Primary Biliary Cholangitis

Educational Objectives

The goal of this program is to improve the management of primary biliary cholangitis. After hearing and assimilating this program, the clinician will be better able to:

1. Recognize manifestations of primary biliary cholangitis.

2. Identify risk factors for primary biliary cholangitis.

Summary

Primary biliary cholangitis (PBC): antimitochondrial antibody (AMA) most sensitive and specific marker; pathogenically, complex autoimmune disease with complex interplay between genetics and environment

Environmental risk factors: proximity to Superfund toxic waste sites (associated with clustering of disease); certain microorganisms (eg, Escherichia coli, Novosphingobium aromaticivorans); exposure to nail polishes, hair dyes, and other xenobiotics; environmental agents create adaptive immune response in which antibodies attack own bile ducts

Pathogenesis: complex interplay between immune cells and biliary epithelial cells, with activation of B and T cells by AMA reaction to self-PBC antigens; macrophages also activated and secrete various cytokines; immune cells attack biliary epithelial cells, leading to progressive cholestasis and ultimately, hepatic stellate cell activation and fibrogenesis

Typical clinical phenotype: age >45 yr; strong female predominance (9:1 ratio); 95% AMA-positive (2 specific antinuclear antibodies may also be positive); elevated immunoglobulin (Ig) M levels; pruritus and fatigue common; normal magnetic resonance cholangiopancreatography

Diagnosis: made or confirmed on histology (hallmark of florid duct lesion [stage 1 PBC] or nonsuppurative cholangitis affecting bile ducts); other autoimmune diseases seen in 35% to 55% of patients; 2 of 3 criteria needed for diagnosis; American Association for the Study of Liver Diseases criteria — biochemical evidence of chronic cholestasis as evidenced by unexplained elevation of alkaline phosphatase (ALP) for >6 mo; positive AMA; histology showing nonsuppurative destructive cholangitis with or without granulomas and lymphoplasmacytic infiltrates

Later stages of PBC: stage 2 — inflammatory cells spill out from around portal tract; considerable inflammation; stage 3 — bridging fibrosis; stage 4 — cirrhosis

Need for liver biopsy: Mayo Clinic study — found that combination of positive AMA, ALP >4 times normal, and mildly elevated aspartate aminotransferase (AST) has positive predictive value >98%, with 80% sensitivity and 92% specificity; minority of patients require biopsy to make histologic diagnosis

Staging of PBC: indications for liver biopsy — AMA negative but suspicion strong; need to rule out overlap between autoimmune hepatitis and PBC; need to establish presence of premature ductopenic variance; evaluation of nonresponders to ursodeoxycholic acid (UDCA); liver stiffness — established as one of best surrogate markers of liver fibrosis in PBC in French data; liver stiffness score of >9.6 kilopascals (kPa) at baseline associated with 5-fold increase in risk for adverse outcomes; increase in score by >2.1 kPa/yr associated with 8-fold increase in risk for adverse outcomes; patients with known diagnosis of PBC typically followed with transient elastography every few years to detect progression (has significant prognostic implications); AST-to-platelet ratio index score — associated with poor transplant-free survival in PBC; score >0.54 associated with poor prognosis

Natural history (Japanese data): divided natural history of PBC into 3 separate cohorts; majority (>70%) of patients have slowly progressive type; subset with development of significant portal hypertension (HTN) in precirrhotic stage likely have positive anticentromere antibody, and present with varices and other complications from portal hypertension early in disease course; more rapidly progressive type associated with very early liver failure with early jaundice (ANA [anti-Gp210] usually positive)

Manifestations of disease

Pruritus: most common (prevalence ≈70%); etiology unknown; can dramatically reduce quality of life; usually has diurnal variation; often localized in limbs, palms, and soles; exacerbated by pregnancy; if scratched, prurigo nodularis can develop; managed in stepwise fashion (start with cholestyramine [bile acid sequestrant] 4 g twice daily and increase dose as tolerated); rifampin (antituberculosis drug) second-line drug; naltrexone (opiate antagonist) third-line drug; selective serotonin reuptake inhibitors (eg, sertraline [Zoloft]); antihistamines have little role

Fatigue: prevalence 70% to 80%; pathogenesis poorly understood; rule out depression, anemia, hypothyroidism, and adrenal insufficiency which can contribute to fatigue; management difficult; some evidence supports use of modafinil

Deficiency of fat-soluble vitamins: speaker checks levels of vitamin A, D, and E every 2 yr and repeats as necessary

Metabolic bone disease: screening recommended; relative risk for osteoporosis ≈4.4, compared with age-matched and sex-matched healthy population; speaker typically obtains dual-energy x-ray absorptiometry every 2 yr and treats if patient has evidence of osteoporosis; if osteopenic, repeat calcium and vitamin D levels and closely follow patient

Hyperlipidemia: lipid profile does not pose atherogenic risk; high-density lipoproteins (HDL) typically disproportionately elevated, compared with low-density lipoproteins (LDL); accumulation of lipoprotein-X possible; obeticholic acid (OCA) may have adverse effects on lipid profile

Ursodeoxycholic acid (UDCA): first-line treatment; typically given at dose of 13 to 15 mg/kg per day; monitoring liver function recommended; ≈40% of patients have inadequate response; therapeutic effects — improves cholesterol and IgM levels; shown to delay histologic progression and development of portal HTN; improves long-term survival without need for liver transplantation (LT)

Risk stratification models: Globe PBC score — developed to validate risk stratification scoring; transplant-free survival assessed via 5 variables (age at time of initiation of UDCA; bilirubin level after 1 yr of treatment; ALP level; albumin level; platelet count); can determine 3-yr, 5-yr, and 10-yr survival; UK-PBC score — based on bilirubin, AST-to-alanine aminotransferase (ALT) ratio, ALP, platelets, and albumin

Proposed stepwise management algorithm: diagnosis; staging and risk assessment; UDCA response and assessment; looking at UK-PBC and Global scores after 1 yr of treatment; monitoring for histologic progression and determining response to UDCA; if no response to UDCA, switch to second-line drug

Obeticholic acid: farnesoid X-receptor agonist; 100 times more potent than chenodeoxycholic acid; primary effect improvement in bile acid homeostasis; also affects inflammation and fibrosis; 2016 POISE trial — compared OCA vs placebo in patients treated for 1 yr; primary end point decrease in ALP to <1.6 times upper limit of normal, with low bilirubin and >15% reduction in ALP; 2 groups who received OCA had response rates of 46% and 47%, vs 10% in placebo group; led to approval by Food and Drug administration as second-line agent for PBC; side effects — pruritus; lipid effects (increase in LDL and decrease in HDL); at time of approval, starting dose of 5 mg/day recommended, with uptitration to 10 mg if ALP response inadequate; postmarketing surveillance noted that some patients with decompensated cirrhosis who received excessively high dose experienced liver failure; black box warning reminds prescribers that, in cirrhotic patients with Child-Pugh score B or C, dose 5 mg once weekly and uptitrated if necessary (maximum dose ≤10 mg twice weekly)

Liver transplantation: absolute number of waitlisted patients with PBC decreasing because PBC slowly progressive disease with excellent response to UDCA, particularly if started early in course of disease

Readings

Ali AH, Lindor KD: Obeticholic acid for the treatment of primary biliary cholangitis. Expert Opin Pharmacother, 2016 Sep;17(13):1809-15; Bian S et al: Cardiac involvement in patients with primary biliary cholangitis: A 14-year longitudinal survey-based study. PLoS One, 2018 Mar 15;13(3):e0194397; Chen J et al: Influence factors and a predictive scoring model for measuring the biochemical response of primary biliary cholangitis to ursodeoxycholic acid treatment. Eur J Gastroenterol Hepatol, 2018 Nov;30(11):1352-60; Cheung KS et al: Prediction of hepatocellular carcinoma development by aminotransferase to platelet ratio index in primary biliary cholangitis. World J Gastroenterol, 2017 Nov 28;23(44):7863-74; Corpechot C et al: A placebo-controlled trial of bezafibrate in primary biliary cholangitis. N Engl J Med, 2018 Jun 7;378(23):2171-81; Floreani A, Mangini C: Primary biliary cholangitis: old and novel therapy. Eur J Intern Med, 2018 Jan;47:1-5; Popp F et al: Improvement of primary biliary cholangitis (PBC) under treatment with sulfasalazine and abatacept. BMJ Case Rep, 2018 May 12;2018. pii: bcr-2018-224205; Tsuneyama K et al: Primary biliary cholangitis: its pathological characteristics and immunopathological mechanisms. J Med Invest, 2017;64(1.2):7-13.

Disclosures

For this program, members of the faculty and planning committee reported nothing to disclose.

Acknowledgements

Dr. Sass was recorded at the 38th Annual Advances in Gastroenterology Conference, held June 16, 2018, in Atlantic City, NJ, and presented by the Sidney Kimmel Medical College at Thomas Jefferson University. For information about upcoming CME activities from Thomas Jefferson University, please visit www.cme.jefferson/edu. The Audio Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

GE331101

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.