Patomorfologia

Aspects of Disease

• Etiology

– cause of disease

• Pathogenesis

– mechanism of development

• Morphologic changes

– structural alterations within cells and organs

caused by a disease

• Clinical & Functional Significance

(Symptoms)

– consequences of morphologic changes

Disease Etiology -

VINDICATE

• Vascular
• Infections

– viral, bacterial, mycobacterial, fungal,

protozoall…

• Neoplastic

– malignant tumors…

• Drugs or toxins

Disease Etiology – VINDICATE,

cd.:

• Idiopathic
• Congetital

– chromosomal abnormalities, gene defects

• Autoimmune disorders
• Trauma or environmental

– heat, cold, vitamin deficiences, nutritional…

• Endocrine / metabolic

– diabetes, acidosois…

Morphologic Changes

• Morphologic changes in cell and

tissue structure may either be
characteristic or suggestive of the
disease process in question

• Morphologic changes which are

diagnostic of a specific disease are

pathognomic

Cell injury

Adaptation

altered steady state
new homeostatis
(i.e.muscle
hypertrophy)

Cell injury

reversible or
irreversible cell
death (necrosis)
(myocardial infarct)

Cell in normal environment – homeostatic (steady state)

physiologic stress / pathologic stimull

adaptive capacity exceeded

Causes Cell Injury

• Hypoxia & ischemia
• Free-radical injury
• Physical agents (heat, cold, radiation,

trauma)

• Chemical agents & drugs
• Infectious organism
• Immunologie reactions
• Genetic derangements
• Nutritional imbalances

Principles of Cell Injury

• A cell / tissue’s response to injury is

dependent upon

– Injury factors

• type of infury (ischemia vs. toxic vs. infection

…)

• duration injury
• severity of the inciting injury

– Cellular factors

• cell type
• stage of cell cycle
• cell adaptability

Principles of Cell Injury

Susceptibility of cells to Ischemic

Necrosis

• High

– neurons

• 3-5 min.  ischemia

• Intermediate

– myocardium, hepatocytes renal

epithelium

• 30 min-2hrs  ischemia

• Low

– Fibroblasts, Epidermis Skeletal Muscles

• several hours  ischemia

Principles of Cell Injury

• Systems hughly vulnerable to injury

– cellular membranes
– mitochondria (aerobic respiration)
– endoplasmic reticulum (protein synthesis)
– genetic apparatus (DNA, RNA)

• Injury at one focus often has a cascade

effect on multiple systems

– impaired aerobic respiration  disruption Na

pump cell membrane

General Biochemical

Mechanisms of Cell Injury

• ATP depletion

• Oxygen free radicals

• Loss of calcium homestatis

• Membrane damage

• Irreversible mitochondrial damage

ATP DEPLETION

• ATP required for

– membrane transport, protein synthesis,

lipogenesis

• Production of ATP

– oxidative phosphorylation of ADP (major

pathway)

• aerobic respiration, requires O

– glycolytic pathway (minot pathway)

• does not require O

Oxygen-Derived Free

Radicals

• Reactive Oxygen Species (ROS)

– O•

(superoxide anion), H

(peroxide), OH

(hydroxyl radical)

– byproduct of mitochondrial respiration & other

causes

– radical scavenging system

• suproxide dismutase, catalase, glutathione

peroxidase

• neutralize ROS, prevent cell injury

– imbalance between ROS production and

scavenging system  cell injury (oxidative stress)

• damage proteins, lipids, nucleic acids

Loss of Calcium (Ca)

Homeostasis

• Normal cell

– High extracellular Ca, Low intracytosolic

•intracellular Ca sequestered in

mitochondria (mito.) & endo plasmic
reticulum (ER)

•gradients maintained by membrane

associated energy (ATP) dependent
ATPases

Loss of Calcium (Ca)

Homeostasis

Cell Injury

• Cell injury (ischemia, certain toxins)
• Influx Ca into cytosol from extracellular

space, mitochondria & endoplasmic
reticulum

• Activates intracellular enzymes  cell injury

– proteases  damage membrane &

cytoskeleton proteins

– phospholipides  damage membranes
– ATPases  deplete ATP
– endonucleases  damage DNA

Membrane Damage

• Loss of membrane selective

permeability

– Ca influx  enzyme activation 

• Causes

– ATP depletion

• effect energy dependent ATPases

– Direct damage

• bacteria, viruses, complement, neutrphile

enzymes & ROS, lymphocytes porphorins,
physical & chemical agent

Irreversible Mitochondrial

Damage

• Causes

– inc. cytoplasmic Ca, phospholipases, ROS …

• Formation of high conductance channels

in inner mitochondrial membrane
(mitochodrial permeability transitions)

– prevent maintenance of proton motive force

(potential) across membrane  cessation of

oxidative phosphorylation

• begins at reversible change becomes irreversible

Cell Injury

Reversible vs. Irreversible Injury

• Cell injury is a continuum, and it is not

possible to precisely identify the exact
point at which injury becomes irreversible

– Certain ultrastructural & light microscopie

changes are associated with each type of
infury

• When irreversible injury occurs, the cell

undergoes

necrosis

, which is the light-

microscopie hallmark of cell death

Cell Injury

Reversible vs. Irreversible Injury

• Permanent organ injury is generally

associated with cellular necrosis

• The cellular response to persistent

sub-lethal injury reflects adaptation
of the cell to a hostile environment

– these changes are usually

reversible

discontinuation of the stress

Manifestation of reversible Cell

Injury (Degeneration)

Electron Microscopic Changes

• Cellular swelling (light microscopy)
• Endoplasmic reticulum swelling
• Ribosome detachment endoplasmic

reticulum

• Mitochondria swelling
• Blebs at cell surface
• Loss at microvilli
• Early clumping of nuclear chromatin

Reversible Cell Injury

Cell swelling – Light Microscopy

Normal

epithelium

Cellular Swelling

Reversible Cell Injury

Electron Microscopy

(EM)

Normal epithelium

Apical blebbing loss of microvilli

Manifestation of Irreversible

Cell Injury (Necrosis)

• Disruption of plasma & cell membranes (EM)
• Rupture of lysosomes (EM)
• Pyknosis – nuclear shrinkage &

condensation (EM & light)

• Karyorrhexis - nuclear shrinkage &

fragmentation (EM & light)

• Karyolysis – nuclear dissolution (EM & light)
• Mitochondrial Dense Bodies (calcium) (EM)

Irreversible Cell Injury

• Irreversible injury is classified into

two types depending on the
underlying mechanism

–

necrosis

apoptosis

– both look similar under the light

microscope

•can be distinguished by electron

microscopy

Ischemia – Reversible Cell

Injury

• Irreversible cell injury is consistently

charakterized by

– Irreversible mitochondrial damage

causing severe ATP depletion

– Severe disruption of membrane function

Mechanisms Reperfusion

Injury

• Increased production of ROS by

parenchymal cells, endothelium &
infiltrating leukocytes due to

– Oxidases derived from parenchyma,

endothelial cells & lekocytes

– Cells biochemically damaged by anoxia

• incomplete reduction of O

by mitochondria

• compromised radical scavenging system

Free Radicals

• Chemical species (usually O

) with a

single unpaired electron in an outar

orbit

• Unstable configuration  reactions with

adjacent molecules (proteins, lipids,

carbohydrates, nucleid acids)

• Can initiate autocatalytic reactions

– react with other molecules & convert them

into free radicals

– chain reaction pf auto-propagation

Formation of Free Radicals

• Cellular respiration (byproduct)

– O

mitochondria O

•- SOD H

• Activated PMNs (neutrophils)during

inflammation  O

•-

• Transition metals (Fe, Cu) in intracellular

reactions donate or accept free electrons

– H

+ Fe

 Fe

+ OH = OH

• Fenton reaction

Formation of Free Radicals

• Nitric Oxide (NO)

– produced by endothelial cells, macrophages,

neurons …

– can act as a free radical or be converted to

• ONOO

, NO

• & NO

• Radiant energy (UV light, ionizing radiation)
• H

O  OH• + H•

• Enzymatic metabolism of chemical or drugs

– CCl

P-450 oxidase CCl

•

Effect of Free Radicals

• Lipid peroxidation of membranes

– double bonds of unsaturated fatty acids

of membrane lipids are attacked by ROS

(especially OH•)  H

 autocatalytic

reaction  severe damage

Effect of Free Radicals

• Oxidative modification of proteins

– oxidation of amino acid residues on protein

side chains  protein-protein x-linkages

– oxidation of amino acid residues on protein

backbone  fragmentation

– oxidative modyfication enhances protein

degradation by peroxisomes  loss of
crical enzymes

Removal of Free Radicals

• Spontaneous degradation
• Antioxidants

– block formation or inactivate ROS
– Vit. E & A, ascorbic acid, glutathione

• Metal binding proteins

– transferrin, ceruloplasmin, lactoferin

Removal of Free Radicals

• Enzymes

– Catalase (within peroxisomes)

• 2H

 2H

O + O

– Superoxide dismutase (SOD)

• 2O

• +2H  H

+ O

– Glutathione peroxidase

• H

+ 2GSH  GSSG = 2H

• 2OH• + 2GSH  GSSG + 2H

Acetaminophen (Tylenol)

Toxicity

• Large doses  depletion GSH

– accumulation of ROS (H

, OH•) 

oxidative damage, lipid peroxidation

• major cause of injury

– accumulation toxic metabolite

• destroys nucleophilic macromolecules, binds

proteins & nucleid acids

• Massive hepatic necrosis 3-5 days after

ingestion

– can be reduced by antuoxidant adminitration

Reversible Cell Injury

(Degeneration)

Electron microscopie change

• Endoplastic reticulum swelling
• Ribosome detachment endoplasmic

reticulum

• Mitochondria swelling
• Blebs at cell surface
• Loss of microvilli
• Early clumping of nuclear

Reversible Cell Injury

(Degeneration)

Light Microscopy

• Cell swelling (hydropic change /

vacuolar degeneration)

– Cells incapable of maintaining ionic /

fluid homeostasis

– First manifestation of almost all forrms of

cell injury

– Microscopie

•swollen cell w / small clear vacuoles in

cytoplasm

– distended pinched-off ER

Reversible Cell Injury

(Degeneration)

Light Microscopy

• Fatty change

– Hypoxic, metabolic & toxic injury in cells

involvedon fat metabolism

• hepatocytes, myocardial cells

– Microscopie

• small & large lipid vacuoles in cytoplasma

Document Outline