I. INTRODUCTION

The definition of pathology, in its broadest sense, is the study of disease. The material presented in this course will encompass this broad definition. Pathology in the clinical sense is the analysis of body fluids and tissues for diagnostic purposes.

Other basic definitions that are important for this course are:

• Disease: any structural or functional change judged to be abnormal in that it produces manifestations (i.e., signs or symptoms).
• Symptom: what the patient himself feels and reports to the examiner. These can be objective, such as a swelling, or subjective, such as a headache.
• Sign: what the examiner observes; thus, signs are always objective, e.g., a mass, abnormal heart sounds, a fever, an abnormal lab result.
• Etiology: the study or theory of the causes of a disease.
• Pathogenesis: the sequence of events that leads from the cause of a disease to its manifestations.

II. THE NORMAL CELL

Diseases reflect damage to or abnormal functioning of the cells that make up the body. To understand what goes wrong in disease, you have to be familiar with how a cell works normally. What follows is a brief review of some aspects of cell biology that are particularly relevant to what happens when cells are damaged. If you are not familiar with this material, you definitely need to buy the textbook and read the first chapter carefully.

The fertilized egg and the early embryonic cells are totipotent, which literally means "all-powerful." These cells have the capability of developing into any kind of cell in the body ­ muscle cell, neuron, red blood cell, etc. The concept of totipotency is vividly demonstrated by the existence of identical twins, where an early embryo splits apart and forms two complete individuals.

As cells of a developing embryo divide (by the process called mitosis) and increase in number, they differentiate. During differentiation, they lose their totipotency and undergo a series of changes that gives them specialized functions. Differentiation still occurs in adults: for example, bone marrow stem cells differentiate into red and white blood cells. Neoplasia is a pathological condition in which cells grow in an uncontrolled and purposeless way, often with a loss of differentiated functions.

In the adult, tissues can be classified as follows. It is useful to know these classifications, since tumors are named according to the type of tissue from which they arose.

• Epithelial cells:
• Lining epithelium serves mainly a protective role (skin; linings of mouth, vagina, bladder)
• Secretory epithelium secretes useful substances and can consist of linings (e.g., the lining of the respiratory tract, which makes mucus) or can be organized into glands (e.g., mammary, sweat, lacrimal, salivary).
• Epithelial cells are tightly connected to one another in sheet-like structures and sit on a basement membrane made up of collagen and other structural molecules.

• Mesenchymal (connective tissue) cells:
• Include cells of tendons, bones, and cartilage.
• Mesenchymal cells are more widely separated from one another than are epithelial cells. They are embedded in a connective tissue matrix (called a stroma) composed of proteins such as collagen and elastin (which gives tissues their resiliency), as well as other structural molecules. This matrix is produced by cells called fibroblasts.
• Some authorities classify muscle cells and cells of the nervous system as connective tissue cells; others place them in separate categories.

Another useful distinction is between eukaryotic and prokaryotic cells. Eukaryotic (meaning "true cell") cells are the cells of higher organisms and are distinguished by having their DNA packaged in a membrane-bound nucleus. Prokaryotic organisms, such as bacteria, have a DNA genome, but it is not compartmentalized into a nucleus.

Viruses contain their genetic material in the form of RNA or DNA, never both. Viruses are obligate intracellular parasites, meaning that they must live inside of eukaryotic or prokaryotic cells. They don’t have sufficient components to live and replicate on their own; they contain no ribosomes or mitochondria, and they have, at most, just a few synthetic enzymes. A complete infective viral particle is called a virion. The nucleic acid core of a virus is surrounded by a protein coat called a capsid. The core and capsid together are referred to as the nucleocapsid. In some (but not all) viruses, the nucleocapsid is surrounded by an outer envelope derived from the plasma membrane of the host cell. This envelope may contain viral proteins.

The mitochondrion is the energy plant of the eukaryotic cell. Mitochondria probably evolved from bacteria that invaded primitive cells and set up a mutually beneficial relationship. A mitochondrion has two membranes, an inner one and an outer. The inner membrane has folds called cristae.

The enzymes of the citric acid cycle (also known as the Krebs cycle or TCA cycle) are located within the mitochondrion. These enzymes take the breakdown products of proteins, sugars, and fats and degrade them even further to form carbon dioxide and water. In the process, high-energy electrons are released. These electrons are passed down the proteins of the respiratory chain, located in the inner membrane of the mitochondrion, where their energy is transferred to adenosine triphosphate (ATP). The last two phosphate groups of ATP are joined to the rest of the molecule by special high-energy chemical bonds. Energy is thus stored in these bonds, which can be broken to release the energy to do the work of the cell (e.g., move, pump out salts, ingest nutrients, etc.).

This process is aerobic, meaning that it requires oxygen. The oxygen is needed to accept the electrons once they have completed their passage down the respiratory chain. The electrons combine with oxygen (O₂) and protons (H⁺) to form water. If there is no oxygen available, cells will make ATP from sugars by anaerobic glycolysis. However, this process is much less efficient than the aerobic version, and its end product, lactic acid, can be harmful to cells. (Long-distance runners may develop muscle cramps as their oxygen supplies diminish and lactic acid builds up in the muscle tissues.)

The plasma membrane of the cell is essential for its normal functioning. It surrounds and protects the cell and regulates the cell’s internal environment by 1) controlling the passage of water, salts, and nutrients, and 2) interacting with the external environment via protein receptors. The plasma membrane is composed of two layers (i.e., a bilayer) of phospholipids, which are lipids connected to a negatively charged phosphate-containing group. The neutral lipids make up the inner part of the membrane; the charged phosphate groups face toward the outside of the cell and toward the cytoplasm within the cell.

Proteins are embedded within the phospholipid bilayer of the plasma membrane. These proteins usually have an external domain, a transmembrane domain, and a cytoplasmic domain. These proteins thus serve as a bridge between the inside of the cell and the outside environment. Some of these proteins are receptors, which bind to specific substances in the outside environment. These substances are called the ligand of the receptor. Receptor and ligand fit together in a lock-and-key fashion. When a ligand binds to its receptor, a signal is transmitted to the inside of the cell that can serve to alter the behavior of the cell. In this way, cells can modify their behavior to adapt to changing environmental conditions. Different receptors have different mechanisms for transmitting signals.

Other membrane proteins can serve as adhesion molecules, which bind cells to one another (e.g., epithelial cells) or to proteins in the basement membrane (epithelial cells) or stroma (mesenchymal cells).

There are several ways by which substances can cross the plasma membrane. Small molecules may cross simply by passive diffusion. Other substances may need to cross the membrane by active transport, in which the cell uses energy (i.e., breaks down ATP) to carry molecules across. A good example of active transport is the sodium pump. Normally the inside of the cell is relatively rich in potassium and poor in sodium compared to the external environment. To maintain this situation, the cell has proteins in the plasma membrane that actively pump out sodium. An important point to remember is that this process requires ATP.

Cells may also take in nutrients by pinocytosis, which literally means "cell drinking." During pinocytosis, small invaginations of the plasma membrane form and pinch off, trapping liquid from the outside environment, and, of course, anything that is dissolved within it. These pinched-off vesicles are brought into the interior of the cell, where they fuse with lysosomes. Lysosomes are small, membrane-bound organelles within the cytoplasm of the cell. They contain a variety of digestive enzymes that can break down ingested nutrients. The small molecules that are produced can then diffuse into the cytoplasm, where they serve to nourish the cell.

Some cells are capable of taking in large particles, such as bacteria or cell debris. This process is called phagocytosis, or "cell eating." The large vesicle that is formed is called a phagocytic vacuole or a phagosome.. This vacuole again fuses with lysosomes to form a phagolysosome. If it is a bacterium that has been ingested, substances within the lysosomes will both kill and digest the bacterium. You will hear much more about this process during the lecture on inflammation. Cells such as neutrophils and macrophages are specifically designed to carry out the process of phagocytosis and are therefore referred to as professional phagocytes.

III. CELL INJURY

Abnormal functioning of cells or damage to cells forms the basis of human disease. It is therefore important to understand the ways in which cells respond to harmful conditions.

There are many causes of cell injury, including:

• Internal factors: genetic, nutritional, immunological
• External factors: physical trauma, chemical toxins, infectious agents, radiation

If cells are not too highly stressed, they may respond by trying to adapt to the injurious agent. There are several different forms of adaptation:

• Atrophy: a decrease in the size and function of cells and/or the number of cells in a tissue. Under stressful conditions, cells may shrink in volume and shut down differentiated functions to minimize their need for energy. If conditions return to normal, the cells are also capable of returning to normal. Examples include a broken limb in a cast or a patient on bed rest, both of which may result in atrophy of muscles; lack of an essential hormone, such as atrophy of endometrium after menopause due to a decrease in estrogen; insufficient blood supply such that not enough nutrients and oxygen are supplied to a tissue, as in coronary artery disease.

Important definitions: Ischemia refers to reduced blood supply to tissues, which may result in tissues receiving less than the normal amount of oxygen (hypoxia) or even no oxygen (anoxia).

• Hypertrophy: an increase in the size and functional capacity of a cell. For example, during lactation, prolactin and estrogen cause hypertrophy of the breast tissue. Also, certain pharmaceutical drugs are recognized by the body as toxic and are broken down in the smooth endoplasmic reticulum of liver cells. If these drugs are administered for long periods of time, the smooth ER proliferates and the liver cells enlarge in an effort to handle the increased demand. The heart may also enlarge when it needs to pump harder, for example in patients with long-standing hypertension or when the aorta is narrowed (aortic stenosis). An example you should remember from class is weight lifters ­ their skeletal muscle cells increase in size (NOT in number ­these cells do not divide in the adult) to handle the increased demand that is placed on them.

• Hyperplasia: an increase in the number of cells in a tissue. Hyperplasia can occur hand-in-hand with hypertrophy. Examples: People who live at high altitude, where there is less oxygen in the atmosphere, produce increased numbers of red blood cells. Pressure from too-tight shoes may cause corns or calluses, which are due to hyperplasia of the epidermal cells. Hyperplasia of the squamous cells of the epithelium is also seen in the disease psoriasis.

• Metaplasia: replacement of one type of differentiated cell with another type. A classic example is the change that takes place in the respiratory tract of a smoker. Normally, bronchi of the lung are lined with a mucus-secreting, glandular epithelium. In smokers, this epithelium is often replaced by a more flattened, non-secreting type of epithelium called squamous epithelium. It is thought that this squamous epithelium is better at protecting the lung cells from the harmful constituents in smoke than is the normal, glandular epithelium. However, this protection comes at a price, since the mucus helps prevent microorganisms from invading the lung. Note that in metaplasia, one type of differentiated cell is not directly converted into another type of differentiated cell. It is rather a process of replacement. Undifferentiated stem cells in the bronchi of the lung, which normally divide to form glandular epithelium, will instead develop into squamous epithelial cells.

Important point: Atrophy can refer to either a decrease in size or function or a decrease in cell number. Increases in size and number have their own specific terms (hypertrophy and hyperplasia, respectively.)

An even more important point: All of these adaptive changes are fully reversible when the injurious agent is removed or the abnormal condition is resolved. You won’t stay pumped up if you stop working out! On the other hand, metaplasia in the lung can be reversed if one stops smoking.

IV. SEVERE DAMAGE TO CELLS AND CELL DEATH

A. Early signs of severe damage:

If cells cannot cope with a particular insult, they will cease to function and die. Pathologists can sometimes see indications that a cell is very stressed, but there are no morphological signs that indicate the exact moment of death ­ you can’t always tell if a cell is dead just by looking. But sometime after a cell has died, the cell undergoes a series of changes that can be observed and serve as definitive proof that the cell has been irreversibly injured. This series of changes is called necrosis.

Before a cell dies, it may exhibit signs that it is becoming severely damaged. These signs are reversible up to a point. A common response of a cell to severe damage is swelling. For example, during ischemia, a cell may not receive enough oxygen to produce adequate amounts of ATP through aerobic respiration. The lack of ATP means that the sodium pump, which needs energy to function, will not be able to transport sodium out of the cell. The cell literally will become too salty. As a result, water will diffuse into the cell in an attempt to equilibrate the concentrations of sodium inside and outside of the cell. The cell becomes waterlogged and swollen. A moderate degree of swelling is referred to as cloudy swelling. At the most severe stages, the swelling is called hydropic degeneration. Hydropic degeneration is reversible up to a point, but if it progresses too far, the integrity of the cell will be irreversibly damaged.

Another sign of damage is excessive accumulation of fats, which occurs with particular frequency in the liver and sometimes in the heart. Fatty liver is often associated with alcoholism. Normally, only the cells of adipose (fat) tissue have detectable stores of fat. Fatty acids from these stores or from the diet are released into the bloodstream and travel to the liver, where they are taken up by the hepatocytes (cells of the liver). The hepatocytes convert these fatty acids into substances that are needed by the body, including phospholipids and lipoproteins. If the hepatocytes are damaged, they can often still take up the fatty acids, but they may no longer have the capacity to convert them into needed products. As a result, the fats accumulate in the hepatocytes, where they may form large, visible fat droplets in the cells. This situation again is reversible up to a point, but it may progress to where it kills the cell, thus leading to necrosis.

B. Necrosis:

In the majority of tissues, the type of necrosis that most commonly occurs is called coagulative necrosis. In coagulative necrosis, proteins in the cytoplasm of the cell denature (unfold). As a result, the tissue as a whole becomes firmer and more opaque than normal. The process is similar to what happens when the white of an egg is cooked. At the cellular level, necrotic cells stain more intensely with a red dye called eosin than do normal cells. The nucleus of a necrotic cell may shrink (which is called pyknosis) and the chromatin (genetic material) may clump. The pyknotic nucleus may break up into fragments that are scattered around the cytoplasm (karyorrhexis) or even disintegrate (karyolysis).

Other types of necrosis may also occur. In the brain, necrotic cells often dissolve, leaving behind a fluid-filled cavity (as opposed to a scar). This is called liquefactive necrosis. Caseous necrosis is typically caused by the tuberculosis bacillus and certain fungi; here the necrotic tissue takes on a "cheesy" appearance. Fat necrosis occurs when enzymes released from damaged tissue convert fats into fatty acids and glycerol. It is most often seen in fatty tissue surrounding a damaged pancreas.

Infection of necrotic tissue with certain types of bacteria may lead to gangrene. Necrosis in the living patient can sometimes be detected by looking in the bloodstream for enzymes that have been released from the dead cells. A good example is creatine phosphokinase (CPK), which is released from dead cardiac muscle cells during a myocardial infarction. Calcium tends to deposit in necrotic tissue. This may be useful diagnostically. For example, malignant tumors may outgrow their blood supply, leading to necrosis at the center of the tumor mass. Deposition of calcium there can be detected radiographically (e.g., by mammography).

Bear in mind that necrosis is a pathological process. As necrotic cells die, they release their contents, some of which may damage other surrounding cells. An inflammatory reaction may ensue, leading to even more damage. How, then, does the body cope when it wants to remove cells for a specific purpose? Examples include developmental processes, remodeling of adult tissues (e.g., bone), removal of white blood cells from areas of inflammation, and elimination within the thymus of lymphocytes that react with the body’s own components. In these situations, cells are removed by a process called apoptosis, or programmed cell death. Apoptotic cells die without lysing (bursting apart). The dead cells are then ingested by macrophages. In this manner, no damaging substances are released from the cells, and injury to surrounding tissue and an inflammatory response are avoided.

To summarize, severely injured cells may undergo cloudy swelling, which can progress to hydropic degeneration. These processes are reversible up to a point. However, if the damage to the cell is too severe, the cell will die and undergo the series of changes that is collectively called necrosis. Necrosis is an irreversible process; it means a cell has died and cannot be resurrected.

CORRECTION TO THE DAMJANOV TEXT

Page 3, top left: The description of protein synthesis is INCORRECT. This paragraph should read as follows:

The genetic information encoded in the DNA is transcribed into messenger RNA (mRNA). The mRNA is transported to the cytoplasm, where it binds to ribosomes. Ribosomes are made up of ribosomal RNA (rRNA) and proteins. The mRNA (not the rRNA) serves as a template for translating genetic messages into protein. This is accomplished when transfer RNAs (tRNAs), to which are linked individual amino acids, bind to the mRNA held in the ribosome according to the sequence of nucleotide subunits in the mRNA. The amino acids carried by the tRNA are then linked together in the proper order to form the protein that is encoded by that particular mRNA. (The rest of the paragraph, describing the functions of proteins, is OK.)