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Flashcards in 8 - Immunology and the Liver Deck (47)
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1

Immunology Considerations

Portal venous blood is antigen rich
Passes through liver sinusoids, comes into contact with complex network of immune cells
Immune system of liver is unique and tightly regulated
Must ensure that inappropriate immune response is not waged against food
Must recognize pathogenic molecules as pathogenic

2

Tolerance

A state of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit an immune response

3

Immune Cells of the liver

Hepatocytes

Endothelial Cells
Kupffer Cells
Lymphocytes
Biliary Cells
Stellate Cells

4

Antigen Presenting Cells

Scavengers
Capture antigens passing through liver or apoptoci cells

Crucial for tolerance:
Kupffer cells
Liver sinusoidal endothelial cells
Dendritic cells

5

Kupffer Cells

20% of nonparenchymal cells of the liver
Part of the reticuloendothelial system
The macrophages of the liver
Derived from bone marrow monocyte progenitors, localize to the liver
Reside in sinusoidal space and phagocytose debris
Migrate along sinusoids and interact with lymphocytes
Can pass through space of Disse and come into contact with hepatocytes

6

Kupffer Cells - Interactions

Activated by bacterial stimuli (LPS, other antigens)
Produce cytokines that influence differentiation and proliferation of other cells (both upregulate and downregulate)
Important in maintaining tolerance - when kupffer cells depleted systemic tolerance to antigens in PV is impaired

7

Liver Sinusoidal Endothelial Cells (LSECs)

Line the sinusoids
Form a sieve-like fenestrated endothelium
Express MHCI/II, costimulatory molecules

8

Dendritic Cells

Rise from bone marrow
Typically located around central vein, portal tracts
Healthy liver - predominantly immature
Poised to capture and process antigens

9

Hepatic Stellate Cells

Under "normal" circumstances, control blood flow through sinusoids
Under pathologic conditions - differentiate into myofibroblasts
Secrete inhibitors of tissue matrics metalloproteinases
Deposit Collagen
Generate fibrosis

10

Lymphocytes

Reside in all parts of liver (portal tract, sinusoids, lobule)

11

Autoimmune Hepatitis

Progressive and chronic hepatitis characterized by:

Hepatocellular necroinflammation
Production of Autoantibodies
Hypergammaglobulinemia
No distinct etiology
No distinct diagnostic features
Responsive to immunosuppressive agents

12

Autoimmune Hepatitis - Pathogenesis

Unknown mechanism
Hypotheses involve triggers, genetic predispositions, T-cell mediated attacks on liver antigens

13

Autoimmune Hepatitis - Potential Triggers

Environmental Agents
Viruses (measles, hepatitis, CMV, EBV)
Molecular Mimicry (Cross-reactivity between epitopes of viruses and liver antigens, a loss of self-tolerance)
Drugs (can mimic or induce AIH)

14

Autoimmune Hepatitis - Epidemiology

F>M, 4:1
All ethnic groups
Affects children and adults
Bimodal age distribution: 10 - 20, 45 - 75
Prevalence 11 - 17 per 100,000 persons/year
Incidence 1 - 2 per 100,000 persons/year

15

Autoimmune Hepatitis - Lab Abnormalities

Aminotransferase Elevations - "Hepatocellular Pattern"
Elevated serum globulin fraction (Gamma Globulin, IgG)
Circulating Autoantibodies

16

Autoantibodies

Antinuclear Antibody (ANA)
Smooth Muscle Antibody (SMA)
Antiactin Antibody (AAA)

Antibodies against Soluble Liver Antigen/Liver Pancrease Antigen (SLA/LP)
Perinuclear Antineutrophil Cytoplasmic Antibody (pANCA)
Anti Liver Kidney Microsomal Antibody-1 (LKM-1)
Anti Liver Cytosol-1 (LC-1)

17

Autoimmune Hepatitis - Type 1

95 - 97%
Characterized - ANA, SMA or both
70% female
Peak incidence 16 or 30 years
50% older than 30 years
23% at least 60 years old
Other AI diseases common (15 - 34%) include thryoid disease, synovitis, celiac disease, ulcerative colitis
Cirrhosis present at diagnosis in 25% of patients
Antibodies to SLA possible prognostic markers of severe AIH who are prone to relapse after corticosteroid withdrawal

18

Autoimmune Hepatitis - Type 2

3 - 5%
Marked by the presence of anti-LKM1 and/or anti LC-1 and/or anti-LKM-3
Most patients are children (2 - 14 years old) but also seen in adults
In Europe, 20% of patients are adults, in US 4% are >18 years old
Serum Ig levels usually elevated (except IgA, which may be reduced)
Concurrent immune disease common
Cirrhosis occurs
Acute severe presentation possible

19

Autoimmune Hepatitis - Type 3

1 - 2%
Least established form of the disease
Designation largely abandoned
Characterized by presence of antibodies to soluble liver antigen and liver/pancrease (anti-SLA, anti- LP)
30 - 50 years old
Target autoantigens: thought to be Glutathione S-transferase, but a transfer ribonucleoprotein (tRNP) 50-kd protein was described in 2000 as the more likely target
Clinical and laboratory features that are indistinguishable from AIH type 1
Also responds well to glucocorticoids

20

Autoimmune Hepatitis - Type 1 Characteristic Antibodies

Characteristic Autoantibodies
ANA
SMA
SLA/LP
pANCA

21

Autoimmune Hepatitis - Type 1 - Antigen

Diverse nuclear antigens
Actin and non-actin components
Polymerized F-actin
tRNP

22

Autoimmune Hepatitis - Type 2 Characteristic Antibodies

LKM-1/3
LC-1

23

Autoimmune Hepatitis - Type 2 - Antigen

CYP-2D6
Formiminotransferase Cyclodeaminase

24

Autoimmune Hepatitis - Type 3 Characteristic Antibodies

SLA/LP

25

Autoimmune Hepatitis - Type 3 - Antigen

tRNP

26

Autoimmune Hepatitis - Diagnosis BROAD STROKES

Determination of serum aminotransferase and globulin levels:
Predominant serum aminotransferase abnormality
Hypergammaglobulinemia

Exclusion of other chronic liver diseases that have similar features

27

Autoimmune Hepatitis - Rule outs

Hereditary causes: Wilson's, α1AT, Hereditary Hemochromatosis
Infectious causes: Chronic Viral Hepatitis A, B, C
Drug-Induced Liver Disease: ETOH, minocycline, nitrofurantoin, INH, propylthiouracil, methyldopa
NASH
Immune cholangiopathies of PBC, PSC, autoimmune cholangitis

28

Autoimmune Hepatitis - Diagnosis SPECIFICS

Detection of Autoantibodies:
ANA
SMA
Anti-LKM1

Liver biopsy

29

Autoimmune Hepatitis - Diagnosis - Liver Biopsy

Essential to establish diagnosis to assess severity and determine need for treatment

Histology - Interface hepatitis (hallmark of the syndrome)

Portal plasma cell infiltration typifies the disorder
Lack of portal plasma cell infiltration does not preclude disease

30

Autoimmune Hepatitis - Treatment Basis

Severity of symptoms
Degree of elevation in transaminases and IgG
Histologic Findings
Potential side effects