CELL INJURY.......pathology

[chetnarayan]

CELL INJURY
 Etiology (cause)
 etiologic agent
- An etiologic agent is fundamental cause of the disease. Without it that disease will not occur. Although the circumstances may modify the severity of the disease, by themselves, they do not cause a disease.
- An etiologic agent can be a quantitative (increase, decrease, absence) or qualitative (foreign substance, "poison") problem for a cell. Excessive water drinking can lead to water intoxication. Botulinum toxin or cyanide can be lethal in very small doses.
Circumstances
- Circumstances are all the factors (except the etiologic agent) that constitute the setting in which a disease occurs. These will classically be the relevant external (environmental) factors. As well, they include the biological factors operative in the affected person (the patient).
Sex
Age (fetus, child, very old adult, post menopausal woman)
Nutritional status
Otherwise abnormal (diabetic, immunocompromised)
- Pathogenesis
- Sequence of events in response of cells or tissues to etiologic agent.
The etiologic agent must make contact with the body and except for surface injury, must penetrate the body. That penetration, the pathways through the body and the significant points (10,20) of damage and the overall body response(s) constitute the disease. As such, pathogenesis is the study of how the disease comes to be. All of the above, regardless of outcome (none to trivial to severe disease; full or partial recovery or death) is the natural history of a disease.
- Morphologic changes in disease
- Structural changes (gross and microscopic)
- Structural changes are a continuum from ultrastructural (transmission EM of swollen mitochondria) to gross (hypertrophied left ventricle). They should be understood as stages of a disease, (stages of a bacterial pneumonia; "development" of a neoplasm). Equally important, these structural changes should be integrated with more basic science data primarily physiology (organ function studies) and biochemistry (lab medicine). Lab Medicine in the broadest sense includes diagnostic microbiology, diagnostic immunology, hematology, and grouped tests on a fluid (urine, CFS). Molecular diagnostics, cytogenetics and genomic (gene analysis) studies are current further developments.
- Two other types of structural change should be noted. Firstly, there is a the direct observation of a lesion (skin, various endoscopies, colposcopy, ophthalmoscopy). Secondly there is the entire field of diagnostic radiology which identifies structural (and functional) abnormalities; these abnormalities are then further evaluated as either a general pathologic process or a specific organ pathologic disease.
Functional changes
---- dysfunction
- pathophysiology failure    acute / chronic
- Proper or improper organ function generally represents the illness or disability aspect of a disease. Pathophysiology so understood is the scientific basis of clinical medicine. Organ failure is critical and although when acute it may be correctable, when chronic it generally indicates the "end- stage" of a disease. Dysfunction is used to cover particular pathophysiologic conditions that do not cause organ failure.
- clinical features - signs and symptoms
- All of the above constitute the scientific basis of clinical medicine. The signs and symptoms relate directly to the structural and functional pathology. Knowledge of the etiologic agent and circumstances are important in diagnosis and critical in prevention. Pathogenesis describes the pathologic process and stages of a disease and is particularly important in early diagnosis. The natural history of a disease (five year survival of a neoplasm, outcome of a pneumonia, evolution of childhood asthma) is central to therapy so as to evaluate the true benefit of any treatment.
Causes of Cell Injury
- Type of injury, (as below) duration, severity (dose)
- Type, state and adaptability of injured cell (quiescent hepatocyte, bone marrow stem cell, rapidly proliferating skin basal cell, cardiac myocyte) - Genetic Derangements
- Abnormal genome (inherited genetic abnormality); acquired genetic abnormality (as in cell injury, spontaneous mutation). Genetic apparatus injury can either be the very particular genome damage so as to alter specific genes or the global nuclear injury with damage to "all" nuclear contents.
 Physical Agents
 mechanical trauma, temperature, electrical injury, atmospheric pressure, radiation
 Chemical Agents
 any chemical depending on dose (recall water intoxication)- certain chemicals (generally water soluble) act directly on cell (molecule or organelles)
- many chemicals (particularly lipid-soluble) are not biologically active but must be converted to reactive toxic metabolites
- drugs (therapeutic; abuse; accidents; poisons)
- nutrition (special case)
- nutritional injury although basically a type of chemical injury is often treated as a separate category. Although there can be very specific nutritional deficiencies (Vitamin C, Folic acid, calcium, iodine) the major human nutritional diseases are protein/calorie deficiencies (starvation) as seen in underdeveloped countries and eating disorders (anorexia nervosa, bulimia nervosa, obesity) in developed countries.
- Infectious (microbiologic) agents
- Various groups of microbiologic agents (virus, bacteria, fungi, etc)
- Dynamic role of host factors
- Diminished delivery of nutrient to cell
- diminished nutrient (hypoxia, hypoglycemia, iron) in circulation (and tissue- cells)
- diminished to absent circulation (ischemia); this obviously "cuts off" all nutrients but in this setting oxygen deprivation is still the most significant cause of cell injury.
- Immunologic Reactions
- Aberration of normal response
- Auto-immune disease
- Immunologic reactions are an integral part of body defense mechanisms, (inflammation, acquired immunity) Aberrations (increase, decrease, qualitatively abnormal) may be an important part of a disease. In some instances the abnormal immune response may be the disease. Such would seem to be the case in autoimmune disease.
- Primary diseae (there are inherited genetic immunodeficiencies with subsequent (mainly infectious) diseases. These can be classified as genetic and/or immunologic in nature).
Mechanisms of Cell Injury
Four vulnerable intracellular systems
1. maintenance of integrity of cell membrane
2. aerobic respiration
3. synthesis of enzymatic and structural proteins
4. preservation of integrity of genetic apparatus of cell
These are the major "up front" structural and/or biochemical systems damaged. There is a wave of intracellular injury such that eventually all cell elements are injured. In certain diseases specific organelles (cytoskeleton, lysosomes, smooth ER) are the major site of injury.
Four common biochemical themes in mediation of cell injury
1. defects in membrane permeability
early  selective
2. ATP depletion
3. Oxygen and oxygen-derived free radicals
(superoxide, hydrogen peroxide, hydroxyl radicals)
4. intracellular calcium increase (loss of calcium homeostasis)
5. One and two relate directly to one and two above (vulnerable intracellular systems). Attention is called to early selective defects in membrane permeability. Such a state has been called the "leaky" cell. Various cytoplasmic chemicals leak out of such a cell. Some of these chemicals (particularly enzymes) are important clinical markers for injured cells (early myocardial ischemia). Number three is a very important mechanism of cell injury. It occurs in various settings (reperfusion, chemical and radiation injury, inflammatory damage). Four is important as significant intracellular calcium movement (and damage) associates with irreversible cell injury.

The process (and progression) of cell injury is a continuum and it is difficult to identify a "point of no return" when irreversible cell injury begins. A schema (below) will deal with the data on reversible/irreversible cell injury, but here we will establish the broad overview of the process.
Cell Injury Reversible - Full recovery
- New steady state (The cell does not return to normal. This can be defined structurally as:
1) a list of adaptations
2) change localized to an intracellular organelle
3) an intracellular accumulation of a substance. The new state can also be defined functionally and/or biochemically. Such a cell may have a more limited range of reponses and may be more vulnerable to injury than a normal cell.
- Adaptations (structural)
- atrophy (hypoplasia), hypertrophy, hyperplasia (physiologic, pathologic), metaplasia, dysplasia, neoplasia
- Subcellular alterations and cell inclusions
- Intracellular accumulations
- Pathologic calcification (is fitted in here as it is a superimposed cellular (and extracellular) injury).
Irreversible cell death Apoptosis - Coagulation
Necrosis  - Liquefaction
- Caseous
- Enzymatic Fat
- Necrosis is the sum of structural changes seen in cell death in living tissues. Almost always a large number of confluent cells are affected. (often can be seen grossly). The biochemical cellular basis for cell necrosis is 1) protein denaturation, and 2) enzymatic digestion. Protein denaturation predominates in coagulation necrosis, whereas enzymatic digestion predominates in liquefaction necrosis. The enzymes may come from the dead cells themselves (autolysis) or reacting inflammatory cells (heterolysis). Apoptosis is a normal programmed cell death that involves single cells or small clusters of cells,(generally physiologic; can be pathologic). Physiologically it occurs in cell destruction during embryogenesis, intestinal epithelium turnover, and involution of the endometrium. Pathologically it is noted in viral diseases and cell-mediated immunity.
Structural nuclear changes in cell death.
Although these could be fitted into the irreversible cell injury ischemia, they are easier to deal with here. They are best appreciated visually on light microscopy.
1. Karyolysis - dissolution of chromatin (fading)
2. Karyorrhexis - fragmentation of chromatin
3. Pyknosis - condensation of chromatin (shrunken mass)
4. "Loss" of nucleus in dead cell - 1 to 2 days Reversible Cell Injury Aerobic respiration (oxidative phosphorylation by mitochondria)
 ATP  cellular swelling (hydropic change)(cell K ; cell NA )
Anaerobic glycolysis (Glycogen  , lactic acid )
 Intracellular pH
Cytosolic free CA; detachment of ribosomes (polysomes  monosomes  protein synthesis)
Cell membrane permeability; mitochondrial swelling
Irreversible Cell Injury
Notes on mechanism of irreversible cell injury ("point of no return")
- progressive loss of membrane phospholipids
- cytoskeletal abnormalities
- toxic oxygen radicals
- toxic oxygen radicals produce damage by:
- lipid peroxidation of membranes
- lesions in DNA (single strand breaks - cell killing, malignant transformation)
- cross linking of proteins ( degradation, loss of enzymatic activity)
- lipid breakdown products
- severe vacuolization of mitochondria
- large flocculent CA rich densities in mitochondrial matrix (massive intracellular CA influx)
Subcellular alterations in cell injury
- Lysosomes; hereditary lysosomal storage disease
- Increased volume of smooth endoplasmic reticulum
- Mitochondrial alterations (size, shape in general or of cristae)
- Cytoskeletal abnormalities (Mallory body, neurofibrillary tangle)
Intracellular Accumulations
1. Fluid (water; hydropic change)
2. Normal cellular constituent (rate of intracellular entry of involved chemicals, rate of formation, rate of metabolism, rate of secretion and/or excretion)
A) Lipid
- increased intracellular fat (mostly triglyceride)
called steatosis or fatty change (generally in liver)
- cause of triglyceride increase
1) fatty acid entry into cells
2) excess production of fatty acids from acetate
3) reduced oxidation of fatty acids
4) increased retention of triglycerides because of inadequate complexing with apoprotein molecules to form lipoproteins
5)  release of lipoproteins from hepatocytes
B) Proteins and proteinaceous products
- globular and filamentous proteins
- Mallory’s alcoholic hyaline (Mallory body)
- Neurofibrillary tangle (Alzheimer’s)
- Abnormal ALPHA-1-Antitrypsin
C) Glycogen and carbohydrates
- Intracellular glycogen in diabetes mellitus
3. Abnormal substance
- exogenous (mineral, infectious product)
- endogenous (abnormal metabolism, amyloid, pigment (hemosiderin))
Calcification (pathologic)
- dystrophic
- occurs in dead or dying tissues
- can occur with normal serum calcium
- deposition can be intracellular or extracellular
- metastatic
- may occur in normal tissue when there is serum hypercalcemia
- deposition in interstitial tissue - gastric mucosa, lungs, kidneys, vasculature
Hyalin Change
- Hyalin is a histopathologic term. On light microscopy with an hematoxylin and eosin stain, it is pink-orange and amorphous (glassy, no fibrils). Hyalin is an umbrella term. On biochemical and/or analytical (interference, polarizing) microscopy it may be many different entities which include a "family" of amyloids.

Thanx.
Source......... books & internet
Never think this is my own compose...... i am not a medical proffesor