8 - Immunology and the Liver Flashcards
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
Tolerance
A state of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit an immune response
Immune Cells of the liver
Hepatocytes
Endothelial Cells Kupffer Cells Lymphocytes Biliary Cells Stellate Cells
Antigen Presenting Cells
Scavengers
Capture antigens passing through liver or apoptoci cells
Crucial for tolerance:
Kupffer cells
Liver sinusoidal endothelial cells
Dendritic cells
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
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
Liver Sinusoidal Endothelial Cells (LSECs)
Line the sinusoids
Form a sieve-like fenestrated endothelium
Express MHCI/II, costimulatory molecules
Dendritic Cells
Rise from bone marrow
Typically located around central vein, portal tracts
Healthy liver - predominantly immature
Poised to capture and process antigens
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
Lymphocytes
Reside in all parts of liver (portal tract, sinusoids, lobule)
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
Autoimmune Hepatitis - Pathogenesis
Unknown mechanism
Hypotheses involve triggers, genetic predispositions, T-cell mediated attacks on liver antigens
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)
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
Autoimmune Hepatitis - Lab Abnormalities
Aminotransferase Elevations - “Hepatocellular Pattern”
Elevated serum globulin fraction (Gamma Globulin, IgG)
Circulating Autoantibodies
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)
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
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
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
Autoimmune Hepatitis - Type 1 Characteristic Antibodies
Characteristic Autoantibodies ANA SMA SLA/LP pANCA
Autoimmune Hepatitis - Type 1 - Antigen
Diverse nuclear antigens
Actin and non-actin components
Polymerized F-actin
tRNP
Autoimmune Hepatitis - Type 2 Characteristic Antibodies
LKM-1/3
LC-1
Autoimmune Hepatitis - Type 2 - Antigen
CYP-2D6
Formiminotransferase Cyclodeaminase
Autoimmune Hepatitis - Type 3 Characteristic Antibodies
SLA/LP
Autoimmune Hepatitis - Type 3 - Antigen
tRNP
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
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
Autoimmune Hepatitis - Diagnosis SPECIFICS
Detection of Autoantibodies:
ANA
SMA
Anti-LKM1
Liver biopsy
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
Autoimmune Hepatitis - Treatment Basis
Severity of symptoms
Degree of elevation in transaminases and IgG
Histologic Findings
Potential side effects
Autoimmune Hepatitis - Treatment Goals
Control of immune system Minimize toxicity Individualize therapy Minimize cost Evidence based data
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
Autoimmune Hepatitis - Treatment Indications
Absolute:
AST >= 10x normal + Symptoms
AST>= 5x normal + Gamma Globulin >= 2x normal
Bridging necrosis hepatitis
Relative:
Symptoms
AST
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
Autoimmune Hepatitis - Chronic Azathioprine Adverse Effects
Bone marrow suppression GI upset Rash Infections Heatotoxicity Malignancy
Prevalence -> 70% with treatment for 5 - 10 years
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
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
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
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
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)
Primary Biliary Cirrhosis - Epidemiology
Mostly Northern Europe
More common in 1st Degree Relatives
Molecular mimicry to certain bacteria or viruses
Environmental chemical exposure
Primary Biliary Cirrhosis - Symptomatic Disease
Fatigue (common) Pruritis Jaundice Hepatosplenomegaly RUQ pain Hyperpigmentation Xanthomas & xanthelasmas Dyslipidemia Extrahepatic autoimmune diseases Complications: Portal Hypertension, Chronic Cholestasis
Primary Biliary Cirrhosis - Portal Hypertension Complications
Varices Ascites Encephalopathy Peritonitis Hepatorenal Syndrome Hepatocellular carcinoma
Primary Biliary Cirrhosis - Chonic Cholestasis Complications
Osteopenia
Malabsorption
Steatorrhea
Vitamin ADEK deficiency
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
Primary Biliary Cirrhosis - Diagnosis
Positive AMA
Abnormal LFTs (Alk Phos & GGT)
Compatible Biopsy
Primary Biliary Cirrhosis - Pathologic Stages
FLORID DUCT lesion (bile duct destruction)
Inflammation beyond portal tracts
Fibrous septa linking portal triads
Cirrhosis
