pbc and psc: back to basics - ucsf cmeama test or use of a more sensitive assay; but could represent...

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PBC and PSC: Back to Basics

[email protected]

Disclosure

No financial interest or other relationship with the manufacturer(s) of the product(s) or provider(s) of the service(s) that will be

discussed in this presentation.

Outline• In chronic cholestatic liver disease, liver biopsy

plays a supporting role • Case-based discussion• Clinical information, including laboratory

findings and radiographic features, must be integrated for diagnosis

Case 1 clinical history• 54 year old woman, asymptomatic,

incidentally discovered to have elevated alkaline phosphatase (ALP) and positive anti-mitochondrial antibodies (AMA)

• Liver biopsy performed

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What finding would you like to see on biopsy so you can diagnosis it as PBC?

A. Portal and lobular inflammationB. Infiltrate with easily identified plasma cellsC. Florid duct lesionD. Ductular reactionE. DuctopeniaF. Periportal copper depositionG. CK7 positive periportal hepatocytesH. Nodular regenerative hyperplasiaI. Biliary pattern of cirrhosis

AASLD and EASL recommendations• 2 of 3 required criteria for PBC diagnosis

– Presence of antimitochondrial antibodies (AMA)– Alkaline phosphatase (ALP) at least 1.5 times

upper limit of normal for >24 weeks– Histologic evidence of PBC, specifically

nonsuppurative cholangitis and duct injury

Bowlus CL, Gershwin ME. The diagnosis of primary biliary cirrhosis. Autoimmun Rev. 2014 Apr-May;13(4-5):441-4.Lindor KD, et al. Primary biliary cirrhosis. Hepatology 2009;50:291–308.

EASL. Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009;51:237–67.







Antimitochondrial antibodies (AMA)• Major autoantigen target by PBC patient sera

– M2 antigen fraction• E2 subunits of

– Pyruvate dehydrogenase complex (PDC-E2)– Branched chain 2-oxo-acid dehydrogenase complex (BCOADC-

E2)– 2-oxo glutarate dehyrogenase complex (OGDC-E2)

• E1α and E3 binding protein of PDC

Muratori L, et al. Antimitochondrial Antibodies and Other Antibodies in Primary Biliary Cirrhosis: Diagnostic and Prognostic Value. Clin Liver Dis 2008 May;12(2):261-76.

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AMA test methodology • Indirect immunofluorescence assay (IFA)

– Positive titer is ≥ 1:40– Sensitivity 70-90%

• Enzyme-linked immunosorbent assay (EIA) – AMA-M2 antibodies is most frequently used

• First generation utilized PDC-E2– 10% of PBC pts only react to BCOADC-E2 and/or OGDC-E2

• MIT3 or BPO expresses BCOADC-E2, PDC-E2 and OGDC-E2 epitopes

– Sensitivity 94%

Dähnrich C, et al. New ELISA for detecting primary biliary cirrhosis-specific antimitochondrial antibodies. Clin Chem. 2009 May;55(5):978-85.Selmi C, Bowlus CL, Gershwin ME, Coppel RL. Primary biliary cirrhosis. Lancet. 2011 May 7;377(9777):1600-9.

Venn diagram of serum reactivity of PBC patients

Dähnrich C, et al. New ELISA for detecting primary biliary cirrhosis-specific antimitochondrial antibodies. Clin Chem. 2009 May;55(5):978-85.

AMA positive also in…• <1% of healthy adults

– Possibly early preclinical stage• Patients with other diseases

– 10-20% of AIH– <10% of HCV– <1% of steatohepatitis– Rare reports associated with DILI

– ~20% of pts have other autoimmune diseases– Infection mycobacteria and E.coli (cross reactivity)

O'Brien C, et al. Long-term follow-up of antimitochondrial antibody-positive autoimmune hepatitis. Hepatology. 2008 Aug;48(2):550-6.Ravi S, et al. Autoimmune Markers Do Not Impact Clinical Presentation or Natural History of Steatohepatitis-Related Liver Disease. Dig Dis Sci. 2015 Dec;60(12):3788-93.

Chantran Y, et al. Autoantibodies in primary biliary cirrhosis: antimitochondrial autoantibodies. Clin Res Hepatol Gastroenterol. 2013 Sep;37(4):431-3.







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• 7829 new requests of autoantibody screen– 29 pts had

• Incidental finding of +AMA by IFA, titer ≥ 1:40• Normal serum bilirubin, ALP, and transaminase• “Diagnostic” liver histology of PBC at presentation in

40% of cases– Liver histology was diagnostic of or compatible with PBC in

24 pts and normal in only 2 pts (7%)

• 10-year follow-up of cohort• Conclusion

– Patients with AMA but no other signs or symptoms of PBC seem to have slow disease progression







Florid duct lesionaka chronic nonsuppurative cholangitis

Lymphohistiocyticinflammation centered on an interlobular bile duct (<100µm) and is associated with bile duct epithelial damage and epithelial reactive changes.

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• First described - 1851• Xanthomatous biliary cirrhosis - 1949

– Xanthoma seen in 15-50% of pts and first finding in <1%

• Primary biliary cirrhosis - 1950– Expected survival no different from the general

population in 2 of 3 patients diagnosed and treated with UDCA and only a minority will ever develop cirrhosis

The name PBC

Addison T, Gull W. On a certain affection of the skin – vitiligoidea a plana, b tuberosa. Guy’s Hospital Reports 1851;7:265–276.Hanot V. Étude sur une forme de cirrhose hypertrophique du foie [cirrhose hypertrophique avec ictere chronique]. Paris: JBBaillère,1876.

Macmahon HE, Thannhauser SJ. Xanthomatous biliary cirrhosis; a clinical syndrome. Ann Intern Med. 1949 Jan;30(1):121-79.Corpechot C, et al. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology. 2005 Feb;128(2):297-303.

• Primary biliary cholangitis 2015– Name change approved by EASL, AASLD, AGA

Acronym PBC

Sherlock S. Primary billiary cirrhosis (chronic intrahepatic obstructive jaundice). Gastroenterology. 1959 Nov;37:574-86.Rubin E, Schaffner F, Popper H. Primary biliary cirrhosis. Chronic non-suppurative destructive cholangitis. Am J Pathol. 1965 Mar;46:387-407.

Beuers U, et al. Changing nomenclature for PBC: From 'cirrhosis' to 'cholangitis'. Hepatology. 2015 Nov;62(5):1620-2

Case 1 pathologic diagnosis• Feature consistent with primary biliary

cirrhosis/primary biliary cholangitis– Meets all three criteria

Case 1 treatment • Ursodeoxycholic acid (UDCA)

– FDA approved drug for PBC since 1998– Well-tolerated– Better prognosis when given at early stage

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Emphasize• Diagnostic criteria• Patchy distribution and range of histologic

features• Stains supportive of chronic biliary disease

Case 2 not much clinical history • 55 year old woman with elevated LFT• Liver biopsy performed

Case 2 pathologic diagnosis• Portal and lobular inflammation or mild

nonspecific changes.

• Do you then . . .1. Go on to next case?2. Send it to UCSF GI/Hepatobiliary Pathology

Consult Service? 3. Inquire about laboratory results?

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Diagnostic approach to cholestasis in adult patients

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We called for laboratory test results• Elevated ALP (264)• Mildly elevated AST (62) and ALT (51)• Positive AMA (M2 157.7)

Case 2 clinical history and labsScenario A

• ALP elevated and AMA positive

• Diagnosis: Portal and lobular inflammation; see comment.– Comment: Describe features, state this can

represent an early manifestation of PBC

Case 2 clinical history and labsScenario B

• If ALP elevated and AMA negative

• Other characteristic clinical features– PBC-specific ANAs (Sp100 and gp210)– Elevated serum IgM– Hypercholesterolemia/Xanthomas– Sicca syndrome– Pruritus– Fatigue

Bowlus CL, Gershwin ME. The diagnosis of primary biliary cirrhosis. Autoimmun Rev. 2014 Apr-May;13(4-5):441-4.

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Diagnostic approach to cholestasis in adult patients

3

4

Case 2 clinical history and labsScenario B

• If ALP elevated and AMA negative

• Diagnosis: Portal and lobular inflammation; see comment.– Comment: Describe features, consider repeat

AMA test or use of a more sensitive assay; but could represent an early manifestation of AMA-negative PBC (autoimmune cholangitis), if DILI and primary and secondary sclerosing cholangitis has been excluded

Bowlus CL, Gershwin ME. The diagnosis of primary biliary cirrhosis. Autoimmun Rev. 2014 Apr-May;13(4-5):441-4.

Range of histologic features in PBC• Non-specific features including portal tracts with

no alterations to mild portal and lobular inflammation

• Duct injury +/- ductular reaction– Patchy ductocentric lymphocytic cholangitis to florid

duct lesion• Duct loss / ductopenia

• Accompanied by portal-based fibrosis to biliary cirrhosis

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Portal tract alteration• Duct injury

– Epithelial cells stratified, hyperplastic, attenuated, or ectatic

– Cytology with swollen, vacuolated, or eosinophilic cytoplasm and pyknotic nuclei

• Inflammation– Lymphoid aggregate, ductocentric, intraepithelial or

completely replace duct, and can have interface activity

– Composed of epithelioid or foamy histiocytes and lymphocytes, plasma cells, and/or eosinophils

Florid duct lesion?

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Florid duct lesion

Other autoantibodies in PBC• Antinuclear antibodies (ANA)

– Positive in ~50% of PBC pts irrespective of AMA status

– Positive in up to 85% of AMA-negative PBC pts• Rim-like pattern with g210 and p62• Multiple nuclear dots with Sp100

• Smooth muscle antibody (SMA)– Positive in 2/3 of PBC pts

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Supportive of chronic biliary disease• Periportal hepatocytes

– Have cytoplasmic copper deposition on copper stain

– Immunoreactive for CK7

Case 3 clinical history• 46 year old woman with elevated ALP (238)• Normal AST (33), ALT (53), Tbili (0.3)

• 10 months later found to have positive AMA (titer 1:640)

• Liver biopsy performed

Copper (rubeanic acid) stain

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40x CK7

Case 3 pathologic diagnosis Liver, core needle biopsy: Features consistent with primary biliary cirrhosis/primary biliary cholangitis; see comment.Comment: • Portal and lobular inflammation• Duct injury and loss (confirmed on CK7)• Cholestatic effect (focal periportal copper and

CK7 positive hepatocytes)• Early stage

Staging systemsStage Ludwig Scheuer

1 Portal inflammation(duct damage can be present)

Florid duct lesion

2 Periportal inflammation Ductular reaction (periportal fibrosis often present)

3 Bridging fibrosis (ductopenia usually present)4 Biliary cirrhosisNot useful in predicting prognosis due to • Heterogeneity in the distribution of features • Combined information about inflammation and fibrosis

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Bridging fibrosis and ductular reaction

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Case 4 clinical history• 50 year old woman

– Negative HCV, HBsAb, and AMA – Positive ANA– Elevated IgM (622) and IgG (4051) – Mildly elevated ALT (94), AST (93), total bili (13.4)

Case 4 pathologic diagnosis• Cirrhosis with ductopenia and cholate stasis

suggestive of AMA-negative PBC; see comment.– If negative imaging studies

• aka autoimmune cholangiopathy or autoimmune cholangitis

• Indistinguishable from PBC pts who are AMA-positive

O'Brien C, et al. Long-term follow-up of antimitochondrial antibody-positive autoimmune hepatitis. Hepatology. 2008 Aug;48(2):550-6.

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Describe the features seen

A. Portal and lobular inflammationB. Infiltrate with easily identified plasma cellsC. Florid duct lesionD. Ductular reactionE. DuctopeniaF. Periportal copper depositionG. CK7 positive periportal hepatocytesH. Nodular regenerative hyperplasiaI. Biliary pattern of cirrhosis

Hepatologist wants to know• Can the described features be seen in PBC• Or is it another disease process

– Autoimmune hepatitis– Overlap syndrome– Primary sclerosing cholangitis– Drug reaction (DILI)– Large duct obstruction– Sarcoidosis

Cholangiography is gold standard for diagnosis of PSC

• Magnetic resonance cholangiopathy (MRCP)– Method of choice because it is non-invasive– Sensitivity of 86% and specificity of 94%

• Endoscopic retrograde cholangiopancreatography(ERCP)– Optimal for early changes when duct have shallow ulcers

without stricture• Distribution

– Frequent involves intra- and extra-hepatic bile ducts, 87%– Intrahepatic ducts alone, 11-25% – Extrahepatic ducts alone, 2%

Case 5 clinical history• 45 year old man with ulcerative colitis and

primary sclerosing cholangitis who undergoes liver transplant

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Cirrhotic with duct ectasia or loss Hilar periductal inflammation

Hilar duct dialation or ulcerated with bile extravasation and inflammation Range of histologic features in PSC*

• Non-specific features including portal tracts with no alterations to mild portal inflammation

• Ductular reaction with duct injury• Can have lobular inflammation• Accompanied by portal-based fibrosis • Periductal fibrosis or fibro-obliterative duct lesion• Biliary cirrhosis

*Histologic features overlaps PBC

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Comparison between PSC vs PBCClinical, immunologic and imaging

PSC PBCAge (years) Wide age range, most

between 25-40; can occur in children

Typically >50, does not occur in children

Gender Male preponderance (2-3:1) Female preponderance (9-14-:1)Disease association

Idiopathic inflammatory bowel disease, especially ulcerative colitis

Other autoimmune diseases suchas Sjogren syndrome, and autoimmune thyroid disease

Serum immunoglobulins

No significant increase Elevated IgM

Autoantibodies No specific antibodies; AMA rare

AMA, ANA-centrometric type

Cholangiography Stricturing and beading of large ducts; normal in small-duct PSC

Normal extrahepatic and large intrahepatic ducts

Modified Table 26.4 Practical Hepatic Pathology: A Diagnostic Approach, 1st Edition

A Volume in the Pattern Recognition Series, Expert Consult 2011 by Saunders, an imprint of Elsevier Inc. Philadelphia, PA

Small duct PSC• Frequency of 11-17%• Involves smaller caliber bile ducts• Liver biopsy required for diagnosis

Comparison between PSC vs PBCPathology

PSC PBCBile duct injury Affects large intra- and

extra-hepatic ductsAffects small interlobular bile ducts

Florid duct lesion Rare CharacteristicPortal inflammation Tends to be less Typically prominentDuctular reaction Typically prominent Typically less prominentObliterative fibrosis of medium and large ducts

Characteristics but often not sampled on biopsy

Absent

Periportal copper* Present Present

Modified Table 26.4Practical Hepatic Pathology: A Diagnostic Approach, 1st Edition

A Volume in the Pattern Recognition Series, Expert Consult 2011 by Saunders, an imprint of Elsevier Inc. Philadelphia, PA

*Nonspecific feature of chronic cholestasis

Fibro-obliterative duct lesion

CK7

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Septal/interlobular ducts with periductal fibrosisNOT A SPECIFIC FEATURE OF

PRIMARY SCLEROSING CHOLANGITIS Case 6 clinical history• 42 year old man with ulcerative colitis and

elevated alkaline phosphatase• Negative “autoimmune panel” and

hyperglobulinemia (IgG 1827)• Normal MRCP• Liver biopsy was performed

Variability in distribution Portal zones

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CK 7 immunohistochemical stain Copper (rubeanic acid) stain

Case 6 pathologic diagnosis• Features consistent with chronic biliary tract

disease; see comment.

• Comment: Describe features (portal information with duct loss/ductopenia and septal and focal bridging fibrosis; chronic biliary process supported by stains). Potential etiology small duct PSC vs AMA-negative PBC.

Chronic biliary tract diseases• Elevated ALP• No visible cholestasis on biopsy

– Small duct PSC– Early stage PSC and PBC

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Case 7 clinical history• 71 year old man with progressive jaundice • Infectious complication following

enolymphatic sac enhancement surgery for vertigo.

• Elevated ALP (245) and Tbili (12)

Is this PSC? Case 7 pathologic diagnosis• Cholestasis, portal inflammation and ductular

reaction; see comment. • Differential includes large duct obstruction or

drug reaction– LiverTox database

• DILI due to Augmentin toxicity

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Secondary sclerosing cholangitis• Infection (AIDS cholangiopathy)• Vascular (ischemic cholangiopathy/ischemic

stricturing)• Toxic (intra-arterial chemotherapy such as

floxuridine)• Congenital (Caroli disease)• Infiltrative (cholangiocarcinoma)• Hepatolithiasis• Trauma (surgical biliary trauma)• Immunologic (IgG4-related sclerosing cholangitis)

Secondary sclerosing cholangitisSchistosomiasis

IgG4-related sclerosing cholangitis• Most have associated autoimmune

pancreatitis type 1 – Isolated cholangitis (10%)

• Two forms– Mass-forming hilar lesion mimics

cholangiocarcinoma– PSC-like intra- and extra-hepatic biliary strictures

mimics PSC• Steroid-responsive strictures

* Case 8 clinical history• 55 year old man with obstructive jaundice• Imaging: common bile duct stricture,

suggestive of cholangiocarcinoma• Cytology and biopsy inconclusive• Resection specimen

*

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Courtesy of Dr. Sanjay Kakar Courtesy of Dr. Sanjay Kakar

Courtesy of Dr. Sanjay Kakar

IgG4 plasma cells >10 HPF

Courtesy of Dr. Sanjay Kakar

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Requests for IgG4 stain• IgG-related sclerosing cholangitis

– One of the criterion is >10 IgG4+ plasma cells/HPF• Also observed in other diseases

– PSC• 23% (23/98 explanted liver large bile duct) • 22% of pts had elevated serum IgG4

– AIH• Rare reports (1/9 and 2/60 liver biopsies)

Zhang L, et al. IgG4+ plasma cell infiltrates in liver explants with primary sclerosing cholangitis. Am J Surg Pathol. 2010 Jan;34(1):88-94.Koyabu M, et al. Analysis of regulatory T cells and IgG4-positive plasma cells among patients of IgG4-related sclerosing cholangitis and autoimmune liver diseases.

J Gastroenterol. 2010 Jul;45(7):732-41.Umemura T, et al. Clinical significance of immunoglobulin G4-associated autoimmune hepatitis. J Gastroenterol. 2011 Jan;46 Suppl 1:48-55.

Case 9 clinical history• 62 year old man with autoimmune

pancreatitis• Elevated AST (47) and ALP (267)• ANA and AMA negative• Elevated IgG4 (226)

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Case 9 pathologic diagnosis• Features of biliary obstruction; see comment.• Comment: No IgG4+ plasma cells, does not

exclude IgG4-related disease.

• ERCP demonstrated pancreatic duct and intrahepatic biliary stricturing felt to be consistent with either PSC or IgG4 cholangiopathy

• Treated with steroids with normalization of liver enzymes and decreased IgG4

Conclusions• Chronic biliary tract diseases: PBC and PSC

– Similarities • Overlapping histologic features

– Patchy distribution that can be non-specific early in the disease process

– Distinctive • Clinical, laboratory and radiographic findings is essential• PBC progresses slowly to cirrhosis and UDCA is available• Periductal fibrosis observed in primary or secondary

sclerosing cholangitis

Nakanuma staging systemScore Fibrosis Bile duct loss Deposition of orcein-

positive granules

0No portal fibrosis or fibrosis limited to portal tracts

No bile duct loss No deposition

1Portal fibrosis with periportal fibrosis or incomplete septal fibrosis

Loss in <1/3 of portal tracts

Deposition of granules in periportal hepatocytes in <1/3 of portal tracts

2Bridging fibrosis with variable lobular disarray

Loss in 1/3-2/3 of portal tracts

Deposition of granules in periportal hepatocytes in 1/3-2/3 of portal tracts

3Cirrhosis with regenerative nodules and extensive fibrosis

Loss in >2/3 of portal tracts

Deposition of granules in periportal hepatocytes in >2/3 of portal tracts

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Stage 4 (total score 9/9) • Fibrosis 9/3, bile duct loss 3/3, orcein (copper)

deposition 3/3 • Hepatitis activity 0/3, cholangitis activity 0/3

Stage Scheuer Ludwig Nakanuma1 Florid duct lesion Portal Sum of 0 points

(no progression)2 Ductular reaction Periportal Sum of 1-3 points

(mild progression)3 Bridging fibrosis Bridging fibrosis Sum of 4-6 points

(moderate progression)

4 Biliary cirrhosis Biliary cirrhosis Sum of 7-9 points (advance progression)

Nakanuma grading system

• adf

Grade Hepatitis Cholangitis GradeHA 0 (no activity)

No interface and no or minimal lobular hepatitis

No cholangitis +/- mild duct epithelial damage CA 0 (no

activity)

HA 1 (mild activity)

Focal interface hepatitis and mild to moderate lobular hepatitis

At least one focus of evident chronic cholangitis

CA 1 (mild activity)

HA 2 (moderate activity)

Between HA1 and HA3 Two more foci of evident chronic cholangitis

CA 2 (moderate activity)

HA 3 (marked activity)

Marked interface hepatitis, moderate to marked lobular hepatitis or zonal necrosis

At least of focus of chronic non-suppurativedestructive cholangitis (granulomatous cholangitis)

CA 3 (marked activity)

Issue with interobserver variability

Case• Granuloma

Diagnosis? Case• Granuloma

Quick look at APeX revealed history of sarcoidosis

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Martin JA. Endoscopic Management of Primary Sclerosing Cholangitis: State of Art. Am J Gastroenterol. 2007;102,S32-37.

Fibro-obliterative duct lesion

CK7

Trichrome and copper stains

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Diagnosis? More information• 66 year old man • History of common bile duct stones and biliary

strictures

• Liver showed focal portal inflammation, minimal ductular reaction, and rare periductal fibrosis

• Pathologic diagnosis: Features of biliary tract disease; see comment.

• Etiology includes early stage PSC, chronic obstruction (hepatolithiasis or recurrent pyogenic cholangitis).

Case 8 clinical history• 52 year old man with BMI of 30 and diabetes

mellitus, and elevated alkaline phosphatase• Negative ANA, ASMA, and AMA

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What is the diagnosis/diagnoses? MRCP “beaded”

Case 8 diagnosis• Features supportive of early stage primary

sclerosing cholangitis.• Can cholestasis occur?• Superimposed steatohepatits, possibly

alcoholic steatohepatitis

Request for IgG4 stain

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PSC and IgG4 related sclerosingcholangitis

• IgG4 stain: 23% of PSC have >5 IgG4+ plasma cells per HPF

Absent:• Portal-based inflammatory nodules:

lymphocytes, plasma cells, eosinophils, fibroblasts

• Obliterative phlebitis not seen• Accentuation of inflammation around bile

ducts uncommon

Pseudotumor-like hilar mass

pbc and psc: back to basics - ucsf cmeama test or use of a more sensitive assay; but could represent...

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