Autoimmune Hepatitis and Overlap Syndromes3.gi.org/meetings/bp2016/16ACG_BestPrac_0026.pdf · hepatitis is associated with an 86% to 100% frequency of relapse ... Disease-specific

Tram T. Tran, MD, FACG

Autoimmune Hepatitis and Overlap Syndrome

Tram T. Tran, MD, FACGMedical Director, Liver TransplantAssociate Professor of Medicine

Cedars Sinai Medical Center

Autoimmune HepatitisDemographics and Epidemiology

Uncommon Afflicts ∼200,000 in U.S.A. Incidence 1.9 per 105 per year Prevalence 16.9 per 105

Female to male ratio= 4:1 Afflicts both children and adults Bimodal age distribution: 10-20 vs. 45-75 yrs 6% liver transplants in US 40% mortality in symptomatic patients ≤6 months if untreated

2016 ACG Governors/ASGE Best Practices Course Copyright 2016 American College of Gastroenterology

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Autoimmune HepatitisClinical Spectrum

Acute Hepatitis 25-30% Usually younger Icteric acute viral hepatitis-like picture

Asymptomatic 15-20% Extrahepatic manifestations may be present

Fulminant Hepatic Failure ∼5% Potentially reversible without OLT

Czaja AJ: Clin Liver Diseases 2002; 6: 317-334

Autoimmune HepatitisClinical Spectrum

Symptomatic Chronic Hepatitis 50% Fatigue, malaisePhysical findings:Hepatomegaly (78%)Splenomegaly (32-56%)Jaundice (46%)

Czaja AJ: Clin Liver Diseases 2002; 6: 317-334

Cryptogenic Cirrhosis: < 5% Decompensated PVHTN event


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AIH Clinical Presentations

Extrahepatic Autoimmune Manifestations AIH Type 2 (40%) > AIH Type 1 (10%) Spectrum Thyroid disease (Hashimoto’s, Graves) Rheumatoid arthritisMiscellaneousDiabetes mellitus type 1 Sjogren’s syndromeVitiligoAddison’sCeliac sprue

AIHLaboratory Testing

Anticipated Results: Elevated aminotransferases Usually not more than 500 U/L ALT ≥ AST

± Elevated bilirubin Moderately elevated alkaline phosphatase Immunoglobulins SPE → Hypergammaglobulinemia Immunoelectrophoresis → Elevated IgG


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AIH Diagnostic Strategy

Exclude other causes of liver disease! Viral hepatitis C Alpha -1 antitrypsin deficiency Cholestatic autoimmune diseasesPBCPSC

Wilson’s Disease Alcohol Drug hepatotoxicityMinocycline Anti-epileptics

AIHSequential Autoantibody Testing

ANASMApANCA

LKM1

Positive

Type 170-80%

Type 24%

+SLA/LPASGP-ROther?

AIH10%

Negative

Positive

Negative

AIH ?

10%

Vogel A, et al: Clin Liver Diseases 2002; 6: 451-466

HLA TestingIAHG Criteria


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Alvarez F, et al: J Hepatol 1999; 31: 929-38

Elevated AST,ALT (> ALKP)

ANA, SMA, anti-LKM1 > 1:80IgG > 1.5x ULN

AMA negative

Negative viral hepatitis serologies

Histology: interface hepatitis, plasma cell infiltration

Normal serum copper, alpha antitrypsin, ceruloplasmin

Fatigue, jaundice, nausea, abdominal pain, female gender

Drug history: minocycline, diclofenac, propylthiouracil, nitrofurantoin, methyldopa, isoniazid

Diagnosis of autoimmune hepatitis


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Plasma Cell Interface Activity and Hepatitic Rosettes

Plasma cell interface activity

Hepatitic rosette

Treatment Regimen Dose

Prednisone alone 40mg - 60mg PO daily

Taper down to 10mg daily in 4 weeks (depending on treatment response)

Preferred Regimen: Prednisone + Azathioprine*

30mg PO daily + 50mg PO daily

Budesonide + Azathioprine* 3mg PO TID + 50mg PO daily

*Azathioprine: Monitor for leukopenia, thrombocytopenia ; Azathioprine: Pregnancy category D


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Autoimmune Hepatitis

Benefits of Prednisolone Therapy

Kirk AP, Jain S, Pocock S, Thomas HC & Sherlock S, Gut, 1980, 21:78

%Survival

Years of follow-up

0

20

60

80

100

40

0 4 102 6 8

Prednisolone (15 mg/d)

No therapy, yrs. 0-5

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10

Per

cen

t P

rob

abili

ty

Duration of Therapy (Years)

No cirrhosis

Cirrhosis during or aftertherapy

Cirrhosis at presentation

Probabilities of Survival During Steroid Therapy

Czaja A, 2003


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0

10

20

30

40

50

60

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100

0 6 12 18 24 30 36 42 48

Pe

rce

nt

Re

mis

sio

n

Duration of Therapy (months)

Clinical Remission

Biochemical Remission

Histological Remission

Probabilities of Clinical, Biochemical andHistological Remission During Steroid Therapy

85% who enter remissiondo so within 3 years.

Czaja A, 2003

0

10

20

30

40

50

60

70

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100

0 1 2 3 4 5 6 7 8 9 10

Per

cen

t P

rob

abili

ty

Duration of Therapy (Years)

During treatment

During follow-up

After treatment

Probability of Cirrhosis During Steroid Therapy

Czaja A, 2003


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AIH TreatmentOld and New Approaches to Immunosuppression

CorticosteroidAzathioprine

Cyclosporine

Tacrolimus

Mycophenolate mofetil

Sirolimus

rHuIL-10

Positive randomized,controlled trials

Positive, open label trials



Investigational

Investigational

Agents Status

Vierling JM & Flores P: Clin Liver Dis 2002; 6: 537-62

TREATMENT END POINTSEnd Point Definition Response

Remission AST< 2X ULN

Histology inactive or portal hepatitis

Taper prednisone azathioprine

Monitor liver tests

Treatment

Failure

AST/TB with elevation (66% of pretreatment level), clinical deterioration

Higher prednisone/ azathioprine doses or other regimen

Intolerance to Therapy

Obesity, depression, diabetes, osteoporosis, cytopenia, cholestasis

Dose reduction, 6-MP, other regimen


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TREATMENT END POINTS• Liver biopsy best method to determine clinical

remission – Should be considered before termination of therapy – normal hepatic architecture associated with a 20%

relapse rate after drug withdrawal – portal hepatitis associated with a 50% frequency of

relapse – Progression to cirrhosis or persistence of interface

hepatitis is associated with an 86% to 100% frequency of relapse

• Histological improvement lags behind clinical and laboratory improvement by 3 to 6 months

AIHResponse to Therapy

TreatmentOutcomes

Remission IncompleteResponse Non-Response

AST >2 X ULNSymptoms

Withdraw Therapy

↑ AST↑ Bilirubin

Histological worseningAscites, PSE

Alternative RxMycophenolate Cyclosporine Tacrolimus Ursodiol

Czaja AJ: Clin Liver Dis 2002; 6: 511-36Vierling JM: Clin Liver Dis 2002; 6: 537-62


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End of Therapy Liver Histology Predicts Relapse

Czaja, AJ, Davis, GL, Ludwig, J, Taswell, HF. Hepatology 1984, 4:622Czaja, AJ, Carpenter, HA. Liver International 2003, 23:116

Risk of Relapse (%)

0 20 40 60 80 100

Portal Plasma Cells

Inactive Cirrhosis

Interface Hepatitis

Normal Histology

End of Therapy Liver Histology Predicts Relapse


Maintenance Therapy

• Lowest effective dose for Prednisone ≤ 10 mg/d

• Azathioprine, 1.5-2.0 mg/kg/d

• Low dose Prednisone ≤10mg/d plus Azathioprine 50 mg/d

• Add Vitamin D (50,000 U/wk) and Ca (1-1.5 g/d) to Prednisone

• Monitor for hypertension, cataracts, glaucoma, bone disease in Prednisone recipients

• Monitor WBC, platelets in Azathioprine recipients

or

or


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0

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0 6 12 18 24 30 36 42 48

Per

cen

t o

f P

atie

nts

Post-OLT Follow-Up (Months)

Survival SMA

ANA Recurrence

Course After Orthotopic Liver Transplantation

Czaja A, 2003

Update on Autoimmune Liver DiseasesSummary

Prevalence 400/106 40/106 17/105

Gender predominance Female Male FemaleAge Adults All AllFamilial Yes Yes YesAssociated diseases AI diseases IBD AI DiseasesInfectious etiology? Possibly Unlikely PossiblyDisease-specific AutoAbs AMA, ANAs None SLA/LPValidated prognostic models Yes Yes NoComplications HCC AdenoCa HCCUDCA safe and effective Yes Yes* NoImmunosuppression effective Early stages No YesOLT effective but with recurrence Yes Yes Yes

PBC PSCFeature

*20-30 mg/kg/d

AIH


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Autoimmune Hepatitis Overlap SyndromesDifferential Diagnostic Dilemmas

AIH

HCV

Crypto PBC

PSC11% 10%

13% 6%

Overlap Syndromes

• AMA positive without features of PBC

• Bile duct lesions in otherwise overt AIH

• Acute AIH plus viral hepatitis

• Cryptogenic AIH (no autoantibodies)

• Cholestatic AIH with co-existent PSC

Variants of Autoimmune Hepatitis

Variants of Autoimmune Hepatitis


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Medical Challenges: Diagnosis

• • 2-19% PBC• 7-14% PSC• Believed to have overlap

with clinical, biochemical, serological, histological criteria

• Sequential development may occur

• Clinical significance is in the treatment options!

IAIHG Position Statement 2011


Prevalence of ANA in Liver Disease

%Positive

0

20

60

80

100

40

PBC HCVAIH PSC NAFLD HBV ALD


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PSC Diagnosed

ALT 5X ULNIgG 2X ULN

IAIHG Position Statement 2011


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Overlap: serologies not that helpful

Medical Challenges: Overlap

• Treatment– AIH: Standard treatment

• Prednisone + AZA• Responsive less often• Progression to transplant more common

Lüth S, et al. J Clin Gastroenterol 2009;43:75–80.


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Medical Challenge: IAC• Immunoglobulin Associated Cholangiopathy

– Cholangiographically looks like PSC– Distinct histology– 127 pts Mayo clinic dx’d with PSC

• 7% had elevated IgG4– Worse tests, higher Mayo risk score– Shorter time to transplant and aggressive course pre/post OLT

– Treatment response to steroids!• 40% re to steroids in 11 weeks• Resolution of strictures

Mendes FD,. Am J Gastroenterol 2006; 101: 2070–5.Ghazale A Gastroenterology 2008; 134: 706–15.

PATHOLOGY DEFINITIVE IAC FEATURES:

PROBABLE IAC Other

Bile duct hasLPC infiltratewith > 10 IgG4positive cellsper hpf.

pancreatic/biliaryresection orcore pancreaticbiopsy withsupportingpathology.ORClassicradiographicfeatures of AIPplus elevatedserum IgG4(>140 mg/dL).

2 or more of thefollowing:• elevated serum

IgG4• Other organ

involvement(ex.retroperitonealfibrosis).

• Supporting bileduct biopsy.

• Suggestivepancreatic imaging

CoexistingIBD isuncommon.

Management: For definitiveIAC,corticosteroidsfor 11 weeks andconsideration ofazathioprine formaintenance ofremission.

For probableIAC,corticosteroidsfor 4 weeks, ifresponsive thencontinue to treatas definitiveIAC.


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Serum IgG4 levels > 2xULN

• PSC patients with serum IgG4> 2 X ULN• Endpoints: mortality, portal HTN, CCA, CR• 349 pts: 14% with abnormal IgG4

median f/u 5 years

Higher frequency of Cholangiocarcinoma7/24 ( 29%) vs. 42/325 (12.9%)

p = 0.03

Iman M, Gores GJ, LaRusso NF, et al. Serum Immunoglobulin G4 Levels in Primary Sclerosing Cholangitis. AASLD. 2013. Abstract 1200.

Primary Biliary Cholangitis:Background

• First described in 1857, but not well characterized until 1970’s

• Chronic, slowly progressive liver disease• Autoimmune in origin• Anti-mitochondrial antibody is key in diagnosis


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Clinical Presentation

• Asymptomatic– 20-80% can have no symptoms– Duration of no symptoms variable 6-10 years– Present with elevated alkaline phosphatase or

+AMA– Osteoporosis or other extrahepatic associations

with PBC

PBC

• Differential diagnosis: extra-hepatic biliary obstruction, primary sclerosing cholangitis, drug-induced cholestasis, sarcoidosis, hepatitis C and overlap with autoimmune hepatitis

• Complications of PBC include pruritus, osteopenia, fat soluble vitamin deficiency and hypercholesterolemia


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Overlap Syndromes

French Scoring System for PBC and AIH Overlap

AIH defined by two or more:

• ALT > 5x normal

• SMA positive and/or Ig G > 2 normal

• Liver biopsy with piecemeal necrosis (moderate/severe)

Chazouillères, Hepatology 1998; 28:296

Associations with PBC

Osteoporosis Sicca syndrome

Arthropathy/arthritis Skin disorders

Sjogren’s syndrome Celiac disease

Raynaud’s disease Pulmonary fibrosis

Scleroderma Gallstones

CREST syndrome Hepatocellular carcinoma

SLE Myasthenia gravis

Glomerulonephritis Hashimoto thyroiditis


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Clinical Presentation

• Symptomatic– Pruritus, scratch marks– Fatigue (most common)– Abdominal pain– Hepato/splenomegaly– Jaundice

• No strong evidence that having symptoms or not predicts histologic stage

Pruritus

• Very common (20-60%)• Usually precedes jaundice• May occur first in pregnancy• Begins in perianal/genital region or on

surfaces of palm/soles• Worse in evening, winter, with dry skin• NOT effectively eased by scratching


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Diagnosis

• Elevated liver enzymes– Alkaline phosphatase

• Positive AMA• Diagnositic liver biopsy findings• Two or more is “probable” diagnosis

– 80% go on to develop classic picture

PRIMARY BILIARY CIRRHOSISAutoantibodies

Autoantibody• AMA• ANA

- Sp100- Promyelocytic leukemia protein- gp210

• SMA• RF• Thyroid• Bile canaliculi• Endomysium• Hsp65kD• Platelet (GP Ib/IX, GP Ib/IIIa)• Alpha-enolase• Lipid A

Frequency (%)95-985-5421192626-4924-6015-2635111003929100


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AMA

• How good is the test?– 98% sensitive– 96% specific

• 10-15% PBC are AMA-negative• May be detectable years before any other

abnormalities• Titers DO NOT correlate to disease severity

– AMA may decrease after liver tx


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Alkaline phosphatase

• Classic cholestatic enzyme• Reaches plateau early in disease• Slightly abnormal 1500-2000 U/l• More elevated than AST/ALT• Fluctuates by 20-30%• Not related to rate of progression

Bilirubin

• Rises in all patients at end stage of disease• Best prognostic indicator• Bilirubin >6 : life expectancy 25 months

>10: life expectancy 20 months


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Treatment

• No specific treatment has definitively improved survival benefit

• Three agents: ursodiol, azathiaprine, and cyclosporine have the strongest scientific proof of efficacy

• Based on current evidence, ursodiol is safest and potentially most effect

Treatment: Urso

• 11 placebo controlled randomized trials• Associated with diminution of symptoms,

improvement in biochemical tests, variable effect on histology

• Trend towards delay in liver transplant in 2 studies


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Overlap Syndromes

• Diagnosis made when a single designation is inadequate to convey the mix of clinical, laboratory, and histologic features of a disease process– AIH but with AMA, high alkaline phosphatase,

biliary pathology– PBC but with markedly elevated transaminases,

elevated IgG, interface hepatitis

Response to combination therapy


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Summary

• Diagnosis of AIH and overlap syndromes can be challenging– Awareness– Biopsy findings– Look for dominant process

• Combination therapy beneficial


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Documents

Autoimmune Hepatitis and Overlap Syndromes3.gi.org/meetings/bp2016/16ACG_BestPrac_0026.pdf · hepatitis is associated with an 86% to 100% frequency of relapse ... Disease-specific