thomas hargrave m.d. november 20, 2009

Autoimmune HepatitisAutoimmune Hepatitis

Thomas Hargrave M.D.

November 20, 2009

Thomas Hargrave M.D.

November 20, 2009


Autoimmune HepatitisAutoimmune HepatitisAutoimmune HepatitisAutoimmune Hepatitis

Intermittently progressive inflammatory liver disease of presumed autoimmune etiology

High gamma globulins, autoantibodies

Predominately periportal plasma cell hepatitis

Usually responds favorably to corticosteroids or immnomodulators

Intermittently progressive inflammatory liver disease of presumed autoimmune etiology

High gamma globulins, autoantibodies

Predominately periportal plasma cell hepatitis

Usually responds favorably to corticosteroids or immnomodulators




First described by Waldenstrom in 1950 in a young woman with idiopathic chronic hepatitis

Now recognized as a chronic multisystem disorder that occurs in males and females of all ages.

AIH can co-exist with other liver diseases (hepatitis C) and can be triggered by drugs (minocycline) and herbal agents

First described by Waldenstrom in 1950 in a young woman with idiopathic chronic hepatitis

Now recognized as a chronic multisystem disorder that occurs in males and females of all ages.

AIH can co-exist with other liver diseases (hepatitis C) and can be triggered by drugs (minocycline) and herbal agents

Often Unrecognized FeaturesOften Unrecognized Features



Annual incidence in North America of 1.9/100,000

Prevalence 16.9/100,000

Accounts for 6% of liver transplantations

Affects all ages and ethnic groups

70-80% of AIH are women but men may predominate over the age of 70

Annual incidence in North America of 1.9/100,000

Prevalence 16.9/100,000

Accounts for 6% of liver transplantations

Affects all ages and ethnic groups

70-80% of AIH are women but men may predominate over the age of 70




Characterized by considerable heterogeniety and fluctuating disease activity over time

Liver injury is the result of cell-mediated immunologic attack against genetically predisposed hepatocytes

HLA association with B8, B14,DR3,Dr4, Dw3

There is little evidence that the autoantibodies have a role in the pathogenesis of AIH

Characterized by considerable heterogeniety and fluctuating disease activity over time

Liver injury is the result of cell-mediated immunologic attack against genetically predisposed hepatocytes

HLA association with B8, B14,DR3,Dr4, Dw3

There is little evidence that the autoantibodies have a role in the pathogenesis of AIH



Clinical Features: ClassicClinical Features: ClassicClinical Features: ClassicClinical Features: Classic 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 FeaturesClinical Features


Clinical Features: Highly VariableClinical Features: Highly VariableClinical Features: Highly VariableClinical Features: Highly Variable

Asymptomatic abnormal LFTs: up to 50%

Acute hepatitis 18-30%

Chronic fatigue, viral-like illness

Fulminant hepatic failure (rare)

Many patients found to have established cirrhosis during initial acute presentation (20%)

Long periods of sub-clinical disease may occur both before and after presentation

Asymptomatic abnormal LFTs: up to 50%

Acute hepatitis 18-30%

Chronic fatigue, viral-like illness

Fulminant hepatic failure (rare)

Many patients found to have established cirrhosis during initial acute presentation (20%)

Long periods of sub-clinical disease may occur both before and after presentation

Clinical FeaturesClinical Features


Often Unrecognized FeaturesOften Unrecognized FeaturesOften Unrecognized FeaturesOften Unrecognized Features

May occur in men, children, or elderly

Auto-antibodies may be absent or only transient

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

Responses to immunosuppressive therapy may be delayed or inadequate

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



Differential Diagnosis: Acute HepatitisDifferential Diagnosis: Acute HepatitisDifferential Diagnosis: Acute HepatitisDifferential Diagnosis: Acute Hepatitis

Viral Hepatitis

Drug induced

Herbal medications

Wilson’s Disease: F:M 4:1, KF Rings, Ceruloplasmin<20

Cirrhosis

Chronic active hepatitis,

Fulminant hepatic failure.

Viral Hepatitis

Drug induced

Herbal medications

Wilson’s Disease: F:M 4:1, KF Rings, Ceruloplasmin<20

Cirrhosis

Chronic active hepatitis,

Fulminant hepatic failure.


Differential DiagnosisDifferential DiagnosisDifferential DiagnosisDifferential Diagnosis Drug-induced Autoimmune Hepatitis

Minocycline

Nitrofurantoin

Orlistat

Meloxicam

Herbal medications

Drug-induced Autoimmune Hepatitis

Minocycline

Nitrofurantoin

Orlistat

Meloxicam

Herbal medications


Inflixamab INH Statins (unmask AIH) Allopurinol Aldomet

Inflixamab INH Statins (unmask AIH) Allopurinol Aldomet

Black cohosh Chaparral leaf Kava Kava Valerian St. John’s Wort

Black cohosh Chaparral leaf Kava Kava Valerian St. John’s Wort

Echinacea Noni Juice

Echinacea Noni Juice


Sub-Types of Autoimmune HepatitisSub-Types of Autoimmune HepatitisSub-Types of Autoimmune HepatitisSub-Types of Autoimmune Hepatitis

Type 1 Type 2

Age at Presentation Any age Predominantly children

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 Predominantly children

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 HepatitisSub-Types of Autoimmune Hepatitis


Auto-Antibodies in AIHAuto-Antibodies in AIHAuto-Antibodies in AIHAuto-Antibodies in AIHAntibody Target Antigen Prevalence

ANA Multiple nuclear 60-80%proteins

SMA Actin 60-80%

pANCA Lactoferrin, Other 65-90%unknown antigen

LKM-1 CYP 2D6 ≈ 4% US/20% EU

SLA/LP UGA repressor 10-30% (high

tRNA-associated specificity)protein

Antibody Target Antigen Prevalence

ANA Multiple nuclear 60-80%proteins

SMA Actin 60-80%

pANCA Lactoferrin, Other 65-90%unknown antigen

LKM-1 CYP 2D6 ≈ 4% US/20% EU

SLA/LP UGA repressor 10-30% (high

tRNA-associated specificity)protein

Auto-Antibodies in AIHAuto-Antibodies in AIH


Other Causes of AIH-Associated Auto-AntibodiesOther Causes of AIH-Associated Auto-AntibodiesOther 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 germander hepatitis

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 germander hepatitis

pANCA PSC, PBC propylthiouracil, and minocycline

LKM HCV dihydralazine, halothane and ticrynafen

SLA/LP HCV

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


Prevalence of ANA in Liver DiseasePrevalence of ANA in Liver Disease

%%PositivePositive

%%PositivePositive

0000

20202020

60606060

80808080

100100100100

40404040

PBCPBCPBCPBC HCVHCVHCVHCVAIHAIHAIHAIH PSCPSCPSCPSC NAFLDNAFLDNAFLDNAFLD HBVHBVHBVHBV ALDALDALDALD

Prevalence of ANA in Liver DiseasePrevalence of ANA in Liver Disease

ANA Testing in Patients with Elevated Transaminases Has Low Specifcity

ANA Testing in Patients with Elevated Transaminases Has Low Specifcity

AIHAIH NAFLDNAFLD HCVHCV

ANA (+) Patients / 100,000

ANA (+) Patients / 100,000

00

5050

100100

150150

200200

Percent ANA (+)Percent ANA (+)

8080

6060

4040

2020

00

*Sem. Liv. Dis 2002, 22:339 Amer. J. Gastro 2004, 99:1316 Hepatology 1995, 21:613**J. Gastro. Hepatol. 2003 18:1118 Hepatology 2004, 40:1387 NEJM 1999, 341:556 *Sem. Liv. Dis 2002, 22:339 Amer. J. Gastro 2004, 99:1316 Hepatology 1995, 21:613**J. Gastro. Hepatol. 2003 18:1118 Hepatology 2004, 40:1387 NEJM 1999, 341:556

Autoimmune HepatitisAutoimmune HepatitisUtility of ANA Testing in Patients with Elevated TransaminasesUtility of ANA Testing in Patients with Elevated Transaminases

16


Extrahepatic ManifestationsExtrahepatic ManifestationsExtrahepatic ManifestationsExtrahepatic Manifestations

Concurrent immunologic disease present in 38% of patients with AIH

Celiac disease 10%

Thyroiditis/ Graves Disease

Ulcerative Colitis

Uveitis

Rheumatoid arthritis

Up to 18% overlap syndromes: AIH/PBC, AIH/PSC

Concurrent immunologic disease present in 38% of patients with AIH

Celiac disease 10%

Thyroiditis/ Graves Disease

Ulcerative Colitis

Uveitis

Rheumatoid arthritis

Up to 18% overlap syndromes: AIH/PBC, AIH/PSC

Recognition and Diagnosis of AIHRecognition and Diagnosis of AIH


Diagnosis of AIHDiagnosis of AIH Diagnosis of AIHDiagnosis of AIH

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

The diagnosis of AIH must be based on a constellation of clinical and lab findings

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

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

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

The diagnosis of AIH must be based on a constellation of clinical and lab findings

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

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



Laboratory FeaturesLaboratory FeaturesLaboratory FeaturesLaboratory Features

In general, transaminase elevations (5-10x) are more impressive than alkaline phosphatase or bilirubin elevations: Alt averages 200-300 U/L

Occasional cholestatic presentation with high conjugated bilirubin and alkaline phosphatase

IgG polyclonal hypergammaglobulinemia almost universal: AIH highly improbable with normal globulins

Gamma globulin typically 3-4 g/dl

IgA deficiency common in children with both type I and type II AIH

In general, transaminase elevations (5-10x) are more impressive than alkaline phosphatase or bilirubin elevations: Alt averages 200-300 U/L

Occasional cholestatic presentation with high conjugated bilirubin and alkaline phosphatase

IgG polyclonal hypergammaglobulinemia almost universal: AIH highly improbable with normal globulins

Gamma globulin typically 3-4 g/dl

IgA deficiency common in children with both type I and type II AIH

IgG Polyclonal Hypergammaglobulinemia

IgG Polyclonal Hypergammaglobulinemia


Criteria for Definite Autoimmune Criteria for Definite Autoimmune HepatitisHepatitis

Criteria for Definite Autoimmune Criteria for Definite Autoimmune HepatitisHepatitis

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

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 HepatitisCriteria for Definite Autoimmune Hepatitis

Pre-treatment Score > 15 : Definite AIH (>17 post-Rx)Score 10-15: Prob. AIH (12-17 post-Rx)

Pre-treatment Score > 15 : Definite AIH (>17 post-Rx)Score 10-15: Prob. AIH (12-17 post-Rx)

Female sex +2 ALP/ALT Ratio

<1.5: +2 1.5-3.0: 0 >3.0: -2

Globulinn >2x: +3 1.5-2.0x: +2 1.0-1.5X: +1

ANA/ASMA/LKM >1:80 +3 1:80: +2 1:40 +1 <1:40 0

AMA + -4

Female sex +2 ALP/ALT Ratio

<1.5: +2 1.5-3.0: 0 >3.0: -2

Globulinn >2x: +3 1.5-2.0x: +2 1.0-1.5X: +1

ANA/ASMA/LKM >1:80 +3 1:80: +2 1:40 +1 <1:40 0

AMA + -4

Negative HBV/HCV +1 ETOH < 25gm/d +2 Other autoimmune +2 Response to steroids

Complete +2 Relapse +3

Liver Biopsy Interface hepatitis +3 Lymphoplasmacytic +1 Neither -5

Negative HBV/HCV +1 ETOH < 25gm/d +2 Other autoimmune +2 Response to steroids

Complete +2 Relapse +3

Liver Biopsy Interface hepatitis +3 Lymphoplasmacytic +1 Neither -5

International AIH Scoring SystemInternational AIH Scoring System


Diagnosis of AIHDiagnosis of AIH Diagnosis of AIHDiagnosis of AIH

Liver biopsy essential in confirming the clinical diagnosis of AIH and stage degree of liver injury

Interface hepatitis is the hallmark of the disease

Plasma cell infiltration typical

Neither finding is disease specific

Absence of plasma cells does not exclude the disease

Liver biopsy essential in confirming the clinical diagnosis of AIH and stage degree of liver injury

Interface hepatitis is the hallmark of the disease

Plasma cell infiltration typical

Neither finding is disease specific

Absence of plasma cells does not exclude the disease


ANA positive,Near normal biopsy

ANA positive,Near normal biopsy

ANA positive steatohepatitis ANA positive

steatohepatitis

Not All Cases With ANA Will Have Autoimmune HepatitisNot All Cases With ANA Will Have Autoimmune Hepatitis

Dig Dis Sci 2003; 48:2173Dig Dis Sci 2003; 48:2173

Not All Cases With ANA Will Have Autoimmune HepatitisNot All Cases With ANA Will Have Autoimmune Hepatitis

Interface Hepatitis of AIHInterface Hepatitis of AIH

Portal tract expanded with mononuclear inflitrate

Limiting plate disrupted

Inflammation extends into acinus

Portal tract expanded with mononuclear inflitrate

Limiting plate disrupted

Inflammation extends into acinus

Portal Tract Inflammation HistologyPortal Tract Inflammation Histology

Plasma cell cluster;

occasional eosinophils

Plasma cell cluster;

occasional eosinophils

Plasma cells

Plasma cells


Natural History of Natural History of UntreatedUntreated Autoimmune Autoimmune HepatitisHepatitis

Natural History of Natural History of UntreatedUntreated Autoimmune Autoimmune HepatitisHepatitis

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, 21:78Kirk 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

%%SurvivalSurvival

%%SurvivalSurvival

0000

20202020

60606060

80808080

100100100100

40404040

Years of follow-upYears of follow-upYears of follow-upYears of follow-up0000 2222 55551111 3333 4444

Natural History of Untreated Autoimmune HepatitisNatural History of Untreated Autoimmune Hepatitis

10-Year Survival for Treated AIH 90%10-Year Survival for Treated AIH 90%Autoimmune HepatitisAutoimmune Hepatitis


Treatment Treatment

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

Appropriate management can: Improve quality of life Prolong survival/ Delay need for liver

transplant Treated patients have a life-expectancy similar

to age and gender matched controls followed up to 20 years

After > 3 decades, prednisone and azathioprine remain the mainstays of treatment

Appropriate management can: Improve quality of life Prolong survival/ Delay need for liver

transplant Treated patients have a life-expectancy similar

to age and gender matched controls followed up to 20 years

After > 3 decades, prednisone and azathioprine remain the mainstays of treatment


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


Indications for Treatment Based on the results ofIndications for Treatment Based on the results of


Monotherapy Monotherapy Combination

Therapy Combination

Therapy

Therapy in AdultsTherapy in Adults


Interval Prednisone Prednisone Azathrioprine mg/d mg/d mg/d

Week 1 60 30 50

Week 2 40 20 50

Week 3 30 15 50

Week 4 30 15 50

Daily until 20 10 50endpoint

Interval Prednisone Prednisone Azathrioprine mg/d mg/d mg/d

Week 1 60 30 50

Week 2 40 20 50

Week 3 30 15 50

Week 4 30 15 50

Daily until 20 10 50endpoint

Therapy in AdultsTherapy in Adults


Reasons for Selecting Treatment RegimensReasons for Selecting Treatment RegimensReasons for Selecting Treatment RegimensReasons for Selecting Treatment Regimens

Prednisone Monotherapy

Severe cytopenia

TPMT deficiency

Prior Aza intolerance

Pregnancy

Malignancy

Prednisone Monotherapy

Severe cytopenia

TPMT deficiency

Prior Aza intolerance

Pregnancy

Malignancy

Combination (Pred+Aza)

Postmenopausal state

Osteoporosis

Brittle diabetes

Obesity

Acne

Emotional lability

Hypertension

Combination (Pred+Aza)

Postmenopausal state

Osteoporosis

Brittle diabetes

Obesity

Acne

Emotional lability

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

Reasons for Selecting Treatment RegimensReasons for Selecting Treatment Regimens


Toxicity of Azathioprine/6-MPToxicity of Azathioprine/6-MPToxicity of Azathioprine/6-MPToxicity of Azathioprine/6-MP


Reasons for Selecting Treatment RegimensReasons for Selecting Treatment Regimens

The toxicity of AZA/6-MP is related to their metabolites Two important enzymes

Thiopurine methyltranferase (TPMT) Hypoxanthine phosphoribosyl tranferase (HPRT)

The toxicity of AZA/6-MP is predominantly related to the activity of TPMT

11% of the population is heterozygous and 0.3% homozygous for TPMT deficiency

Testing for TPMT before initiating AZA/6MP becoming the standard of care

The toxicity of AZA/6-MP is related to their metabolites Two important enzymes

Thiopurine methyltranferase (TPMT) Hypoxanthine phosphoribosyl tranferase (HPRT)

The toxicity of AZA/6-MP is predominantly related to the activity of TPMT

11% of the population is heterozygous and 0.3% homozygous for TPMT deficiency

Testing for TPMT before initiating AZA/6MP becoming the standard of care

TPMT

HPRT


Response To TreatmentResponse To TreatmentResponse To TreatmentResponse To TreatmentDefinition of RemissionDefinition of Remission

90% of adults have improvement in bilirubin, transaminases, and globulin levels within 2 weeks

Histologic improvement lags behind laboratory improvement by 3-6 months

Remission is rarely achieved in less than 12 months 65% remission at 18 months 80% remission at 3 years 13% partial response 9% treatment failure

90% of adults have improvement in bilirubin, transaminases, and globulin levels within 2 weeks

Histologic improvement lags behind laboratory improvement by 3-6 months

Remission is rarely achieved in less than 12 months 65% remission at 18 months 80% remission at 3 years 13% partial response 9% treatment failure


Definition of RemissionDefinition of RemissionDefinition of RemissionDefinition of Remission

All of the following:Disappearance of symptoms

Normal serum bilirubin, -globulin

AST, AST < 2x normal

Normal hepatic histology or minimal inflammation, no interface hepatitis

All of the following:Disappearance of symptoms

Normal serum bilirubin, -globulin

AST, AST < 2x normal

Normal hepatic histology or minimal inflammation, no interface hepatitis

Definition of RemissionDefinition of Remission


Maintenance TherapyMaintenance TherapyMaintenance 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 TherapyMaintenance Therapy


Maintenance TherapyMaintenance TherapyMaintenance TherapyMaintenance Therapy

Prednisone taper 2.5 mg/mo. until lowest dose reached which maintains clinical remission 87% can be maintained on </= 10 mg/day

Azathioprine 2.0 mg/kg monotherapy also 87% effective in maintaining remissions for up to 67 months

Prednisone taper 2.5 mg/mo. until lowest dose reached which maintains clinical remission 87% can be maintained on </= 10 mg/day

Azathioprine 2.0 mg/kg monotherapy also 87% effective in maintaining remissions for up to 67 months


Should Therapy Be Discontinued?Should Therapy Be Discontinued? Should Therapy Be Discontinued?Should Therapy Be Discontinued?

Once remission is achieved steroids should first be tapered and eventually discontinued, followed by azathioprine 50 mg/12 weeks

Between 10-40% can be withdrawn from treatment for up to 5 years

Liver biopsy assessment is preferred, but not essential, prior withdrawing patients from therapy

Relapse occurs in 20-90% of AIH depending on the histologic findings at time of withdrawal

Once remission is achieved steroids should first be tapered and eventually discontinued, followed by azathioprine 50 mg/12 weeks

Between 10-40% can be withdrawn from treatment for up to 5 years

Liver biopsy assessment is preferred, but not essential, prior withdrawing patients from therapy

Relapse occurs in 20-90% of AIH depending on the histologic findings at time of withdrawal


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


Options When Conventional Treatments FailOptions When Conventional Treatments FailOptions 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 FailOptions When Conventional Treatments Fail

Pregnancy and AIHPregnancy and AIHPregnancy and AIHPregnancy and AIH

If AIH in remission, pregnancy well tolerated unless complications of portal hypertension are present

Increased frequency of prematurity and fetal loss

Pregnancy or planned pregnancy are not a contraindication to immunosuppression

Teratogenicity observed with azathioprine treatment in mice but little evidence for teratogenicity in humans

Many reports of AIH flares post-partum, but AIH also may exacerbate or present during pregnancy

If AIH in remission, pregnancy well tolerated unless complications of portal hypertension are present

Increased frequency of prematurity and fetal loss

Pregnancy or planned pregnancy are not a contraindication to immunosuppression

Teratogenicity observed with azathioprine treatment in mice but little evidence for teratogenicity in humans

Many reports of AIH flares post-partum, but AIH also may exacerbate or present during pregnancy

Autoimmune HepatitisAutoimmune HepatitisPregnancyPregnancy


Pitfalls in Therapy of AIHPitfalls in Therapy of AIHPitfalls 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 AIHPitfalls in Therapy of AIH


Liver TransplantationLiver TransplantationLiver 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 TransplantationLiver Transplantation


AIH Treatment: SummaryAIH Treatment: SummaryAIH Treatment: SummaryAIH Treatment: Summary

Treatment Indications:

ALT> 10 fold

ALT>5 fold with hyper globulinemia

ALT <5x with symptoms

Bridging necrosis or multiacinar necrosis

Interface hepatitis without necrosis does not

compel treatment

Treatment Indications:

ALT> 10 fold

ALT>5 fold with hyper globulinemia

ALT <5x with symptoms

Bridging necrosis or multiacinar necrosis

Interface hepatitis without necrosis does not

compel treatment




Start therapy with prednisone alone, adding

azathioprine/6MP if remission not achieved

within 3 months

Test for TPMT before starting azathioprine/6-MP

Maintain fixed daily dose of medication until

remission

Continue treatment until remission, treatment

failure or drug toxicity

Start therapy with prednisone alone, adding

azathioprine/6MP if remission not achieved

within 3 months

Test for TPMT before starting azathioprine/6-MP

Maintain fixed daily dose of medication until

remission

Continue treatment until remission, treatment

failure or drug toxicity




Vaccination for for HBV and HAV

recommended

Drug withdrawal should be attempted once

remission obtained, preferably based on liver

biopsy findings

10-40% can eventually be maintained off

medication but multiple relapses may occur

before sustained remission achieved

Vaccination for for HBV and HAV

recommended

Drug withdrawal should be attempted once

remission obtained, preferably based on liver

biopsy findings

10-40% can eventually be maintained off

medication but multiple relapses may occur

before sustained remission achieved


Overlap SyndromesOverlap Syndromes

What are Overlap Syndromes?What are Overlap Syndromes?

Two simultaneous autoimmune liver diseases AIH/PBC, AIH/PSC

Two sequential autoimmune liver diseases

One autoimmune liver disease with features of another

Two simultaneous autoimmune liver diseases AIH/PBC, AIH/PSC

Two sequential autoimmune liver diseases

One autoimmune liver disease with features of another


Diagnostic CriteriaDiagnostic CriteriaAIH PBC PSC

Symptoms malaise, fatigue, fatigue jaundice pruritus pruritus

Asymptomatic occasionally often often

Gender female>male female>male female>male

Biochemistry ALT ALP ALP and/or GGT

Immunoglobulins IgG IgM IgM/IgG(low Ig A type2)

Autoantibodies SMA/anti LKM1 AMA none specific

ERC/MRC overlap PSC normal Diagnostic (young) hallmark

AIH PBC PSC

Symptoms malaise, fatigue, fatigue jaundice pruritus pruritus

Asymptomatic occasionally often often

Gender female>male female>male female>male

Biochemistry ALT ALP ALP and/or GGT

Immunoglobulins IgG IgM IgM/IgG(low Ig A type2)

Autoantibodies SMA/anti LKM1 AMA none specific

ERC/MRC overlap PSC normal Diagnostic (young) hallmark

Overlap SyndromesOverlap SyndromesDiagnostic CriteriaDiagnostic Criteria

Overlap SyndromesOverlap Syndromes

How to Treat Overlap Syndromes How to Treat Overlap Syndromes


thomas hargrave m.d. november 20, 2009

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autoimmune hepatitistype

initial acute presentation

histological features

fluctuating disease

sma interface hepatitis

liver transplantationsaffects

chronic fatigue

liver diseases hepatitis