Autoimmune Hepatitis
Diagnosis & Management
• Autoimmune hepatitis has diverse clinical
phenotypes.
• This diversity has complicated its diagnosis
and management.
• Diagnostic boundaries now encompass
patients of both genders, all ages, and various
ethnic groups
Patients may have
• acute,
• acute severe(fulminant), or
• asymptomatic presentations;
• they may lack conventional serological
markers; and
• they may have atypical histological features.
• Autoimmune hepatitis must now be
considered in all patients with
– acute and chronic hepatitis of undetermined
cause,
– including patients with graft dysfunction
after liver transplantation
DIAGNOSTIC CRITERIA AND SCORING
SYSTEMS
1. Codified diagnostic criteria of the IAIHG
• The diagnostic criteria of the IAIHG require the
presence of• serum aspartate [AST] and alanine
aminotransferase [ALT] abnormalities,
• hypergammaglobulinemia,
• increased serum IgG level),
• serological (ANA, SMA or anti- LKM1 positivity)
• histological findings (interface hepatitis with or
without plasma cell infiltration)
DIAGNOSTIC CRITERIA AND SCORING
SYSTEMS
2. Revised original diagnostic scoring system of
the IAIHG
• The revised original scoring system is a
comprehensive template that evaluates 13
clinical categories and renders 27 possible
grades
3. Simplified diagnostic scoring system of the
IAIHG
• A simplified scoring system has been
developed to ease clinical application.
• It evaluates four clinical categories and
renders nine possible grades.
Simplified Diagnostic Scoring System
• The original revised scoring system has greater
sensitivity for autoimmune hepatitis (100% vs
95%),
• whereas the simplified scoring system has
superior specificity (90% vs 73%) and accuracy
(92% vs 82%), using clinical judgment as the
gold standard.
Standard Antibodies for the Diagnosis
of Autoimmune Hepatitis
1)ANA• Antigenic target-Centromere, ribonucleoproteins,
ribonucleoprotein complexes, histones
• Lacks organ and disease specificity
• Present in 80% of adults with AIH
• Occurs in 20%–40% with non-AIH
• Sensitivity for AIH when isolated finding, 32%
• Specificity for AIH when isolated finding, 76%
• Diagnostic accuracy for AIH, 56%
• Concurrent ANA and SMA most diagnostic (74%)
• Titers can vary outside disease activity
2)SMA• Target-Filamentous (F) actin, 86%
Nonactin components, 14%
• Lacks organ and disease specificity
• Present in 63% of adults with AIH
• Occurs in 3%–16% with non-AIH
• Sensitivity for AIH when isolated finding, 16%
• Specificity for AIH when isolated finding, 96%
• Diagnostic accuracy for AIH, 61%
• Concurrent SMA and ANA most diagnostic (74%)
• Titers >1:80 associated with disease activity
3)Anti-LKM1• Target-Cytochrome P450 2D6
• Present in 3% of North American adults with AIH
• Detected in 14%–38% of British children with
AIH,
• Occurs in 0%–10% of chronic hepatitis C
• Low concurrence with SMA and ANA, 2%
• High specificity (99%), low sensitivity (1%)
• Diagnostic accuracy in North American adults,
57%
Nonstandard autoantibodies
1) Antibodies to actin (antiactin)
• Target-Filamentous (F) actin ,Nonactin
components
• Present in 87% with AIH
• Concurrent with SMA in 86%–100% with AIH
• SMA without antiactin in 14% with AIH
• Indirect marker of disease activity
• No standardized assay
Nonstandard autoantibodies
2) Antibodies to α-actinin
• Target-α-Actinin
• Present in 42% of patients with AIH
• Antiactin+anti-α-actinin associated with
severity
• Baseline level predictive of treatment
response
• Investigational assay not generally available
Nonstandard autoantibodies
3)Antibodies to soluble liver antigen (anti-SLA)
• Target-Sep (O-phosphoserine) tRNA:Sec
(selenocysteine) tRNA synthase (SEPSECS)
• Present in 7%–22% with AIH
• Genetic association with HLA DRB1*030124,
• Associated with severity, response, relapse,
survival
• Useful in diagnosing seronegative patients
• Specificity, 99%, and sensitivity, 11%
Nonstandard autoantibodies
4) Atypical perinuclear antineutrophil cytoplasmic
antibodies (pANCA)
• Target-β-Tubulin isotype 5
• Cross reacts with precursor bacterial protein
(FtsZ)
• Present in 50%–92% with typical AIH
• Absent in anti-LKM1-positive AIH
• Detected in CUC, PSC, PBC, minocycline injury
• Useful in classifying seronegative AIH
Nonstandard autoantibodies
5) Antibodies to asialoglycoprotein receptor (antiASGPR)
• Target-Asialoglycoprotein receptor
• Present in 67%–88% with AIH
• Occurs in other acute and chronic liver diseases
• Useful in classifying seronegative AIH
• Correlates with laboratory and histological
activity
• May predict relapse and define treatment end
points
Nonstandard autoantibodies
6) Antibodies to liver cytosol type 1 (anti-LC1)
• Target-Formiminotransferase cyclodeaminase
• Present in 24%–32% of anti-LKM1-positive AIH
• Occurs in chronic hepatitis C and anti-LKM1
• Useful in classifying seronegative AIH
• Rare in North American adults with AIH
CLINICAL FEATURES
• Autoimmune hepatitis has a variety of clinical
phenotypes; therefore, it is included in the
differential diagnosis for patients with
abnormal liver biochemical tests, acute
hepatitis, cirrhosis, or acute liver failure .
• It may present as either an acute or chronic
disease with a fluctuating pattern
CLINICAL FEATURES
• At the far end of the spectrum are those
patients who present with acute liver failure,
jaundice, and coagulopathy, but such a
presentation is generally uncommon
• Physical findings range from a normal physical
examination to findings suggestive of cirrhosis
or liver failure (eg, jaundice, ascites,
splenomegaly)
CLINICAL FEATURES
• Patients with autoimmune hepatitis may
present with a coexisting extrahepatic
disorder, which may also be autoimmunemediated
Laboratory features
• Liver biochemical and function tests —
• In acute presentations, elevations in
aminotransferases (alanine aminotransferase
[ALT] and aspartate aminotransferase [AST])
may exceed 10 to 20 times the upper limit of
the reference range, and
• the ratio of alkaline phosphatase to AST (or
ALT) is often <1:5, and in some cases is <1:10
Laboratory features
• In patients with chronic symptoms or those
with cirrhosis at initial presentation, AST and
ALT elevations are less profound,
• while the ratio of alkaline phosphatase to AST
(or ALT) is lower and approaches 1:2.
Laboratory features
• Gamma globulins — One characteristic
laboratory feature of autoimmune hepatitis,
although not universally present, is an
elevation in gamma globulins, particularly
immunoglobulin G (IgG).
Hypergammaglobulinemia is generally
associated with circulating autoantibodies.
• Levels of immunoglobulin A and
immunoglobulin M are typically normal
Histology • A portal mononuclear cell infiltrate (generally
lymphoplasmacytic, often with occasional
eosinophils), invades the sharply demarcated
hepatocyte boundary (limiting plate)
surrounding the portal triad and infiltrates
into the surrounding lobule and beyond
Histology • The periportal lesion, sometimes referred to
as piecemeal necrosis or interface hepatitis,
essentially spares the biliary tree but may
involve more of the lobule . There may also be
centrizonal necrosis.
Histology • Bile duct changes (eg, destructive and
nondestructive cholangitis, ductal injury, and
ductular reaction) are increasingly recognized
in patients with autoimmune hepatitis .
• In particular, ductal injury and ductular
reaction may be seen in over 80 percent of
patients at the time of diagnosis.
Histology • A plasma cell infiltrate, rosettes of
hepatocytes, and multinucleated giant cells,
may be seen.
• The presence of infiltrate in the portal areas
and plasma cell infiltrates can help distinguish
such patients from those with other forms of
acute hepatitis
• On the basis of the autoantibody profiles,
patients can be categorized into two disease
subtypes: type 1 or type 2
Autoantibody negative autoimmune
hepatitis • Approximately 20 percent of patients who
present with all the features of autoimmune
hepatitis lack circulating ANA, ASMA, or ALKM-1
antibodies .
• These patients are usually regarded as having
autoantibody negative autoimmune hepatitis or
cryptogenic chronic hepatitis.
• A therapeutic response to anti-inflammatory
therapy may be the only indication that
autoimmune hepatitis is the underlying disease in
these patients.
DIAGNOSTIC DIFFICULTIES1) Mixed Clinical and Histological Features• PSC and PBC can have clinical, laboratory,
histological, and genetic findings that
resemble those of AIH, and
• AIH can have features that resemble each of
these cholestatic syndromes.
DIAGNOSTIC DIFFICULTIES2)Serological Overlap
• AIH patients may demonstrate serological
features that suggest another diagnosis. AMA
occur in about 5% of AIH patients in the
absence of other biliary features.
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Drugs such as –
minocycline,
diclofenac,
infliximab,
propylthiouracil,
atorvastatin,
nitrofurantoin,
methyl dopa,
isoniazid can cause a syndrome that resembles
AIH
• replete with autoantibodies that generally
disappear after discontinuation of the drug
DIAGNOSTIC DIFFICULTIES3)Acute Severe Presentation• Can be mistaken for a viral or toxic hepatitis.
• Sometimes autoimmune hepatitis may
present as acute liver failure.
• Corticosteroid therapy can be effective in
suppressing the inflammatory activity in 36%100% of patients
DIAGNOSTIC DIFFICULTIES4)Concurrent Immune Diseases• Autoimmune thyroiditis, Graves’ disease,
synovitis and ulcerative colitis are the most
common immune-mediated disorders
associated with AIH in North American adults,
• Whereas type I diabetes mellitus, vitiligo, and
autoimmune thyroiditis are the most common
concurrent disorders in European anti-LKM1þ
AIH patients.
TREATMENT
• Treat patients who fulfill any of the
following criteria:
• Serum aminotransferase levels greater than 10fold the upper limit of normal
• Serum aminotransferase levels greater than twice
the upper limit of normal along with:
– Symptoms
– An elevated gamma globulin level, even if less than
twice the upper limit of normal
– An elevated conjugated bilirubin level
– Interface hepatitis on biopsy
TREATMENT
• Serum gamma globulin level greater than
twice the upper limit of normal
• Histologic features of bridging necrosis or
multiacinar necrosis
• Cirrhosis with any degree of inflammation on
biopsy
• Children
AASLD
• The AASLD guideline only recommends treatment
for patients with –
• Gamma globulin levels greater than twice the
upper limit of normal if the aminotransferases
are at least fivefold the upper limit of normal,
• Does not recommend treatment for patients
with gamma globulin levels less than twice the
upper limit of normal unless the
aminotransferases are greater than 10-fold the
upper limit of normal.
BSG
• BSG guideline, recommends treating if the
serum aminotransferase levels are greater
than fivefold the upper limit of normal,
regardless of other criteria for treatment.
Treatment duration
• Normal liver tests are achieved in 66% to 91%
of patients within 2 years.
• The average treatment duration until normal
liver tests and normal or near-normal liver
tissue is 22 months.
Treatment duration
• Treatment may be extended for ≥3 years, but
the frequency of remission decreases to 14%
and progression to cirrhosis (54% vs 18%,
p=0.03) and
• Need for liver transplantation (15% vs 2%,
p=0.048) increases compared to patients who
respond fully within 12 months.
Treatment duration
• In Europe, treatment is usually continued for
at least 2 years before any decision regarding
the discontinuation of therapy.
• Histological improvement commonly lags
behind clinical and laboratory improvement
by 3 to 8 months, and treatment should be
continued beyond laboratory resolution
before any attempt at drug withdrawal.
Treatment duration
• Liver tissue examination is the preferred
method of documenting histological
resolution, but
• stable normal laboratory tests for 12 to 18
months may be sufficient to indicate the
absence of histological activity and justify the
termination of treatment.
Response to induction therapy
• Remission – Approximately 65 to 80 percent
• Incomplete response to therapy –
Approximately 13 percent
• Failure to respond to treatment –
Approximately 10 percent
Response to induction therapy
Remission -defined as• Resolution of symptoms
• Normalization of serum aminotransferase
levels
• Normalization of serum bilirubin and gamma
globulin levels
• Improvement in liver histology to normal or
only mild portal hepatitis (or minimal to no
activity in patients with cirrhosis)
Response to induction therapy
Incomplete response to treatment • Some or no improvement in clinical,
laboratory, and histologic features despite
compliance with treatment for two to three
years.
• No worsening of the condition
Response to induction therapy
Treatment failure-characterized by:
• Sustained biochemical and histologic activity
leading to the development or worsening of
cirrhosis with eventual complications and
death
• The need for orthotopic liver transplantation
• Wilson disease and the overlap syndrome of
autoimmune hepatitis/primary sclerosing
cholangitis (autoimmune sclerosing
cholangitis) should be considered in young
patients with treatment failure since the
histologic findings are similar to autoimmune
hepatitis..
• Treatment failure is more frequent in three
groups of patients :
1)Those with established cirrhosis
2)Those who develop disease at a younger age
or have had a longer duration of disease
before treatment
3)Those who possess the human leukocyte
antigens (HLA)-B8 and/or HLA-DR3
phenotypes
SUBSEQUENT MANAGEMENT
Patients in remission • Guidelines from the American Association for
the Study of Liver Diseases and the European
Association for the Study of the Liver
recommend an attempt at withdrawing
therapy for patients in remission for at least
24 months .
• If therapy is being withdrawn, the first step is
typically tapering the glucocorticoid.
• The dose of prednisone can be decreased by
10 mg/day every week until a dose of 20
mg/day is reached.
• Tapering should then be by increments of 5
mg/day each week until a dose of 10 mg/day
is reached.
• At that point, tapering should be done in
increments of 2.5 mg/day every week until
the drug is withdrawn.
• Monitor the serum aminotransferases, total
bilirubin, and gamma globulin levels every
three weeks during withdrawal and
• for three months after withdrawal.
• Monitor the levels every six months for one
year, and yearly thereafter.
• For patients who are also being treated
with azathioprine, we generally withdraw it
after the glucocorticoid has been
discontinued.
• For patients taking 50 mg daily, we simply stop
the azathioprine.
• For patients taking higher doses, we reduce
the dose by 50 mg/day every three months
with serologic monitoring every three
months.
Signs of relapse
• Relapse may be heralded by the development
of fatigue, arthralgias, and anorexia,
accompanied by a rise in serum
aminotransferase levels and/or an increase in
serum gamma globulin levels.
• A rise in serum aminotransferases to more
than three times the upper limit of normal
• or a rise in serum gamma globulins to more
than 2 g/dL correlates strongly with the
presence of histologic deterioration .
• Treatment of relapses — A reasonable
approach following the first relapse is to
resume the treatment that initially led to
remission.
• Treatment should be initiated at induction
doses, followed by glucocorticoid tapering
ALTERNATIVE DRUG REGIMENS
Rapamycin, rituximab, and infliximab
as emerging rescue drugs
• Small clinical experiences with rapamycin
(sirolimus), rituximab, and infliximab have
illustrated the continuing effort that is being
expended to develop rescue therapies that
can supplant or supplement current
corticosteroid-based regimens for
autoimmune hepatitis.
Role of Rapamycin
• Rapamycin (1 to 3 mg daily adjusted to
maintain blood levels of 5 to 8 µg/dL) has
– suppressed the inflammatory manifestations of six
patients with recurrent or de novo autoimmune
hepatitis after liver transplantation, including five
patients who were refractory to conventional
corticosteroid treatment.
Role of Rituximab
• Rituximab has improved isolated cases of
autoimmune hepatitis with
– idiopathic thrombocytopenic purpura,
– cryoglobulinemic glomerulonephritis,
– previous B cell lymphoma,and
-- Evans syndrome (hemolytic anemia and idiopathic
thrombocytopenia),
Role of Rituximab
• Rituximab (two infusions of 1,000 mg 2 weeks
apart) has– reduced serum AST levels in all six treated
patients,
– improved histological features in four biopsied
patients, and
– allowed corticosteroid withdrawal in three of four
patients in a small treatment trial
Role of Infliximab
• A small trial of infliximab (infusions of
5 mg/kg body weight at time zero, 2 weeks, 6
weeks, and every 4 to 8 weeks thereafter) in 11
patients with refractory autoimmune hepatitis
has
1.normalized liver tests in eight patients,
2.improved histological activity indices in five
patients, and
3.allowed treatment withdrawal in three
patients .
Role of BAFF Inhibitors
• Selective inhibitors of BAFF which should
ameliorate the pathogenesis by inhibiting
autoreactive B cell activation and
autoantibody production are in clinical trials
Role of BAFF Inhibitors
• Belimumab is a fully human monoclonal
antibody that antagonizes BAFF thus inhibiting
B cell survival and differentiation.
• Belimumab directly reduces activation of
naïve and transitional B cells and indirectly
inhibits development of IgD CD27 class
switched memory B cells,plasmablasts and
plasma cells.
Role of BAFF Inhibitors
• Other Anti-BAFF agents Tabalumab and
blisibimod are also being assessed in phase 3
trials.
LIVER TRANSPLANTATION
• Liver transplantation is the ultimate rescue
therapy for patients that present with features
of liver failure or who develop these features
during standard treatment.
LIVER TRANSPLANTATION
• The 5- and 10- year patient survivals after liver
transplantation exceed 70% in adults,and the
5-year survival is as high as 86% in children.
• Recurrent disease can progress to cirrhosis,
and 13% to 50% of adults with recurrent
disease develop graft failure.
Diagnosis and management of the
overlap syndromes
of autoimmune hepatitis
THANK YOU..!