Guideline sources The following summarized guidelines for the evaluation and management of primary biliary cholangitis are prepared by our editorial team based on guidelines from the Asian Pacific Association for the Study of the Liver (APASL 2022), the American Association for the Study of Liver Diseases (AASLD 2021; 2019), the British Society of Gastroenterology (BSG 2018), the Italian Association for the Study of the Liver (AISF 2016), and the American College of Gastroenterology (ACG 2016). 1 2 3 4 5 6 Calculator Diagnostic criteria for primary bi https://web.pathway.md/diseases/rec3JLXm1d12eJxpQ 1/10 6/29/23, 11:29 PM Primary biliary cholangitis Pathway Guidelines 1. Screening and diagnosis Indications for screening: as per BSG 2018 guidelines, do not obtain routine screening for PBC in relatives of patients with PBC. D Diagnostic criteria: As per APASL 2022 guidelines: Diagnose PBC if 2 the following criteria are met: biochemical evidence of cholestasis based mainly on the elevation of ALP and glutamyl transpeptidase with the exclusion of extrahepatic biliary obstruction by imaging presence of antimitochondrial antibody or other PBC-specific ANA including anti-sp100 or anti-gp210 histologic evidence of non-suppurative destructive cholangitis mainly affecting the interlobular bile ducts. A Do not diagnose PBC solely based on anti mitochondrial antibody reactivity. D As per AASLD 2019 guidelines, diagnose PBC in patients meeting 2 of the following criteria: biochemical evidence of cholestasis based on ALP elevation presence of antimitochondrial antibodies or other PBC-specific autoantibodies, including anti-SP100 or anti-GP210 histologic evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts. E As per BSG 2018 guidelines: Establish the diagnosis of PBC in the presence of antimitochondrial antibodies (> 1 in 40) or highly PBC-specific ANA, in the appropriate context of cholestatic liver biochemistry, without alternative explanation. A Obtain further investigations before establishing a diagnosis of PBC or initiating therapy in patients with high clinical suspicion for PBC, if classical indicators of disease are discordant (such as normal liver biochemistry, serology at a low titer). B 2. Classification and risk stratification Risk assessment: Evaluate disease severity and activity at baseline and on treatment during risk assessment of patients with PBC. Consider using the combination of the following to aid risk stratification: serum liver tests (to identify patients with an elevated bilirubin, a platelet count < 150 or biochemical disease activity on treatment) imaging (liver ultrasound to identify overt cirrhosis and splenomegaly, transient elastography to identify increased liver stiffness) recognition of young age at disease onset (< 45 years) and male sex. B https://web.pathway.md/diseases/rec3JLXm1d12eJxpQ 2/10 6/29/23, 11:29 PM Primary biliary cholangitis Pathway 3. Diagnostic investigations History and physical examination: evaluate all patients for the presence of symptoms, particularly fatigue and itch, recognizing that the severity of symptoms does not correlate with stage of disease. B Laboratory tests: obtain antimitochondrial antibody and anti-nuclear autoantibodies reactivity in patients with persistently elevated cholestatic liver biochemistry (raised ALP or GGT) without an alternative cause. A Diagnostic imaging: obtain baseline abdominal ultrasound as part of assessment of patients with suspected PBC. A Evaluation for osteoporosis: Check serum vitamin D status in all patients with PBC. B Evaluate all patients with PBC, especially postmenopausal women, for osteoporosis. B Screening for comorbidities: Consider screening all patients with PBC for celiac, thyroid disease, and Sj gren's syndrome at baseline. Monitor patients clinically during follow-up and consider testing for the development of associated autoimmune conditions including celiac, thyroid disease, and Sj gren's syndrome based on clinical need. C Recognize that hyperlipidemia of PBC is not associated with an elevated cardiac risk. Obtain cardiovascular risk assessment to evaluate the need for lipid-lowering therapy, focusing on the identification of patients with PBC and metabolic syndrome (with high cholesterol, low HDL cholesterol, and high LDL cholesterol levels). B 4. Diagnostic procedures Upper gastrointestinal endoscopy: As per APASL 2022 guidelines, perform screen endoscopy for gastroesophageal varices in patients with features of portal hypertension (splenomegaly, thrombocytopenia). B As per AASLD 2019 guidelines, perform endoscopic screening for varices at the time of diagnosis in patients with suspected cirrhosis. E As per BSG 2018 guidelines, screen patients with suspected portal hypertension for gastroesophageal varices according to published guidelines. B Liver biopsy: As per APASL 2022 guidelines, perform liver biopsy in patients presenting with otherwise unexplained cholestatic liver biochemistry and negative anti mitochondrial antibody, anti- gp210 or anti-sp100, to confirm the diagnosis of PBC. B As per AASLD 2019 guidelines: Avoid routine liver biopsy in patient with PBC who are negative for antimitochondrial antibodies if other criteria are met, including cholestatic liver tests and PBC-specific autoantibodies such as anti-SP100 or anti-GP210. D Consider liver biopsy to rule out concomitant AIH or other liver disease should be considered when the ALT activity is > 5 times the ULN. E https://web.pathway.md/diseases/rec3JLXm1d12eJxpQ 3/10 6/29/23, 11:29 PM Primary biliary cholangitis Pathway As per BSG 2018 guidelines, do not perform a liver biopsy for the diagnosis of PBC or for monitoring disease progression unless its use is within the context of clinical trials. D Show 4 more 5. Medical management Setting of care: Consider providing hospital-led care in patients with any of the following: UDCA non-responsive disease advanced liver fibrosis/cirrhosis features of portal hypertension complex symptoms. C Show 2 more First-line therapy: As per APASL 2022 guidelines: Initiate oral UDCA (13 ~ 15 mg/kg/day) as standard therapy in all patients with PBC. Continue UDCA treatment for prolonged periods and check compliance to therapy. A Evaluate all patients with PBC for biochemical response with appropriate criteria after 6 B or 12 months of UDCA treatment. B As per AASLD 2019 guidelines, initiate oral UDCA at a dose of 13-15 mg/kg/day for patients with PBC with abnormal liver enzymes, regardless of histologic stage. E Show 2 more As per BSG 2018 guidelines, initiate oral UDCA at 13-15 mg/kg/day as first-line therapy in all patients with PBC. Continue treatment life-long, if tolerated. A Show 2 more Second-line therapy: As per APASL 2022 guidelines, add obeticholic acid (starting at 5 mg/day, increasing to 10 mg/day after 6 months if tolerated well) to UDCA in patients with PBC (non-cirrhotic or cirrhosis with Child-Pugh class A) and an inadequate response to UDCA. Discuss in detail, carefully evaluate and appropriately monitor potential risks and adverse events of obeticholic acid. A Show 3 more As per AASLD 2021 guidelines: Consider initiating fibrates as an off-label alternative in patients with an inadequate response to UDCA. Avoid using Fibrates in patients with decompensated liver disease. E Do not use obeticholic acid in patients with advanced cirrhosis, defined as cirrhosis with current or prior evidence of liver decompensation (such as encephalopathy, coagulopathy) or portal hypertension (such as ascites, gastroesophageal varices, or persistent thrombocytopenia). Obtain careful monitoring of any patient with cirrhosis, even if not advanced, receiving obeticholic acid. D As per AASLD 2019 guidelines, consider initiating obeticholic acid (starting at 5 mg/day) in patients with an inadequate response to UDCA. E Management of pruritus: https://web.pathway.md/diseases/rec3JLXm1d12eJxpQ 4/10 6/29/23, 11:29 PM Primary biliary cholangitis Pathway As per APASL 2022 guidelines: Initiate cholestyramine (4-16 g/day) as first-line therapy for pruritus. Instruct patients to take other medications including UDCA at least 1 hour before or 4-6 hours after taking cholestyramine to avoid interference with the absorption. B Consider initiating rifampicin (150-300 mg BID) as second-line therapy for pruritus with close monitoring of side effects. C As per AASLD 2019 guidelines: Use anion-exchange resins as initial therapy for patients with PBC who have pruritus. E Consider the following agents for pruritus refractory to anion-exchange resins: rifampicin (150 to 300 mg PO BID) naltrexone (titrated to a dose of 50 mg PO daily) sertraline (75 to 100 mg PO daily). E As per BSG 2018 guidelines: Initiate cholestyramine as first-line therapy for pruritus, given the safety profile of bile acid resins, and instruct patients to take it separately to UDCA to avoid interaction. B Consider initiating rifampicin as second-line therapy for pruritus, taking account the risks and benefits of its use and ensuring appropriate monitoring for side effects. B Management of fatigue: As per APASL 2022 guidelines, insufficient evidence to recommend any specific medical therapy for fatigue. Treat co-existent conditions such as anemia, extra-hepatic autoimmune disease, sleep disturbance and depression to manage fatigue. I As per BSG 2018 guidelines, evaluate for and treat alternative causes of fatigue. B Management of sicca symptoms: use artificial tears as initial therapy for dry eyes. E Show 2 more Management of vitamin deficiencies: initiate parenteral or water-soluble supplements to treat fat-soluble vitamin deficiencies. E Management of osteoporosis: As per APASL 2022 guidelines: Consider initiating bisphosphonates (alendronate 70 mg weekly or ibandronate 150 mg monthly or others) in patients with osteoporosis. Be cautious when initiating bisphosphonates in patients with esophageal varices. Monitor for side effects in all patients. C Insufficient evidence to support the use of denosumab in patients with PBC with osteoporosis. I As per AASLD 2019 guidelines, consider oral alendronate or other effective bisphosphonates in patients with osteoporosis. Avoid oral bisphosphonates if patients have acid reflux or known varices. E As per BSG 2018 guidelines, assess risk of osteoporosis in all patients with PBC. Treat and follow-up according to national guidelines. A Management of ascites and hepatic encephalopathy: treat ascites and hepatic encephalopathy as in standard practice. B https://web.pathway.md/diseases/rec3JLXm1d12eJxpQ 5/10 6/29/23, 11:29 PM Primary biliary cholangitis Pathway Management of dyslipidemia: As per AASLD 2019 guidelines, consider lipid-lowering therapy for patients with elevated lipid levels who are at risk for CVD. E As per BSG 2018 guidelines, recognize that there is no added contraindication to the use of HMG-CoA reductase inhibitors in patients with PBC. B 6. Nonpharmacologic interventions Lifestyle modifications: encourage patients with PBC to quit smoking, stop alcohol drinking and keep on ideal body weight because of the negative impacts of these factors on human health. B Calcium and vitamin D supplementation: As per APASL 2022 guidelines, advise patients taking enough calcium (1,000-1,500 mg/day) and vitamin D (1,000 IU/day) in the diet or as supplements if needed, according to the local practice. B As per AASLD 2019 guidelines, assist patients in maintaining a daily intake 1,000-1,500 mg of calcium and 1,000 IU of vitamin D, using dietary modification and supplements if needed. E Psychosocial support: offer patients with PBC the chance to seek support from patient support groups. B 7. Surgical interventions Liver transplantation: As per APASL 2022 guidelines: Consider performing liver transplantation in patients with any of the following: decompensated cirrhosis model for end-stage liver disease 15 mayo Risk Score > 7.8 severe, intractable pruritus. B Initiate post-transplant UDCA to improve LFTs and prevent PBC recurrence. B As per BSG 2018 guidelines, discuss the suitability of liver transplantation, with a hepatologist linked to a liver transplant program, in all patients with bilirubin > 50 mcmol/L (including patients treated with UDCA) or evidence of decompensated liver disease. A Show 3 more 8. Specific circumstances Pregnant patients: As per APASL 2022 guidelines: Counsel patients with PBC at chilebearing age that pregnancy can be attempted. Inform patients with features of cirrhosis about the possible maternal and fetal complications. B https://web.pathway.md/diseases/rec3JLXm1d12eJxpQ 6/10 6/29/23, 11:29 PM Primary biliary cholangitis Pathway Consider continuing UDCA during pregnancy and breastfeeding after special counseling on these particular issues. C As per BSG 2018 guidelines: Recognize that pregnancy is typically well tolerated in patients with non-cirrhotic PBC, but pruritus can be exacerbated. Counsel pregnant patients with PBC appropriately, including guidance over use of UDCA and treatment of pruritus. Consider continuing UDCA periconception, peripartum and postpartum. B Recognize that pregnancy in patients with cirrhosis carries a higher risk of maternal and fetal complications. Provide preconception counseling and subsequent interdisciplinary specialist monitoring during pregnancy in patients with features suggesting advanced liver disease. B As per ACG 2016 guidelines, continue treatment with UDCA in pregnant patients with PBC. B As per AISF 2016 guidelines, recognize that pregnancy in patients with PBC in the pre- cirrhotic stage (histological stage I-III) has a favorable outcome and there is no contraindication for pregnancy continuation. B Show 2 more Patients with PBC/AIH overlap: As per APASL 2022 guidelines: Diagnose PBC with AIH in patients with PBC if 2 of the following criteria are met: moderate/severe interface hepatitis in liver histology (mandatory) serum ALT/AST > 5 times the ULN igG level > 1.3 times the ULN or presence of anti-smooth muscle antibody. B Consider initiating immunosuppressive agents (including corticosteroids with or without azathioprine or mycophenolate mofetil) as add-on therapy to UDCA or, de novo combination therapy with UDCA. C As per AASLD 2019 guidelines, target treatment at the predominant histological pattern of injury in patients with primary biliary cirrhosis/AIH overlap syndrome. E As per BSG 2018 guidelines, consider initiating immunosuppressive therapy in the presence of severe interface hepatitis in the correct context after discussing the risks and benefits of treatment, particularly for corticosteroids, with the patient. C 9. Follow-up and surveillance Indications for referral: As per AASLD 2019 guidelines, refer patients with manifestations of end-stage PBC for liver transplantation when their Model for End-Stage Liver Disease score exceeds 14. E As per BSG 2018 guidelines, consider referring patients with symptoms resistant to medical therapy for specialist management regardless of disease severity. C Follow-up: As per APASL 2022 guidelines, monitor antimitochondrial antibody-positive patients with normal serum liver tests by an annual biochemical reassessment for the presence of liver https://web.pathway.md/diseases/rec3JLXm1d12eJxpQ 7/10 6/29/23, 11:29 PM Primary biliary cholangitis Pathway disease. Consider performing liver biopsy in selected patients (such as patients with elevated IgM, high titer of antimitochondrial antibody or ALP close to ULN) to identify preclinical PBC. B As per BSG 2018 guidelines, recognize that there is a range of noninvasive tools to stage and monitor disease progression. Insufficient evidence to recommend an optimal strategy. B Show 4 more Surveillance for hepatocellular carcinoma: As per APASL 2022 guidelines, obtain close monitoring for HCC in male patients as well as patients with advanced-stage disease and nonresponders to UDCA. B As per AASLD 2019 guidelines, obtain liver cross-sectional imaging every 6 months in male patients as well as patients with cirrhosis to screen for HCC. E As per BSG 2018 guidelines, obtain HCC surveillance in patients with suspected cirrhosis according to published guidelines. B 10. Quality improvement Clinical audit: consider implementing clinical audit tools to document and improve the quality of care delivered to patients with PBC. B Clinical findings Patient demographics Symptoms Female sex Abdominal pain Ankle swelling Past medical history Bone pain Darkening of the skin Autoimmune disorders Diarrhea Hypercholesterolemia Dry eyes Hypothyroidism Dry mouth Inflammation Fatigue Osteoporosis Generalized pruritus Toxins Infection Social history Joint pain Muscle pains Current cigarette smoking Steatorrhea Weight loss Abdominal exam Family history Ascites Splenomegaly PBC Lab findings Ocular exam serum ALP Xanthelasma palpebrarum https://web.pathway.md/diseases/rec3JLXm1d12eJxpQ 8/10 6/29/23, 11:29 PM Primary biliary cholangitis Pathway serum ALT Integument exam serum AST serum immunoglobulin Jaundice serum total cholesterol Serological findings serum AMA Likelihood Ratios Pertinent positives The following findings increase the probability of primary biliary cholangitis in adults. 2 Finding LR+ Value Positive serum AMA 95 Pertinent negatives The following findings decrease the probability of primary biliary cholangitis in adults. 2 Finding LR- Value Negative serum AMA 0.05 References 1. Hirschfield GM, Dyson JK, Alexander GJM et al. The British Society of Gastroenterology/UK PBC primary biliary cholangitis treatment and management guidelines. Gut. 2018 Sep;67 9 1568 1594. Open 2. Hong You, Xiong Ma, Cumali Efe et al. APASL clinical practice guidance: the diagnosis and management of patients with primary biliary cholangitis. Hepatol Int. 2022 Feb;16 1 1 23. Open 3. Keith D Lindor, Christopher L Bowlus, James Boyer et al. Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology. 2019 Jan;69 1 394 419. Open 4. Keith D Lindor, Christopher L Bowlus, James Boyer et al. Primary biliary cholangitis: 2021 practice guidance update from the American Association for the Study of Liver Diseases. Hepatology. 2021 Aug 24. Open 5. Italian Association for the Study of the Liver AISF , Italian Association for the Study of the Liver AISF. AISF position paper on liver disease and pregnancy. Dig Liver Dis. 2016 Feb;48 2 120 37. Open 6. Tram T Tran, Joseph Ahn, Nancy S Reau. ACG Clinical Guideline: Liver Disease and Pregnancy. Am J Gastroenterol. 2016 Feb;111 2 176 94; quiz 196. Open 7. Paul Martin, Andrea DiMartini, Sandy Feng et al. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology. 2014 Mar;59 3 1144 65. Open 8. Monika Sarkar, Carla W Brady, Jaquelyn Fleckenstein et al. Reproductive Health and Liver Disease: Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021 Jan;73 1 318 365. Open https://web.pathway.md/diseases/rec3JLXm1d12eJxpQ 9/10 6/29/23, 11:29 PM Primary biliary cholangitis Pathway https://web.pathway.md/diseases/rec3JLXm1d12eJxpQ 10/10