Pathophysiology

Core Science

Cellular injury, inflammation, hemodynamic disorders, neoplasia, immunopathology, genetic disease mechanisms, and every pathophysiologic process, mediator, and disease mechanism across the full scope of general pathology.

01 Overview & Scope of Pathophysiology

Pathophysiology is the study of disordered physiological processes that underlie disease. It bridges the gap between basic science and clinical medicine by explaining how and why diseases develop, progress, and produce clinical manifestations. General pathology encompasses the core mechanisms — cell injury, inflammation, hemodynamic derangements, neoplasia, and immune dysfunction — that recur across virtually every organ system and clinical specialty.

WHY PATHOPHYSIOLOGY MATTERS

Every clinical sign, laboratory abnormality, and imaging finding reflects an underlying pathophysiologic mechanism. A clinician who understands the “why” behind disease can predict complications, interpret atypical presentations, choose rational therapies, and avoid diagnostic pitfalls that rote memorization alone cannot address.

The Four Pillars of Pathology

Pillar	Focus	Key Questions
Etiology	Cause of disease	What agent or defect initiates the process?
Pathogenesis	Mechanism of disease development	What sequence of events leads from cause to lesion?
Morphologic Changes	Structural alterations in cells/tissues	What do gross and microscopic changes look like?
Clinical Significance	Functional consequences	What symptoms, signs, and lab findings result?

When evaluating any disease, always organize your thinking around etiology → pathogenesis → morphology → clinical manifestation. This framework applies universally from myocardial infarction to systemic lupus to colon cancer.

Causes of Disease

Genetic — inherited mutations, chromosomal abnormalities, single-gene defects
Acquired — infectious, immunologic, nutritional, chemical/physical, iatrogenic
Multifactorial — gene-environment interactions (atherosclerosis, diabetes, cancer)
Idiopathic — cause unknown despite investigation

Acute Phase Reactants

Systemic inflammation triggers the liver to produce acute phase proteins under the influence of IL-6, IL-1, and TNF-α. These proteins serve as important clinical markers and mediators of the inflammatory response.

Positive Acute Phase Reactants (↑)	Function / Clinical Use
C-reactive protein (CRP)	Opsonin (binds phosphocholine on bacteria); activates complement; most widely used clinical marker of inflammation; rises within 6 hours
Fibrinogen	Coagulation factor I; elevates ESR (promotes rouleaux formation); contributes to hypercoagulable state in inflammation
Ferritin	Iron storage protein; sequesters iron from pathogens; very high in adult-onset Still disease and hemophagocytic lymphohistiocytosis (HLH)
Hepcidin	Master regulator of iron; blocks ferroportin → traps iron in macrophages and enterocytes; mediates anemia of chronic disease
Serum amyloid A (SAA)	Precursor of AA amyloid in chronic inflammation; lipoprotein associated
Complement (C3, C4)	Enhanced complement activation during inflammation

Negative Acute Phase Reactants (↓)	Significance
Albumin	Decreased hepatic synthesis during inflammation; shifts to producing positive APRs; hypoalbuminemia contributes to edema
Transferrin	Decreased iron transport capacity; contributes to functional iron deficiency in chronic disease
Transthyretin (prealbumin)	Short half-life (~2 days) makes it a sensitive marker of nutritional status; drops rapidly in inflammation

The ESR (erythrocyte sedimentation rate) is elevated in inflammation primarily because increased fibrinogen promotes RBC rouleaux formation, causing faster sedimentation. ESR is not a direct measure of inflammation but rather reflects the protein milieu. CRP is more specific and responsive (rises and falls faster). ESR is disproportionately elevated in multiple myeloma and Waldenström macroglobulinemia due to high immunoglobulin levels promoting rouleaux.

02 Cellular Homeostasis & Adaptation

Normal cells operate within a narrow range of structure and function defined by their genetic program, metabolic demands, and extracellular signals. When stressed, cells can adapt through reversible changes in size, number, or phenotype. Adaptation is a key concept distinguishing reversible from irreversible cell injury.

Cellular Adaptations

Adaptation	Definition	Mechanism	Classic Example
Hypertrophy	Increase in cell size	Increased protein synthesis; mechanical sensors, growth factors (IGF-1), vasoactive agents (angiotensin II)	Left ventricular hypertrophy in hypertension; skeletal muscle hypertrophy with exercise
Hyperplasia	Increase in cell number	Growth factor–driven cell proliferation	Endometrial hyperplasia from excess estrogen; compensatory liver regeneration after partial hepatectomy
Atrophy	Decrease in cell size and organelle content	Decreased protein synthesis + increased degradation (ubiquitin-proteasome pathway, autophagy)	Disuse atrophy of immobilized limb; denervation atrophy; senile atrophy of brain
Metaplasia	Replacement of one differentiated cell type by another	Reprogramming of stem cells by cytokines, growth factors, extracellular matrix	Squamous metaplasia of bronchial epithelium in smokers; Barrett esophagus (squamous → columnar)
Dysplasia	Disordered growth with loss of uniformity and architectural orientation	Accumulated genetic alterations in proliferating cells	Cervical dysplasia (CIN); colonic dysplasia in ulcerative colitis

CLINICAL CORRELATION

Barrett esophagus is the prototypical example of metaplasia → dysplasia → carcinoma sequence. Chronic GERD causes squamous-to-columnar metaplasia of the distal esophagus, which can progress through low-grade and high-grade dysplasia to esophageal adenocarcinoma. This progression underscores why metaplasia and dysplasia are considered precancerous conditions requiring surveillance.

Diagram of cellular adaptations including hypertrophy, hyperplasia, atrophy, and metaplasia — **Figure 1 — Cellular Adaptations.** Non-neoplastic changes a cell can undergo in response to stress, including hypertrophy (increased cell size), hyperplasia (increased cell number), atrophy (decreased cell size), and metaplasia (change from one cell type to another).

Hypertrophy and hyperplasia often coexist. The gravid uterus undergoes both smooth muscle hypertrophy (estrogen-driven increase in cell size) and hyperplasia (estrogen-driven increase in cell number). Only cells capable of division can undergo hyperplasia — cardiac myocytes and neurons primarily undergo hypertrophy alone.

03 Key Terminology & Abbreviations

Abbreviation	Full Term
ROS	Reactive oxygen species
TNF	Tumor necrosis factor
IL	Interleukin
NF-κB	Nuclear factor kappa-light-chain-enhancer of activated B cells
COX	Cyclooxygenase
LOX	Lipoxygenase
PG	Prostaglandin
LT	Leukotriene
NO	Nitric oxide
VEGF	Vascular endothelial growth factor
TGF-β	Transforming growth factor beta
DIC	Disseminated intravascular coagulation
DVT	Deep vein thrombosis
PE	Pulmonary embolism
MI	Myocardial infarction
MHC	Major histocompatibility complex
HLA	Human leukocyte antigen
DAMP	Damage-associated molecular pattern
PAMP	Pathogen-associated molecular pattern
TLR	Toll-like receptor
MAC	Membrane attack complex (C5b-9)
Rb	Retinoblastoma protein (tumor suppressor)
BRCA	Breast cancer susceptibility gene
AFP	Alpha-fetoprotein
CEA	Carcinoembryonic antigen
PSA	Prostate-specific antigen

04 Mechanisms of Cell Injury

Cell injury occurs when stresses exceed the cell’s ability to adapt. Injury is initially reversible — the cell can return to normal if the stimulus is removed — but persistent or severe stress crosses a “point of no return” leading to irreversible injury and cell death.

Major Causes of Cell Injury

Cause	Mechanism	Examples
Hypoxia / Ischemia	Decreased O₂ delivery → impaired oxidative phosphorylation → ATP depletion	Atherosclerotic coronary occlusion (MI); anemia; CO poisoning; respiratory failure
Toxins	Direct damage to membranes, enzymes, or DNA; or generation of toxic metabolites	CCl₄ (hepatotoxicity via free radical P-450 metabolism); acetaminophen (NAPQI); ethanol
Infectious agents	Direct cytopathic effect, exotoxins, endotoxins, immune-mediated damage	Viral lysis (influenza); bacterial exotoxins (diphtheria); granulomatous inflammation (TB)
Immunologic reactions	Autoimmunity, hypersensitivity, complement activation	SLE (Type III); Goodpasture (Type II); anaphylaxis (Type I)
Physical agents	Mechanical trauma, thermal injury, radiation, electrical injury	Burns, frostbite, ionizing radiation (DNA double-strand breaks)
Nutritional imbalance	Deficiency or excess of nutrients	Scurvy (vitamin C deficiency); kwashiorkor (protein deficiency); obesity

Diagram of reversible and irreversible ischemic cell injury mechanisms — **Figure 2 — Ischemic Cell Injury Pathway.** Schematic showing the sequence of events in ischemic cell injury, from initial ATP depletion and reversible changes through the point of no return to irreversible injury and cell death.

Sequence of Ischemic Cell Injury

ISCHEMIA → CELL DEATH TIMELINE

Seconds: Cessation of oxidative phosphorylation; ATP begins to fall
1–2 minutes: Na⁺/K⁺-ATPase fails → cellular swelling; anaerobic glycolysis begins → lactic acid ↓ pH
5–10 minutes: Ribosomes detach from rough ER → decreased protein synthesis
10–40 minutes: Progressive membrane damage; calcium influx; mitochondrial swelling
>40 minutes (variable): Point of no return — mitochondrial permeability transition pore opens; massive Ca²⁺ influx; lysosomal enzyme release → irreversible injury

Comparison of normal cell, reversible injury, and irreversible injury morphology — **Figure 3 — Normal, Reversible, and Irreversible Cell Injury.** Morphologic comparison showing progression from normal cell structure through reversible changes (cellular swelling, ER dilation) to irreversible injury (membrane disruption, nuclear changes, organelle breakdown).

Reversible vs Irreversible Injury

Feature	Reversible	Irreversible
ATP	Decreased but recoverable	Severely depleted
Cell swelling	Present (hydropic change)	Severe; membrane blebs rupture
Mitochondria	Mild swelling	Dense amorphous densities; permeability transition
Membrane integrity	Intact	Disrupted — lysosomal enzymes leak
Nuclear changes	Clumping of chromatin	Pyknosis, karyorrhexis, karyolysis
Calcium	Mild elevation	Massive intracellular calcium accumulation

Overview of cell injury pathways leading to necrosis and apoptosis — **Figure 4 — Cell Injury, Necrosis, and Apoptosis.** Overview of the major pathways of cell injury, illustrating how different insults lead to either necrosis (with inflammation) or apoptosis (without inflammation) depending on the nature and severity of the stimulus.

Role of cytosolic calcium in cell injury mechanisms — **Figure 5 — Calcium in Cell Injury.** The role of increased cytosolic calcium in mediating cell injury. Massive calcium influx activates destructive enzymes including phospholipases, proteases, endonucleases, and ATPases, contributing to irreversible damage.

Acute cell swelling process in ischemic injury — **Figure 6 — Acute Cell Swelling.** Histologic and ultrastructural features of acute cell swelling (hydropic change), the earliest and most common manifestation of reversible cell injury caused by failure of the Na+/K+-ATPase pump.

The two morphologic hallmarks of irreversible cell injury are (1) mitochondrial dense amorphous densities (flocculent densities on EM) and (2) plasma membrane disruption. These distinguish the “point of no return” from reversible changes such as cellular swelling and fatty change.

05 Free Radical & Oxidative Injury

Free radicals are chemical species with a single unpaired electron in an outer orbital, making them highly reactive. Reactive oxygen species (ROS) are the most important free radicals in biological systems and play a central role in cell injury, aging, and cancer.

Major Reactive Oxygen Species

Species	Symbol	Source
Superoxide anion	O₂^•−	Mitochondrial electron transport chain leak; NADPH oxidase (phagocytes); xanthine oxidase
Hydrogen peroxide	H₂O₂	Superoxide dismutase conversion; peroxisomal oxidases
Hydroxyl radical	•OH	Fenton reaction (Fe²⁺ + H₂O₂ → Fe³⁺ + OH⁻ + •OH); Haber-Weiss reaction; ionizing radiation
Peroxynitrite	ONOO⁻	NO + O₂^•− → ONOO⁻

Mechanisms of Free Radical Damage

Lipid peroxidation — ROS attack polyunsaturated fatty acids in membranes, generating lipid peroxides and malondialdehyde (MDA); propagates as chain reaction damaging cell and organelle membranes
Protein oxidation — oxidation of amino acid side chains, cross-linking, fragmentation → loss of enzymatic activity
DNA damage — single- and double-strand breaks, base modifications (8-hydroxydeoxyguanosine) → mutagenesis, aging, carcinogenesis

Antioxidant Defense Systems

Defense	Mechanism
Superoxide dismutase (SOD)	O₂^•− → H₂O₂
Catalase	H₂O₂ → H₂O + O₂ (peroxisomes)
Glutathione peroxidase	H₂O₂ + 2GSH → 2H₂O + GSSG (cytoplasm, mitochondria)
Vitamin E (α-tocopherol)	Lipid-soluble chain-breaking antioxidant in membranes
Vitamin C (ascorbate)	Water-soluble antioxidant; regenerates vitamin E
Ferritin & ceruloplasmin	Sequester free iron and copper, preventing Fenton reaction

Reactive oxygen species and free radical mechanisms of cell injury — **Figure 7 — ROS and Free Radical Toxicity.** Mechanisms of free radical generation and the pathways by which reactive oxygen species damage cellular components through lipid peroxidation, protein oxidation, and DNA damage, along with the antioxidant defense systems that counteract them.

The Fenton reaction is the single most important mechanism for generating the highly destructive hydroxyl radical. This is why iron overload states (hemochromatosis, transfusional hemosiderosis) and copper excess (Wilson disease) cause tissue damage — free transition metals catalyze hydroxyl radical formation.

06 Necrosis: Types & Mechanisms

Necrosis is the morphologic pattern of cell death that occurs after irreversible injury in a living organism. It is characterized by enzymatic digestion of the cell (autolysis or heterolysis) and always elicits an inflammatory response due to leakage of cellular contents into the extracellular space.

Types of Necrosis

Type	Mechanism	Morphology	Classic Locations
Coagulative	Ischemia → protein denaturation preserves cell outlines; proteolytic enzymes denatured	Firm, pale tissue; ghost outlines of cells on H&E; preserved architecture	Heart, kidney, spleen (all solid organs except brain)
Liquefactive	Enzymatic digestion dominates (hydrolytic enzymes from neutrophils or microglial cells)	Soft, liquefied tissue; pus (abscess); cystic spaces	Brain infarction; bacterial abscesses (anywhere); pancreatic necrosis
Caseous	Incomplete digestion; combination of coagulative and liquefactive	Cheese-like, friable white-yellow material; granulomatous inflammation; amorphous debris on H&E	Tuberculosis (lung, lymph node); systemic fungal infections
Fat necrosis	Lipase release → hydrolysis of triglycerides → free fatty acids + calcium → saponification	Chalky white foci (calcium soap deposits); “ghost” outlines of fat cells	Acute pancreatitis (enzymatic); breast (traumatic)
Fibrinoid	Immune complex or antibody deposition in vessel walls + fibrin → vessel wall damage	Bright pink, smudgy material in vessel walls on H&E	Malignant hypertension; vasculitis (PAN); rheumatic heart disease (Aschoff bodies)
Gangrenous	Not a distinct histologic pattern; refers to necrosis of a limb or organ	Dry gangrene = coagulative; wet gangrene = liquefactive (superimposed infection)	Diabetic foot; bowel ischemia; gas gangrene (Clostridium perfringens)

HIGH-YIELD DISTINCTION

Brain infarcts undergo liquefactive necrosis (not coagulative), making the brain the only solid organ exception to the “coagulative necrosis in solid organ infarcts” rule. The abundance of hydrolytic enzymes in neural tissue and the high lipid content favor enzymatic digestion.

Structural comparison of necrosis versus apoptosis — **Figure 8 — Necrosis vs. Apoptosis.** Structural alterations during necrosis compared to apoptosis. Necrosis features cell swelling, membrane disruption, and inflammatory response, while apoptosis involves cell shrinkage, chromatin condensation, and formation of apoptotic bodies without inflammation.

Nuclear Changes in Necrosis

Pyknosis — nuclear shrinkage and increased basophilia (chromatin condensation)
Karyorrhexis — fragmentation of the pyknotic nucleus
Karyolysis — dissolution of chromatin due to DNase activity; nucleus fades away

07 Apoptosis & Programmed Cell Death

Apoptosis is a tightly regulated, energy-dependent mechanism of programmed cell death that eliminates unwanted, damaged, or aged cells without eliciting an inflammatory response. Unlike necrosis, apoptotic cells shrink, their chromatin condenses, and they fragment into membrane-bound apoptotic bodies that are rapidly phagocytosed.

Apoptosis vs Necrosis

Feature	Apoptosis	Necrosis
Cell size	Shrinkage	Swelling (oncosis)
Membrane	Intact; phosphatidylserine flips to outer leaflet (“eat me” signal)	Disrupted; contents leak out
Nucleus	Fragmentation into nucleosomal-size fragments (DNA ladder on gel)	Pyknosis → karyorrhexis → karyolysis
Inflammation	Absent (no leakage of contents)	Present (DAMP release)
Energy	ATP-dependent (active process)	ATP-depleted (passive)
Mechanism	Caspase cascade	Enzymatic digestion by released lysosomal enzymes

Intrinsic (Mitochondrial) Pathway

Triggered by DNA damage, growth factor withdrawal, ER stress, or misfolded proteins. Pro-apoptotic BH3-only proteins (Bad, Bim, Bid) activate Bax and Bak, which oligomerize in the mitochondrial outer membrane, forming pores that release cytochrome c. Cytochrome c binds Apaf-1 to form the apoptosome, which activates caspase-9 (initiator caspase) → caspase-3 (executioner caspase). Anti-apoptotic proteins Bcl-2 and Bcl-xL prevent Bax/Bak oligomerization and are overexpressed in many cancers (e.g., follicular lymphoma with t(14;18)).

Intrinsic and extrinsic apoptosis pathways diagram — **Figure 9 — Apoptosis Pathways.** The intrinsic (mitochondrial) and extrinsic (death receptor) pathways of apoptosis. Both converge on executioner caspases (caspase-3, -6, -7) that dismantle the cell. The intrinsic pathway is regulated by the Bcl-2 family; the extrinsic pathway is initiated by death receptor signaling (Fas/FasL, TNF/TNFR).

Extrinsic (Death Receptor) Pathway

Initiated by binding of death ligands to death receptors: Fas ligand → Fas (CD95) or TNF → TNF receptor 1. Receptor trimerization recruits adaptor proteins (FADD) to form the death-inducing signaling complex (DISC), which activates caspase-8 (initiator) → caspase-3 (executioner). Both pathways converge on the executioner caspases (caspase-3, -6, -7) that cleave cytoskeletal proteins, nuclear lamins, and activate endonucleases (CAD/DFF40).

CLINICAL CORRELATION

Dysregulated apoptosis underlies many diseases: too little apoptosis → cancer (e.g., Bcl-2 overexpression in follicular lymphoma), autoimmune disease (failure to eliminate self-reactive lymphocytes); too much apoptosis → neurodegenerative diseases (Alzheimer, Parkinson), aplastic anemia, ischemia-reperfusion injury. The p53 tumor suppressor is a critical pro-apoptotic regulator — loss of p53 function (mutated in >50% of human cancers) impairs the cell’s ability to undergo apoptosis in response to DNA damage.

08 Intracellular Accumulations & Calcification

Abnormal intracellular accumulations result from excessive intake, abnormal metabolism, defective transport/secretion, or inability to degrade a substance. These accumulations provide important diagnostic clues on histopathology.

Types of Intracellular Accumulations

Substance	Mechanism	Example	Histologic Appearance
Lipid (steatosis)	Excess triglycerides in parenchymal cells (usually hepatocytes)	Alcoholic/non-alcoholic fatty liver disease	Clear vacuoles pushing nucleus to periphery (macrovesicular); or small droplets (microvesicular)
Cholesterol	Phagocytosis of lipid by macrophages	Atherosclerotic plaque (foam cells); xanthomas	Foamy macrophages; cholesterol clefts (needle-shaped clear spaces)
Protein	Reabsorption droplets; Mallory-Denk bodies; Russell bodies	Nephrotic syndrome (proximal tubule); alcoholic hepatitis; myeloma	Eosinophilic droplets (tubular); glassy eosinophilic inclusions
Glycogen	Abnormal glucose/glycogen metabolism	Diabetes mellitus; glycogen storage diseases	Clear vacuoles (PAS-positive, diastase-sensitive)
Hemosiderin	Iron storage in macrophages; local or systemic overload	Hemochromatosis; chronic hemorrhage; transfusions	Golden-brown granular pigment; Prussian blue stain positive
Lipofuscin	“Wear and tear” pigment from lipid peroxidation of membranes; not harmful	Aging (heart, liver, brain — “brown atrophy”)	Yellow-brown granular perinuclear pigment
Melanin	Endogenous pigment from melanocytes	Melanoma; nevi; melanosis coli	Brown-black pigment; bleached by melanin bleach
Carbon (anthracosis)	Inhaled carbon particles engulfed by macrophages	Coal workers’ pneumoconiosis; urban air pollution	Black pigment in lung macrophages and hilar lymph nodes

Histologic examples of intracellular accumulations and inclusion bodies — **Figure 10 — Intracellular Accumulations.** Histologic examples of abnormal intracellular accumulations including lipid droplets, protein inclusions, and pigment deposits that provide important diagnostic clues in pathology specimens.

Pathologic Calcification

Type	Serum Ca²⁺	Mechanism	Examples
Dystrophic	Normal	Calcium deposits in dead/dying tissue; nucleation on membrane-bound phospholipids or denatured proteins	Atherosclerotic plaques; aortic stenosis (calcific); TB granulomas (caseous necrosis); psammoma bodies
Metastatic	Elevated (hypercalcemia)	Calcium deposits in normal tissue due to systemic hypercalcemia	Hyperparathyroidism; renal failure (secondary hyperPTH); sarcoidosis; metastatic bone destruction; vitamin D excess

Psammoma bodies are concentric, laminated calcifications found in papillary thyroid carcinoma, papillary serous cystadenocarcinoma of the ovary, meningioma, and mesothelioma. Their presence on cytology or biopsy is a useful diagnostic clue (“PSaMMoma” mnemonic: Papillary thyroid, Serous ovarian, Meningioma, Mesothelioma).

09 Acute Inflammation

Acute inflammation is the rapid, initial response to tissue injury or infection, characterized by vasodilation, increased vascular permeability, and recruitment of leukocytes (predominantly neutrophils). It occurs within minutes to hours and typically resolves within days.

Cardinal Signs of Inflammation (Celsus + Virchow)

Sign	Latin	Mechanism
Redness	Rubor	Vasodilation → increased blood flow
Heat	Calor	Vasodilation → warm blood to surface
Swelling	Tumor	Increased vascular permeability → exudate
Pain	Dolor	Bradykinin, PGE₂ sensitize nociceptors; pressure from edema
Loss of function	Functio laesa	Pain, swelling, tissue destruction impair function

Vascular Events

Transient vasoconstriction (seconds) → arteriolar vasodilation (histamine, NO, PGI₂) → increased blood flow (hyperemia)
Increased vascular permeability — endothelial cell contraction creates inter-endothelial gaps in post-capillary venules; allows protein-rich exudate to enter interstitium
Stasis — fluid loss concentrates RBCs, increasing viscosity and slowing flow; facilitates leukocyte margination

Leukocyte extravasation showing cadherins, integrins, and receptors involved — **Figure 11 — Leukocyte Extravasation Overview.** Diagram illustrating the molecules involved in leukocyte extravasation from the vascular lumen into tissues, including cadherins, integrins (LFA-1, Mac-1), selectins, and their endothelial ligands (ICAM-1, VCAM-1, PECAM-1).

Leukocyte Recruitment Cascade

STEPS OF LEUKOCYTE EXTRAVASATION

Margination — slowed blood flow allows WBCs to move to vessel periphery
Rolling — loose, transient adhesion via selectins (E-selectin, P-selectin on endothelium; L-selectin on leukocytes) binding sialyl-Lewis X carbohydrates
Firm adhesion — chemokine-activated integrins (LFA-1/Mac-1) on leukocytes bind ICAM-1 and VCAM-1 on endothelium
Transmigration (diapedesis) — leukocytes squeeze between endothelial cells via PECAM-1 (CD31) interactions, traversing the basement membrane with collagenases
Chemotaxis — directed migration along chemical gradient (C5a, LTB₄, IL-8, bacterial peptides [fMLP])

Leukocyte adhesion deficiency type 1 (LAD-1) is caused by a defect in the CD18 β₂-integrin subunit, preventing firm adhesion. Patients have markedly elevated WBC counts (neutrophilia — cells cannot leave the bloodstream), recurrent severe bacterial infections, impaired wound healing, and delayed umbilical cord separation.

Phagocytosis & Killing

Neutrophils and macrophages recognize pathogens via opsonin receptors (Fc receptor for IgG, C3b receptor/CR1), pattern recognition receptors (TLRs for PAMPs), and mannose receptors. Engulfment creates a phagosome that fuses with lysosomes. Killing mechanisms include:

Oxygen-dependent (respiratory burst): NADPH oxidase generates O₂^•− → H₂O₂ → myeloperoxidase (MPO) + Cl⁻ → HOCl (hypochlorous acid, the most potent bactericidal agent)
Oxygen-independent: lysozyme, lactoferrin, defensins, major basic protein (eosinophils), bactericidal/permeability-increasing protein (BPI)

Chronic granulomatous disease (CGD) results from defective NADPH oxidase (most commonly X-linked defect in gp91phox). Patients cannot generate the respiratory burst and are susceptible to catalase-positive organisms (S. aureus, Aspergillus, Serratia, Nocardia, Burkholderia cepacia) because catalase-positive organisms destroy their own H₂O₂, removing the substrate that could otherwise fuel the MPO system. Catalase-negative organisms (Streptococci) produce H₂O₂ that CGD neutrophils can still use. Diagnosed by dihydrorhodamine (DHR) flow cytometry or nitroblue tetrazolium (NBT) test.

10 Chemical Mediators of Inflammation

Inflammatory mediators are derived from plasma proteins or cells and orchestrate every step of the inflammatory response. They are produced in response to tissue injury, PAMPs, and DAMPs, and their actions are tightly regulated to limit collateral tissue damage.

Cell-Derived Mediators

Mediator	Source	Actions
Histamine	Mast cell granules, basophils, platelets	Vasodilation; increased vascular permeability (venules); bronchoconstriction
Serotonin (5-HT)	Platelet dense granules	Vasodilation; increased vascular permeability
PGE₂	COX pathway of arachidonic acid (mast cells, macrophages)	Vasodilation; pain (sensitizes nociceptors); fever (hypothalamic PGE₂)
PGI₂ (prostacyclin)	Endothelial cells (COX pathway)	Vasodilation; inhibits platelet aggregation
TXA₂	Platelets (COX pathway)	Vasoconstriction; promotes platelet aggregation
LTB₄	Neutrophils, macrophages (5-LOX pathway)	Potent chemotaxis for neutrophils; activates leukocytes
LTC₄/D₄/E₄	Mast cells, eosinophils, macrophages (5-LOX)	Bronchoconstriction (1000× more potent than histamine); increased vascular permeability; vasoconstriction
PAF	Platelets, neutrophils, mast cells, endothelium	Platelet aggregation; vasodilation; bronchoconstriction; WBC priming
Nitric oxide (NO)	Endothelium (eNOS), macrophages (iNOS)	Vasodilation; cytotoxic to microbes (iNOS); inhibits platelet adhesion and leukocyte recruitment

Key Cytokines in Inflammation

Cytokine	Source	Major Actions
TNF-α	Macrophages, T cells	Fever; acute phase proteins; endothelial activation (E-selectin, ICAM-1); cachexia; septic shock (at high levels: hypotension, DIC, multi-organ failure)
IL-1	Macrophages, dendritic cells, epithelium	Fever; acute phase proteins; endothelial activation (similar to TNF); neutrophil chemotaxis
IL-6	Macrophages, T cells, endothelium	Fever; acute phase protein induction (major driver of CRP, fibrinogen from liver); B cell differentiation
IL-8 (CXCL8)	Macrophages, endothelium	Major neutrophil chemotactic factor; activates neutrophils
IL-12	Macrophages, dendritic cells	Activates NK cells; induces T_H1 differentiation; stimulates IFN-γ production
IFN-γ	T_H1 cells, NK cells	Most potent macrophage activator; induces MHC II; promotes T_H1; antiviral
IL-4	T_H2 cells, mast cells	B cell class switch to IgE; promotes T_H2 differentiation; inhibits T_H1
IL-5	T_H2 cells	Eosinophil activation, differentiation, and chemotaxis; IgA class switching
IL-10	T_reg cells, macrophages	Anti-inflammatory: suppresses macrophage and dendritic cell function; inhibits IL-12 and TNF production
IL-13	T_H2 cells	Similar to IL-4; mucus hypersecretion; IgE class switch; airway remodeling in asthma
IL-17	T_H17 cells	Recruits neutrophils; promotes inflammation; key in psoriasis, RA, and mucosal immunity against extracellular bacteria/fungi
TGF-β	Macrophages, T cells, platelets	Anti-inflammatory; promotes fibrosis (collagen synthesis); induces T_reg differentiation; inhibits proliferation

Arachidonic acid metabolism pathway showing COX and LOX branches — **Figure 13 — Arachidonic Acid Metabolism Pathway.** The COX and lipoxygenase (LOX) pathways of arachidonic acid metabolism. Phospholipase A2 liberates arachidonic acid from membrane phospholipids; COX produces prostaglandins and thromboxane, while 5-LOX produces leukotrienes. Key pharmacologic targets are indicated.

Plasma-Derived Mediators: Complement System

The complement system comprises >30 plasma proteins activated by three pathways: classical (antibody-antigen complexes → C1q binding), alternative (spontaneous C3 hydrolysis on microbial surfaces; no antibody needed), and lectin (mannose-binding lectin binds microbial mannose residues). All three pathways converge at C3 convertase, which cleaves C3 into C3a and C3b — the central event in complement activation.

Component	Function	Clinical Deficiency
C3a, C5a	Anaphylatoxins — mast cell degranulation, vasodilation, increased permeability; C5a is also the most potent neutrophil chemotactic factor	C3 deficiency: severe recurrent pyogenic infections + immune complex disease (C3 is the convergence point)
C3b	Opsonization — facilitates phagocytosis by macrophages and neutrophils
C5b-9 (MAC)	Membrane attack complex — lysis of target cells by forming transmembrane pores	C5–C9 deficiency: increased susceptibility to Neisseria infections (meningococcal meningitis/sepsis)
C1 esterase inhibitor	Regulates classical pathway and kinin system	Hereditary angioedema (HAE): recurrent episodes of non-pruritic, non-pitting edema of face, larynx, and bowel; does NOT respond to epinephrine or antihistamines
C1q, C2, C4	Early classical pathway components	C2 deficiency (most common complement deficiency): SLE-like illness due to impaired immune complex clearance
DAF (CD55), MIRL (CD59)	GPI-anchored complement regulatory proteins on cell surfaces; prevent MAC assembly on self cells	Paroxysmal nocturnal hemoglobinuria (PNH): loss of GPI anchor (PIGA mutation) → complement-mediated hemolysis, thrombosis, pancytopenia

The most common complement deficiency is C2 deficiency, which presents with SLE-like illness. However, the most clinically devastating is C3 deficiency (C3 is the convergence point of all pathways), and the most testable association is terminal complement (C5–C9) deficiency with recurrent Neisseria infections. Any patient with recurrent meningococcal infections should be evaluated for complement deficiency.

Complement system classical, alternative, and lectin pathways — **Figure 14 — Complement Pathways.** The three activation pathways of the complement system: classical (C1q-antibody complex), alternative (spontaneous C3 hydrolysis), and lectin (mannose-binding lectin). All converge at C3 convertase, generating C3a/C5a (anaphylatoxins), C3b (opsonin), and the membrane attack complex (C5b-9).

Kinin System

Factor XII (Hageman factor) activates prekallikrein → kallikrein, which cleaves high-molecular-weight kininogen to produce bradykinin. Bradykinin causes vasodilation, increased vascular permeability, pain, and bronchoconstriction. It is inactivated by ACE (kininase II) — this is why ACE inhibitors can cause angioedema and dry cough (via accumulated bradykinin).

ARACHIDONIC ACID PATHWAY SUMMARY

Phospholipase A₂ liberates arachidonic acid from membrane phospholipids. AA is metabolized by: (1) COX-1/COX-2 → prostaglandins (PGE₂, PGI₂, PGD₂) and thromboxane (TXA₂); (2) 5-lipoxygenase → leukotrienes (LTB₄, LTC₄/D₄/E₄); (3) 12-lipoxygenase → lipoxins (anti-inflammatory, resolve inflammation). Corticosteroids inhibit phospholipase A₂ (blocking both pathways). NSAIDs inhibit COX only. Zileuton inhibits 5-LOX. Montelukast/zafirlukast block leukotriene receptors.

11 Chronic Inflammation & Granulomatous Disease

Chronic inflammation is a prolonged inflammatory response (weeks to years) characterized by simultaneous tissue destruction and repair. The dominant cell types shift from neutrophils to macrophages, lymphocytes, and plasma cells. It may follow acute inflammation or arise de novo.

Acute vs Chronic Inflammation

Feature	Acute	Chronic
Duration	Hours to days	Weeks to years
Dominant cells	Neutrophils	Macrophages, lymphocytes, plasma cells
Tissue injury	Usually mild, self-limited	Often severe and progressive
Fibrosis	Usually absent	Prominent
Mediators	Histamine, prostaglandins, complement, kinins	IFN-γ, TNF, IL-12, growth factors (TGF-β, PDGF, VEGF)

Causes of Chronic Inflammation

Persistent infection — organisms that resist killing (TB, fungi, viruses, parasites)
Autoimmune disease — self-antigens drive perpetual immune activation (RA, SLE, MS)
Prolonged toxic exposure — silicosis, asbestosis, atherosclerosis (oxidized LDL)
Foreign bodies — suture material, talc, implants

Granulomatous Inflammation

A distinctive pattern of chronic inflammation characterized by aggregates of activated macrophages that transform into epithelioid cells (elongated macrophages with pale pink cytoplasm), often with multinucleated giant cells (Langhans type with peripheral horseshoe nuclei, or foreign-body type with scattered nuclei). Granulomas may be caseating (central necrosis, classic for TB) or non-caseating (sarcoidosis, Crohn disease, berylliosis).

Cellular organization model of a granuloma showing epithelioid cells and giant cells — **Figure 15 — Granuloma Cellular Organization.** Model of granuloma structure showing the organized aggregate of epithelioid macrophages, multinucleated giant cells, and a peripheral cuff of lymphocytes. T helper 1 cells secrete IFN-gamma to activate macrophages, and TNF-alpha is critical for granuloma maintenance.

Histology of caseating granuloma in tuberculosis — **Figure 16 — Caseating Granuloma (Tuberculosis).** Histopathology of a necrotizing (caseating) granuloma in tuberculosis showing central caseous necrosis surrounded by epithelioid histiocytes and Langhans-type giant cells with a peripheral lymphocytic cuff.

Histology of non-caseating granulomas in sarcoidosis — **Figure 17 — Non-Caseating Granulomas (Sarcoidosis).** Non-necrotizing granulomas characteristic of sarcoidosis, composed of tightly clustered epithelioid histiocytes without central necrosis. Sarcoidosis is the most common cause of non-caseating granulomas.

Causes of Granulomatous Inflammation

Caseating Granulomas	Non-Caseating Granulomas
Tuberculosis (most common worldwide)	Sarcoidosis (most common cause of non-caseating granulomas)
Histoplasmosis, coccidioidomycosis, blastomycosis	Crohn disease
	Berylliosis
	Foreign body reactions (talc, sutures)
	Cat scratch disease (Bartonella henselae) — stellate granulomas
	Wegener granulomatosis (granulomatosis with polyangiitis)

The T_H1 immune response drives granuloma formation: macrophages present antigen → T_H1 cells secrete IFN-γ → macrophages activated to epithelioid cells. TNF-α is critical for maintaining granuloma integrity. This is why anti-TNF therapy (infliximab, adalimumab) requires TB screening before initiation — blocking TNF can reactivate latent TB by disrupting granuloma containment.

12 Tissue Repair, Regeneration & Fibrosis

After inflammation, tissue integrity is restored by regeneration (replacement of damaged cells with cells of the same type) or repair by connective tissue (scar formation/fibrosis). The outcome depends on the tissue’s regenerative capacity and the extent of damage.

Cell Proliferative Capacity

Category	Definition	Examples
Labile cells	Continuously dividing throughout life	Skin epidermis, GI epithelium, hematopoietic cells, cervical epithelium
Stable (quiescent) cells	In G₀ but can re-enter cell cycle when stimulated	Hepatocytes, proximal tubular cells, endothelium, fibroblasts, smooth muscle
Permanent cells	Cannot divide; left cell cycle permanently	Neurons, cardiac myocytes, skeletal muscle

Wound Healing by Primary vs Secondary Intention

Feature	Primary Intention	Secondary Intention
Wound type	Clean, surgically closed, minimal gap	Large defect with tissue loss, left open
Granulation tissue	Minimal	Abundant (fills the wound from base)
Wound contraction	Minimal	Significant (myofibroblasts)
Scar	Thin line	Large scar
Time	Faster	Slower
Infection risk	Lower	Higher

Phases of Wound Healing

WOUND HEALING TIMELINE

Hemostasis (minutes): Platelet plug + fibrin clot; platelets release PDGF and TGF-β
Inflammation (1–3 days): Neutrophils clear debris (peak day 1–2); macrophages arrive (peak day 3–5) — macrophages are the most important cell in wound healing
Proliferation (3–21 days): Granulation tissue forms (new capillaries via angiogenesis + fibroblasts producing collagen type III); epithelial migration covers wound surface
Remodeling (weeks to months): Type III collagen replaced by type I collagen; wound strength increases to maximum ~80% of original (never reaches 100%)

Stages of wound repair including hemostasis, inflammation, proliferation, and remodeling — **Figure 18 — Stages of Wound Repair.** The four overlapping phases of wound healing: hemostasis (platelet plug, fibrin clot), inflammation (neutrophil and macrophage recruitment), proliferation (granulation tissue, angiogenesis, re-epithelialization), and remodeling (collagen maturation, scar formation).

Growth Factors in Repair

Factor	Source	Action
PDGF	Platelets, macrophages	Fibroblast and smooth muscle chemotaxis and proliferation
TGF-β	Platelets, macrophages, T cells	Fibroblast chemotaxis; stimulates collagen synthesis; anti-inflammatory; key driver of fibrosis
VEGF	Macrophages, keratinocytes	Angiogenesis (new blood vessel formation)
FGF	Macrophages, fibroblasts	Angiogenesis; fibroblast proliferation
EGF	Platelets, macrophages, saliva	Epithelial and fibroblast proliferation

Factors That Impair Wound Healing

Factor	Mechanism of Impairment
Infection	Most important local cause; persistent inflammation delays repair; increases tissue destruction
Diabetes mellitus	Microangiopathy → poor perfusion; neuropathy → unrecognized trauma; impaired leukocyte function
Malnutrition / Vitamin C deficiency	Vitamin C required for prolyl and lysyl hydroxylase (collagen cross-linking); protein deficiency impairs collagen synthesis
Corticosteroids	Anti-inflammatory; inhibit collagen synthesis; impair angiogenesis
Foreign bodies	Persistent inflammation and granuloma formation; nidus for infection
Ischemia / Poor perfusion	Peripheral vascular disease, venous stasis; oxygen is essential for collagen hydroxylation and leukocyte killing
Zinc deficiency	Zinc is a cofactor for collagenase and metalloproteinases needed in remodeling
Copper deficiency	Copper is cofactor for lysyl oxidase, which cross-links collagen

Molecular and cellular regulators of wound healing and scarring — **Figure 19 — Wound Healing Regulators.** Key molecular, biological, and mechanical factors that modulate each phase of wound healing. Dysregulation of these factors can lead to either impaired healing (chronic wounds) or excessive scarring (keloids, hypertrophic scars, fibrosis).

Abnormal Wound Healing

Keloid — excessive collagen deposition that extends beyond the original wound borders; more common in African Americans; does not regress spontaneously; recurs after excision; type III and type I collagen
Hypertrophic scar — excessive collagen but remains within wound borders; may regress over time
Dehiscence — wound rupture, most common at abdominal surgical sites; risk factors: obesity, increased abdominal pressure, infection, poor nutrition
Contracture — exaggerated wound contraction causing deformity; common after burns; myofibroblasts are responsible

The tensile strength of a wound reaches only about 80% of normal even after complete healing and remodeling, which is why surgical incisions and healed wounds remain vulnerable to re-injury. Collagen cross-linking is the primary determinant of tensile strength, requiring vitamin C (for prolyl and lysyl hydroxylase) and copper (for lysyl oxidase).

13 Edema & Fluid Dynamics

Edema is the accumulation of excess fluid in the interstitial space (or body cavities, where it is termed effusion). Understanding the Starling forces is essential to comprehending the pathophysiology of edema formation.

Starling Forces

Force	Normal Value (capillary end)	Effect
Capillary hydrostatic pressure (P_c)	~35 mmHg (arterial), ~15 mmHg (venous)	Pushes fluid OUT of capillary
Interstitial hydrostatic pressure (P_i)	~0 mmHg	Pushes fluid INTO capillary (opposing Pc)
Plasma oncotic pressure (π_c)	~25 mmHg	Pulls fluid INTO capillary (albumin-dependent)
Interstitial oncotic pressure (π_i)	~1 mmHg	Pulls fluid OUT of capillary

Pathophysiologic Mechanisms of Edema

Mechanism	Pathophysiology	Examples
Increased hydrostatic pressure	Elevated venous pressure transmits retrograde to capillary bed	CHF (pulmonary edema, peripheral edema); DVT (unilateral leg edema); portal hypertension (ascites)
Decreased oncotic pressure	Hypoalbuminemia (<2 g/dL) reduces plasma oncotic pressure	Nephrotic syndrome; cirrhosis; malnutrition (kwashiorkor); protein-losing enteropathy
Increased vascular permeability	Endothelial damage allows protein-rich exudate into interstitium	Inflammation; burns; anaphylaxis; ARDS
Lymphatic obstruction	Impaired lymphatic drainage causes protein-rich lymphedema	Post-mastectomy; filariasis (elephantiasis); tumor invasion of lymph nodes
Sodium/water retention	Renal retention of Na⁺ and H₂O expands plasma volume	Heart failure (neurohumoral activation); renal failure; RAAS activation

Transudate vs Exudate

Feature	Transudate	Exudate
Mechanism	Hydrostatic/oncotic imbalance	Increased vascular permeability (inflammation)
Protein	<3 g/dL	>3 g/dL
Specific gravity	<1.012	>1.020
Cells	Few	Many (inflammatory cells)
LDH	Low	High
Light’s criteria (pleural)	Does not meet	Meets ≥1 criterion

Dependent edema in CHF is pitting edema (finger pressure leaves a temporary depression). Lymphedema is characteristically non-pitting because the interstitial fluid is protein-rich and undergoes fibrosis over time. This distinction helps identify the underlying mechanism at the bedside.

Body Cavity Effusions

Location	Term	Common Causes
Peritoneal cavity	Ascites	Cirrhosis (portal HTN + hypoalbuminemia); CHF (hepatic congestion); peritoneal carcinomatosis; nephrotic syndrome; Budd-Chiari syndrome
Pleural space	Pleural effusion	Transudate: CHF (most common), cirrhosis, nephrotic; Exudate: pneumonia (parapneumonic), TB, malignancy, PE, autoimmune (SLE, RA)
Pericardial sac	Pericardial effusion	Viral pericarditis; uremia; malignancy; post-MI (Dressler syndrome); SLE; hypothyroidism
Joint space	Joint effusion	Osteoarthritis (non-inflammatory); RA, gout, septic arthritis (inflammatory)

SERUM-ASCITES ALBUMIN GRADIENT (SAAG)

SAAG = serum albumin − ascites albumin. SAAG ≥1.1 g/dL indicates portal hypertension (cirrhosis, CHF, Budd-Chiari) with 97% accuracy. SAAG <1.1 g/dL indicates non-portal hypertensive causes (peritoneal carcinomatosis, TB peritonitis, nephrotic syndrome, pancreatitis). SAAG has replaced the older transudate/exudate classification for ascitic fluid.

14 Thrombosis & Virchow’s Triad

Thrombosis is the pathologic formation of a blood clot (thrombus) within an intact blood vessel. It is governed by Virchow’s triad: (1) endothelial injury, (2) stasis or turbulence, and (3) hypercoagulability.

Virchow’s Triad

Factor	Mechanism	Clinical Examples
Endothelial injury	Loss of anti-thrombotic properties; exposure of subendothelial collagen and tissue factor	Atherosclerosis; vasculitis; MI; trauma; prosthetic valves; indwelling catheters
Stasis / turbulence	Disrupts laminar flow; promotes endothelial activation; prevents dilution of clotting factors	Atrial fibrillation; venous stasis (immobility, DVT); aneurysms; hyperviscosity (polycythemia vera)
Hypercoagulability	Altered coagulation pathway favoring thrombosis	Factor V Leiden; prothrombin 20210A; antithrombin III deficiency; protein C/S deficiency; antiphospholipid syndrome; malignancy (Trousseau syndrome); OCPs; nephrotic syndrome

Coagulation cascade showing tissue factor pathway and thrombin generation — **Figure 22 — Coagulation Cascade.** The coagulation pathway from tissue factor initiation through thrombin generation to fibrin clot formation. The intrinsic and extrinsic pathways converge at factor X activation, leading to the common pathway and ultimately cross-linked fibrin.

Hereditary Thrombophilias

Disorder	Defect	Inheritance	Key Points
Factor V Leiden	Factor V resistant to inactivation by activated protein C	AD	Most common hereditary thrombophilia (5% of Caucasians); heterozygous = 5× risk; homozygous = 50× risk of VTE
Prothrombin G20210A	Gain-of-function mutation → elevated prothrombin levels	AD	Second most common; 2–3× risk of VTE
Antithrombin III deficiency	Decreased inhibition of thrombin and factor Xa	AD	Heparin resistance (heparin requires ATIII to work)
Protein C deficiency	Cannot inactivate factors Va and VIIIa	AD	Warfarin-induced skin necrosis (protein C has short half-life, drops first)
Protein S deficiency	Protein S is cofactor for protein C	AD	Similar phenotype to protein C deficiency

Warfarin skin necrosis occurs during the first few days of warfarin initiation because protein C (an anticoagulant with a short half-life of ~8 hours) is depleted faster than the procoagulant factors (factor II t_1/2 = 60 hours), creating a transient hypercoagulable state. This is why heparin bridging is essential when starting warfarin, especially in patients with known protein C or S deficiency.

15 Embolism

An embolus is a detached intravascular mass (solid, liquid, or gaseous) carried by the blood to a site distant from its point of origin, where it lodges and obstructs a vessel. Approximately 99% of emboli arise from thrombi (thromboembolism).

Coagulation and clotting factor signaling in thrombus formation leading to pulmonary embolism — **Figure 23 — Thromboembolism Pathophysiology.** Coagulation and clotting factor signaling in thrombus formation. Over 95% of pulmonary emboli originate from deep vein thrombi in the lower extremities, traveling through the IVC and right heart to lodge in the pulmonary arteries.

Types of Embolism

Type	Source / Mechanism	Consequences
Pulmonary thromboembolism (PE)	>95% from deep veins of legs (DVT); travels through IVC → right heart → pulmonary arteries	Saddle embolus → sudden death (obstructs bifurcation); medium arteries → pulmonary infarction (wedge-shaped, hemorrhagic); small arteries → may be silent or cause pulmonary HTN if recurrent
Systemic (arterial) thromboembolism	~80% from intracardiac mural thrombi (LV wall post-MI, LA in atrial fibrillation); also aortic aneurysms, atherosclerotic plaque	Lower extremity (most common), brain (stroke), kidneys, spleen, intestines
Fat embolism	Long bone fractures or orthopedic surgery → marrow fat enters veins	Triad: respiratory distress + neurologic symptoms + petechial rash (24–72 hours post-injury)
Air embolism	Surgery, trauma, IV access, decompression sickness (“the bends”)	>100 mL needed to cause symptoms; air locks in right ventricle
Amniotic fluid embolism	Amniotic fluid enters maternal circulation during labor/delivery or C-section	Sudden dyspnea, shock, DIC, seizures; 80% mortality; squamous cells and fetal debris in pulmonary vessels
Cholesterol / atheroemboli	Cholesterol crystals dislodge from ulcerated atherosclerotic plaques	“Blue toe syndrome”; livedo reticularis; renal failure; biconvex cleft-shaped spaces on biopsy

Effects of pulmonary embolism on vascular endothelium — **Figure 24 — Endothelial Effects of Pulmonary Embolism.** The pathophysiologic effects of pulmonary embolism on the vascular endothelium, including disruption of normal endothelial function, platelet activation, inflammatory cascade initiation, and right ventricular pressure overload.

HIGH-YIELD: PARADOXICAL EMBOLISM

A venous thrombus can reach the systemic arterial circulation through a right-to-left shunt, most commonly a patent foramen ovale (PFO), which is present in ~25% of adults. This is called a paradoxical embolism and should be suspected in a young patient with a cryptogenic stroke and DVT. Diagnosis: transesophageal echocardiography with agitated saline (“bubble study”) showing early bubble transit from RA to LA.

16 Infarction & Ischemia

An infarct is an area of ischemic necrosis caused by occlusion of the arterial supply or (less commonly) venous drainage. Infarcts are classified as white (anemic/pale) or red (hemorrhagic) based on the amount of hemorrhage and the tissue architecture.

White vs Red Infarcts

Feature	White (Anemic) Infarct	Red (Hemorrhagic) Infarct
Mechanism	Arterial occlusion in solid organs with single (end-artery) blood supply	Venous occlusion; arterial occlusion in loose tissue with dual blood supply; reperfusion of previously ischemic tissue
Organs	Heart, kidney, spleen	Lung (dual supply: bronchial + pulmonary arteries); liver (portal vein + hepatic artery); intestine; brain (with reperfusion); testes (venous torsion)
Morphology	Pale, wedge-shaped (base at capsule, apex at occlusion site)	Dark red, hemorrhagic, irregular borders

Ischemia-Reperfusion Injury

Paradoxically, restoration of blood flow after ischemia can exacerbate tissue damage beyond what occurred during the ischemic period. Mechanisms include:

ROS burst — re-oxygenation generates massive free radicals from damaged mitochondria, xanthine oxidase, and recruited neutrophils
Calcium overload — reperfusion floods cells with Ca²⁺
Complement activation — IgM antibodies bind neo-antigens exposed on ischemic cells, activating complement cascade
Neutrophil influx — restored flow delivers activated neutrophils that release proteases and ROS

Ischemia-reperfusion injury is clinically significant in myocardial infarction (post-PCI reperfusion arrhythmias), organ transplantation (cold ischemia time), and stroke (hemorrhagic transformation after thrombolysis). In cardiac surgery, cardioplegia solutions are designed to minimize this injury.

17 Shock & Hemodynamic Collapse

Shock is a state of systemic hypoperfusion due to reduced cardiac output or reduced effective circulating blood volume, resulting in inadequate tissue oxygenation and cellular hypoxia. If uncorrected, shock progresses to irreversible organ damage and death.

Types of Shock

Type	Mechanism	CO	SVR	PCWP	Examples
Cardiogenic	Pump failure — heart cannot generate adequate CO	↓	↑	↑	Massive MI (>40% LV); acute mitral regurgitation; cardiac tamponade; myocarditis
Hypovolemic	Decreased blood or plasma volume	↓	↑	↓	Hemorrhage (trauma, GI bleed); burns; severe dehydration; third-spacing
Distributive (septic)	Systemic vasodilation; maldistribution of blood flow	↑ (early, “warm shock”)	↓↓	↓ or N	Sepsis (most common cause of death in ICU); anaphylaxis; neurogenic shock (spinal cord injury)
Obstructive	Mechanical obstruction to blood flow	↓	↑	Variable	Massive PE; tension pneumothorax; cardiac tamponade; constrictive pericarditis

Stages of Shock

PROGRESSIVE SHOCK STAGES

Compensated (non-progressive): Neurohumoral reflexes maintain perfusion — tachycardia, vasoconstriction, RAAS activation, ADH release; BP may be near normal; reversible
Decompensated (progressive): Compensatory mechanisms overwhelmed; tissue hypoxia → lactic acidosis; endothelial dysfunction; microvascular thrombosis; organ dysfunction begins; potentially reversible with aggressive intervention
Irreversible: Widespread cell death; lysosomal enzyme release; myocardial depression (myocardial depressant factor); DIC; multi-organ failure; fatal regardless of treatment

Diagnostic algorithm for differentiating types of shock — **Figure 26 — Shock Diagnostic Algorithm.** Clinical algorithm for the differential diagnosis of shock based on hemodynamic parameters, physical examination findings, and laboratory data to distinguish cardiogenic, hypovolemic, distributive, and obstructive etiologies.

Septic Shock Pathophysiology

Bacterial products (LPS/endotoxin from gram-negatives, lipoteichoic acid from gram-positives) activate innate immune cells via TLR4/TLR2 → massive cytokine release (“cytokine storm”: TNF-α, IL-1, IL-6). This produces: (1) systemic vasodilation (NO-mediated) → hypotension; (2) endothelial activation → increased permeability, edema, DIC; (3) myocardial depression; (4) metabolic derangements (insulin resistance, hyperglycemia). Early septic shock is “warm shock” with vasodilation and high CO; late septic shock transitions to “cold shock” with myocardial depression and low CO.

Anaphylactic Shock

A subset of distributive shock caused by systemic type I hypersensitivity (IgE-mediated mast cell degranulation). Massive histamine and leukotriene release causes: profound vasodilation → hypotension; bronchoconstriction → respiratory distress; laryngeal edema → airway obstruction; urticaria and angioedema. Treatment: intramuscular epinephrine (0.3–0.5 mg IM in anterolateral thigh) is the first-line and most important intervention. Epinephrine reverses vasodilation (α-1), bronchoconstriction (β-2), and stabilizes mast cells (β-2). Secondary agents: IV fluids, H1/H2 blockers, corticosteroids (prevent late-phase reaction), and albuterol for persistent bronchospasm.

Neurogenic Shock

Caused by disruption of sympathetic outflow, typically from spinal cord injury above T6. Loss of sympathetic tone produces vasodilation (decreased SVR) and bradycardia (unopposed vagal tone). Unlike other forms of shock, neurogenic shock presents with warm, dry skin and bradycardia (rather than cool, clammy skin and tachycardia). Treatment: IV fluids + vasopressors (norepinephrine or phenylephrine) + atropine for significant bradycardia.

The Surviving Sepsis Campaign emphasizes the Hour-1 Bundle: measure lactate, obtain blood cultures before antibiotics, administer broad-spectrum antibiotics, begin rapid fluid resuscitation with 30 mL/kg crystalloid for hypotension or lactate ≥4, and apply vasopressors (norepinephrine first-line) if hypotension persists after fluids. Each hour of delay in antibiotics increases mortality.

18 Disseminated Intravascular Coagulation (DIC)

DIC is a consumptive coagulopathy characterized by widespread activation of the coagulation cascade, leading to formation of microthrombi throughout the vasculature with simultaneous consumption of platelets and clotting factors, resulting paradoxically in both thrombosis and hemorrhage.

Pathophysiology

Triggering event releases tissue factor or other procoagulants into the circulation → widespread thrombin generation → fibrin deposition in microvasculature → consumption of platelets, fibrinogen, and clotting factors (II, V, VIII) → secondary fibrinolysis (plasmin activation) generates fibrin degradation products (FDPs) including D-dimers, which further impair platelet function and fibrin polymerization.

**Figure 27 — DIC Pathogenesis.** Pathogenetic pathways in disseminated intravascular coagulation. Tissue factor overexpression leads to explosive thrombin generation, widespread fibrin deposition in the microvasculature, consumption of clotting factors and platelets, and secondary fibrinolysis with D-dimer elevation.

Causes of DIC

Category	Examples
Obstetric	Placental abruption; amniotic fluid embolism; eclampsia; retained dead fetus
Infection (sepsis)	Gram-negative sepsis (endotoxin → tissue factor from monocytes); meningococcemia (Waterhouse-Friderichsen syndrome)
Malignancy	Acute promyelocytic leukemia (APL, M3 — granules release procoagulants); mucin-secreting adenocarcinomas (pancreas, lung)
Trauma	Massive tissue injury; burns; crush injuries; brain injury (tissue thromboplastin release)
Vascular	Giant hemangioma (Kasabach-Merritt); aortic aneurysm; vasculitis
Other	Snake envenomation; transfusion reactions; heat stroke

Laboratory Findings in DIC

Test	Result	Reason
Platelets	↓↓	Consumed in microthrombi
PT / aPTT	↑↑	Consumption of clotting factors
Fibrinogen	↓↓	Consumed; also cleaved by plasmin
D-dimer / FDP	↑↑↑	Fibrinolysis of cross-linked fibrin
Peripheral smear	Schistocytes (fragmented RBCs)	Mechanical shearing on fibrin strands in microvasculature (microangiopathic hemolytic anemia)
Thrombin time	↑	Low fibrinogen + FDP interference

Peripheral blood smear showing schistocytes (fragmented red blood cells) — **Figure 28 — Schistocytes on Peripheral Blood Smear.** Peripheral blood smear showing schistocytes (fragmented red blood cells, arrows) characteristic of microangiopathic hemolytic anemia seen in DIC, TTP, and HUS. The mechanical shearing of RBCs on fibrin strands within the microvasculature produces these diagnostic fragments.

The combination of schistocytes on blood smear + thrombocytopenia + elevated D-dimer + prolonged PT/aPTT + low fibrinogen is virtually diagnostic of DIC. In acute promyelocytic leukemia (APL), DIC is the most common cause of early death, and treatment with all-trans retinoic acid (ATRA) is initiated immediately upon suspicion of APL even before confirmatory testing, because it induces differentiation and rapidly improves the coagulopathy.

19 Neoplasia Fundamentals & Nomenclature

Neoplasia (“new growth”) refers to unregulated cell proliferation that is autonomous and persists after removal of the inciting stimulus. A neoplasm (tumor) consists of neoplastic cells and supportive stroma (connective tissue and blood vessels).

Benign vs Malignant Neoplasms

Feature	Benign	Malignant
Differentiation	Well-differentiated; resembles tissue of origin	Variable; ranges from well-differentiated to anaplastic
Growth rate	Usually slow	Variable; often rapid
Growth pattern	Expansile, often encapsulated	Infiltrative, invasive, often not encapsulated
Metastasis	Absent	Present (defines malignancy)
Mitotic rate	Low	Often high; atypical mitoses
Nuclear features	Normal N:C ratio	Pleomorphism, hyperchromasia, high N:C ratio

Tumor Nomenclature

Tissue of Origin	Benign	Malignant
Epithelial — glandular	Adenoma	Adenocarcinoma
Epithelial — squamous	Squamous papilloma	Squamous cell carcinoma
Mesenchymal — bone	Osteoma	Osteosarcoma
Mesenchymal — cartilage	Chondroma	Chondrosarcoma
Mesenchymal — fat	Lipoma	Liposarcoma
Mesenchymal — smooth muscle	Leiomyoma	Leiomyosarcoma
Mesenchymal — skeletal muscle	Rhabdomyoma	Rhabdomyosarcoma
Mesenchymal — blood vessels	Hemangioma	Angiosarcoma
Lymphoid	—	Lymphoma / Leukemia
Melanocytes	Nevus	Melanoma
Germ cells	Mature teratoma	Immature teratoma; seminoma; choriocarcinoma

NAMING EXCEPTIONS (“-OMA” BUT MALIGNANT)

Several malignant tumors retain the “-oma” suffix despite being malignant: lymphoma, melanoma, mesothelioma, seminoma, hepatoblastoma, glioblastoma. These are important board-tested exceptions to the standard nomenclature rules.

Routes of Metastasis

Route	Mechanism	Classic Examples
Lymphatic spread	Most common initial route for carcinomas; tumor cells invade lymphatic channels and colonize regional lymph nodes	Breast CA → axillary nodes; lung CA → mediastinal nodes; colorectal CA → mesenteric nodes; Virchow node (left supraclavicular) = gastric CA
Hematogenous spread	Most common route for sarcomas; tumor cells enter bloodstream; venous drainage determines metastatic site	Renal cell CA → IVC → lung; colorectal CA → portal vein → liver; prostate CA → Batson vertebral venous plexus → vertebral mets
Seeding of body cavities	Direct spread across serosal surfaces	Ovarian CA → peritoneal carcinomatosis (omental caking); lung CA → malignant pleural effusion
Perineural invasion	Tumor tracks along nerve sheaths	Pancreatic adenocarcinoma; prostate cancer; salivary gland tumors (adenoid cystic carcinoma)

The invasion-metastasis cascade showing steps from primary tumor to distant colonization — **Figure 29 — The Invasion-Metastasis Cascade.** Steps of tumor metastasis: local invasion through basement membrane and stroma, intravasation into blood or lymphatic vessels, survival in the circulation, arrest at distant sites, extravasation, and colonization to form secondary tumors.

Common Sites of Metastasis by Primary Cancer

Primary Cancer	Most Common Metastatic Sites
Lung	Brain, bone, liver, adrenal glands (most common cancer to metastasize to adrenal)
Breast	Bone (most common), lung, liver, brain
Colon	Liver (via portal circulation; most common cancer to metastasize to liver), lung
Prostate	Bone (osteoblastic/sclerotic mets via Batson plexus)
Renal cell	Lung, bone, brain (can invade renal vein and IVC)
Melanoma	Can metastasize to virtually any organ; brain mets very common

Carcinomas spread first by lymphatics (sentinel node biopsy concept); sarcomas spread first by blood (hematogenous). The most common overall site of distant metastasis is the liver (portal drainage from GI tract), followed by lung. The most common primary malignancy of bone in adults is metastatic disease (not primary bone tumors), with breast, prostate, lung, kidney, and thyroid being the most common sources.

20 Hallmarks of Cancer & Molecular Oncology

The Hallmarks of Cancer (Hanahan & Weinberg, 2000; updated 2011) define the fundamental capabilities acquired during multistep tumorigenesis.

The Hallmarks

Hallmark	Mechanism	Key Examples
Sustaining proliferative signaling	Oncogene activation provides constitutive growth signals	RAS mutations (~30% of cancers); EGFR amplification; BCR-ABL in CML
Evading growth suppressors	Loss of tumor suppressor function	RB loss (retinoblastoma); p53 mutation (>50% of cancers); APC loss (colon cancer)
Resisting cell death	Evasion of apoptosis	BCL-2 overexpression [t(14;18), follicular lymphoma]; p53 loss
Enabling replicative immortality	Telomerase activation prevents telomere shortening	~90% of cancers reactivate telomerase (hTERT)
Inducing angiogenesis	Stimulate new blood vessel growth to supply nutrients	VEGF upregulation; HIF-1α activation in hypoxic tumor core
Activating invasion & metastasis	Loss of cell adhesion; ECM degradation; motility	E-cadherin loss (lobular breast CA); MMP upregulation; EMT
Reprogramming energy metabolism	Warburg effect: aerobic glycolysis even in presence of O₂	Basis of FDG-PET scanning (tumors take up more glucose)
Evading immune destruction	Immune checkpoint upregulation; immunoediting	PD-L1 expression (target of pembrolizumab, nivolumab); CTLA-4 (target of ipilimumab)

Key Oncogenes

Oncogene	Function	Associated Cancer	Mechanism of Activation
RAS (KRAS, HRAS, NRAS)	GTPase signal transduction (MAPK/RAS pathway)	Pancreatic, colon, lung adenocarcinoma	Point mutation (constitutively active GTP-bound form)
MYC	Transcription factor (cell proliferation, growth)	Burkitt lymphoma [t(8;14)]; neuroblastoma (N-MYC)	Translocation; gene amplification
BCR-ABL	Constitutively active tyrosine kinase	CML [t(9;22) Philadelphia chromosome]	Translocation (fusion gene)
HER2/neu (ERBB2)	Receptor tyrosine kinase	Breast cancer (~20%); gastric	Gene amplification
RET	Receptor tyrosine kinase	MEN 2A/2B; medullary thyroid carcinoma	Point mutation
BRAF	Serine/threonine kinase in MAPK pathway	Melanoma (~60%); hairy cell leukemia; papillary thyroid	Point mutation (V600E)

Key Tumor Suppressors

Gene	Function	Associated Cancer Syndromes
TP53 (“guardian of the genome”)	Cell cycle arrest (G1/S checkpoint); DNA repair; apoptosis	Li-Fraumeni syndrome; mutated in >50% of all sporadic cancers
RB	G1/S checkpoint control (binds E2F transcription factor)	Retinoblastoma; osteosarcoma
APC	Negative regulator of WNT/β-catenin signaling	Familial adenomatous polyposis (FAP); sporadic colon cancer
BRCA1/BRCA2	DNA double-strand break repair (homologous recombination)	Hereditary breast/ovarian cancer; BRCA2 also pancreatic, prostate
VHL	Degradation of HIF-1α (prevents angiogenesis signaling under normoxia)	von Hippel-Lindau syndrome (renal cell carcinoma, hemangioblastoma, pheochromocytoma)
WT1	Transcription factor (kidney development)	Wilms tumor (nephroblastoma)
NF1	GAP protein (inactivates RAS)	Neurofibromatosis type 1 (neurofibromas, optic glioma, café-au-lait spots)

Knudson's two-hit hypothesis plot for retinoblastoma — **Figure 30 — Knudson’s Two-Hit Hypothesis.** The original statistical analysis that led Knudson to propose the two-hit hypothesis. In hereditary retinoblastoma (one germline hit), a single somatic mutation suffices, producing the straight line. In sporadic cases (two somatic hits required), the age-incidence curve is hyperbolic, reflecting the lower probability of two independent mutations occurring in the same cell.

Knudson’s two-hit hypothesis: both alleles of a tumor suppressor must be inactivated for loss of function. In hereditary cancers (e.g., retinoblastoma), one hit is inherited (germline mutation) and only one somatic hit is needed — explaining earlier onset and bilateral/multifocal tumors. In sporadic cases, both hits must occur somatically in the same cell, which is much less likely and occurs later in life.

Chemical & Radiation Carcinogenesis

Carcinogen	Target / Mechanism	Associated Cancer
Aflatoxin B1 (Aspergillus flavus/parasiticus)	p53 mutation (codon 249, G→T transversion)	Hepatocellular carcinoma (synergistic with HBV)
Asbestos	Chronic inflammation; direct mesothelial cell toxicity	Mesothelioma (pleural); bronchogenic carcinoma (synergistic with smoking)
Vinyl chloride	Direct DNA alkylation	Hepatic angiosarcoma
Benzene	Bone marrow toxicity; DNA damage	Acute myeloid leukemia (AML)
Nitrosamines	DNA alkylation	Gastric cancer; esophageal cancer
Arsenic	Oxidative stress; epigenetic changes	Skin (squamous cell CA); lung; liver (angiosarcoma)
UV radiation (UVB)	Pyrimidine dimers in DNA; p53 mutations	Basal cell carcinoma; squamous cell carcinoma; melanoma
Ionizing radiation	DNA double-strand breaks; ROS generation	Thyroid cancer (children); leukemia (AML, CML); breast; lung; sarcomas

Oncogenic Viruses

Virus	Mechanism	Associated Cancer
HPV (types 16, 18)	E6 protein degrades p53; E7 protein inactivates Rb	Cervical carcinoma; oropharyngeal SCC; anal carcinoma; penile carcinoma
EBV	Immortalizes B cells; LMP-1 mimics CD40 signaling	Burkitt lymphoma; nasopharyngeal carcinoma; Hodgkin lymphoma; post-transplant lymphoproliferative disorder (PTLD)
HBV / HCV	Chronic hepatitis → cirrhosis → hepatocellular carcinoma; HBx protein (HBV) activates oncogenes	Hepatocellular carcinoma
HHV-8	Viral cytokine homologs; anti-apoptotic proteins	Kaposi sarcoma; primary effusion lymphoma
HTLV-1	Tax protein activates NF-κB and cyclin D	Adult T-cell leukemia/lymphoma
H. pylori (bacterium)	Chronic gastritis → intestinal metaplasia → dysplasia → carcinoma; CagA protein	Gastric adenocarcinoma; gastric MALT lymphoma

21 Tumor Markers & Paraneoplastic Syndromes

Clinically Important Tumor Markers

Marker	Associated Cancer(s)	Clinical Use
PSA	Prostate cancer	Screening (controversial); monitoring treatment response
AFP	Hepatocellular carcinoma; yolk sac tumor (endodermal sinus tumor); mixed germ cell tumors	Screening in cirrhosis; monitoring germ cell tumors
CEA	Colorectal, pancreatic, gastric, breast, lung	Monitoring recurrence (not screening)
CA-125	Ovarian cancer (epithelial, especially serous)	Monitoring treatment; elevated in many benign conditions
CA 19-9	Pancreatic cancer; cholangiocarcinoma	Monitoring
β-hCG	Choriocarcinoma; hydatidiform mole; testicular germ cell tumors	Diagnosis and monitoring
S-100	Melanoma; schwannoma; Langerhans cell histiocytosis	Immunohistochemical staining
Calcitonin	Medullary thyroid carcinoma (C cells)	Diagnosis; screening in MEN 2
Chromogranin A	Neuroendocrine tumors (carcinoid, pheochromocytoma)	Diagnosis and monitoring
TRAP (tartrate-resistant acid phosphatase)	Hairy cell leukemia	Diagnosis
Alkaline phosphatase (bone isoenzyme)	Osteosarcoma; Paget disease; bone metastases (osteoblastic)	Monitoring

Paraneoplastic Syndromes

Syndrome	Mechanism	Associated Cancer
Hypercalcemia of malignancy	PTHrP secretion (most common); osteolytic metastases; 1,25-(OH)₂D production (lymphoma)	Squamous cell lung CA (PTHrP); breast, renal, myeloma (osteolytic); lymphoma (vitamin D)
SIADH	Ectopic ADH production → hyponatremia	Small cell lung carcinoma (SCLC)
Cushing syndrome	Ectopic ACTH production	SCLC; carcinoid tumors
Polycythemia	Ectopic erythropoietin (EPO)	Renal cell carcinoma; hepatocellular carcinoma; hemangioblastoma
Lambert-Eaton myasthenic syndrome	Antibodies against presynaptic voltage-gated Ca²⁺ channels at NMJ	SCLC
Trousseau syndrome	Migratory superficial thrombophlebitis; hypercoagulable state	Pancreatic adenocarcinoma; other mucin-secreting cancers
Acanthosis nigricans	Insulin-like growth factors from tumor	Gastric adenocarcinoma
Dermatomyositis	Autoimmune; immune cross-reactivity	Ovarian, lung, gastric cancers
Limbic encephalitis	Anti-Hu antibodies (anti-neuronal)	SCLC
Cerebellar degeneration	Anti-Yo antibodies (anti-Purkinje cell)	Ovarian, breast

Small cell lung carcinoma (SCLC) is the most common cancer associated with paraneoplastic syndromes, including SIADH, ectopic ACTH/Cushing, and Lambert-Eaton syndrome. SCLC is a neuroendocrine tumor with the ability to produce diverse peptide hormones. Always consider occult malignancy in a patient presenting with unexplained endocrine or neurologic syndromes.

22 Hypersensitivity Reactions (Types I–IV)

Hypersensitivity reactions are exaggerated or inappropriate immune responses to antigens that result in tissue damage. They are classified by the Gell and Coombs system into four types.

Overview of four types of hypersensitivity reactions — **Figure 31 — Types of Hypersensitivity Reactions.** The Gell and Coombs classification of hypersensitivity: Type I (IgE-mediated immediate), Type II (antibody-mediated cytotoxic), Type III (immune complex-mediated), and Type IV (T cell-mediated delayed). Each type has a distinct immunologic mechanism and clinical time course.

Classification of Hypersensitivity

Type	Name	Mechanism	Timing	Classic Examples
I	Immediate (anaphylactic)	Preformed IgE on mast cells/basophils; cross-linking by antigen → degranulation (histamine, leukotrienes, prostaglandins)	Minutes	Anaphylaxis; allergic asthma; allergic rhinitis; urticaria; food allergy
II	Antibody-mediated (cytotoxic)	IgG/IgM bind cell surface or extracellular matrix antigens → complement activation, opsonization, ADCC, or receptor dysfunction	Hours	Autoimmune hemolytic anemia; Goodpasture syndrome; Graves disease; myasthenia gravis; Rh hemolytic disease; transfusion reactions
III	Immune complex–mediated	Antigen-antibody complexes deposit in tissues → complement activation → neutrophil recruitment → tissue damage	Hours to days	SLE (renal, skin, joints); serum sickness; polyarteritis nodosa (PAN); Arthus reaction; post-streptococcal GN
IV	Delayed-type (cell-mediated)	Sensitized T cells (CD4+ T_H1 or CD8+ CTLs) recognize antigen → cytokine release → macrophage activation or direct cytotoxicity	24–72 hours	TB skin test (PPD); contact dermatitis (poison ivy); transplant rejection (acute cellular); type 1 diabetes (T cell destruction of β cells); MS

TYPE II: SUBTYPES BY MECHANISM

Opsonization & phagocytosis: IgG/IgM coat cells → recognized by macrophage Fc receptors → phagocytosis (autoimmune hemolytic anemia, ITP)
Complement-dependent cytotoxicity: antibody binds → classical complement activation → MAC formation → cell lysis (transfusion reactions, Goodpasture)
Antibody-mediated cellular dysfunction (non-cytotoxic): antibodies bind receptors without destroying the cell — stimulatory (Graves: anti-TSH receptor → hyperthyroidism) or inhibitory (myasthenia gravis: anti-AChR → blocked neuromuscular transmission)

Type I Hypersensitivity — Phases

Sensitization: First antigen exposure → T_H2 activation → IL-4 drives B cell class switch to IgE → IgE binds FcεRI on mast cells
Immediate phase (minutes): Re-exposure → antigen cross-links IgE → mast cell degranulation releasing preformed mediators (histamine, tryptase, heparin) + newly synthesized mediators (PGD₂, LTC₄/D₄/E₄)
Late phase (6–24 hours): Recruitment of eosinophils, basophils, T_H2 cells → sustained inflammation; responsible for the “second wave” of symptoms in asthma

Serum tryptase is the best confirmatory test for anaphylaxis; it peaks 1–2 hours after onset and remains elevated for several hours. Total IgE and specific IgE (RAST/ImmunoCAP) confirm atopic sensitization but do not confirm clinical allergy. Skin prick testing remains the most sensitive in vivo test for IgE-mediated allergy.

23 Autoimmune Disease & Transplant Rejection

Mechanisms of Autoimmunity

Autoimmune disease results from failure of self-tolerance — the immune system attacks the body’s own tissues. Central tolerance (deletion of self-reactive T and B cells in thymus and bone marrow) and peripheral tolerance (anergy, regulatory T cells, apoptosis of self-reactive lymphocytes) normally prevent autoimmunity. Breakdown of these mechanisms, often in genetically susceptible individuals (HLA associations), leads to autoimmune disease.

HLA Associations in Autoimmune Disease

HLA Allele	Disease	Relative Risk
HLA-B27	Ankylosing spondylitis	~90×
HLA-B27	Reactive arthritis (Reiter syndrome)	~40×
HLA-DR4	Rheumatoid arthritis	~6×
HLA-DR3/DR4	Type 1 diabetes mellitus	~20×
HLA-DR2	Multiple sclerosis; Goodpasture syndrome; SLE	Variable
HLA-DQ2/DQ8	Celiac disease	>95% carry DQ2 or DQ8

Chemokine-mediated immune cell recruitment in graft rejection — **Figure 32 — Transplant Rejection Mechanisms.** Immunologic mechanisms involved in graft rejection, showing chemokine-mediated recruitment of immune effector cells to the transplanted organ. Host T cells recognize donor MHC antigens through direct and indirect pathways, leading to cellular and humoral rejection.

Transplant Rejection

Type	Timing	Mechanism	Pathology
Hyperacute	Minutes to hours	Preformed anti-donor antibodies (anti-ABO or anti-HLA) → complement activation → graft thrombosis	Fibrinoid necrosis of vessel walls; thrombosis; graft infarction
Acute cellular	Weeks to months	Host CD4+ and CD8+ T cells recognize donor MHC → direct cytotoxicity and macrophage activation	Lymphocytic infiltrate (interstitial); tubulitis (renal); endothelialitis
Acute humoral (antibody-mediated)	Weeks to months	Donor-specific antibodies against graft endothelium → complement activation	C4d deposition in peritubular capillaries (renal); neutrophilic capillaritis
Chronic	Months to years	Antibody- and T cell–mediated vascular injury → intimal fibrosis (“graft vasculopathy”)	Vascular intimal fibrosis; interstitial fibrosis; tubular atrophy (renal); bronchiolitis obliterans (lung)

Graft-versus-host disease (GVHD) occurs when immunocompetent donor T cells in a bone marrow transplant attack immunocompromised host tissues. Target organs: skin (dermatitis), liver (jaundice), GI tract (diarrhea). Acute GVHD occurs within 100 days; chronic GVHD after 100 days with features resembling autoimmune disease (scleroderma-like skin, sicca syndrome).

Key Autoantibody Associations

Autoantibody	Disease
ANA (antinuclear antibody)	Sensitive (but not specific) for SLE; also positive in drug-induced lupus, scleroderma, Sjögren
Anti-dsDNA	Specific for SLE; correlates with disease activity and lupus nephritis
Anti-Smith (anti-Sm)	Most specific for SLE (but low sensitivity)
Anti-histone	Drug-induced lupus (hydralazine, isoniazid, procainamide, phenytoin, sulfonamides)
Anti-centromere	Limited scleroderma (CREST syndrome)
Anti-Scl-70 (anti-topoisomerase I)	Diffuse scleroderma (systemic sclerosis)
Anti-SSA (Ro) / Anti-SSB (La)	Sjögren syndrome; neonatal lupus (anti-Ro crosses placenta → congenital heart block)
Anti-CCP	Most specific for rheumatoid arthritis
c-ANCA (anti-PR3)	Granulomatosis with polyangiitis (Wegener)
p-ANCA (anti-MPO)	Microscopic polyangiitis; eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
Anti-GBM	Goodpasture syndrome (type IV collagen of glomerular and alveolar basement membranes)
Anti-phospholipid (lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I)	Antiphospholipid syndrome: recurrent thrombosis, pregnancy loss; paradoxically prolongs aPTT in vitro but causes thrombosis in vivo

24 Amyloidosis

Amyloidosis is a group of disorders characterized by extracellular deposition of misfolded proteins in an abnormal fibrillar configuration (cross-beta-pleated sheet). These deposits are insoluble, resistant to proteolysis, and progressively damage organs by displacing normal parenchyma.

Diagnosis

Amyloid deposits stain with Congo red and display apple-green birefringence under polarized light. This is the gold standard histologic test. Tissue can be obtained from abdominal fat pad aspirate, rectal biopsy, or affected organ biopsy.

Amyloid deposits stained with Congo red showing apple-green birefringence under polarized light — **Figure 33 — Amyloid Deposits (Congo Red Stain).** Histologic demonstration of amyloid deposits using Congo red stain. Under polarized light, amyloid displays characteristic apple-green birefringence due to the ordered cross-beta-pleated sheet configuration of the misfolded fibrillar proteins. This is the gold standard histologic test for amyloidosis.

Types of Amyloidosis

Type	Precursor Protein	Fibril Protein	Associated Condition	Organs Affected
AL (primary)	Immunoglobulin light chains	AL	Plasma cell dyscrasias (multiple myeloma, Waldenström); B cell lymphomas	Heart, kidney, liver, tongue (macroglossia), peripheral nerves, skin
AA (secondary)	Serum amyloid A (SAA) — acute phase reactant produced by liver	AA	Chronic inflammatory diseases (RA, IBD, FMF, chronic infections [osteomyelitis, TB])	Kidney (most common), liver, spleen
ATTR (hereditary)	Transthyretin (TTR, formerly prealbumin)	ATTR	Familial amyloid polyneuropathy (FAP); senile cardiac amyloidosis (wild-type TTR, age >70)	Peripheral nerves; heart (especially senile cardiac amyloidosis)
Aβ₂M (dialysis-related)	β₂-microglobulin	Aβ₂M	Long-term hemodialysis (>10 years)	Joints, synovium, tendon sheaths (carpal tunnel syndrome common)
Aβ (cerebral)	Amyloid precursor protein (APP)	Aβ	Alzheimer disease; Down syndrome	Brain (senile plaques, cerebral amyloid angiopathy)

CARDIAC AMYLOIDOSIS

The heart is the most important organ involved in AL amyloidosis and is the leading cause of death. Presents as restrictive cardiomyopathy with diastolic dysfunction, thick ventricular walls (but NOT hypertrophy — infiltration), low voltage on ECG (paradox with thick walls on echo), and heart failure. Senile cardiac amyloidosis (wild-type ATTR) is increasingly recognized in elderly patients with HFpEF and can now be diagnosed non-invasively with technetium pyrophosphate (Tc-PYP) scan. Treatment with tafamidis (TTR stabilizer) reduces mortality in ATTR cardiac amyloidosis.

25 Genetic Disorders & Inheritance Patterns

Autosomal Dominant Disorders

One mutant allele is sufficient to cause disease. Affected individuals typically have one affected parent. Variable expressivity and incomplete penetrance are common. Key examples:

Disorder	Gene / Defect	Key Features
Marfan syndrome	FBN1 (fibrillin-1) on chr 15	Tall stature, arachnodactyly, lens subluxation (upward), aortic root dilation/dissection, MVP, dural ectasia
Ehlers-Danlos syndrome (classical)	COL5A1/COL5A2 (type V collagen)	Joint hypermobility, skin hyperextensibility, easy bruising, poor wound healing
Familial hypercholesterolemia	LDL receptor gene	Severely elevated LDL; xanthomas; premature atherosclerosis and MI; homozygotes may have MI in childhood
Hereditary spherocytosis	Spectrin, ankyrin, band 3 (RBC membrane proteins)	Spherocytes on smear; ↑ MCHC; positive osmotic fragility test; splenomegaly; pigment gallstones
von Willebrand disease (type 1)	vWF gene (quantitative deficiency)	Most common inherited bleeding disorder; mucocutaneous bleeding; ↑ bleeding time; ↑ aPTT; ↓ ristocetin cofactor activity
Huntington disease	HTT gene (CAG trinucleotide repeat expansion) on chr 4	Chorea, dementia, psychiatric symptoms; onset 30–50s; caudate atrophy; anticipation

Autosomal Recessive Disorders

Both alleles must be mutant. Carriers (heterozygotes) are phenotypically normal. Often involve enzyme deficiencies. Key examples:

Disorder	Defect	Key Features
Cystic fibrosis	CFTR gene (chr 7); ΔF508 most common mutation	Thick mucus in lungs, pancreas, GI; recurrent Pseudomonas infections; pancreatic insufficiency; meconium ileus; male infertility (absent vas deferens); ↑ sweat chloride (>60 mEq/L)
Sickle cell disease	Point mutation in β-globin (Glu → Val at position 6)	Vaso-occlusive crises; autosplenectomy; acute chest syndrome; functional asplenia → encapsulated organism infections
Phenylketonuria (PKU)	Phenylalanine hydroxylase deficiency	Intellectual disability if untreated; musty body odor; fair skin and hair (decreased melanin); eczema
Hemochromatosis	HFE gene (C282Y mutation)	Iron overload: cirrhosis, diabetes (“bronze diabetes”), cardiomyopathy, arthropathy, skin hyperpigmentation
Wilson disease	ATP7B (copper-transporting ATPase)	Copper accumulation in liver (cirrhosis), brain (basal ganglia → movement disorders), cornea (Kayser-Fleischer rings); ↓ ceruloplasmin

X-Linked Recessive Disorders

Primarily affect males (hemizygous). Carrier females are usually asymptomatic. No male-to-male transmission.

Duchenne muscular dystrophy — dystrophin gene (frameshift/deletion); progressive proximal muscle weakness starting age 2–5; Gowers sign; pseudohypertrophy of calves; ↑↑ CK; wheelchair-bound by 12, death by 20s–30s
Hemophilia A — factor VIII deficiency; hemarthroses, deep tissue bleeding; ↑ aPTT, normal PT and BT
G6PD deficiency — oxidative stress → hemolytic anemia; Heinz bodies, bite cells; triggered by fava beans, sulfonamides, primaquine, infections
Fragile X syndrome — CGG repeat expansion in FMR1 → intellectual disability, long face, large ears, macroorchidism; most common inherited cause of intellectual disability

Chromosomal Disorders

Disorder	Karyotype	Key Features
Down syndrome (Trisomy 21)	47,XX/XY,+21	Most common viable autosomal trisomy; intellectual disability; flat facies; epicanthal folds; simian crease; duodenal atresia; Hirschsprung disease; AV canal defect; increased risk of ALL and early-onset Alzheimer (APP gene on chr 21); maternal age >35 is major risk factor
Edwards syndrome (Trisomy 18)	47,XX/XY,+18	Severe intellectual disability; rocker-bottom feet; clenched fists (overlapping fingers); micrognathia; congenital heart defects; most die within 1 year
Patau syndrome (Trisomy 13)	47,XX/XY,+13	Holoprosencephaly; cleft lip/palate; polydactyly; microphthalmia; congenital heart defects; cutis aplasia; most die within 1 year
Turner syndrome	45,X	Short stature; shield chest; webbed neck; lymphedema of hands/feet at birth; streak gonads; coarctation of aorta; horseshoe kidney; no intellectual disability; most common cause of primary amenorrhea
Klinefelter syndrome	47,XXY	Tall stature; gynecomastia; small firm testes; infertility (azoospermia); ↑ FSH/LH; female pattern hair distribution; increased risk of breast cancer and SLE

Trinucleotide Repeat Disorders

Disease	Repeat	Gene	Key Feature
Huntington	CAG	HTT (chr 4)	Anticipation (paternal transmission)
Fragile X	CGG	FMR1 (X-linked)	Anticipation (maternal transmission)
Myotonic dystrophy	CTG	DMPK (chr 19)	Most common adult muscular dystrophy; myotonia; cataracts
Friedreich ataxia	GAA	FXN (chr 9)	AR; cerebellar ataxia, hypertrophic cardiomyopathy, diabetes

26 Metabolic & Storage Diseases

Lysosomal storage diseases result from inherited deficiency of specific lysosomal enzymes, leading to accumulation of undigested substrates within lysosomes. Most are autosomal recessive.

Lysosomal Storage Diseases

Disease	Enzyme Deficiency	Accumulated Substrate	Key Features
Tay-Sachs	Hexosaminidase A	GM2 ganglioside	Cherry-red spot on macula; progressive neurodegeneration; death by age 3; common in Ashkenazi Jewish; NO hepatosplenomegaly (distinguishes from Niemann-Pick)
Niemann-Pick (type A)	Sphingomyelinase	Sphingomyelin	Cherry-red spot; hepatosplenomegaly; foam cells; progressive neurodegeneration; Ashkenazi Jewish
Gaucher (type 1)	Glucocerebrosidase (β-glucosidase)	Glucocerebroside	Most common lysosomal storage disease; hepatosplenomegaly; pancytopenia; bone crises (Erlenmeyer flask deformity); Gaucher cells (“crumpled tissue paper” macrophages); Ashkenazi Jewish; enzyme replacement therapy available
Fabry	α-Galactosidase A	Globotriaosylceramide (Gb3)	X-linked recessive; peripheral neuropathy (burning pain in hands/feet); angiokeratomas; renal failure; cardiomyopathy; corneal opacities
Krabbe	Galactocerebrosidase	Galactocerebroside	Severe CNS demyelination; globoid cells; optic atrophy; death by age 2
Metachromatic leukodystrophy	Arylsulfatase A	Sulfatide (cerebroside sulfate)	Central and peripheral demyelination; metachromatic granules stain brown with cresyl violet
Hurler syndrome (MPS I)	α-L-Iduronidase	Heparan sulfate, dermatan sulfate	Coarse facies; corneal clouding; hepatosplenomegaly; joint stiffness; intellectual disability; gargoylism
Hunter syndrome (MPS II)	Iduronate sulfatase	Heparan sulfate, dermatan sulfate	X-linked recessive; similar to Hurler but milder; NO corneal clouding; aggressive behavior

Glycogen Storage Diseases

Type	Disease	Enzyme Deficiency	Key Features
I	Von Gierke	Glucose-6-phosphatase	Severe fasting hypoglycemia; hepatomegaly; lactic acidosis; hyperuricemia; hyperlipidemia
II	Pompe	Acid maltase (α-1,4-glucosidase) — lysosomal	Cardiomegaly (most prominent); hypotonia; early death (infantile form); only GSD that is a lysosomal storage disease
III	Cori (Forbes)	Debranching enzyme	Similar to Von Gierke but milder; gluconeogenesis intact
V	McArdle	Muscle glycogen phosphorylase	Exercise intolerance; myoglobinuria; no rise in blood lactate with exercise; “second wind” phenomenon

Mnemonics for lysosomal storage diseases: “Tay-Sachs lacks heXosaminidase” (X for hex); “Niemann-Pick has No sphingomyelinase”; “Gaucher has Glucocerebrosidase deficiency” (G for G). Remember that Fabry and Hunter are the only X-linked lysosomal storage diseases (“Fabulous Hunters are X-linked”).

27 Organ System Pathology Overview

General pathology principles recur across organ systems. This section provides a rapid-reference map linking pathophysiologic mechanisms to their most important organ-specific manifestations.

Cardiovascular Pathology Highlights

Process	Manifestation
Atherosclerosis	Coronary artery disease (MI); stroke; peripheral arterial disease; aortic aneurysm
Coagulative necrosis	Myocardial infarction (subendocardial or transmural); renal infarction
Thromboembolism	Pulmonary embolism (from DVT); arterial thromboembolism (from AF or LV thrombus)
Immune-mediated	Rheumatic heart disease (Type II + molecular mimicry); myocarditis (viral); Libman-Sacks endocarditis (SLE)
Amyloidosis	Restrictive cardiomyopathy (AL or ATTR)

Pulmonary Pathology Highlights

Process	Manifestation
Acute inflammation	Pneumonia (lobar, bronchopneumonia); ARDS (diffuse alveolar damage with hyaline membranes)
Chronic inflammation	Pulmonary fibrosis (IPF — UIP pattern); sarcoidosis (non-caseating granulomas)
Neoplasia	Lung adenocarcinoma (most common); squamous cell (central, PTHrP); SCLC (neuroendocrine, paraneoplastic)
Hemodynamic	Pulmonary edema (CHF); pulmonary embolism; pulmonary hypertension

Renal Pathology Highlights

Process	Manifestation
Immune complex (Type III)	Membranous nephropathy; post-streptococcal GN; lupus nephritis; IgA nephropathy
Anti-GBM (Type II)	Goodpasture syndrome (linear IgG on IF)
Thrombotic microangiopathy	HUS (Shiga toxin — E. coli O157:H7); TTP (ADAMTS13 deficiency)
Amyloidosis	AA amyloidosis — nephrotic syndrome; AL amyloidosis — nephrotic syndrome
Neoplasia	Renal cell carcinoma (clear cell most common; VHL association)

Hepatic Pathology Highlights

Process	Manifestation
Steatosis → steatohepatitis → cirrhosis	NAFLD/NASH; alcoholic liver disease
Viral hepatitis	Hepatitis B (serum sickness-like Type III; carrier state; HCC risk); Hepatitis C (chronic → cirrhosis → HCC)
Autoimmune	Autoimmune hepatitis (anti-smooth muscle Ab); primary biliary cholangitis (anti-mitochondrial Ab)
Hemochromatosis	Iron deposition → cirrhosis + HCC + diabetes + cardiomyopathy
Wilson disease	Copper deposition → hepatitis/cirrhosis + neuropsychiatric + Kayser-Fleischer rings

Hematologic Pathology Highlights

Process	Manifestation
Hemolytic anemias	Intrinsic (membrane: spherocytosis; enzyme: G6PD; hemoglobin: sickle cell, thalassemia) vs extrinsic (autoimmune, mechanical/microangiopathic)
Coagulation disorders	DIC (consumptive); hemophilia A (VIII def); vWD (most common inherited bleeding disorder); ITP (anti-GpIIb/IIIa antibodies); TTP (ADAMTS13 deficiency)
Lymphoproliferative	Hodgkin lymphoma (Reed-Sternberg cells, bimodal age); non-Hodgkin lymphoma (follicular, diffuse large B cell, Burkitt)
Myeloproliferative	CML (BCR-ABL); polycythemia vera (JAK2 V617F); essential thrombocythemia; myelofibrosis
Leukemia	ALL (most common childhood cancer; TdT+); AML (Auer rods; M3/APL = t(15;17) treated with ATRA); CLL (most common adult leukemia; smudge cells)

Endocrine Pathology Highlights

Process	Manifestation
Autoimmune endocrine	Type 1 DM (T cell destruction of β cells; anti-GAD, anti-insulin antibodies); Hashimoto thyroiditis (anti-TPO, anti-thyroglobulin → hypothyroidism); Graves disease (anti-TSH receptor stimulatory → hyperthyroidism); Addison disease (anti-21-hydroxylase)
Neoplastic endocrine	MEN 1 (3 P’s: pituitary, parathyroid, pancreas); MEN 2A (medullary thyroid CA, pheo, parathyroid hyperplasia; RET mutation); MEN 2B (medullary thyroid CA, pheo, mucosal neuromas, marfanoid habitus)
Pituitary pathology	Prolactinoma (most common pituitary adenoma); Sheehan syndrome (postpartum pituitary necrosis); craniopharyngioma (calcified, Rathke pouch remnant)
Adrenal pathology	Cushing syndrome (cortisol excess); Conn syndrome (aldosterone-producing adenoma); Waterhouse-Friderichsen (adrenal hemorrhage in meningococcemia)

CNS Pathology Highlights

Process	Manifestation
Vascular	Ischemic stroke (80%); hemorrhagic stroke (intracerebral: hypertension; subarachnoid: berry aneurysm rupture); epidural hematoma (middle meningeal artery); subdural hematoma (bridging veins)
Demyelinating	Multiple sclerosis (Type IV hypersensitivity; oligoclonal bands in CSF; periventricular plaques); Guillain-Barré (ascending paralysis; anti-ganglioside antibodies; albuminocytologic dissociation)
Neurodegenerative	Alzheimer (Aβ plaques + neurofibrillary tangles of hyperphosphorylated tau); Parkinson (loss of dopaminergic neurons in substantia nigra; Lewy bodies = α-synuclein)
Neoplastic	Glioblastoma (most common primary brain tumor in adults; GBM = grade IV; pseudopalisading necrosis); meningioma (2nd most common; dural-based; psammoma bodies); schwannoma (S-100+; CN VIII → acoustic neuroma)

A systematic approach to organ pathology applies the general pathology framework: for any organ, consider (1) vascular/hemodynamic causes, (2) inflammatory/infectious causes, (3) neoplastic causes, (4) degenerative/metabolic causes, and (5) genetic/developmental causes. This exhaustive list prevents you from missing diagnoses on differential.

28 High-Yield Review & Board Pearls

CELL INJURY & DEATH

Most common cause of cell injury: hypoxia/ischemia
First biochemical change in ischemia: decreased oxidative phosphorylation → ATP depletion
First morphologic change in reversible injury: cellular swelling (hydropic change)
Most reliable markers of irreversible injury: mitochondrial dense amorphous densities + plasma membrane disruption
Hallmark of necrosis: inflammation; hallmark of apoptosis: no inflammation
Brain infarcts: liquefactive necrosis (exception to solid organ rule)
Caseous necrosis: think tuberculosis
Fat necrosis with saponification: think acute pancreatitis
Fibrinoid necrosis in vessel walls: think malignant hypertension or vasculitis

INFLAMMATION

First cells to arrive in acute inflammation: neutrophils (peak 6–24 hours)
Most important cell in chronic inflammation: macrophage
Most important cell in wound healing: macrophage
Most important mediator of fever: PGE₂ (produced in hypothalamus in response to IL-1, TNF, IL-6)
C5a: most potent chemotactic factor for neutrophils (also anaphylatoxin)
LTB₄: potent neutrophil chemotaxis
LTC₄/D₄/E₄: bronchoconstriction (slow-reacting substances of anaphylaxis)
LAD-1 (CD18 deficiency): recurrent infections + delayed cord separation + neutrophilia (cells cannot leave blood)
CGD (NADPH oxidase deficiency): susceptible to catalase-positive organisms
Non-caseating granulomas: think sarcoidosis
Granuloma maintenance requires TNF-α — anti-TNF therapy → TB reactivation risk

HEMODYNAMIC DISORDERS

Virchow’s triad: endothelial injury + stasis + hypercoagulability
Most common hereditary thrombophilia: Factor V Leiden
Most PE originate from: deep veins of the legs
Fat embolism triad: respiratory distress + neurologic changes + petechial rash
Paradoxical embolism: venous thrombus → arterial via PFO
White infarcts: heart, kidney, spleen (end-artery organs)
Red infarcts: lung, liver, intestine (dual blood supply); brain with reperfusion
Septic shock: early = warm (high CO, low SVR); late = cold (low CO)
DIC: schistocytes + ↓platelets + ↑D-dimer + ↑PT/aPTT + ↓fibrinogen

NEOPLASIA

Most common oncogene mutated in human cancer: RAS (~30%)
Most commonly mutated tumor suppressor: TP53 (>50%)
Two-hit hypothesis: both alleles of tumor suppressor must be knocked out
Warburg effect: cancer cells prefer aerobic glycolysis (basis of PET scan)
Tumor markers are for monitoring, not screening (exceptions: PSA, AFP in cirrhosis)
SCLC paraneoplastic: SIADH, ectopic ACTH, Lambert-Eaton
Most common paraneoplastic syndrome overall: hypercalcemia (PTHrP from squamous cell cancers)
t(14;18): Bcl-2 — follicular lymphoma
t(8;14): c-MYC — Burkitt lymphoma
t(9;22): BCR-ABL (Philadelphia chromosome) — CML

IMMUNOPATHOLOGY & GENETICS

Type I hypersensitivity: IgE-mediated mast cell degranulation (minutes)
Type II: IgG/IgM against cell surface antigens (Graves = stimulatory; MG = inhibitory)
Type III: immune complexes deposited in tissues (SLE, serum sickness, PSGN)
Type IV: T cell–mediated, delayed (PPD test, contact dermatitis, transplant rejection)
Amyloid: Congo red stain + apple-green birefringence under polarized light
AL amyloid: plasma cell dyscrasia; AA amyloid: chronic inflammation
Strongest HLA association: HLA-B27 with ankylosing spondylitis
Most common inherited bleeding disorder: von Willebrand disease
Most common lysosomal storage disease: Gaucher disease
X-linked lysosomal storage diseases: Fabry and Hunter
Cherry-red spot + NO hepatosplenomegaly: Tay-Sachs
Cherry-red spot + hepatosplenomegaly: Niemann-Pick

CARCINOGENESIS & GENETIC DISEASE

HPV oncoproteins: E6 degrades p53; E7 inactivates Rb
EBV → Burkitt lymphoma, nasopharyngeal CA, Hodgkin lymphoma, PTLD
Aflatoxin B1 + HBV → synergistic risk for hepatocellular carcinoma
Asbestos: mesothelioma (independent of smoking) AND bronchogenic carcinoma (synergistic with smoking)
Metaplasia → dysplasia → carcinoma sequence: Barrett esophagus; cervical CIN
Carcinomas metastasize via lymphatics first; sarcomas via blood first
Most common cancer metastasizing to bone: breast (lytic); prostate (blastic)
Down syndrome: increased risk of ALL in children and early-onset Alzheimer
Cystic fibrosis: ΔF508 mutation; sweat chloride >60; Pseudomonas lung infections
Sickle cell trait (HbAS): protective against Plasmodium falciparum malaria
Autoantibody specificity: anti-dsDNA = lupus nephritis activity; anti-Smith = most specific for SLE; anti-CCP = most specific for RA
Antiphospholipid syndrome: prolonged aPTT but thrombosis in vivo (not bleeding)

Board Strategy: Pathophysiology is the highest-yield subject for USMLE Step 1. For each disease, know the mechanism (etiology + pathogenesis), the expected morphologic changes (gross and microscopic), and the clinical consequences (symptoms, lab findings, complications). Questions typically present a clinical vignette and ask you to identify the underlying mechanism or predict the next step in the disease process. Recognize patterns: all forms of necrosis, the cardinal features of each type of hypersensitivity, Virchow’s triad, and the hallmarks of cancer are tested repeatedly.