Hepatocellular Carcinoma Thomas Hargrave M.D. January 16, 2009.
Thomas Hargrave M.D. November 20, 2009
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Transcript of 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 Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
Autoimmune HepatitisAutoimmune Hepatitis
Autoimmune HepatitisAutoimmune HepatitisAutoimmune 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
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
Autoimmune HepatitisAutoimmune Hepatitis
Autoimmune HepatitisAutoimmune HepatitisAutoimmune 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
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
Often Unrecognized FeaturesOften Unrecognized Features
Autoimmune HepatitisAutoimmune Hepatitis
Autoimmune HepatitisAutoimmune HepatitisAutoimmune 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
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
Often Unrecognized FeaturesOften Unrecognized Features
Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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
Often Unrecognized FeaturesOften Unrecognized Features
Autoimmune HepatitisAutoimmune Hepatitis
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.
Autoimmune HepatitisAutoimmune Hepatitis
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
Often Unrecognized FeaturesOften Unrecognized Features
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
Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune 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
Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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”
Recognition and Diagnosis of AIHRecognition and Diagnosis of AIH
Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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
Recognition and Diagnosis of AIHRecognition and Diagnosis of AIH
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
Autoimmune HepatitisAutoimmune Hepatitis
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
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
Autoimmune HepatitisAutoimmune Hepatitis
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 ofIndications for Treatment Based on the results of
Autoimmune HepatitisAutoimmune Hepatitis
Monotherapy Monotherapy Combination
Therapy Combination
Therapy
Therapy in AdultsTherapy in Adults
AASLD Practice Guidelines, Hepatology 2002, 36:479AASLD Practice Guidelines, Hepatology 2002, 36:479
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
Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
Toxicity of Azathioprine/6-MPToxicity of Azathioprine/6-MPToxicity of Azathioprine/6-MPToxicity of Azathioprine/6-MP
AASLD Practice Guidelines, Hepatology 2002, 36:479AASLD Practice Guidelines, Hepatology 2002, 36:479
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
Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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
Liver TransplantationLiver Transplantation
Autoimmune HepatitisAutoimmune Hepatitis
AIH Treatment: SummaryAIH Treatment: SummaryAIH 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
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
Liver TransplantationLiver Transplantation
Autoimmune HepatitisAutoimmune Hepatitis
AIH Treatment: SummaryAIH Treatment: SummaryAIH 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
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
Liver TransplantationLiver Transplantation
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
What are Overlap Syndromes?What are Overlap Syndromes?
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
What are Overlap Syndromes?What are Overlap Syndromes?