1. CHAIRED BY : Dr. Raminderpal Singh Sibia
PRESENTED BY : Dr. Rintu Sharma
Immunity
2. Case scenarios
HISTORY AND CLINICAL FINDINGS:
Case 1: A 46-year old female patient presented with a recently
occurred icterus of unknown origin as well as dark urine and
decolored stool. No diseases were found in the patient's medical
history. Clinical examination showed no other findings except
from the icterus.
Case 2: A 48-year old female patient was admitted to hospital
with epigastric pain and icterus. Similar symptoms reoccurred
regularly since several years.
She reported chronic pain in her finger joints and appearance of
haematomas without adequate trauma.
3. CLINICAL INVESTIGATIONS:
Case 1: Highly elevated liver enzymes and bilirubin.
Ultrasound examination was unremarkable.
Negative serology for hepatitis A, B and C
Marked immunoglobulin G (IgG) elevation and
hypergammaglobulinaemia.
ANA and smooth muscle antibodies (SMA)+++
Case 2:
reduced liver function with low albumin and prothrombin time
moderate elevation of liver enzymes and a high bilirubin.
Ultrasound examination revealed hepatic parenchymal changes,
splenomegaly, and ascites.
Oesophagogastroduodenoscopy showed oesophageal varices I°.
Serology for hepatitis A, B, and C was negative.
a marked IgG elevation and hypergammaglobulinaemia
Autoimmune antibodies (ANA and SMA)++
4. AUTOIMMUNE HEPATITIS
Continuing/unresolving hepatocellular
inflammation and necrosis of unknown etiology
Can progress to cirrhosis
Exclusion of other chronic liver diseases
Characteristics include:
presence of autoimmune antibody
evidence of hepatitis (interface being
characteristic)
elevation of serum globulins
5. OTHER NAMES
Active chronic hepatitis or chronic active hepatitis
Chronic aggressive hepatitis
Lupoid hepatitis
Plasma cell hepatitis
Autoimmune chronic active hepatitis
6. BACKGROUND
First described in 1950’s
Accounts for 5.6% of liver transplants in the US
Affects women more than men (3.6:1)
If untreated approximately 40% die within 6 months
40% develop cirrhosis
54% develop esophageal varices
20% die of hemorrhage
7. EPIDEMIOLOGY
Incidence: 1.9 cases per 100,000 persons per yr
Frequency of AIH among patients with chronic
liver disease in North America is between 11%-
22%
Accounts for 5.6% of liver transplants in the US
Prevalence greatest among northern European
white persons
Japenese have a lower frequency
Scand J Gastroenterol1998;33:99.
8. PATHOGENESIS
Unknown mechanism but several proposed
mechanisms
Genetically predisposed individual with exposure to an
environmental agent triggers the autoimmune
pathogenic process
Genetic predisposing factors:
HLA-DR3: early onset, severe form
HLA-DR4: caucasian, late onset, better response to steroids,
higher incidence of extrahepatic manifestations
9. Triggering factors
Infections (HAV, HBV, HCV, HSV, EBV, measles)?
Medications (ABX, statins, NSAIDs etc.)?
Toxins?
Molecular mimicry?
Recognition of antigen-MHC II complex by
uncommitted CD4 cells
Cytokine release from TH1 and TH2 CD4 cells
IL-12 and IL-2: proliferation of CD8 cells
IL-4 and IL-10: proliferation of B cells
10.
11. Evidence supporting autoimmune
pathogenesis
Histopathological lesions composed of cytotoxic Tcells
and plama cells
Circulating autoantibodies
Hyperglobulinemia
Other autoimmune disorders: thyroiditis, RA ,
autoimmune hemolytic anemia, ulcerative colitis,
membranoproliferative glomerulonephritis, diabetes
mellitus, celiac disease, sjogren’s syndrome
Histocompatibility haplotypes assosciations
Response to steroids and immunosuppression.
13. TYPE 1
Classically in young females
ANA or Anti-Smooth Muscle antibody
positive
Titer usually > 1:100
10% will have an antibody to Soluble
Liver antigens (SLA)
Other Antibodies: anti-DNA, pANCA,
Anti-mitochondrial, Anti-Actin (AAA),
cytoskeletal antibody, nuclear envelope
proteins lamin A and C, plasma
membrane sulfatides
Anti-actin antibodies have greater
specificity
14. TYPE 1
Bimodal Age distribution (ages 10-20 and 45-70)
Female:male (3.6:1)
HLA DR3 or DR4 assosciation
Associated with extrahepatic
manifestations(38%):
Autoimmune thyroiditis, Graves disease, Chronic UC
Less commonly with RA, pernicious anemia, systemic
sclerosis, ITP, SLE,coombs positive hemolytic anemia,
leucocytoclastic vasculitis, erythema nodosum
40% present with acute onset of symptoms
similar to toxic hepatitis or acute viral hepatitis
15. TYPE 2
Seen in children (2-14 years)in
Meditteranean population
HLA DR1 or DQB1 assosciation
Presence of anti-Liver/Kidney
Microsome Antibodies (anti-
LKM1 )directed against
cytochrome p450 2D6 {same as
LKM seen in patients with
chronic hepatitis C}
Anti-Liver Cytosol antibody
(ALC-1)
Acute or fulminant presentation
possible
16. TYPE 3
Antibodies to soluble liver
antigen / liver pancreas antigen
Lack ANA and anti- LKM 1
antibodies
More in women, part of
spectrum of type 1 AIH
% Concurrent autoimmune
disease: 58
Elevated gamma-globulin: ++
Steroid responsive: +++
% progression to cirrhosis: 75
17.
18. OVERLAP SYNDROMES
Primary Biliary Cirrhosis
Primary Sclerosing Cholangitis
5% of patients with chronic hepatitis C will have an
ANA titer of >1:100
A homogeneous pattern of staining is more common
in ANA positive autoimmune hepatitis compared to
that of ANA positive chronic hepatitis C
19.
20. Autoimmune hepatitis and
Chronic hepatitis C
8% of white North American adults have Concurrent
infection with HCV
52% of chronic hepatitis C patients have
autoantibodies
Interferon therapy can enhance immune
manifestations of AIH and concurrent HCV infection
Immunosuppressive treatment can increase serum
viral levels in patients with chr hepatitis C
Treatment should be appropriate for predominant
disease , based on nature of concurrent immune
disease
22. CLINICAL PRESENTATION
Similar as chronic hepatitis
May be confused with acute hepatitis
Can hav acute severe or fulminant presntation;
history of recurrent bouts
Asymptomatic in 34%-45% cases
28. Clinical criteria
Presence of characteristic clinical features
Liver histology
Exclusion of other diseases
Scoring criteria
Assess the strength of the diagnosis
Pretreatment and post-treatment
Helpful with variant or atypical forms of AIH
Diagnostic criteria
33. Simplified scoring system
Greater specificity vs original scoring system ( 90% vs
73%)
Greater predictability ( 92% vs 82% )
Useful for excluding AIH in patients with other
conditions and concurrent immune features
Less sensitivity (95% vs 100 %)
40. TREATMENT
Should be based on:
Severity of symptoms
Degree of elevation in transaminases and IgG
Histologic findings
Potential side effects of treatment
41. AASLD RECOMMENDATIONS
Treat if serum aminotransferases are greater than
10 times normal
Treat if serum aminotransferases are greater than
5 times normal and IgG is elevated to greater than
2 times normal, bridging fibrosis or multilobular
necrosis, presence of symptoms
In patients with inactive cirrhosis , evaluate for
preexisting comorbidities (hep C), pregnancy, and
drug intolerances (increased risk of steroid side
effects in pts with DM, osteoporosis, HTN)
43. Preferred treatment regimens
Combination therapy Single drug
therapy
Prednisolone
(mg/day)
Azathioprine (mg/d) Prednisolone
(mg/day)
30mg 1 week 50 mg until the end
point
60mg 1 week
20mg 2 week 40mg 2 week
15mg 3 weeks 30mg 3 weeks
10mg until the end
point
20mg until the end
point
44. PREDNISONE ONLY
Prednisone 60mg PO daily with a taper down to 30mg at
the 4th week into treatment and then maintenance of
20mg daily until reach endpoint
Reasons for Prednisone only:
Cytopenia
TPMT deficiency
Malignancy
Pregnancy
Therapy response expected in upto 80% of cases
45. COMBINATION THERAPY
Prednisone + Azathioprine
Prednisone: start at 30mg daily and taper down to
15mg at week 4, then maintain on 10mg daily until
therapy endpoint
Azathioprine 50mg daily
48. TREATMENT REMISSION
Disappearance of symptoms
Normal serum bilirubin and IgG
Serum aminotransferases normal or less than twice
normal
Normal hepatic tissue or minimal inflammation and
no interface hepatitis.
Action
Gradual withdrawal of prednisone
Discontinuation of azathioprine
Regular monitoring for relapse
49. TREATMENT FAILURE
Worsening clinical, laboratory and histologic findings
despite compliance with therapy
Onset of ascites or encephalopathy
Increase in aminotransferases by >67%
Action
Pred 60 mg/d or pred 30 mg/d with aza 150 mg/d x 1
month
Reduction of the dose each month of improvement
until maintenance levels
50. TREATMENT FAILURE
Treatment failures are frequent in patients with
established cirrhosis, HLA-DR3 or in patients who
present with disease at a younger age and with a
longer duration of symptoms
51. INCOMPLETE RESPONSE
Some or no improvement in clinical, laboratory or
histologic features that does not satisfy remission
criteria
Failure to achieve remission after 3 years
Action
Reduction of dose to lowest levels possible to prevent
worsening
Indefinite treatment
52. RELAPSE
An exacerbation after drug withdrawal in patients who
enter remission
Reappearance of histological disease
AST >3 folds ULN
Cirrhosis develops commonly
Reinstitute original treatment: azathioprine continued
indefinitely
Liver transplantation
55. LIVER TRANSPLANT: Indications
Patients with ascites and hepatic encephalopathy
Failed glucocorticoid therapy.
HCC
MELD score >15
Multilobar necrosis and have at least one
laboratory parameter which does not normalize
within 2 weeks of treatment
Worsen while on glucocorticoid therapy
56. LIVER TRANSPLANTATION
Recurrence of disease after transplant is common in
those with AIH but has only been described in
patients who are not adequately immunosuppressed.
5 year patient & graft survival 83-92%
Auto antibodies disappear within 1y
59. SUMMARY
Chronic hepatocellular disease of unknown etiology
Clinical presentation is variable
Diagnosis based upon LFTs, serology, gamma globulins,
and histology
Immunosuppressive therapy is the mainstay of treatment
Tailor therapy based upon treatment endpoints
Of patients who survive the most early and active stage of
disease, approximately 41% of them develop inactive
cirrhosis.
Of patients who have severe initial disease and survive
the first 2 years, typically survive long term.