Cellular Pathology PDF

# CHAPTER 1 ## CELLULAR PATHOLOGY ### OVERVIEW Pathology, in the broadest terms, is the study of disease. Disease occurs for many reasons. Some diseases represent spontaneous alterations in the ability of a cell to proliferate and function normally, and in other cases, disease results when exte...

# CHAPTER 1 ## CELLULAR PATHOLOGY ### OVERVIEW Pathology, in the broadest terms, is the study of disease. Disease occurs for many reasons. Some diseases represent spontaneous alterations in the ability of a cell to proliferate and function normally, and in other cases, disease results when external stimuli produce changes in the cell's environment that make it impossible for the cell to maintain homeostasis. In such situations, cells must adapt to the new environment. These adaptations include hyperplasia, hypertrophy, atrophy, and metaplasia, and can be physiologic or pathologic, depending upon whether the stimulus is normal or abnormal. A cell can adapt to a certain point, but if the stimulus continues beyond that point, failure of the cell, and hence the organ, can result. If cells cannot adapt to the pathologic stimulus, they can die. This chapter will discuss cellular adaptation, cell injury, cellular accumulations, and cellular aging. ### CELLULAR ADAPTATION **Overview:** The four basic types of cellular adaptation to be discussed in this section are hyperplasia, hypertrophy, atrophy, and metaplasia. #### HYPERPLASIA **Basic description:** Increase in the number of cells. **Types of hyperplasia** * **Physiologic hyperplasia:** Occurs due to a normal stressor. For example, increase in the size of the breasts during pregnancy, increase in thickness of endometrium during menstrual cycle, and liver growth after partial resection. * **Pathologic hyperplasia:** Occurs due to an abnormal stressor. For example, growth of adrenal glands due to production of adrenocorticotropic hormone (ACTH) by a pituitary adenoma, and proliferation of endometrium due to prolonged estrogen stimulus. **Important point regarding hyperplasia:** Only cells that can divide will undergo hyperplasia; therefore, hyperplasia of the myocytes in the heart and neurons in the brain does not occur. #### HYPERTROPHY **Basic description:** Increase in the size of the cell. **Types of hypertrophy** * **Physiologic hypertrophy:** Occurs due to a normal stressor. For example, enlargement of skeletal muscle with exercise. * **Pathologic hypertrophy:** Occurs due to an abnormal stressor. For example, increase in the size of the heart due to aortic stenosis. Aortic stenosis is due to a change in the aortic valve, which obstructs the orifice, resulting in the left ventricle working harder to pump blood into the aorta. **Morphology of hyperplasia and hypertrophy:** Both hyperplasia and hypertrophy result in an increase in organ size; therefore, both cannot always be distinguished grossly, and microscopic examination is required to distinguish the two. **Mechanisms by which hyperplasia and hypertrophy can occur:** Up regulation or down regulation of receptors and induction of new protein synthesis. The two processes can occur together. For example, up regulation of receptors results in the induction of new protein synthesis; or up and down regulation of receptors and induction of new protein synthesis can occur as independent processes. The types of new proteins induced include transcription factors (e.g., c-Jun, c-Fos), contractile proteins (e.g., myosin light chain), and embryonic proteins (e.g., ß-myosin heavy chain). #### ATROPHY **Basic description:** Decrease in the size of a cell that has at one time been of normal size. **Types of atrophy** * **Physiologic atrophy:** Occurs due to a normal stressor. For example, decrease in the size of the uterus after pregnancy. * **Pathologic atrophy:** Occurs due to an abnormal stressor. In general, atrophy is due to the loss of stimulus to the organ. Specific types of loss of stimulus include loss of blood supply or innervation, loss of endocrine stimulus, disuse, mechanical compression, decreased workload, or aging. **Gross morphology of atrophy:** The organ is smaller than usual. Atrophy occurs in a once normally developed organ. If the organ was never a normal size (i.e., because it did not develop normally), the condition is called hypoplasia. #### METAPLASIA **Basic description:** Change of epithelium at a site, or location, from one type of epithelium to another type. In metaplasia, the epithelium is normal in appearance but in an abnormal location. **Mechanism of metaplasia:** The epithelium normally present at a site cannot handle the new environment so it converts to a type of epithelium that can adapt. **Examples:** Barrett esophagus is due to reflux of gastric contents into the esophagus, which causes the epithelium type to convert from squamous to glandular. Squamous metaplasia in the lungs is due to exposure of respiratory epithelium to toxins in cigarette smoke. ### CELL INJURY **Overview:** Cell injury occurs when the cells cannot adapt to their new environment. **Causes of cell injury:** Hypoxia (decreased oxygen), ischemia (decreased blood flow), physical and chemical agents, trauma, infectious agents, radiation and toxins, metabolic abnormalities (genetic or acquired), immune dysfunction (hypersensitivity reactions and autoimmune disease), aging, and nutritional imbalances. **Important points regarding cell injury** * Hypoxia and ischemia are two common sources of cellular injury. Of the two, ischemia is much more damaging because it involves hypoxia plus a lack of other nutrients and an accumulation of toxic cellular metabolites. * When does injury occur? This varies from cell to cell. It depends upon the type, duration, and severity of injury, and the type, adaptability, and makeup of the affected cell. * Cellular injury may or may not result in the death of the cell. Four cellular systems are especially vulnerable to cellular injury, and include: * DNA * Cell membranes * Protein generation * Adenosine triphosphate (ATP) production Although some of the causes of cellular injury have specific mechanisms, the mechanism of cellular injury due to many substances is not understood. **Mechanisms of cellular injury** 1. **Hypoxia:** In general, decreased oxygen results in decreased production of ATP. ATP is normally required by the Na/K+ pump and Ca2+ pump. When ATP levels decrease, these pumps fail and sodium (along with water, which follows sodium) enters the cell, causing swelling. Also, calcium enters the cell, which activates endonucleases, proteases, phospholipases, and DNAses, which damage the cell. Cells switch to anaerobic respiration to produce ATP, which results in accumulation of lactic acid. The accumulation of lactic acid decreases the cellular pH. Decreased pH causes disaggregation of ribosomes from endoplasmic reticulum. 2. **Generation of oxygen-derived free radicals by a stressing agent** **Basic description of free radical:** A free radical is a molecule with an unpaired electron in the outer orbit. Another term for oxygen-derived free radicals is reactive oxygen species. **How free radicals are generated:** Free radicals are generated by normal physiologic reduction-oxidation reactions, ultraviolet light, x-rays and ionizing radiation, and transitive metals. Also, metabolism of exogenous chemicals, such as carbon tetrachloride, induces formation of reactive oxygen species. **Damage by free radicals:** Lipid peroxidation (damages cell membranes), DNA fragmentation, and protein cross-linking (e.g., sulfhydryl groups), which results in increased degradation and decreased activity. **Methods to prevent formation of reactive oxygen species** * Catalase, which degrades hydrogen peroxide. * Superoxide dismutase, which converts superoxide to hydrogen peroxide. * Glutathione, which catalyzes breakdown of hydroxyl radicals. * Vitamins A, C, and E, which have an antioxidant effect. 3. **Chemical injury:** Some chemicals are directly toxic to the cells, and others require conversion to a toxic metabolite. For example, ethylene glycol (antifreeze) is not toxic, but its metabolite, oxalic acid, is. In contrast, cyanide directly inactivates cytochrome oxidase, which impairs the formation of ATP. 4. **Increased mitochondrial cytosolic calcium:** Increased mitochondrial cytosolic calcium leads to lipid peroxidation and formation of mitochondrial permeability transition (a nonselective pore that dissipates the proton gradient). Also, increased mitochondrial cytosolic calcium causes release of cytochrome c, which in turn activates apoptosis. **Two types of cellular injury** * **Reversible cellular injury:** As described above in the discussion of mechanisms of cellular injury, the decreased production of ATP causes sodium to enter the cell, bringing water and causing cellular and organelle swelling. The conversion from aerobic to anaerobic respiration decreases the pH of the cell. These changes are all reversible. If ATP is once again produced by the cell, the Na/K+ ratio and pH will be corrected. * **Irreversible cellular injury:** This type of injury occurs with damage to plasma or lysosomal membranes, loss of DNA, or loss of mitochondria. In these cases, the damage cannot be reversed. The two most important factors determining irreversible damage are membrane disturbances and the inability to reverse mitochondrial dysfunction.. **Light microscope morphologic changes of cellular injury** * **Reversible injury:** Cellular swelling and fatty change. * **Irreversible injury:** Nuclear karyolysis (loss of basophilia), pyknosis (shrinkage of nucleus), and karyorrhexis (fragmentation of nucleus). * **Electron microscope morphologic changes of cellular injury** * **Reversible injury:** Cellular blebs and small mitochondrial densities. * **Irreversible injury:** Ruptured lysosomes, myelin figures (which indicate phospholipid precipitation), lysis of endoplasmic reticulum, and large calcium rich mitochondrial densities. ### CELL DEATH **Overview:** There are two forms of cell death, apoptosis and necrosis. Apoptosis is controlled (programmed) breakdown of cells occurring in response to damage to DNA or as part of normal growth and development. Necrosis is uncontrolled breakdown of cells in response to injurious stimuli. #### APOPTOSIS **Basic description:** Programmed cell death. **Patterns of occurrence of apoptosis** * During growth and development, some cells serve a function in the growth phase but need to be removed after their purpose is fulfilled. In neonates, a rapid cell growth rate is necessary; in adults, however, unrestrained cell growth can lead to cancer. * When DNA sustains irreparable damage (e.g., after low-dose radiation exposure), the cell must be destroyed so mutations that have developed will not be propagated. In this manner, apoptosis serves as a safety step by removing damaged cells from the body. **Phases of apoptosis** * **Initiation** is the phase in which caspases (cysteine aspartic acid proteases) become catalytically active. * **Execution**is the phase in which the action of caspases causes death of the cell. **Mechanism of apoptosis:** There are multiple pathways by which apoptosis is initiated, including the extracellular and intracellular pathways. Both pathways share similar endpoints, culminating with the use of caspases and prevention of inflammatory reaction. * **Initiation of extracellular pathway:** In Fas-Fas ligand binding, the Fas ligand binds to a member of the tumor necrosis factor family known as the Fas receptor. The activated Fas receptor in turn activates FADD (Fas-associated death domain), which in turn activates caspases. * **Initiation of intracellular pathway:** The mitochondria release cytochrome c, which combines with Apaf-1 (apoptosis activating factor-1) to activate caspases. * **Caspases**, which cleave DNA, are activated. DNA is cleaved in a coordinated manner so the fragments, if analyzed on a gel, will form a ladder. In contrast, in necrosis (an uncoordinated breakdown of DNA), the gel will be a smear. * Apoptosis does not generate an inflammatory reaction as necrosis does. Fragments of cells express phosphatidyl serine, which is recognized by macrophages; therefore, fragments can be engulfed without generating an inflammatory reaction. **Morphology of apoptosis:** The key feature microscopically is chromatin condensation and fragmentation. #### NECROSIS **Basic description:** Necrosis is a term used to describe uncontrolled death of cells due to one of the various causes of cellular injury. **Gross morphology of necrosis:** Necrosis is typically manifested by softening and discoloration of the organ. Other processes can have a similar appearance, so the gross appearance of necrosis is not specific. **Microscopic morphology of necrosis:** The two main types of necrosis are coagulative necrosis and liquefactive necrosis; however, there are several other variants. #### Coagulative necrosis **Basic description:** Coagulative necrosis is the type of necrosis in which protein denaturation is more prominent than enzymatic breakdown. **Microscopic morphology of coagulative necrosis:** There is increased eosinophilia of the cytoplasm and decreased basophilia of the nucleus; both are associated with preservation of the general cellular architecture (the organ type is identifiable). **Organs affected by coagulative necrosis:** Coagulative necrosis may occur in any organ. In organs with a high fat content, such as the brain, coagulative necrosis is followed rapidly by liquefactive necrosis. #### Liquefactive necrosis **Basic description:** Liquefactive necrosis occurs in situations in which enzymatic breakdown is more prominent than protein denaturation or in organs that lack a substantial protein-rich matrix (e.g., lipid-rich organs such as the brain). **Microscopic morphology of liquefactive necrosis:** There is loss of organ cellular architecture. In liquefactive necrosis of the brain, there are sheets of lipid-laden macrophages that replace the dead tissue. **Organs affected by liquefactive necrosis:** Liquefactive necrosis is most commonly associated with organs that have a high fat and low protein content (e.g., the brain), or those with a high enzymatic content (e.g., the pancreas). **Fat necrosis:** Fat necrosis is a term applied to a change in adipose tissue due to trauma or the release of enzymes from adjacent organs (e.g., the pancreas). The trauma or enzymatic action causes a breakdown of lipid and a release of fatty acids, which combine with calcium to form chalky deposits. **Caseous necrosis:** Caseous necrosis is a "cheesy-looking" necrosis associated with tuberculosis infections and other granulomatous disease processes. Granulomas are a form of chronic inflammation due to some infections (e.g., mycobacterial), foreign bodies, and other chronic stimuli. **Important points regarding necrosis** * The terms coagulative and liquefactive necrosis are not mutually exclusive. For example, the death of heart muscle begins as coagulative necrosis, but once neutrophils enter the tissue as part of an inflammatory reaction and release enzymes, cellular architecture is lost (more consistent with liquefactive necrosis). * Cell death involves the release of intracellular enzymes into blood. These enzymes in the blood can be measured and used clinically to detect disease. * Cell death affects morphology (the shape of the cell) and function. Morphologic changes (both gross and microscopic) can develop over a period of time, while loss of function may occur almost immediately. Because of this immediate loss of function, the clinical manifestations of cellular injury may be present before the morphologic changes occur. ### CELLULAR ACCUMULATIONS **Overview:** Substances can accumulate in cells as a result of damage to the cell, or they can accumulate in the cells as the result of an intrinsic abnormality in metabolic function (e.g., genetic disease). The accumulation of substances in a cell may or may not cause damage to the cell. Substances that commonly accumulate are lipofuscin (also referred to as wear-and-tear pigment), calcium, protein, iron, fat, cholesterol, glycogen, and pigments. **General mechanisms of cellular accumulations:** Include acquired or hereditary enzymatic defects, deposition of exogenous substances, and decreased metabolism of substances, which then accumulate. #### LIPOFUSCIN **Basic description:** Wear-and-tear pigment. **Mechanism of formation:** Lipofuscin is a product of lipid peroxidation, which accumulates in lysosomes as the cell ages. The cell cannot rid itself of these lipofuscin-laden lysosomes. **Organs with lipofuscin accumulation:** The most common organs where lipofuscin accumulates are the heart and liver. **Gross morphology of lipofuscin accumulation:** Lipofuscin accumulation can impart brown discoloration to organ. Such organs may also be atrophic, giving rise to the term "brown atrophy." **Microscopic morphology of lipofuscin accumulation:** Finely granular, yellow-brown pigment, which often surrounds the nucleus. #### CALCIUM ACCUMULATION **Two forms of calcium deposition:** Metastatic and dystrophic **Mechanism of metastatic calcification:** Patients who have hypercalcemia have deposition of the calcium within normal or abnormal tissue. Some causes of hypercalcemia include increased parathyroid hormone (PTH) by a parathyroid adenoma or parathyroid gland hyperplasia; destruction of bone by tumors, vitamin D intoxication, or renal failure; and sarcoidosis, where macrophages activate vitamin D precursor. **Mechanism of dystrophic calcification:** Patients who have normal levels of calcium have deposition of the calcium only within abnormal tissue, such as necrotic tissue. **Organs most commonly affected by calcium accumulation:** Vasculature, kidneys, and lungs. **Gross morphology of calcium accumulation:** Hard yellow nodules. **Microscopic morphology of calcium accumulation:** Chunky, smooth, purple granules. #### PROTEIN ACCUMULATION There are many different causes of protein accumulation. Accumulations often involve intermediate filaments; for example, Mallory hyaline in the liver and neurofibrillary tangles seen in Alzheimer disease. #### IRON ACCUMULATION **Two forms of iron accumulation:** Hemosiderosis and hemochromatosis * **Hemosiderosis:** Accumulation of iron in organs without resultant side effects. The iron pigment is frequently within macrophages. Hemosiderin is a term used for aggregates of ferritin micelles (it stains positive with a Prussian blue stain). * **Hemochromatosis** **Basic description:** Accumulation of iron in parenchymal cells resulting in side effects, including congestive heart failure, diabetes mellitus (from damage to the pancreas), and cirrhosis. Hemochromatosis can be acquired or hereditary. **Organs affected by hemochromatosis:** Most common organs affected are the liver, skin, pancreas, and heart. **Microscopic morphology of iron accumulation:** Chunky, yellow-brown granules #### FAT ACCUMULATION (STEATOSIS) **Organs affected:** Most common organs affected are the liver, kidney, heart, and skeletal muscle. **Gross morphology of steatosis:** Yellow discoloration of an organ. **Microscopic morphology of steatosis:** One or several clear vacuoles within the cell. **Important point regarding steatosis:** Steatosis can indicate reversible damage or may be the sign of an intrinsic abnormality in fat metabolism. #### CHOLESTEROL ACCUMULATION **Organs affected:** Blood vessels (by the process of atherosclerosis) or at sites of hemorrhage. Cholesterol accumulates within phagocytic cells. #### GLYCOGEN ACCUMULATION **Organs affected:** Glycogen accumulates as part of glycogen storage disorders (genetic diseases with a defect in enzymatic pathway of glycogen, such as McArdle syndrome). The most common organs affected are liver and skeletal muscle. #### PIGMENTS * **Exogenous pigments:** Tattoos and anthracotic pigment, which is carbonaceous debris from urban dwelling or cigarette smoking. * **Endogenous pigments:** Melanin; bilirubin #### CELLULAR AGING **Basic description:** Tissue cells have a fixed number of divisions, which they are capable of undergoing. Telomeres, or TTAGGG repeats, protect the ends of the chromosome, and they shorten with cell divisions. When the telomere is too short, the DNA is interpreted as broken. **Immortal cells:** Telomerase (present in germ cells and stem cells) adds telomeres to the end of the chromosome, allowing the cell's lifespan to continue indefinitely. **WERNER SYNDROME** **Manifestation:** Premature aging. **Mutation:** Defective DNA helicase.