primary biliary cirrhosis: a 2010 update · primary biliary cirrhosis: a 2010 update raoul poupon*...

Review

Primary biliary cirrhosis: A 2010 update

Raoul Poupon*

UPMC Univ Paris 06, France; INSERM, UMR_S 938, Paris, France; Service d’Hépatologie et Centre de Référence des maladiesinflammatoires des voies biliaires, Hôpital Saint-Antoine, AP-HP, Paris, France

Primary biliary cirrhosis (PBC) is a chronic inflammatory auto- in their modern description of the disease affecting middle-aged
immune disease that mainly targets the cholangiocytes of theinterlobular bile ducts in the liver. The condition primarily affectsmiddle-aged women. Without treatment, PBC generally pro-gresses to cirrhosis and eventually liver failure over a period of10–20 years. PBC is a rare disease with prevalence of less than1/2000. PBC is thought to result from a combination of multiplegenetic factors and superimposed environmental triggers. Thecontribution of the genetic predisposition is evidenced by thefamilial clustering. Several risk factors, including exposure toinfectious agents and chemical xenobiotics, have been suggested.Ursodeoxycholic acid (UDCA) is currently the only FDA-approvedmedical treatment for PBC. When administered at doses of 13–15 mg/kg/day, a majority of patients with PBC have a normal lifeexpectancy without additional therapeutic measures. One out ofthree patients does not adequately respond to UDCA therapy andmay need additional medical therapy and/or liver transplanta-tion. This review summarises current knowledge on the epidemi-ology, ethiopathogenesis, clinical, and therapeutic aspects of PBC.� 2010 European Association for the Study of the Liver. Publishedby Elsevier B.V. All rights reserved.
Introduction

The condition of prolonged obstructive jaundice with patent bileducts was first described by Addison and Gull in 1851 [1]. Theterm primary biliary cirrhosis (PBC) was coined to distinguishthe disease from obstructive biliary cirrhosis by Dauphinée andSinclair in 1949 [2] and used by Ahrens and colleagues in 1950

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Keywords: Antimitochondrial antibody; Apoptosis; Cholestasis; Inflammation;Fibrosis; Cirrhosis; Genetics; Xenobiotics; Autoimmunity; Innate immunity;Adaptative immunity; Epidemiology; Ursodeoxycholic acid; Immunosuppressivedrugs; Pruritus; Hypercholesterolemia; Portal hypertension; Osteoporosis; Livertransplantation.Received 14 October 2009; received in revised form 27 November 2009; accepted 30November 2009*Address: Service d’Hépatologie, Hôpital Saint-Antoine, 184, rue du FaubourgSaint-Antoine, 75571 Paris Cedex 12, France. Tel.: +33 1 49 28 23 78; fax: +33 1 4928 21 07.E-mail address: [email protected]: UDCA, ursodeoxycholic acid; PBC, primary biliary cirrhosis; NSDC,non-suppurative destructive cholangitis; AMA, antimitochondrial Antibody; AE2,Cl� HCO�3 exchanger 2; NHE, Na+ H+ exchanger; MHC, major histocompatibilitycomplex; NRAMP1, natural resistance-associated macrophage antigen 1; CTLA4,cytotoxic lymphocyte antigen-4; VDR, vitamin D receptor; M2Ab, M2 antibodies;AIH, autoimmune hepatitis; MBL, mannose binding lectin.

to older women with progressive jaundice, pruritus, and hepato-splenomegaly [3]. In 1965, Rubin and colleagues coined the fun-damental histological lesion as non-suppurative destructivecholangitis (NSDC) [4]. The disease specific hallmark – the anti-mitochondrial antibody (AMA) – was identified the same yearby Walker and colleagues and has allowed for a confident diagno-sis earlier in the course of the disease [5]. Among the variousmitochondrial antigens, the so-called M2 was shown to be specif-ically associated to PBC [6]. Five years later, the cDNA for themajor mitochondrial antigen of PBC was cloned from a geneexpression library and identified as the pyruvate dehydrogenasecomplex [7,8].

Although the aetiologies and aetiopathogenesis are still elu-sive, most patients benefit from liver transplantation, a procedureroutinely performed since 1989 [9], and ursodeoxycholic acid, amedical therapy now used worldwide for early stage disease [10].

Epidemiology

In a systematic review of studies of PBC frequency [11], Princeand James identified 37 studies, 29 of which were performedafter 1980. Incidence of PBC ranged from 0.7 to 49 per millionper year in most recent studies. The point prevalence was esti-mated to range from 6.7 to 402 per million. In the French metro-politan area, a prospective study performed in 2006–7 shows thatthe incidence was 9 per million per year, with an estimate of 36per million in women over 45 years. Assuming a life expectancyof 20 years after diagnosis, the point prevalence was estimatedto be 207 per million, and for women above 45 years, 860 permillion [12]. As in some other studies [13,14], the incidence ofAMA positivity without evidence of liver disease was two timeshigher than the incidence of AMA positivity with evidence of liverdisease. It has been observed that the incidence and prevalencerates are highest in Northern European countries (e.g., Englandand Scotland) [15,16] and in the Northern United States (e.g.,Minnesota) [17]. The systematic review of PBC frequency [11]suggests that there is an increase incidence and prevalence ofPBC worldwide. A good example comes from studies carriedout in the region of Victoria (Australia). The first population-based study carried out in this region identified 84 cases, givingan estimate of PBC prevalence of 19.1 per million [18]. A subse-quent study from the same region identified 249 cases, for acumulative incidence that is almost 10-fold higher [19]. The rea-sons appear complex. Indeed, many explanations may be pro-vided, e.g., true increase due to increased exposure to an

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environmental factor, demographic changes with an increasedelderly at-risk population, increase survival of already diagnosedpersons, earlier diagnosis, improved care, and increase clinicianas well patient awareness, among other reasons.
As discussed later, environmental factors preferentially affect-ing women may be implicated in the aetiopathogenesis of PBC. Ifchanges in the incidence of PBC reflect a true epidemiologicalphenomenon, differing exposure to environmental risk factorscould explain it. Marked geographic variation in the burden ofPBC has been found in several studies [20–25]. In a study fromNortheast England [22], there were very substantial anomaliesin the spatial distribution of patients. Extraordinary clusters ofdisease were noticed in several urban areas (up to 13 cases/km2). No obvious demographic or geographical features werefound to explain this variation, although they do suggest thepresence of one or more unidentified environmental factor(s).North American studies have similarly localised clusters of PBC.A relationship between the location of toxic waste sites andincrease prevalence of PBC, as well a relationship between indi-viduals listed for liver transplantation and mean daily airbornepollutant concentrations was observed [23].

Etiologies

PBC is thought to result from a combination of multiple geneticfactors and superimposed environmental triggers. All these fac-tors may affect one or more components of the immune systemand the tissue that is targeted by the disease (Fig. 1).

The contribution of the genetic predisposition is evidenced bythe familial clustering [26–28] and the high concordance of

Genetic factors (Loci)

PBC• Immune sy

• Liver

IL12A, IL12RB2

CTLA4, ILβ, TNFα

C4B*2/C4Q0,SLC11A1, MBL

HLA DR, DQ

Gender

Fig. 1. PBC results from a combination of multiple genetic and environ

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monozygotic twins [29]. The prevalence of PBC is 100 timeshigher in first-degree relatives than in the general population.

Allelic variations in MHC class II (DR, DQ), components of theinnate (C4*Q0, C4B*2, NRAMP1/SLC11A1, MBL, VDR) and of theadaptative (CTLA4, IL beta, TNF alpha, IL12A, IL12RB2) immunesystems have been shown to be associated with the susceptibilityof PBC [30–34]. The possible role of allelic variation of severalcomponents of the innate immune system suggests some distur-bances of host resistance to microbial infection in PBC and theirimplication in the initiation or perpetuation of the inflammatoryprocess. The same point can be made for the association withvariants of the IL12 pathway since several data link inheriteddeficiencies of IL12, IL12R, and interferon gamma to increasedsusceptibility and severity of infectious diseases in particularmycobacterial diseases [35].

CTLA4 encodes a coinhibitory immunoreceptor that is a keyregulator of self-tolerance with established genetic associationsto multiple autoimmune diseases and in most, but not all, geneticstudies of PBC [31,33,34,36–38]. Interestingly, there is an associ-ation of genetic variation at the VDR locus and susceptibility toPBC [32] thanks to the role of vitamin D not only in adaptativeimmunity but also in the regulation of innate immunity of thebiliary tree [39].

The genetic basis of variability in disease progression is poorlyunderstood. A French prospective study of genetic factors relatedto PBC severity has shown that two variants of TNF alpha andSLCA2/AE2 [33] were independent prognostic factors involvedin the profile of PBC treated with UDCA. This human study, alongwith the recently reported Ae2a,b-deficient mouse model of PBC,provides further evidence for a pathogenic role of SLCA2 defi-ciency in PBC [40].

Environmental factors

stem

Chemical, smoking

Pathogen exposure

mental factors that may affect the immune system and the liver.

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Regarding environmental factors, association with mucosal
infections, particularly urinary tract infections, and cigarettesmoking, have been consistently found [41–44]. The contributionof other risk factors, such as the use of cosmetics, frequency ofpregnancy, and hormone replacement therapy, is not alwaysclear [41,43].

Most xenobiotics are metabolised in the liver and some ofthem are known to induce autoimmunity and hepatitis. One ofthe best examples is the case of halothane hepatitis, which occursin susceptible individuals who mount an immune response to tri-fluoroacetylated protein adducts [45]. Thus, it is tempting toimagine exposure to a xenobiotic, which is then transformed intoa reactive intermediate that binds to proteins and results in neo-antigen formation in PBC initiation. Moreover, using flucloxacil-lin, an isoxazolyl-penicillin known to induce cholestasis andcholangiocyte injury, we have found that the molecule was bio-transformed by hepatocytes to a reactive intermediate eliminatedin bile and responsible for cholangiocyte death, suggesting thatbiliary reactive intermediate could induce cholangiocyte damageand further autoinflammation [46]. However, it should be notedthat flucloxacillin has never been implicated in PBC.

The lipoic acid binding domain of the 2-oxo-acid dehydrogen-ases, to which immune reactivity in PBC is seen, has a highly con-served domain structure containing a lipoic acid factor. The lipoicacid binding domain forms the core of the dominant autoepitope.Immunologic cross-reactivity between lipoic acid and structur-ally-related xenobiotics may represent a mechanism for break-down tolerance against lipoic acid-containing autoantigens inPBC. Lipoic acid is exposed to the exterior part of the oxo-dehy-drogenase complex, thus forming an ideal target for xenobioticmodifications. The role of xenobiotics is suggested by a seriesof experimental data. First, halogenated compounds, such as 6-bromohexanoic acid, can be incorporated naturally into PDC inplace of lipoic acid [47]. Second, sensitisation with 6-bromohexa-noic acid-modified bovine serum albumin can lead to the appear-ance of AMA and portal tract inflammation [48]. Third, specificorganic structures attached to mitochondrial antigens are recog-nised by PBC sera with higher affinity than the native form ofthese antigens [49]. 2-Nonynoic acid, a compound found in sev-eral cosmetic products, is also recognised by PBC sera with highaffinity [50]. Fourth, xenobiotic-induced PBC murine modelsmade by immunisation with 2-octynoic acid of NOD.1101 orC57BL/6 strains have been reported [51,52].

AMA in PBC sera cross-reacts with a number of bacteria. Thiswas the basis for the bacterial aetiology of PBC. This hypothesisremains highly uncertain because of a number of controversialdata and the fact that there is no evidence of excess T cellresponse to bacterial proteins in PBC. The cross-reactivitybetween PBC sera and bacteria is explained by the highly con-served sequence of PDC throughout phylogeny. However, theGerswhin group has recently provided some convincing evidencethat a free living Gram-negative bacterium called Novosphingobi-um aromaticivorans (NA) could have a role in inducing PBC [53].Indeed, NA has one of the highest degrees of homology withthe human PDCE2 autoepitope. NA is capable of inducing autore-active AMA and chronic T cell-mediated autoimmunity againstthe small bile duct in a murine model of PBC [54].

There is also evidence that raises the possibility of a transmissi-ble virus in PBC lymph nodes. Cholangiocytes, isolated from normalindividuals incubated with homogenised lymph node from a PBCpatient, develop aberrant mitochondrial antigen staining on


plasma membranes, a phenotype trait characteristic of PBC[55,56]. Retroviral sequences cloned from the lymph nodes sug-gested a role for a retrovirus resembling the mouse mammaliantumour virus (MMTV). However, this finding has not been repro-duced [57,58], and the data of a randomised control trial of zidovu-dine and lamivudine in PBC patients do not convincingly supportthe role of a retrovirus in PBC pathogenesis [59]. Nevertheless, itis worth noting that the NOD.c3c4 mouse model of PBC [60] hasbeen found to express MMTV proteins in biliary epithelium [61].These mice treated with anti MMTV had no evidence of thepathological traits of PBC, suggesting that MMTV triggers viralcholangitis in this experimental model [62].

Any infectious agent present in the liver or bile in an immuno-genetically susceptible individual may generate a transient orchronic immune response that is cross-reactive with self PDC. Asecond hit (hormonal, viral, xenobiotics) in cholangiocytes,resulting in increased apoptosis and increased presentation ofimmunoreactive PDC via dendritic cells, may then be sufficientto convert this transient autoimmunity into autoimmune disease.The innate immune system relies on its capacity to detect path-ogenic microbes and danger-associated molecular patternsreleased by injured cells through toll-like and nod-like receptors.Our knowledge of the complexity of the innate immune responseis just beginning and could be crucial for the understanding ofautoimmune diseases such as PBC.

Several spontaneous and induced animal models of PBC havebeen described in the last few years [40,60,63]. They all providefurther evidence that abnormal immune regulation, with or with-out superimposed triggers, is involved in the breakdown of toler-ance against PDCE2 and early cholangitis. A mouse model,expressing a dominant negative form of transforming growth fac-tor receptor restricted to T cells (dnTGFRII), develops an inflam-matory biliary ductular disease with elevated serum levels ofIL12p40. Interestingly, the IL12p40 KO dnTGFRII mice have a dra-matic reduction in histological cholangitis and significantdecrease in the levels of intrahepatic proinflammatory cytokinesbut similar levels of AMA compared to dnTGFRII controls [64].These findings support recent genetic data implicating the IL12pathway in susceptibility to human PBC [34]. As mentionedabove, KO mice, with a disruption of most isoforms of AE2,develop features of PBC and a decreased number of T regulatorycells [40]. Genetic data in human PBC have also shown that onevariant of the SLCA2/AE2 gene may be involved in evolving theprofile of PBC treated with UDCA [33]. Whether AE2 dysfunctionmay lead to altered cholangiocyte homeostasis, increased rate ofapoptosis, and subsequent enhanced presentation of antigenicepitopes or lymphocytes dysfunction, remains to be examined[65].

Female preponderance of PBC

The ratio of women to men with the disease is 10–1. The femalepreponderance may hold an important key to PBC aetiology.Potential mechanisms for the gender imbalance may include anincreased risk of exposure to a disease-promoting factor (suchas urinary infection or 2-octynoic acid) or altered response to acommon trigger in females. There is no evidence that foetalmicrochimerism may contribute to disease pathogenesis [66–70].

Although none of the currently identified disease-associatedloci for PBC are X or Y chromosome encoded, recent data have

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suggested that defects in the X chromosome are detectable in PBCpatients. There is a significantly higher frequency of monosomyof the X chromosome in peripheral leukocytes in women withPBC [71] compared to age-matched control women. Systemicsclerosis and autoimmune thyroiditis also show the same differ-ence [72]. X loss in PBC was not random and more frequentlyaffected the parentally-inherited chromosome [73].
Pathophysiology

Although a unified theory of PBC pathogenesis may not be possi-ble currently, a paradigm that considered the pathobiologicalevents contributing to disease progression may be presented(Fig. 2).

The preclinical phase is marked by autoimmunity. Autoimmu-nity is manifested by M2 antibodies (M2Ab) that specificallyreact with the lipoyl domain of the E2 subunits of the 2-oxo-aciddehydrogenase complexes of the mitochondria. The T and B cellsinfiltrating the liver in PBC are specific for the M2 antigen. TheM2 epitope is detectable in cholangiocytes undergoing apoptosisand in the luminal domain of the biliary cells of the small bileducts [74–76]. This luminal staining precedes the expression ofBB1/B7 and MHC II molecules, suggesting that aberrant expres-sion occurs early in the natural history of PBC [77]. The aberrantexpression may be present in cholangiocytes in allografts ofpatients with recurrent PBC following transplantation [78],

Insult(

AMA

Cholangiocyte

Inflammation / C

Fibrosis / Du

Cirrhosis / Liv

Host geneticbackground

Fig. 2. PBC sequential events: from PDCE2-breakd


suggesting the role of an exogenous factor. However, others wereunable to document this finding in the allograft in either thepresence or absence of PBC recurrence [79].

In contrast to other cell types, cholangiocytes undergoingapoptosis fail to bind glutathione to the lysine-lipoyl residue ofthe dehydrogenase and thereby fail to cleave the autoreactiveepitope [80]. Neighbouring cholangiocytes have the ability todestroy the apoptotic cells by phagocytosis and to express theM2 epitope [81,82]. This is a rational explanation for the tissuespecificity of the autoimmune process.

IgAM2ab may induce caspase and cholangiocyte injuryin vitro [83], which suggests that cholangiocyte apoptosis occursearly in the natural history and participates in the initiation oramplification of the autoimmune process. Normal cholangiocyteslining the small bile ducts express Bcl2 and are more resistant toapoptosis than those lining large bile ducts [84]. However, stress-induced glutathione depletion in cholangiocytes markedlyreduced Bcl2 expression, and activity and threshold of apoptosis[85,86]. In PBC, small bile duct-Bcl2 expression is reduced andassociated with features of oxidative stress, replicative senes-cence, and apoptosis [87]. Thus, a simple pathogenetic modelmay rely on the presence of IgAM2ab with a superimposedacquired dysfunction or glutathione depletion in cholangiocytesof the interlobular bile ducts. This model could explain at leastin part the beneficial effect of UDCA, a bile acid that reducesAMA titre and exerts antiapoptotic properties in cholangiocytesin the early natural history of PBC [10,88,89].

s)

apoptosis

holestasis

ctopenia

er failure

Environmentalfactors

own tolerance to cirrhosis and liver failure.

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Inflammation and cholestasis are early events in the clinical phase
of the disease. In the nonductopenic stage, inflammation is associ-ated with similar rates of apoptosis and proliferation of the biliarycells [90–92]. Cytolytic T cells, mainly, CD8, CD4, and NKT cells areattracted to the target-cells by the release of several chemokines[87,93–98]. The killing of biliary cells is mainly mediated by activa-tion of TNF, CD 40, and Fas receptors [99]. Under the pressure of thisenvironment, cholangiocytes proliferate to compensate for death.Mediators possibly involved in this process include those of thecholinergic pathway, the IGF1 system, and oestrogens actingthrough their alpha receptors [100,101].

The inflammatory process spreads into the lobule in twoways, through the lymphocytic piecemeal necrosis and the biliarypiecemeal necrosis [89,102–104]. The piecemeal lymphocyticnecrosis observed in PBC is an inflammatory destruction of agroup of hepatocytes associated with lymphohistocytic cells,similar to that found in autoimmune hepatitis (AIH) (Fig. 3A).Lymphocytes invade or are in close contact with hepatocytes.Hepatocytes show degenerative features, swelling, shrinkage,and apoptosis while some other liver cells seem to survive,becoming hyperplastic while growing in a tubular fashion (so-called rosetting). As a result, the limiting plates are replaced bynewly form connective tissue, sometimes accompanied by ductu-lar profiles. The biliary piecemeal necrosis is marked by a strik-ingly increase in the number of ductular profiles extending inthe periportal area accompanied by oedema, neutrophil infiltra-tion, periductular fibroplasia, and features of hepatocellular deathassociated with cholate stasis (Fig. 3B). This form is usually asso-ciated with severe ductopenia. The interface hepatitis is a turningpoint in the natural history of PBC because its severity constitutesthe signal that announces the onset of fibrosis and eventually cir-rhosis [89,103,105]. A schematic view of the putative sequencesinvolved in the biliary fibrogenic process is depicted in Fig. 4.Hepatocellular death triggers expansion of progenitor cellsmarked by the appearance of reactive ductules, which have thepotential to secrete a series of mediators that may attract andactivate fibroblasts of different origins, monocytes, bone mar-row-derived cells, epithelial–mesenchymal transition, stellatecells and periductal portal fibroblasts [106–113].

Cholestasis is a key feature of PBC. Cholestasis in early PBCcannot be attributed exclusively to the loss of bile ducts because

Fig. 3. (A) Typical aspect of the lymphocytic interface hepatitis in PBC; (B) biliary poedema, neutrophils, and fibroplasia.


serum markers of cholestasis and pruritus may already be pres-ent before the onset of significant ductopenia, indicating a certainfunctional component. Cholestasis in early PBC is mainly a ductalcholestasis and secondarily a canalicular cholestasis as the conse-quence of the outflow functional blockade. One of the main fea-tures of the signalling pathways involved in ductal choleresis isits ability to induce alkalinisation and dilution of canalicular bileupon stimulation by secretin and several neuropeptides [114–117]. This unique property is lost in PBC and is associated withdefective regulation of cholangiocyte AE2 (SLCA2) and NHE(SLC9A3) exchanger activities and expression [118,119], and lossof the expression of inositol 1,4,5-triphosphate receptorsinvolved in Ca2+-mediated bicarbonate secretion [120]. Inflam-matory cytokines inhibit cAMP-dependent fluid secretion in cho-langiocytes and impair the barrier function of biliary epithelia[121,122], an effect that may be mediated by nitric oxide [123].UDCA therapy partially restores AE2 activity and expression aswell as secretin-induced bicarbonate and fluid secretion [124].Dilution and alkalinisation of bile are critical for the defence ofthe biliary epithelium against microbes and pathogen-associatedmolecular patterns. The impaired generation of a bicarbonate-rich choleresis may hinder the activity of antimicrobial peptidesbecause of the high salt concentration of bile [125]. The absenceof an alkaline pH in bile could also alter the activity of the biliaryalkaline phosphatase, thus inhibiting its ability to dephosphory-late endotoxin and to prevent LPS-induced inflammation [126].Circumstantial evidence supporting this view includes the simul-taneous effects of UDCA therapy on dilution and alkalinisation ofbile, the accumulation of endotoxins in cholangiocytes [127], andserum markers of cholestasis and immune reaction against endo-toxins [128].

Alterations in hepatocellular transporter gene expressionevolve in PBC in stage-dependent fashion. In the early anictericstage, no changes in bile salt and bilirubin transporters aredetectable [129–131]. With disease progression, OATP2 and NTCPexpression is down-regulated while BSEP, MDR3 and MRP2expression is up-regulated or maintained. These changes mayrepresent adaptive mechanisms to limit bile acid burden inchronic cholestasis. As these changes do not sufficiently counter-act cholestatic liver damage, therapeutic strategies should aim atstimulating the bile acid detoxification pathways.

iecemeal necrosis with marked increase of ductular profiles accompanied by

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Fibroblasts

Portal fibroblast

EMT

Stellate cell

BMD

Monocyte

Activated portaland periportalmyofibroblasts

Ductular proliferation

TGFβNGF

CCL2ET1PDGFVEGF

Hedgehog

Hepatocytedeath

Expansion of hepaticprogenitor cells

Biliary fibrosis

Fig. 4. Schematic representation of the putative sequence events in the fibrogenesis process of PBC (ET1: endothelin 1, PDGF: platelet-derived growth factor, VEGF:vascular epithelial growth factor, CCL2: chemokine ligand 2, TGFb: transforming growth factor b, NGF: nerve growth factor, BMD: bone marrow derived-cells, EMT:epithelial–mesenchymal transition).

Review

Natural history

PBC progresses through three irreversible states: (a) cirrhosis; (b) aterminal phase defined when serum bilirubin reaches 100 lmol/L(6 mg/dl) with or without GI bleeding, ascites, or encephalopathy;and (c) death unless OLT is performed.

The patterns of clinical disease and natural history have chan-ged significantly in the last two decades.

Natural history in the pre-UDCA era

In 1979, Shapiro and colleagues [132] showed that after a relativelystable phase, serum bilirubin increased sharply in the months pre-ceding death. In patients with serum bilirubin levels above34 lmol/L, the mean survival was 4 years; in those with valuesabove 102 lmol/L, it was 2 years. The multicentre European study,initially aimed at evaluating the efficacy of azathioprine in PBC,provided precise data on the natural history in this era [133]. Atenrolment, 54% and 19% of a total of 236 patients had stage 1–2and stage 3 disease, respectively. During a 4-year follow-up period,half of the patients developed histologically-proven cirrhosis and25–35% acquired one or several criteria (see above) of the terminalphase of PBC. In the large community based study of 770 patients inNortheast England [134], 15% of them developed signs of liverfailure during a 5-year follow-up period. The rate of histologicalprogression, assessed in three large groups of patients in theabsence of a therapeutically effective agent, has shown that the


median time to develop extensive fibrosis was 2 years and theprobability of remaining in the early stage was 29% (95% confi-dence interval: 15–52%) after 4 years of follow-up [133,135,136].The rate of development of oesophageal varices, in a prospectivestudy of 256 patients during a median follow-up of 5.6 years, wasestimated to be 31% [137].

Natural history in the UDCA era

Patients receiving UDCA therapy have a delayed rate of histolog-ical progression to cirrhosis. In an early study [138], the rate ofprogression to cirrhosis after a follow-up period of 6 years was13% in patients receiving UDCA and 49% in the control group ofpatients. In a French trial [136], UDCA therapy was associatedwith a 5-fold lower progression rate from early stage disease toextensive fibrosis or cirrhosis (7% per year under UDCA vs. 34%per year under placebo, p <0.002). At 4 years, the probability ofUDCA-treated patients to remain in early stage disease was 76%(95% confidence interval: 58–88%), as compared to 29% (15–52%) in placebo-treated patients. The effect of UDCA therapy onthe development of oesophageal varices was addressed in a pro-spective study of 180 patients followed up for 4 years [139]. Therisk of developing varices was 16% for the UDCA-treated patientsand 58% for those receiving the placebo.

Long-term observational studies and Markov modelling havebeen used to study the effect of UDCA on survival. In 262 patientswho had received 13–15 mg/kg UDCA daily for a mean of 8 years

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(range 1–20 years), the overall survival rates without liver trans-plantation were 84% and 66% at 10 and 20 years, respectively. Inearly-stage patients, 6% were predicted to progress to liver trans-plantation or death after 10 years and 22% by 20 years. The survivalof these patients was similar to that of the control population. Incontrast, the probability of death or liver transplantation wassignificantly increased in patients treated in the late stages of thedisease (relative risk: 2.2) [140]. The degree of the biochemicalresponse to UDCA identifies patients with a good long-termprognosis [141–143]. Patients, showing ALP <3 upper limit ofnormal (ULN), AST <2 ULN, and bilirubin 61 mg/dl after 1 year ofUDCA, had a 10-year transplant-free survival rate of 90% (95% con-fidence interval, 81–95%), compared to 51% (95% confidence inter-val, 38–64%) for those who did not (p <0.001) [142].
Clinical presentation, diagnosis investigation, and patientevaluation

Clinical presentation

There are three major forms of PBC (Fig. 5). The typical or classi-cal form is represented by the slowly progressive decline of smallbile ducts and parallel increase in liver fibrosis, leading to biliarycirrhosis over a period of 10–20 years. A second form, whichaffects 10–20% of patients, is characterised by the fluctuating orpersistent presence of the features of AIH [144]. These patientshave a more severe disease course, with early development ofliver fibrosis and liver failure. A third form, which affects 5–10%of patients, is represented by the so-called premature ductopenicvariant [145]. Its hallmark is a very rapid onset of ductopenia andsevere icteric cholestasis, progressing very quickly towards cir-rhosis in less than 5 years.

PBC is now diagnosed earlier in its clinical course than it wasin the past. Half of the patients are asymptomatic at diagnosis.Fatigue and pruritus are the two symptoms of the early phaseof the disease. Fatigue, a frequent complaint, is unrelated to theseverity. Whether fatigue is a specific symptom or not remainsunknown [146]. Nevertheless, it has a major impact on the qual-ity of life of PBC patients [147–151]. It is associated with cogni-tive and emotional dysfunction, depression, sensory andautonomic abnormalities. It may be associated with excessive

0 5 10years

15

Typical PBC

0 5

PBC wit

Fibrosis

Interlobularbile ducts

Fig. 5. Patterns of development of ductopenia and fib


day-time somnolence [152,153]. A mild pruritus affects abouthalf of the patients at diagnosis. It may be severe in the prema-ture ductopenic variant, affecting the patients’ quality of life. Insome patients, the diagnosis is made in the work-up of anotherautoimmune disease. In 5–10% of patients, the diagnosis is madebecause of signs of compensated or decompensated cirrhosis. Inthe variant associated with features of AIH, the diagnosis maybe made in a patient with acute cytolytic hepatitis [154].

In the typical form, patient biochemistry is characterised bypredominant elevation of serum alkaline and gammaglutamyl-transpeptidase activities while serum activities of transaminasesare mildly or moderately increased. In the premature ductopenicvariant, there is great cholestasis and it is associated with consid-erable hypercholesterolemia affecting both HDL and LDL frac-tions, and the non-atherogenic lipid particle LPX [155]. Inpatients with both the features of AIH and PBC, serum activitiesof transaminases may be markedly elevated and are usually asso-ciated with marked increase of IgG. Increased IgM levels are aconstant feature in all forms of PBC. Thrombocytopenia, poly-clonal hyperglobulinemia, and hyperbilirubinemia are indices ofcirrhosis. Low prothrombin index and hypoalbuminemia occursusually in the late phase of the disease [156,157].

Diagnostic investigation

Good ultrasound investigation of the liver and biliary tree is man-datory in all patients presenting with liver abnormalities. If thebiliary system appears normal by ultrasound and the AMA ispositive, no further radiologic delineation of the bile ducts is nec-essary. If the diagnosis of PBC is uncertain, cholangiography maybe necessary.

The major hallmark of PBC is the presence of AMA in serum.AMA that reacts with the E2 component of pyruvate dehydroge-nase is diagnostic of PBC. A variety of antinuclear antibodies areassociated with PBC. Of these, those reacting with the proteins ofthe pore complex (gp210, nucleoporin 62) and of the protein ofthe nuclear body (sp100) are specific.

Histological examination of the liver is only mandatory fordiagnosis if the AMA is negative or if the patient has the biochem-ical picture of atypical PBC or is suspected of superimposedcomorbidity. Nevertheless, it should be emphasised that histol-ogy is valuable for prognostic evaluation and treatment strategy.

10years

15

h AIH features

0 5 10years

Preductopenic variant

15

rosis in the three major clinical forms of PBC.

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The diagnosis is based on the following three criteria: (a)
abnormal biochemical tests with preferential elevation of serumalkaline phosphatase and gammaglutamyltranspeptidase activi-ties; (b) presence of antimitochondrial antibodies with M2 spec-ificity as confirmed by ELISA or immunoblotting; and (c) evidenceof NSDC at histology. Criteria a and b or c are sufficient for thediagnosis considering the high specificity of the anti-M2 antibodyand NSDC [158,159].

Patients with AMA and normal biochemical tests are at risk ofdeveloping true PBC. Patients with biochemical evidence of cho-lestasis but negative AMA may have PBC if NSCD or portal inflam-mation and ductopenia are demonstrated in the liver biopsy. Thediagnosis is further supported in this setting if antinuclear anti-bodies against gp210, Nucleoporin 62, sp100 giving nuclear-rimor nuclear-dot pattern are present. NSDC is highly suggestive ofPBC but is not pathognomonic since it may be present in patientswith AIH, primary sclerosing cholangitis, lymphoma, and viralhepatitis C and E.

Variant forms of AIH may result from several concurrent fea-tures of PBC in AIH and may pose diagnostic difficulties. Specificautoantibodies to M2 autoantigen may be found in a minority ofAIH [160–162]. Up to 24% of patients with AIH may have histo-logical evidence of bile duct injury without biochemical chole-stasis [163]. All of these patients respond to AIH-conventionaltherapy. Finally, up to 2.4% of patients with typical PBC developan acute AIH-superimposed on their PBC [154,164]. In this con-text, the so-called PBC-AIH overlap syndrome is defined by thesimultaneous or consecutive concurrent main characteristics ofthe two conditions. The following score has been proposed toestablish the diagnosis, e.g., presence of two of the three ofthe following features: (1) ALT activity P5 times upper limitsof normal; (2) IgG P2 times upper limits of normal and/or posi-tive anti–smooth muscle antibody; and (3) liver biopsy withmoderate or severe periportal or periseptal inflammation[158,159,165].

Patient evaluation

Mucosal infections, especially recurrent urinary infections andcigarette smoking, two potential risk factors of PBC, should berecognised, treated or prevented. About 20% of the patients exhi-bit other simultaneous or consecutive autoimmune diseases, themost frequent being AIH, CREST syndrome, and/or sclerodermaand thyroiditis. Celiac disease is not so frequent but should berecognised because of the beneficial effect of the gluten free diet.

First-degree relatives of patients with PBC are at high risk ofPBC or other autoimmune diseases. The patients and their rela-tives should be informed and evaluated for these conditions.While the pathogenesis of fatigue and pruritus is still unknownand their treatment empirical, these two symptoms should becarefully analysed and if possible, quantified.

The attention should focus on the severity or potential sever-ity of the disease.

Is there evidence of cirrhosis? Asymptomatic cirrhosis is prob-able if splenomegaly is disclosed, prothrombin index is lowerthan 80%, serum albumin is lower than 38 g/L, serum bilirubinis more than 2 mg/dl, and the platelet count is less than150,000/ll. In these patients, oesophageal varices should be eval-uated and treated if they are large. The cirrhotic patients are atrisk of developing hepatocellular carcinoma and as such needto be regularly investigated by appropriate imaging techniques.


Is there any evidence of indices of severity and predictors ofpoor response to UDCA therapy apart from cirrhosis? Fatigue andpruritus are in most cases not related to the severity of PBC anddo not have major prognostic value. Serum bilirubin level is thebest predictor of prognosis and of long-term response to UDCAtreatment. Patients with even a mild elevation (more than 1 mg/dl) are at risk of developing extensive fibrosis or cirrhosis in thenext 10 years. Patients with high serum bilirubin level (more than3 mg/L), high serum alkaline phosphatase activity, and cholesterolhave usually severe ductopenia at presentation (the prematureductopenic variant of PBC) and will not respond to any medicaltherapy. These patients should be informed that liver transplanta-tion is the only therapeutic alternative.

Is there any evidence of features of AIH? Patients with boththe criteria of PBC and AIH need to be given both UDCA and glu-cocorticoids. High levels of serum bilirubin, together with highALT and IgG as well as the presence of antiactine and anti-SLAantibodies, are very suggestive of this condition.

Liver histology may help to fully evaluate the prognosis and toestablish the best medical treatment. Given the risk of samplingerror, at least 10 portal tracts should be available. The individuallesions have to be graded. The Metavir score could be used to assessboth fibrosis and interface hepatitis (under the form of lympho-cytic piecemeal necrosis). The presence and extent of the NSDCshould be noted. Ductopenia should be quantified. However, incase of heavy portal inflammation, this quantification may be dif-ficult even with the use of cytokeratin histochemical staining.The presence and extent of biliary piecemeal necrosis should beassessed. Nodular regenerative hyperplasia, which is sometimespresent, may indicate portal vascular damage by inflammatorycells. The presence of numerous fibrous septa, loss of more than50% of the interlobular bile ducts, moderate to severe lymphocyticor biliary piecemeal necrosis are indices of severe prognosis.

Because the prognosis of PBC is far better than two or threedecades ago, two associated conditions deserve particular atten-tion. Hypercholesterolemia with increased LDL cholesterol isobserved in about 20% of the patients. Accordingly, the risk of car-diovascular disease should be evaluated and medical therapypossibly proposed. Osteoporosis and osteopenia might be morefrequent in women with PBC than in a control population,although this remains controversial [166]. Nevertheless, meta-bolic bone disease should be assessed and prevented in particularin those at risk of receiving glucocorticoids.

Treatment

Specific therapy

UDCA therapyAll PBC patients with abnormal liver biochemistry should be con-sidered for specific therapy. UDCA, at the dose of 13–15 mg/kg/day, is currently considered the mainstay of therapy for PBC. Ran-domised, double-blinded, placebo-control trials have consistentlyshown that UDCA improves parameters of liver biochemistryincluding serum bilirubin, the major prognostic marker in PBC.UDCA delays the progression of fibrosis and histological stage.A combined analysis of three randomised-controlled trials,including 548 patients with PBC, showed improved survival with-out liver transplantation in patients with moderate to severe dis-ease treated with UDCA at doses of 13–15 mg/kg/day for up to4 years [167]. Long-term observational studies have shown that

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UDCA therapy provides a better survival rate than that predictedby the Mayo model [140–142,168,169]. The survival rate ofUDCA-treated patients in early stages of disease is similar to thatin a control population [142,143]. In both Europe and NorthAmerica, the number of liver transplants for PBC is falling in par-allel with the increased use of UDCA therapy [170,171]. Somemeta-analysis (but not all) including short-term trials with lowdoses of UDCA (<12 mg/kg/day) has questioned the efficacy ofUDCA. However, based on all available data, it is currently recom-mended to treat PBC with UDCA using doses of at least 13 mg/kg/day and to start early [158,159]. UDCA could be taken in divideddoses or as a single dose. Because UDCA is an acid, it can producegastric discomfort, burning sensation and symptomatic reflux insome patients. These symptoms are easily managed with protonpump inhibitors or by ingesting the bile acid at the end of meals.
Overall, UDCA is extremely safe. The majority of the patientsnote a weight gain (2 kg, on average). Whether this is due tochanges in endogenous bile acid composition and subsequentlyon signalling through the TGR5 pathway remains to be explored[172]. The weight gain may be more significant in patients whohave stopped smoking. In patients with pruritus and frank chole-stasis, UDCA may increase pruritus if given at a dose of 13–15 mg/kg/day. In these patients it is recommended to start UDCAtherapy at a low dose, 200–400 mg/day, and to progressivelyincrease the daily dosage over a period of 4–8 weeks.

The aim of UDCA therapy is to provide the normalisation ofthe serum bilirubin, alkaline phosphatase, and ALT or AST levelsduring the first year of therapy. Patients with complete normali-sation of serum bilirubin, ALT or AST, and alkaline phosphatasehave a null risk to progress to cirrhosis (unpublished data). Inmany patients, this cannot be achieved. We defined an optimalresponse to UDCA when serum bilirubin is less than 1 mg/dl,AST less than two times the upper limit of normal, and alkalinephosphatase less than three times the upper limit of normal atthe end of the first year of therapy. Indeed, patients with thesecriteria have a 10-year life expectancy without liver transplanta-tion similar to that of the control population [142]. Others haveobserved that, patients with a decline of serum alkaline phospha-tase of more than 50% achieve an excellent long-term prognosis[141]. In a subset of patients, the daily dose of 13–15 mg is notsufficient to achieve the best biochemical response. In thepatients who do not respond adequately, measurement of theblood and biliary enrichment in UDCA by LC–MS may be useful.In those with a low enrichment of total serum bile acids withUDCA (less than 40%) a trial with daily doses up to 20 mg/kg/day may be proposed to achieve a better response.

About 40% of our patients have a suboptimal response toUDCA. These patients need an adjuvant therapy.

Adjuvant therapiesPatients with features of AIH, severe interface hepatitis, abnormalserum bilirubin level or suboptimal response to UDCA as definedabove, require trials with adjuvant therapies. Currently, glucocor-ticoids (prednisone or budesonide) and methotrexate could beconsidered for these patients. The rationale for the use of gluco-corticoids is based on the following arguments: glucocorticoidsand specifically budesonide have been shown to provide benefitin patients treated with UDCA. A combination of both leads tobetter biochemical response and better histological response interms of inflammation and fibrosis in de novo PBC patients[173,174].


Budesonide is given at 6–9 mg/day in non-cirrhotic patients.The drug is contraindicated in patients with cirrhosis. Preliminarystudies in our patients indicate that patients with a suboptimalresponse to UDCA and frank biliary and periportal inflammationbenefit from the combination of UDCA and glucocorticoids (in par-ticular budesonide) in terms of survival without liver transplanta-tion. In this setting, the use of glucocorticoids sparing agents, suchas azathioprine or mycophenolate mofetil, may be recommended.

Methotrexate improved biochemical test results and liver his-tological findings when it was added to UDCA in patients whohad an incomplete response to UDCA [175,176]. However, otherstudies found no efficacy of methotrexate when used alone orin combination with UDCA [177–179]. In a 10-year study, sur-vival was the same in patients taking methotrexate and UDCAas in those taking colchicine and UDCA and was similar to thatpredicted by the Mayo model. However, one-third of the patientshad few signs of PBC after 10 years of treatment. No patient whowas in the precirrhotic stage at baseline and receiving methotrex-ate showed progression to cirrhosis, suggesting that methotrex-ate could be useful in a small subset of patients [180].Randomised control trials of cyclosporine monotherapy in PBChave shown that the drug was effective in terms of clinical, bio-chemical, and histological progression [181] and significantlyprolonged the time to death or transplantation [182] despitethe well-known detrimental influence of cyclosporine on hepa-tobiliary transport systems [183]. However, because of the highrate of side effects, there has been little enthusiasm to furtherexamine the potential benefit of cyclosporine, particularly inassociation with UDCA, a hydrophilic bile acid able to preventcyclosporine-induced cholestasis [184].

Several drugs such as colchicine, chlorambucil, penicillamine,azathioprine, mycophenolate mofetil, malotilate, and thalido-mide have been evaluated for PBC treatment. Many of them areeither ineffective or toxic. None of them have been shown to beeffective in UDCA-treated patients at risk of development of cir-rhosis or liver failure as defined above [185].

Taking into account the considerable progress made in theunderstanding of the pathobiology of PBC, many novel therapeuticapproaches could be proposed to target patients with no or incom-plete biochemical response to UDCA [186]. Among them, PPARalpha agonists [187,188], FXR agonists [189] and biotherapies suchas antiCD20 [190,191], GLP1 receptor agonists [192,193], and oest-rogen-alpha receptor agonists [100] could be promising.

Liver transplantationLiver transplantation has greatly improved the survival ofpatients with PBC [9]. It is the only effective treatment for thosewith decompensated cirrhosis or liver failure. Patients, who pres-ent with the features of the premature ductopenic variant of PBC,do not respond to any medical therapy and despite the absence ofany decompensation draw a major benefit from liver transplanta-tion. PBC recurs in about 20% of patients at 5 years [194]. Recur-rence is more frequent in patients without a glucocorticoid andcyclosporine regimen. The beneficial long-term effect of UDCAin this setting remains unknown [195].

Treatment of symptoms and complications

PruritusCholestyramine is widely used as first-line treatment, althoughthe evidence to support this is limited. When both agents are

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used, UDCA and cholestyramine should be spaced a minimum of4 h apart to prevent binding and loss of efficacy [196]. Rifampicinhas a strong evidence base [197,198]. Daily dosage up to 600 mg/day may be used in patients receiving UDCA. However, the drugmay induce hepatitis in some cases [199]. Other therapies includeglucocorticoids, sertraline, and opiate antagonists [200]. Plasma-pheresis or biliary drainage may be successful when other treat-ments fail. In very rare patients, resistant pruritus may be anindication for liver transplantation.
FatigueFatigue may be multifactorial; causes other than PBC should beconsidered. Modafinil, a drug approved for the treatment of nar-colepsy, has been reported in open studies to provide significantbenefit in PBC patients with fatigue [201,202]. The drug used atdoses up to 400 mg/day seems well tolerated and very effectivein those with excessive fatigue and day-time somnolence.

HypercholesterolemiaUDCA induces an average 15–20% decrease in total and LDL cho-lesterol at 1 year of therapy [203]. Statins are safe and effective inPBC [204,205].

Portal hypertensionA minority of patients with PBC develop presinusoidal portalhypertension before becoming cirrhotic. Management of portalhypertension in patients with PBC should be the same as thatfor other cirrhotic patients. Severe portal hypertension, evenwithout any other sign of decompensation, is a good indicationfor liver transplantation. Liver transplantation should be pre-ferred to TIPS [206].

Osteopenia and osteoporosisCurrent treatments for osteopenia and osteoporosis, which affectup to 30% of PBC patients, included: physical activity, calcium andvitamin D supplementation to achieve at least 30 ng/ml of serum25OH D3, bisphosphonates or oestrogens supplementation[158,159,166].

Key points:

� Progressive immune-mediated destruction of the smallintrahepatic bile ducts.

� Affects predominantly middle-aged women.� Risk factors: history of familial autoimmune disease, active

or passive smoking, recurrent urinary tract infections.� AMA, targeting the 2-oxo-acid dehydrogenase complex, is

diagnostic.� Associated with autoimmune hepatitis in 10% of the

patients.� UDCA (13–15 mg/kg/day) is recommended as first-line

medical therapy by the 2009 EASL and AASLD practiceguidelines.

� Absence or incomplete biochemical response to UDCA hasmajor prognostic implication and represents a simple anduseful tool in identifying patients requiring further thera-peutic intervention.

� Liver transplantation is the only treatment for patient withdecompensated cirrhosis or the features of the preductope-nic variant.


Acknowledgments

Author thanks Yves Chrétien for editing the manuscript.Financial disclosure: The author certifies that he has no commer-cial associations (e.g., consultancies, stock ownership, equityinterests, patent-licensing arrangements, etc.) that pose a conflictof interest in connection with the submitted article, except as dis-closed on a separate attachment.

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