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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

31

Autoimmune Hepatitis - Treatment Goals

Control of immune system
Minimize toxicity
Individualize therapy
Minimize cost
Evidence based data

32

Autoimmune Hepatitis - Immunosuppresive Agents

Corticosteroids:
Inhibit lymphocyte activation
Suppress Ab production
Block inflammatory protein transcription
Induce antiinflammtory protein expression

Azathioprine:
Inhibit purine nucleotide synthesis

Cyclosporine/Tacrolimus:
Caclineurin inhibition

Mycophenolate:
Inhibit purine synthesis

33

Autoimmune Hepatitis - Treatment Indications

Absolute:
AST >= 10x normal + Symptoms
AST>= 5x normal + Gamma Globulin >= 2x normal
Bridging necrosis hepatitis

Relative:
Symptoms
AST

34

Autoimmune Hepatitis - Chronic Steroid Adverse Effects

Fluid retention/Electrolyte Disturbance
Hypertension
Glaucoma, cataracts
Osteoporosis
Acne
Poor wound healing
Glucose intolerance
Mood disturbance
Amenorrhea
Impotence

Prevalence -> 70% with treatment for 5 - 10 years

35

Autoimmune Hepatitis - Chronic Azathioprine Adverse Effects

Bone marrow suppression
GI upset
Rash
Infections
Heatotoxicity
Malignancy

Prevalence -> 70% with treatment for 5 - 10 years

36

Autoimmune Hepatitis - Transplantation

Indication for 4 - 6% of US liver transplants
Treatment failure requiring LT is often associated with HLA genotype DRB1*0301
5 and 10 yr post transplant survival >80%
Often thought to need increased immunosuppression relative to other transplant indications

37

Autoimmune Hepatitis - Post-Transplant

Recurs in 20% of post-LT patients
Average time to recurrence - 4.6 years
Accelerates after discontinuation steroids
Histological signs of recurrence may precede serum lab evidence
No validated diagnostic scoring systems or treatment algorithms for post-LT AIH

38

Primary Biliary Cirrhosis (PBC)

Definition: PBC is a chronic cholestatic disease with progressive course which may extend over many decades

Unique feature: High degree of specificity for involvement of the small intrahepatic bile ducts

The rate of progression varies greatly among individual patients

39

Primary Biliary Cirrhosis - Antibody

96% have anti-mitochondrial antibody (AMA)
0.5% of US population is AMA+
PBC prevalence 200,000 Americans, approximately 10% AMA+ will develop symptomatic PBC

40

Primary Biliary Cirrhosis - Autoimmune Responses

Targets of antimitochondrial antibodies
4 autoreactive mitochondrial antigens:
Pyruvate dehydrogenase E2 complex (PDC-E2)
E-3 binding protein (E3-BP)
Ketoglutaric acid dehydrogenase E2 complex (OGDC-E2)
2 oxo-acid dehydrogenase E2 complex (BCKD-E2)

41

Primary Biliary Cirrhosis - Epidemiology

Mostly Northern Europe
More common in 1st Degree Relatives
Molecular mimicry to certain bacteria or viruses
Environmental chemical exposure

42

Primary Biliary Cirrhosis - Symptomatic Disease

Fatigue (common)
Pruritis
Jaundice
Hepatosplenomegaly
RUQ pain
Hyperpigmentation
Xanthomas & xanthelasmas
Dyslipidemia
Extrahepatic autoimmune diseases
Complications: Portal Hypertension, Chronic Cholestasis

43

Primary Biliary Cirrhosis - Portal Hypertension Complications

Varices
Ascites
Encephalopathy
Peritonitis
Hepatorenal Syndrome
Hepatocellular carcinoma

44

Primary Biliary Cirrhosis - Chonic Cholestasis Complications

Osteopenia
Malabsorption
Steatorrhea
Vitamin ADEK deficiency

45

Primary Biliary Cirrhosis - Hypercholesterolemia

Elevated cholesterol seen in 85%
Stage I or II PBC - Increased HDL predominates
Stage III or IV - Increased LDL
No increased risk for cardiovascular disease
Lipid lowering agents not indicated
Plasmapheresis for Xanthomatous neuropathy and symptomatic xanthomas

46

Primary Biliary Cirrhosis - Diagnosis

Positive AMA
Abnormal LFTs (Alk Phos & GGT)
Compatible Biopsy

47

Primary Biliary Cirrhosis - Pathologic Stages

FLORID DUCT lesion (bile duct destruction)
Inflammation beyond portal tracts
Fibrous septa linking portal triads
Cirrhosis