Cellular Pathology and its Morphology

Cellular Pathology

§  Pathology includes study of etiology (what initiates a process), pathogenesis (mechanism), morphology (how it’s recognized) and functional consequences (how it produces disease).
§  The three fundamental processes of cellular pathology are cell injury, cell death and cellular adaptation.  In response to stressors, cells may adapt or die/be injured. 
§  The etiology of cell injury may be extrinsic or intrinsic, including hypoxia, physical/chemical agents, drugs, infection, immunologic reactions, genetic, or nutritional problems.
§  Hypoxia is the reduction or absence of normal oxygen supply.  It may be a result of ischemia, which is the reduction or absence of blood supply.  They most often go together, but ischemia alone can be damaging from a lack of trophic substances or accumulation of toxins, and hypoxia alone can still be damaging (ex: anemia, pulmonary disease, cyanide poisoning).
§  Infarction is the process in which a portion of a tissue dies as a result of ischemia. An infarct is the end result of this process.  They may be white or red (still some blood supply to the dead tissue), but both result from the same underlying mechanism.
§  The mechanisms by which ischemia causes cell death are inter-dependent and synergistic.  Toxins often influence one of these mechanisms.  They include: 
o   Decreases in ATP – oxidative phosphorylation shuts down first in ischemia.  Pumps stop running and cells/organelles swell and have blebs, glycolysis lowers pH and chromatin clumps, protein synthesis decreases and lipids accumulate since proteins aren’t available to export lipids as lipoproteins.  These early changes are reversible. 
o   Increased intracellular Ca, which is critical to homeostasis.  Many enzymes only function within a very narrow range of [Ca].  Ischemia inactivates calcium pumps, resulting in calcium activation of enzymes and increased membrane breakdown along with decreased membrane synthesis. 
o   Membrane damage (considered the point of no return)
o   Reactive oxygen species – endogenous or exogenous free radicals.  Reperfusion of an ischemic area can add to ischemic damage, likely by sudden calcium influx or exposure to free radicals from an influx of inflammatory cells.  We have some level of antioxidant defense from vitamins C and E, glutathione peroxidase, catalase and superoxide dismutase.  But oxidative stress can result from imbalance between ROS and antioxidants.  Oxidative stress is associated with aging, diabetes, atherosclerosis, Alzheimer, etc.
§  Cell injury becomes irreversible most quickly in neurons, followed by myocardium and hepatocytes, and most slowly in skeletal muscle. 
§  Reversible cell injury is characterized by cell swelling, vacuolar degeneration, and lipid deposition (especially in the myocardium and liver).
§  Irreversible injury:  necrosis – the morphological changes in the nucleus and cytoplasm occurring after death in a living tissue, regardless of the cause of injury.  By the time necrosis is observed, the cell is dead.  This need not occur at the tissue level.
o   Features of necrosis include:  eosinophilia due to loss of RNA/ribosomes and denatured protein, nuclear changes (small-pyknosis, broken apart-karyorrhexis, or dissolved-karyolysis), INFLAMMATION.  The inflammation is the big distinguishing feature, and it usually occurs about 8 hours after cell death.  Thus, it won’t occur if the cell dies and organism also dies at the same time. 
§  Types of Necrosis:
o   Coagulative:  Results from ischemic cell death, and is seen in most tissues except for the brain.  In this type of necrosis, the tissue architecture is retained.  You typically see ‘tombstones’ of hyper-eosinophilic cells.  It typically resolves by scar formation.
o   Liquefactive:  Characterized by complete hydrolysis of dead cells, resulting in a loss of tissue architecture and usually resulting in a cyst or cavity.  This is the usual response to infarction in the brain. 
o   Abscess:  Liquefactive necrosis resulting from localized bacterial/fungal/parasitic infections.  It usually has lots of neutrophils within the abscess (pus=dead neutrophils and debris) which are the source of hydrolytic enzymes.  It often requires surgical drainage, since vasculature is commonly damaged and antibiotics won’t be delivered effectively.
o   Caseous (cheese-like): Characteristic of TB and fungal infections.  It has a center of cheese-like necrosis surrounded by a rim of inflammatory cells (all together called a granuloma).
o   Fat:  Common in the pancreas (from release of pancreatic enzymes) and breast (from minor trauma).  Membrane lipids are digested into FFAs, and combine with calcium (saponification) to form chalky white deposits.  May mimic a carcinoma clinically.
§  Cellular adaptations include hyperplasis, hypertrophy, atrophy, and metaplasia. 
§  Hyperplasia is an increase in the number of cells in a tissue/organ.  In hyperplasia, you see dividing, mitotic cells.  Hyperplasia may be physiologic, such as in lactating breasts.  But is can also be pathologic, as in endometrial hyperplasia with unopposed estrogen stimulation that results in prolonged cycles with menorrhagia (heavy bleeding).  Another example of hyperplasia is in BPH. 
§  Hypertrophy is an increase in individual cell mass, and is usually reversible.  In benign prostatic hyperplasia, bladder muscle hypertrophies as a results of needing to push the urine out with more force.  Other examples of pathologic hypertrophy may be hypertrophy of the heart in someone with aortic valve stenosis or chronic hypertension.  Hypertrophy may results from greater workload, as above, but also from increased levels of hormones (anabolic or in pregnancy, etc).  Genetic mutation in the myostatin gene has been shown to cause muscle hypertrophy in animals. 
§  Atrophy is cellular shrinkage due to a loss of substance, and may result from disuse, denervation (polio), ischemia, starvation (protein-calorie malnutrition, or marasmus), or absence of endocrine stimulation.  Ex:  menopause can result in atrophy of cells making up endometrial glands.  Ex:  cachexia, a wasting associated with cancer, AIDS and other chronic inflammatory diseases.
o   Cellular atrophy may culminate or be accompanied by progressive cell loss, and if enough occurs an organ or tissue may shrink.  In these cases, atrophy describes both cell shrinkage and cell loss. 
§  Metaplasia is the reversible replacement of one differentiated cell type by another differentiated cell type.  It can be considered an adaptive substitution by cells that can better withstand an adverse environment.  In smokers, you see squamous metaplasia where respiratory epithelium is replaced by stratified squamous cells.  Stem cells at the basement layer differentiate into squamous cells.  Metaplastic epithelium may undergo neoplastic progression to dysplasia (not yet cancer, but cells lose normal architecture on the way there), and ultimately to neoplasia (cancer w/ clonal cells having a genetic mutation).  Not all metplasias become cancers, but if the stimulus persists, they may. 
§  Cells may accumulate endogenous or exogenous substances (lipids, protein, glycogen, carbs, minerals, pigments, etc). 
o   Pigment accumulations:  anthracosis (accumulation of dark carbon pigment in city dwellers) or lipofuscin (wear and tear pigment where you have lots of cell turnover) are examples of benign pigment accumulations.
o   Intracellular lipid accumulation:  Fatty change (steatosis) is potentially reversible.  It most commonly occurs in the liver, and is caused most commonly by obesity or alcoholic liver disease.  The liver is typically enlarged and rather than red, it appears yellow/white. 
§  Cell death is not always pathologic; apoptosis is normal in embryogenesis, immune cell differentiation, menstruation, etc.  Apoptosis may be pathologic too, resulting from DNA damage (w/ p53 as a principal mediator), viral infection or CD8 T cell mediated injury. 
o   Apoptosis is mediated by caspases, cysteine protesases that require activation.  Bcl-2 is an anti-apoptotic protein, and its family contains both pro and anti apoptotic factors.  P53 stops cell division in response to DNA damage in order to facilitate recovery, and if recover fails it initiates apoptosis. 
o   Morphologically, apoptosis is characterized by nuclei breaking into apoptotic bodies.  This occurs in single cells with apoptosis, whereas necrosis tends to occur in large regions of an organ.  In apoptosis, DNA is systematically fragmented and shows as a ladder on a gel, whereas necrotic cell death breaks it down at random, resulting in a smear. 
o   Basically, apoptosis is usually physiologic, occurs in single cells, fragments DNA between nucleosomes, and produces apoptotic bodies WITHOUT inflammation.  Necrosis is usually pathologic, occurs in groups of cells, randomly fragments DNA and shows swelling, degeneration, and inflammation. 
o   Inhibition of apoptosis facilitates tumorigenesis.  HPV blocks p53 and apoptosis, and can result in squamous cell carcinoma of the cervix.  Constitutive activation of Bcl-2 blocks apoptosis and facilitates follicular lymphomas.