Primary biliary cirrhosis in 2014 Avegail Flores and Marlyn J. Mayo

Purpose of review Primary biliary cirrhosis (PBC) was first described in the 1950s as a clinical syndrome of progressive cholestatic liver disease resulting from chronic inflammatory destruction of the intrahepatic bile ducts. In the 1980s, the autoimmune nature of the disease was appreciated with the discovery of disease-specific loss of immune tolerance to the pyruvate dehydrogenase complex and subsequent development of antimitochondrial antibodies and autoreactive T cells. Then, in the 1990s, multiple clinical trials demonstrating the efficacy of ursodiol as a treatment for PBC were published, although it has been clear that ursodiol is not a cure and only delays progression in some patients. Recent findings The study of PBC in the 2000s has been buoyed by two basic science advances: rapid sequencing technologies that have led to genome wide association studies, and elucidation of the role of nuclear hormone receptors in the regulation of bile salt metabolism, which has led to novel therapies under study for cholestatic diseases. Summary Today’s clinician should be able to determine which patients with PBC are likely to progress despite treatment with ursodiol and understand the putative new bile acid and immunosuppressant treatment strategies under development, as well as be aware of the recently described genetic factors at play in the development of PBC. Keywords bezafibrate, budesonide, fenofibrate, obeticholic acid, overlap



Primary biliary cirrhosis (PBC) is characterized by chronic, immune-mediated destruction of the small-to-medium-sized bile ducts in the liver, resulting in chronic cholestasis and eventually, cirrhosis. It is an archetypal autoimmune disorder that occurs predominantly in middle-aged women with characteristic autoantibodies and frequently coexisting autoimmune diseases. Asymptomatic patients typically are diagnosed through elevations in alkaline phosphatase (ALP), presence of antimitochondrial antibody (AMA) titers 1 : 40 or greater, or a chronic nonsuppurative cholangiopathy on histology. Symptomatic patients usually present with fatigue and pruritus and sometimes with complications of portal hypertension. Ursodeoxycholic acid (UDCA) is the only Food and Drug Administration-approved treatment for PBC, but is not universally effective. Recognition of AMA-negative PBC, PBC–autoimmune hepatitis (AIH) overlap, and UDCA nonresponders is important in appropriate disease management. In addition, sequelae of chronic cholestasis, such as osteoporosis and fat-soluble vitamin deficiencies should be sought and treated.

The incidence and prevalence rates of PBC vary widely geographically and appear to be increasing. A systematic review of population-based epidemiological studies reported PBC incidence rates range from 0.33 to 5.8 per 100 000 inhabitants/year and prevalence rates range from 1.91 to 40.2 per 100 000 inhabitants [1]. Incidence and prevalence were highest in studies that applied more rigorous methodology to identify PBC cases. The three studies that reported the highest prevalence rates had similar search methods wherein PBC patients were identified through elevations in ALP, presence of AMA, or a compatible liver histology when AMA titers were equivocal. These studies reported prevalence Division of Digestive and Liver Diseases, University of Texas Southwestern, Dallas, Texas, USA Correspondence to Marlyn J. Mayo, Associate Professor, Division of Digestive and Liver Diseases, 5323 Harry Hines Boulevard, Room K.5.140C, Dallas, TX 75390-9151, USA. Tel: +1 214 648 3986; fax: +1 214 638 0391; e-mail: [email protected] Curr Opin Gastroenterol 2014, 30:245–252 DOI:10.1097/MOG.0000000000000058

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KEY POINTS  The diagnosis of PBC can be made without histology if the ALP and AMA are both elevated.  Multiple GWASs identified shared genetic loci involving NF-kB signaling, T-cell differentiation, and Toll-like receptor and tumor necrosis factor signaling.  New therapies such as fibrates and obeticholic acid, in the final phase of development can augment UDCA in patients at risk for progression with suboptimal biochemical response (no significant drop in ALP).  Overlap of PBC and AIH is more clearly defined using the definition of two out of three of the following criteria for each disease: AIH: moderate-to-severe interface hepatitis, elevated IgG or antismooth muscle antibody, and transaminases five-fold elevated and PBC: positive AMA, elevated ALP, and compatible liver biopsy.  Patients with PBC and AIH may benefit most from UDCA and immunosuppressive therapy, although the long-term risk/benefit ratio is still under study.

rates per 100 000 inhabitants of 39.2 in Newcastle, UK [2], 40.2 in Olmstead, Minnesota, USA [3], and 38.3 in Iceland [4]. It has been suggested that these high prevalence rates would be reflective of standard values that can be presently obtained with a similarly adequate methodology performed by highly experienced investigators [5]. In clinical practice, PBC, once a rare disease, has become more common due to increasing clinician awareness, the wider use of liver biochemical testing, and the availability of AMA assays.

SEX DIFFERENCES PBC is predominantly a female disease. The reported female : male ratio ranges from 3 : 1 to 22 : 1, with a median ratio of 9 : 1 [6]. One hypothesis is that estrogens play an important role in the development and/or clinical expression of PBC, as has been noted for other autoimmune diseases [7]. Studies have shown the role of estrogens in lymphocyte maturation, activation, and synthesis of antibodies and cytokines [8]. It is also known that estrogen receptors are present in cholangiocytes and cholestasis from PBC may first manifest itself during pregnancy. Interestingly, a study of environmental risk factors for PBC had suggested that exogenous estrogens may partly account for the female predominance of the disease [9]. PBC has not yet been reported in a prepubertal female, which seems to support this hypothesis. However, 246

estrogen’s role in the pathogenesis of PBC is yet to be explained. Meanwhile, there is little published with regard to sex differences in clinical presentation of PBC. A UK study that compared PBC disease course in men and women described similar survival in both sexes, but less pruritus and more hepatocellular carcinoma in men [10]. A small study in Japan reported less coexisting autoimmune disease and a more favorable prognosis in men, but also with increased rates of hepatocellular carcinoma [11].

PATHOGENESIS The serological hallmark of PBC is the formation of AMAs against the pyruvate dehydrogenase complex subunit E2 (PDC-E2). Both environmental and genetic factors are important in the pathogenesis of PBC [12]. Exposure to chemicals, infection (molecular mimicry or microorganisms that contain immunogenic epitopes similar to self-antigen), or xenobiotics (natural substances that are foreign to the body) has been proposed to be responsible for altering native mitochondrial protein target of AMA, rendering it immunogenic and triggering a promiscuous immune response [13]. The loss of tolerance to this ubiquitous antigen is described as a key step in the development of the disease. Although associations with environmental exposures do exist, a positive family history of autoimmune disease (systemic lupus, Sjogren’s, or PBC) confers the greatest risk of developing PBC [14], underscoring the clear role of genetic susceptibility in acquiring this disease. This is supported by three lines of evidence: familial clustering of PBC; a high risk of developing PBC in siblings of PBC patients (relative risk of 10.5) [15]; and a high disease concordance rate in monozygotic (63%) versus dizygotic (0%) twin pairs [16].

GENETICS Much of the earlier work on the genetics of PBC investigated its associations with genes implicated in other autoimmune diseases. These studies suffered from weak associations and lack of robust replication [17]. Significant strides have been made in understanding individual genetic susceptibility to PBC and potential molecular pathways involved since the first genome-wide association study (GWAS) was performed in 2009. In a landmark study by Hirschfield et al. [18] using DNA from 2072 white participants from North America (536 cases and 1536 controls), the investigators reported significant associations between PBC and common genetic variants at the human leukocyte antigen Volume 30  Number 3  May 2014

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Primary biliary cirrhosis in 2014 Flores and Mayo

(HLA) class II, interleukin 12A (IL12A), and IL12RB2 loci, thereby confirming the HLA class II association and suggesting an IL-12 signaling pathway relevant to the pathogenesis of the disease. This was shortly followed by a GWAS of an Italian cohort (453 PBC and 945 controls) that replicated IL12A and IL12RB associations and identified three new loci at SPIB, IRF5-TNPO3, and 17q12-21 [19]. The third GWAS study of patients of European descent in the United Kingdom (1840 cases and 5163 controls) contributed 12 new susceptibility loci, including STAT4, DENND1B, CD80, IL7R, CXCR5, TNFRSF1A, CLEC16A, and NFKB1, thereby expanding the genetics of PBC [20]. Meanwhile, a Japanese GWAS (487 PBC and 476 controls) suggested ethnic differences in genetic susceptibility loci to PBC when it reported only three loci of the 21 non-HLA susceptibility loci of European descent (IL7R, IKZF3, and CD80) showed significant associations. It also discovered two other new susceptibility loci TNFSF15 and POU2AF1 [19]. Altogether, these four GWASs (three European descent and one Asian study) have identified 27 non-HLA PBC risk loci and have highlighted the role of nuclear factor (NF)-kB signaling, T-cell differentiation, and Toll-like receptor and tumor necrosis factor signaling in disease pathogenesis [18–21]. The discovery through GWAS of the association between the risk of developing PBC and the IL-12/ IL 23 inflammatory pathway led to exploring the use of anti-IL12 strategies as a treatment for PBC. GWASs revolutionized our understanding of the genetic basis of PBC by emphasizing shared genetic loci across different regions and giving a glimpse of the genetic heterogeneity of the disease between different ethnic groups

URSODEOXYCHOLIC ACID AND EMERGING TREATMENTS UDCA is the only drug approved by the US Food and Drug Administration for PBC, and at a dose of 13–15 mg/kg/day has become the mainstay of therapy for PBC. The proposed protective mechanisms of actions include inhibition of the absorption of toxic endogenous bile salts, stabilization of hepatocyte membranes, replacement of endogenous toxic bile salts, and reduction of major histocompatibility complex class I and class II antigens expression [22]. However, the ability of UDCA to impact the natural history of PBC is still controversial, and the lack of sufficiently long placebo-controlled trials precludes a definitive statement on UDCA’s effect on actual (not predicted) survival. Lowering of ALP usually begins within 2–3 weeks of starting UDCA. Almost 90% of the improvement in ALP will be achieved by 6 months of therapy [23].

Retrospective studies have now demonstrated that patients who achieve a reduction of ALP to about 1.5–3 times the upper limit of normal or 40% reduction from baseline will have a normal survival [24,25]. However, those who do not achieve these benchmarks are at risk for progressive decline [25]. On the basis of these studies, it has recently become accepted that biochemical response to UDCA in PBC is a strong predictor of long-term outcome. Numerous criteria (Table 1) [24–29] for defining biochemical response have been studied to predict outcomes and to facilitate the identification of patients needing new therapeutic approaches. A recent prospective study aimed to determine whether these criteria were valid using earlier biochemical response at different time points from 3 to 12 months. These investigators found the previously published criteria, but not the Rotterdam, significantly discriminated the patients in terms of long-term outcome. Biochemical responses at the 6th month can be used in place of those evaluated after 1 year of UDCA therapy allowing for a more rapid identification of patients who would need new therapies [30 ]. &

Budesonide Budesonide is a glucocorticoid mainly absorbed in the small intestine with 90% of the dose undergoing first pass metabolism in the liver. The beneficial effect of combination therapy with UDCA was first shown in a prospective, controlled double-blind trial of 20 patients with mainly early-stage disease Table 1. Definitions of biochemical response to ursodeoxycholic acid in patients with primary biliary cirrhosis Criteria


Barcelona [24]

ALP decline of >40% after 1 year of UDCA

Paris 1 [25]


Primary biliary cirrhosis in 2014.

Primary biliary cirrhosis (PBC) was first described in the 1950s as a clinical syndrome of progressive cholestatic liver disease resulting from chroni...
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