thomas hargrave m.d. november 20, 2009

Autoimmune Hepatitis

Thomas Hargrave M.D.November 20, 2009


Autoimmune HepatitisAutoimmune HepatitisIntermittently progressive inflammatory liver disease of presumed autoimmune etiology

High gamma globulins, autoantibodies

Predominately periportal plasma cell hepatitis

Usually responds favorably to corticosteroids or immnomodulators



Autoimmune HepatitisAutoimmune Hepatitis 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 Features


Autoimmune HepatitisAutoimmune Hepatitis 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



Autoimmune HepatitisAutoimmune Hepatitis 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: 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

Clinical Features


Clinical 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

Clinical Features


Often 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



Differential 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.


Differential DiagnosisDifferential Diagnosis Drug-induced Autoimmune Hepatitis

Minocycline

Nitrofurantoin

Orlistat

Meloxicam

Herbal medications


Inflixamab INH Statins (unmask AIH) Allopurinol Aldomet

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

Echinacea Noni Juice


Sub-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%

Sub-Types of Autoimmune Hepatitis


Auto-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

Auto-Antibodies in AIH


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

Antibody 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-Antibodies


Prevalence of ANA in Liver Disease

%%PositivePositive

00

2020

6060

8080

100100

4040

PBCPBC HCVHCVAIHAIH PSCPSC NAFLDNAFLD HBVHBV ALDALD

Prevalence of ANA in Liver Disease

ANA Testing in Patients with Elevated Transaminases Has Low Specifcity

AIH NAFLD HCV

ANA (+) Patients / 100,000

0

50

100

150

200

Percent ANA (+)

80

60

40

20

0

*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 HepatitisUtility of ANA Testing in Patients with Elevated Transaminases

16


Extrahepatic 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

Recognition and Diagnosis 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”



Laboratory 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

IgG Polyclonal Hypergammaglobulinemia


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

Criteria for Definite Autoimmune Hepatitis

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

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 System


Diagnosis of AIHDiagnosis of AIHLiver 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 steatohepatitis

Not All Cases With ANA Will Have Autoimmune Hepatitis

Dig Dis Sci 2003; 48:2173

Not All Cases With ANA Will Have Autoimmune Hepatitis

Interface Hepatitis of AIH

Portal tract expanded with mononuclear inflitrate

Limiting plate disrupted

Inflammation extends into acinus

Portal Tract Inflammation Histology

Plasma cell cluster;

occasional eosinophils

Plasma cells


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, 21:78

%%SurvivalSurvival

00

2020

6060

8080

100100

4040

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

Natural History of Untreated Autoimmune Hepatitis

10-Year Survival for Treated AIH 90%Autoimmune Hepatitis


Treatment

AASLD 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


Indications for TreatmentAbsolute 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 of


Monotherapy Combination

Therapy

Therapy 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

Therapy in Adults


Reasons for Selecting Treatment RegimensReasons for Selecting Treatment Regimens

Prednisone Monotherapy Severe cytopenia TPMT deficiency Prior Aza intolerance Pregnancy Malignancy

Combination (Pred+Aza) Postmenopausal state Osteoporosis Brittle diabetes Obesity Acne Emotional lability Hypertension


Reasons for Selecting Treatment Regimens


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


Reasons 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

TPMT

HPRT


Response To TreatmentResponse To TreatmentDefinition 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


Definition of RemissionDefinition of RemissionAll 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 Remission


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 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

Maintenance Therapy


Maintenance 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


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


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, 23:116

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


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)

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

Options When Conventional Treatments Fail

Pregnancy 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

Autoimmune HepatitisPregnancy


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

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

Liver Transplantation


AIH 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



AIH Treatment: SummaryAIH Treatment: Summary 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



AIH Treatment: SummaryAIH Treatment: Summary 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 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


Diagnostic CriteriaAIH PBC PSC

Symptoms malaise, fatigue, fatigue jaundice pruritus pruritusAsymptomatic occasionally often oftenGender female>male female>male female>maleBiochemistry ALT ALP ALP

and/or GGTImmunoglobulins IgG IgM IgM/IgG

(low Ig A type2)

Autoantibodies SMA/anti LKM1 AMA none specificERC/MRC overlap PSC normal Diagnostic (young) hallmark

Overlap SyndromesDiagnostic Criteria

Overlap Syndromes

How to Treat Overlap Syndromes


thomas hargrave m.d. november 20, 2009

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