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Diagnosis and Management of Primary Biliary Cholangitis

This article discusses the diagnosis and management of primary biliary cholangitis, including its characteristics, pathogenesis, and recommended evaluation and treatment approaches.

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Diagnosis and Management of Primary Biliary Cholangitis

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  1. The diagnosis and managementof patients with primary biliary cholangitisEuropean Association for the Study of the Liver 2017 Peresented by: m.rouhani,GI FELLOW Tabriz Medical University, GI DEPARTMENT

  2. DR GAVIDEL • Drgavidel • Journal club govaresh Clinical Gastroenterology and Hepatology

  3. TBZMED,GI DEP

  4. Introduction Primary biliary cholangitis (PBC; formerly known as primary biliary cirrhosis • uncommon disease • women • Autoimmune • chronic and • progressive TBZMED,GI DEP

  5. Characteristics including: cholestasis, serologic reactivity to AMA or ANA with accompanying histologic evidence of chronic non-suppurative, granulomatous, lymphocytic small bile duct cholangitis TBZMED,GI DEP

  6. , interaction of immune and biliary pathways cholestasis, ductopenia, and progressive biliary fibrosis PBC pathogenesis TBZMED,GI DEP

  7. incidence and prevalence incidence prevalence 1.9–40.2, per 100,000 • 0.3–5.8 per 100,000 population per year TBZMED,GI DEP

  8. Age at onset, male, stage at presentation, selected biochemical/serologic indices pre- and post-therapy with UDCA areused to identify those at greatest risk TBZMED,GI DEP

  9. Fig. 1. Antimitochondrial antibodies production specific to PDC-E2 Immune cell (including macrophage) activation Activated T cells produce cytokines including IFNc,TNFa , and IL-4 .increase in Th17 positive cells. T cells induce apoptosis or senescence convert cholesterol to bile acids (BA), BA are chaperoned by phosphatidylcholineand exported by MDR3. In PBC, impaired activity of the apical AE2 and bicarbonate secretion lead to unchaperoned BA directly interfering with the BEC membrane. Both senescent and apoptotic cells secrete mediators that activate hepatic stellate cells ,perpetuate inflammation, and promote fibrosis and further biliary stasis.

  10. The diagnostic approach to cholestasis • Early increased serum ALP and GGT, followed by conjugated hyperbilirubinemia • chronic if it lasts 6 months • intrahepatic or extrahepatic • includes hepatocellular and cholangiocellular • Serum ALP elevation : • rapid bone growth in children, • Paget’s disease • vitamin D deficiency • pregnancy. TBZMED,GI DEP

  11. History, physical examination, abdominal ultrasound • A history of intensive care therapy and/or severe polytrauma is linked with secondary sclerosingCholangitis • long-term exposure to paints, diesel and other oil products or industrial gases has been observed in IgG4 associated cholangitis. • herbal • anabolic steroids • Laxatives • alcohol and smoking • amoxicillin/clavulanic acid • trimethoprim/sulfamethoxazole, • azathioprine • 30% of DILI show a cholestaticpattern • administered 5 and 90 days ago TBZMED,GI DEP

  12. TBZMED,GI DEP

  13. Recomendations 1. EASL recommends taking PE& HX when evaluating patients with biochemical tests that suggest cholestaticliver disease (III, 1). • hepatosplenomegaly • extrahepatic signs • icterus of sclera, • xanthelasma, • palmar and plantar erythema, • nail abnormalities, • scratch lesions TBZMED,GI DEP

  14. Recomendations • 2. EASL recommends ultrasound as the first-line non-invasive imaging procedure, in order to differentiateintra- from extrahepatic cholestasis (III, 1). TBZMED,GI DEP

  15. Serological tests • serum AMA and PBC-specificANA(immunofluorescence and/or specific anti-sp100/anti-gp210 testing • AMA may be of limited specificity in acute hepatic injury • AMA testing is not specific for PBC, and should always be targeted • the population frequency of AMA positivity is high (up to 1/1000) whereas PBC prevalence is lower (up to 0.4/1000) TBZMED,GI DEP

  16. Recomendations • 3. EASL recommends performing serologic screening for AMA and PBC-specific-ANA by immunofluorescence in all patients with unexplained cholestasis (III, 1). • 4. EASL recommends imaging by MRCP in patients with unexplained cholestasis. • EUS can be an alternative to MRCP for evaluation of distal biliary disease (III, 1). TBZMED,GI DEP

  17. Liver biopsy Biopsy findings • Disorders involving the bile ducts • Disorders not involving bile ducts • (iii) Hepatocellular cholestasis • 5. EASL recommends considering liver biopsy after serologic screening and extended imaging, in patients with ongoing unexplained intrahepatic cholestasis (III, 1). TBZMED,GI DEP

  18. Table 3. Differential diagnosis of biliary lesions at histological analysis afterliver biopsy. TBZMED,GI DEP

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  20. Recomendations • mutations in ATP8B1, ABCB11 and ABCB4 • should be used when all other diagnoses have been R/O, and FH, clinical symptoms, biochemical and imaging findings suggest an underlying genetic cholestatic disorder 6. EASL recommends considering genetic tests for inherited cholestaticsyndromes in patients where clinically appropriate (III, 1). TBZMED,GI DEP

  21. Genetic testing • progressive familial intrahepatic cholestasis type 1–3 (PFIC1-3) • BRIC, • persistent hepatocellular secretory failure (PHSF) • intrahepatic cholestasis of pregnancy (ICP) • low phospholipid associated cholelithiasis syndrome. extremely rare: • Alagillesyndrome , • PFIC4 (TJP2), • mutations in MYO5B (Villin) TBZMED,GI DEP

  22. Initial diagnosis of PBC • ALP :associated with ductopeniaand disease progression • other factors can modulate ALP values independently of cholestasis, such as: • blood group • ABH secretor phenotype • High IgGvalues inAIH-PBC ‘overlap’ syndromes • Increased immunoglobulin concentrations, particularly IgM • elevated AST and ALT activity, especially when associated with increased IgG • An AST/ALT ratio greater than 1 may be a marker of ongoing liver fibrosis • elevated GGT can be identified prior to rises in ALP TBZMED,GI DEP

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  24. Recomendations • can have raised cholesterol as well as development of xanthoma and xanthelasma • Individual risk factors for PBC mucosal infections especially recurrent UTI and cigarette smoking • 7. EASL recommends that in adult patients with cholestasis and no likelihood of systemic disease, a diagnosis of PBC can be made based on elevated ALP and the presence of AMA at a titre [1:40 (III, 1). TBZMED,GI DEP

  25. 8. EASL recommends that in the correct context, a diagnosis of AMA negative PBC can be made in patients with cholestasis and specific ANA immunofluorescence (nuclear dots or perinuclear rims) or ELISA results (sp100, gp210) (III, 1). • 9. EASL recommends against liver biopsy for the diagnosis of PBC, unlessPBC-specific antibodies are absent, co- existent AIH or NASH is suspected, or other (usually systemic) co-morbidities are present (III, 1). TBZMED,GI DEP

  26. Recomendations • 10. AMA reactivity alone is not sufficient to diagnose PBC. • EASL recommends following-up patients with normalserum liver tests who are AMA positive with annual bio-chemical reassessment for the presence of liver disease(III, 1). TBZMED,GI DEP

  27. Immunological markers • AMA positivity is observed in more than 90%of patients with PBC • Only one patient out of six with AMA positivity andnormal ALP develops PBC within 5 years • ANA are present in approximately 30% of patients with PBC • Immunofluorescent staining of nuclear dots (suggesting anti-sp100 reactivity) and perinuclear rims (suggestinganti-gp210 reactivity) are useful in the diagnosis of PBC , • 5–10% (depending on the assay) of patients with PBC who areAMA negative TBZMED,GI DEP

  28. Imaging • PBC does not cause any abnormality to liver morphology thatmay be detected by imaging. • should have an abdominal ultrasound to rule out extrahepatic causes • signs of advanced PBCinclude: focal liver lesions, portalhypertension, splenomegaly or ascites. • The presence of hilarlymphadenopathy is frequent in patients with PBC. TBZMED,GI DEP

  29. Histology • infiltrate consists mostlyof T lymphocytes associated with few B lymphocytes, macro-phages and eosinophils; • epithelioidgranulomas • ductopenia, inflammation and collagen deposition a score of 0–3 to three histologic components: fibrosis, bile duct loss and deposition of orcein-positive granules. • Stage 1 (no or minim progression),0 score • stage 2 (mild progression), 1-3 • stage 3(moderate progression) ,4-6 • stage 4(advanced progression)7-9 TBZMED,GI DEP

  30. Demographics • Patients who present at a younger age (\45 years) are often symptomatic and less likely to respond well to standard treatment with UDCA • Male sex is associated with later diagnosis, more advanced disease at presentation, poorer biochemical response to UDCA therapy, and higher risk of developing HCC TBZMED,GI DEP

  31. Symptoms • Fatigue or pruritus affects over 50% of patients with PBC • A premature ductopenicvariant of PBC has been described, is not responsive to UDCA • Histology reveals bile duct loss without significant fibrosis or cirrhosis, progress to needing transplantation TBZMED,GI DEP

  32. Standard serum liver tests • UDCA-treated patients efficiently: • low(both normal biliand alb), • medium(abnormal bilior alb) • high(both abnormal biliand alb) risk groups • bilirubin and albumin values are not realistic markers for the risk stratification of early-stage populations TBZMED,GI DEP

  33. Serological profiles Anti-centromere antibodies have also been reported to have potential prognostic impact (portal hypertensive phenotype) TBZMED,GI DEP

  34. Serum markers of fibrosis • Hyaluronic acid was the first marker to show significant association with clinical outcomes • the aspartate aminotransferase-to- platelet ratio index (APRI) TBZMED,GI DEP

  35. Liver stiffness measurement • assessed by vibration-controlled transient elastography(VCTE), one of the best surrogate markers for the detection of cirrhosis or severe fibrosis (i.e. bridging fibrosis) in patients with PBC TBZMED,GI DEP

  36. Liver biopsy • Given the high specificity of serological markers, is not necessary for the diagnosis of PBC; • it is still essential when PBC-specific antibodies are absent, or when co-existent AIH or NASH is Suspected • Liver biopsy may also be appropriate in the presence of other co-morbidities • may therefore add to risk stratification in PBC. • may be advocated in patients with poor biochemical response to UD TBZMED,GI DEP

  37. Direct measurement of portal pressure • Reduction in the HVPG after 2 years of UDCA therapy may identify a subgroup of patients with good outcomes • the emergence of non-invasive methods (e.g. elastography) for assessing portal hypertension indirectly, now avoids the use of an invasive procedure in routine practice. TBZMED,GI DEP

  38. inadequate response to treatment • Inadequate biochemical response to UDCA is observed in 25% to 50% of the patients • The international consensus is that the two most important parameters in evaluating response to UDCA are ALP and total bilirubin • although all thresholds of ALP are predictive of outcomes, their accuracy for use in identifying high-risk patients was not found to differ significantly between 1.5x upper limit of normal (ULN), 1.67 ULN, and 3.0 ULN TBZMED,GI DEP

  39. Prognostic tools for PBC in practice: Guidance • The biochemical response to UDCA measured after 12 months of treatment are the most validated and easily applicable means to select patients in needs for second-line therapies • defined as early or advanced disease according to: • Histology (when a biopsy is available) absent or mild fibrosis vs. bridging fibrosis or cirrhosis. • Elastography(LSM 69.6 kPa vs. [9.6 kPa). • Serum levels of bilirubin and albumin – both parameters normal vs. at least one parameter abnormal. TBZMED,GI DEP

  40. TBZMED,GI DEP 12. EASL recommends evaluating all patients for their risk of developing progressive PBC (III, 1) 11. EASL recommends that therapy in PBC should aimto prevent end-stage complications of liver disease and manageassociated symptoms. (III, 1).

  41. 13. EASL recommends recognition that patients at greatest risk of complications from PBC are those with inadequate biochemical responseto therapy, and cirrhosis(II-2, 1). TBZMED,GI DEP 14. EASL recommends actively recognising that the strongest risk factors for inadequate biochemical response to therapy are early age at diagnosis (e.g. \45), and advanced stage at presentation (III, 1).

  42. TBZMED,GI DEP 16. EASL recommends that elevated serum bilirubin and ALP can be used as surrogate markers of outcome for patients with PBC, and routine biochemistry and haematologyindices should underpin the clinical approaches to stratify individual risk of disease progression (II-2, 1). 15. EASL recommends evaluating all patients for their stage of disease using a combination of non-invasive tests (bilirubin, alkaline phosphatase, AST, albumin, platelet count, and elastography) at baseline, and during follow-up (III, 1).

  43. TBZMED,GI DEP 18. EASL recommends using elastography and risk scores (such as the GLOBE and UK-PBC score) for patients with PBC, to help better define the individual risk of development of complications of advanced liver diseasein the future (III, 1). 17. EASL recommends recognising that the transplant-free survival for early-stage patients with ALP \1.5 ULN and a normal bilirubin after one year of therapy with UDCA, is not significantly different to a control healthy population (II-2, 1).

  44. Treatment: Therapies to slow disease progression 19. EASL recommends oral UDCA at 13–15 mg/kg/day as the first-linepharmacotherapy for all patients with PBC. UDCA is usually continued for life (I, 1). • Licensed indications • Ursodeoxycholicacid TBZMED,GI DEP

  45. 20. In a phase III study, evidence of biochemical efficacy of oral OCA has been demonstrated in patients with ALP [1.67 ULN and/or bilirubin elevated \2 ULN. Oral OCA has been conditionally approved for patients withPBC in combination with UDCA for those with an inadequate response to UDCA, or as monotherapy in thoseintolerant to UDCA.EASL suggests considering its usein such patients (initial dose 5 mg; dose titration to10 mg according to tolerability at six months) (I, 2). Obeticholicacid(OCA) TBZMED,GI DEP

  46. Unlicensed indicationsBudesonide,Fibric acid derivatives • 21. Data from phase III randomised trials for budesonide (in non-cirrhotic patients), and bezafibrate, both in combination with UDCA, are not yet published; EASL suggests currently a recommendation for therapy cannot be made (II-2, 2). TBZMED,GI DEP

  47. Special settings: Pregnancy • pregnancy is typically well tolerated in non-cirrhotic patients with PBC. • EASL recommends the continued use of UDCA in pregnancy, even though supporting data are limited. • rifampicin has been used by experts during the third trimester (III, 1). • 23. Pregnancy in patients with cirrhosis carries a higher risk of maternal and foetalcomplications • EASL recommends offering patients pre-conception counselling and relevant specialist monitoring (III, 1). TBZMED,GI DEP

  48. PBC with features of autoimmune hepatitis • Classical PBC presents with only minimal lobular and interface hepatitis activity, • 8–10% of patients demonstrate features characteristic of AIH • These patients are referred to as having ‘AIH-PBC overlap syndrome • patients with PBC that does not sufficiently respond to treatment with UDCA treatment after 6–12 months, features of additional AIH should always be investigated TBZMED,GI DEP

  49. Patients presenting with features of PBC and AIH simultaneously with at least two of the following: (i) ALP [2 ULN or GGT [5 ULN. (ii) AMA [1:40. (iii) Florid bile duct lesion on histology. Andtwo of the following three features: (i) ALT [5 ULN. (ii) IgG serum levels[2 ULN orASMA positive. (iii) Moderate or severe interface hepatitis on histology. TBZMED,GI DEP

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