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© 2018 the author(s) The American Journal of GastroenteroloGy

Review ARTicle

IntroductIonPrimary biliary cholangitis (PBC) is a chronic, cholestatic, auto-immune disease with a progressive course that may extend over many decades. PBC is thought to be caused by a combination of genetic predisposition and environmental triggers, and is most commonly recognized in women in their 5th or 6th decade of life. The serologic hallmark of PBC is the anti-mitochondrial anti-body (AMA), a highly disease-specific auto-antibody detected in 90–95% of PBC patients and less than 1% of non-diseased controls [1]. The presentation of PBC can range from asymptomatic (early disease) and slowly progressive to symptomatic and rapidly evolv-ing liver disease. Clinical features of PBC include fatigue, pruri-tus, concurrent autoimmune disease(s), osteopenia/osteoporosis, hypercholesterolemia, and xanthelasma. PBC is a chronic disease that frequently leads to cirrhosis, liver failure and is a common indication for liver transplantation [2].

In recent years, there have been important advances in PBC. For example, the designation “primary biliary cirrhosis” was deemed no longer accurate since, with early diagnosis and treat-ment, many patients do not progress to cirrhosis. Therefore, to adequately describe the histologic hallmark of dense inflammatory infiltrates around damaged intralobular bile ductules, “cholangitis” has replaced “cirrhosis”, while retaining the acronym “PBC” [3]. In

addition, diagnosis and treatment guidelines are changing and a number of guidelines have been updated [4, 5].

Because of important changes in the PBC landscape, and a num-ber of unanswered questions, the American College of Gastroen-terology (ACG) Institute for Clinical Research & Education and the Chronic Liver Disease Foundation (CLDF) have collaborated to provide a practical guidance document for practicing gastroen-terologists to help with their clinical practice. As part of this pro-cess, an exhaustive review of the literature was carried out from 1985 to 2018 by each member of the panel to obtain relevant infor-mation about their topics. Each member summarized their section based on the relevance and the validity of the data presented and summarized the information. All sections of the guidance docu-ment underwent several rounds of review by the entire panel. Any area of disagreement was resolved by searching for additional evi-dence. When evidence did not exist, a consensus agreement was reached through individual member surveys by the chair and sum-marized as the “expert opinion”. In summary, this guidance docu-ment for PBC, intended for practicing healthcare providers, was developed by a panel of hepatology experts and supported by the ACG Institute to provide specific recommendations about clini-cally relevant topics in PBC based on the most recent evidence as well their extensive experience and clinical expertise.

diagnosis and Management of Primary Biliary cholangitisZobair M. Younossi, MD, MPH, FACG, AGAF, FAASLD1, David Bernstein, MD, FAASLD, FACG, AGAF, FACP2, Mitchell L. Shiffman, 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 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

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

mailto:[email protected]

The American Journal of GastroenteroloGy www.nature.com/ajg

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EPIdEMIologyPBC is considered a relatively rare disease that has historically been predominantly reported in white females aged 40 to 50 years old. There has been no appreciable change in the incidence, or the rate of new cases of PBC within a population. Data from the Rochester Epidemiology Project support this conclusion. Patients in Olmsted County, Minnesota were studied between 1975 and 1995. Of the 46 new cases of PBC that were diagnosed, the median age at diagnosis was 52 years, and patients were mostly women (89%), white (100%), and AMA positive (89%). The age-adjusted (to 1990 US whites) incidence of PBC per 100,000 person-years for years 1975–1995 was 4.5 (95% confidence interval [CI], 3.1–5.9) for women, 0.7 (95% CI, 0.1–1.3) for men, and 2.7 (95% CI, 1.9–3.5) overall. The age-adjusted and sex-adjusted prevalence per 100,000 persons as of 1995 was 65.4 (95% CI, 43.0–87.9) for women, 12.1 (95% CI, 1.1–23.1) for men, and 40.2 (95% CI, 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 to 2014, the prevalence of PBC increased from 21.7 to 39.2 per 100,000 persons [7]. This data suggests a possible increase in the prevalence of PBC between 2004 and 2014.

There is increasing evidence that PBC can be seen in most regions of the world. The previous lower inclusion of minorities in the clinical trials of PBC [8] and lower rates in Asians may have been due to under reporting. In fact, recent data from Japan and China report that the prevalence of PBC is 55/100,000 adults [9] and 49/100,000 adults, respectively [10].

PathoPhysIologyPBC is characterized by an inflammatory, predominantly T-cell mediated destruction of intrahepatic bile ducts [11]. Although there is no absolute certainty as to what causes PBC, the most widely accepted theory is that a genetically susceptible patient comes into contact with an autoimmune triggering event. This triggering event could be an environmental factor, virus, allergen, chemical or medication. There is no one trigger and every patient has their own immune triggering event [12–28]. Genetic factors include MHC class II (DR8, DQA1*0102, DQ/β1*0402), MHC class III (C4 null,c4B2), and non-MHC genes (Exon 1 of CTLA-4) [29–31]. Familial factors have also been identified, including 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 PBC [13, 15, 35]. Potential environmental factors, especially in genetically vulnerable individuals, include recurrent urinary tract infections (potentially related to exposure to bacterial compo-nents or the antibiotic use) [35, 36], exposure to toxic chemicals [37] and cigarette smoking [34, 36–39].

Regardless of stimuli, the immunological response triggered in PBC is directed against biliary epithelial cells. Anti-mitochondrial antibodies (AMA), which are highly disease specific, are directed against the 2-oxo acid dehydrogenase family of multi-enzyme complexes located on the inner mitochondrial membrane, of

which the main target is the E2 subunit of the Pyruvate Dehy-drogenase Complex (PDC). Expression of PDC-E2 or a molecule that cross-reacts with certain anti-PDC-E2 antibodies is increased on biliary epithelial cells of patients with PBC. In addition, sev-eral molecular mimicry peptides (found in viral or bacterial pro-teins) to PDC-ER have structurally similar epitopes to those of self-peptides. Increased PDC-E2 may result in a loss of humoral tolerance and an increase of autoreactive cluster of differentiation (CD)4+CD8+PDC-E2-specific T cells in the liver [40]. The auto-immune T cell response that follows is characterized by damage to the biliary epithelial cells that line the intrahepatic bile ducts, resulting in inflammation, scarring, and destruction of the inter-lobular and septal bile ducts. This leads to bile leaking though bile ducts into the liver parenchyma. Hepatocytes are injured by bile salts followed by necrosis, apoptosis, and leading to fibrosis, and cirrhosis [25, 31, 41–48] (Fig. 1).

natural hIstory and outcoMEsPBC is commonly characterized by slow progression of cholesta-sis followed by hepatic dysfunction and decompensation (Fig. 2). Widespread use of AMA testing in the community has enabled the diagnosis of PBC patients before they develop symptoms of chol-estasis or hepatic decompensation. In some cases, the presence of AMA may be found some time before serum alkaline phosphatase becomes abnormal (“preclinical” phase). Since the presentation varies amongst patients, so does the progression through these phases. Based on the clinical experience of this expert panel, some patients rapidly advance to end-stage disease and liver transplanta-tion at a young age while others remain asymptomatic for decades.

Given the variability of the natural history among PBC patients, individual predictive tools may be useful in patient counseling and management planning, including referral for liver transplantation. Over the years, a number of mathematical models have been devel-oped, which incorporate variables of prognostic significance [49, 50]. One such example is the Mayo Natural History Model, with which the survival probability can be predicted for up to 7 years in an untreated patient with PBC based on variables such as age, bili-rubin, albumin, prothrombin time, peripheral edema status, and diuretic therapy status [50, 51]. Additional prognostic models that assess the risk of developing PBC-related complications in patients receiving treatment will be discussed later in this guidance.

dIagnosIs of PBcWithout identification and subsequent intervention, a substan-tial number of PBC patients progress to liver failure, transplant, or death within 10 years [52]. In fact, in one study, only 17.4% of patients remained symptom-free 10 years after their diagno-sis [52]. In addition, in some patients, PBC progresses quickly, advancing through the histological stages as rapidly as every 2 years [53]. Furthermore, up to 30% of patients can have a severe, progressive form of PBC resulting in early development of liver fibrosis and liver failure [54]. In this context, early diagnosis and treatment of PBC is essential. Historically, a number of criteria


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Diagnosis and Management of Primary Biliary cholangitis

were required to establish the diagnosis of PBC [55]. Although these diagnostic criteria captured most patients with PBC, it did allow for some ambiguity that may have led to delay in diagnosis. Therefore, the panel recommends the following scenarios are sup-portive of the diagnosis of PBC:

• Scenario 1: Chronic elevation of alkaline phosphatase (ALP) with a positive AMA (immunofluorescent assay titer of >1:40 or EIA > 25 units) in the absence of other liver diseases and systemic diseases

• Scenario 2: Chronic elevation of ALP with negative AMA and antinuclear antibodies (ANA) tests but a liver biopsy that shows destructive cholangitis and destruction of interlobular bile ducts

• Scenario 3: Chronic elevation of ALP with negative AMA but positive PBC-specific ANA (sp-100, gp-210) tests (these tests are not widely available in the US)

It is important to note that liver biopsy is not required for PBC, unless specific antibodies are absent or co-existence of NASH or autoimmune hepatitis (AIH) is suspected. Also, AMA positivity alone is not sufficient to make the diagnosis of PBC. These patients require follow up but not additional intervention of treatment [4, 5].

Figure 3 provides a structured approach, recommended by a practical and easy to follow algorithm, to reach a safe and secure diagnosis of PBC and facilitate prompt intervention.

Laboratory testsThe PBC panel advises that additional tests (Table 1) can be helpful, but not essential. PBC should be suspected in patients with chronic elevations in AST, alanine aminotransferase (ALT), ALP, and total bilirubin with or without PBC-specific symptoms, such as pruritus or fatigue [4]. Although different laboratories have different upper limits of normal (ULNs) for these tests, in general, patients whose

ALP remains persistently below 1.5 times ULN appear to have a better prognosis [55]. In clinical practice, the hepatic origin of ele-vated serum ALP is usually supported by simultaneous elevation of serum gamma-glutamyl transferase (GGT) and/or conjugated bilirubin [4].

Increased immunoglobulin concentrations, particularly immu-noglobulin M (IgM), can be observed in patients with PBC. Nev-ertheless, this is not specific for diagnosing PBC and therefore this panel does not consider this a diagnostic requirement. In contrast, elevated immunoglobulin G (IgG) is seen in AIH while isolated elevated serum immunoglobulin G (IgA) can be observed in patients with alcoholic liver disease [56].

As PBC progresses, hyperbilirubinemia may occur and signifi-cant hyperbilirubinemia indicates advanced disease. An elevated bilirubin level is generally regarded as the reliable predictor of adverse outcomes in PBC. When hyperbilirubinemia co-occurs with thrombocytopenia, reduced albumin concentration, and ele-vated international normalized ratio (INR), it signifies the devel-opment of decompensated cirrhosis [4]. Patients with suspicion of cirrhosis (thrombocytopenia with or without hepatic dysfunc-tion) should be screened for hepatocellular carcinoma (HCC) and esophageal varices according to established guidelines.

History, physical, and abdominal ultrasoundA physical examination should include screening for hepatomeg-aly and splenomegaly as well as extrahepatic signs of advanced liver disease (e.g., icterus of sclera, skin and mucous mem-branes, xanthelasma, palmar and plantar erythema, nail abnor-malities, or scratch lesions particularly on the arms and legs). PBC does not cause any abnormality of liver morphology that may be detected by imaging. Regardless, abdominal ultrasound should be performed to exclude mechanical bile duct obstruc-tion including obstructive mass lesions and abnormalities of the gallbladder [4].

Serum autoantibodiesSerum autoantibodies are important tools for clinicians when diagnosing autoimmune diseases. AMA is a highly specific anti-body for PBC and is considered the serologic hallmark for this disease [56, 57]. The measurement of AMA may be reported as a ratio when determined by indirect immunofluorescence (IIF) or as an absolute value when determined by an enzyme linked immunosorbent assay (ELISA). An AMA of 1:40 or greater when determined by IIF or ≥25 units when determined by ELISA is considered positive. The sensitivity and specificity of these assays are similar [58–60]. AMA titers do not correlate with disease activity and severity and therefore should not be serially followed. Despite the fact that AMA positivity is a strong indicator of PBC, the presence of AMA in the blood or serum alone is not sufficient to diagnose PBC [4, 5]. AMA reactivity, with an elevated ALP and no significant elevation in AST, is associated with a >95% positive predictive value of histologic PBC [55]. The panel believes that, despite the lack of association of AMA titer with disease severity, AMA is highly specific for diagnosing PBC in the vast majority of patients.

Genetics

Environment

Immuneresponse

Bile ductdamage

• Female gender• MHC, IL-12A, and IL-12RB2 risk alleles• Innate immunity (IgM)

• Defective regulatory T cells• Production of AMAs• Autoreactive CD4/CD8 T cells to PDC-E2

• Immune response, with bile duct apoptotic blebs and AMAs combined with macrophages

• Bacterial mimics

• Xenobiotic chemicals(e.g., Novosphingobium aromaticivorans)

Fig. 1 A Summary of the Pathogenesis of PBC. AMA, antimitochondrial antibodies; IgM, immunoglobulin M; IL, interleukin; MHC, major histocom-patability complex; PBC, primary biliary cholangitis


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A family of antibodies to various nuclear antigens, ANA, is also associated with PBC. About 50% of patients with PBC are positive for PBC-specific ANA target antigens. ANA immunofluorescence is described either as a perinuclear/rim-like membranous pat-tern formed by antiglycoprotein (anti-gp)210 or lamin B receptor (constituents of the nuclear envelope), a multiple nuclear dot-like pattern formed by anti-sp100 and promyelocytic leukemia protein (two autoantibodies that colocalize), or a centromere pattern [61]. Therefore, patients with AMA-negative PBC can be diagnosed with PBC if they have cholestasis and ANA positivity for either anti-gp210 or anti-sp100. Specific ANA testing is readily available in Europe and as such is recommended in the European Associa-tion for the Study of Liver (EASL) PBC guidelines [4]. However, this panel feels that it is important to point out that these specific ANA tests are not readily available in the US and therefore their utility is limited.

Extended imagingMagnetic resonance cholangiopancreatography (MRCP) in chole-static patients is a safe and accurate imaging method for the intra-hepatic and extrahepatic biliary tree [4]. Detection of intrahepatic and/or extrahepatic bile duct stenoses and dilatation is essential for the diagnosis of primary or secondary sclerosing cholangi-tis, which are included in the differential diagnosis of cholestatic

patients. Both magnetic resonance (MRE) and transient elastog-raphy (TE) are useful for determining the degree of fibrosis in a PBC patient. The panel emphasizes the importance of noting that TE stiffness cutoffs are different from those established for chronic hepatitis C. For PBC, TE cutoffs are: F1 < 7.1 kPa, F2 7.1–11.2 kPa, F3 11.2–17.4 kPa, F4 > 17.5 kPa [62]. As for other liver diseases, patients with PBC found to have cirrhosis should be screened for HCC and esophageal varices.

Liver biopsyMost patients with PBC do not require liver biopsy and the diagno-sis is based on clinical and laboratory tests. However, liver biopsy should be performed when the diagnosis of PBC is uncertain or where another superimposed diagnosis (AIH or non-alcoholic steatohepatitis) is suspected. As noted previously, if a liver biopsy is performed, histologic evidence of PBC, such as non-suppurative cholangitis and destruction of small or medium-sized bile ducts, is highly suggestive of the diagnosis of PBC [5]. It is also impor-tant to note that if an overlap syndrome is suspected because of laboratory features of AIH, biopsy is essential (see below).

The overlap syndromes: PBC with autoimmune featuresIn a small proportion of PBC patients, for which precise figures vary considerably amongst different sources, laboratory and/

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Asymptomatic

Intact bile ducts

Hep

atic

func

tion

(%)

Cholestasis

Compensated Decompensated

Fig. 2 Schematic Representation of the Natural History of PBC

ALP/GGTAlternate diagnosisBilary tract obstruction/pathologyDrug induced liver injuryPrimary sclerosing cholangitisProgressive familial intrahepatic cholestasisBenign recurrent intrahepatic cholestasis

HistoryExaminationImaging (US, MRCP)

AMA

ANA

Liver biopsy

PBC diagnosisestablished

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


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or histological features raise the possibility of an overlap syn-drome encompassing elements of both PBC and AIH. Although the term “overlap syndrome” has been historically used, most experts favor the term “PBC with autoimmune features”. In clini-cal practice, these patients present a markedly elevated ALT level (e.g., >5 × ULN), raising the possibility of this overlap, and the impression is further supported if the level of gamma globulins is elevated, particularly if over 1.5–2 × ULN. Histologically, moder-ate or severe interface hepatitis, and/or an inflammatory infiltrate rich in plasma cells, raises the same possibility.

No scoring system with widespread acceptance analogous to that of the International AIH Group has been developed to diag-nose PBC/AIH overlap syndrome [63], although useful parame-ters have been proposed [64, 65]. There is general agreement that a distinct group of patients with features strongly suggestive of both disorders does exist, a concept strongly supported by studies show-ing distinctly more adverse prognoses in patients so identified [66, 67]. On the other hand, there has been a tendency to diagnose this syndrome with excessive frequency by clinicians in PBC patients with weak or moderate ANA or AMA titers. This is particularly true when it is not sufficiently recognized that significant inter-face hepatitis can exist in the liver biopsy of patients with PBC and that plasma cells can be prominently featured in the inflammatory infiltrates of some PBC patients.

In patients who are thought to have overlap syndrome based upon laboratory features such as liver enzyme levels and/or gamma-globulin elevations and suggestive serologic features, such

as high titers of ANA and/or F-actin antibodies, liver biopsy is essential to formulate management decisions [5]. If biopsy sup-ports this diagnosis, corticosteroids should be given along with ursodeoxycholic acid (UDCA), with addition of immunosup-pressive therapy (e.g., azathioprine) at an appropriate time point to maintain remission [68]. In patients without advanced fibrosis, withdrawal of immunosuppressive therapy might be considered at an earlier time point than would be the case in a patient with AIH alone, particularly if the diagnosis, although strongly suspected, had initial ambiguity (e.g., if there was moderate rather than severe interface hepatitis). Conversely, if the diagnosis is suggestive but not entirely clear at the outset, the clinician may consider starting treatment with UDCA and adding therapy for AIH only if ade-quate biochemical response is not achieved.

Deciphering diagnostic scenarios observed in clinical practiceThe following are potential scenarios that would lead a clinician to suspect PBC:• AMA positive; elevated ALP• AMA negative; elevated ALP• AMA negative; elevated AST, ALT, and ALP

The most obvious scenario for confirming the diagnosis of PBC is the first scenario, a patient who is AMA positive with an elevated ALP. Additionally, the second and third scenarios can represent AMA-negative PBC, which require additional assessment. With-out an obvious PBC marker, and the limitations of AMA testing in the US, there are questions regarding how to assess AMA nega-tive patients in the right clinical setting such as elevated ALP and aminotransferases. This panel recommends that a liver biopsy be considered for patients with high suspicion for PBC, elevated ALP but negative AMA.

In contrast, there are a number of scenarios that may be clini-cally relevant. There are patients who are AMA negative with nor-mal ALP but have elevated GGT. Given the sensitivity of GGT to alcohol consumption and medication use, this scenario should not instigate an extensive evaluation but will require follow up in 3–6 months.

Another scenario is presence of AMA positive tests with nor-mal ALP, aminotransferases, and GGT. There are limited data in these patients but what is published suggests that the presence of a positive AMA in a patient with or without abnormalities in liver enzymes may indicate the possibility of having underlying PBC [69, 70]. In this context, the panel believes that these patients may have a propensity to develop PBC but currently cannot be diag-nosed with PBC. It is recommended that these patients are fol-lowed periodically (every 6–12 months) with repeat liver enzyme panels to make sure they do not manifest other clinical and laboratory signs of PBC.

syMPtoMs dIrEctly assocIatEd wIth PBcPruritusPruritus occurs in 20–70% of patients with PBC and is not asso-ciated with the degree of laboratory abnormalities, disease dura-tion, or histologic severity. The classic cholestatic pattern is itching

Table 1 Laboratory tests in PBC

Test Finding Suspicion Diagnosis Prognosis

Biochemical

ALP ↑ x x x AST/ALT ↑ x x GGT ↑ xPrimary immunology

IgM ↑ x AMA (>1/40) + x Specific ANA + xSecondary immunology

Anti-centromere + xLiver function

Bilirubin ↑ x INR ↑ x Albumin ↓ xPortal hypertension

Platelets ↓ x↑, increasing values; ↓, decreasing values; +, serologic positivity; x, poorer prog-nosis; ALP, alkaline phosphatase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, gamma-glutamyltranspeptidase; IgM, immunoglobulin M; AMA, antimitochondrial antibodies; ANA, antinuclear antibodies; INR, international normalised ratio


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prominently on the palms and soles and worsening at night. Bile salts and endogenous opioids may play a role in the development of pruritus. Lysophosphatidic acid (LPA), a potent neuronal itch activator mostly formed by the lysophospholipase enzyme auto-taxin (ATX), may also play a role. In PBC, an unknown biliary fac-tor may increase ATX, thus increasing LPA. Data indicate that, in PBC patients, serum ATX activity correlates with itch intensity and response to anti-pruritic treatments [71]. Recent animal data led to a postulate that itch may be caused by bile salt activation of TGR5, a plasma membrane receptor expressed on sensory neurons [72].

A patient with PBC presenting with suspected pruritus needs to be evaluated for skin lesions and, if necessary, referred to a derma-tologist to rule out other conditions. Administering questionnaires like the grading scale, VAS, PBC-40 questionnaire, and 5D itch scale can be useful in grading itch severity [72]. In patients with pruritus not conforming to the classic cholestatic pattern an assay for serum bile acids may help determine if the itching is likely due to liver disease.

Treatment of pruritus is important in PBC patients in order to improve mood, quality of sleep, and social functioning. AASLD and EASL guidelines recommend a number of non-pharmaco-logic interventions to manage pruritus [4, 5]. Recommended medications for pruritus are listed in Fig. 4; however, the following is based on the opinions of this panel regarding these treatments. Anion exchange resins may need to be given twice daily and dosed separately from other drugs by 4 hours. If cholestyramine is not tolerated, colesevelam is an option, but data are limited on its use in PBC. A small, randomized controlled trial comparing colesevelam hydrochloride (taken orally as three 625-mg tablets twice daily) versus placebo demonstrated decreases in serum bile acid levels but no improvement of pruritus in patients receiving colesevelam [73]. Rifampicin is effective, but risk of liver toxicity requires mon-itoring of liver function tests and the patient must be informed of the hepatic risks. Expert opinion varies with regard to the use of rifampicin; some avoid it because of the risk of liver toxicity while others consider the benefit:risk profile favorable especially in patients with severe itching and when other treatments have failed. Other drugs are available, such as naltrexone and sertra-

line, but the evidence base for these drugs is not strong. Although used in clinical practice, there is not a great deal of strong evidence supporting the use of antihistamines for the treatment of pruritus. Nevertheless, antihistamines such as hydroxyzine may have non-specific antipruritic effects in patients with cholestasis, which may result from their sedative properties. The resultant sedative effects may help patients sleep, but antihistamine-associated mucosal drying may limit use in PBC patients [5]. Finally, it is impor-tant to point out that UDCA does not relieve pruritus and may exacerbate it [72].

Recent advances in the understanding of bile acid physiology and pathophysiology of cholestatic pruritus have led to the devel-opment of novel therapies to treat pruritus in PBC. The main class of drugs being investigated in clinical trials is apical sodium-dependent bile acid transporter (ASBT) inhibitor (also called ileal bile acid transporter (IBAT) inhibitor). In addition, anecdotal observations suggest that fibrates improve itch in some patients with PBC. Inhibiting ATX or blocking the LPA receptors could also improve pruritus, but clinical trials aimed at these targets have not been performed [72].

FatigueIn patients with PBC and fatigue, it is important to exclude or identify and manage potential causes of fatigue such as anemia [74], depression [74], sleep disorders [74], hypothyroidism [74, 75], and medications that can cause or contribute to fatigue (such as excessive antihypertensive medications) [4]. Patients should be encouraged to maintain regular physical activity [76]. Modafinil 100–200 mg has been used, but evidence is limited. An open label trial on the use of modafinil in PBC patients demonstrated efficacy in 42 patients given a 3-day trial of 100–200 mg modafinil. During the initial trial period, 31 (73%) patients had complete response, which was defined as increased energy, decreased somnolence and sleep requirements, and improved daily function. In long-term follow-up (average 17.7 months), 25 (81%) patients continued to take 100–200 mg of modafinil daily [77]. It is important to discuss the side effects of modafinil, such as fever, sore throat, headache, vomiting,

Cholestyramine up to 4g × 4dayMorning and afternoon doseSeparate 4 hours from other drugsColesevelam if other not tolerated

Drug induced hepatitis in up to 12%Monitor especially first 2 months

Monitor for (infrequent) hepatotoxicity

Has not lived up to early hopes

Rifampicin 150 mg/day

Increase up to 60 mg/day every other week

Naltrexone up to 50 mg/day

Sertraline up to 100 mg/day

Consider transplantation

Extracorporeal albumin dialysisPlasmapheresis

MARScommon bile duct drainage

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 effects, with patients. After proper discussion of risks and benefits, modafinil may be very selectively considered for some patients with severe fatigue in PBC.

hEPatIc coMPlIcatIons of PBcPBC typically progresses slowly and can lead to cirrhosis and related complications though progression from cholestasis to cirrhosis to liver-related morbidity/mortality can vary amongst patients. This guidance underscores the point that untreated patients are at increased risk for disease progression. Longitudi-nal studies have shown that in the absence of effective treatment, the median time to development of extensive fibrosis was 2 years. After 4 years, the probability of remaining in the early stage was only 29% (confidence interval: 15–52%). In addition, 50% of PBC patients, who initially had only interface hepatitis without fibro-sis, progressed to cirrhosis [78–80].

Recent studies suggest that patients are increasingly being iden-tified at an early stage of the disease and a minority of (~15%) of patients have evidence of advanced disease at presentation [81, 82]. Furthermore, treatment with UDCA is associated with slower histologic progression compared to untreated patients [83, 84]. Nevertheless, the cumulative incidence of cirrhosis over 10 years has been estimated to be ~40% [85]. Since a substantial propor-tion of PBC patients have or will develop cirrhosis, they remain at risk for cirrhosis-associated complications, including esophageal varices, ascites, and hepatic encephalopathy. As in other chronic liver diseases, development of hepatic complications is associated with poor prognosis [86].

Impact of hepatic complications on morbidity and mortalityLiver-related complications primarily occur in patients with cir-rhosis, but bleeding from esophageal varices may occasionally develop in patients without cirrhosis. In contrast to other liver diseases, portal hypertension may also develop in patients with pre-cirrhotic PBC. Although liver function is normal or near normal in these patients, esophageal varices, gastric varices, or portal gastropathy may develop. Nodular regenerative hyperpla-sia is associated with obliteration of the portal venules and may lead to portal hypertension in some of these patients [87, 88]. Patients with complications of portal hypertension in the absence of cirrhosis may require endoscopic or radiologic management of their varices and can survive for many years without liver transplantation [87, 89].

Prognostic models assess risk of complicationsSeveral prognostic models have been developed and validated for use in patients with PBC. As previously discussed, the Mayo score has been extensively validated and considered as the classic prog-nostic model for survival in untreated PBC patients. In addition, multiple models such as the Rotterdam criteria [90], Barcelona criteria [91], Paris I criteria [92], Paris II criteria [82], and Toronto criteria [93] are available to identify the risks of developing com-plications such as cirrhosis, HCC, and mortality. However, these

risks are stratified based on treatment response, which will be dis-cussed in subsequent paragraphs [94].

Hepatocellular carcinomaIn comparison to patients without cirrhosis, patients with PBC have an increased risk of HCC in the setting of cirrhosis. The inci-dence of HCC has been estimated to be approximately 0.35 per 1000 person years; male gender and advanced histological stage are risk factors for HCC in PBC [95]. A systematic review and meta-analysis suggested that PBC patients with cirrhosis have an 18-fold increased relative risk of HCC [96].

A study from Japan suggested that men with PBC might have an increased risk of HCC even in the absence of cirrhosis [97]. A recent study of UDCA confers a higher risk of HCC in PBC patients; of 4565 patients with PBC, 123 developed HCC, yield-ing an incidence rate (IR) of 3.4 cases/1000 patient-years. HCC was significantly more common in men (p < 0.0001), patients with advanced disease and hepatic decompensation (HR 9.89, p < 0.0001). Nonresponse to UDCA based on the Paris I crite-ria was the most significant factor predictive of future HCC risk (adjusted HR 3.44, p < 0.0001) [98].

These data suggest that HCC surveillance is appropriate in PBC patients with cirrhosis. This is especially important in men and those with a biochemical non-response to UDCA and may improve outcomes in PBC [99]. All patients with PBC and cirrho-sis (F4) should undergo surveillance for HCC using ultrasonogra-phy every 6 months. Surveillance of PBC patients with earlier stage of liver disease (i.e., F3) may be considered for men and those with additional risk for HCC (family history of HCC).

Management of hepatic complications in PBCThe management of liver-related complications in PBC is the same as the management for patients with advanced liver dis-ease related to other types of chronic liver diseases. For example, screening for esophageal varices and HCC as well as their man-agement in cirrhotic patients with PBC should be carried out according to the AASLD and ACG guidelines [5].

Extra-hEPatIc coMPlIcatIons of PBcMetabolic bone diseasePatients with PBC have an increased incidence of osteoporosis (14–52%), osteopenia (30–50%), and risk of fractures. Major risk factors for osteoporosis in PBC include severe cholestasis and advanced histological stage, but patients with less advanced dis-ease can also be affected. Post-menopausal women are at particu-lar risk [100–102].

Bone mineral density (BMD) should be assessed at baseline and every 2 years in PBC patients depending on the severity of osteoporosis at baseline and the severity of cholestasis which could negatively impact bone disease. Various authors and guidelines have made different recommendations regarding the use of cal-cium and vitamin D in patients with PBC. The most recent EASL guidelines state that patients with normal nutrition and absence of features of calcium malabsorption do not need calcium supple-


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mentation, and vitamin D can be supplemented as indicated by serum levels [4]. In contrast, the recent AASLD Guidance docu-ment suggests that all patients with PBC should be provided 1000 to 1500 mg of calcium and 1000 International Units of vitamin D daily in the diet and as supplements if needed [5]. The panel believes that strong evidence supporting these specific recommendations are lacking and clinicians are advised to check vitamin D levels at least annually and provide vitamin D and calcium supplemen-tation accordingly. Patients should also be counseled on smoking cessation, limited or no alcohol consumption, and weight-bearing activities as recommended by primary care guidelines.

Pharmacological therapy is recommended for patients with the highest risk of fracture, as indicated by BMD score and clini-cal risk factors. Patients with a T score ≥ −2.5 should be treated; while treatment of patients with T scores between −1.0 and −2.5 are more controversial. Drug choices are the same as those used in post-menopausal osteoporosis and data on their use in PBC are available. Bisphosphonates are indicated for osteoporosis, but if esophageal varices are present other classes of drugs should be used. In a study by Zein et al., PBC patients were randomized to alendronate 70 mg/week (n = 17) or placebo (n = 17). Alendronate patients demonstrated significant improvement in BMD of the lumbar spine and proximal femur as compared to placebo, with similar safety demonstrated in both groups [103]. Another study randomized 42 patients to monthly ibandronate (150 mg; n = 14) and weekly alendronate (70 mg; n = 19) for 2 years and showed similar improvements with either medication in both lumbar spine and hip density, comparable safety, but better adherence to the monthly ibandronate [104]. Finally, raloxifene 60 mg/day was administered for 1 year to 7 post-menopausal PBC patients. Each patient was compared with three age-matched controls. Femoral neck BMD remained stable with a statistical trend in improvement in the lumbar spine BMD versus placebo [105].

HyperlipidemiaHyperlipidemia is common in PBC; in early disease, 75% of patients have total cholesterol levels >200 mg/dL. Mild eleva-tions in low-density lipoproteins (LDL) and marked elevations in high-density lipoproteins (HDL) are common which tend to decline over time, though still often remaining high in the normal range or above normal. Conversely, late stage disease is associated with marked LDL elevations, which may in part be attributable to a decline in functional LDL receptors [106–108]. However, in patients with advanced PBC, increases in cholesterol levels are mostly attributable to increased levels of lipoprotein-X (LP-X), an abnormal lipoprotein particle within the LDL density region that is rich in free cholesterol and phospholipids. LP-X inhibits oxida-tion of normal LDL, thereby reducing the risk of atherosclerosis [109]. Although LP-X levels can be measured by lipoprotein elec-trophoresis, this is rarely performed. Therefore, in PBC patients there is often uncertainty with individual patients as to whether increases in LDL are in fact true increases or if they represent the de novo appearance of increased LP-X.

Alloca et al. studied 103 patients with PBC (37 with total cho-lesterol ≥ 6.21 mmol/L), 37 controls with hypercholesterolemia,

and 141 matched controls with normal serum cholesterol for signs of subclinical atherosclerosis. The investigators concluded that hypercholesterolemia is not consistently associated with sub-clinical atherosclerosis in PBC, but patients should be treated for high cholesterol if other cardiovascular risk factors are present [110]. In a 6-year study of 400 PBC patients, marked hypercholes-terolemia was not associated with an excess risk of cardiovascular disease, but hypertension did increase the risk of cardiovascular events [107]. Given the ubiquitous nature of risk factors for car-diovascular disease in the US population, the panel agreed that the usual criteria for treating hypercholesterolemia are appro-priate to apply to PBC patients. However, clinicians should be mindful that in early PBC, elevated total cholesterol levels may be attributed to elevated HDL rather than elevated LDL. Further-more, in more advanced liver disease, LP-X, which is measured as LDL on routine assays of cholesterol, may be largely responsible for elevated LDL levels. At present, hypertension appears to be the most important risk factor for cardiovascular disease in PBC patients.

Data on atorvastatin [111] and simvastatin [112] indicate that these drugs are safe and effective for use in PBC. A recent meta-analysis has demonstrated that patients with cirrhosis from any cause who are taking statins chronically had a 46% lower risk of either hepatic decompensation or mortality [113].

Sicca syndromeSicca syndrome is common in patients with PBC. This syndrome is associated with dry eyes, dry mouth, vaginal dryness/dyspareu-nia, an increased frequency of oral candidiasis, and extra-glan-dular symptoms (i.e., fatigue, arthralgias, myalgias, cytopenias, peripheral neuropathy, vasculitis, Raynaud’s phenomenon). It is important to note that dry mouth can be associated with dental caries and require treatment. Dry eyes can be managed with arti-ficial tears, artificial saliva preparations are available to treat dry mouth and moisturizers recommended by primary caregivers can be helpful for vaginal dryness. Pilocarpine, a cholinergic agonist, may be effective for Sicca syndrome. For those who are refractory to artificial tears, the AASLD Guidance document recommends considering the use of pilocarpine or cevimeline and even cyclo-sporine or lifitegrast ophthalmic emulsion under the supervision of an ophthalmologist [5].

Additional extra-hepatic manifestations of PBCDecreased bile acid secretion may lead to impaired absorption of the fat-soluble vitamins A, D, E, and K [114]. Clinicians should be aware of potential fat-soluble vitamin deficiencies in patients with PBC and supplementation should be considered on an individual basis.

Clinicians need to be mindful that PBC is also associated with scleroderma, mixed connective tissue disease, or CREST syn-drome. If a patient presents with these disorders, and elevated liver tests, PBC should be ruled out. Conversely, PBC patients should be questioned and examined for features of such signs and symp-toms of Raynaud’s syndrome, dysphagia, reflux, sclerodactyly, and telangiectasias.


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orthotoPIc lIvEr transPlantatIon In PBcIn the mid-1980s, PBC was the leading indication for orthotopic liver transplantation (OLT) in the United States. Over time, the number of patients with PBC requiring transplant has declined by about 20%, mostly due to effective treatment. The outcome of liver transplant is more favorable in patients with PBC than for almost all other disease categories. Indications for liver transplan-tation for PBC are no different from those of other etiologies of cirrhosis. PBC may recur after OLT in ~20% of patients; rates may vary depending on diagnostic criteria and may also be associated with increasing AMA titers post OLT [2, 5]. With PBC, severe treatment-resistant pruritus and/or severe hepatic encephalopa-thy may also merit consideration for transplantation [115].

There are unique post-transplant factors regarding PBC. Follow-ing OLT, osteopenia may worsen for the first 6 months, yet BMD returns to baseline after 12 months and improves thereafter. Fur-thermore, there are reports showing patients transplanted for PBC suffer more frequently from acute cellular rejection. It has also been reported that patients transplanted for PBC have one of the highest risks of late acute rejection [116]. However, chronic rejection and graft loss are not more common. Regarding recurrent PBC post-OLT, cyclosporine-based anti-rejection regimens seem to be asso-ciated with reduced incidence and prolonged time to recurrence as compared to tacrolimus-based regimens [117, 118]. Preventive administration of UDCA after liver transplantation for PBC may also be beneficial. In a retrospective study that evaluated 90 PBC patients with a 1-year minimum follow-up, 21% received UDCA. Recurrence was diagnosed in 48 (53%) of these patients and pre-ventative UDCA was the only factor that significantly decreased the risk of recurrence [119]. Another retrospective study suggested that UDCA reduced the rate of recurrence of PBC post-transplant, but there was no impact on survival. Additional data demonstrated that UDCA administration post-OLT improved ALP levels but did not improve survival [120]. Prospective trials that help deter-mine optimal methods to diagnose post-OLT PBC and who may benefit from treatment are needed. Despite the lack of evidence supporting improvement in post-OLT survival, there seems to be some biochemical and disease prevention benefits with treatment. Therefore, it is the opinion of this panel that it is reasonable to give UDCA to patients post-OLT.

trEatMEnt of PBc: old and nEwRecently, a large database of comprehensive and continuous elec-tronic medical records claims data from over 500 US healthcare practices or systems were examined. Adults with PBC comprised 36,317 patients in the database and, after applying exclusion criteria, 15,875 patients were included in the final PBC cohort. The average patient age was 63.0 ± 13.5 years, 78% were female, 57% had other autoimmune diseases, and 46% had cirrhosis. 6083 (38%) had a more progressive course of PBC, indicated by ALP ≥ 1.5×ULN. In a multivariate analysis, older age, female gender, the presence of other autoimmune diseases, and having compensated or decom-pensated cirrhosis were independently associated with having ALP ≥ 1.5×ULN. The authors concluded that, patients with these

characteristics should be more carefully monitored and treated to reduce their chances of progression [121].

Both EASL and AASLD recommend that therapy in PBC should prevent disease progression, complications of cirrhosis, and man-age associated symptoms of the disease [4, 5]. Over the past four decades a number of therapeutic agents including azathioprine [122], chlorambucil [123], prednisolone [123], cyclosporine [124], and colchicine/methotrexate [125] have been evaluated for the management of PBC. Some of these agents, particularly the immu-nosuppressants, did show some efficacy but side effects limited their use. Currently two drugs are approved for the treatment of PBC: UDCA and obeticholic acid (OCA).

Ursodeoxycholic acidUDCA is a naturally occurring hydrophilic and non-toxic bile acid. UDCA was initially developed and was first FDA approved to dissolve gallstones. It was subsequently noted that patients who received UDCA had a decline in their ALP. This observation led to clinical trials of UDCA for the treatment of PBC [126]. Bile acids are detergents and therefore dissolve cell membranes and cause cell lysis. In contrast, the hydrophilic properties of UDCA make this a non-toxic bile acid that does not cause cell lysis [127]. When patients are treated with UDCA, the bile acid pool becomes enriched with this less toxic bile acid [128].

The first study using UDCA to treat PBC demonstrated that the levels of GGT, ALP, AST, and bilirubin were all reduced by 36–78% [129]. This led to the first randomized, controlled study of UDCA vs placebo in patients with PBC. Patients treated with UDCA (13 to 15 mg/kg/day; n = 73) for two years had significant improve-ments in serum levels of bilirubin, ALP, ALT, AST, GGT, and IgM (all P < 0.001). A significant improvement in mean liver histol-ogy score, inflammation, and bile duct injury was also observed in patients treated with UDCA. The long-term benefits of UDCA were later analyzed in this patient population and it was established that PBC progressed significantly less frequently in patients who were treated with UDCA when compared to placebo (P < 0.002; relative risk, 0.28; 95 percent confidence interval, 0.12 to 0.63). In addition, the probability of death or liver transplantation were sig-nificantly lower in the UDCA group vs the placebo group [130].

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 effective when initiated early in the course of the disease. In one study, patients treated with UDCA were com-pared to matched controls by assessing survival as predicted by the Mayo model. The study showed that good biochemical response after 1 year, defined as a 40% reduction in ALP from pre-treatment baseline, was associated with a survival similar to that estimated for the matched control population (P = 0.15). By contrast, the survival of patients without biochemical response was lower than that estimated for controls (P < 0.001). Patients with a total biliru-bin of <2 mg/dl and mild fibrosis had a greater decline in serum ALP and greater histologic improvement than patients with a bili-rubin > 2 mg/dl and more advanced fibrosis or cirrhosis. Major complications of liver disease, progression to liver transplantation or death, occurred in 10.5% and 76.6%, respectively, in patients


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who had an entry serum bilirubin of <2 or ≥2 mg/dL [91]. These results indicate that higher bilirubin levels predict greater disease progression and that initiating treatment too late has minimal impact on slowing disease progression [128].

UDCA is safe and has limited side effects. The most common complaint experienced by patients with or without cirrhosis is itching, which occurs in about 2% of patients, and diarrhea, which occurs at a similar rate (2%). Based on these data, the panel recom-mends the use of UDCA, at a dose of 13–15 mg/kg/day, as first-line treatment for patients with PBC. Higher doses of UDCA have not shown to be effective in PBC and should not be used.

PrognosIs In udca-trEatEd PatIEnts wIth PBcA recent long-term, international study by Harms and colleagues sought to describe the incidence of cirrhosis-associated complica-tions in patients with PBC and assess risk factors and impact on survival. Patient data from 15 liver units across 10 countries in Europe and Northern America participating in the Global PBC Study Group were included. The study population comprised 3224 UDCA-treated patients (91% female; 73% in early biochemical disease stage). Over 8.1 median years of follow-up, ascites, variceal bleeding and/or encephalopathy were noted in 278 patients (inci-dence rate of 9.7 cases/1000 patient years). The overall cumula-tive incidence of major non-neoplastic hepatic complications was 9% after 10 years and 15% after 15 years which was a reduction in hepatic complications as compared to previous decades. The 10-year transplantation-free survival after a complication was 9% (time-dependent hazard ratio 21.5; 20.1–22.8). Patients with both biochemical non-response and an aspartate aminotransferase to platelet ratio index (APRI) > 0.54 after 12 months of UDCA had a 10-year complication rate of 37.4%, as compared to 3.2% in biochemical responders with an APRI ≤ 0.54. Therefore, both biochemical non-response after 1 year of UDCA and an APRI of >0.54 were determined to be independent predictors of future hepatic complications [86].

The panel feels that these data confirm many important points on early diagnosis and treatment in PBC. First, hepatic complica-tions are of critical importance in the clinical course of the disease and are predictive of poor survival. Furthermore, the decreasing incidence of major hepatic complications may demonstrate the value of earlier diagnosis and treatment with UDCA [86]. Also, other developments, such as timely detection and widespread pri-mary prophylaxis of variceal bleeding, may have contributed to a decreasing incidence of complications [86].

Most predictive models are based on single center data, but the recent GLOBE score, proposed by Lammers et al., is based on data from multiple international cohorts of more than 4500 patients with PBC. The GLOBE score assesses the transplant-free survival of patients receiving UDCA therapy. Therefore, this is a more generalizable PBC predictive model that incorporates age at the time of initiating UDCA therapy, serum ALP, total bilirubin, albumin, and platelet counts. The GLOBE score formulates the risk of liver transplantation or death as a function of serum ALP and total bilirubin after 1 year of UDCA treatment [132]. GLOBE

is the most widely cited, clinically relevant international study of PBC. As such the GLOBE score has become the most frequently used predictive model in PBC and is now being validated in other clinical research settings.

In addition to GLOBE and its predictive models, a number of other scoring systems have been used for patients with PBC. In this context, Mayo PBC scoring has been quite useful, especially in patients being considered for liver transplantation. Additionally, the prognostic MELD model has become the standard scoring sys-tem for listing patients for liver transplant and is used in all candi-dates for liver transplantation, including those with PBC.

Assessment of response to UDCA treatment in patients with PBCAs noted previously, over the past decades, a number of groups have developed algorithms or predictive scoring models to deter-mine if a patient with PBC has had adequate response to treat-ment (Table 2).

As the information in the table indicates, there is lack of agree-ment on the exact definition of non-response. Nevertheless, a number of common themes have emerged supporting biochemi-cal response (decrease in ALP) as the most important surrogate for defining response to treatment. As previously noted, some of

Table 2 Scoring systems predicting non-reponse to UDCA

Scoring Systems Predicting Non-Reponse to UDCA

UK-PBCa Bilirubin, ALP, and AST or ALT at 12 months. Albumin and platelet count at baseline

GLOBEb Bilirubin, ALP, albumin, and platelet count at 12 months. Age at baseline

Non-response after 6 months of treatment with UDCA

Rochesterc ALP≥2 × ULN or Mayo score ≥ 4.5

Ehimd Decrease in GGT ≤ 70% and GGT ≥ 1 × ULN

Non-response after 12-24 months of treatment with UDCA

Barcelonae Lack of decrease in ALP ≤ 40% and ALP ≥ 1.0 × ULN

Paris-If ALP ≥ 3 × ULN or AST ≥ 2 × ULN or bilirubin >1.0

Rotterdamg Bilirubin ≥ 1 × ULN and/or albumin < 1 × ULN

Torontoh ALP >1.67 × ULN after 2 years on UDCA

Paris-IIi All three of the following: ALP > 1.5 × ULN, AST > 1.5 × ULN, bilirubin > 1 mg/dl after 1 year on UDCA

aUK-PBC Risk Score Calculator [143]bLammers et al. [81]cAngulo et al. [144]dAzemoto et al. [145]eParés et al. [91]fCorpechot et al. [92]gKuiper et al. [90]hKumagi et al. [93]iCorpechot et al. [84]jALP, alkaline phosphatase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; UDCA, ursodeoxycholic acid; ULN, upper limit of normal; GGT, gamma-glutamyltranspeptidase


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these have been used in designing the most recent clinical trials for patients with PBC (ALP of 1.67 × ULN). It is important to note that a study of 5000 patients with PBC suggested that any increase in ALP is associated with increased adverse outcomes [133]. In this context, one can argue that the clinical goal of treatment should be to normalize ALP. In fact, a lower threshold of ALP > 1.5 × ULN has been favored by some experts [4].

It is the opinion of the panel that the goal of treatment is to achieve a serum ALP level as close to normal as possible. Second-line therapies (such as OCA) may be considered in patients who have persistent elevation of serum ALP despite an adequate trial of UDCA therapy. However, the decision to add a second agent should consider the absolute level of ALP elevation, serum biliru-bin level, stage of disease, and the risks and benefits of second-line treatments.

Criteria for adding a second agent may include:

• Persistently elevated serum ALP after 12 months of therapy with UDCA

• Lack of normalization of bilirubin after 12 months of therapy with UDCA

• High risk using available predictive models (UK-PBC, GLOBE PBC)

• Evidence of fibrosis progression by any modality (TE, MRE, histology or clinically) while on UDCA. Progression to cir-rhosis by any definition will be considered as non-response.

Obeticholic acidThe farnesoid X receptor (FXR), a ligand-activated transcription factor and a member of the nuclear receptor superfamily, is highly expressed in the liver, intestine, adrenal glands, and kidneys [134]. As a transcription factor, FXR induces the small heterodimer partner (SHP, gene symbol NR0B2/Nr0b2) in the liver that down-regulates the expression of cholesterol 7α-hydroxylase (CYP7A1/Cyp7a1) and sterol 12α-hydroxylase (CYP8B1/Cyp8b1) genes. These genes encode enzymes that synthesize bile acids from cho-lesterol. Therefore, FXR is a critical regulator in bile formation and enterohepatic circulation and as such plays a crucial role in bile acid homeostasis and hepatic regeneration, among other things [135]. OCA is a bile acid analog, derived from the primary human bile acid chenodeoxycholic acid, and is a highly selective, natural ligand for FXR [136]. Administration of OCA results in decreases in bile salt synthesis, uptake and absorption; reduction in cytokines associated with inflammation; and reduction in hepatic fibrogen-esis. A common misconception is that OCA is “super-UDCA”. This is not the case, since these drugs have different mechanisms of action. Unlike OCA, UDCA has no effect on the FXR.

A 12-month, double-blind, placebo-controlled phase 3 trial was conducted to assess the long-term efficacy, safety, and adverse event profile of OCA in patients with PBC. Two-hundred and six-teen patients who had an inadequate response to UDCA (defined as ALP ≥ 1.67 × ULN or bilirubin > 2 × ULN) or were intolerant of UDCA were randomly assigned to receive 10 mg OCA, 5 mg OCA (with adjustment to 10 mg if applicable; the 5–10 mg group) or placebo. A total of 93% of patients took UDCA at baseline and

throughout the trial. The primary endpoint, an ALP < 1.67 × ULN (with a reduction of at least 15% from baseline) and a normal total bilirubin level, occurred in significantly more patients in the 5–10-mg group (46%) and the 10-mg group (47%) than in the pla-cebo group (10%; P < 0.001 for both comparisons). Response to OCA was rapid, as significant differences were observed between each OCA group and the placebo group by week 2 and at each time point thereafter (P < 0.001 for all comparisons). Decreases were significantly greater in patients in the 5–10-mg group and 10 mg group than in the placebo group for ALP levels (−113 and −130 U/L, respectively, vs. −14 U/L; P < 0.001 for both compari-sons) and total bilirubin levels (−0.02 and −0.05 mg/dL [−0.3 and−0.9 μmol/L], respectively, vs. 0.12 mg/dL [2.0 μmol/L]; P < 0.001 for both comparisons) [131].

Pruritus was the most common adverse event across all groups, 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 pruritus was reported more often in the 10-mg group (23%) and 5–10-mg group (19%) than in the placebo group (7%). Severe pruritus was defined as intense or widespread itching, interfering with activities of daily living, or causing severe sleep disturbance, or intolerable discomfort, and typically requiring medical inter-ventions [131]. It is important to point out that the most common adverse effect with UDCA is also pruritus, but, as mentioned pre-viously, it occurs at a lower rate.

Based on these data, the FDA granted accelerated approval in May 2016 for OCA 5–10 mg orally once daily for the treatment of PBC in combination with UDCA in adults with an inadequate response to UDCA, or as a single therapy in adults unable to toler-ate UDCA. Prescribers need to be aware of liver-related adverse reactions, specifically jaundice, worsening ascites and PBC flares, that have been observed in doses exceeding 10 mg.

Dosage adjustments were not being followed in patients with hepatic impairment, so an increased risk of serious liver injury and death was being observed when these patients were admin-istered OCA. Therefore, in September of 2017, the FDA issued a black-boxed warning on OCA that reiterates that the recom-mended starting dosage of OCA is 5 mg once weekly for patients with Child-Pugh Class B or C hepatic impairment or a prior decompensation event. After the first 3 months, this dose can be increased to a maximum of 10 mg twice weekly (at least 3 days apart) [137].

The expert panel feels that OCA should be used in PBC patients with inadequate response or intolerant to UDCA. The panel also emphasizes the importance of close monitoring of patients with PBC who are being treated with UDCA and OCA, especially those with severe hepatic impairment, as delineated by the new FDA warning. Although pruritus can be seen with OCA, it is the expert opinion of the panel that developing pruritus with UDCA does not predict that this will also occur during OCA treatment.

In addition to those with inadequate response, the panel feels that patients with UDCA non-response, as defined above, need to be considered for addition of OCA to the treatment regimen. This should be done after careful consideration of risk and benefits of additional treatment. Finally, the panel feels that the addition


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of OCA to those individuals who are considered as “suboptimal responders” should be individualized on a case-by-case basis until further evidence becomes available.

It is also important to consider the financial impact of new drugs such as OCA. In this context, the cost effectiveness of an optimal treatment strategy of UDCA followed by OCA for the appropri-ate group of patients with PBC must be considered. These types of economic analyses should not only include the most relevant cost data but also the most realistic transition rates and health utility data. Although some preliminary data has been published, more in-depth and robust models are needed [138].

Future treatments for PBCThe lipid-lowering agent, bezafibrate, has gained attention over the last few years as a potential treatment for PBC, in combination with UDCA, for patients refractory to UDCA therapy [139, 140]. The most recent data on bezafibrate, presented at the 2017 AASLD annual meeting, demonstrated that 2 years of combined bezafi-brate/UDCA treatment resulted in normalization of biochemical prognostic markers, improvement in pruritus, and prevention of worsening liver stiffness in PBC patients with inadequate response to UDCA [141]. However, because phase 3 trials have not been completed and since there is not regulatory approval for use in PBC, the panel does not currently recommend its routine use in patients with PBC [4]. A smaller body of data exists for fenofibrate but again is insufficient to warrant a recommendation for use in PBC. The panel also observes that the use of these drugs can be associated with increases in serum transaminases and the risk of myopathy and rhabdomyolysis, especially in patients with renal insufficiencies [142].

Treatment algorithm for PBCAfter establishing PBC as previously described, patients should be started on UDCA (Fig. 5). Those with advanced liver disease should also be evaluated for liver transplantation. For those patients with evidence of PBC and autoimmune features of the overlap syn-drome, treatment of AIH must be undertaken concurrently.

After 6–12 months of treatment with UCDA, for those who have inadequate response, addition of OCA (appropriately dosed for liver disease) should be undertaken. Additionally, in patients who are intolerant to UDCA for any period of time, OCA mono-therapy is recommended. The panel also feels that the expansion of the definition of non-response beyond ALP > 1.67 × ULN may be justified and addition of OCA to the regimen may be considered after a risk-benefit discussion with patients. Additionally, lower-ing the threshold of inadequate response to ALP > 1.5 × ULN or reducing the duration of use for UDCA to 3 months have been considered by some members of the panel. However, until further evidence is provided, the panel recommends ALP > 1.67 × ULN and 6–12 months for assessment of inadequate response to UDCA. Finally, the addition of OCA to those individuals who are considered as suboptimal responders should be considered on a case-by-case basis. Individuals who are inadequate responders to both UDCA and OCA should be considered for clinical trials of new agents for PBC.

In addition to medical treatment, all other preventive and screening issues that are applicable to all patients with chronic liver disease must be considered (e.g., screening for HCC and varices, immunization against hepatitis A and hepatitis B viruses, optimizing body weight, minimizing alcohol consumption). Addi-tionally, there are PBC-specific issues related to bone disease, pru-ritus, Sicca syndrome and dyslipidemia that must be managed, as described in this review.

Answers to commonly asked treatment questionsWhat if side effects are a treatment concern? If there are con-cerns about side effects from PBC treatment, it is always better to start treatment at half the dose, especially in patients with advanced liver disease.

If a patient is stable on UDCA, can the dose be lowered? If a patient is stable on UDCA for the long-term, there are no data to support lowering the dose. It is the opinion of this panel that the effective dose should be maintained.

When can OCA be administered? Based on clinical trials, OCA can be added when the ALP remains >1.67 × ULN 6 months after initiating UDCA. Although some consideration can be given to extend the duration of initial treatment to 12 months [5], the panel members recognize that most responders to UDCA will be evi-dent after 6 months of treatment. On the other hand, prolonging this initial trial period to 12 months may also seem reasonable and should be considered on a case-by-case basis. Furthermore, if patient has already been on a stable dose of UDCA for a longer period of time but meets this ALP threshold, OCA can be added. Finally, if any patient with PBC is intolerant to UDCA, monother-apy with OCA is indicated.

Should transient elastography, such as FibroScan, be used for treatment selection? TE or other non-invasive assessments of fibrosis should not be used as a means to select patients for initial treatment. The data strongly suggest that UDCA is most effective in patients with mild fibrosis and a total bilirubin < 2.0 mg/dl. There-fore, even patients with early stage PBC should be treated with UDCA. Even in the absence of any evidence for cirrhosis, a base-line FibroScan is helpful to assess the degree of fibrosis and to serve as a basis for future comparison. The optimal frequency of repeat testing with FibroScan is not known and may be individualized. In some cases, longitudinal elastography may be useful as an adjunct to biochemical monitoring in patients with suboptimal response of ALP to assess whether treatment with OCA is warranted.

Should patients with established or suspected cirrhosis be handled differently than non-cirrhotic patients? Yes. Cirrhotic patients with advanced liver disease must be treated with OCA according to the FDA’s recommendation. These patients must also be screened for HCC and screened for esophageal varices accord-ing to the established guidelines. Also, depending on age and Mayo risk score, some cirrhotic patients should be considered for liver transplantation.

How should Overlap Syndrome be treated? Patients require a liver biopsy to confirm Overlap Syndrome. If the histology is consistent with PBC, then UDCA needs to be initiated. On the other hand, if the biopsy suggests AIH, then treat AIH. Overlap


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syndrome should be treated based upon liver histologic findings, not by serologic or biochemical results.

Summary and top-line recommendations• Given the importance of early diagnosis, all patients present-

ing with cholestatic elevation of liver enzymes should be eval-uated for PBC.

• The panel recommends that PBC can be diagnosed if: 1. Scenario 1: Chronic elevation of ALP with a positive

AMA (immunofluorescent assay titer of >1:40 or EIA > 25 u) in the absence of other liver diseases and systemic diseases

2. Scenario 2: Chronic elevation of ALP with negative AMA and ANA tests but a liver biopsy that shows non-

suppurative destructive cholangitis and destruction of in-terlobular bile ducts.

3. Scenario 3: Chronic elevation of ALP with negative AMA but positive PBC specific ANA (sp-100, gp-210) tests (these tests are not widely available in the US).

• Given the importance of establishing the stage of liver disease and prognosis, the panel recommends calculating the Mayo score for all PBC patients.

• The panel recommends that patients with advanced liver dis-ease should also be screened for HCC, esophageal varices and, depending on their age and Mayo risk score, some should be considered for liver transplantation. Other preventive steps for advanced liver disease in patients with PBC must be con-sidered according to guidelines.

ALP/GGT Alternate diagnosisBilary tract obstruction/pathologyDrug-induced liver injuryPrimary sclerosing cholangitisProgressive familial intrahepatic cholestasisBenign recurrent intrahepatic cholestasis

HistoryExaminationImaging (US, MRCP)

AMA

ANA

Liver biopsy

Screen for varices

Overlap syndromeor PBC with autoimmune features

Cirrhosis?

UDCA

Goodresponse

Goodresponse

Goodresponse

Poorresponse

Consider clinical trials AppropriatelydosedOCA

ALP>1.67

ALP>1.67and/or progressiveliver disease

LT evaluation

Decompensated>Child’s B

UDCA

OCA

HCCsurveilance

Yes

Compensated

No

Consider glucocorticoids± azathioprine; UDCA

PBC diagnosisestablished

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;HCC, hepatocellular carcinoma; LT, liver transplantation.

Fig. 5 Algorithm for the Diagnosis and Treatment of PBC 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; HCC, hepatocellular carcinoma; LT, liver transplantation


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• PBC patients with features of AIH may require a liver biopsy. The panel recommends that if the histology is consistent with PBC, then UDCA needs to be initiated. On the other hand, if histology is consistent with AIH, treatment should be modi-fied accordingly.

• The development of cirrhosis-related complications is associ-ated with poor prognosis and reduced life expectancy.

• The panel recommends that the first line treatment for PBC patients should be UDCA. For PBC patients who are intoler-ant to UDCA, OCA monotherapy should be started.

• For patients who are non-responsive to the appropriate dose of UDCA at 6-12 months, OCA should be added to the regimen.

• For patients with PBC treated with UDCA who have “subop-timal response”, as defined by increasing liver stiffness/fibrosis and increasing total bilirubin despite normal ALP, the panel recommends that the addition of OCA be considered.

• For PBC patients with advanced liver disease, reduced dose of OCA and close monitoring according to the FDA warning should be carried out.

CONFLICT OF INTERESTGuarantor of the article: None.Specific author contributions: Rachel E. Bejarano, PharmD and Lisa D. Pedicone, PhD provided medical writing assistance.Financial support: Supported by an educational grant from Inter-cept Pharmaceuticals, Inc.Potential competing interests: None.

Study HighlightsWHAT IS CURRENT kNOWLEDGE?✓ PBc is a relatively rare but important cause of chronic liver

disease

✓ although effective treatment for PBc has been available for some time, about 40% of patients have a suboptimal response and experience a progressive course

WHAT IS NEW HERE?✓ a number of algorithms have been developed to identify

patients who are sub-optimally responsive

✓ new treatment options are available for patients who have no or suboptimal response to ucda

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