Rheumatic fever (RF) is an acute, immunologically mediated, multisystem inflammatory disease involving heart, joints, CNS, skin and other tissues that occurs a few weeks after an episode of group A β-hemolytic streptococcal pharyngitis. Acute rheumatic heart disease (RHD) is the cardiac manifestation of RF and is associated with inflammation of the valves, myocardium, or pericardium. Rheumatic fever is said to “lick the knee but bite the heart”.

Pathogenesis:

Phase 1:

1. β-hemolytic streptococci (Group A) pharygitis
2. Formation of antistreptococcal antibodies which cross reacts with endogenous tissue antigens in heart (Antibody against Streptococcal M protein cross reacts with Cardiac myosin and Sarcolemma), joints (Antibody against Streptococcal hyaluronic acid cross reacts with connective tissue proteoglycans) and other tissues

Phase 2 (2 weeks Post-infection):

1. Joints: Acute febrile polyarthritis
2. Heart: Pancarditis
3. Eye: Uveitis
4. Kidney: Acute glomerulonephritis
5. Brain: Sydenham chorea (rare)

Morphology:

A. Acute Rheumaic Heart Disease:

1. Aschoff bodies or Rheumatic granuloma: Fibrinoid necrosis demarcated by:

• Antischkow cells (Specialized histiocytes resembling Epithelioid cells which appears catterpillar like in cross section and owl’s eye in longitudinal section)
• Lymphoplasmacytic infiltrate (Sparse)
• Rarely Aschoff cells (Inflammatory Giant cells)

2. Pancarditis: Diffuse inflammation and Aschoff Bodies in any of the 3 layers of heart – pericardium, myocardium, endocardium (including valves)

• Pericardium: “Bread and Butter” Pericarditis (Fibrinous or Serofibrinous)
• Myocardium: Myocarditis (Scattered Aschoff bodies within interstitial connective tissue)
• Endocardium: Fibrinoid necrosis along the lines of closure of valves forming 1 to 2 mm vegetations (verrucae); Macculum plaques usually in left atrium

B. Chronic Rheumatic Heart Disease:

1. Organization of Acute Inflammation and Subsequent Fibrosis:

• Valve leaflet thickening
• Commisural fusion and shortening
• Thickening and fusion of chordae tendinae
• “Fish mouth” or “Button hole” Stenoses: Fibrous bridging across the valvular commisures and calcification

2. Microscopical Examination:

• Diffuse fibrosis and neovascularization
• Aschoff bodies replaced by fibrous scar

Functional Consequences:

1. Valvular stenosis and regurgitation
2. Stenosis > Regurgitation
3. Involvement of Mitral valve alone: 70%
4. Involvement of both Mitral and Aortic valve: 25%
5. Mitral stenosis: 99% (Left atrium dilate and may harbor mural thrombi)
6. Long-standing congestive pulmonary changes: Leads to Right ventricular hypertrophy

Jone’s Criteria:

A. Major: “SPACE”

1. Subcutaneous nodules
2. Pancraditis
3. Migratory polyArthritis
4. Sydenham Chorea
5. Erythema Marginatum of Skin

B. Minor: LEAF

1. Fever
2. Arthralgia
3. Leukocytosis and Raised ESR (Erythrocyte Sedimentation Rate)

Diagnosis: Either of the following

1. Essential criteria (serologic evidence of a previous streptococcal infection) + 2 or more Major Criteria
2. 1 Major Criteria + 2 Minor Criteria

Notes:

• The clinical course of rheumatic fever involves a childhood infection with complications in adulthood (cardiac defect).
• Myocardial scarring following ischemia occurs far from vascular structures but in rheumatic fever scarring occurs close to vascular structures.
• Rheumatic fever in children proceeds from the myocardium to the endocardium to the joints; in adults, it proceeds from the joints to the endocardium to the myocardium.

1. Acute Myocardial Infarction (MI)
2. Angina Pectoris
3. Chronic Ischemic Heart Disease (IHD)
4. Sudden Cardiac Death

Myocardial Infarction (MI) Commonly known as a heart attack, is an anemic infarct with coagulative necrosis of a large area of the myocardium due to occlusion of one of the three main trunks of the coronary arteries.

Types:

Risk Factors:

1. Age: Increased
2. Sex: Male
3. Other Predisposing factors of atherosclerosis (Predisposing factors and Pathogenesis of Atherosclerosis)

Pathogenesis:

A) Coronary Artery Occlusion:

Mechanisms:

1. Coronary Atherosclerosis:
Distribution: Left Anterior Descending (LAD) CA> Right Coronary Artery (RCA)> Left Circumflex (LCX) CA

Process:

• Atherosclerotic Plaque Disruption (rupture/fissuring, erosion/ulceration, hemorrhage i.e. complicated atherosclerosis) leading to exposure of subendothelial collagen and necrosis of plaque. Plaques having more foam cells, extracellular lipid, inflammatory cells, less smooth muscle cells and thin fibrous cap are the vulnerable plaques. Activated macrophages and T-lymphocytes localized at the site of plaque rupture are thought to release metalloproteases and cytokines which weaken the fibrous cap.
• Sequence of process of hemostasis:
• Adhesion, aggregation and activation of platelets and release of aggregators including TXA2 (Thromboxane A2), serotonin, etc.
• Vasospasm
• Extrinsic pathway of coagulation cascade activated to form thrombus
• Complete occlusion of coronary vessel lumen

2. Non-atherosclerotic Vasospasm
3. Emboli: Left sided mural thrombus, Endocarditis, Paradoxical emboli
4. Unexplained: Amyloid, Hemoglobinopathies

B) Myocardial Response:

• Loss of critical blood supply to myocardium
• Decreased aerobic glycolysis and Increased anaerobic glycolysis
• Decreased ATP and Increased Lactate accumulation
• Loss of contractility
• Acute Heart Failure
• Microvascular injury leading to Coagulative necrosis

Morphology

1. Anterior wall infarcts: Occlusion of Left Anterior Descending (LAD) Coronary artery
2. Posterior wall infarcts: Occlusion of Right Coronary artery
3. Lateral wall infarcts: Occlusion of Left Circumflex (LCX) Coronary artery

Gross Features by Time from Onset:

Acute Infarction: Pale infarction with cyanotic areas of hemorrhages and yellow border (Correlate with Microscopic changes of Coagulative necrosis and Acute inflammatory changes)

• 12-24 hours: Pallor
• 24-72 hours: Pallor, sometimes hyperemia; yellowing at periphery (due to neutrophilic infiltration)

Subacute Infarction: Central yellow softening with hyperemic border (Correlate with Microscopic features of phagocytosis and healing)

• 3-7 days: Hyperemic border; central yellow-brown softening
• 1-3 weeks: Maximally yellow and soft with depressed red-brown hyperemic margins (due to growth of granulation tissue)

Old Infarction: Fibrosis

• 6 weeks: Mature Grey white fibrous scar and compensatory hypertrophy of the rest of the myocardium

Acute: Pale areas of infarction and Old: White fibrous scar

Microscopic features by Time from Onset:

Acute Infarction: Caogulative necrosis with loss of striations and Acute Inflammatory reaction

• 1/2 to 4 hours: Waviness of fibers at border
• 4-12 hours: Beginning coagulation necrosis; edema; focal hemorrhage, beginning neutrophilic infiltration
• 12-24 hours: Continuing coagulation necrosis with loss of cross striations; pyknotic nucleus; myocyte contraction bands
• 1 -3 days: Coagulation necrosis completes with loss of nucleus and striations; neutrophilic infiltrate

Subacute: Appearance of macrophages, phagocytosis and Healing reaction

• 3-7 days: Disintegration of myofibers and phagocytosis by macrophages
• 1-3 weeks: Completion of phagocytosis; prominent granulation tissue with neuvascularization and fibrovascular reaction

Old: Fibrosis

• 6 weeks: Mature fibrous scar

Electron microscopy:

1. Reversible phase (0-1/2 hours): Glycogen depeltion; mitochondrial swelling and relaxation of myofibrils
2. Irreversible phase (>1/2 hours): Sarcolemmal disruption, Mitochondrial amorphous densities

Reperfusion Injury:
Reperfusion after ischemia overloads the tissue surrounding the necrotic area with calcium. This produces a continuous spasm leading to necrosis with contraction bands.

Complications:

1. Arrhythmias and Conduction defects with possible sudden cardiac death
2. Cardiogenic shock
3. Mural thrombosis with possible embolization
4. Myocardial rupture leading to cardiac tamponade and arrest
5. Infarct extension or re-infarction
6. Fibrinous pericarditis
7. Papillary muscle necrosis with possible valvular insufficiency
8. Congestive Heart Failure
9. Myocardial aneurysm resulting from ventricular akinesis

Mnemonic: HEART PASs away during MI

• H: Heart Failure
• E: Embolism following Mural thrombus formation
• A: Arrhythmia which may lead to Sudden cardiac death
• R: Re-infarction
• T: Tamponade following Myocardial rupture
• P: Pericarditis and Dressler’s syndrome; Papillary muscle necrosis
• A: Aneurysm (Ventricular) resulting from Akinesis
• Ss: Shock (Cardiogenic)

Cardiac markers:

Clinical Features, Diagnosis and Treatment of Myocardial Infarction

Initiator of the disease process by:

1. Antibody mediated injury: immune complex deposition or cytotoxic antibodies
2. T-cell mediated immune injury: non-immune complex deposition mechanism

Secondary immunopathogenic mechanism:

Role of mediators of the disease:

A) Cells:

• Neutrophils and monocytes
• Macrophages, T lymphocytes and NK cells
• Platelets
• Resident glomerular cells (Mesagnial cells)

B) Soluble mediators:

• Complement components
• Eicosanoids, NO, angiotensin and endothelin
• Cytokines: IL-1 and TNF
• Chemokines: MCP-1, RANTES, TGF-B
• Coagulation system

Antibody Mediated Injury

Include:

1. Membranous glomerulonephritis
2. IgA nephropathy
3. Membranoproliferative glomerulonephritis
4. Postinfectious glomerulonephritis
5. Anti-glomerular basement membrane disease

Immune complexes activates complement pathway through classic pathway.

A) In-situ immune complex deposition

1. Fixed intrinsic tissue (Glomerular) antigens:

Mechanism: Circulating antibodies form immune complex against the normal glomerular components

• Glomerular basement mebrane antigens : NC1 domain of collagen type IV antigen (anti-GBM disease)
  • Immunofluorescence: Linear pattern immune-complex deposition
• Podocyte antigens: Heymann antigen (membranous glomerulonephritis)
  • Immunofluorescence: Granular pattern immune-complex deposition
• Mesangial antigens
• Others

2. Planted (Deposited) antigens

Mechanisms: Non-glomerular antigens are deposited in GBM from the circulation firstly and then the circulating antibodies form immune-complex.

Immunofluorescence: Granular pattern immune-complex deposition

• Exogenous antigens (infectious agents, drugs)
• Endogenous antigens (DNA, nuclear proteins, immunoglobulins, immune complexes, IgA)

Factors influencing antigen trapping are: size, charge, molecular configuration and carbohydrate content of antigens.

B) Circulating immune complex deposition

Immunofluorescence: Granular pattern immune-complex deposition

Mechanism: Type III hypersensitivity initiated by antigen-antibody complex formed in the circulation.

• Exogenous antigens (infectious products)
• Endogenous antigens (DNA, tumor antigens)

Localisation of complexes and Factors enhancing it:

Primary immune complex deposition in one site is often accompanied by deposition of lesser amounts in other sites. The factors influencing the localisation complexes are: molecular charge of complexes, size, avidity (strength of bond between antigen and antibody), blood flow, etc.

1. Subendothelial (between capillary endothelium and GBM):

• Charge: Highly anionic complexes excluded from GBM
• Size: Intermediate
• Avidity: High

2. Intramembranous (within GBM):

• Charge: Represents the transitional phase in which complexes migrate from subendothelial position to subepithelial
• Blood flow: Increased

3. Subepithelial (between epithelial cells and GBM):

• Charge: Highly cationic complexes
• Size: Smallest (pass freely through the glomerulus without being trapped)
• Avidity: Low

4. Mesangial (within mesangium):

• Charge: Neutral charge
• Size: Large
• Blood flow: Decreased

C) Cytotoxic antibodies

Cell mediated immune injury

Mechanism: Non-immune complex deposition glomerulonephritis

This may occur through regulation of B-cell differentiation and antibody production or by local cell-mediated immunity i.e. delayed-type hypersensitivity reaction. The later is initiated by CD4+ cells by activating monocytes/macrophages which produces cytokines: IL12, IL2, INF-γ and TNF-a which are powerful inflammatory mediators causing injury. CD8+ cells acts by their cytotoxic ability.

Includes:

1. Minimal Change Disease (Lipoid necrosis)
2. Focal segmental glomerulosclerosis

Activation of Alternative Complement Pathway

Alternative pathway of complement pathway is activated by complex polysaccharides.

Role of Complement: C₃ & C₅ are chemoattractant for leukocytes, neutrophils in particular which causes damage by releasing proteolytic enzymes and by generating reactive oxygen metabolites. Terminal complement components C₅b-9, membrane attack complex (MAC) causes injury by basement membrane lysis.

Non-immunologic Mechanism

Hemodynamic and physical forces that cause intraglomerular HTN and abnormal stress and strain on the vascular wall.

Relationship of Physiologic role of glomerular components with consequences of glomerular injury

A) Endothelial cells:

Physiologic function –> Consequence of injury –> Related Disease

1. Maintain glomerular perfusion –> Vasoconstriction –> Acute renal failure
2. Prevent leukocyte adhesion –> Leukocyte infiltration –> Focal/diffuse GN
3. Prevent platelet aggregation –> Intravascular microthrombi –> Thrombotic microangiopathies

B) Mesangial cells:

• Physiologic function: Control glomerular filtration
• Consequence of injury: Proliferation and increased matrix
• Related Disease: Membranoproliferative GN

C) Visceral epithelial cells (Podocytes):

• Physiologic function: Prevent plasma protein filtration
• Consequence of injury: Proteinuria
• Related disease: Minimal change disease, Focal Segemntal Glomerulosclerosis

D) Glomerular Basement Membrane (GBM):

• Physiologic function: Prevents plasma protein filtration
• Consequence of injury: Proteinuria
• Related disease: Membranous GN

E) Parietal epithelial cells:

• Physiologic function: Maintain Bowman’s space
• Consequence of injury: Crescent formation
• Related disease: Rapidly Progressive Glomerulonephritis (RPGN)

Summary:

a) Non-immune mechanisms are involved in Diabetic nephropathy

b) Detected anibody deposition pattern: Granular except in Anti-GBM Nephritis (Linear)

c) Sites of Immune complex or Antigen Deposition:

• Subepithelial: Poststreptococcal Glomerulonephritis
• Epimembranous: Membranous Glomerulonephritis
• Subendothelial: SLE, Type I Membranoproliferative Glomerulonephritis (MPGN)
• Mesangial: IgA Nephropathy
• Basement membrane: Type II MPGN

The 3 stages of Alcoholic Liver Disease are:

1. Hepatic steatosis (fatty change)
2. Alcoholic hepatitis
3. Alcoholic cirrhosis

Interrelationships among stages of Alcoholic Liver Disease:

Gross appearance of Normal Liver:

Microscopic examination of Normal Liver and Hepatocytes:

Hepatic Steatosis:

Steatosis is a condition characterized by abnormal accumulations of triglycerides within parenchymal cells. Hepatic steatosis (fatty change) is reversible even when extensive.

Gross appearance:

No gross change occurs with mild steatosis. Later, the liver is:

1. Soft
2. Yellow
3. Greasy
4. Large (up to 4 to 6 kg)

Microscopic examination:

1. Moderate alcohol intake: small (microvesicular) lipid droplets acculmulate in hepatocytes that doesn’t compress and displace nucleus to periphery
2. Chronic alcohol intake: large (macrovesicular) globules, compressing and displacing the nucleus to the periphery of hepatocytes
3. Initially, cell damage produces centrilobular fat depositions.
4. But in severe cases entire lobule may be involved.
5. Little or no perivenular fibrosis

Alcoholic Hepatitis

Alcoholic hepatitis develops acutely, usually following a bout of heavy drinking. In 10% to 35% of heavy drinkers, alcoholic hepatitis is superimposed on pre-existing hepatic steatosis increasing the risk of cirrhosis.

Gross appearance:

The liver is:

1. Mottled red with bile stained areas
2. Of normal or increased size
3. Often contains visible nodules and fibrosis

Microscopic examination:

1. Hepatocyte swelling (ballooning): due to accumulation of fat, water and protein.
2. Hepatocyte necrosis (ballooning degeneration) which attracts neutrophils
3. Mallory bodies (Cytokeratin aggresomes): Eosinophilic cytoplasmic inclusions in degenerating hepatocytes
4. Neutrophilic reaction: Neutrophils surround the mallory bodies like “jackals around a campfire”
5. Fibrosis: “Chicken wire” fibrosis surrounds the hepatocytes (sinusoidal, perivenular and ocassionaly periportal)

Alcoholic Cirrhosis:

Alcoholic cirrhosis is the final and irreversible form of alcoholic liver disease which usually evolves slowly and insidiously. Cirrhosis is a diffuse process (affecting whole liver) characterized by fibrosis and conversion of the liver architecture into nodules.

Gross appearance:

At Beginning: Micronodular (nodules <3cm in diameter), Yellow, Fatty, Enlarged (>2 kg)

After years: Macronodular (nodules >3cm in diameter), Brown, Non-fatty, Shrunken (<1 kg)

Microscopic examination:

1. Lobular architecture: No normal lobular architecture can be identified and central veins are hard to find.
2. Fibrous septa: The fibrous septa that divide the hepatic parenchyma into modules are initially delicate and extend through sinusoids from:
   • Central vein to portal regions and
   • Portal tract to portal tract
3. Hepatic parenchyma:
   • Hepatocyte regeneration generates micronodules (parenchyma shows extensive fatty change) .
   • As fibrous septa widens and surround nodules, liver becomes more fibrotic, loses fat and shrinks progressively in size.
   • Mixed micronodular and macronodular pattern seen
   • Laennec cirrhosis: Ischemic necrosis and fibrous obliteration of nodules create broad expanses of tough, pale, scar tissue.
4. Inflammation: Sparse infiltrate of mononuclear cells in the fibrous septa
5. Bile stasis

References:

1. Robins and Cotran Pathological Basis of Disease 7th edition
2. Robins Basic Pathology 8th edition
3. Textbook of Pathology by Harsh Mohan
4. Riede / Werner Color Atlas of Pathology – Thieme
5. Pathology Illustrated 6th Edition by Robin Reid and Fiona Roberts
6. Library.med.utah.edu

Prepared for Correlation Seminar for Gastrointestinal System in KIST Medical College by:

• Srijana Shakya (Roll no.79)
• Sulabh Shrestha (Roll no.80)