autoimmune hepatitis in clinical practice - nwrsmeeting.org · sla/lp uga repressor 10-30% hcv...

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Autoimmune Hepatitis in Clinical

Practice

Autoimmune Hepatitis in Clinical

PracticeAtif Zaman, MD MPH

Professor of Medicine

Senior Associate Dean for Clinical and Faculty Affairs

School of Medicine

Oregon Health & Science University

Atif Zaman, MD MPH

Professor of Medicine

Senior Associate Dean for Clinical and Faculty Affairs

School of Medicine

Oregon Health & Science University

DisclosureDisclosure

Nothing to disclose Nothing to disclose

ObjectivcesObjectivces

Delineate the hepatic manifestations of various autoimmune diseases

Outline the diagnostic approach to a patient with autoimmune hepatic diseases

Discuss the management approach to autoimmune hepatic diseases

Delineate the hepatic manifestations of various autoimmune diseases

Outline the diagnostic approach to a patient with autoimmune hepatic diseases

Discuss the management approach to autoimmune hepatic diseases

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Autoimmune HepatitisAutoimmune Hepatitis


Intermittently progressive inflammatory liver disease of presumed autoimmune etiology

High gamma globulins, autoantibodies

Predominately periportal hepatitis

Usually responds favorably to corticosteroids

Intermittently progressive inflammatory liver disease of presumed autoimmune etiology

High gamma globulins, autoantibodies

Predominately periportal hepatitis

Usually responds favorably to corticosteroids

Autoimmune Hepatitis

PathogenesisPathogenesis

Most of the evidence supports a central role for an alteration in T cell

function in the pathogenesis of AIH

although abnormalities in B cell function also may be important.

Implicit in this loss of tolerance is an escape from normal suppression of self-reactive T cells, which results in ongoing inflammation and necrosis.

Most of the evidence supports a central role for an alteration in T cell

function in the pathogenesis of AIH

although abnormalities in B cell function also may be important.

Implicit in this loss of tolerance is an escape from normal suppression of self-reactive T cells, which results in ongoing inflammation and necrosis.


Another hypothesis: environmental trigger in a genetically predisposed individual. The exact relationships between the genes

and the autoimmune process remain largely undefined

at the molecular level, they are thought to involve the antigen, the major histocompatibility complex, and the T cell receptor

Another hypothesis: environmental trigger in a genetically predisposed individual. The exact relationships between the genes

and the autoimmune process remain largely undefined

at the molecular level, they are thought to involve the antigen, the major histocompatibility complex, and the T cell receptor

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Form a ternary complex in which short segments called complementary determining regions (CDR) identify and contact the antigen-MHC complex

Viruses, drugs, herbs, and immunizations have been suggested as triggering agents

Form a ternary complex in which short segments called complementary determining regions (CDR) identify and contact the antigen-MHC complex

Viruses, drugs, herbs, and immunizations have been suggested as triggering agents


Contrasting Features of Viral and Autoimmune Hepatitis


Viral Autoimmune

Prevalence: High, >1% in many Low, ~0.02%countries

Diagnostic Tests: Highly specific No single screening and pathognomonicconfirmatory tests marker

Therapy: Subject of ongoing, Based on RCT large, multicenter completed > 30 yrstrials ago!

Viral Autoimmune

Prevalence: High, >1% in many Low, ~0.02%countries

Diagnostic Tests: Highly specific No single screening and pathognomonicconfirmatory tests marker

Therapy: Subject of ongoing, Based on RCT large, multicenter completed > 30 yrstrials ago!



Natural History of Untreated Autoimmune Hepatitis


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

%Survival

%Survival

00

2020

6060

8080

100100

4040

Years of follow-upYears of follow-up00 22 5511 33 44


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Benefits of Prednisolone TherapyBenefits of Prednisolone Therapy

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

%Survival

%Survival

Years of follow-upYears of follow-up

00

2020

6060

8080

100100

4040

00 44 101022 66 88

Prednisolone (15 mg/d)Prednisolone (15 mg/d)

No therapy, yrs. 0-5No therapy, yrs. 0-5

Benefits of Prednisolone Therapy


Clinical FeaturesClinical Features

Middle-aged (or teenage) woman, non-drinker without viral hepatitis

Fatigue, arthralgias/myalgias, oligomenorrhea, jaundice

Increased ALT, AST, gamma globulins

Positive ANA and SMA

Interface hepatitis with lymphoplasmacytic infiltrate

Responds to corticosteroids

Middle-aged (or teenage) woman, non-drinker without viral hepatitis

Fatigue, arthralgias/myalgias, oligomenorrhea, jaundice

Increased ALT, AST, gamma globulins

Positive ANA and SMA

Interface hepatitis with lymphoplasmacytic infiltrate

Responds to corticosteroids

Clinical Features


Often Unrecognized FeaturesOften Unrecognized Features

May occur in men, children, or elderly

Auto-antibodies may be absent or only transient

Minimal overlap with lupus erythematosus

Responses to immunosuppressive therapy may be delayed or inadequate

May have an acute presentation with no laboratory, clinical or histological features indicating chronicity

May occur in men, children, or elderly

Auto-antibodies may be absent or only transient

Minimal overlap with lupus erythematosus

Responses to immunosuppressive therapy may be delayed or inadequate

May have an acute presentation with no laboratory, clinical or histological features indicating chronicity

Often Unrecognized Features

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Auto-Antibodies in AIHAuto-Antibodies in AIHAntibody Target Antigens Prevalence Other Disease

ANA Multiple nuclear 60-80% PBC, PSC, HCV,proteins NAFLD

SMA Actin 60-80% HCV, NAFLD, Acute viral hepatitis

pANCA Lactoferrin, Other 65-90% PSC, PBCunknown Ag

LKM-1 CYP 2D6 ≈ 4% HCV

SLA/LP UGA repressor 10-30% HCVtRNA-associatedprotein

Antibody Target Antigens Prevalence Other Disease

ANA Multiple nuclear 60-80% PBC, PSC, HCV,proteins NAFLD

SMA Actin 60-80% HCV, NAFLD, Acute viral hepatitis

pANCA Lactoferrin, Other 65-90% PSC, PBCunknown Ag

LKM-1 CYP 2D6 ≈ 4% HCV

SLA/LP UGA repressor 10-30% HCVtRNA-associatedprotein

Auto-Antibodies in AIH


Other Causes of AIH-Associated Auto-AntibodiesOther Causes of AIH-Associated Auto-Antibodies

Other DiseaseAntibody Associations Drug

ANA PBC, PSC, HCV, nitrofurantoin, NAFLD minocycline and methyldopa

SMA HCV, NAFLD, nitrofurantoin, Acute viral methyldopa and germanderhepatitis

pANCA PSC, PBC propylthiouracil, and minocycline

LKM HCV dihydralazine, halothane and ticrynafen

SLA/LP HCV

Other DiseaseAntibody Associations Drug

ANA PBC, PSC, HCV, nitrofurantoin, NAFLD minocycline and methyldopa

SMA HCV, NAFLD, nitrofurantoin, Acute viral methyldopa and germanderhepatitis

pANCA PSC, PBC propylthiouracil, and minocycline

LKM HCV dihydralazine, halothane and ticrynafen

SLA/LP HCV

Other Causes of AIH-Associated Auto-Antibodies

Portal Tract Inflammation Histology

Plasma cell cluster;

occasional eosinophils

Plasma cell cluster;

occasional eosinophils

Plasma cells

Plasma cells

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Prevalence of ANA in Liver DiseasePrevalence of ANA in Liver Disease

%Positive

%Positive

00

2020

6060

8080

100100

4040

PBCPBC HCVHCVAIHAIH PSCPSC NAFLDNAFLD HBVHBV ALDALD

Prevalence of ANA in Liver Disease


Sub-Types of Autoimmune HepatitisSub-Types of Autoimmune Hepatitis

Type 1 Type 2

Age at Presentation Any age Predominantlychildren

Female:Male 4:1 8:1

Ig G Levels Elevated IgG Variable Ig G

Ig A Levels Normal +/- Low IgA

Auto-antibodies ANA, SMA LKM-1

Cirrhosis at 3 yrs ~ 40% ~ 80%

Type 1 Type 2

Age at Presentation Any age Predominantlychildren

Female:Male 4:1 8:1

Ig G Levels Elevated IgG Variable Ig G

Ig A Levels Normal +/- Low IgA

Auto-antibodies ANA, SMA LKM-1

Cirrhosis at 3 yrs ~ 40% ~ 80%

Sub-Types of Autoimmune Hepatitis


Recognition and Diagnosis of AIHRecognition and Diagnosis of AIH

Should be considered in patient with elevated AST/ALT or cirrhosis of uncertain etiology

ANA, SMA and other autoantibody tests are poor “screening tests”

The diagnosis of AIH must be based on a constellation of findings

A diagnosis of AIH is often a “work in progress”

Should be considered in patient with elevated AST/ALT or cirrhosis of uncertain etiology

ANA, SMA and other autoantibody tests are poor “screening tests”

The diagnosis of AIH must be based on a constellation of findings

A diagnosis of AIH is often a “work in progress”

Recognition and Diagnosis of AIH

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Criteria for Definite Autoimmune HepatitisCriteria for Definite Autoimmune Hepatitis

Not all cases are straight-forward

Elevated AST, ALT, IgG

ANA, SMA or anti-LKM-1 ≥ 1:80 (≥ 1:20 in children)

Liver biopsy showing interface hepatitis with no biliary lesions, granulomas, or prominent steatosis

Absence of: Genetic liver disease

HCV RNA

HBV DNA, IgM anti-HAV

Alcohol, drugs, toxins

Not all cases are straight-forward

Elevated AST, ALT, IgG

ANA, SMA or anti-LKM-1 ≥ 1:80 (≥ 1:20 in children)

Liver biopsy showing interface hepatitis with no biliary lesions, granulomas, or prominent steatosis

Absence of: Genetic liver disease

HCV RNA

HBV DNA, IgM anti-HAV

Alcohol, drugs, toxins

Criteria for Definite Autoimmune Hepatitis


International Autoimmune Hepatitis Group Scoring System: Patient History


Favor AIH Favor other diagnosis(points) (points)

Gender Female (+2) Male (0)

Alcohol < 25 g/d (+2) > 60 g/d (–2)

Hepatotoxic drugs None (+1) Present (-4)

Other autoimmune Present (+2) None (0)diseases


Gender Female (+2) Male (0)

Alcohol < 25 g/d (+2) > 60 g/d (–2)

Hepatotoxic drugs None (+1) Present (-4)

Other autoimmune Present (+2) None (0)diseases



International Autoimmune Hepatitis Group Scoring System: Biochemistries



Alkaline phosphatase < 1.5 (+2) > 3.0 (-2)elevation: ALT elevation

Serum globulins, > 2 x normal (+3) Normal (0) globulin or IgG >1.5-2 x normal (+2)

> 1-1.5 x normal (+1)


Alkaline phosphatase < 1.5 (+2) > 3.0 (-2)elevation: ALT elevation

Serum globulins, > 2 x normal (+3) Normal (0) globulin or IgG >1.5-2 x normal (+2)

> 1-1.5 x normal (+1)


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International Autoimmune Hepatitis Group Scoring System: Serologies


ANA, SMA or LKM-1 > 1:80 (+3) < 1:40 (0)1:80 (+2)1:40 (+1)

AMA Negative (0) Positive (-4)

Hepatitis Markers Negative (+3) Positive (-3)

Other autoantibodies Present (+2) Absent (0)

HLA-DR3 or DR4 Present (+1) Absent (0)


ANA, SMA or LKM-1 > 1:80 (+3) < 1:40 (0)1:80 (+2)1:40 (+1)

AMA Negative (0) Positive (-4)

Hepatitis Markers Negative (+3) Positive (-3)

Other autoantibodies Present (+2) Absent (0)

HLA-DR3 or DR4 Present (+1) Absent (0)

International Autoimmune Hepatitis Group Scoring System: Serologies


International Autoimmune Hepatitis Group Scoring System: Histology


Interface Hepatitis +3

Lymphoplasmacytic +1Infiltrate

Rosetting of liver cells +1

None of Above -5

Biliary Changes -3

Other changes -3


Interface Hepatitis +3

Lymphoplasmacytic +1Infiltrate

Rosetting of liver cells +1

None of Above -5

Biliary Changes -3

Other changes -3

International Autoimmune Hepatitis Group Scoring System: Histology

International Autoimmune Hepatitis Group Scoring System: Response to Therapy



Favor AIH(points)

Complete Remission (normal ALT, IgG, +2bilirubin within 12 mo and for >6 monthduration or: all tests > 50% improved in1 mo. and AST/ALT < 2x normal within 6 mos.or: liver biopsy with minimal activity)

Remission with relapse (return of +3symptoms, abnormal biopsy and /or > 2 x normal AST/ALT)

Favor AIH(points)

Complete Remission (normal ALT, IgG, +2bilirubin within 12 mo and for >6 monthduration or: all tests > 50% improved in1 mo. and AST/ALT < 2x normal within 6 mos.or: liver biopsy with minimal activity)

Remission with relapse (return of +3symptoms, abnormal biopsy and /or > 2 x normal AST/ALT)


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Autoimmune Hepatitis - CriteriaAutoimmune Hepatitis - Criteria

Interpretation of International Autoimmune Hepatitis Group Score


Score Interpretation

Pre-therapy:

>15 Definite AIH

10-15 Probable AIH

Post-therapy:

>17 Definite AIH

12-17 Probable AIH

Score Interpretation

Pre-therapy:

>15 Definite AIH

10-15 Probable AIH

Post-therapy:

>17 Definite AIH

12-17 Probable AIH


A Simplified CriteriaA Simplified Criteria

Autoantibodies: assign one point if the ANA or ASMA are 1:40 OR assign two points if the ANA or ASMA are ≥1:80 (OR if the LKM ≥1:40 OR if the SLA is positive).

IgG: assign one point if the IgG is > the upper limit of normal OR assign two points if the IgG is >1.10 times the upper limit of normal.

Liver histology (evidence of hepatitis is a mandatory condition): assign one point if the histological features are compatible with autoimmune hepatitis OR two points if the histological features are typical of autoimmune hepatitis.

Absence of viral hepatitis: assign two points if viral hepatitis has been excluded.

A probable diagnosis of autoimmune hepatitis is made if the total points are six, while a definite diagnosis is made if the total points are ≥seven.

Autoantibodies: assign one point if the ANA or ASMA are 1:40 OR assign two points if the ANA or ASMA are ≥1:80 (OR if the LKM ≥1:40 OR if the SLA is positive).

IgG: assign one point if the IgG is > the upper limit of normal OR assign two points if the IgG is >1.10 times the upper limit of normal.

Liver histology (evidence of hepatitis is a mandatory condition): assign one point if the histological features are compatible with autoimmune hepatitis OR two points if the histological features are typical of autoimmune hepatitis.

Absence of viral hepatitis: assign two points if viral hepatitis has been excluded.

A probable diagnosis of autoimmune hepatitis is made if the total points are six, while a definite diagnosis is made if the total points are ≥seven.


Indications for TreatmentIndications for Treatment

Absolute Relative None

AST 10x normal Symptoms No symptoms

AST 5x normal AST < 5x normal Inactiveand -globulin -globulin cirrhosis 2x normal < 2x normal

Bridging necrosis Interface Portal hepatitis hepatitis

Absolute Relative None

AST 10x normal Symptoms No symptoms

AST 5x normal AST < 5x normal Inactiveand -globulin -globulin cirrhosis 2x normal < 2x normal

Bridging necrosis Interface Portal hepatitis hepatitis

AASLD Practice Guidelines, Hepatology 2002, 36:479AASLD Practice Guidelines, Hepatology 2002, 36:479

Indications for Treatment Based on the results of

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Adapted from Soloway, et al, Gastroenterology 1972; 63:828 Adapted from Soloway, et al, Gastroenterology 1972; 63:828

Comparison of Various TreatmentsComparison of Various Treatments

%Treatment

failures

%Treatment

failures

00

4040

6060

2020

YearsYears00 2211 33

Pred + AzaPred + Aza

Prednisone Prednisone

AzathioprineAzathioprine

PlaceboPlacebo

Comparison of Various Treatments


Definition of RemissionDefinition of Remission

All of the following: Disappearance of symptoms

Normal serum bilirubin, -globulin

ALT, AST < 2x normal

Normal hepatic histology or minimal inflammation, no interface hepatitis

Histology lags biochemical remission by ~6 months

All of the following: Disappearance of symptoms

Normal serum bilirubin, -globulin

ALT, AST < 2x normal

Normal hepatic histology or minimal inflammation, no interface hepatitis

Histology lags biochemical remission by ~6 months

Definition of Remission


Managing Patients in RemissionManaging Patients in Remission

Gradual withdrawal of corticosteroids

Discontinuation of azathioprine

Long term, regular monitoring for expected relapse

Gradual withdrawal of corticosteroids

Discontinuation of azathioprine

Long term, regular monitoring for expected relapse

Managing Patients in Remission

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End of Therapy Liver Histology Predicts RelapseEnd of Therapy Liver Histology Predicts Relapse

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

Risk of Relapse (%)Risk of Relapse (%)

00 2020 4040 6060 8080 100100

Portal Plasma CellsPortal Plasma Cells

Inactive CirrhosisInactive Cirrhosis

Interface HepatitisInterface Hepatitis

Normal HistologyNormal Histology

End of Therapy Liver Histology Predicts Relapse


Maintenance TherapyMaintenance 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

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

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

oror

oror

Maintenance Therapy


Options When Conventional Treatments FailOptions When Conventional Treatments Fail

Treatment failures: Prednisone 60 mg/d or Prednisone 30 mg/d +

Azathioprine 150 mg/d

Drug intolerance or treatment failure:

Mycophenolate mofetil (1 g BID)

Tacrolimus (4 mg BID, trough level = 6-10 ng/ml)

Cyclosporin (5-6 mg/kg/d, trough level = 200-250 ng/ml)

Treatment failures: Prednisone 60 mg/d or Prednisone 30 mg/d +

Azathioprine 150 mg/d

Drug intolerance or treatment failure:

Mycophenolate mofetil (1 g BID)

Tacrolimus (4 mg BID, trough level = 6-10 ng/ml)

Cyclosporin (5-6 mg/kg/d, trough level = 200-250 ng/ml)

Heneghan MA, McFarlane, IG. Hepatology 2002, 35:7Cjaga, AJ. Seminars in Liv. Dis., 2002, 22:365Heneghan MA, McFarlane, IG. Hepatology 2002, 35:7Cjaga, AJ. Seminars in Liv. Dis., 2002, 22:365

Options When Conventional Treatments Fail

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Pitfalls in Therapy of AIHPitfalls in Therapy of AIH

Inadequate initial therapy (histological remission lags behind biochemical remission)

Failure to consider steroid-sparing (or steroid free) regimens

Initiation of therapy without appropriate indication (mild hepatitis, inactive cirrhosis, wrong disease)

Persistent (“lifelong”) therapy in those in first complete remission with benign follow-up biopsies

Inadequate initial therapy (histological remission lags behind biochemical remission)

Failure to consider steroid-sparing (or steroid free) regimens

Initiation of therapy without appropriate indication (mild hepatitis, inactive cirrhosis, wrong disease)

Persistent (“lifelong”) therapy in those in first complete remission with benign follow-up biopsies

Pitfalls in Therapy of AIH


Liver TransplantationLiver Transplantation

Overall 5-year survival rates 80-90%

Increased frequency of acute allograft rejection

AIH recurrence in 30-40%

Surveillance liver biopsies may be warranted

Manage with corticosteroids

Overall 5-year survival rates 80-90%

Increased frequency of acute allograft rejection

AIH recurrence in 30-40%

Surveillance liver biopsies may be warranted

Manage with corticosteroids

Liver Transplantation

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