1. CELL ADAPTATIONS
CELL INJURY
CELL DEATH

2. 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

3. 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

4. OBJECTIVES
Identify common INTRA-cellular accumulations---Fat, Hyaline, CA++, Proteins, Glycogen, Pigments
Understand aging and differentiate the concepts of preprogrammed death versus wear and tear.

5. PATHOLOGY
Pathos (suffering)
Logos

6. PATHOLOGY GENERAL SYSTEMIC General = Pathology I
Systemic = Pathology II, to be in SYNCH with a “systemic” curriculum!

7. PATHOLOGY ETIOLOGY (“Cause”) PATHOGENESIS (“Insidious development”)
MORPHOLOGY (ABNORMAL ANATOMY)
CLINICAL EXPRESSION
These are the four aspects about every disease you should keep in mind as a knee jerk reflex every time you hear the name of a disease.

8. ETIOLOGY Cause Risk Factors vs.
Often risk factors are divided into major and minor, as in atherosclerosis

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

10. MORPHOLOGY
Abnormal Anatomy
Gross
Microscopic
Radiologic
Molecular

11. CLINICAL EXPRESSION
Ironically, even though “clinical expression” is not often present in subclinical diseases, it is the “pathos” of pathology.

12. 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.

13. The Father of Modern Pathology
CLINICAL/FUNCTIONAL
Rudolph Virchow
The Father of Modern Pathology
The second most profound thing ever said, in the 2nd millenium, after E=mc2, was by Rudolph Virchow. He said, “All diseases are the results of visible cell abnormalities”, i.e., abnormal histology, i.e., histopathology. For this, he earned the undisputed title of “father of pathology.”

14. FUNCTIONAL DEFINITION OF DISEASE
HOMEOSTASIS

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

16. The –plasia brothers HYPER- HYPO- (A-) META- DYS- ANA- NORMO-
“Frank” ANA-
Know the definitions of all these terms, for the rest of your life, even if it is only from the dictionary. Most are cellular/tissue reactions to injury.
PLASIA = GROWTH

17. IN-CREASE IN NUMBER OF CELLS
HYPER-PLASIA
IN-CREASE IN NUMBER OF CELLS
Hyperplasia is an increase of the size or weight of an organ or tissue due to increased NUMBERS of cells. Hypoplasia is the opposite.
Adrenal cortex is usually about a 1 mm ribbon.

18. DE-CREASE IN NUMBER OF CELLS
HYPO-PLASIA
DE-CREASE IN NUMBER OF CELLS

19. The –trophy brothers HYPER- DYS- HYPO- (A-)
Hypertrophy is increase in the size (weight) of an organ or tissue due to increase of the size of the cells. Hypotrophy (more commonly called atrophy) is the opposite. There are many common violations to this concept.

20. IN-CREASE IN SIZE OF CELLS
HYPER-TROPHY
IN-CREASE IN SIZE OF CELLS

21. DE-CREASE IN SIZE OF CELLS?
HYPO-TROPHY?
DE-CREASE IN SIZE OF CELLS?
RARELY
USED
TERM

22. A-TROPHY*? DE-CREASE IN SIZE OF CELLS? YES
SHRINKAGE IN CELL SIZE DUE TO LOSS OF CELL SUBSTANCE
* Often used erroneously, but commonly, with hypoplasia or aplasia

23. ATROPHY DECREASED WORKLOAD DENERVATION DECREASED BLOOD FLOW
DECREASED NUTRITION
AGING (involution)
PRESSURE
“EXHAUSTION”

24. METAPLASIA
A SUBSTITUTION of one NORMAL CELL or TISSUE type, for ANOTHER
COLUMNAR SQUAMOUS (Cervix)
SQUAMOUS COLUMNAR (Glandular) (Stomach)
FIBROUS BONE
WHY?

25. CELL DEATH DEATH is IRREVERSIBLE APOPTOSIS vs. NECROSIS
What is DEATH? (What is LIFE?)
DEATH is IRREVERSIBLE
The precise differentiation between cell life and cell death is about as controversial as human life or human death.

26. So the question is….
…NOT what is life or death, but what is REVERSIBLE or IRREVERSIBLE injury

27. REVERSIBLE CHANGES REDUCED oxidative phosphorylation ATP depletion
Cellular “SWELLING”
These are three indisputable reversible changes

28. IRREVERSIBLE CHANGES MITOCHONDRIAL IRREVERSIBILITY
IRREVERSIBLE MEMBRANE DEFECTS
LYSOSOMAL DIGESTION
These are three indisputable IR-reversible changes.
1) If the mitochondria die, the cell dies
2) If the membrane can’t keep the sodium out, the cell dies
3) If the lysosomes start to autodigest the cell, the cell is dead
THREE VITAL ORGANS, THREE VITAL ORGANELLES.

29. SOME INJURIES CAN LEAD TO DEATH IF PROLONGED and/or SEVERE enough
REVERSIBLE = INJURY
IRREVERSIBLE = DEATH
SOME INJURIES CAN LEAD TO DEATH IF PROLONGED and/or SEVERE enough

30. INJURY CAUSES (REVERSIBLE)
THE
USUAL
SUSPECTS
But…WHO are the THREE WORST?

31. INJURY CAUSES (REVERSIBLE)
Hypoxia, (decreased O2)
PHYSICAL Agents
CHEMICAL Agents
INFECTIOUS Agents
Immunologic
Genetic
Nutritional
The usual suspects are always suspected in carcinogenesis, teratogenesis, inflammations, or, really, any disease in general.
So just as you always tend to think of diseases as inflammatory, neoplastic, degenerative, you should always think of causes as physical, chemical, and infectious.

32. INJURY MECHANISMS (REVERSIBLE)
DECREASED ATP
MITOCHONDRIAL DAMAGE
INCREASED INTRACELLULAR CALCIUM
INCREASED FREE RADICALS
INCREASED CELL MEMBRANE PERMEABILITY

33. What is Death? What is Life?
DEATH is
IRREVERSIBLE MITOCHONDRIAL DYSFUNCTION
PROFOUND MEMBRANE DISTURBANCES
LIFE is……..???
Death is easier to define than life. These two definitions of cell death are indisputable. The best definition of life is not death, in all honesty.

34. CONTINUUM REVERSIBLE  IRREVERSIBLE DEATH EM LIGHT MICROSCOPY
GROSS APPEARANCES
The closer we look at something, the easier it is to tell if it is dead, alive, or dying.

35. DEATH: ELECTRON MICROSCOPY

36. DEATH: LIGHT MICROSCOPY
In light microscopy inability to recognize nuclei because they broke up (karyorhexis, karyolysis) is a common criterion of cell death.

37. 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
OneLook lists 172 terms preceding the word “necrosis”:
On routine gross or microscopic examination “necrosis” is used as synonymous with cell or tissue death. These are not really good terms but have been used as common adjectives over the ages. If you want to convince somebody you are a Nobel prize winning Prussian pathologist, you can pronounce the word as neg-ROW-zeese

38. LIQUEFACTIVE NECROSIS, BRAIN
When the brain tissue dies it tends to soften, then liquefy, so there can be more water (i.e., protons) to cause increased MRI signals.

39. MORE LIQUID  MORE WATER  MORE PROTONS
T2 weighted MRI images emphasize water density but some anatomic resolution is lost.

40. CASEOUS NECROSIS, TB
“Caseous” means “cheese-like” this is a GROSS observation, not a microscopic one. Cheese has less texture than meat, and is flaky. Many people from Wisconsin have been called caseous, i.e., cheeseheads.

41. FIBRINOID NECROSIS
Fibrinoid necrosis looks like fibrin microscopically. In fact, often, it IS fibrin. Fibrinoid necrosis is most often applied to blood vessel walls.

42. “WET” GANGRENE
Wet gangrene may come BEFORE or AFTER dry gangrene. Why? Gangrene is also a type of necrosis, and the term “gangrenous necrosis” is common, most gangrenous necroses are due to lack of blood flow, or “ischemic” necrosis.

43. “DRY” GANGRENE
Dry gangrene is deader, i.e., longer standing, than the death of wet gangrene.

44. EXAMPLES of Cell INJURY/NECROSIS
Ischemic (Hypoxic)
Ischemia/Reperfusion
Chemical
In reperfusion injury, damage occurs AFTER the oxygen, or blood, is restored! Chemical injury can be DIRECT, or INDIRECT, if the chemical is converted into a toxic metabolite.

45. ISCHEMIC INJURY REVERSIBLE IRREVERSIBLE DEATH (INFARCT)
An infarct is defined as “dead tissue” due to lack of blood flow, and therefore lack of oxygen, nutrients, etc.

46. ISCHEMIA/RE-PERFUSION INJURY
NEW Damage “Theory”
The restored blood flow reintroduces oxygen within cells that damages cellular proteins, DNA, and the plasma membrane (Wikipedia definition). Reperfusion injury is of great concern in coronary bypass operations.

47. CHEMICAL INJURY “Toxic” Chemicals, e.g CCl4 Drugs, e.g tylenol
Dose Relationship
Free radicals, organelle, DNA damage
As in pharmacology, EVERY chemical can be toxic, even pure water, so its always a question of dosage.

48. APOPTOSIS NORMAL (preprogrammed) PATHOLOGIC (associated with Necrosis)
Apoptosis come from the Greek word which means “falling off”.

49. “NORMAL” APOPTOSIS Embryogenesis Hormonal “Involution”
Cell population control, e.g., “crypts”
Post Inflammatory “Clean-up”
Elimination of “HARMFUL” cells
Cytotoxic T-Cells cleaning up
Cells which have shorter life spans are subject to apoptosis.

50. “PATHOLOGIC” APOPTOSIS
“Toxic” effect on cells, e.g., chemicals, pathogens
Duct obstruction
Tumor cells
Apoptosis/Necrosis spectrum
There is often a grey area between apoptosis and necrosis, especially in the area of “pathologic”, rather than normal, apoptosis.

51. APOPTOSIS MORPHOLOGY DE-crease in cell size, i.e., shrinkage
IN-crease in chromatin concentration, i.e., hyperchromasia, pyknosis karyorhexis karyolysis
IN-crease in membrane “blebs”
Phagocytosis
Nuclei get smaller, “darker”, then fragment, then dissolve. What is the correct name for EACH of these 4 processes?
The cellular changes in apoptosis may look exactly the cellular changes in necrosis.
Do you think this is the EXACT same appearance seen in necrosis (not apoptosis)? YES

52. SHRINKAGE/HYPERCHROMASIA
Shrinkage (pyknosis), increased nuclear staining (hyperchromasia), nuclear fragmentation (karyorrhexis, karryolysis), are classic features of apoptosis.

53. PHAGOCYTOSIS
The two main cell which clean up dead cell fragments are macrophages (also called “histiocytes”) and neutrophils.

54. APOPTOSIS BIOCHEMISTRY
Protein Digestion (Caspases)
DNA breakdown
Phagocytic Recognition
Caspases, or cysteine-aspartic proteases, are a family of cysteine proteases, which play essential roles in apoptosis (programmed cell death), necrosis and inflammation.

55. SUB-Cellular Responses to Injury (APOPTOSIS/NECROSIS)
Lysosomal Auto-Digestion
Smooth Endoplasmic Reticulum (SER) activation
Mitochondrial “SWELLING”
Cytoskeleton Breakdown
Thin Filaments (actin, myosin)
Microtubules
Intermediate Filaments (keratin, desmin, vimentin, neurofilaments, glial filaments)

56. INTRAcellular ACCUMULATIONS
Lipids
Neutral Fat
Cholesterol
“Hyaline” = any “proteinaceous” pink “glassy” substance
Glycogen
Pigments (EX-ogenous, END-ogenous)
Calcium
The term “hyaline” is the most commonly confused concept in pathology. ANY eosinophilic staining, amorphic substance, can be correctly called hyaline, especially necrosis, amyloid, various proteinaceous secretions, fibrin are the most common.

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

58. FATTY LIVER
Name the three most common causes of fatty liver: Ans: diabetes, obesity, alcoholism (toxic)

59. FATTY LIVER
Sometimes the terms MICROvesicular versus MACROvesicular steatosis is used dependong whether the fat droplets are smaller or bigger than a cell. Sometime the term “fatty change” is also used.

60. The slit-like spaces are cholesterol clefts, a classic feature of atherosclerosis.

61. PIGMENTS EX-ogenous--- (tattoo, Anthracosis)
END-ogenous--- they all look the same, (e.g., hemosiderin, melanin, lipofucsin, bile), in that they are all golden yellowish brown on “routine” Hematoxylin & Eosin (H&E) stains
If you see a golden brown, slightly refractile pigment on routing light H&E microscopy, it is either hemosiderin, melanin, or bile derived. A few other degenerative pigments, such as lipofucsin, are also possible. Special stains can prove it is one or the other, if it is not abundantly clear from its cellular or pathologic setting and/or location

62. TATTOO, MICROSCOPIC
This tiny amount of microscopic tattoo pigment can make white skin look quite black! Is this EXogenous or ENDogenous?

63. ANTHRACOSIS
Why does anthracosis look worse along the pleural surface than on cut sections?
Why are MANY extrathoracic lymph nodes also anthracotic?
What in the body is black and NOT due to EXOGENOUS pigments?

64. Hemosiderin/Melanin/etc.
Why would somebody order a prussian blue stain, or a S-100 immunoperoxidase stain or a HMB-45 stain?

65. *NOT to be confused with “metastatic” calcification
DYSTROPHIC (LOCAL CAUSES) (often with FIBROSIS)
METASTATIC (SYSTEMIC CAUSES)
HYPERPARATHYROIDISM
“METASTATIC*” Disease
Calcium stains deep blue (very basophilic) and crunchy in all settings.
*NOT to be confused with “metastatic” calcification

66. CELL AGING parallels ORGANISMAL AGING
PROGRAMMED THEORY (80%)
vs.
WEAR AND TEAR THEORY (20%)
Cellular death is analogous to human death. We don’t die because we exercise, we die because we run out of steam.