DR. MUHAMMAD MUDASSARMBBS., FCPS ( HISTOPATH )

HEAD PATHOLOGY DEPT & ASST. PROFESSORBMC, KSA

Introduction of Pathology

Pathology

Pathos---sufferingLogos---- study

Study of suffering or disease

A bridging science

PATHOLOGYGENERALSYSTEMIC

PATHOLOGYETIOLOGY (“Cause”)PATHOGENESIS (“Insidious development”)

MORPHOLOGY (ABNORMAL ANATOMY)

CLINICAL EXPRESSION

ETIOLOGY

Causevs.

Risk Factors

PATHOGENESIS“sequence of events from the initial stimulus to the ultimate expression of the disease”

MORPHOLOGYAbnormal AnatomyGrossMicroscopic

RadiologicMolecular

Most long term students of pathology, like myself, will strongly agree that the very best way for most minds to remember, or identify, or understand a disease is to associate it with

a morphologic IMAGE.This can be gross, electron microscopic, light microscopic, radiologic, or molecular.

In MOST cases it is at the LIGHT MICROSCOPIC LEVEL.

CLINICAL/FUNCTIONAL

Rudolph Virchow

1821-1902

The Father of Modern Pathology“All diseases are the results of visible

cell abnormalities”, i.e., abnormal histology, i.e., histopathology’’

Diagnosis and treatment guidelines

CELL ADAPTATIONSCELL ADAPTATIONS

CELL INJURYCELL INJURY

CELL DEATHCELL DEATH

OBJECTIVESUnderstand the 3 main anatomic concepts of disease---Degenerative, Inflammatory, Neoplastic

Understand the concepts of cellular growth adaptations---Hyperplasia, Hypertrophy, Atrophy, Metaplasia

Understand the factors of cell injury and death---O2, Physical, Chemical, Infection, Immunologic, Genetic, Nutritional

OBJECTIVESUnderstand the pathologic mechanisms at

the SUB-cellular level---ATP, Mitochondria, Ca++, Free Radicals, Membranes

Understand and differentiate the concepts of APOPTOSIS and NECROSIS

Understand SUB-cellular responses to injury---Lysosomes, Smooth endoplasmic reticulum, Mitochondria, Cytoskeleton

Understand the concept of Aging.

Adaptation

Adaptations are reversible changes in the size, number, phenotype, metabolic activity, or functions of cells in response to changes in their environment

The –plasia brothersHYPER-HYPO- (A-)NORMO-META-

DYS-ANA-

HYPERPLASIA

Hyperplasia is an increase in the number of cells in an organ or tissue, usually resulting in increased mass of the organ or tissue.

physiologic or pathologic.

Physiologic Hyperplasia

(1) hormonal hyperplasiafemale breast at puberty and during

pregnancy

(1) compensatory hyperplasiaone lobe of the liver for transplantation

Pathological hyperplasia

Endometrial hyperplasiaBenign prostatic hyperplasiaviral infections, such as papillomaviruses

hyperplasia is distinct from cancer, but pathologic hyperplasia constitutes a fertile soil in which cancerous proliferation may eventually arise.

Mechanisms of Hyperplasia

Hyperplasia is the result of growth factor–driven proliferation of mature cells and, in some cases, by increased output of new cells from tissue stem cells.

after partial hepatectomy growth factors are produced in the liver that engage receptors on the surviving cells and activate signaling pathways that stimulate cell proliferation.

HYPER-PLASIAIN-CREASE IN NUMBER OF CELLS

HYPO-PLASIADE-CREASE IN NUMBER OF CELLS

The –trophy brothers

HYPER- HYPO- (A-)

DYS-

HYPER-TROPHYIN-CREASE IN SIZE OF CELLS

Hypertrophy

Hypertrophy refers to an increase in the size of cells, resulting in an increase in the size of the organ

Physiological and pathological

Uterus during pregnancyHypertrophy of skeletal muscles, in body

buildersHypertrophy of cardiac muscles

HYPO-TROPHY?

DE-CREASE IN SIZE OF CELLS?

RARELY

USED

TERM

A-TROPHY?DE-CREASE IN SIZE OF CELLS? YES

SHRINKAGE IN CELL SIZE DUE TO LOSS OF CELL SUBSTANCE

Atrophy examples

Normal physiological atrophy of tissues during intrauterine development e.g notochord and thyroglossal duct.

Physiological atrophy of uterus after pregnancy

Pathological atrophy

DECREASED WORKLOAD*disuse atrophy,,, e.g plaster of paris and muscles atrphy

DENERVATION atrophyDECREASED BLOOD FLOW…old age and

atrophy of brain and heartDECREASED NUTRITION.. Marasmus,

cachexiaAGING (involution)PRESSURELoss of endocrine stimulation

METAPLASIAMetaplasia is a reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type

COLUMNAR SQUAMOUS (Cervix and lung)

SQUAMOUS COLUMNAR (Glandular) (Stomach)

FIBROUS BONE

Mechanism of metaplasia

the result of a reprogramming of stem cells that are known to exist in normal tissues, or of undifferentiated mesenchymal cells present in connective tissue

CELL DEATHAPOPTOSIS vs. NECROSISWhat is DEATH? (What is LIFE?)

DEATH is

IRREVERSIBLE

So the question is….

…NOT what is life or death, but what is REVERSIBLE or IRREVERSIBLE injury

REVERSIBLE CHANGES

REDUCED oxidative phosphorylation

ATP depletionCellular “SWELLING”

IRREVERSIBLE CHANGES

MITOCHONDRIAL IRREVERSIBILITY

IRREVERSIBLE MEMBRANE DEFECTS

LYSOSOMAL DIGESTION

REVERSIBLE = INJURY

IRREVERSIBLE = DEATH

SOME INJURIES CAN LEAD TO DEATH IF PROLONGED

and/or SEVERE enough

INJURY CAUSES (REVERSIBLE)

THE

USUAL

SUSPECTS

But…WHO are the THREE

WORST?

INJURY CAUSES (REVERSIBLE)Hypoxia, (decreased O2)

PHYSICAL Agents

CHEMICAL Agents

INFECTIOUS Agents

Immunologic

Genetic

Nutritional

INJURY MECHANISMS (REVERSIBLE)

DECREASED ATP

MITOCHONDRIAL DAMAGE

INCREASED INTRACELLULAR CALCIUM

INCREASED FREE RADICALS

INCREASED CELL MEMBRANE PERMEABILITY

What is Death?What is Life?

DEATH isIRREVERSIBLE MITOCHONDRIAL DYSFUNCTION

PROFOUND MEMBRANE DISTURBANCES

LIFE is……..???

CONTINUUMREVERSIBLE IRREVERSIBLEDEATHEMLIGHT MICROSCOPYGROSS APPEARANCES

DEATH:ELECTRON

MICROSCOPY

DEATH:LIGHT MICROSCOPY

CELL DEATHAPOPTOSIS (“normal” death)

NECROSIS (“premature” or “untimely” death due to “causes”

Necrosis & Apoptosis

Morphology of cell injury

ReversibleIrreversible

NECROSIS BROTHERS:Liquefactive (Brain)Gangrenous (Extremities, Bowel, non-

specific) WET DRY

Fibrinoid (Rheumatoid, non-specific)Caseous (cheese) (Tuberculosis)Fat (Breast, any fat)Ischemic (non-specific)Avascular (aseptic), radiation, organ

specific, papillaryYAHOO!

LIQUEFACTIVE NECROSIS, BRAIN

MORE LIQUID MORE WATER MORE PROTONS

CASEOUS NECROSIS, TB

FIBRINOID NECROSIS

“WET” GANGRENE

“DRY” GANGRENE

Mechanism of cell injury

Depletion of ATP

Mitochondrial damage

Membrane damage by Influx of calcium

Free radical injury

Damage to DNA & Proteins

ATP depletionATP depletion Free radical injuryFree radical injury

EXAMPLES of Cell INJURY/NECROSIS

Ischemic (Hypoxic)Ischemia/Reperfusion

Chemical

ISCHEMIA/RE-PERFUSION INJURY

NEW Damage “Theory”

CHEMICAL INJURY“Toxic” Chemicals, e.g CCl4

Drugs, e.g tylenolDose RelationshipFree radicals, organelle, DNA damage

APOPTOSISa pathway of cell death that is induced

by a tightly regulated suicide program in which cells destined to die activate enzymes capable of degrading the cells' own nuclear DNA and nuclear and cytoplasmic proteins

NORMAL (preprogrammed)PATHOLOGIC (associated with Necrosis)

“NORMAL” APOPTOSIS

Embryogenesis Hormonal “Involution”Cell population control, e.g., “crypts”

Post Inflammatory “Clean-up”Elimination of “HARMFUL” cells

Cytotoxic T-Cells cleaning up

“PATHOLOGIC” APOPTOSIS

DNA damage Accumulation of misfolded proteins“Toxic” effect on cells, e.g., chemicals, pathogens

Cell injury in certain infections.e.g. ViralDuct obstructionTumor cellsApoptosis/Necrosis spectrum

Morphology of Apoptosis

Shrinkage (pyknosis), increased nuclear staining (hyperchromasia), nuclear fragmentation (karyorrhexis, karryolysis), are classic features of apoptosis

Apoptotic bodies

Mechanism of Apoptosis

Examples of Apoptosis

Growth Factor Deprivation DNA DamageAccumulation of Misfolded ProteinsApoptosis of Self-Reactive LymphocytesCytotoxic T Lymphocyte-Mediated Apoptosis

INTRAcellular ACCUMULATIONS

Lipids Neutral Fat Cholesterol

“Hyaline” = any “proteinaceous” pink “glassy” substance

GlycogenPigments (EX-ogenous, END-ogenous)Calcium

LIPID LAW

ALL Lipids are YELLOW grossly and WASHED out (CLEAR) microscopically

FATTY LIVER

FATTY LIVER

PIGMENTS

EX-ogenous--- (tattoo, Anthracosis)

END-ogenous--- they all look the same, (e.g., hemosiderin, melanin, lipofucsin, bile), in that hey are all golden yellowish brown on “routine” Hematoxylin & Eosin (H&E) stains

TATTOO, MICROSCOPIC

ANTHRACOSIS

Hemosiderin/Melanin/etc.

CALCIFICATIONDYSTROPHIC (LOCAL CAUSES) (often

with FIBROSIS)Normal calcium and dead and dying tissues

METASTATIC (SYSTEMIC CAUSES)Hypercalcemia and viable tissue

HYPERPARATHYROIDISM Destruction of bone Vit. D disorders & Sarcoidosis Renal failure

“METASTATIC*” Disease

*NOT to be confused with “metastatic” calcification

CELL AGING parallels

ORGANISMAL AGING

PROGRAMMED THEORY (80%)

vs.

WEAR AND TEAR THEORY (20%)

Mechanisms of cellular aging

DNA damageDecreases cellular replicationDefective protein homeostasis