Fatty Change (p11,17,18) (Steatosis) - occurring in hypoxic injury and various forms of toxic or metabolic injury, is manifested by the appearance of lipid vacuoles in the cytoplasm. It is a less universal reaction, principally encountered in cells participating in fat metabolism, such as:
•	Liver (Hepatocytes) (Fatty change most often found in the liver) May not affect the gross appearance. With accumulation, the organ enlarges and becomes progressively yellow until it may weigh 3-6 kg and appear bright yellow, soft and greasy.
•	Heart (Myocardial cells) - Found in the form of small droplets. In hypoxia, it appears as bands of yellowed myocardium alternating with bands of darker, red-brown, uninvolved heart “tigered effect”
•	Skeletal muscle
•	Kidney
Fatty change refers to any abnormal accumulation of triglycerides within the parenchyma cells. It is an indicator of reversible injury, and is sometimes encountered in cells adjacent to those that have undergone necrosis.
 4 Main mechanisms for fat accumulation in cells:
1.	Increased conversion of fatty acids to triglycerols - Alcohol
2.	Increased perpherial mobilization of free fatty acids and uptake to cell - Diabetes Mellitus
3.	Reduced oxidation of triglycerides to acetylCoA - Hypoxia & Alcohol
4.	Deficiency of lipid acceptor proteins(apoproteins), preventing export of formed triglyerides - protein malnutrition & genetic disease
Alcohol abuse is the most common cause of fatty change in the liver in industrialized nations.

Accumulation of lipids within macrophages results in foam cells. Macrophages become filled with lipids from phagocytes of necrotic debris or abnormal lipids. (P18)

Russell bodies are found in the RER of some plasma cells and they are rounded, eosinophilic accumulations of newly synthesized immunoglobulins. (p18)

Glycogen storage disease are a type of genetic disorder. In these diseases, enzymatic defects in the synthesis or breakdown of glycogen result in massive stockpiling, with secondary injury and cell death.(p19) Diabetes mellitus is the rime example of a disorder of glucose metabolism.

Endogenous Pigments
Lipofuscin aka lipchrome, aging pigment, or “wear-and-tear” - derived through lipid peroxidation of polyunsaturated lipids of subcellular membranes. It is not injurious to the cell but is important as a marker of past free radical injury. It is an insoluble, brownish-yellow granular intracellular material that accumulates in a tissues such as, heart, liver, and brain as a function of age or atrophy.  It is prominent in patients with severe malnutrition and cancer cachexia. It is usually accompanied by organ shrinkage (brown atrophy). Liver spots are an accumulation of lipofuscin. 
Melanin - brown-black pigment formed by melanocytes when the enzyme tyrosinase catalyzes the oxidation of tyrosine to dihydroxyphenalanine. Synthesized by only melanocytes which are found in the epidermis, and acts as an endogenous screen to UV radiation. Adjacent basal keratinocytes and dermal macrophages can accumulate the melanin pigment.
Hemosiderin - hemoglobin derived, golden-yellow to brown and accumulates in tissues when there is a local or systemic excess of iron. Iron is normally carried by transport proteins (transferrin) and stored in cells with the protein apoferritin to form ferritin micelles. Although usually pathologic, small amounts of hemosiderin are normal in the mononuclear phagocytes of bone marrow, spleen, and liver where there is extensive red cell breakdown. 
Common bruise is an example of localized excess of iron which is a result of a hemorrhage accompanying severe vascular congestion.
Phases of bruising:
1.	Macrophages phagocytize the red cell debris
2.	Hemoglobin is then catbolized by lysosomes with accumulation of the heme iron
3.	The original red-blue shade of hemoglobin is transformed to green-blue by local formation of biliverdin (green bile) and bilirubin (red bile)
4.	The iron ions of the hemoglobin are then accumulated as golden-yellow hemosiderin.

Atrophy -  shrinkage in the size of the cell by loss of cell substance.  When a number of cells are involved, the entire tissue or organ diminishes in size. Although the cells may have diminished function they are not dead. Upon relief of the stress on cells, cell function and size begins to increase. 
Causes of Atrophy
•	Decreased workload
•	Loss of innervation
•	Diminished blood supply
•	Inadequate nutrition
•	Loss of endocrine stimulation
•	Aging
Hypertrophy - increase in size of cells and increase in size of organ and function. No new cells just larger cells. Cells increase by synthesis of more structural proteins and organelles. Adaptive hypertrophy is exemplified by skeletal muscle in the weight lifter or cardiac enlargement in the chronically hypertensive patient. They undergo hypertrophy because they can’t adapt to increased demands by mitotic division to generate more cells to share the work. Triggers that change the gene expression in the heart are mechanical (stretching) and trophic (activation of alpha adrenergic receptors). 
Physiological growth of the uterus during pregnancy involves both smooth muscle hypertrophy and hyperplasia.
Hyperplasic - increase in the number of cells in an organ or tissue by cell division.  Skeletal muscle, cardiac muscle, renal epithelial cells, and nerve cells do not undergo hyperplasic because these cells do not divide. 
Physiological
•	Hormonal - female breast at puberty and uterus at pregnancy
•	Compensatory - removal of kidney results in hyperplasic of other kidney
Pathological is the result of hormonal or growth factor stimulation
•	Graves Disease
•	Endometriosis
Metaplasia - reversible change in which one adult cell type (mesenchymal or epithelial) is replace by another adult cell type. Cells sensitive to stress with go metaplasia in order to withstand the adverse environment.
Examples:
•	In normal ciliated columnar epithelial cells of the trachea and bronchi are focally or widely replaced by stratified squamous epithelial cells. A deficiency in vitamin A may also induce squamous metaplasia in the respiratory epithelium. 
•	In the urinary bladder the normal transitional epithelial cells are replaced by stratified squamous epithelial cells in response to chronic irritation by bladder infections.
Involution -  reduction in the number of cells in the form of physiological organ atrophy, through programmed cell death (apoptosis)

Apoptosis is a relatively distinctive mode of cell death that should be differentiated from coagulation necrosis. It is responsible for the programmed cell death in several important physiological process, including: 
•	Destruction of cells during embryo genesis
Implantation
Organogenesis
Developmental involution
•	Hormone Dependant involution such as, endometrium(menstruation) and lactating breast (after weaning), prostate (after castration)
•	Cell deletion as in cell death in tumors
•	Deletion of auto reactive T-cells in the thymus, cytokine-starved lymphocytes, or cytotoxin T cells.
Apoptosis is centered on the synthesis and activation of a number of cytosolic proteases. This activation can be triggered by a growth factors, specific receptors, of initiation of programmed cell death during embryogenesis.

Chediak-Higashi syndrome  is a microtubule polymerization deficiency where the lysosomes do not fuse with phagosomes and leukocytes can’t destroy bacteria.

Immotile cilia syndrome are defects involving the organization of microtubules that cause sterility be inhibiting sperm motility as well as immobilizing cilia of the respiratory epithelium. (p15)

Dystophic Calcification
Occurs in nonviable or dying tissue
Inevitable when atherosclerosis is present and may be due to previous cell injury.
Often a cause of organ dysfunction

Metastatic Calcification
Occurs in normal tissue if hypocalcaemia is present
Caused by primary endocrine dysfunction or because of advanced renal failure.
Calcium deposits do not generally cause clinical dysfunction 
(p20)

Hypocalcaemia may be seen with metastatic calcification, It may also arise in advanced renal failure, where the resulting phosphate retention leads to secondary hyperparathyroism.

Cell injury can be caused by:
•	Hypoxia - oxygen deficiency impinges on aerobic oxidative respiration. Hypoxia result from:
Ischemia is the most common cause 
inadequate oxygenation of the blood (cardio-respiratory failure)
loss of oxygen-carrying capacity of the blood (anemia or carbon monoxide poisoning)
•	Physical Agents -
	 Trauma
	 extreme temperatures
	 Radiation
	 Electric Shock
	 Atmospheric pressure
•	Chemicals and Drugs
Glucose, oxygen, or salt if sufficiently concentrated can derange the osmotic environment that injury or cell death results.
Poisons may alter membrane potential, osmotic homeostasis, or integrity of an enzyme or cofactor.
•	Microbiologic Agents - viruses, tapeworms, bacteria, fungi, rickettsiae, parasites.	
•	Immunologic Reactions - anaphylactic reactions and autoimmune diseases.
•	Genetic Defects - Downs Syndrome, Sickle cell anemia
•	Nutritional Imbalances - vitamin deficiencies, diabetes mellitus, pickwickian syndrome, atherosclerosis (animal fats)
•	Aging 

The main targets for cell injury are 
1.	Cell membrane
2.	Mitochondria
3.	Cytoskeleton
4.	Cellular DNA

The first effect of hypoxia is on the cell’s aerobic oxidative respiration (oxidative phosphorylation by the mitochondria). As a result, of reduced oxygen, the intracellular generation of ATP is reduced. (p6)

A reduction or depletion of intracellular cAMP results in decrease in production of ATP(?)

Increased free calcium in the cell cytoplasm causes cell damage through the activation of:
•	Protein Kinase (phosphorylation of proteins)
•	Phospholipases (promoting membrane damage)
•	Proteases (catabolizing structural and membrane proteins)
•	ATPases (accelerating ATP depletion)
•	endonucleases (fragmenting genetic material) (p6)

A central factor in the pathogenesis of irreversible cell injury is cell membrane damage

Maturation of granulocytic leukocytes is reflected in free radicals which are,
chemical species with a single un-paired electron in an outer orbit

Free radical formation through the Fenton reaction involves transition metals such as copper and iron to accept or donate free electrons during certain intracellur reactions. 
Fe++  +   H2O2          Fe+++   +   OH.  + OH-
Since most intracellular free iron is in the Ferric Fe+++   state, it must first reduce to ferrous Fe++  to participate in Fenton reaction. The reduction is enhanced by superoxide ion.

Superoxide dismutase, catalase, and vitamin E degrade free radicals. The rate at which free radicals are inherently unstable and decay spontaneously is increased by the action of Superoxide dismutase. It rapidly breaks down super oxide in the presence of water into oxygen and hydrogen perioxide.
Catalase directs the degradation of hydrogen peroxide. 
Vitamin E may either block free radical formation or scavenge them once they have formed. (p11)

Carbon tetrachloride and acetaminophen can cause cell damage by converting to toxic free radicals in the liver. The free radicals cause auto catalytic membrane phospholipid peroxidation with rapid breakdown of the endoplasmic reticulum.  In less than 30 minutes, there is a decline in hepatic protein synthesis of both enzymes and plasma proteins; within 2 hours, swelling of SER ad dissociation of ribosomes for the RER  has occurred. There is reduced lipid export from the hepatocytes, contributing to their inability to synthesize apoprotein to complex with glycosides ad facilitate lipoprotein secretion. The result is fatty liver poisoning. Mitochondria injury follows with diminished ATP resulting in defective ion transport and progressive cell swelling. Membrane is damaged by baldheaded and the end result is a massive Ca influx and cell death.

Removal of a portion of the liver results in hyperplasic by stimulation from polypeptide growth factors. (p22)

Necrosis is a sequence of morphologic changes that follow cell death in living tissue. Morphologic appearance of necrosis is the result of enzumic digestion of the cell and denaturation of proteins. (p12)

Caseous necrosis is most often in foci of tuberculosis infection. The term caseous is derived form the cheesy, white gross appearance of the central necrotic area. The tissue architecture is completely obliterated.
Fat necrosis is fat destruction typically occurring following pancreatic injury. It results for the release of activated pancreatic enzymes into adjacent parenchyma or the peritoneal cavity. This occurs in acute pancreatic. Activated pancreatic enzymes escape form acinar cells and ducts, liquefying fate cell membranes and hydrolyzing the triglyceride esters contained within them. The released fatty acids combine with calcium to produce chalky white areas., which enable the surgeon to identify this disease on simple inspection.
Gangrenous necrosis is ischemic coagulative necrosis (frequently of a limb) when there is superimposed infection with a liquefactive component this lesion is called “wet gangrene”.
Coagulative necrosis implies preservation of the basic structural outline of the coagulated cell or tissue for a span of days. Presumable the injury or increasing acidosis denatures not only the structural proteins but also the enzymic proteins blocking cellular proteolysis. Myocardial infarctions is a prime example in which acidophilus, coagulated, anucleate cells may persist for weeks. The general tissue architecture is characteristic of hypoxic death of cells in all tissues except the brain.
Fibrinoid necrosis describes the appearance of arteries in cases of vasculitis and 
hypertension when fibrin is deposited in the damaged necrotic vessel wall.

Hypoxic death of the cells in the CNS produces liquefactive necrosis.
Pathology could be defined as the specialty that 
•	employs morphological techniques to explain symptoms and signs
•	determine the cause of death
•	guide therapy
•	predict the evolution of disease
Pathology is also the bridging discipline involving both basic science and clinical practice and is devoted to the study of the structural and functional changes in cells, tissues, and organs that underlie diseases.

The father of modern pathology is Rudolph Virchow (1821-1902)His tenet was that the ultimate explanation of normal and abnormal biological facts lie within the cell.

The etiology of disease is the cause of it.

Karyolysis the basophilia of the chromatin fades.
Pyknosis the nucleus shrinks and basophilia increases. The DNA condenses into a solid shrunken mass.
Karyorrhexis the pyknotic nucleus fragments. In  1 to 2 days the nucleus in a dead cell completely disappears.

The first morphologic manifestation f almost all forms of cell injury is cellular swelling.

Mallory bodies are “alcoholic hyaline” is an eosinophilic intracytoplasmic inclusion in liver cells highly characteristic of alcoholic liver disease. Composed of predominantly prekeratin intermediate filaments.

Pinocytosis is the uptake of soluble smaller macromolecules.
Autophagy is intracellular organelles & portions of cytosol are sequestered from the cytoplasm in an autophagic vacuole and this is fused with lysosomes.

Enlarged mitochondria are seen in non lethal pathologic conditions, nutritional deficiencies and alcoholic liver disease
lnduction of the smooth endoplasmic reticulum(SER) is caused by increased tolerance of barbiturates. It increases volume of the hepatocytes SER which metabolizes the drug.
Heat shock proteins are stress proteins in response to potentially injuries stimuli
Hepatitis B virus causes damage or death to a cell by indirect cytopathic its DNA is first transcribed into mRNA, then into protein by the host’s DNA – dependent RNA polymerase
Polio virus causes damage or death to a cell by directly cytopathic: produces channels in cell membrane