Diagnosis and Management of Primary Biliary Cholangitis Ticle

Review Article 1

see related editorial on page x Diagnosis and Management of Primary Biliary Cholangitis ticle

Zobair M. Younossi, MD, MPH, FACG, AGAF, FAASLD1, David Bernstein, MD, FAASLD, FACG, AGAF, FACP2, Mitchell L. Shifman, MD3, Paul Kwo, MD4, W. Ray Kim, MD5, Kris V. Kowdley, MD6 and Ira M. Jacobson, MD7

Primary biliary cholangitis (PBC) is a chronic, cholestatic, autoimmune disease with a variable progressive course. PBC can cause debilitating symptoms including fatigue and pruritus and, if left untreated, is associated with a high risk of cirrhosis and related complications, liver failure, and death. Recent changes to the PBC landscape include a Review A r name change, updated guidelines for diagnosis and treatment as well as new treatment options that have recently become available. Practicing clinicians face many unanswered questions when managing PBC. To assist these healthcare providers in managing patients with PBC, the American College of Gastroenterology (ACG) Institute for Clinical Research & Education, in collaboration with the Chronic Liver Disease Foundation (CLDF), organized a panel of experts to evaluate and summarize the most current and relevant peer-reviewed literature regarding PBC. This, combined with the extensive experience and clinical expertise of this expert panel, led to the formation of this clinical guidance on the diagnosis and management of PBC.

Am J Gastroenterol https://doi.org/10.1038/s41395-018-0390-3

Introduction addition, diagnosis and treatment guidelines are changing and a Primary biliary cholangitis (PBC) is a chronic, cholestatic, auto- number of guidelines have been updated [4, 5]. immune disease with a progressive course that may extend over Because of important changes in the PBC landscape, and a num- many decades. PBC is thought to be caused by a combination of ber of unanswered questions, the American College of Gastroen- genetic predisposition and environmental triggers, and is most terology (ACG) Institute for Clinical Research & Education and commonly recognized in women in their 5th or 6th decade of the Chronic Liver Disease Foundation (CLDF) have collaborated life. Te serologic hallmark of PBC is the anti-mitochondrial anti- to provide a practical guidance document for practicing gastroen- body (AMA), a highly disease-specifc auto-antibody detected in terologists to help with their clinical practice. As part of this pro- 90–95% of PBC patients and less than 1% of non-diseased controls cess, an exhaustive review of the literature was carried out from [1]. Te presentation of PBC can range from asymptomatic (early 1985 to 2018 by each member of the panel to obtain relevant infor- disease) and slowly progressive to symptomatic and rapidly evolv- mation about their topics. Each member summarized their section ing liver disease. Clinical features of PBC include fatigue, pruri- based on the relevance and the validity of the data presented and tus, concurrent autoimmune disease(s), osteopenia/osteoporosis, summarized the information. All sections of the guidance docu- hypercholesterolemia, and xanthelasma. PBC is a chronic disease ment underwent several rounds of review by the entire panel. Any that frequently leads to cirrhosis, liver failure and is a common area of disagreement was resolved by searching for additional evi- indication for liver transplantation [2]. dence. When evidence did not exist, a consensus agreement was In recent years, there have been important advances in PBC. reached through individual member surveys by the chair and sum- For example, the designation “primary biliary cirrhosis” was marized as the “expert opinion”. In summary, this guidance docu- deemed no longer accurate since, with early diagnosis and treatment for PBC, intended for practicing healthcare providers, was ment, many patients do not progress to cirrhosis. Terefore, to developed by a panel of hepatology experts and supported by the adequately describe the histologic hallmark of dense infammatory ACG Institute to provide specifc recommendations about clini- infltrates around damaged intralobular bile ductules, “cholangitis” cally relevant topics in PBC based on the most recent evidence as has replaced “cirrhosis”, while retaining the acronym “PBC” [3]. In well their extensive experience and clinical expertise.

1Department of Medicine, Inova Fairfax Hospital, 3300 Gallows Rd, Falls Church, VA, 22042, USA. 2Department of Hepatology and Sandra Atlas Bass Center for Liver Diseases, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA. 3Bon Secours Liver Institute of Virginia, Bon Secours Medical Group, Richmond, VA, 23226, USA. 4Stanford University Medical Center, Palo Alto, CA, USA. 5Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, CA, USA. 6Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, WA, 98107, USA. 7NYU Langone Health, New York, NY, 10016, USA. Correspondence: Z.M.Y. (email: [email protected]) Received 15 August 2018; accepted 17 September 2018

Epidemiology which the main target is the E2 subunit of the Pyruvate Dehy- PBC is considered a relatively rare disease that has historically drogenase Complex (PDC). Expression of PDC-E2 or a molecule been predominantly reported in white females aged 40 to 50 years that cross-reacts with certain anti-PDC-E2 antibodies is increased old. Tere has been no appreciable change in the incidence, or on biliary epithelial cells of patients with PBC. In addition, sev- the rate of new cases of PBC within a population. Data from the eral molecular mimicry peptides (found in viral or bacterial pro- Rochester Epidemiology Project support this conclusion. Patients teins) to PDC-ER have structurally similar epitopes to those of

ticle in Olmsted County, Minnesota were studied between 1975 and self-peptides. Increased PDC-E2 may result in a loss of humoral 1995. Of the 46 new cases of PBC that were diagnosed, the median tolerance and an increase of autoreactive cluster of diferentiation age at diagnosis was 52 years, and patients were mostly women (CD)4+CD8+PDC-E2-specifc T cells in the liver [40]. Te auto- (89%), white (100%), and AMA positive (89%). Te age-adjusted immune T cell response that follows is characterized by damage (to 1990 US whites) incidence of PBC per 100,000 person-years to the biliary epithelial cells that line the intrahepatic bile ducts, for years 1975–1995 was 4.5 (95% confdence interval [CI], 3.1– resulting in infammation, scarring, and destruction of the inter- 5.9) for women, 0.7 (95% CI, 0.1–1.3) for men, and 2.7 (95% CI, lobular and septal bile ducts. Tis leads to bile leaking though bile

Review A r 1.9–3.5) overall. Te age-adjusted and sex-adjusted prevalence ducts into the liver parenchyma. Hepatocytes are injured by bile per 100,000 persons as of 1995 was 65.4 (95% CI, 43.0–87.9) salts followed by necrosis, apoptosis, and leading to fbrosis, and for women, 12.1 (95% CI, 1.1–23.1) for men, and 40.2 (95% CI, cirrhosis [25, 31, 41–48] (Fig. 1). 27.2–53.1) overall [6]. In a more recent analysis of data from 3488 patients receiving routine clinical care in Fibrotic Liver Disease Consortium health systems, investigators found that, from 2004 Natural history and outcomes to 2014, the prevalence of PBC increased from 21.7 to 39.2 per PBC is commonly characterized by slow progression of cholesta- 100,000 persons [7]. Tis data suggests a possible increase in the sis followed by hepatic dysfunction and decompensation (Fig. 2). prevalence of PBC between 2004 and 2014. Widespread use of AMA testing in the community has enabled the Tere is increasing evidence that PBC can be seen in most diagnosis of PBC patients before they develop symptoms of chol- regions of the world. Te previous lower inclusion of minorities estasis or hepatic decompensation. In some cases, the presence of in the clinical trials of PBC [8] and lower rates in Asians may have AMA may be found some time before serum alkaline phosphatase been due to under reporting. In fact, recent data from Japan and becomes abnormal (“preclinical” phase). Since the presentation China report that the prevalence of PBC is 55/100,000 adults [9] varies amongst patients, so does the progression through these and 49/100,000 adults, respectively [10]. phases. Based on the clinical experience of this expert panel, some patients rapidly advance to end-stage disease and liver transplantation at a young age while others remain asymptomatic for decades. Pathophysiology Given the variability of the natural history among PBC patients, PBC is characterized by an infammatory, predominantly T-cell individual predictive tools may be useful in patient counseling and mediated destruction of intrahepatic bile ducts [11]. Although management planning, including referral for liver transplantation. there is no absolute certainty as to what causes PBC, the most Over the years, a number of mathematical models have been devel- widely accepted theory is that a genetically susceptible patient oped, which incorporate variables of prognostic signifcance [49, comes into contact with an autoimmune triggering event. Tis 50]. One such example is the Mayo Natural History Model, with triggering event could be an environmental factor, virus, allergen, which the survival probability can be predicted for up to 7 years in chemical or medication. Tere is no one trigger and every patient an untreated patient with PBC based on variables such as age, bili- has their own immune triggering event [12–28]. Genetic factors rubin, albumin, prothrombin time, peripheral edema status, and include MHC class II (DR8, DQA1*0102, DQ/β1*0402), MHC diuretic therapy status [50, 51]. Additional prognostic models that class III (C4 null,c4B2), and non-MHC genes (Exon 1 of CTLA- assess the risk of developing PBC-related complications in patients 4) [29–31]. Familial factors have also been identifed, including receiving treatment will be discussed later in this guidance. PBC/positive AMA [32] and impaired T-cell regulation [33], extrahepatic autoimmune diseases [34] and a higher prevalence in people with a family member, especially an identical twin, with Diagnosis of PBC PBC [13, 15, 35]. Potential environmental factors, especially in Without identifcation and subsequent intervention, a substan- genetically vulnerable individuals, include recurrent urinary tract tial number of PBC patients progress to liver failure, transplant, infections (potentially related to exposure to bacterial compo- or death within 10 years [52]. In fact, in one study, only 17.4% nents or the antibiotic use) [35, 36], exposure to toxic chemicals of patients remained symptom-free 10 years afer their diagno- [37] and cigarette smoking [34, 36–39]. sis [52]. In addition, in some patients, PBC progresses quickly, Regardless of stimuli, the immunological response triggered in advancing through the histological stages as rapidly as every 2 PBC is directed against biliary epithelial cells. Anti-mitochondrial years [53]. Furthermore, up to 30% of patients can have a severe, antibodies (AMA), which are highly disease specifc, are directed progressive form of PBC resulting in early development of liver against the 2-oxo acid dehydrogenase family of multi-enzyme fbrosis and liver failure [54]. In this context, early diagnosis and complexes located on the inner mitochondrial membrane, of treatment of PBC is essential. Historically, a number of criteria

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• Female gender ALP remains persistently below 1.5 times ULN appear to have a Genetics • MHC, IL-12A, and IL-12RB2 risk alleles better prognosis [55]. In clinical practice, the hepatic origin of ele- • Innate immunity (IgM) vated serum ALP is usually supported by simultaneous elevation of serum gamma-glutamyl transferase (GGT) and/or conjugated bilirubin [4]. • Bacterial mimics Environment (e.g., Novosphingobium aromaticivorans) Increased immunoglobulin concentrations, particularly immu- • Xenobiotic chemicals noglobulin M (IgM), can be observed in patients with PBC. Nev- ticle ertheless, this is not specifc for diagnosing PBC and therefore this panel does not consider this a diagnostic requirement. In contrast, • Defective regulatory T cells Immune elevated immunoglobulin G (IgG) is seen in AIH while isolated • Production of AMAs response • Autoreactive CD4/CD8 T cells to PDC-E2 elevated serum immunoglobulin G (IgA) can be observed in patients with alcoholic liver disease [56]. As PBC progresses, hyperbilirubinemia may occur and signif- Review A r Bile duct • Immune response, with bile duct apoptotic blebs and cant hyperbilirubinemia indicates advanced disease. An elevated damage AMAs combined with macrophages bilirubin level is generally regarded as the reliable predictor of adverse outcomes in PBC. When hyperbilirubinemia co-occurs Fig. 1 A Summary of the Pathogenesis of PBC. AMA, antimitochondrial with thrombocytopenia, reduced albumin concentration, and ele- antibodies; IgM, immunoglobulin M; IL, interleukin; MHC, major histocom- vated international normalized ratio (INR), it signifes the devel- patability complex; PBC, primary biliary cholangitis opment of decompensated cirrhosis [4]. Patients with suspicion of cirrhosis (thrombocytopenia with or without hepatic dysfunction) should be screened for hepatocellular carcinoma (HCC) and were required to establish the diagnosis of PBC [55]. Although esophageal varices according to established guidelines. these diagnostic criteria captured most patients with PBC, it did allow for some ambiguity that may have led to delay in diagnosis. History, physical, and abdominal ultrasound Terefore, the panel recommends the following scenarios are sup- A physical examination should include screening for hepatomeg- portive of the diagnosis of PBC: aly and splenomegaly as well as extrahepatic signs of advanced liver disease (e.g., icterus of sclera, skin and mucous mem- • Scenario 1: Chronic elevation of alkaline phosphatase (ALP) branes, xanthelasma, palmar and plantar erythema, nail abnor- with a positive AMA (immunofuorescent assay titer of >1:40 malities, or scratch lesions particularly on the arms and legs). or EIA > 25 units) in the absence of other liver diseases and PBC does not cause any abnormality of liver morphology that systemic diseases may be detected by imaging. Regardless, abdominal ultrasound • Scenario 2: Chronic elevation of ALP with negative AMA should be performed to exclude mechanical bile duct obstruc- and antinuclear antibodies (ANA) tests but a liver biopsy that tion including obstructive mass lesions and abnormalities of the shows destructive cholangitis and destruction of interlobular gallbladder [4]. bile ducts • Scenario 3: Chronic elevation of ALP with negative AMA but Serum autoantibodies positive PBC-specifc ANA (sp-100, gp-210) tests (these tests Serum autoantibodies are important tools for clinicians when are not widely available in the US) diagnosing autoimmune diseases. AMA is a highly specifc antibody for PBC and is considered the serologic hallmark for this It is important to note that liver biopsy is not required for PBC, disease [56, 57]. Te measurement of AMA may be reported as unless specifc antibodies are absent or co-existence of NASH or a ratio when determined by indirect immunofuorescence (IIF) autoimmune hepatitis (AIH) is suspected. Also, AMA positivity or as an absolute value when determined by an enzyme linked alone is not sufcient to make the diagnosis of PBC. Tese patients immunosorbent assay (ELISA). An AMA of 1:40 or greater when require follow up but not additional intervention of treatment [4, 5]. determined by IIF or ≥25 units when determined by ELISA is Figure 3 provides a structured approach, recommended by a considered positive. Te sensitivity and specifcity of these assays practical and easy to follow algorithm, to reach a safe and secure are similar [58–60]. AMA titers do not correlate with disease diagnosis of PBC and facilitate prompt intervention. activity and severity and therefore should not be serially followed. Despite the fact that AMA positivity is a strong indicator of PBC, Laboratory tests the presence of AMA in the blood or serum alone is not sufcient Te PBC panel advises that additional tests (Table 1) can be helpful, to diagnose PBC [4, 5]. AMA reactivity, with an elevated ALP and but not essential. PBC should be suspected in patients with chronic no signifcant elevation in AST, is associated with a >95% positive elevations in AST, alanine aminotransferase (ALT), ALP, and total predictive value of histologic PBC [55]. Te panel believes that, bilirubin with or without PBC-specifc symptoms, such as pruritus despite the lack of association of AMA titer with disease severity, or fatigue [4]. Although diferent laboratories have diferent upper AMA is highly specifc for diagnosing PBC in the vast majority limits of normal (ULNs) for these tests, in general, patients whose of patients.

100

50 Hepatic function (%)

ticle Intact bile ducts Cholestasis 0

Asymptomatic Compensated Decompensated Fig. 2 Schematic Representation of the Natural History of PBC

ALP/GGT Alternate diagnosis Bilary tract obstruction/pathology Review A r Drug induced liver injury History Primary sclerosing cholangitis Examination Progressive familial intrahepatic cholestasis Imaging (US, MRCP) Benign recurrent intrahepatic cholestasis

AMA

ANA

Liver biopsy

PBC diagnosis established

Fig. 3 Algorithm for the Diagnosis of PBC. US, ultrasound; MRCP, magnetic resonance cholangiopancreatography; ALP, alkaline phosphatase; GGT, gamma-glutamyl transferase; AMA, anti-mitochondrial antibodies; ANA, anti-nuclear antibodies

A family of antibodies to various nuclear antigens, ANA, is also patients. Both magnetic resonance (MRE) and transient elastog- associated with PBC. About 50% of patients with PBC are positive raphy (TE) are useful for determining the degree of fbrosis in a for PBC-specifc ANA target antigens. ANA immunofuorescence PBC patient. Te panel emphasizes the importance of noting that is described either as a perinuclear/rim-like membranous pat- TE stifness cutofs are diferent from those established for chronic tern formed by antiglycoprotein (anti-gp)210 or lamin B receptor hepatitis C. For PBC, TE cutofs are: F1 < 7.1 kPa, F2 7.1–11.2 kPa, (constituents of the nuclear envelope), a multiple nuclear dot-like F3 11.2–17.4 kPa, F4 > 17.5 kPa [62]. As for other liver diseases, pattern formed by anti-sp100 and promyelocytic leukemia protein patients with PBC found to have cirrhosis should be screened for (two autoantibodies that colocalize), or a centromere pattern [61]. HCC and esophageal varices. Terefore, patients with AMA-negative PBC can be diagnosed with PBC if they have cholestasis and ANA positivity for either Liver biopsy anti-gp210 or anti-sp100. Specifc ANA testing is readily available Most patients with PBC do not require liver biopsy and the diagno- in Europe and as such is recommended in the European Associa- sis is based on clinical and laboratory tests. However, liver biopsy tion for the Study of Liver (EASL) PBC guidelines [4]. However, should be performed when the diagnosis of PBC is uncertain or this panel feels that it is important to point out that these specifc where another superimposed diagnosis (AIH or non-alcoholic ANA tests are not readily available in the US and therefore their steatohepatitis) is suspected. As noted previously, if a liver biopsy utility is limited. is performed, histologic evidence of PBC, such as non-suppurative cholangitis and destruction of small or medium-sized bile ducts, Extended imaging is highly suggestive of the diagnosis of PBC [5]. It is also impor- Magnetic resonance cholangiopancreatography (MRCP) in chole- tant to note that if an overlap syndrome is suspected because of static patients is a safe and accurate imaging method for the intra- laboratory features of AIH, biopsy is essential (see below). hepatic and extrahepatic biliary tree [4]. Detection of intrahepatic and/or extrahepatic bile duct stenoses and dilatation is essential The overlap syndromes: PBC with autoimmune features for the diagnosis of primary or secondary sclerosing cholangi- In a small proportion of PBC patients, for which precise fgures tis, which are included in the diferential diagnosis of cholestatic vary considerably amongst diferent sources, laboratory and/

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Table 1 Laboratory tests in PBC as high titers of ANA and/or F-actin antibodies, liver biopsy is essential to formulate management decisions [5]. If biopsy sup- Test Finding Suspicion Diagnosis Prognosis ports this diagnosis, corticosteroids should be given along with Biochemical ursodeoxycholic acid (UDCA), with addition of immunosup- ALP ↑ x x x pressive therapy (e.g., azathioprine) at an appropriate time point to maintain remission [68]. In patients without advanced fbrosis, AST/ALT ↑ x x withdrawal of immunosuppressive therapy might be considered at ticle GGT ↑ x an earlier time point than would be the case in a patient with AIH Primary immunology alone, particularly if the diagnosis, although strongly suspected, IgM ↑ x had initial ambiguity (e.g., if there was moderate rather than severe AMA (>1/40) + x interface hepatitis). Conversely, if the diagnosis is suggestive but not entirely clear at the outset, the clinician may consider starting Specifc ANA + x treatment with UDCA and adding therapy for AIH only if ade- Secondary immunology quate biochemical response is not achieved. Review A r Anti-centromere + x Liver function Deciphering diagnostic scenarios observed in clinical practice Bilirubin ↑ x Te following are potential scenarios that would lead a clinician to suspect PBC: INR ↑ x • AMA positive; elevated ALP Albumin ↓ x • AMA negative; elevated ALP Portal hypertension • AMA negative; elevated AST, ALT, and ALP Platelets ↓ x Te most obvious scenario for confrming the diagnosis of PBC ↑, increasing values; ↓, decreasing values; +, serologic positivity; x, poorer prog- is the frst scenario, a patient who is AMA positive with an elevated nosis; ALP, alkaline phosphatase; AST, aspartate aminotransferase; ALT, alanine ALP. Additionally, the second and third scenarios can represent aminotransferase; GGT, gamma-glutamyltranspeptidase; IgM, immunoglobulin AMA-negative PBC, which require additional assessment. With- M; AMA, antimitochondrial antibodies; ANA, antinuclear antibodies; INR, international normalised ratio out an obvious PBC marker, and the limitations of AMA testing in the US, there are questions regarding how to assess AMA negative patients in the right clinical setting such as elevated ALP and or histological features raise the possibility of an overlap syn- aminotransferases. Tis panel recommends that a liver biopsy be drome encompassing elements of both PBC and AIH. Although considered for patients with high suspicion for PBC, elevated ALP the term “overlap syndrome” has been historically used, most but negative AMA. experts favor the term “PBC with autoimmune features”. In clini- In contrast, there are a number of scenarios that may be clinical practice, these patients present a markedly elevated ALT level cally relevant. Tere are patients who are AMA negative with nor- (e.g., >5 × ULN), raising the possibility of this overlap, and the mal ALP but have elevated GGT. Given the sensitivity of GGT to impression is further supported if the level of gamma globulins is alcohol consumption and medication use, this scenario should not elevated, particularly if over 1.5–2 × ULN. Histologically, moder- instigate an extensive evaluation but will require follow up in 3–6 ate or severe interface hepatitis, and/or an infammatory infltrate months. rich in plasma cells, raises the same possibility. Another scenario is presence of AMA positive tests with nor- No scoring system with widespread acceptance analogous to mal ALP, aminotransferases, and GGT. Tere are limited data in that of the International AIH Group has been developed to diag- these patients but what is published suggests that the presence of nose PBC/AIH overlap syndrome [63], although useful parame- a positive AMA in a patient with or without abnormalities in liver ters have been proposed [64, 65]. Tere is general agreement that a enzymes may indicate the possibility of having underlying PBC distinct group of patients with features strongly suggestive of both [69, 70]. In this context, the panel believes that these patients may disorders does exist, a concept strongly supported by studies show- have a propensity to develop PBC but currently cannot be diag- ing distinctly more adverse prognoses in patients so identifed [66, nosed with PBC. It is recommended that these patients are fol- 67]. On the other hand, there has been a tendency to diagnose this lowed periodically (every 6–12 months) with repeat liver enzyme syndrome with excessive frequency by clinicians in PBC patients panels to make sure they do not manifest other clinical and with weak or moderate ANA or AMA titers. Tis is particularly laboratory signs of PBC. true when it is not sufciently recognized that signifcant interface hepatitis can exist in the liver biopsy of patients with PBC and that plasma cells can be prominently featured in the infammatory Symptoms directly associated with PBC infltrates of some PBC patients. Pruritus In patients who are thought to have overlap syndrome based Pruritus occurs in 20–70% of patients with PBC and is not asso- upon laboratory features such as liver enzyme levels and/or ciated with the degree of laboratory abnormalities, disease dura- gamma-globulin elevations and suggestive serologic features, such tion, or histologic severity. Te classic cholestatic pattern is itching

prominently on the palms and soles and worsening at night. Bile line, but the evidence base for these drugs is not strong. Although salts and endogenous opioids may play a role in the development used in clinical practice, there is not a great deal of strong evidence of pruritus. Lysophosphatidic acid (LPA), a potent neuronal itch supporting the use of antihistamines for the treatment of pruritus. activator mostly formed by the lysophospholipase enzyme auto- Nevertheless, antihistamines such as hydroxyzine may have non- taxin (ATX), may also play a role. In PBC, an unknown biliary fac- specifc antipruritic efects in patients with cholestasis, which may tor may increase ATX, thus increasing LPA. Data indicate that, in result from their sedative properties. Te resultant sedative efects

ticle PBC patients, serum ATX activity correlates with itch intensity and may help patients sleep, but antihistamine-associated mucosal response to anti-pruritic treatments [71]. Recent animal data led to drying may limit use in PBC patients [5]. Finally, it is impor- a postulate that itch may be caused by bile salt activation of TGR5, tant to point out that UDCA does not relieve pruritus and may a plasma membrane receptor expressed on sensory neurons [72]. exacerbate it [72]. A patient with PBC presenting with suspected pruritus needs to Recent advances in the understanding of bile acid physiology be evaluated for skin lesions and, if necessary, referred to a derma- and pathophysiology of cholestatic pruritus have led to the devel- tologist to rule out other conditions. Administering questionnaires opment of novel therapies to treat pruritus in PBC. Te main

Review A r like the grading scale, VAS, PBC-40 questionnaire, and 5D itch class of drugs being investigated in clinical trials is apical sodium- scale can be useful in grading itch severity [72]. In patients with dependent bile acid transporter (ASBT) inhibitor (also called ileal pruritus not conforming to the classic cholestatic pattern an assay bile acid transporter (IBAT) inhibitor). In addition, anecdotal for serum bile acids may help determine if the itching is likely due observations suggest that fbrates improve itch in some patients to liver disease. with PBC. Inhibiting ATX or blocking the LPA receptors could Treatment of pruritus is important in PBC patients in order to also improve pruritus, but clinical trials aimed at these targets have improve mood, quality of sleep, and social functioning. AASLD not been performed [72]. and EASL guidelines recommend a number of non-pharmaco- logic interventions to manage pruritus [4, 5]. Recommended Fatigue medications for pruritus are listed in Fig. 4; however, the following In patients with PBC and fatigue, it is important to exclude or is based on the opinions of this panel regarding these treatments. identify and manage potential causes of fatigue such as anemia Anion exchange resins may need to be given twice daily and dosed [74], depression [74], sleep disorders [74], hypothyroidism [74, separately from other drugs by 4 hours. If cholestyramine is not 75], and medications that can cause or contribute to fatigue tolerated, colesevelam is an option, but data are limited on its use in (such as excessive antihypertensive medications) [4]. Patients PBC. A small, randomized controlled trial comparing colesevelam should be encouraged to maintain regular physical activity [76]. hydrochloride (taken orally as three 625-mg tablets twice daily) Modafnil 100–200 mg has been used, but evidence is limited. versus placebo demonstrated decreases in serum bile acid levels An open label trial on the use of modafnil in PBC patients but no improvement of pruritus in patients receiving colesevelam demonstrated efcacy in 42 patients given a 3-day trial of [73]. Rifampicin is efective, but risk of liver toxicity requires mon- 100–200 mg modafnil. During the initial trial period, 31 (73%) itoring of liver function tests and the patient must be informed patients had complete response, which was defned as increased of the hepatic risks. Expert opinion varies with regard to the use energy, decreased somnolence and sleep requirements, and of rifampicin; some avoid it because of the risk of liver toxicity improved daily function. In long-term follow-up (average 17.7 while others consider the beneft:risk profle favorable especially months), 25 (81%) patients continued to take 100–200 mg of in patients with severe itching and when other treatments have modafnil daily [77]. It is important to discuss the side efects failed. Other drugs are available, such as naltrexone and sertra- of modafnil, such as fever, sore throat, headache, vomiting,

Morning and afternoon dose Cholestyramine up to 4g × 4day Separate 4 hours from other drugs Colesevelam if other not tolerated Drug induced hepatitis in up to 12% Rifampicin 150 mg/day Monitor especially first 2 months

Increase up to 60 mg/day every other week

Naltrexone up to 50 mg/day Monitor for (infrequent) hepatotoxicity

Sertraline up to 100 mg/day Has not lived up to early hopes

Extracorporeal albumin dialysis MARS Plasmapheresis common bile duct drainage

Consider transplantation

Fig. 4 Proposed Schema for the Management of Pruritus. d, day; h, hours; EOW, every other week; MARS, Molecular Adsorbent Recirculating System; CBD, common bile duct

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skin reaction, and other more serious but rare side efects, with risks are stratifed based on treatment response, which will be dis- patients. Afer proper discussion of risks and benefts, modafnil cussed in subsequent paragraphs [94]. may be very selectively considered for some patients with severe fatigue in PBC. Hepatocellular carcinoma In comparison to patients without cirrhosis, patients with PBC have an increased risk of HCC in the setting of cirrhosis. Te inci-

Hepatic complications of PBC dence of HCC has been estimated to be approximately 0.35 per ticle PBC typically progresses slowly and can lead to cirrhosis and 1000 person years; male gender and advanced histological stage related complications though progression from cholestasis to are risk factors for HCC in PBC [95]. A systematic review and cirrhosis to liver-related morbidity/mortality can vary amongst meta-analysis suggested that PBC patients with cirrhosis have an patients. Tis guidance underscores the point that untreated 18-fold increased relative risk of HCC [96]. patients are at increased risk for disease progression. Longitudi- A study from Japan suggested that men with PBC might have nal studies have shown that in the absence of efective treatment, an increased risk of HCC even in the absence of cirrhosis [97]. the median time to development of extensive fbrosis was 2 years. A recent study of UDCA confers a higher risk of HCC in PBC Review A r Afer 4 years, the probability of remaining in the early stage was patients; of 4565 patients with PBC, 123 developed HCC, yield- only 29% (confdence interval: 15–52%). In addition, 50% of PBC ing an incidence rate (IR) of 3.4 cases/1000 patient-years. HCC patients, who initially had only interface hepatitis without fbro- was signifcantly more common in men (p < 0.0001), patients sis, progressed to cirrhosis [78–80]. with advanced disease and hepatic decompensation (HR 9.89, Recent studies suggest that patients are increasingly being iden- p < 0.0001). Nonresponse to UDCA based on the Paris I crite- tifed at an early stage of the disease and a minority of (~15%) of ria was the most signifcant factor predictive of future HCC risk patients have evidence of advanced disease at presentation [81, (adjusted HR 3.44, p < 0.0001) [98]. 82]. Furthermore, treatment with UDCA is associated with slower Tese data suggest that HCC surveillance is appropriate in histologic progression compared to untreated patients [83, 84]. PBC patients with cirrhosis. Tis is especially important in men Nevertheless, the cumulative incidence of cirrhosis over 10 years and those with a biochemical non-response to UDCA and may has been estimated to be ~40% [85]. Since a substantial propor- improve outcomes in PBC [99]. All patients with PBC and cirrho- tion of PBC patients have or will develop cirrhosis, they remain at sis (F4) should undergo surveillance for HCC using ultrasonogra- risk for cirrhosis-associated complications, including esophageal phy every 6 months. Surveillance of PBC patients with earlier stage varices, ascites, and hepatic encephalopathy. As in other chronic of liver disease (i.e., F3) may be considered for men and those with liver diseases, development of hepatic complications is associated additional risk for HCC (family history of HCC). with poor prognosis [86]. Management of hepatic complications in PBC Impact of hepatic complications on morbidity and mortality Te management of liver-related complications in PBC is the Liver-related complications primarily occur in patients with cir- same as the management for patients with advanced liver dis- rhosis, but bleeding from esophageal varices may occasionally ease related to other types of chronic liver diseases. For example, develop in patients without cirrhosis. In contrast to other liver screening for esophageal varices and HCC as well as their man- diseases, portal hypertension may also develop in patients with agement in cirrhotic patients with PBC should be carried out pre-cirrhotic PBC. Although liver function is normal or near according to the AASLD and ACG guidelines [5]. normal in these patients, esophageal varices, gastric varices, or portal gastropathy may develop. Nodular regenerative hyperplasia is associated with obliteration of the portal venules and may Extra-hepatic complications of PBC lead to portal hypertension in some of these patients [87, 88]. Metabolic bone disease Patients with complications of portal hypertension in the absence Patients with PBC have an increased incidence of osteoporosis of cirrhosis may require endoscopic or radiologic management (14–52%), osteopenia (30–50%), and risk of fractures. Major risk of their varices and can survive for many years without liver factors for osteoporosis in PBC include severe cholestasis and transplantation [87, 89]. advanced histological stage, but patients with less advanced disease can also be afected. Post-menopausal women are at particu- Prognostic models assess risk of complications lar risk [100–102]. Several prognostic models have been developed and validated for Bone mineral density (BMD) should be assessed at baseline use in patients with PBC. As previously discussed, the Mayo score and every 2 years in PBC patients depending on the severity of has been extensively validated and considered as the classic prog- osteoporosis at baseline and the severity of cholestasis which could nostic model for survival in untreated PBC patients. In addition, negatively impact bone disease. Various authors and guidelines multiple models such as the Rotterdam criteria [90], Barcelona have made diferent recommendations regarding the use of cal- criteria [91], Paris I criteria [92], Paris II criteria [82], and Toronto cium and vitamin D in patients with PBC. Te most recent EASL criteria [93] are available to identify the risks of developing com- guidelines state that patients with normal nutrition and absence plications such as cirrhosis, HCC, and mortality. However, these of features of calcium malabsorption do not need calcium supple-

mentation, and vitamin D can be supplemented as indicated by and 141 matched controls with normal serum cholesterol for serum levels [4]. In contrast, the recent AASLD Guidance docu- signs of subclinical atherosclerosis. Te investigators concluded ment suggests that all patients with PBC should be provided 1000 that hypercholesterolemia is not consistently associated with sub- to 1500 mg of calcium and 1000 International Units of vitamin D clinical atherosclerosis in PBC, but patients should be treated for daily in the diet and as supplements if needed [5]. Te panel believes high cholesterol if other cardiovascular risk factors are present that strong evidence supporting these specifc recommendations [110]. In a 6-year study of 400 PBC patients, marked hypercholes-

ticle are lacking and clinicians are advised to check vitamin D levels terolemia was not associated with an excess risk of cardiovascular at least annually and provide vitamin D and calcium supplemen- disease, but hypertension did increase the risk of cardiovascular tation accordingly. Patients should also be counseled on smoking events [107]. Given the ubiquitous nature of risk factors for car- cessation, limited or no alcohol consumption, and weight-bearing diovascular disease in the US population, the panel agreed that activities as recommended by primary care guidelines. the usual criteria for treating hypercholesterolemia are appro- Pharmacological therapy is recommended for patients with priate to apply to PBC patients. However, clinicians should be the highest risk of fracture, as indicated by BMD score and clini- mindful that in early PBC, elevated total cholesterol levels may

Review A r cal risk factors. Patients with a T score ≥ −2.5 should be treated; be attributed to elevated HDL rather than elevated LDL. Further- while treatment of patients with T scores between −1.0 and −2.5 more, in more advanced liver disease, LP-X, which is measured as are more controversial. Drug choices are the same as those used LDL on routine assays of cholesterol, may be largely responsible in post-menopausal osteoporosis and data on their use in PBC for elevated LDL levels. At present, hypertension appears to be are available. Bisphosphonates are indicated for osteoporosis, but the most important risk factor for cardiovascular disease in PBC if esophageal varices are present other classes of drugs should be patients. used. In a study by Zein et al., PBC patients were randomized to Data on atorvastatin [111] and simvastatin [112] indicate that alendronate 70 mg/week (n = 17) or placebo (n = 17). Alendronate these drugs are safe and efective for use in PBC. A recent meta- patients demonstrated signifcant improvement in BMD of the analysis has demonstrated that patients with cirrhosis from any lumbar spine and proximal femur as compared to placebo, with cause who are taking statins chronically had a 46% lower risk of similar safety demonstrated in both groups [103]. Another study either hepatic decompensation or mortality [113]. randomized 42 patients to monthly ibandronate (150 mg; n = 14) and weekly alendronate (70 mg; n = 19) for 2 years and showed Sicca syndrome similar improvements with either medication in both lumbar Sicca syndrome is common in patients with PBC. Tis syndrome spine and hip density, comparable safety, but better adherence to is associated with dry eyes, dry mouth, vaginal dryness/dyspareu- the monthly ibandronate [104]. Finally, raloxifene 60 mg/day was nia, an increased frequency of oral candidiasis, and extra-glan- administered for 1 year to 7 post-menopausal PBC patients. Each dular symptoms (i.e., fatigue, arthralgias, myalgias, cytopenias, patient was compared with three age-matched controls. Femoral peripheral neuropathy, vasculitis, Raynaud’s phenomenon). It is neck BMD remained stable with a statistical trend in improvement important to note that dry mouth can be associated with dental in the lumbar spine BMD versus placebo [105]. caries and require treatment. Dry eyes can be managed with artifcial tears, artifcial saliva preparations are available to treat dry Hyperlipidemia mouth and moisturizers recommended by primary caregivers can Hyperlipidemia is common in PBC; in early disease, 75% of be helpful for vaginal dryness. Pilocarpine, a cholinergic agonist, patients have total cholesterol levels >200 mg/dL. Mild eleva- may be efective for Sicca syndrome. For those who are refractory tions in low-density lipoproteins (LDL) and marked elevations to artifcial tears, the AASLD Guidance document recommends in high-density lipoproteins (HDL) are common which tend to considering the use of pilocarpine or cevimeline and even cyclo- decline over time, though still ofen remaining high in the normal sporine or liftegrast ophthalmic emulsion under the supervision range or above normal. Conversely, late stage disease is associated of an ophthalmologist [5]. with marked LDL elevations, which may in part be attributable to a decline in functional LDL receptors [106–108]. However, in Additional extra-hepatic manifestations of PBC patients with advanced PBC, increases in cholesterol levels are Decreased bile acid secretion may lead to impaired absorption of mostly attributable to increased levels of lipoprotein-X (LP-X), an the fat-soluble vitamins A, D, E, and K [114]. Clinicians should be abnormal lipoprotein particle within the LDL density region that aware of potential fat-soluble vitamin defciencies in patients with is rich in free cholesterol and phospholipids. LP-X inhibits oxida- PBC and supplementation should be considered on an individual tion of normal LDL, thereby reducing the risk of atherosclerosis basis. [109]. Although LP-X levels can be measured by lipoprotein elec- Clinicians need to be mindful that PBC is also associated with trophoresis, this is rarely performed. Terefore, in PBC patients scleroderma, mixed connective tissue disease, or CREST syn- there is ofen uncertainty with individual patients as to whether drome. If a patient presents with these disorders, and elevated liver increases in LDL are in fact true increases or if they represent the tests, PBC should be ruled out. Conversely, PBC patients should de novo appearance of increased LP-X. be questioned and examined for features of such signs and symp- Alloca et al. studied 103 patients with PBC (37 with total cho- toms of Raynaud’s syndrome, dysphagia, refux, sclerodactyly, and lesterol ≥ 6.21 mmol/L), 37 controls with hypercholesterolemia, telangiectasias.

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Orthotopic liver transplantation in PBC characteristics should be more carefully monitored and treated to In the mid-1980s, PBC was the leading indication for orthotopic reduce their chances of progression [121]. liver transplantation (OLT) in the United States. Over time, the Both EASL and AASLD recommend that therapy in PBC should number of patients with PBC requiring transplant has declined prevent disease progression, complications of cirrhosis, and man- by about 20%, mostly due to efective treatment. Te outcome of age associated symptoms of the disease [4, 5]. Over the past four liver transplant is more favorable in patients with PBC than for decades a number of therapeutic agents including azathioprine almost all other disease categories. Indications for liver transplan- [122], chlorambucil [123], prednisolone [123], cyclosporine [124], ticle tation for PBC are no diferent from those of other etiologies of and colchicine/methotrexate [125] have been evaluated for the cirrhosis. PBC may recur afer OLT in ~20% of patients; rates may management of PBC. Some of these agents, particularly the immu- vary depending on diagnostic criteria and may also be associated nosuppressants, did show some efcacy but side efects limited with increasing AMA titers post OLT [2, 5]. With PBC, severe their use. Currently two drugs are approved for the treatment of treatment-resistant pruritus and/or severe hepatic encephalopa- PBC: UDCA and obeticholic acid (OCA). thy may also merit consideration for transplantation [115].

Tere are unique post-transplant factors regarding PBC. Follow- Ursodeoxycholic acid Review A r ing OLT, osteopenia may worsen for the frst 6 months, yet BMD UDCA is a naturally occurring hydrophilic and non-toxic bile returns to baseline afer 12 months and improves thereafer. Fur- acid. UDCA was initially developed and was frst FDA approved thermore, there are reports showing patients transplanted for PBC to dissolve gallstones. It was subsequently noted that patients who sufer more frequently from acute cellular rejection. It has also been received UDCA had a decline in their ALP. Tis observation led reported that patients transplanted for PBC have one of the highest to clinical trials of UDCA for the treatment of PBC [126]. Bile risks of late acute rejection [116]. However, chronic rejection and acids are detergents and therefore dissolve cell membranes and graf loss are not more common. Regarding recurrent PBC post- cause cell lysis. In contrast, the hydrophilic properties of UDCA OLT, cyclosporine-based anti-rejection regimens seem to be asso- make this a non-toxic bile acid that does not cause cell lysis [127]. ciated with reduced incidence and prolonged time to recurrence When patients are treated with UDCA, the bile acid pool becomes as compared to tacrolimus-based regimens [117, 118]. Preventive enriched with this less toxic bile acid [128]. administration of UDCA afer liver transplantation for PBC may Te frst study using UDCA to treat PBC demonstrated that the also be benefcial. In a retrospective study that evaluated 90 PBC levels of GGT, ALP, AST, and bilirubin were all reduced by 36–78% patients with a 1-year minimum follow-up, 21% received UDCA. [129]. Tis led to the frst randomized, controlled study of UDCA Recurrence was diagnosed in 48 (53%) of these patients and pre- vs placebo in patients with PBC. Patients treated with UDCA (13 ventative UDCA was the only factor that signifcantly decreased to 15 mg/kg/day; n = 73) for two years had signifcant improve- the risk of recurrence [119]. Another retrospective study suggested ments in serum levels of bilirubin, ALP, ALT, AST, GGT, and IgM that UDCA reduced the rate of recurrence of PBC post-transplant, (all P < 0.001). A signifcant improvement in mean liver histol- but there was no impact on survival. Additional data demonstrated ogy score, infammation, and bile duct injury was also observed that UDCA administration post-OLT improved ALP levels but in patients treated with UDCA. Te long-term benefts of UDCA did not improve survival [120]. Prospective trials that help deter- were later analyzed in this patient population and it was established mine optimal methods to diagnose post-OLT PBC and who may that PBC progressed signifcantly less frequently in patients who beneft from treatment are needed. Despite the lack of evidence were treated with UDCA when compared to placebo (P < 0.002; supporting improvement in post-OLT survival, there seems to be relative risk, 0.28; 95 percent confdence interval, 0.12 to 0.63). In some biochemical and disease prevention benefts with treatment. addition, the probability of death or liver transplantation were sig- Terefore, it is the opinion of this panel that it is reasonable to give nifcantly lower in the UDCA group vs the placebo group [130]. UDCA to patients post-OLT. Approximately 60% of patients with PBC respond to UDCA with a decline in ALP to normal or near normal [131]. UDCA appears to be most efective when initiated early in the course of Treatment of PBC: old and new the disease. In one study, patients treated with UDCA were com- Recently, a large database of comprehensive and continuous elec- pared to matched controls by assessing survival as predicted by the tronic medical records claims data from over 500 US healthcare Mayo model. Te study showed that good biochemical response practices or systems were examined. Adults with PBC comprised afer 1 year, defned as a 40% reduction in ALP from pre-treatment 36,317 patients in the database and, afer applying exclusion criteria, baseline, was associated with a survival similar to that estimated 15,875 patients were included in the fnal PBC cohort. Te average for the matched control population (P = 0.15). By contrast, the patient age was 63.0 ± 13.5 years, 78% were female, 57% had other survival of patients without biochemical response was lower than autoimmune diseases, and 46% had cirrhosis. 6083 (38%) had a that estimated for controls (P < 0.001). Patients with a total biliru- more progressive course of PBC, indicated by ALP ≥ 1.5×ULN. In bin of <2 mg/dl and mild fbrosis had a greater decline in serum a multivariate analysis, older age, female gender, the presence of ALP and greater histologic improvement than patients with a bili- other autoimmune diseases, and having compensated or decom- rubin > 2 mg/dl and more advanced fbrosis or cirrhosis. Major pensated cirrhosis were independently associated with having complications of liver disease, progression to liver transplantation ALP ≥ 1.5×ULN. Te authors concluded that, patients with these or death, occurred in 10.5% and 76.6%, respectively, in patients

who had an entry serum bilirubin of <2 or ≥2 mg/dL [91]. Tese is the most widely cited, clinically relevant international study of results indicate that higher bilirubin levels predict greater disease PBC. As such the GLOBE score has become the most frequently progression and that initiating treatment too late has minimal used predictive model in PBC and is now being validated in other impact on slowing disease progression [128]. clinical research settings. UDCA is safe and has limited side efects. Te most common In addition to GLOBE and its predictive models, a number of complaint experienced by patients with or without cirrhosis is other scoring systems have been used for patients with PBC. In

ticle itching, which occurs in about 2% of patients, and diarrhea, which this context, Mayo PBC scoring has been quite useful, especially occurs at a similar rate (2%). Based on these data, the panel recom- in patients being considered for liver transplantation. Additionally, mends the use of UDCA, at a dose of 13–15 mg/kg/day, as frst-line the prognostic MELD model has become the standard scoring sys- treatment for patients with PBC. Higher doses of UDCA have not tem for listing patients for liver transplant and is used in all candi- shown to be efective in PBC and should not be used. dates for liver transplantation, including those with PBC.

Assessment of response to UDCA treatment in patients with PBC

Review A r Prognosis in UDCA-treated patients with PBC As noted previously, over the past decades, a number of groups A recent long-term, international study by Harms and colleagues have developed algorithms or predictive scoring models to deter- sought to describe the incidence of cirrhosis-associated complica- mine if a patient with PBC has had adequate response to treat- tions in patients with PBC and assess risk factors and impact on ment (Table 2). survival. Patient data from 15 liver units across 10 countries in As the information in the table indicates, there is lack of agree- Europe and Northern America participating in the Global PBC ment on the exact defnition of non-response. Nevertheless, a Study Group were included. Te study population comprised 3224 number of common themes have emerged supporting biochemi- UDCA-treated patients (91% female; 73% in early biochemical cal response (decrease in ALP) as the most important surrogate disease stage). Over 8.1 median years of follow-up, ascites, variceal for defning response to treatment. As previously noted, some of bleeding and/or encephalopathy were noted in 278 patients (incidence rate of 9.7 cases/1000 patient years). Te overall cumula- Table 2 Scoring systems predicting non-reponse to UDCA tive incidence of major non-neoplastic hepatic complications was 9% afer 10 years and 15% afer 15 years which was a reduction Scoring Systems Predicting Non-Reponse to UDCA in hepatic complications as compared to previous decades. Te 10-year transplantation-free survival afer a complication was 9% UK-PBCa Bilirubin, ALP, and AST or ALT at 12 months. (time-dependent hazard ratio 21.5; 20.1–22.8). Patients with both Albumin and platelet count at baseline biochemical non-response and an aspartate aminotransferase GLOBEb Bilirubin, ALP, albumin, and platelet > count at 12 months. to platelet ratio index (APRI) 0.54 afer 12 months of UDCA Age at baseline had a 10-year complication rate of 37.4%, as compared to 3.2% Non-response after 6 months of treatment with UDCA in biochemical responders with an APRI ≤ 0.54. Terefore, both biochemical non-response afer 1 year of UDCA and an APRI of Rochesterc ALP≥2 × ULN or Mayo score ≥ 4.5 >0.54 were determined to be independent predictors of future Ehimd Decrease in GGT ≤ 70% and GGT ≥ 1 × ULN hepatic complications [86]. Non-response after 12-24 months of treatment with UDCA Te panel feels that these data confrm many important points Barcelonae Lack of decrease in ALP ≤ 40% and on early diagnosis and treatment in PBC. First, hepatic complica- ALP ≥ 1.0 × ULN tions are of critical importance in the clinical course of the disease Paris-If ALP ≥ 3 × ULN or AST ≥ 2 × ULN and are predictive of poor survival. Furthermore, the decreasing or bilirubin >1.0 incidence of major hepatic complications may demonstrate the Rotterdamg Bilirubin ≥ 1 × ULN and/or albumin < 1 × ULN value of earlier diagnosis and treatment with UDCA [86]. Also, Torontoh ALP >1.67 × ULN after 2 years on UDCA other developments, such as timely detection and widespread primary prophylaxis of variceal bleeding, may have contributed to a Paris-IIi All three of the following: ALP > 1.5 × ULN, AST > 1.5 × ULN, bilirubin > 1 mg/dl after decreasing incidence of complications [86]. 1 year on UDCA Most predictive models are based on single center data, but aUK-PBC Risk Score Calculator [143] the recent GLOBE score, proposed by Lammers et al., is based bLammers et al. [81] on data from multiple international cohorts of more than 4500 cAngulo et al. [144] dAzemoto et al. [145] patients with PBC. Te GLOBE score assesses the transplant-free eParés et al. [91] survival of patients receiving UDCA therapy. Terefore, this is a fCorpechot et al. [92] gKuiper et al. [90] more generalizable PBC predictive model that incorporates age at hKumagi et al. [93] the time of initiating UDCA therapy, serum ALP, total bilirubin, iCorpechot et al. [84] albumin, and platelet counts. Te GLOBE score formulates the jALP, alkaline phosphatase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; UDCA, ursodeoxycholic acid; ULN, upper limit of normal; risk of liver transplantation or death as a function of serum ALP GGT, gamma-glutamyltranspeptidase and total bilirubin afer 1 year of UDCA treatment [132]. GLOBE

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these have been used in designing the most recent clinical trials throughout the trial. Te primary endpoint, an ALP < 1.67 × ULN for patients with PBC (ALP of 1.67 × ULN). It is important to note (with a reduction of at least 15% from baseline) and a normal that a study of 5000 patients with PBC suggested that any increase total bilirubin level, occurred in signifcantly more patients in the in ALP is associated with increased adverse outcomes [133]. In this 5–10-mg group (46%) and the 10-mg group (47%) than in the pla- context, one can argue that the clinical goal of treatment should be cebo group (10%; P < 0.001 for both comparisons). Response to to normalize ALP. In fact, a lower threshold of ALP > 1.5 × ULN OCA was rapid, as signifcant diferences were observed between has been favored by some experts [4]. each OCA group and the placebo group by week 2 and at each ticle It is the opinion of the panel that the goal of treatment is to time point thereafer (P < 0.001 for all comparisons). Decreases achieve a serum ALP level as close to normal as possible. Second- were signifcantly greater in patients in the 5–10-mg group and line therapies (such as OCA) may be considered in patients who 10 mg group than in the placebo group for ALP levels (−113 and have persistent elevation of serum ALP despite an adequate trial −130 U/L, respectively, vs. −14 U/L; P < 0.001 for both compari- of UDCA therapy. However, the decision to add a second agent sons) and total bilirubin levels (−0.02 and −0.05 mg/dL [−0.3 should consider the absolute level of ALP elevation, serum biliru- and−0.9 μmol/L], respectively, vs. 0.12 mg/dL [2.0 μmol/L]; bin level, stage of disease, and the risks and benefts of second-line P < 0.001 for both comparisons) [131]. Review A r treatments. Pruritus was the most common adverse event across all groups, Criteria for adding a second agent may include: with a higher incidence reported in the 5–10-mg group (56%) and the 10-mg group (68%) than in the placebo group (38%). Severe • Persistently elevated serum ALP afer 12 months of therapy pruritus was reported more ofen in the 10-mg group (23%) and with UDCA 5–10-mg group (19%) than in the placebo group (7%). Severe • Lack of normalization of bilirubin afer 12 months of therapy pruritus was defned as intense or widespread itching, interfering with UDCA with activities of daily living, or causing severe sleep disturbance, • High risk using available predictive models (UK-PBC, GLOBE or intolerable discomfort, and typically requiring medical inter- PBC) ventions [131]. It is important to point out that the most common • Evidence of fbrosis progression by any modality (TE, MRE, adverse efect with UDCA is also pruritus, but, as mentioned pre- histology or clinically) while on UDCA. Progression to cir- viously, it occurs at a lower rate. rhosis by any defnition will be considered as non-response. Based on these data, the FDA granted accelerated approval in May 2016 for OCA 5–10 mg orally once daily for the treatment Obeticholic acid of PBC in combination with UDCA in adults with an inadequate Te farnesoid X receptor (FXR), a ligand-activated transcription response to UDCA, or as a single therapy in adults unable to toler- factor and a member of the nuclear receptor superfamily, is highly ate UDCA. Prescribers need to be aware of liver-related adverse expressed in the liver, intestine, adrenal glands, and kidneys [134]. reactions, specifcally jaundice, worsening ascites and PBC fares, As a transcription factor, FXR induces the small heterodimer that have been observed in doses exceeding 10 mg. partner (SHP, gene symbol NR0B2/Nr0b2) in the liver that down- Dosage adjustments were not being followed in patients with regulates the expression of cholesterol 7α-hydroxylase (CYP7A1/ hepatic impairment, so an increased risk of serious liver injury Cyp7a1) and sterol 12α-hydroxylase (CYP8B1/Cyp8b1) genes. and death was being observed when these patients were admin- Tese genes encode enzymes that synthesize bile acids from cho- istered OCA. Terefore, in September of 2017, the FDA issued lesterol. Terefore, FXR is a critical regulator in bile formation and a black-boxed warning on OCA that reiterates that the recom- enterohepatic circulation and as such plays a crucial role in bile mended starting dosage of OCA is 5 mg once weekly for patients acid homeostasis and hepatic regeneration, among other things with Child-Pugh Class B or C hepatic impairment or a prior [135]. OCA is a bile acid analog, derived from the primary human decompensation event. Afer the frst 3 months, this dose can be bile acid chenodeoxycholic acid, and is a highly selective, natural increased to a maximum of 10 mg twice weekly (at least 3 days ligand for FXR [136]. Administration of OCA results in decreases apart) [137]. in bile salt synthesis, uptake and absorption; reduction in cytokines Te expert panel feels that OCA should be used in PBC patients associated with infammation; and reduction in hepatic fbrogen- with inadequate response or intolerant to UDCA. Te panel also esis. A common misconception is that OCA is “super-UDCA”. emphasizes the importance of close monitoring of patients with Tis is not the case, since these drugs have diferent mechanisms PBC who are being treated with UDCA and OCA, especially those of action. Unlike OCA, UDCA has no efect on the FXR. with severe hepatic impairment, as delineated by the new FDA A 12-month, double-blind, placebo-controlled phase 3 trial warning. Although pruritus can be seen with OCA, it is the expert was conducted to assess the long-term efcacy, safety, and adverse opinion of the panel that developing pruritus with UDCA does not event profle of OCA in patients with PBC. Two-hundred and six- predict that this will also occur during OCA treatment. teen patients who had an inadequate response to UDCA (defned In addition to those with inadequate response, the panel feels as ALP ≥ 1.67 × ULN or bilirubin > 2 × ULN) or were intolerant that patients with UDCA non-response, as defned above, need of UDCA were randomly assigned to receive 10 mg OCA, 5 mg to be considered for addition of OCA to the treatment regimen. OCA (with adjustment to 10 mg if applicable; the 5–10 mg group) Tis should be done afer careful consideration of risk and benefts or placebo. A total of 93% of patients took UDCA at baseline and of additional treatment. Finally, the panel feels that the addition

of OCA to those individuals who are considered as “suboptimal In addition to medical treatment, all other preventive and responders” should be individualized on a case-by-case basis until screening issues that are applicable to all patients with chronic further evidence becomes available. liver disease must be considered (e.g., screening for HCC and It is also important to consider the fnancial impact of new drugs varices, immunization against hepatitis A and hepatitis B viruses, such as OCA. In this context, the cost efectiveness of an optimal optimizing body weight, minimizing alcohol consumption). Addi- treatment strategy of UDCA followed by OCA for the appropri- tionally, there are PBC-specifc issues related to bone disease, pru-

ticle ate group of patients with PBC must be considered. Tese types of ritus, Sicca syndrome and dyslipidemia that must be managed, as economic analyses should not only include the most relevant cost described in this review. data but also the most realistic transition rates and health utility data. Although some preliminary data has been published, more Answers to commonly asked treatment questions in-depth and robust models are needed [138]. What if side efects are a treatment concern? If there are con- cerns about side efects from PBC treatment, it is always better Future treatments for PBC to start treatment at half the dose, especially in patients with

Review A r Te lipid-lowering agent, bezafbrate, has gained attention over advanced liver disease. the last few years as a potential treatment for PBC, in combination If a patient is stable on UDCA, can the dose be lowered? If a with UDCA, for patients refractory to UDCA therapy [139, 140]. patient is stable on UDCA for the long-term, there are no data to Te most recent data on bezafbrate, presented at the 2017 AASLD support lowering the dose. It is the opinion of this panel that the annual meeting, demonstrated that 2 years of combined bezaf- efective dose should be maintained. brate/UDCA treatment resulted in normalization of biochemical When can OCA be administered? Based on clinical trials, OCA prognostic markers, improvement in pruritus, and prevention can be added when the ALP remains >1.67 × ULN 6 months afer of worsening liver stifness in PBC patients with inadequate initiating UDCA. Although some consideration can be given to response to UDCA [141]. However, because phase 3 trials have extend the duration of initial treatment to 12 months [5], the panel not been completed and since there is not regulatory approval for members recognize that most responders to UDCA will be evi- use in PBC, the panel does not currently recommend its routine dent afer 6 months of treatment. On the other hand, prolonging use in patients with PBC [4]. A smaller body of data exists for this initial trial period to 12 months may also seem reasonable fenofbrate but again is insufcient to warrant a recommendation and should be considered on a case-by-case basis. Furthermore, for use in PBC. Te panel also observes that the use of these drugs if patient has already been on a stable dose of UDCA for a longer can be associated with increases in serum transaminases and the period of time but meets this ALP threshold, OCA can be added. risk of myopathy and rhabdomyolysis, especially in patients with Finally, if any patient with PBC is intolerant to UDCA, monother- renal insufciencies [142]. apy with OCA is indicated. Should transient elastography, such as FibroScan, be used Treatment algorithm for PBC for treatment selection? TE or other non-invasive assessments of Afer establishing PBC as previously described, patients should fbrosis should not be used as a means to select patients for initial be started on UDCA (Fig. 5). Tose with advanced liver disease treatment. Te data strongly suggest that UDCA is most efective in should also be evaluated for liver transplantation. For those patients patients with mild fbrosis and a total bilirubin < 2.0 mg/dl. Tere- with evidence of PBC and autoimmune features of the overlap syn- fore, even patients with early stage PBC should be treated with drome, treatment of AIH must be undertaken concurrently. UDCA. Even in the absence of any evidence for cirrhosis, a base- Afer 6–12 months of treatment with UCDA, for those who line FibroScan is helpful to assess the degree of fbrosis and to serve have inadequate response, addition of OCA (appropriately dosed as a basis for future comparison. Te optimal frequency of repeat for liver disease) should be undertaken. Additionally, in patients testing with FibroScan is not known and may be individualized. In who are intolerant to UDCA for any period of time, OCA mono- some cases, longitudinal elastography may be useful as an adjunct therapy is recommended. Te panel also feels that the expansion of to biochemical monitoring in patients with suboptimal response of the defnition of non-response beyond ALP > 1.67 × ULN may be ALP to assess whether treatment with OCA is warranted. justifed and addition of OCA to the regimen may be considered Should patients with established or suspected cirrhosis be afer a risk-beneft discussion with patients. Additionally, lower- handled diferently than non-cirrhotic patients? Yes. Cirrhotic ing the threshold of inadequate response to ALP > 1.5 × ULN or patients with advanced liver disease must be treated with OCA reducing the duration of use for UDCA to 3 months have been according to the FDA’s recommendation. Tese patients must also considered by some members of the panel. However, until further be screened for HCC and screened for esophageal varices accord- evidence is provided, the panel recommends ALP > 1.67 × ULN ing to the established guidelines. Also, depending on age and Mayo and 6–12 months for assessment of inadequate response to risk score, some cirrhotic patients should be considered for liver UDCA. Finally, the addition of OCA to those individuals who are transplantation. considered as suboptimal responders should be considered on a How should Overlap Syndrome be treated? Patients require case-by-case basis. Individuals who are inadequate responders to a liver biopsy to confrm Overlap Syndrome. If the histology is both UDCA and OCA should be considered for clinical trials of consistent with PBC, then UDCA needs to be initiated. On the new agents for PBC. other hand, if the biopsy suggests AIH, then treat AIH. Overlap

The American Journal of Gastroenterology www.nature.com/ajg Diagnosis and Management of Primary Biliary cholangitis 13

ALP/GGT Alternate diagnosis Bilary tract obstruction/pathology History Drug-induced liver injury Examination Primary sclerosing cholangitis Imaging (US, MRCP) Progressive familial intrahepatic cholestasis Benign recurrent intrahepatic cholestasis

AMA ticle ANA

Liver biopsy

Screen for varices Overlap syndrome PBC diagnosis or PBC with autoimmune features Consider glucocorticoids established ± azathioprine; UDCA Review A r

Cirrhosis? Ye s

UDCA Compensated Decompensated >Child’s B

HCC Good ALP>1.67 UDCA LT evaluation response surveilance

OCA Good response ALP>1.67 Good Poor and/or progressive response response liver disease

Consider clinical trials Appropriately dosed OCA

US, ultrasound; MRCP, magnetic resonance cholangiopancreatography; ALP, alkaline phosphatase; GGT, gamma-glutamyl transferase; AMA, anti-mltochondrial antibodies; ANA, antinuclear antibodies; PBC, primary biliary cholangitis; UDCA, ursodeoxycholic acid; OCA, obeticholic acid; Fig. 5 Algorithm for the Diagnosis and Treatment of PBC US, ultrasound; MRCP, magnetic resonance cholangiopancreatography; ALP, alkaline HCC, hepatocellular carcinoma; LT, liver transplantation. phosphatase; GGT, gamma-glutamyl transferase; AMA, anti-mltochondrial antibodies; ANA, antinuclear antibodies; PBC, primary biliary cholangitis; UDCA, ursodeoxycholic acid; OCA, obeticholic acid; HCC, hepatocellular carcinoma; LT, liver transplantation

syndrome should be treated based upon liver histologic fndings, suppurative destructive cholangitis and destruction of in- not by serologic or biochemical results. terlobular bile ducts. 3. Scenario 3: Chronic elevation of ALP with negative AMA Summary and top-line recommendations but positive PBC specifc ANA (sp-100, gp-210) tests • Given the importance of early diagnosis, all patients present- (these tests are not widely available in the US). ing with cholestatic elevation of liver enzymes should be eval- • Given the importance of establishing the stage of liver disease uated for PBC. and prognosis, the panel recommends calculating the Mayo • Te panel recommends that PBC can be diagnosed if: score for all PBC patients. 1. Scenario 1: Chronic elevation of ALP with a positive • Te panel recommends that patients with advanced liver dis- AMA (immunofuorescent assay titer of >1:40 or ease should also be screened for HCC, esophageal varices and, EIA > 25 u) in the absence of other liver diseases and depending on their age and Mayo risk score, some should be systemic diseases considered for liver transplantation. Other preventive steps 2. Scenario 2: Chronic elevation of ALP with negative for advanced liver disease in patients with PBC must be con- AMA and ANA tests but a liver biopsy that shows non- sidered according to guidelines.

• PBC patients with features of AIH may require a liver biopsy. 5. Lindor KD, Bowlus CL, Boyer J et al. Primary Biliary Cholangitis: 2018 Te panel recommends that if the histology is consistent with Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018. https://doi.org/10.1002/hep.30145. PBC, then UDCA needs to be initiated. On the other hand, if 6. Kim WR, Lindor KD, Locke GR, et al. Epidemiology and natural his- histology is consistent with AIH, treatment should be modi- tory of primary biliary cirrhosis in a US community. Gastroenterology. fed accordingly. 2000;119:1631–6. 7. Lu M, Zhou Y, Haller IV et al. Increasing prevalence of primary biliary • Te development of cirrhosis-related complications is associ- cholangitis and reduced mortality with treatment. Clin Gastroenterol ticle ated with poor prognosis and reduced life expectancy. Hepatol. 2018; 16:1342–50.e1. https://doi.org/10.1016/j.cgh.2017.12.033. • Te panel recommends that the frst line treatment for PBC 8. Peters MG, DiBisceglie AM, Kowdley KV, et al. Diferences between Caucasian, African American, and Hispanic patients with primary biliary patients should be UDCA. For PBC patients who are intoler- cirrhosis in the United States. Hepatology. 2007;46:769–75. ant to UDCA, OCA monotherapy should be started. 9. Hirohara J, Nakano T, Seki T, et al. 2010 Government disease registry, • For patients who are non-responsive to the appropriate dose Hirohara. Nihon Shokakibyo Gakkai Zasshi. 2013;110:8–15. 10. Liu H, Liu Y, Wang L, et al. Prevalence of primary biliary cirrhosis in of UDCA at 6-12 months, OCA should be added to the adults referring hospital for annual health check-up in Southern China. regimen. BMC Gastroenterol. 2010;10:100. 11. Arndtz K, Hirschfeld GM. Te pathogenesis of autoimmune liver disease. Review A r • For patients with PBC treated with UDCA who have “subop- Dig Dis. 2016;34:327–33. timal response”, as defned by increasing liver stifness/fbrosis 12. Burroughs AK, Rosenstein IJ, Epstein O et al. Bacteriuria and primary and increasing total bilirubin despite normal ALP, the panel biliary cirrhosis. Gut 1984;25:133–37. recommends that the addition of OCA be considered. 13. Padgett KA, Selmi C, Kenny TP, et al. Phylogenetic and immunological defnition of four lipoylated proteins from Novosphingobium aromati- • For PBC patients with advanced liver disease, reduced dose civorans, implications for primary biliary cirrhosis. J Autoimmun. of OCA and close monitoring according to the FDA warning 2005;24:209–19. should be carried out. 14. Selmi C, Balkwill DL, Invernizzi P, et al. Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium. Hepatology. 2003;38:1250–57. CONFLICT OF INTEREST 15. Selmi C, Mayo MJ, Bach N, et al. 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