Autoimmune Hepatitis in Clinical Practice - nwrsmeeting.org · SLA/LP UGA repressor 10-30% HCV tRNA-associated protein Auto-Antibodies in AIH Autoimmune Hepatitis Other Causes of
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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
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.
PathogenesisPathogenesis
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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PathogenesisPathogenesis
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
Autoimmune HepatitisAutoimmune Hepatitis
Contrasting Features of Viral and Autoimmune Hepatitis
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!
Contrasting Features of Viral and Autoimmune Hepatitis
Autoimmune HepatitisAutoimmune Hepatitis
Natural History of Untreated Autoimmune Hepatitis
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
Natural History of Untreated Autoimmune Hepatitis
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Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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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Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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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Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune 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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Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
International Autoimmune Hepatitis Group Scoring System: Patient History
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
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
International Autoimmune Hepatitis Group Scoring System: Patient History
Autoimmune HepatitisAutoimmune Hepatitis
International Autoimmune Hepatitis Group Scoring System: Biochemistries
International Autoimmune Hepatitis Group Scoring System: Biochemistries
Favor AIH Favor other diagnosis(points) (points)
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)
Favor AIH Favor other diagnosis(points) (points)
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)
International Autoimmune Hepatitis Group Scoring System: Biochemistries
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Autoimmune HepatitisAutoimmune Hepatitis
International Autoimmune Hepatitis Group Scoring System: Serologies
Favor AIH Favor other diagnosis(points) (points)
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)
Favor AIH Favor other diagnosis(points) (points)
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
Autoimmune HepatitisAutoimmune Hepatitis
International Autoimmune Hepatitis Group Scoring System: Histology
Favor AIH Favor other diagnosis(points) (points)
Interface Hepatitis +3
Lymphoplasmacytic +1Infiltrate
Rosetting of liver cells +1
None of Above -5
Biliary Changes -3
Other changes -3
Favor AIH Favor other diagnosis(points) (points)
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
International Autoimmune Hepatitis Group Scoring System: Response to Therapy
Autoimmune HepatitisAutoimmune Hepatitis
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)
International Autoimmune Hepatitis Group Scoring System: Response to Therapy
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Autoimmune Hepatitis - CriteriaAutoimmune Hepatitis - Criteria
Interpretation of International Autoimmune Hepatitis Group Score
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
Interpretation of International Autoimmune Hepatitis Group Score
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.
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 of
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Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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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Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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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Autoimmune HepatitisAutoimmune Hepatitis
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
Autoimmune HepatitisAutoimmune Hepatitis
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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