Introduction to Pathology

1. Introduction to Pathology • Study of disease • Disease: • Defined as: an abnormal state in which part or all of the body is not properly adjusted or is not capable of maintaining homeostasis. • The extent of a diseased condition and its effects may vary from person to person; no two people have the same disease in the same way. • Some diseases will be more uniform in their presentation, others will be variable

2. Disease: depends on a number of factors, which we will explore this term. • It is important to recognize that diseases are not things in and of themselves, but rather, they refer to the condition of a person who is experiencing: • A particular complex of causes • Pre‑conditions • Physiological states • Emotional states • Mental states • Genetic factors • Exposure to infectious agents • Exposure to environmental agents

3. We need to stay focused on the individual who is in a state of disease and not on a disease entity which possesses a person. • Injuries are abnormal states too. The major difference between an injury and a disease is that injuries refer to damage to tissues as the result of excessive external physical or chemical forces or violence.

4. Definitions Related to Pathology • Etiology: study of the cause or theory of origin of a disease. • Idiopathic: In cases where the etiology is not known (which is much of the time) • Iatrogenic: In cases where the condition is caused by a medical treatment. • Iatros = doctor). • For example, if someone develops liver failure due to use of acetaminophen (a common over the counter pain‑killer). • Pathogenesis: refers to the way in which the disease develops

5. Incidence: the range of occurrence of a disease. Indicates a disease's tendency to occur among a certain population, gender, age group, or geographic location. • Example, women are more prone to developing auto‑immune diseases. • Sickle cell anemia has a higher incidence in African Americans than in Native Americans and people of European or Asian descent. • Pathologic changes (pathophysiology): • The changes in structure and function characteristic of the disease.

6. Signs and Symptoms: the manifestation of the disease. • Signs: are the objective facts; what the practitioner can observe. • Symptoms: are the subjective aspects; what the patient feels. • Syndrome: is a characteristic set of signs and symptoms. • Diagnosis: a statement about the, nature of the disease. The doctor determines what the patient is suffering from based on signs and symptoms and diagnostic tests.

7. Prognosis: a statement about the probable outcome of the disease. • In spite of the shortcomings of prognoses they give a useful estimate of what is likely to happen and how long it is likely to take so the therapist can develop a treatment plan accordingly. • Remember though that prognoses are educated guesses; they are not definitive statements. • Contraindications: statements about what kinds of treatment are not appropriate for the condition. • Complications: those things which may occur as a result of the treatment that the practitioner should be on the lookout for.

8. Related Definitions: • Acute: Sudden rapid onset. • Often denotes “severe” symptoms. Generally up to 48 hours. • Chronic: Of longer duration, slow progression, shows little signs of change. • Communicable Disease: A disease that is spread from person to person • Epidemic: appearance of an infectious disease throughout a general area • Endemic: disease continuously occurring in a particular population or area, usually of low mortality. • Pandemic: when an infectious disease is at epidemic proportions in many places around the world. • It has world‑wide distribution. For example, there is currently a pandemic of HIV/AIDS.

9. Related Definitions • Sporadic: occasional outbreak. A few occurrences of the disease in different locations; nothing out of the ordinary. • Congenital: present at birth • Acquired: not present at birth, develops later in life • Inherited: passed on through genetic makeup (Cystic Fibrosis, Huntington’s Chorea) • Familial: “runs in the family,” but not directly inherited (cancer, heart disease, hypertension etc.) • Mortality rate: The death rate for a specific region or population affected by a specific disease • Morbidity: The ratio of those who are disease to those who are well.

10. Related Definitions • Trauma: physical, chemical, or radioactive damage to the body • Infection: invasion of a pathogenic microorganism • Degeneration: Breakdown of body tissues, usually due to “wear and tear” • Autoimmunity: condition in which the body’s own immune system destroy its own tissues • Virulence: the ability of an organism to cause a disease; a measure of potency of a microorganism • Aerobe: An organism that lives in the presence of oxygen • Anaerobe: An organism that can live without oxygen

11. Related Definitions • Asepsis: state of being without infection or contamination; sterile • Antisepsis: inhibiting microorganism growth; preventing reproduction • Disinfection: process used to KILL microorganisms but not necessarily bacterial spores • Sterilization: process of completely removing all living organisms, including bacterial spores

12. CELLULAR ADAPTATION, INJURY/DEATH, AND WOUND HEALING

13. Cellular Adaptation When STRESSED cells undergoes adaptive changes that permit survival and maintenance of function It is only when the stress becomes so overwhelming in conjunction with ineffective cellular adaptation that cell injury and death occur Typical cell adaptation processes include: 1. changes in size (Atrophy and Hypertrophy) 2. changes in cell number (Hyperplasia) 3. changes in cell type (Metaplasia) 4. changes in cell structure (Dysplasia)

14. Mechanisms of cellular adaptation depend on signals transmitted by chemical messengers that can alter gene function in the cell. • Generally two classes of genes in the cell: • “Housekeeping” genes • Necessary for normal function of the cell • Differentiating characteristic genes • Genes which determine differentiating characteristics of a cell • When under stress the expression of the differentiating gene is altered, whereas the housekeeping genes maintain normal expression • Once stress is removed gene expression returns to normal

15. Atrophy • Def: The ability of cells to revert to a smaller size when confronted with decreased work demands or adverse environmental conditions • Purpose of atrophy is allow the cell to function at an efficient level that is compatible with survival • Rate of atrophy is directly related to the workload of a cell • Cellular atrophy results in a decrease in the size and number of organelles • Causes of atrophy include: • Disuse - Loss of endocrine stimulation • Denervation - Decrease in blood flow • Inadequate nutrition

16. Hypertrophy • Hypertrophy: represents an increase in cell size which results in an increase in the amount of functioning tissue mass • Results from increased workload imposed on an organ or body part • At the cellular level, hypertrophy involves an increase in the functional components of the cell. • Normal muscle hypertrophy: occurs as a result of exercise • Pathologic hypertrophy occurs as a result of adaptation or compensation: • Thicken urinary bladder: from long-term outflow obstruction • Myocardial hypertrophy from hypertension

17. Hyperplasia Def: An increase in the number of cells in an organ or tissue • Occurs in tissues with cells that are capable of mitotic division such as: • epidermis of the skin • intestinal epithelium • glandular tissue

18. Hyperplasia • Two Types: • Physiologic induction • Two types • 1. Hormonal: example of breast and uterine enlargement during pregnancy • 2. Compensatory: removal of one kidney results in an increase in the other kidney • Nonphysiologic induction: due to excessive hormonal stimulation or the effects of growth factors on target tissues. Example of excessive estrogen production causing endometrial hyperplasia and abnormal menstrual bleeding.

19. Metaplasia Def: Represents a reversible change in which one adult cell type is replaced by another adult cell type • The conversion of cells never oversteps the boundaries of the primary groups of tissues (epithelial tissue will only convert to other types of epithelium) • Usually occurs in response to chronic irritation and inflammation • New cells are better able to survive, whereas, the more fragile cell previously there would die • Cell types are normal. For example simple cuboidal epithelium changing to stratified squamous epithelium in response to smoking

20. Metaplasia of laryngeal respiratory epithelium has occurred here in a smoker. The chronic irritation has led to an exchanging of one type of epithelium (the normal respiratory epithelium at the right) for another (the more resilient squamous epithelium at the left). Metaplasia is not a normal physiologic process and may be the first step toward neoplasia.

21. Dysplasia Def: is characterized by abnormal cell growth of a specific tissue that results in cells that vary in shape, size and appearance • is strongly implicated as a precursor of cancer • Frequently seen in areas of metaplastic squamous epithelium of the respiratory tract and uterine cervix. • Usually reversible once irritating cause is removed.

23. Intracellular Accumulations • Intracellular accumulations are the buildup of substances that cells cannot use or immediately dispose of. • Accumulations can be: • Normal body substances • Occurs when a substance is produced at a rate exceeding metabolism or removal. • Example is fatty changes in the liver due to accumulation intracellular triglycerides secondary to alcoholism • Abnormal endogenous products • Can occur from genetic disorders where a normal enzyme may be replaced with an abnormal one. • As a result substances are formed that the cell cannot use or eliminate • Example is Von Gierke’s disease in which there is an accumulation of glycogen in the cells due to a deficiency of glucose-6-phosphate. • Exogenous products • Include pigments which accumulate in the cell • Example is jaundice caused by the retention of bilirubin.

24. Pathologic Calcifications Def: The abnormal deposition of calcium salts, together with small amounts of iron, magnesium, and other minerals. • Two types of calcification: • Dystrophic calcification: • The deposition of calcium in injured tissue • Often visible to the naked eye • Deposits range from gritty sand like grains to firm, hard rock material • Results from the crystallization of calcium phosphate which is derived from dead or dying cells, the circulation, and interstitial fluid • Commonly seen in atheromatous lesions, the aorta, large blood vessels, and damaged heart valves

25. 2. Metastatic calcification • Occurs in normal tissue as the result of increased serum calcium levels (from any condition increasing blood calcium levels) • Common causes • Hyperparathyroidism • Renal failure • Increase mobilization of calcium from bone (Paget’s disease, metastatic carcinoma) • Vitamin D intoxication • Commonly occurs in the lung, renal tubules, and blood vessels.

26. Cell Injury and Death Causes of cell injury include: 1. Physical Agents 2. Radiation 3. Chemical 4. Biologic Agents 5. Nutritional Imbalances

27. Injury From Physical Agents 1. Mechanical Forces: injury due to mechanical forces occurs as the result of body impact with another object. • Examples include bone fractures, soft tissue injuries, bruises • Extremes of Temperature: extremes of heat and cold can cause damage to the cell, cellular organelles, and enzymes. • extreme heat may cause: inactivation of enzymes, disruption of cell membrane, and coagulation of blood vessels • extreme cold may cause: severe vasoconstriction or ice crystal formation 3. Electrical Injuries: can affect the body through extensive tissue injury and disruption of nervous impulses • the body acts as a conductor of the electrical current from its source to the ground • tissue damage results from heat production produced by electrical current

28. Radiation Injury • Ionizing Radiation- affects cells by causing the ionization of molecules and atoms in the cell. Commonly caused by localized irradiation used in the treatment of cancer • Effects on cell include: a. cell death b. interruption of cell replication c. development of genetic mutations 2. Ultraviolet Radiation (sunlight)- mainly causes sunburn and increased risk of skin cancers a. skin damage induced by UV radiation is caused by the accumulation of free radicals that damage the melanin- producing processes in the skin b. Xeroderma pigmentosum- a genetic disorder due to the lack of an enzyme needed to repair the sunlight-induced damage to DNA in skin cells, results in extreme photosensitivity 3. Nonionizing Radiation- includes infrared light, ultrasound, microwaves and laser energy a. causes tissue damage by inducing the vibration and rotation of atoms and molecules within cells b. the molecular vibrational and rotational energy is eventually converted to thermal energy

29. Chemical Injury Chemical agents can cause cellular damage by: 1. destruction of cell membrane 2. inhibiting normal function of enzymes 3. denaturation of cell proteins 4. disruption of the osmotic and ionic balance of the cell Drugs: including alcohol, prescription drugs, OTC drugs, and street drugs can directly or indirectly damage tissues. Many drugs are metabolized by the body into chemicals that are toxic to cells Lead Toxicity- lead is a very toxic metal that is absorbed through the lungs or GI tract into the bloodstream 1. lead has the ability to: a. inactivate key cellular enzymes b. compete with calcium for incorporation into bone c. interfere with nerve transmission d. inhibit brain development 2. the major targets of lead toxicity are: red blood cells, cells of the GI tract, kidneys, and nervous system

30. Biologic Agents and Nutritional Deficiencies • Biologic agents include viruses, bacteria, and parasites which invade the cell • Viruses cause cellular damage by incorporating itself into the cellular DNA, resulting in the production of viral proteins • Bacteria may injure cells by producing either exotoxins or endotoxins. • Nutritional excesses or deficiencies may also cause cellular injury. • Diets high in saturated fats predispose persons to atherosclerosis. In contrast diets deficient in nutrients predispose persons to numerous diseases (iron deficiency anemia, scurvy)

31. Mechanisms of Cell Injury 1. Free Radical Injury: a. Free radical- is a highly reactive molecule arising from an atom that has a single unpaired electron in its chemical outer orbit causing the free radical to be unstable and enter into reactions with key cellular molecules b. Free radicals are produced by many normal cellular reactions in the body. Including from the breakdown of lipids and proteins, and from the inflammatory process c. Unfortunately, molecular oxygen (O2), with its 2 unpaired outer electrons is the most frequent source of free radicals d. free radical-induced cellular damage may include: 1. damage to cell membranes 2. destruction of key cellular proteins 3. inactivation of enzymes 4. genetic mutation e. most cells, under normal conditions have chemical mechanisms that protect them from the free radical damage

34. Mechanisms of Cell Injury 2. Hypoxic Cell Injury: a. Hypoxia- condition in which a cell is deprived of oxygen resulting in the interruption of normal metabolic processes, most importantly ATP synthesis b. common causes of hypoxia include: 1. Inadequate concentration of oxygen in the environment 2. Respiratory disease 3. Ischemia- decreased blood flow 4. Anemia c. Hypoxia causes a power failure in the cell, affecting the cell’s functional and structural components 1. As oxygen levels fall, aerobic respiration, resulting in the cells changing to anaerobic methods and the accumulation of lactic acid in the cell (decreasing the pH) which damages organelles within the cell.

35. 2. As ATP levels decrease membrane Na+/K+ pumps begin to fail resulting in increased levels of Na+ within the cell. As a result water enters the cell via osmosis and causes cellular swelling. 3. In addition, the endoplasmic reticulum and cell membranes become more permeable. 4. If oxygen levels continue to decrease the lysosomal membranes also become hyperpermeable resulting in the release of enzymes into the cytoplasm and the digestion of cellular components. 5. Leakage of cellular enzymes into the extracellular fluid is used as an important clinical indicator of cell injury and death.

36. Impaired Calcium Homeostasis • Calcium functions as an messenger in the release of many intracellular enzymes. • Normally intracellular calcium levels are low in comparison to extracellular levels. This gradient is kept via calcium/magnesium pumps. • Ischemia and certain toxins lead to an increase in cytosolic calcium because of increased influx across the cell membrane and the release of calcium from the ER and mitochondria. • The calcium in the cytoplasm activates a number of enzymes which can damage the cell. Activated enzymes include phospholipidases, proteases, ATPases, and endonucleases.

37. Cell Death Apoptosis- involves controlled cell destruction and is involved in the normal process of cell deletion and renewal • main goal is to eliminate worn out cells, cells produced in excess, improperly developed cells, or genetically damaged cells. • Apoptosis is characterized by controlled autodigestion of cell components. • cells appear to initiate their own death through the activation of endogenous enzymes • This results in cell shrinkage, condensation of organelles, disruption and clumping of nuclear DNA, and wrinkling of the cell membrane. • Normally apoptosis occurs during the involution of endometrial cells during the menstrual cycle and the regression of breast tissue following the cessation of breast feeding f. Apoptosis is thought to be involved in cell death with certain viral infections, cell death with a variety of injurious agents (mild thermal and radiation injury)

39. Necrosis- is a pathologic form of cell death in an organ or tissue that is part of a living person. a. Differs from apoptosis in that it involves unregulated enzymatic digestion of cell components, loss of cell membrane integrity, and the initiation of the inflammatory response. b. Necrosis interferes with cell replacement and tissue regeneration. c. Types of necrosis; 1. Liquefaction necrosis: occurs when cells die, but their catalytic enzymes are not destroyed. Example is seen in the softening in the center of an abscess. 2. Coagulative necrosis: Seen in infarcted areas in hypoxic cellular injury resulting in acidosis and denaturation of enzymes and structural proteins of the cell. 3. Caseous necrosis: Form of cell death where dead cells persist indefinitely as soft cheeselike debris. Commonly seen in the tubercle granulomas of tuberculosis.

41. Gangrene Gangrene is the term applied when a considerable mass of tissue undergoes necrosis. Three types • Dry gangrene: a. Results from interference with arterial blood supply without the interference of venous return and is a form of coagulative necrosis. b. Tissue becomes dry and shrinks, skin wrinkles, and color changes to dark brown or black. c. There is a line of demarcation between dead tissue and healthy tissue d. Spread of dry gangrene is slow e. Usually confined to the extremities

43. 2. Moist (Wet) gangrene: a. Results from interference of venous return from the body part. b. Area is cold, swollen, pulseless. Skin is moist, black, and under tension. c. Blebs form on the surface, liquefaction occurs and there is a foul odor due to bacterial action. d. There is no line of demarcation. e. Spread of tissue damage is rapid. f. Death may occur unless the condition is controlled. g. Can occur in the extremities and/or the internal organs h. If bacteria invade the necrotic tissue, dry gangrene can be converted to wet gangrene.

44. 3. Gas Gangrene: a. Type of gangrene resulting from infection of tissues from one of several anaerobic Clostridium bacteria, commonly Clostridium perfringens b. Gas gangrene tends to occur in wounds where dirt and debris are embedded as Clostridium is found in the soil. c. The bacteria produce enzymes that dissolve cell membranes, causing death of muscle cells, massive spreading edema, hemolysis of RBC’s, hemolytic anemia, hemoglobinurea, and renal failure. d. Characteristics include bubbles of hydrogen sulfide gas that form in the muscle. e. Potentially fatal, possibly requiring amputation

45. Connective Tissue Repair Wound healing is divided into three phases: 1. Inflammatory Phase: a. begins at the time of injury is described as the stage that prepares the wound environment for healing b. there is vasoconstriction of any injured blood vessels and the initiation of the blood clotting mechanism in order to prevent excessive bleeding c. once any bleeding has been controlled, the blood vessels of the wound environment vasodilate allowing plasma and blood components to enter the injured area d. migration of WBCs to area initiates the digestion and removal of any foreign organisms and tissue debris and to stimulate the re-growth of tissue components

46. 2. Proliferative Phase: a. usually begins within 2-3 days of injury and may last as long as 3 weeks b. the processes of this stage focus on the building of new tissue to fill the wound space c. the cellular workhorse of this stage is the fibroblast- cell that synthesizes and secretes collagen d. physical manifestation of this stage is scab formation 3. Remodeling Phase: a. begins approximately 3 weeks after the initial injury and can continue for 6 months or longer b. this stage is marked by continued remodeling of scar tissue by the simultaneous synthesis of collagen by fibroblasts and the breakdown of collagen by enzymes in order to increase the tensile strength of the wound area