8 - Immunology and the Liver Flashcards

1
Q

Immunology Considerations

A

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

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2
Q

Tolerance

A

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

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3
Q

Immune Cells of the liver

A

Hepatocytes

Endothelial Cells
Kupffer Cells
Lymphocytes
Biliary Cells
Stellate Cells
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4
Q

Antigen Presenting Cells

A

Scavengers
Capture antigens passing through liver or apoptoci cells

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

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5
Q

Kupffer Cells

A

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

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6
Q

Kupffer Cells - Interactions

A

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

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7
Q

Liver Sinusoidal Endothelial Cells (LSECs)

A

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

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8
Q

Dendritic Cells

A

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

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9
Q

Hepatic Stellate Cells

A

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

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10
Q

Lymphocytes

A

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

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11
Q

Autoimmune Hepatitis

A

Progressive and chronic hepatitis characterized by:

Hepatocellular necroinflammation
Production of Autoantibodies
Hypergammaglobulinemia
No distinct etiology
No distinct diagnostic features
Responsive to immunosuppressive agents
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12
Q

Autoimmune Hepatitis - Pathogenesis

A

Unknown mechanism

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

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13
Q

Autoimmune Hepatitis - Potential Triggers

A

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)

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14
Q

Autoimmune Hepatitis - Epidemiology

A

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

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15
Q

Autoimmune Hepatitis - Lab Abnormalities

A

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

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16
Q

Autoantibodies

A
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)

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17
Q

Autoimmune Hepatitis - Type 1

A

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

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18
Q

Autoimmune Hepatitis - Type 2

A

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

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19
Q

Autoimmune Hepatitis - Type 3

A

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
Q

Autoimmune Hepatitis - Type 1 Characteristic Antibodies

A
Characteristic Autoantibodies
ANA
SMA
SLA/LP
pANCA
21
Q

Autoimmune Hepatitis - Type 1 - Antigen

A

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

22
Q

Autoimmune Hepatitis - Type 2 Characteristic Antibodies

A

LKM-1/3

LC-1

23
Q

Autoimmune Hepatitis - Type 2 - Antigen

A

CYP-2D6

Formiminotransferase Cyclodeaminase

24
Q

Autoimmune Hepatitis - Type 3 Characteristic Antibodies

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