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