Primary Biliary Cirrhosis: Overlaps with Other Autoimmune Disorders Annarosa Floreani, MD1

Irene Franceschet, MD1

Nora Cazzagon, MD1

1 Department of Surgery, Oncology and Gastroenterology, University

of Padova, Padova, Italy

Address for correspondence Annarosa Floreani, MD, Department of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani, 2, Padova, Italy (e-mail: annarosa.fl[email protected]).



► primary biliary cirrhosis ► autoimmune hepatitis ► overlap syndrome ► Sjögren syndrome ► Hashimoto thyroiditis

In this article, the authors use the term “overlaps” to refer to the coexistence of primary biliary cirrhosis (PBC) with another autoimmune condition that involves the liver or extrahepatic organs. Diagnosing PBC-autoimmune hepatitis (PBC-AIH) overlap syndrome remains a challenge, especially because there is still no consensus on the most appropriate diagnostic criteria. The prevalence of this condition varies considerably among series of PBC patients, and its treatment demands a combination of ursodeoxycholic acid and immunosuppressive drugs. Overlap syndrome between PBC and primary sclerosing cholangitis is described in exceptional cases. About one in three PBC patients have a concomitant extrahepatic autoimmune disease, which may include rheumatological, endocrinological, gastrointestinal, pulmonary, or dermatological conditions. Overlaps raise several questions, about whether they share much the same genetic susceptibility, as is generally assumed. The pathogenesis of these conditions includes the production of both innate and adaptive immune responses targeting cholangiocytes as well as different extrahepatic tissues. In this sense, overlaps in PBC represent a continuous spectrum of autoimmunity involving liver and extrahepatic tissues.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease that is considered a model of autoimmune disease for several reasons: It is characterized by (1) a specific hallmark of autoimmunity represented by antimitochondrial antibody (AMA), (2) an antigen-specific T-cell infiltrate that specifically targets biliary epithelial cells, and (3) an association with several autoimmune conditions that can involve the liver and/ or extrahepatic organs. ►Table 1 provides a summary of the most important autoimmune conditions involving the liver and extrahepatic organs that may overlap with PBC.

Overlap Conditions with PBC and Autoimmune Liver Disorders Within liver disorders, the term “overlap syndrome” is used to define the coexistence of autoimmune hepatitis (AIH) and another hepatic autoimmune condition, namely PBC or pri-

Issue Theme Primary Biliary Cirrhosis; Guest Editor, PietroInvernizzi, MD, PhD

mary sclerosing cholangitis (PSC).1 Various clinical presentations have been described, with the conditions occurring one after the other or the concomitant presence of two distinct disorders, but standardized definitions of overlap syndromes are lacking. In the majority of cases, overlap syndromes involve AIH and PBC.2 Although there have also been reports of single cases of AIH and autoimmune cholangitis (AMAnegative PBC) overlap syndrome, overlapping PBC and PSC has been described in only a minority of cases.

Overlap between Primary Biliary Cirrhosis and Autoimmune Hepatitis The prevalence of the overlap syndrome in patients with PBC has ranged from 2% to 20% in series published since 1998.3–11 Such a broad variation in this prevalence may be owing partly to the difficulty of diagnosing two distinct autoimmune liver

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DOI http://dx.doi.org/ 10.1055/s-0034-1383734. ISSN 0272-8087.

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Semin Liver Dis 2014;34:352–360.

Table 1 Overlaps between PBC and autoimmune conditions involving the liver and extrahepatic organs Liver autoimmune conditions PBC/AIH PBC/PSC Extrahepatic autoimmune conditions Rheumatologic disease Sjögren syndrome Scleroderma CREST syndrome Rheumatoid arthritis Polymyalgia rheumatic Systemic lupus erythematosus Endocrinologic diseases Thyroid diseases Autoimmune diabetes mellitus Addison disease Gastrointestinal diseases Celiac disease Pancreatic diseases Inflammatory bowel diseases Pulmonary diseases Fibrosing alveolitis Sarcoidosis Dermatological diseases Vitiligo Lichen ruber planus Bullous pemphigoides Abbreviations: AIH, autoimmune hepatitis; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis.

diseases in the same patient, and to the lack of a standard definition of this entity. ►Table 2 presents a summary of the prevalence of AIH-PBC syndrome reported in the literature according to the different diagnostic criteria used in each report.3,5,6,8–18 Diagnosing AIH-PBC overlap syndrome remains a challenge, especially because no consensus has been reached on the most appropriate diagnostic criteria. In different studies, the PBC-AIH overlap syndrome has been described as presenting features of both diseases. In general, the criteria for diagnosing PBC were cholestatic serum biochemistry, positivity for AMA (anti-M2 antibody), and liver histology (granulomatous cholangitis). For diagnosing AIH they were high levels of aminotransferases and immunoglobulin G (IgG), antinuclear antibody (ANA) or antismooth muscle antibody (ASMA) positivity, and/or histological features of moderateto-severe interface hepatitis or lobular hepatitis. The combination of these patterns may be seen at the time of diagnosis or develop during the follow-up of patients

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previously diagnosed with autoimmune liver disease. The criteria for diagnosing overlap syndrome most often used and validated in the literature come from two research teams, the Paris study group,3 and the International Autoimmune Hepatitis Group (IAIHG).19 The Paris criteria defined PBC-AIH overlap syndrome as the simultaneous or consecutive association of PBC with AIH. The diagnosis of overlap syndrome should be based on the presence of at least two of three diagnostic criteria for each disease. The PBC criteria include (1) serum alkaline phosphatase (AP) levels at least twice the upper limit of normal, or serum γ-glutamyltranspeptidase (γGT) levels at least 5 times the upper limit of normal; (2) a positive test for AMA; and (3) a liver biopsy specimen showing florid bile duct lesions. The AIH criteria include the following (1) serum alanine transaminase (ALT) level at least 5 times the upper limit of normal; (2) serum IgG level at least twice the upper limit of normal, or a positive test for ASMA; (3) liver biopsy showing moderate or severe periportal or periseptal lymphocytic piecemeal necrosis. Other causes of liver injury should be excluded (biliary obstruction, viral hepatitis, excessive alcohol consumption, and exposure to hepato- or cholangiotoxic drugs). The IAIHG suggested applying the AIH diagnostic score to PBC patients to identify cases with features of AIH too, i.e. patients with an overlap syndrome. Since 1993, the IAIHG has published three reports on the criteria for diagnosing AIH.5,19–21 The initially defined criteria were first revised to increase their diagnostic specificity for AIH5: In the revised diagnostic score, positivity for AMA or histological evidence of biliary changes were assigned a negative value to rule out PBC, so the revised score was not suitable for the diagnosing PBC-AIH syndrome. In 2008, the IAIHG proposed a new, simplified score for the early diagnosis of AIH and consequent introduction of corticosteroid therapy for patients reaching scores compatible with AIH. This new score uses simplified criteria and considers eight points: A diagnosis of “definite” AIH coincides with a cumulative score of  7 points, while a score  6 points means “probable” AIH. In this scoring system, three liver histology grading categories indicate a typical AIH histology— interface hepatitis, lymphocytic/lymphoplasmacytic infiltrate in portal tracts and extending into the lobule, and rosetting of liver cells. Features compatible with an AIH histology are a picture of chronic hepatitis with lymphocytic infiltration, but without all the features considered to be typical. Importantly, the simplified score does not include a negative value for AMA and biliary changes,19 suggesting that it may be more suitable for diagnosis of PBC-AIH overlap syndrome.8,14 Kuiper et al5 analyzed the efficacy of Paris criteria and the revised and the simplified IAIHG scores in diagnosing PBCAIH overlap syndrome. Although no statistical comparison can be drawn between the three score because they included different parameters, Paris criteria appeared to diagnose overlap syndrome better than the IAIHG scores, and the authors attributed this to the fact that Paris criteria were specifically designed to diagnose overlap syndrome. The diagnostic performance of the simplified IAIHG score demonstrated a higher specificity and sensitivity than the revised Seminars in Liver Disease

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Primary Biliary Cirrhosis: Overlaps with Other Autoimmune Disorders

Primary Biliary Cirrhosis: Overlaps with Other Autoimmune Disorders

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Table 2 Differences between different series of patients with overlap syndrome Author

Prevalence of PBC-AIH overlap (%)

Study population

Time period

Diagnostic criteria

Floreani et al, 200310


169 PBC patients


Paris criteria

Chazouilleres et al, 19983


130 PBC patients


Paris criteria


227 patients with autoimmune liver disease (162 AIH, 37 PBC, 26 PSC)


IAIHG scoring system

Talwalkar et al, 20029


137 PBC patients


Revised IAIHG scoring system

Suzuki et al, 200411


227 patients with autoimmune liver disease


Revised IAIHG scoring system, Japanese criteria

Poupon et al, 200612


282 PBC patients


Revised IAIHG scoring system and Paris criteria

Gossard & Lindor, 200713


1476 PBC patients


IAIHG scoring system

Kuiper et al, 20105


134 PBC and AIH patients


Paris criteria

Neuhauser et al, 20108

12% 6%

368 PBC patients


Revised IAIHG Simplified IAIHG scoring system

Tanaka et al, 201114


1081 PBC patients, 597 AIH patients

Revised IAIHG scoring system

Bonder et al, 201115


624 patients (609 PBC, 15 AIH)


Paris criteria

Yokokawa et al, 200916


144 PBC patients


Paris criteria


317 PBC patients


Revised IAIHG scoring system


280 patients



Czaja, 1998


Wang et al, 2013


Yoshioka et al, 201318

Abbreviations: AIH, autoimmune hepatitis; IAIHG, International Autoimmune Hepatitis Group; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis

score, considering both definite and probable AIH in PBC patients (sensitivity 73% vs. 60%, specificity 78% vs. 83%, for the simplified and revised scores, respectively). Bonder et al subsequently proposed an additional criterion for identifying patients with AIH-PBC overlap syndrome.15 In an article on the prevalence of this condition, they included patients with a diagnosis of PBC who met the Paris criteria for concomitant AIH (6/609, 1%). In a later analysis, they also included PBC patients who failed to respond fully to ursodeoxycholic acid (UDCA) alone, or UDCA and methotrexate or colchicine, but responded when prednisolone (generally used to treat AIH) was added. The criteria for response included a normalization of liver enzyme tests and an improvement in liver histology of at least one point on the Metavir activity index, without any increase in fibrosis score. Using these more inclusive criteria, the prevalence of overlap syndrome observed in PBC patients was as high as 2.8%, near the lower range reposted by other authors.3,4,6,8,9,12,15 The authors indicated response to corticosteroid therapy as a valid addiSeminars in Liver Disease

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tional criterion for diagnosing patients who have AIH overlapping with PBC. To differentiate PBC-AIH overlap syndrome from “pure” autoimmune liver disease, Muratori et al22 analyzed the clinical, biochemical, and histological features, autoantibody profile, and response to therapy in 15 patients with PBC-AIH overlap according to the Paris criteria, comparing them with 120 patients who had PBC and another 120 patients who had AIH. In particular, analyzing patients’ complete autoantibody patterns showed that anti-dsDNA were more common among overlap patients (60% in overlap, 26% in AIH, 3% in PBC, p ¼ 0.01); and positivity for both AMA and anti-dsDNA was seen in 47% of overlap patients as opposed to 1% and 3% of AIH and PBC patients, respectively. In addition, when overlap cases were compared with PBC patients, ANA positivity was seen much more in the former (93% vs. 33%, respectively; p ¼ 0.001), whereas ASMA positivity was similar in the two groups (33% vs. 25%, respectively; p ¼ ns). No significant differences emerged for the other parameters considered in

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the study. These results indicate that a concomitant antidsDNA and AMA positivity represents a serological pattern extremely specific for AIH-PBC overlap syndrome. In AIH patients, susceptibility genes are associated with the major histocompatibility complex (MHC), and particularly with the locus HLA-DR3/DR4 and HLA-B8.23 Information about genetic susceptibility in overlap syndrome is limited. A German study found much the same presence of the characteristic haplotypes of AIH (HLA-DR3/DR4 and HLA-B8) in AIHPBC overlap patients as in AIH patients (17/20 vs. 18/20, respectively; p ¼ ns), while it was significantly lower in pure PBC patients (4/20, respectively; p < 0.05).24 A recent study by Adam et al showed that among different HLA-DR alleles, HLA-DR7 is more common in AIH-PBC overlap than in AIH patients.25 Although the diagnostic criteria hitherto adopted for overlap syndromes are arbitrary, it is important to establish internationally accepted criteria for AIH-PBC overlap due to the need to identify patients necessitating appropriate therapy, and particularly to select those who might benefit from corticosteroid therapy in addition to UDCA. The lack of well-validated diagnostic criteria and shortage of large-scale therapeutic trials make the treatment of overlap conditions empirical, extrapolated from data relating to primary autoimmune liver diseases. In the European Association for the Study of Liver (EASL) guidelines on the management of cholestatic liver diseases,26 the recommendations on treatment of AIH-PBC overlap syndrome are based on experience gained from treating either PBC or AIH, and on retrospective, nonrandomized studies. These guidelines recommend combined therapy with UDCA and corticosteroids for patients with PBC-AIH overlap syndrome. An alternative approach is to start with UDCA alone, adding corticosteroids if it does not induce an adequate biochemical response within 3 months. Steroid-sparing agents should be considered in patients requiring long-term immunosuppression. In a study by Joshi et al, 331 PBC patients, 16 (4.8%) of them with an AIH-PBC overlap diagnosis according to the Paris criteria,27 were randomized for treatment with UDCA (171 patients) or a placebo (160 patients); 12 of the patients with overlap syndrome were randomized to receive UDCA and 4 to placebo. The response in terms of serum biochemistry and immunoglobulin values was much the same in the PBC patients with and without features of AIH after 2 years of therapy with UDCA. There was also a slight improvement in the histological features of AIH, indicating that patients with pure PBC and those with AIH-PBC overlap syndrome respond equally well to UDCA therapy. However, most studies analyzing response to therapy in overlap patients have involved the use of a combined therapy (UDCA þ corticosteroids). Chazouillères et al4 compared treatment with UDCA alone (13– 15 mg/kg/d) or UDCA combined with immunosuppressants (IS; prednisolone 0.5 mg/kg/d, and secondarily azathioprine and mycophenolate mofetil). A complete biochemical response with no progression of fibrosis was more frequently seen in the UDCA þ IS group then in the UDCA group. Ursodeoxycholic acid combined with IS was consequently proposed for patients not responding to UDCA alone, leading

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to an improvement in their biochemical and histological response. The authors also found that IS could be stopped successfully after a median 2.7 years of therapy, suggesting that lifelong immunosuppressive treatment is not always necessary. These data were confirmed in a Japanese cohort18 in which 20 of 28 patients with AIH-PBC overlap syndrome were treated with UDCA plus corticosteroids: 15 responded to this treatment, obtaining a normalization of transaminases within 4 months. Corticosteroid treatment was stopped in eight patients after their transaminases remained within the standard range for 2 years; the other seven relapsed, but responded well when corticosteroids were administered again. The prognosis for responders was excellent, and none of these patients showed any clinical disease progression of their disease, unlike the nonresponders. Kaplan-Meier analysis showed that responders had a significantly longer transplant-free survival than nonresponders (5-year survival rate: 100% vs. 81%, respectively; 10-year survival rate: 100% vs. 54%, respectively). Features such as a high AP levels, negativity for ASMA, and positivity for envelope glycoprotein gp120 appear to predict a poor prognosis. Therapy with corticosteroids alone is not recommended because it has been seen to coincide with worsening clinical and biochemical parameters, and overall transplant-free survival rates.3,16 Prognostic data in overlap patients are often at odds among different studies. Some studies indicate a worse prognosis for overlap syndrome than for pure PBC.8,28,29 When 26 patients with probable overlap syndrome according to the revised IAIHG score were compared with 109 PBC patients, the former had higher rates of ascites (35% vs. 15%; p < 0.01), varices (50% vs. 23%; p < 0.01), gastrointestinal bleeding (35% vs. 15%; p ¼ 0.03), portal hypertension (54% vs. 28%; p ¼ 0.01) and adverse outcomes (death or liver transplantation).28 During the study concerned, overlap patients were treated with either UDCA alone (54%) or UDCA þ methotrexate or colchicine; only 8% of patients were given UDCA þ corticosteroids, however, although this is currently the most effective treatment for AIH-PBC. When Jung et al29 analyzed the factors influencing the prognosis for PBC, the presence of AIH overlap and a higher revised IAIHG score correlated with a higher rate of progression to liver cirrhosis. On comparing the previous revised version with the simplified IAIHG score, the latter seems to be more specific in determining prognosis. In terms of liver cirrhosis and portal hypertension, only patients who met the new criteria for overlap with AIH had more liver-related deaths and transplants, suggesting that this latest scoring system is more specific for patients with more aggressive overlap syndrome.8 Several different studies have demonstrated a good prognosis (in terms of the progression of liver fibrosis, survival and transplant-free survival) for AIH-PBC overlap, however, especially if a combined therapy with UDCA and corticosteroids is administered.4,5,22,27 In conclusion, AIH-PBC overlap syndrome is not a rare condition. Globally accepted diagnostic criteria are needed Seminars in Liver Disease

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Primary Biliary Cirrhosis: Overlaps with Other Autoimmune Disorders

Primary Biliary Cirrhosis: Overlaps with Other Autoimmune Disorders with a view to providing the appropriate therapy. For the time being, a combination of UDCA and prednisolone (and azathioprine or mycophenolate mofetil later on) seems to be the therapy of choice in these patients to achieve a good outcome in terms of clinical and histological progression and overall and transplant-free survival.

Overlap between Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis Primary biliary cirrhosis overlapping with PSC has only been described in six cases to date (►Table 3 30–34). The first reported case was described in a 52-year-old male whose cholestatic history started at the age of 44 with jaundice, fever, arthralgia, pneumonitis and pericarditis.30 An oral cholecystography was performed when he was 51 revealed multiple strictures and dilatations of intrahepatic biliary tree. Needle biopsy of the liver demonstrated a portal inflammation with periductal fibrosis and mild ductular proliferation. This picture was unspecific for either PBC or PSC, and the authors hypothesized a coexisting PBC and PSC, but they could not rule out biliary carcinoma or a drug-induced cholestasis. The second case31 to be reported was in a 40-year-old woman who had undergone cholecystectomy, and suffered from recurrent bouts of ascending cholangitis. Her liver biopsy was consistent with PBC, and intra- and extrahepatic PSC was well documented by endoscopic retrograde cholangiopancreatography. Kingham et al32 described two cases of PBC coexisting with PSC among consecutive cohort of 261 patients with autoimmune liver diseases followed up prospectively in secondary care over a 20-year period. Jevaagan33 reported a case of AMA-negative PBC overlapping with PSC. The more recent report in the literature concerns a PBC patient with normal cholangiographic findings, but liver histology showing “onion-skin” type periductal fibrosis.34 None of the cases reported in the literature were associated with inflammatory bowel disease. The diagnosis of overlap

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syndrome was also controversial in some cases, mainly due to an inadequate description of the biliary tree using newgeneration imaging techniques, few details of extrahepatic manifestations, and incomplete information on the patient’s autoimmune serologic profile.

Overlap Conditions between PBC and Extrahepatic Autoimmune Disorders Several autoimmune diseases have frequently been found in association with PBC due to a shared autoimmune mechanism.35 In particular, about one in three patients with PBC have another extrahepatic autoimmune disease.36 Among the rheumatological diseases, Sjögren syndrome (SS) is the most common associated condition, occurring in proportions ranging from one in three to up to nearly 100% of cases.37–41 Sjögren syndrome results from a lymphocytemediated destruction of the salivary, lacrimal, and other exocrine glands leading to minimal or no secretions. The term “autoimmune exocrinopathy” was coined in 1979,42 replaced more recently by the term “autoimmune epithelitis,” which clearly identifies the immune-mediated damage.43 Diagnostic criteria for SS include clinical features, histological and functional tests, and immunological markers.44 The clinical symptoms include ocular and oral dryness persisting for more than 3 months or the use of artificial tears more than 3 times a day, or the recurrent need to drink to swallow dry food. Abnormal Schirmer or rose bengal test findings are highly specific, whereas even more specific functional tests include sialometry or salivary gland scintigraphy, or parotid sialography. Diagnostic histological signs include a lacrimal gland biopsy with a focus score > 1, or a salivary gland biopsy with a focus score > 1. Patients with SS have detectable serum antibodies reacting with the 52KDa Ro protein (SSA), antiLa/SSB, and anti-UIRNP.45 The association of SS with PBC represents a paradigm for a common immunopathogenesis.46 In both conditions, environmental triggers (putatively infectious agents and xenobiotics) induce salivary or biliary epithelial cell apoptosis and contribute to the breakdown of

Table 3 Reported cases of PBC/PSC overlap syndrome Author

Gender, age (y)






Rubel et al, 198430

M, 52

þ (1:1280)

Periductal fibrosis, PMN


(Percutaneous: intra- and extrahepatic PSC

Congestive heart failure

Burak et al, 200131

F, 42




Intra- and extrahepatic PSC

Kingham & Abbasi, 200532

F, 49 F, 72

Pos (1:640) Pos (1:320)

PBC stage IV ND


Intrahepatic PSC Intra- and extrahepatic PSC

– –

Jeevagan, 201033

F, 64



Intrahepatic PSC

Intrahepatic PSC


Oliveira et al, 201234

F, 48


“Onion skin type” fibrosis



Abbreviations: AMA, antimitochondrial antibody; ERCP, endoscopic retrograde cholangiopancreatography; F, female; M, male; MRI, magnetic resonance imaging; ND, not done; neg, negative; pos, positive; RA, rheumatoid arthritis.

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tolerance to self-antigen exposed to the apoptotic blebs (SSA or SSB) and not protected by posttranslational modifications (PDC-E2). Salivary and biliary epithelial cells also contribute to the autoimmune process by expressing cytokines, HLA class II, and adhesion molecules. The treatment is symptomatic and consists in the use of several artificial saliva preparations with a neutral pH that contain a balance of electrolytes corresponding to normal saliva. Symptoms associated with dry eyes can be relieved by artificial tears, which may contain hypromellose and mucolytic agents. Vaginal dryness may be relieved by using appropriate lubricants. Scleroderma is a multisystem autoimmune rheumatic disorder characterized by fibrosis in the skin and several internal organs, though hepatic involvement is rare.47 The first case of extensive scleroderma associated with PBC was described by O’Brien et al in 1972.48 The prevalence of scleroderma in PBC is unknown, but the CREST variant is more common. The CREST acronym encompasses the major components of the syndrome: calcinosis, Raynaud syndrome, esophageal dysmotility, sclerodactyly, and telangiectasia. A retrospective study of 558 patients with PBC identified 22 cases, all of them female, with two or more symptoms of CREST syndrome.49 In many cases, the symptoms or signs of CREST dated from before PBC was diagnosed. Metcalf et al found broadly similar results in a survey of 1,000 PBC patients: 1.2% of them had CREST syndrome, and scleroderma was found in 2.7%.50 In the Royal Free Hospital database, 43 of 580 PBC patients were identified as having scleroderma,51 and it was found that PBC patients with associates SS had a slower progression of their disease than matched patients with PBC alone.51 Several patients with scleroderma have circulating autoantibodies reacting with anticentromere antigens (ACA). Those patients present Raynaud phenomenon and CREST syndrome52; 20% of patients with scleroderma have the antibodies used in screening for.53 The prevalence of clinically evident PBC among patients with scleroderma was reported in up to 2.5% in a registry of 1,700 scleroderma patients,51 and 2% in a series of 817 patients with SS.54 Nodular regenerative hyperplasia has been described in association with PBC and limited scleroderma.55,56 The prevalence of rheumatoid arthritis (RA) in PBC patients has been suggested to range between 1.8% and 5.6%,57,58 whereas the prevalence of AMA in patients with RA has been estimated at 18%.59 One study found that 182 autoptic cases of RA had a 65% association with liver pathology, including mild inflammatory infiltration of portal tracts, small foci of necrosis, and steatosis,60 but whether any of these patients fulfilled the criteria for the diagnosis of PBC is impossible to say. Interestingly, a study conducted by Gershwin et al in a cohort of 1,032 patients with PBC using a NHANES-style questionnaire found that 26% of the firstdegree relatives of patients reported having RA.61 Mothers of PBC patients were the most affected (13.8%), followed by sisters (11%). In a French study using a standardized questionnaire, RA was found in 3% of PBC patients and 2% of their first-degree relatives, with no statistical difference between cases and age-, sex-, and residence-matched controls.62 On

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the other hand, the rates of RA were higher in PBC cohorts as well as in their first-degree female relatives, which may suggest a common background for the two conditions in some cases. The interest of the association between PBC and RA regards the two conditions’ management with immunosuppressants, and in more recent years, with tumor necrosis α (TNFα) antagonists. Methotrexate (MTx) is one first-line agent frequently used for RA, whereas it is ineffective for PBC, either alone or combined with UDCA.63–65 Rheumatoid arthritis is associated with synovial production of rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPA), and with the production of inflammatory cytokines, including interleukin- (IL-) 1, IL-6, IL-17, and TNFα. In humans, treatment with biological agents gives us the opportunity to shed light on the cytokine and signaling pathways regulating ACPA levels, and the impact of changes in ACPA levels on disease activity.66 Encouraging results have been recently reported on the use of biological agents in two patients with PBC associated with RA.67,68 Recent genome-wide association studies (GWASs) have postulated a common genetic background between PBC and RA.69–71 These studies have identified several non-HLA risk loci for autoimmune liver disease. Overlap genes between PBC and RA include HLA-DQB1, STAT4, IRF5, MMEL1, CTLA4, and CXCR5. All these studies suggest, however, that GWASs reflect interacting genetic and nongenetic factors in autoimmune disease. In particular, environmental factors add a comprehensive interpretation and exploration of each specific genetic findings. The model proposed by Mellset al71 is illustrated by the heat map showing risk loci shared by PBC and other autoimmune disease based on data on risk loci obtained from ImmunoBase (http://www.immunobase.org/) and the catalog of published GWASs (http://www.genome. gov/gwasstudies/). According to this model each specific genetic finding in GWASs requires the incorporation of complementary environmental factors. The complete interaction between genetic and nongenetic factor leads to the acquisition of each specific phenotype. Epigenetic studies have been extensively performed in RA patients, but are rather limited in PBC.72 The association between PBC and polymyalgia rheumatic has been described mainly in single case reports.73,74 Associations between PBC and systemic lupus erythematosus (SLE) have also been reported, though a broad spectrum of liver disease may be associated to SLE. Studies before the 1990s are rather limited, due mainly to the inability to test a patient’s complete immunological profile, and to the lack of histological findings. In 1959 McKay coined the term “lupoid hepatitis” to indicate a liver condition with histological features of infiltrate with plasma cells invading the limiting plate of hepatocytes, and serum with nonorgan-specific autoantibodies and hypergammaglobulinaemia.75 This typical picture was subsequently termed chronic autoimmune hepatitis. Altered liver enzymes are rather common in SLE, being found in 25% to 55% of cases.76 End-stage liver disease is rarely reported. Primary biliary cirrhosis occurs in 2.7% to 7.5% of cases.77 Conversely, SLE has been described only Seminars in Liver Disease

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Primary Biliary Cirrhosis: Overlaps with Other Autoimmune Disorders

Primary Biliary Cirrhosis: Overlaps with Other Autoimmune Disorders sporadically in cohorts of patients with PBC.76 There are also few reports of single cases of PBC-AIH overlap syndrome in association with SLE.79,80 In short, it is not uncommon in clinical practice to find SLE associated with PBC or AIH-PBC overlap syndrome. Particular attention should be paid to any alteration of these patients’ liver function test findings, bearing in mind that the use of immunosuppressants for SLE may masquerade overt clinical and laboratory findings of underlying autoimmune liver disease.81 Among the endocrinological autoimmune overlaps, thyroid diseases are the most common associations, whereas Addison disease and autoimmune diabetes are exceptional. Hashimoto thyroiditis is predominant, occurring in up to 20% of cases; biochemical or clinical hypothyroidism is less common, but regular TSH screening is warranted in all female patients with PBC.82 Among the gastrointestinal disorders, celiac disease (CD) has been the most often studied, ever since it was first described by Logan et al.83 Sorensen et al84 subsequently reported an increased risk of PBC in patients with CD in Denmark and Sweden, with a standardized incidence ratio around 26. In a population of South Wales, the prevalence of CD among patients with PBC was 6%, and the prevalence of PBC in those followed for CD was 3%.85 These findings were not confirmed in Poland.86 A more recent report from the United Kingdom indicated that the association between PBC and CD was weaker than previously reported.87 Moreover, in an Italian population, IgA and IgG tissue transglutaminase antibodies gave a high rate of false-positive in PBC.88 For these reasons, serological screening testing for CD is not recommended in PBC patients, unless there is a strong suspicion of CD. Pancreatic diseases overlapping with PBC were described early in the 1980s in the contest of “dry gland syndrome”89, but this association does not pose a problem in clinical practice. Likewise, PBC in combination with inflammatory bowel diseases does not represent a peculiar association among the autoimmune disorders because this picture is described only exceptionally.90 Finally, there may be an overlap between lung diseases and PBC, mainly involving fibrosing alveolitis and sarcoidosis.91 Autoimmune dermatological associations, especially vitiligo, lichen ruber planus, and bullous pemphigoid are common in PBC patients, and might be the first sign of the autoimmune disorder.

4 Chazouillères O, Wendum D, Serfaty L, Rosmorduc O, Poupon R.


6 7






13 14







References 1 Boberg KM, Chapman RW, Hirschfield GM, Lohse AW, Manns MP,

Schrumpf E; International Autoimmune Hepatitis Group. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol 2011;54(2):374–385 2 Trivedi PJ, Hirschfield GM. Review article: overlap syndromes and autoimmune liver disease. Aliment Pharmacol Ther 2012;36(6): 517–533 3 Chazouillères O, Wendum D, Serfaty L, Montembault S, Rosmorduc O, Poupon R. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: clinical features and response to therapy. Hepatology 1998;28(2):296–301

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Primary biliary cirrhosis: overlaps with other autoimmune disorders.

In this article, the authors use the term "overlaps" to refer to the coexistence of primary biliary cirrhosis (PBC) with another autoimmune condition ...
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