
One well-recognized feature of autoimmune disease is the tendency for multiple autoimmune conditions, affecting different organs, to co-exist in individual patients and their families (reflecting, it is believed, shared genetic susceptibility factors).6–8 The presence of a significant rate of non-liver autoimmune disease in PBC patients and their families might therefore be regarded as being supportive evidence for the autoimmune aetiology hypothesis. There are numerous case reports in the literature describing PBC in association with other autoimmune diseases and descriptions, largely anecdotal, of both immune abnormalities and increased susceptibility to autoimmune disease in the relatives of PBC patients.9 To date, however, there have been no large systematic studies specifically addressing the question of the prevalence and patterns of shared susceptibility to autoimmunity in PBC. Where series have been reported, they have been flawed in terms of size or patient selection (typically recruiting patients from trial series in tertiary referral centres, which are not representative of the PBC patient population as a whole)10–12 or have relied on retrospective analysis of case records. Moreover, recent changes in perceptions of disease prevalence and spectrum13 have led to wider diagnosis of PBC, with recognition of the disease in relatively large numbers of patients with milder disease forms. These patients with milder forms of disease may well not have been appropriately represented in some earlier studies. In this study we set out, therefore, to characterize systematically the autoimmune associations of PBC using direct interview in a comprehensive, geographically-based patient cohort identified using modern diagnostic criteria.
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Methods |
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Study design and setting
This was a geographically-based study performed in the North-East of England. Previously described exhaustive case finding approaches have allowed the identification of extant cases of PBC within the geographical area NE1–NE25.14,15 The characterization of this geographically-based, and therefore fully representative, patient cohort has previously been described in detail.4 All PBC patients in this unselected group were assessed by a single investigator and questioned regarding their family history. The relevant local ethical committees approved this study.
Patients
The patients in the study cohort were identified as previously described.4,16 Patients were classified as having ‘definite’ PBC if they exhibited the diagnostic triad of positive serum anti-mitochondrial antibody (titre 
1/40), cholestatic liver function tests and liver histology diagnostic of, or compatible with, PBC.17 Patients exhibiting two of these parameters were classified as having ‘probable’ PBC. A total of 173 probable or definite PBC cases (including transplanted PBC patients) were identified within the geographical study area at the study point.
Diagnostic criteria for autoimmune conditions
A detailed personal and family history of twelve autoimmune conditions was taken from all patients and their autoantibody status checked using standard diagnostic laboratory approaches. The conditions selected had either been specifically reported in PBC patients, or were felt to be representative of the spectrum of organ- and non-organ-specific autoimmune disease. Established diagnostic criteria were used in all cases.
Sjögren's syndrome
Schirmer's tests were administered to all patients who had ocular symptoms, and were considered to be definitely positive when the total linear extent of tear wetting was <10 mm. Total linear tear wetting values of 11–30 mm were interpreted as representing possible positive tests. Results of salivary studies were searched for in the case records. A diagnosis of definite Sjögren's syndrome was made if patients fulfilled the European diagnostic criteria.18 A further category of probable Sjögren's syndrome was defined as symptoms fulfilling validated criteria and: (i) one of: positive Ro autoantibodies, or a definite positive Schirmer's test; or (ii) two of: a possible positive Schirmer's test, a documented previously positive Schirmer's test, high-titre rheumatoid factor, obvious clinical pathology, a positive salivary pool test.
Autoimmune thyroid disease
A history of interventions (surgery or medical treatment) was sought, plus either current or previously abnormal thyroid function tests (TFTs). In the presence of positive history or abnormal TFTs, a current or previous titre of 1/400 of microsomal autoantibodies was taken as confirmatory evidence of autoimmune thyroid disease. In their absence, other causes of thyroid disease were excluded, and a diagnosis of ‘probable autoimmune thyroid disease’ was made.19,20 Sub-clinical disease, and presence of thyroid autoantibodies alone, was also noted.
Rheumatoid arthritis
Patients had to fulfil the 1987 American Rheumatism Association (ARA) revised criteria for the classification of rheumatoid arthritis.21,22 A probable diagnosis was made if three or more of these criteria were present.
Scleroderma
The 1980 American Rheumatism Association criteria for the classification of scleroderma23 were adopted. Cases were defined as diffuse or limited where possible, and the CREST subtype was also noted. A diagnosis of probable scleroderma was made if the patient had Raynaud's and two of: digital scars, sclerodactyly, contractures of the fingers, telangiectasia, a decreased diffusing capacity or oesophageal hypomotility.24
Systemic lupus erythematosus (SLE)
ARA revised criteria for the classification of SLE were used.25
Insulin-dependent diabetes mellitus (IDDM)
This was confirmed if the patient was diagnosed under the age of 30 years, and had been insulin-dependent since diagnosis.26
Polymyositis
The 1995 classification criteria were used.27
Myaesthenia gravis
Enquiry was made regarding muscle weakness and fatigability, of oral anticholinesterase treatment, and neurological follow-up. Tensilon and serum anticholinesterase antibody test results were noted where available.
Autoimmune thrombocytopenic purpura (AITP)
All patients were questioned regarding history of bruising and bleeding tendency, and a platelet count was recorded. Where abnormal, exclusion of other confounding causes of thrombocytopaenia was sought.
Pernicious anaemia
Patients were questioned regarding vitamin B12 injections, and an MCV and haemoglobin were recorded for all patients. Confirmatory investigations were sought.
Addison's disease
Patients were questioned regarding requirement for steroid replacement. Adrenal antibodies and synacthen tests were recorded where possible.
Coeliac disease
All patients were questioned regarding previous endoscopy and requirement for a gluten-free diet, and ongoing clinical features (steatorrhea and weight loss) compatible with malabsorption. Case records of patients who had undergone endoscopy were searched for results of duodenal histology. All patients were screened for serological (anti-reticulin antibodies with anti-endomysial antibody testing in cases of clinical doubt and for confirmation as per local protocols at the time of the study) and haematological abnormality. A diagnosis of coeliac disease was confirmed where there was an existing compatible histological result, or where diagnostic duodenal histological abnormality was identified in a patient prospectively investigated by duodenal biopsy performed, according to the study protocol, because of the ongoing presence of clinical and/or serological features suggestive of coeliac disease.
Family history of autoimmune disease
Family history was documented as extensively as possible using similar criteria. Details of all affected relatives were recorded by proxy. ‘Disconfirming’ questions were used where possible to avoid biased allocation of relatives to diseased groups.
Statistical analysis
Statistical analysis was principally by 2 x 2 contingency tables using Fisher's exact test. The Mantel-Haenszel test was used to allow for further stratification of the population where necessary. The threshold for significance was set at the 5% level.
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Results |
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Of the 173 identified patients, 160 (92%) participated in the study (clinical details in Table 1), 108 (68%) of whom had definite PBC. Of the 52 patients with probable disease, 19 were AMA-negative. Of these 10/19 (53%) were positive (
1/40) for antinuclear antibodies (ANA), and 5/19 (26%) were positive for anti-smooth muscle antibodies. Of 160 participants, 101 (63%) had one or more serum autoantibodies other than AMA on routine laboratory analysis (Table 2).
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Personal history of autoimmunity
Some 84 (53%) patients had one or more either probable or definite autoimmune conditions (Table 3), with 32 (20%) having two or more (Figure 1). Other autoimmune disease was seen significantly more frequently in ANA+ (12/16, 75%) than in ANA– patients (72/144, 50%; p < 0.01). A significantly higher proportion of AMA– than AMA+ PBC patients had additional autoimmune disease (15/19, 79% vs. 69/141, 49%; p < 0.01).
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Sjögren's syndrome
Forty patients (25%) had definite or probable Sjögren's syndrome, with 29 (18%) having a positive Schirmer's test and 19 (12%) a positive salivary pool test. Three patients had previous histological confirmation of disease. A further 33 patients (21%) described classical sicca symptoms, but did not fulfil any other diagnostic criteria for Sjögren's syndrome. Patients with ocular symptoms were much more likely to suffer from the classical symptoms of PBC (pruritus and fatigue) than were those without ocular symptoms (58/73, 79% vs. 31/87, 36%; p < 0.0001). Seven patients with sicca symptoms were positive for anti-Ro antibodies. Of these, four had definite positive Schirmer's tests and one had had histological confirmation of Sjögren's syndrome. All seven were also positive for rheumatoid factor.
Autoimmune thyroid disease
Probable or definite autoimmune thyroid disease was found in 37/160 patients (23%). Hyperthyroidism was present in 9/37 (24%), compared with hypothyroidism in 22/37 (59%). Six of 160 (4%) patients were positive for microsomal antibodies at a titre 1/400, without any other evidence of thyroid disease. Sixteen of 37 (43%) patients developed thyroid disease prior to the detection of PBC, while 19/37 (51%) had thyroid disease detected at the same time as, or following their diagnosis of PBC.
Rheumatoid arthritis
Twenty-one patients (13%) had definite disease. A further six fulfilled criteria for ‘probable’ disease, giving a prevalence of probable/definite rheumatoid arthritis of 27/160 (17%). In the group with definite disease, 71% were rheumatoid-factor-positive.
Scleroderma and Raynaud's phenomenon
Twelve (8%) patients had probable/definite scleroderma. Five (3%) had definite scleroderma in line with ARA criteria, and a further seven (5%) fulfilled the criteria for a diagnosis of probable scleroderma. The majority of patients had limited disease (8/12, 66%). The CREST variant was extremely common (10/12, 83%) both in definite and probable groups, and in both diffuse and limited disease. No patients had severe visceral disease, although some showed extensive skin involvement. Four patients showed oesophageal involvement as part of their CREST syndrome, and were classified as ‘diffuse’ subtype. No patients had proven lung involvement. Ten of 12 (83%) patients developed their symptoms prior to detection of PBC. Anti-centromere antibodies were found in 4/5 definite scleroderma patients. ANA, although less sensitive, were still significantly more common in the group with definite disease (3/5, 60%) compared with the population without disease (18/155, p = 0.01). Four patients tested for anti-Scl-70 were all negative.
While 38/160 (24%) patients had symptoms that fulfilled criteria for Raynaud's phenomenon. 26/160 (16%) had no other features of scleroderma. Twenty-one of those with Raynaud's phenomenon were tested for anti-centromere antibodies, but only those with associated scleroderma were found to be positive.
Other conditions
Other autoimmune conditions (2 SLE, 2 AITP, 6 pernicious anaemia) were seen in 10/160 patients (6%). No patients were identified as having type 1 diabetes mellitus, myaesthenia gravis, Addison's disease or coeliac disease in this cohort.
Patterns of autoimmunity in the study population
While autoimmune thyroid disease was the sole additional autoimmune disease in 57% of PBC patients affected by this disorder, the majority of patients with conditions such as rheumatoid arthritis, scleroderma and AITP also had other autoimmune conditions (67%, 83% and 100%, respectively). Pairs of conditions occurring together were studied and expected frequencies (the product of individual frequencies of conditions in the study population x 160) were calculated (Table 4). All pairs of conditions were seen more frequently than would be expected by chance, although numbers were too small to be statistically tested. Twenty-five (78%) of the 32 patients with multiple conditions had two or more of: Sjögren's syndrome, autoimmune thyroid disease, rheumatoid arthritis, scleroderma. The combination of PBC, Sjögren's and scleroderma gave the highest specific clustering (seen 2.9 times more frequently than expected from the individual disease frequencies (analysis restricted to combinations seen in more than three patients)).
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Family history of autoimmune conditions
Ten (6%) of 160 patients had a family history of PBC, as previously described.4 The total number of first-degree relatives for the 160 subjects was 1118. Some 97/160 (61%) patients reported a family history of autoimmune disease (excluding PBC) (Table 5). Of these, 52/97 (54%) patients had a history of just one condition in their family, whilst 45/97 (46%) had a history of multiple conditions in their family. The frequency of reported family history for each condition was calculated. (Table 5). A total of 235 relatives with autoimmune disease were documented; 191 (81%) were female, and 155 were first-degree relatives, giving a prevalence of autoimmunity in first-degree relatives of 155/1118 (14%). Most autoimmune conditions were significantly less common in family members than in PBC patients themselves (e.g. thyroid disease 37/160 vs. 44/1118; p < 0.0001; Tables 3 and 5). Exceptions were seen, however, the most striking being type 1 diabetes mellitus (17 cases in relatives compared with no cases in the PBC group; p < 0.0005). The presence of autoantibodies other than AMA in patients’ sera, although a predictor of personal autoimmunity, was not a predictor of familial autoimmunity: 66/99 (67%) of patients with other antibodies had a positive familial autoimmune history, compared to 35/58 (60%) of those without other autoantibodies (p = 0.49). The only significant predictor of other familial autoimmunity was having a family history of PBC (other autoimmune disease present in the families of all 10 PBC patients with a familial history of PBC; p = 0.01).
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Discussion |
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This is the first comprehensive, geographically-based study of the prevalence and association patterns of autoimmune disease in PBC, extending the findings of previous more restricted, and pre-selected, case series. The design of the study, using a geographical basis for patient recruitment, independent of referral to a specialist clinic, allowed us to minimize selection bias. Approximately half of the PBC patients suffered from at least one additional autoimmune disease, with specific susceptibility to a limited range of conditions being seen. A significant subgroup of patients (20%) had multiple additional autoimmune conditions. These multiple autoimmune disease cases were accounted for by some combination of Sjögren's syndrome, autoimmune thyroid disease, rheumatoid arthritis and scleroderma in more than 80% of individuals. Such patterns of multiple disease have only previously been documented in case reports, giving no information regarding actual prevalence. Our findings suggest that some of these previously observed associations in PBC occur in an appreciable proportion of patients. Others, in contrast, are rare in population terms. Observed population frequencies of previously reported associations are given in Table 6. The high incidence of autoimmune disease in PBC patients would be supportive of an autoimmune, as opposed to infectious, aetiology for the disease.
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Probable or definite Sjögren's syndrome was documented in just 25% of this PBC study population, a prevalence in keeping with other recent estimates of 32%28 and 20.7%.29 Three subgroups of disease were identified. The majority were similar to the secondary Sjögren's described in rheumatoid arthritis. This suggests that PBC is important for the development of disease, a finding that accords with previous studies.30–32 There is debate as to whether PBC patients have the same ‘secondary’ syndrome as those with connective tissue disease.33 The PBC autoantigen PDC-E2 has been demonstrated to be present on the surface of salivary epithelial cells (as is also the case with biliary epithelial cells) in the salivary glands of PBC patients with Sjögren's, suggesting a unique pathology.34 A further small subgroup of PBC patients with more severe sicca features was also observed in the current study. Interestingly, the absolute association of Ro antibodies and rheumatoid factor seen in these patients has previously been thought to only occur in subjects with primary Sjögren's syndrome.35 Most studies in PBC have assigned all patients to either a primary or a secondary syndrome. The current study supports the idea that both subtypes can coexist. The third subgroup comprised one fifth of the PBC population, who have sicca symptoms but no measurable abnormality in tear or saliva production. Although difficulties in classification have been identified in previous studies of Sjögren's,36 this unexpected subgroup has not previously been so clearly demarcated. As well as sicca symptoms, cold hands, muscle weakness and arthralgia were all associated with more traditional ‘symptoms’ of PBC. Unexplained by a formal disease, these symptoms develop after the onset of PBC, apparently as part of a ‘PBC syndrome’.
One of the unexpected findings of the study was the absence of any identified cases of coeliac disease. This finding is apparently at odds with several recent studies suggesting an association between PBC and coeliac disease.37,38 Is our observation reliable? Certainly none of the patients were following, or had been advised to follow a gluten-free diet at the time of the study, suggesting that an established diagnosis of coeliac disease had not previously been made in any of our 160 patients. The question of sub-clinical and non-diagnosed disease is more complex. According to the study protocol, patients underwent endoscopy and duodenal biopsy only if clinical features suggestive of malabsorption and/or serological features suggestive of coeliac disease were present at the time of assessment. Serological assessment was by anti-reticulin antibody as per then current local unit protocol, with anti-endomysial antibody assessment being performed in cases of uncertainty or for confirmation. It is possible that this approach (as compared to either screening all patients for anti-endomysial antibodies—a more sensitive serological approach39—or, to obtain the definitive prevalence, screening all patients histologically) resulted in some degree of under-diagnosis of sub-clinical disease. It is, however, worth noting that one of the key studies identifying an association between PBC and coeliac disease used a similar protocol to ours.
Autoimmunity in the families of PBC patients was common, with 1:7 (14%) first-degree relatives suffering from autoimmune disease other than PBC, further supporting the autoimmune hypothesis. This rate is over three times the frequency of autoimmunity in the general population, suggesting a real increase in predisposition in these individuals.40 Individual autoimmune conditions were, however, generally seen at a markedly lower frequency in first degree relatives than in PBC patients themselves (with the notable exception of type 1 diabetes mellitus). The only apparent risk factor identified for other familial autoimmunity was having family members with PBC. This phenomenon has previously been noted in a smaller study.9
The principal aim of this study was to characterize patterns of development of autoimmunity in individuals and families. A ‘normal’ population control group was therefore not studied. Comparison with historic prevalences of diseases documented in female populations from the same region as our study do provide us with some insight into changes in absolute autoimmune disease prevalence associated with the presence of PBC. Such comparisons suggest that there are probably true increases in the prevalence of Sjögren's syndrome, scleroderma, Raynaud's phenomenon, pernicious anaemia and SLE (seen in 25%, 7.5%, 24%, 4% and 1.5% of the PBC population, respectively, vs. 2.7%,41 0.01%,24 10%,42 0.5%43 and 0.2%44 in the normal local population). In contrast, rheumatoid arthritis and autoimmune thyroid disease, although common in our patient series, may not in fact be occurring, at a particularly increased rate. An estimate of the prevalence of probable rheumatoid arthritis in a similarly-aged local female population was almost identical to that seen in our PBC patient population (16%).45 Similarly, the prevalence of autoimmune thyroid disease seen in the PBC patients (23%) is not greatly different to that reported in a previous local normal population survey (16%, correcting to approximately 20% when the control population studied was adjusted to give the same average age as the PBC patients46–48). These observations regarding the associations between PBC and single additional autoimmune diseases suggest that the ‘associated’ conditions fall into three groups. The first group consists of conditions which are probably truly associated with PBC (Sjögren's syndrome, scleroderma, pernicious anaemia, Raynaud's phenomenon and possibly SLE). The second group consists of conditions (rheumatoid arthritis and thyroid disease) seen at high frequency in PBC, but which are perhaps no more frequent than in the equivalent normal population, the apparent ‘association’ probably resulting from the demographics of the PBC population. The third group (including IDDM, myaesthenia gravis and polymyositis) consists of conditions which are so uncommon in the PBC population as to preclude us from drawing any conclusions regarding prevalence from a study of this size. It may be, however, that some of these conditions are in fact negatively associated with PBC.
In conclusion, this study provides further evidence for an autoimmune basis to PBC. Over half of the PBC population suffer from an additional autoimmune disease, although prevalences of conditions are generally lower than previous estimates, and some traditional associations are not supported. Their relatives seem to have a broader predisposition to autoimmunity, with autoimmune disease being seen up to three times more frequently than might be expected in the ‘normal’ population. The presence of PBC alone, and not its associated autoimmune phenomena, appears to be associated with an increased risk of an ‘autoimmune phenotype’ in relatives, and this supports our hypothesis of a selective ‘autoimmune genotype’ predisposing to PBC and autoimmunity in general. The search for candidate genes for PBC should be targeted at ‘autoimmunity genes’, particularly those associated with Sjögren's syndrome and scleroderma, in addition to examining purely liver-specific factors.
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Footnotes |
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Address correspondence to Professor D.E.J. Jones, Centre for Liver Research, 4th Floor William Leech Building, The Medical School, Framlington Place, Newcastle-upon-Tyne NE2 4HH. email: D.E.J.Jones{at}ncl.ac.uk
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