DR. MUHAMMAD MUDASSAR MBBS., FCPS ( HISTOPATH ) HEAD PATHOLOGY DEPT & ASST. PROFESSOR BMC, KSA Introduction of Pathology

Pathology Pathos---suffering Logos---- study Study of suffering or disease A bridging science

PATHOLOGY GENERAL SYSTEMIC

PATHOLOGY ETIOLOGY (“Cause”) PATHOGENESIS (“Insidious development”) MORPHOLOGY (ABNORMAL ANATOMY) CLINICAL EXPRESSION

ETIOLOGY Cause vs. Risk Factors

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

MORPHOLOGY Abnormal Anatomy  Gross  Microscopic  Radiologic  Molecular

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 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 ADAPTATIONS CELL INJURY CELL DEATH

OBJECTIVES Understand 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

OBJECTIVES Understand 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 brothers HYPER- 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 hyperplasia female breast at puberty and during pregnancy (1) compensatory hyperplasia one lobe of the liver for transplantation

Pathological hyperplasia Endometrial hyperplasia Benign prostatic hyperplasia viral 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-PLASIA IN- CREASE IN NUMBER OF CELLS

HYPO-PLASIA DE- CREASE IN NUMBER OF CELLS

The –trophy brothers HYPER- HYPO- (A-) DYS-

HYPER-TROPHY IN - 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 pregnancy Hypertrophy of skeletal muscles, in body builders Hypertrophy 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 atrophy DECREASED BLOOD FLOW…old age and atrophy of brain and heart DECREASED NUTRITION.. Marasmus, cachexia AGING (involution) PRESSURE Loss of endocrine stimulation

METAPLASIA  Metaplasia 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 DEATH APOPTOSIS vs. NECROSIS What 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 depletion Cellular “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 is  IRREVERSIBLE MITOCHONDRIAL DYSFUNCTION  PROFOUND MEMBRANE DISTURBANCES LIFE is……..???

CONTINUUM REVERSIBLE  IRREVERSIBLE  DEATH  EM  LIGHT MICROSCOPY  GROSS APPEARANCES

DEATH: ELECTRON MICROSCOPY

DEATH: LIGHT MICROSCOPY

CELL DEATH APOPTOSIS (“normal” death) NECROSIS (“premature” or “untimely” death due to “causes”

Necrosis & Apoptosis

Morphology of cell injury Reversible Irreversible

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, papillary YAHOO!

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 depletion Free 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 tylenol Dose Relationship Free radicals, organelle, DNA damage

APOPTOSIS a 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. Viral Duct obstruction Tumor cells Apoptosis/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 Damage Accumulation of Misfolded Proteins Apoptosis of Self-Reactive Lymphocytes Cytotoxic T Lymphocyte-Mediated Apoptosis

INTRAcellular ACCUMULATIONS Lipids  Neutral Fat  Cholesterol “Hyaline” = any “proteinaceous” pink “glassy” substance Glycogen Pigments (EX-ogenous, END-ogenous) Calcium

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

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.

CALCIFICATION DYSTROPHIC (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 damage Decreases cellular replication Defective protein homeostasis