Review

Diagnosis and management of primary biliary cirrhosis

Expert Review of Clinical Immunology 2014.10:1667-1678. Downloaded from informahealthcare.com by Emory University on 04/19/15. For personal use only.

Expert Rev. Clin. Immunol. 10(12), 1667–1678 (2014)

Ahmad H Ali*1, Elizabeth J Carey1 and Keith D Lindor1,2 1 Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA 2 College of Health Solutions, Arizona State University, 550 North 3rd Street, Phoenix, AZ 85004, USA *Author for correspondence: Tel.: +1 480 831 0665 Fax: +1 480 831 0665 [email protected]

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized histologically by destruction of intrahepatic bile ducts and serologically by the presence of antimitochondrial antibodies. The incidence and prevalence of PBC are increasing. Fatigue and pruritus are common symptoms in PBC, although the proportion of asymptomatic PBC is increasing due to the widespread use of screening biochemical tests and antimitochondrial antibody assays. PBC may eventually lead to cirrhosis and its consequent complications. In the 1980s, PBC was the leading indication for liver transplantation. Ursodeoxycholic acid is the only US FDA-approved therapeutic agent for PBC. Clinical trials have shown that the use of ursodeoxycholic acid in PBC results in reduction of liver biochemistries, a delay in histological progression, a delay in the development of varices and improvement in survival without liver transplantation. KEYWORDS: antimitochondrial antibody • liver transplantation • primary biliary cirrhosis • ursodeoxycholic acid

Primary biliary cirrhosis (PBC), or chronic nonsuppurative destructive cholangitis, is an autoimmune cholestatic liver disease characterized histologically by the destruction of the small intrahepatic bile ducts, periportal inflammation and fibrosis, leading ultimately to cirrhosis and consequent complications such as liver failure and portal hypertension [1,2]. The characteristic serological hallmark of PBC is the antimitochondrial antibody (AMA), a highly disease-specific autoantibody found in 95% of PBC patients [3]. The targets of the AMA are members of a family of enzymes, the 2-oxo-acid dehydrogenase complexes, and include pyruvate dehydrogenase complex (PDC-E2), branched chain 2-oxo-acid dehydrogenase complex (BCOADC-E2) and 2-oxo-glutaric acid dehydrogenase complex (OADC-E2) [4,5]. The disease was first described in 1851 by Addison et al., but it was not until 1949 that Ahrens et al. introduced the term ‘primary biliary cirrhosis’ [6]. The disease predominantly affects middle-aged women, with a female-to-male ratio of 10:1 [7], although younger patients have been described in the literature including rare pediatric cases [8]. In addition to female sex, several other clinical variables have been proposed as risk factors for PBC. Past or present smoking, infectious agents, a family history of PBC or other autoimmune disorders, frequent use of nail polish or hair dye have all been associated with PBC [9,10].

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10.1586/1744666X.2014.979792

Epidemiology of PBC

Data from large PBC case series report a prevalence ranging from 19 to 365 cases per million in the USA, Australia and Europe [11–13]. In the USA, the reported age-adjusted incidence of PBC per 100,000 persons in a US community was 4.5 for women, and 0.7 for men; the overall incidence of PBC was 2.7 per 100,000 persons [12]. European epidemiological studies have estimated PBC incidence rates of 0.4–5.8 per 100,000 person-years and prevalence of 0.5–39 per 100,000 population [14–21]. There is evidence that the incidence of PBC may be increasing. Among the residents of Sheffield, UK, the incidence of PBC has increased from 5.8 to 20.5 cases per million between the years 1980 and 1999 [22,23]. Newcastle-upon-Tyne, UK reports an increase from 11 to 32 cases per million between the years 1976 and 1994 [17,19]. Similarly, in the time period between 1988 and 1999 in Finland, the incidence and prevalence of PBC increased from 12 to 17 cases and from 103 to 180 cases per million, respectively [13]. The incidence and prevalence of PBC in a Dutch population-based study has increased over time between 2000 and 2008 [11]. Whether the change in incidence and prevalence of PBC is due to a true increase, increasing awareness by physicians, prolonged survival of PBC patients or increase in frequency of detection of asymptomatic and early PBC

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remains to be determined. However, in the Dutch populationbased study in PBC patients which is the largest up to now, including 992 PBC patients, the observed increase in incidence and prevalence between 2000 and 2008 was independent of the number of deaths or improved survival in PBC, suggesting that there is a true increase in PBC occurrence [11]. The reason(s) for the increase in PBC occurrence remain unknown. Besides lifestyle, infections, cigarette smoking [24], wastes and toxins [25] have been linked to PBC but are yet to be confirmed.

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Genetics of PBC

Family studies reveal that the prevalence of PBC is approximately 0.72 and 1.2% in first-degree relatives and offspring of affected patients, respectively [26]. Some investigators have found higher rates of family concordance that approach 5% [27]. The highest relative risk is observed in daughters of affected females; the point relative risk in this group reaches 87% [27]. A large study of first-degree relatives found that 20% of sisters, 15% of mothers and 10% of daughters of PBC patients were positive for AMAs [28]. A significant genetic basis for PBC is also implicated by the much higher diseaseconcordance rates in monozygotic twins than in dizygotic twins (0.6) [29]. Studies from northern and southern Europe and from North America have identified HLA-DR8 (DRB1*0801) as significantly overrepresented in patients with PBC compared with controls [30]. Different HLA types may relate to immunological phenotypes. A recent study found a strong association between the HLA locus (rs9277535 at HLA-DPB1) and disease in anti-sp100-positive individuals versus anti-sp100-negative individuals [31]. A further analysis incorporating available genome-wide association studies (GWAS) data determined that three polymorphisms at the HLA-DPB1 locus were the most strongly associated with disease in anti-sp100-positive individuals but not in anti-sp100-negative individuals [31]. The Canadian GWAS identified three susceptibility loci, HLA, IL12A and IL12RB2, as strongly associated with a diagnosis of PBC [32]. The results from the Italian GWAS replicated IL12A and IL12RB associations, and a combined meta-analysis using a Canadian dataset identified newly associated loci at SPIB, IRF5TNPO3 and 17q12-21 [33]. The UK GWAS [34] has identified three new loci strongly associated with PBC. The new candidate genes identified are STAT4, DENND1B, CD80, IL7R, CXCR5, TNFRSF1A, CLEC16A and NFKB1. These studies helped unravel some of the genetic architecture of PBC, which could potentially help understand the disease mechanism and identify potential targets for future therapeutic interventions. Why PBC has such a high predominance [7] in women remains unknown. Several genes implicated in the immunological tolerance are located on the X chromosome [35]. Conditions related to missing or structurally abnormal X chromosomes, such as Turner’s syndrome and premature ovarian failure, are often accompanied by autoimmune features [36]. Similarly, specific mutations of the X-linked genes are associated with immunodeficiencies [37]. Invernizzi et al. found a significantly higher frequency of X monosomy among female patients with PBC 1668

compared with control subjects [38]. These results suggest that abnormalities of the X chromosome lead to female susceptibility to PBC [39]. Natural history of PBC

The natural history of PBC has been studied in large cohorts of patients with PBC. PBC is a progressive disease that leads to substantial loss of intrahepatic bile ducts, leading to advanced fibrosis, cirrhosis and liver failure. PBC is an important indication for liver transplantation across North America and Europe [40–42]. It is believed that patients who test positive for AMA but have no symptoms of PBC and normal liver chemistries might eventually develop symptomatic but slowly progressive PBC. In one small study, patients incidentally discovered to have positive AMA (titers ‡1:40) but no symptoms of liver disease and normal liver biochemistries were followed for over 18 years [43]. Liver biopsies were diagnostic or compatible with PBC in 83% of patients at baseline [43]. Nearly 60% of patients had other autoimmune diseases such thyroid disorders, rheumatoid arthritis, lupus erythematosus and scleroderma [43]. Over the 18-year follow-up periods, 76% of patients developed symptoms of PBC, and 83% had persistently elevated alkaline phosphatase levels [43]. Repeat liver biopsies in 10 patients showed that two patients progressed histologically by one stage and two other patients progressed histologically by two stages [43]. No patient developed cirrhosis and five patients died during the follow-up; no deaths were attributable to liver disease [43]. Patients with PBC have a shorter survival than the healthy population. In one follow-up study, the 10-year survival of the PBC patients was 59%, compared with an expected 81% in the age- and sex-matched healthy population [12]. Histological stages have been found to predict survival in patients with PBC. The rate of histological progression of PBC has been assessed in large cohorts of PBC patients. Serial liver biopsies were assessed in 222 patients with PBC during a prospective, randomized, placebocontrolled clinical trial in which therapy with D-penicillamine was shown to be ineffective [44]. At study entry, 7, 25 and 43% of patients were Ludwig stages I, II and III, respectively [44]. After 2 years, histological progression was observed in 62, 62 and 50% of patients who were stage I, II and III at entry, respectively. After 4 years, hepatic biopsies showed cirrhosis in 31 and 50% of the patients in stage I and stage II at entry, respectively [44]. These data clearly show that the vast majority of patients with PBC will progress histologically within 2 years and that a significant proportion will eventually develop cirrhosis of the liver. In the pre-ursodeoxycholic acid (UDCA) era, the 10-year survival of PBC patients was 50–70%, even worse in symptomatic PBC patients, with a reported median survival of 5–8 years [45]. Following the introduction of UDCA, the natural history of PBC has changed significantly. Responders to UDCA survive age- and sex-matched healthy subjects [45]. The liver transplantation-free survival rates among PBC patients have improved with UDCA therapy [46]. In a combined analysis of randomized controlled trials using UDCA in PBC patients, high serum bilirubin, low serum albumin, high Mayo risk score and advanced histological stage have been identified as independent Expert Rev. Clin. Immunol. 10(12), (2014)

Diagnosis and management of PBC

predictors of poor outcomes in PBC [47]. PBC also increases an individual’s risk for hepatocellular carcinoma [48].

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Symptoms of PBC

Fatigue is a common symptom in PBC patients [21], affecting nearly 80% of individuals [49]. Severe fatigue can affect patients’ overall quality of life, and may be associated with overall decrease in survival [49–56]. Fatigue is often associated with depression among PBC patients [49–53]. The severity of fatigue in patients with PBC correlates poorly with the severity and the clinical stage of the disease and appears to be unresponsive to the current therapies, including UDCA and liver transplantation [57]. Fatigue in PBC is a very complex symptom and its etiology is poorly understood. It is thought that chronic cholestasis in PBC causes degenerative changes affecting areas in the brain regulating autonomic functions leading to impaired peripheral tissue oxygen delivery, which leads to the expression of fatigue and its associated cognitive impairment through secondary dysfunction of the peripheral muscles [57,58]. Evidence in favor of organic CNS process in PBC comes from the neurophysiological studies which suggest organic brain changes in patients with PBC. Newton et al. [59] found that a significant proportion of PBC patients (53%) had moderate-to-severe concentration and memory problems. In addition, they found that PBC patients had reduced scores on the neuropsychiatric tests (that included assessing the processing skills and the ability to recall a series of verbalized numbers) compared with a matched control group. Importantly, these cognitive impairments continued to worsen over time, indicating that this is a progressive process [59]. Whether the change in cognitive function is associated with a change in the fatigue scores in PBC is an issue that remains unresolved but certainly an interesting area of research. Symptomatic PBC seems to have an impact on the rate of progression of PBC to clinically relevant end points. In one study [60], the clinical course of patients with symptomatic PBC (defined as fatigue and/or pruritus) at presentation was compared with that of asymptomatic PBC patients at presentation over a mean period of 81 ± 75 months. Patients with symptomatic PBC at presentation achieved clinically relevant outcomes (development of cirrhosis, liver failure, development of portal hypertension and development of hepatocellular carcinoma) more often than patients with asymptomatic PBC. In addition, irrespective of the histological staging of the disease, patients who presented with symptoms at onset achieved clinical outcomes more rapidly than the asymptomatic PBC group of patients [60]. At presentation, symptomatic patients were more often women, younger in age, with more pronounced biochemical activity as demonstrated by higher serum alkaline phosphatase and aspartate aminotransferase levels. These patients were also less responsive to UDCA [60]. Similar results have been reported from the UK-PBC cohort [61,62]. These findings suggest that symptomatic presentation of PBC is an important risk factor for rapid disease progression, and that these are the patients who mostly need the innovative therapeutic strategies. informahealthcare.com

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The impact of liver transplantation on fatigue in PBC patients has not been thoroughly investigated. Carbone et al. [63] prospectively evaluated the effect of liver transplantation on fatigue using the PBC-40 questionnaire in 31 patients with PBC over a 2-year period. Eighty-nine percent of PBC patients suffered from fatigue before liver transplantation. The incidence of fatigue decreased to 48 and 44% at 1 and 2 years, respectively. The mean scores of fatigue have significantly reduced over the follow-up period when comparing values before and after liver transplantation. Fatigue scores at 2 years after liver transplantation were higher in the transplant PBC cohort compared with a cohort of community controls [63]. These results indicate that liver transplantation is associated with improvement of fatigue in patients with PBC. However, a substantial proportion of PBC patients continue to suffer severe fatigue even after liver transplantation, indicating that specific therapies for fatigue in PBC patients are needed. Pruritus is another clinical manifestation of PBC [21,64]. It affects 20–70% of patients with PBC [8,21,56,64–67]. The cause of pruritus in PBC is largely unknown, although some speculate that the components of bile may contribute [67]. Recently, lysophosphatidic acid (LPA) and autotaxin, the serum enzyme converting lysophosphatidylcholine into LPA, have been found in higher concentrations in the sera of patients with cholestatic disorders compared with control, suggesting that LPA and autotaxin play a critical role in cholestatic pruritus [68] and may serve as potential targets for future therapeutic interventions. Serum aspartate aminotransferase, serum alkaline phosphatase and total bilirubin have been identified as independent predictors of pruritus in PBC [64]. One study [64] examined the rate of resolution of pruritus among PBC patients enrolled in a multicenter, placebocontrolled trial of UDCA. There was no significant change in the overall prevalence of pruritus in the placebo-treated group at study entry and follow-up at 36 months (56 vs 49%). In that same report [64], 30% of patients in the UDCA arm reported symptom improvement compared with 24% of the placebotreated patients after 1 year of therapy. Conversely, only 7.9% of patients who received UDCA developed pruritus compared with 14.5% of the placebo-treated patients at 1 year [64]. These data indicate that whereas some PBC patients gain symptom relief, pruritus continues to be significant problem in PBC patients and that anti-pruritic agents are needed. Similar to fatigue, pruritus can have a negative impact on patients’ quality of life [69]. Agents such as cholestyramine, rifampin, antihistamines and antidepressives such as sertraline have been used to treat pruritus in PBC [70]. In some PBC patients with refractory cases of pruritus, liver transplantation may be the only curative option [69]. Other symptoms related to PBC include Sicca syndrome, cutaneous calcinosis and Raynaud’s phenomenon [70]. Diagnosis of PBC

The diagnosis of PBC relies on establishment of two of the following criteria: diagnosis of cholestasis evidenced by persistently elevated alkaline phosphatase levels, presence of AMA and histological findings consistent with PBC. These criteria have been 1669

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endorsed by the leading organizations in the field of the liver diseases including the American Association for the Study of Liver Diseases [45]. AMA, a highly disease-specific autoantibody, is found in 95% of PBC patients [3]. The targets of the AMA are members of a family of enzymes, the 2-oxo-acid dehydrogenase complexes located in the inner mitochondrial membrane, and include PDC-E2, BCOADC-E2 and OADC-E2. More specifically, the lipoylated domains of the E2- and E3-binding protein (E3BP) components of the PDC-E2 and the E2 components of the OADC-E2 and BCOADC-E2 are the epitopes recognized by the AMAs [4,5]. In HEp-2 cell monolayers, AMAs typically exhibit cytoplasmic ‘string of pearls’ fluorescence staining with a coarse, filamentous, granular and speckled pattern [71]. The presence of AMA in the sera of patients with PBC was first described in 1965 [72], and in 1987, the AMA antigens were cloned and identified [3,73,74]. There are several methods used today for the detection of AMA in the sera of patients with PBC, including indirect immunofluorescence, immunoblotting and ELISA. ELISA techniques using recombinant proteins to the three known autoantigens are widely available and most frequently used by commercial laboratories [75]. AMAs are rarely detected in the healthy population. The prevalence of AMAs was examined in a cohort of 1530 people from northern Italy using ELISA and immunoblotting techniques [76]. Only 0.5% of the people were positive for AMA. Further analysis revealed that the AMA pattern of reactivity differed from that seen in patients with histologically proven PBC [76]. The presence or absence of the AMA, rather than the magnitude of antibody level, is most important. The magnitude of antibody level correlates poorly with the severity and clinical stage of the disease [45]. It is now accepted that AMA-2 is specific to PBC [77] and enables distinction between PBC and jaundice caused by obstruction of the extrahepatic biliary ductal system [78]. Nevertheless, AMA-2 may be found in other autoimmune diseases such as scleroderma and Sjo¨gren’s syndrome [77]. AMA-2 positivity is occasionally found in the PBC-autoimmune hepatitis (AIH) overlap syndrome (about 20% of cases) [79]. Survey data derived from PBC patients have revealed epidemiological associations that underpin a number of pathophysiological principles, in particular environmental and genetic risks of PBC [9,10,80,81]. Having a first-degree family member with PBC, smoking, a history of urinary tract infection and using hormone-replacement therapies are associated with risks for developing PBC [27]. Two triggering pathways have been extensively explored as potential triggering factors for the development of PBC: infections and xenobiotics [82,83]. An early association between PBC and UTI has been observed; in one study [9], 59% of 1032 PBC reported having a UTI. This association has sparked interest in examining the role of some bacterial strains in the etiology of PBC. Escherichia coli has gained the most attention, as it is one of the leading causes of UTI. Indeed, PBC patient sera react with both E. coli and PDC-E2, and there is cross-reactivity between antibodies in PBC patients and enzymes secreted by E. coli [84,85]. 2-Octynoic acid is a 1670

xenobiotic, present in nail polish and as a food additive. It reacts to AMAs, and when injected into mice, it results in development of high titers of AMA and histological features of PBC [86,87]. Taken all together, these data suggest that environmental triggers are important for the development of PBC. The need for liver biopsy to establish a diagnosis of PBC in AMA-positive patients is controversial. Biopsy is not needed in the setting of a positive AMA and an elevated alkaline phosphatase to establish a diagnosis of PBC. However, approximately 5% of patients with PBC are AMA-negative. In such cases, a liver biopsy that demonstrates the typical bile duct destruction seen in PBC is required to establish a diagnosis of PBC [45]. Patients who have AMA-negative PBC are believed to have a similar clinical course, response to treatment, and prognosis as their AMApositive counterparts [88]. Recently, more sensitive ELISA techniques have been developed to increase the detection rates of AMAs in patients who were originally classified as AMA-negative PBC. Oertelt et al. recently designed a more sensitive ELISA technique for AMA detection and applied it to 30 AMA-negative patients with PBC [89]. Twenty percent of patients reacted to the new ELISA technique, indicating the diminished number of truly AMA-negative PBC patients [89]. In addition to the AMA, antinuclear antibodies (ANAs) and antismooth muscle antibodies are present in nearly half of patients with PBC [48]. In some PBC patients, ANAs may have important prognostic implications. In a Japanese study of 276 patients with biopsy-proven PBC, the presence of antigp210 antibodies, male sex and late stage (Scheuer’s stage 3, 4) were identified as significant risk factors for the end points of death due to hepatic failure and need for liver transplantation, using Cox proportional hazard regression analysis [90]. Moreover, when clinical progression to death of hepatic failure or liver transplantation (i.e., hepatic failure progression type) or to the development of esophageal varices or hepatocellular carcinoma (i.e., portal hypertension progression type) was defined as an end point in early histological stage PBC, positive antigp210 antibodies was a significant risk factor for the hepatic failure progression type, whereas positive anti-centromere antibodies was a significant risk factor for portal hypertension progression type [90]. These results indicate that ANAs in patients with PBC could be used in clinical practice as predictive tools for the development of clinically important end points in patients with PBC. The results of this study need to be confirmed in larger and long-term studies. In addition to the anti-gp210 and anti-centromere antibodies, there are other ANAs that have been found to have diagnostic and prognostic value in PBC, commonly referred to as the PBC-specific ANAs. Anti-Sp100 antibodies, discovered in 1987 [91], are found in 17–41% of PBC patients [92–97]. They are considered highly specific for PBC; only occasionally found in patients without PBC [93,96,97]. Therefore, they could be used as disease markers in AMA-negative PBC patients. In addition, they appear to be of prognostic value: PBC patients who test positive for anti-Sp100 appear to have a more rapidly progressive disease and worse outcomes [94,96]. Anti-promyelocytic Expert Rev. Clin. Immunol. 10(12), (2014)

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Diagnosis and management of PBC

leukemia (PML) protein antibodies are frequently detected in PBC patients who are anti-Sp100 antibody positive [98]. AntiPML antibodies have been found in other autoimmune disorders, but never in healthy individuals [98]. They are found in ~19% of PBC patients, and PBC patients who test positive for anti-PML protein antibodies appear to have worse outcomes [96]. AntiSUMO antibodies are closely linked to the anti-Sp100 and antiPML antibodies. Anti-SUMO antibodies are found in 15–42% of anti-Sp100 and anti-PML antibody-positive patients [99]. Their clinical significance is unknown and remains to be elucidated. Anti-Sp140 antibodies are seen in 11–15% of PBC patients and may coexist with anti-Sp100 and anti-PML antibodies. They are highly specific for PBC; almost never found in patients without PBC [100]. Therefore, anti-Sp140 antibodies could serve as disease markers of PBC in patients who are AMA-negative. Antibodies against nucleoporin p62 have been reported in PBC patients with a prevalence of 13–32%. They are also regarded as highly specific for PBC [101,102]. The anti-lamin B receptor antibodies [103,104] have been reported in PBC patients with a prevalence of 1.2%, and have never been detected among healthy controls [105]. Their clinical significance remains unclear. Complications of PBC

Portal hypertension, with ascites and varices, can develop in patients with advanced-stage PBC. The development and burden of esophageal varices in PBC was examined prospectively in a clinical trial of 265 patients with PBC (69% had advanced histological stage [III–IV] PBC at baseline) who were followed for a median of 5.6 years [106]. Esophageal varices developed in 31% of patients, and 48% of those with esophageal varices experienced one or more episodes of esophageal variceal bleeding. After the development of varices, the 3-year survival was 59%, and after the initial variceal bleeding, the 3-year survival was 46% [106]. Unlike other liver diseases, patients with early histological stage PBC can develop portal hypertension and gastroesophageal varices [107,108]. In a retrospective study of 325 PBC patients enrolled in two clinical trials, 127 were identified as early stage PBC (stages I–II); 6% of those early stage PBC patients had varices at baseline [107]. The mechanisms of portal hypertension development in early stage PBC are poorly understood, although nodular regenerative hyperplasia may play a key role [109]. Osteopenic bone disease is prevalent among PBC patients, occurring in up to one-third of patients [110–113]. Risk factors for development of osteoporosis in patients with PBC are older age, lower BMI, severity of cholestasis and advanced histological stage [114]. Patients with advanced-stage PBC have a fivefold increase in risk of developing osteoporosis than those with early stage PBC [112]. Bone densitometry is the gold standard for diagnosis of osteoporosis in PBC. Bisphosphonates have been shown to be effective for the treatment of osteoporosis in PBC [115–117], although are contraindicated in the presence of esophageal varices. Supplementation with calcium and vitamin D is generally recommended [70]. Other metabolic abnormalities associated with PBC are hyperlipidemia [118,119] and fat-soluble vitamin deficiencies [120,121]. informahealthcare.com

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PBC-AIH overlap syndrome

AIH can occur in association with PBC, a condition known as the PBC-AIH overlap syndrome. The prevalence of the PBCAIH overlap syndrome ranges between 2 and 20% [122]. Diagnosis of PBC-AIH overlap syndrome remains challenging, due to the lack of consensus on the diagnostic criteria for this syndrome. The PBC-AIH overlap syndrome usually presents with features of both diseases; for PBC, a hepatic cholestatic picture and positive AMA, and for AIH, a significant rise in liver transaminases, high levels of IgG, positive ANAs, positive antismooth muscle antibodies and histological features of interface hepatitis consistent with AIH [122]. The two most widely used criteria for the diagnosis of PBC-AIH overlap syndrome are the Paris Study Group Criteria [123] and the International Autoimmune Hepatitis Group (IAIHG) criteria [124]. The diagnosis of the PBC-AIH overlap syndrome is based on the presence of at least two of three diagnostic criteria for each disease. For PBC, the diagnostic criteria include: serum ALP levels at least twice the upper limit of normal, positive AMA and a liver biopsy showing bile duct lesions consistent with PBC. The AIH criteria include the following: serum alanine aminotransferase at least five-times the upper limit of normal, serum IgG levels at least twice the upper limit of normal and live specimen showing periportal or periseptal lymphocytic piecemeal necrosis [122]. Other causes of liver injury such as toxins, alcohol and drugs should be excluded. In addition to the proposed diagnostic criteria for PBC-AIH overlap syndrome, some of the serological markers have been found to be of diagnostic value. In particular, the anti-dsDNA antibodies are more common in overlap patients than PBC or AIH alone (60% in overlap, 26% in AIH and 3% in PBC), and positivity for both AMA and anti-dsDNA was seen in 47% of overlap patients as opposed to 1 and 3% in AIH and PBC, respectively [125]. Moreover, ANAs were seen much more often in overlap patients (93 vs 33% in PBC) [125]. These data suggest that a concomitant anti-dsDNA and AMA positivity represents a serological pattern that is specific for PBC-AIH overlap syndrome. The natural history of PBC-AIH syndrome is poorly understood, although one study reported that patients with PBC-AIH overlap syndrome had worse outcomes in terms of complications of portal hypertension, death or need for liver transplantation than patients with pure PBC [126]. There are no randomized clinical trials as to how to treat patients with PBC-AIH overlap syndrome. At this point, the combination of UDCA and immunosuppressive agents seems to be a reasonable approach in the treatment of PBC-AIH overlap syndrome [122], with an excellent transplant-free survival rate among the responders (10-year survival rate of 100% in the responders vs 54% in the non-responders) [127]. Given the rarity of the condition, randomized trials are unlikely to occur. Therapy for PBC Therapies other than UDCA

Methotrexate has been investigated in PBC patients and has shown no benefit on mortality or need for liver transplantation [128]. A large clinical trial found no benefit from the addition 1671

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of methotrexate to UDCA on survival free of liver transplantation [129,130]. Rituximab is a humanized ant-CD20 monoclonal antibody used for treatment of B-cell lymphomas. Pilot studies using rituximab in PBC patients showed only moderate effects [131,132]. In light of the drug toxicity profile, future progress of rituximab in PBC is very unlikely.

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Ursodeoxycholic acid

Although there is no cure for PBC, several randomized clinical trials, combined analyses and large and long-term observational studies have shown that UDCA improves outcomes including: reduction in hepatic enzyme abnormalities, reduction in the risk of developing esophageal varices, delay in the histological progression to cirrhosis and prolongation of survival without liver transplantation [133–140]. Treatment with UDCA results in a slower rate of progression to cirrhosis: 13 versus 49% in a placebo group [133]. In a clinical trial of 192 PBC patients, therapy with UDCA significantly delayed histological progression after a median follow-up of 3.4 years [141]. In the French UDCA PBC trial, the risk of progression from histological stages I–II to stages III–IV was 7 ± 2% in the UDCA-treated group compared with 34 ± 9% in the control group [135]. The effect of UDCA on the rate of development of esophageal varices was prospectively evaluated in a study of 180 PBC patients who received either UDCA versus placebo and were followed for up to 4 years [142]. At baseline, 139 patients had no varices and 41 patients had varices. After 4 years of follow-up, the risk of development of esophageal varices was 16% in the UDCA-treated group and 58% in those receiving placebo [142]. Currently, UDCA at a dose of 13–15 mg/kg/day is the only therapy for PBC approved by the US FDA. The drug is approved for PBC patients with all histological stages of PBC with abnormal hepatic biochemistries [45]. The dose of UDCA is important. A study comparing three different UDCA doses in PBC patients has shown that a dose of 13–15 mg/kg/day was superior to either a lower dose of 5–7 mg/kg/day or a higher dose of 23–25 mg/kg/day in terms of biochemical responses and cost [143]. Liver transplantation

Several randomized controlled clinical trials have shown that the use of UDCA in patients with PBC delays the need for liver transplantation. Moreover, the liver transplantation burden of PBC in the USA seems to have decreased. Recently, Lee et al. reported the transplantation trends in PBC in the USA over a 12-year period, and compared that with the trends of liver transplantation for primary sclerosing cholangitis (PSC) [144]. PBC and PSC transplant data were collected from the United Network for Organ Sharing database between the years 1995 and 2006 [144]. The absolute number of liver transplants in the USA increased an average of 249 transplants per year, and the absolute number of transplants for PBC decreased an average of 5.4 transplants per year [144]. The absolute number of transplantation for PSC showed no change over the same time periods [144]. These data suggest that the use of UDCA in patients with PBC results in a favorable outcome. 1672

Acute rejection of the transplanted graft occurs in 46–56% of PBC patients [145–147] and is rarely of clinical significance because it responds well to increased immunosuppression [148]. Chronic rejection of the transplanted graft is a more serious complication, commonly leading to graft loss [148]. The incidence of chronic graft rejection in PBC ranges between 2 and 9.3% [148]. Causes of death after liver transplantation for PBC were reported in two studies. In the first study [149], 102 deaths after liver transplantation were reported, with 60% dying within the first 6 months because of sepsis and multiorgan failure. De novo malignancies, renal failure, sepsis and chronic rejection were the most common causes of late deaths. In the second study, 10 out of 100 patients who underwent liver transplantation for PBC died because of infections, de novo malignancies and disease recurrence. Patients who underwent liver transplantation for PBC in 1997 in North America had a 5-year survival rate of 86.2% [40]; these data are comparable with those reported from large European centers, in which the 5-year survival rate was reported to be between 78 and 87% [149,150]. Overall, a significant improvement of post-transplant survival is seen compared with PBC patients who underwent transplantation in the 1980s and 1990s [151,152]. Recurrence of PBC

Studies have shown that PBC recurs after liver transplantation. It is important to note that the only reliable criterion for diagnosis of recurrent PBC after liver transplantation remains liver histology [148], since AMAs may persist in many patients with PBC after transplantation [153]. The prevalence of recurrent PBC was found to be between 11 and 34%, with median time to diagnosis of recurrence between 36 and 61 months after transplantation [148]. Tacrolimus-based immunosuppression post-transplantation, male gender and recipient age have been identified as risk factors for PBC recurrence [145,147]. The effect of UDCA on the incidence of recurrence of PBC and on the outcome of patients with recurrent PBC has not been fully evaluated. In one study [145], subjects who had recurrent PBC and were treated with UDCA had a significant improvement of their transaminases and serum ALP at 3 years after transplantation but no significant effect on the progression of histologic stage of the disease. Predictive models in PBC

Models using time-fixed Cox proportional hazards have been developed to predict survival in patients with PBC. Among the well-validated models, the Mayo PBC risk score is the most widely used and includes the following variables: age, total serum bilirubin, serum albumin, prothrombin time, presence/ absence of peripheral edema and response to diuretics [154]. This model helps monitor treatment success in patients with PBC and guide timing for liver transplantation. Of all the markers proposed, both serum alkaline phosphatase and serum bilirubin are the best predictors of survival and clinical outcomes in patients with PBC [155]. Thus, serum alkaline Expert Rev. Clin. Immunol. 10(12), (2014)

Diagnosis and management of PBC

phosphatase and serum bilirubin might be used as surrogate markers when designing therapeutic trials in patients with PBC.

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Pediatric onset PBC

PBC in the pediatric population is extremely rare. Dahlan et al. [8] reported two cases of PBC diagnosed at 15 and 16 years of age. Both cases presented with elevated liver enzymes, positive AMA and liver biopsy findings consistent with stage II PBC. On case continued to deteriorate clinically despite therapy with UDCA, eventually requiring liver transplantation. The second case responded to UDCA therapy, as evident by near normalization of her liver biochemistries. The risk factors, natural history and long-term outcomes of pediatric PBC are unknown. Future therapies for PBC

Obeticholic acid (OCA, also known as INT-747), a 6a-ethyl derivative of chenodeoxycholic acid (ECDCA), is a first-in-class selective Farnesoid X receptor (FXR) agonist [156]. ECDCA was first described in 2002 as a potent and selective steroidal FXR agonist [157]. In addition to its potent role in promoting bile flow, ECDCA protected hepatocytes against acute necrosis caused by lithocholic acid in a male Wistar rat model of cholestasis [157]. OCA has an approximately 100-fold greater FXR agonistic activity than ECDCA. OCA has shown promising results in Phase II clinical studies in PBC patients with incomplete response to UDCA [158]. A Phase III clinical trial of OCA in PBC is ongoing. NGM282, a novel specific inhibitor of the cholesterol 7ahydroxylase enzyme, is currently evaluated in a Phase II clinical trial in PBC patients. Conclusion

PBC is a progressive cholestatic liver disease characterized by destruction of the intrahepatic bile ducts, leading eventually to advanced fibrosis, cirrhosis and its complications and liver failure. The incidence and prevalence of PBC is increasing. The serological hallmark of the disease is the AMA, a highly disease-specific autoantibody, found in nearly 95% of patients with PBC. These autoantibodies recognize the lipoylated domains of the E2- and E3-binding protein components of the PDC and the E2 components of the 2-oxo glutarate dehydrogenase and branched-chain 2-oxo acid dehydrogenase complexes. The diagnosis of PBC is established when two of the three following criteria are met: evidence of persistently elevated serum alkaline phosphatase levels, presence of AMA and histological findings compatible with PBC. The need for a liver biopsy in a patient with persistently elevated serum alkaline phosphatase levels and positive AMA is controversial. Symptoms of PBC include fatigue, pruritus and in some, abdominal pain. Associated conditions in patients with PBC include osteopenic bone disease, hyperlipidemia, Sicca syndrome, AIH and

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Review

Raynaud’s phenomenon. UDCA at a dose of 13–15 mg/kg/day is currently the only therapeutic agent approved by the FDA for the treatment of PBC. Several randomized clinical trials have shown that UDCA administration in patients with PBC not only improves liver biochemistries, but also delays histological progression, delays the development of esophageal varices and prolongs survival without need for liver transplantation. The liver transplantation burden of PBC in the USA decreased between 1995 and 2006, indicating a favorable outcome of patients with PBC treated with UDCA. Expert commentary

UDCA at a dose of 13–15 mg/kg/day is currently the only FDA-approved therapy for PBC. The safety and efficacy of UDCA in PBC has been demonstrated in several well-designed randomized controlled clinical trials. Long-term use of UDCA in PBC has shown to prolong the survival without liver transplantation. The frequent use of screening biochemical tests and the rapid AMA assays increased the proportion of asymptomatic PBC patients. Patients with AMA-negative PBC refer to those who lack AMA but whose clinical presentation, liver histology and natural history are nearly identical to patients with typical AMA-positive PBC. The frequency of AMA-negative PBC patients may reduce in the future with the development of more sensitive ELISA techniques. Five-year view

Despite the efficacy of UDCA, 40% of patients with PBC have an incomplete response to therapy and are at high risk for disease progression. Therefore, there is a critical need for newer therapeutic agents for patients with PBC with incomplete response to UDCA. The FXRs belong to a family of receptors known as the nuclear hormone receptors. They are expressed in high amounts in the liver, intestines and kidneys. In addition to their key role in the bile acids (BAs) homeostasis, FXRs also modulate liver regeneration during liver injury and inflammation. BAs are natural ligands of FXRs. ECDCA or OCA is a novel derivative of the primary human BA, chenodeoxycholic acid. Preclinical studies have shown that OCA may have anticholestatic and antifibrotic properties. A recent international placebo controlled trial using OCA in patients with PBC showed substantial improvement in liver biochemistries including serum alkaline phosphatase. A Phase III clinical trial of OCA in PBC is currently underway. Financial & competing interests disclosure

KD Lindor is an unpaid advisor for Lumena and Intercept. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

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Key issues • Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by destruction of the intrahepatic bile ducts. It may eventually lead to cirrhosis and its complications such as portal hypertension and hepatocellular carcinoma. • The serological hallmark of PBC is the antimitochondrial antibody (AMA), present in nearly 95% of patients. ELISA is the most widely used method by the commercial laboratories for the detection of AMA. • AMAs are absent in 5% of patients with PBC. • Symptoms and conditions associated with PBC are fatigue, pruritus, osteopenic bone disease, autoimmune hepatitis, scleroderma, Sicca syndrome and Raynaud’s phenomenon. • The diagnosis of PBC requires the establishment of persistently elevated serum alkaline phosphatase and presence of AMA. In such scenario, liver biopsies are not required.

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• Liver biopsies are required in the setting of cholestasis and absence of AMA in order to establish a diagnosis of PBC. • Ursodeoxycholic acid is safe and effective in the majority of patients with PBC, and is the only US FDA-approved agent in PBC. Dosing is important. Currently, the recommended dose is 13–15 mg/kg/day. • The use of ursodeoxycholic acid in PBC prolongs the survival without liver transplantation. • The liver transplantation burden of PBC in the USA decreased between 1995 and 2006.

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Possible more effective therapies for PBC trials are underway.

Expert Rev. Clin. Immunol. 10(12), (2014)

Diagnosis and management of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized histologically by destruction of intrahepatic bile ducts and sero...
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