Autoimmune Liver Disease

Educational Objectives

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

1. Choose the appropriate tests to diagnose major autoimmune diseases of the liver.
2. Recognize the diagnostic features of autoimmune hepatitis-primary biliary cholangitis overlap syndrome.

Summary

Primary Biliary Cholangitis (PBC)

Epidemiology: most common autoimmune liver disease; 90% of those affected women; median age at diagnosis 50 yr; positive antimitochondrial antibody (AMA) hallmark; symptoms – most patients asymptomatic; first sign is isolated elevation in alkaline phosphatase (ALP); pruritus and fatigue; 50% of women with PBC have concomitant autoimmune disease; exclude nonliver sources of elevated ALP and biliary obstruction

Diagnostic criteria: requires 2 of 3 — elevated ALP >1.5 times upper limit of normal [ULN], positive AMA with titer ≥1:40, and findings on liver biopsy consistent with PBC

Histologic findings on liver biopsy: florid bile duct lesions, significant inflammation, and injury to bile duct epithelium; granulomas and ductopenia occasionally seen; AMA-negative PBC — previously called autoimmune cholangiopathy; negative AMA, elevated ALP, and PBC on biopsy; usually has positive antinuclear antibody

Clinical variants: autoimmune hepatitis (AIH)-PBC overlap syndrome — components of AIH and PBC present; elevated alanine aminotransferase (AST) and ALT, or elevated ALP alone; if >5 times ULN, consider concomitant hepatocyte process; liver biopsy indicated if immunoglobulin (Ig)G and antismooth muscle antibody (ASMA) elevated and features of both AIH and PBC present; premature ductopenic variant – rare; most often seen in younger women; severe cholestatic pattern that rapidly develops into cirrhosis

Treatment: ursodeoxycholic acid (UDCA) – first-line drug; dose of 13 to 15 mg/kg body weight; improves liver tests and delays progression of fibrosis; decreases need for liver transplantation and mortality; pruritus is symptom most difficult to treat; speaker recommends dual-energy x-ray absorptiometry on all patients (metabolic bone disease common) as well as calcium 15 mg and vitamin D 800 IUs daily; 40% of patients have inadequate response or incomplete response (ALP not decreasing)

Obeticholic acid (OCA): regulates genes involved in bile acid synthesis; study – 3 groups (placebo; 5 mg of OCA; 10 mg of OCA); found that in those who received OCA, 46% met primary end point (reduction in ALP by 1.67 times ULN); 93% of patients also on UDCA and 90% women; recommended for noncirrhotic or Child-Pugh class A patients; starting dose 5 mg/day (10 mg associated with pruritus); after 3 mo, uptitrate as tolerated up to 10 mg; itching main side effect and dose-dependent; postmarketing safety data showed hepatic decompensation and failure in incorrectly dosed PBC patients with Child-Pugh class B and C decompensated cirrhosis; if giving drug to patients with Child-Pugh class B or C cirrhosis, dose at only 5 mg/wk (vs per day); monitor closely with liver tests; monitor patient for side effects

Fibrates: fenofibrate currently used off-label in United States; associated with increased transaminases, creatine phosphokinase, and serum creatinine

Liver transplantation (LT): despite treatment, 10% of patients require LT; post-LT – survival 90% at 1 yr and 83% at 5 yr; 60% recurrence rate at 15 yr; patients maintained on UDCA after transplantation

Autoimmune Hepatitis (AIH)

Epidemiology: chronic inflammatory condition, mostly affecting women; incidence and prevalence rising, with bimodal age distribution (puberty and at 40-60 yr of age); consider antibodies, hypergammaglobulinemia, interface hepatitis on biopsy, and association with other autoimmune diseases; response to prednisone hallmark of disease; presentation – 30% present with cirrhosis, but 70% have nonspecific symptoms or asymptomatic

Laboratory findings: hepatocellular pattern of injury; AST and ALT elevated, but elevation does not always correspond to severity of disease; liver tests fluctuate; autoantibodies (ANA and SMA hallmark); antiliver-kidney microsomal antigen type 1 and antisoluble liver antigen more commonly seen in pediatric population with AIH; interface hepatitis, plasma cells, and rosettes seen on liver biopsy; biopsy remains important in AIH

Treatment: based on European Association for the Study of the Liver (EASL) or American Association for the Study of Liver Diseases guidelines; start with prednisone or prednisone plus azathioprine (AZT); prednisone has significant side effects; presence of jaundice contraindication for starting prednisone and AZT; consider dual therapy if bilirubin normal and AST and ALT elevated; normalization of AST and ALT goal of treatment

Withdrawal of treatment: controversial; high risk for relapse; EASL recommends treatment for ≥3 yr, and normal AST and ALT for ≥2 yr, before considering discontinuation of treatment; liver biopsy recommended for staging and prognosis

Second-line treatment: mycophenolate mofetil 500 mg orally twice daily for patients who respond to AZT, but unable to tolerate its side effects; teratogenic; consider budesonide in patients unable to tolerate prednisone because of side effects; contraindicated in cirrhosis

Primary Sclerosing Cholangitis (PSC)

Background: chronic cholestatic liver disease that affects intra- and extrahepatic biliary tree; large-duct PSC seen on magnetic resonance cholangiopancreatography (MRCP); MRCP normal in small-duct PSC, so liver biopsy indicated; variable rates of progression and biliary cirrhosis; prevalence – affects mostly men 30 to 40 yr of age; strong association with inflammatory bowel disease (IBD; rule out with colonoscopy with biopsy); prognosis “terrible”; patients mostly asymptomatic; elevated ALP hallmark of disease; 10% have elevated IgG4 (more aggressive disease)

Diagnosis: strictures on cholangiography; MRCP preferred (cost-effective, accurate, and noninvasive); endoscopic retrograde CP (previous gold standard) has better sensitivity for subtle changes in distal bile ducts, and simultaneous therapeutic intervention possible; liver biopsy not necessary unless considering small-duct PSC or overlap AIH (more common in children)

Management: use of UDCA controversial (high dose of 25-35 mg/kg body weight associated with treatment failure, death, liver transplantation, and bleeding; dose of 17-23 mg/kg results in improvement of liver tests and trend toward improved survival; on low dose, liver tests improve, but with no changes in survival); re-evaluate every 6 mo to determine whether drug effective; case-by-case assessment whether to stop drug; surveillance – expert opinion recommends imaging every 6 to 12 mo; serum carbohydrate antigen 19-9 every 12 mo; cholecystectomy if gallbladder polyps >8 mm found; annual colonoscopy if IBD present; complications – 50% develop dominant strictures (25% malignant); endoscopic therapy – balloon dilation; if significant strictures present, consider short-term stenting

Readings

Floreani A et al: Primary biliary cirrhosis: overlaps with other autoimmune disorders. Semin Liver Dis, 2014 Aug;34(3):352-60; Floreani A et al: The overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis. Dig Liver Dis, 2015 May;47(5):432-5; Gatselis NK et al: Autoimmune hepatitis, one disease with many faces: etiopathogenetic, clinico-laboratory and histological characteristics. World J Gastroenterol, 2015 Jan 7;21(1):60-83; Lindor KD et al: American College of Gastroenterology. ACG Clinical Guideline: Primary sclerosing cholangitis. Am J Gastroenterol, 2015 May;110(5):646-59; quiz 660; Nguyen HH et al: Evaluation of classical and novel autoantibodies for the diagnosis of primary biliary cholangitis-autoimmune hepatitis overlap syndrome (PBC-AIH OS). PLoS One, 2018 Mar 19;13(3):e0193960.

Disclosures

For this program, members of the faculty and planning committee reported nothing to disclose. In her lecture, Dr. Choi presents information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Choi was recorded at the 6th Annual UCLA-Mellinkoff Gastroenterology and Hepatology Symposium, held March 9-10, 2018, in Beverly Hills, CA, and presented by the David Geffen School of Medicine at the University of California, Los Angeles, and its Office of Continuing Medical Education. For information about upcoming CME activities from this sponsor, please visit their website at www.cme.ucla.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:

GE322002

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.