The following section focuses on the causes of disease rather than on a detailed description of each entity. It represents one method of classification. There is considerable overlap in categories; certain diseases grouped as metabolic-endocrine in origin could also be classified as diseases of genetic origin. Indeed, the interdependence of the organ systems, the metabolic pathways, and the defense systems renders finite classification in medicine difficult. The human body acts as a unit—an individual—both in health and in disease.
The causes of disease
The search for the causes (etiologies) of human diseases goes back to antiquity. Hippocrates, a Greek physician of the 4th and 5th centuries b c, is credited with being the first to adopt the concept that disease is not a visitation of the gods but rather is caused by earthly influences. Scientists have since continually searched for the causes of disease and, indeed, have discovered the causes of many.
In the development of a disease (pathogenesis) more is involved than merely exposure to a causative agent. A room full of people may be exposed to a sufferer from a common cold, but only one or two may later develop a cold. Many host factors determine whether the agent will induce disease or not. Thus, in the pathogenesis of disease, the resistance, immunity, age, and nutritional state of the person exposed, as well as virulence or toxicity of the agent and the level of exposure, all play a role in determining whether disease develops.
In the following sections the many types of human disease will be divided into categories, and in each only a few examples will be given to establish the nature of the process. These categories are divided on the basis of the presumed etiology of the disease. Many diseases are still of unknown (idiopathic) origin. With others the cause may be suspected but not yet definitively proved. In a few instances the discovery of the etiology of a disease represents the individual achievement of a solitary investigator who may have worked many years on the problem; the story of Louis Pasteur and the discovery of the cause of anthrax is a classic example. More often the individual investigator who makes the final breakthrough stands on the shoulders of hundreds of earlier workers who provided bits and pieces of knowledge vital to the final understanding.
Certain human diseases result from mutations in the genetic complement (genome) contained in the deoxyribonucleic acid (DNA) of chromosomes. A gene is a discrete linear sequence of nucleotide bases (molecular units) of the DNA that codes for, or directs, the synthesis of a protein, and there may be as many as 100,000 genes in the human genome. Proteins, many of which are enzymes, carry out all cellular functions. Any alteration of the DNA may result in the defective synthesis and subsequent malfunctioning of one or more proteins. If the mutated protein is a key enzyme in normal metabolism, the error may have serious or fatal consequences. More than 5,000 distinct diseases have been ascribed to mutations that result in deficiencies of critical enzymes.
Mutations are classified on the basis of the extent of the alteration. Large mutations, which include alterations to chromosome structure and number, are relatively rare because most cause such major disruptions to development that the fetus is naturally aborted. However, certain alterations are not so immediately lethal, and the fetus can survive with a characteristic disorder. Down syndrome is one such case. It involves an error in the division of chromosome 21 that results in trisomy (three copies of a chromosome instead of two are inherited), bringing the total number of chromosomes to 47 instead of 46. Many characteristics such as distinctive facial features and mental retardation result from the presence of this extra chromosome. Smaller mutations are more common and include point mutations, in which substitution of a single nucleotide base occurs, and deletion or insertion mutations, which involve several bases. Point, deletion, and insertion mutations may cause an abnormal protein to be synthesized or may prevent the protein from being made at all.
Mutations that occur in the DNA of somatic (body) cells cannot be inherited, but they can cause congenital malformations and cancers (see below Abnormal growth of cells); however, mutations that occur in germ cells—i.e., the gametes, ova and sperm—are transmitted to offspring and are responsible for inherited diseases. Each gamete contributes one set of chromosomes and therefore one copy (allele) of each gene to the resultant offspring. If a gene bearing a mutation is passed on, it may cause a genetic disorder.
Genetic diseases caused by a mutation in one gene are inherited in either dominant or recessive fashion. In dominantly inherited conditions, only one mutant allele, which codes for a defective protein or does not produce a protein at all, is necessary for the disorder to occur. In recessively inherited disorders, two copies of a mutant gene are necessary for the disorder to manifest; if only one copy is inherited, the offspring is not affected, but the trait may continue to be passed on to future offspring. In addition to dominant or recessive transmission, genetic disorders may be inherited in an Autosomal or X-linked manner.
Autosomal genes are those not located on the sex chromosomes, X and Y; X-linked genes are those located on the X chromosomes that have no complementary genes on the Y chromosome. Females have two copies of the X chromosome, but males have an X and a Y chromosome. Because males have only one copy of the X chromosome, any mutation occurring in a gene on this chromosome will be expressed in male offspring regardless of whether its behaviour is recessive or dominant in females. Autosomal dominant disorders include Huntington’s chorea, a degenerative disease of the nervous system that usually does not develop until the carrier is between 30 and 40 years of age. The delayed onset of Huntington’s chorea allows this lethal gene to be passed on to offspring. Autosomal recessive diseases are more common and include cystic fibrosis, Tay-Sachs disease, and sickle cell anemia. X-linked dominant disorders are rare, but X-linked recessive diseases are relatively common and include Duchenne’s muscular dystrophy and hemophilia A.
Most genetic disorders can be detected at birth because the child is born with characteristic defects. Thus these abnormalities are congenital (existing at birth) genetic disorders. A few genetic defects, such as Huntington’s chorea mentioned above, do not become manifest until later in life. Hence it may be said that most but not all genetic diseases are congenital.
Conversely, some congenital diseases are not genetic in origin; instead they may arise from some direct injury to the developing fetus. If a woman contracts the viral disease German measles (rubella) during pregnancy, the virus may infect the fetus and alter its normal development, leading to some malformations, principally of the heart. These malformations constitute a congenital disease that is not genetic.
Further confusion often arises over the terms genetic and familial. A familial disease is hereditary, passed on from one generation to the next. It resides in a genetic mutation that is transmitted by mother or father (or both) through the gametes to their offspring. Not all genetic disorders are familial, however, because the mutation may arise for the first time during the formation of the gametes or during the early development of the fetus. Such an infant will have some genetic abnormality, though the parents themselves do not. Down syndrome is an example of a genetic disease that is not familial.
The causes of mutations are still poorly understood. Certain factors, however, are thought to be important. Maternal age plays an important role in predisposing toward genetic injury. The frequency of Down syndrome and of congenital malformations increases with the age of the mother. This may be so for a variety of reasons. Unlike men, who produce new sperm continually, women are born with all the eggs (ova) they will ever have. Thus the eggs are exposed to the same internal and external agents that the woman comes in contact with. The longer the exposure to such factors (i.e., the older the mother), the greater the chance of genetic injury to the ova. A paternal contribution to the disease also has been discovered—roughly 25 percent of cases may be caused by extra chromosomal material from the father. At present, the nature of the factors responsible for impaired division of chromosomes remains unknown.
Radiation is a well-recognized cause of chromosomal damage. The survivors of the atomic bomb blasts in Japan in 1945 have shown definite chromosomal abnormalities in certain types of their circulating white blood cells. Indeed, a higher incidence of leukemia (a form of cancer of white cells), as well as other cancers, has been reported in this population, suggesting that the chromosomal changes may have played some role in the induction of the disease (see also radiation: Biologic effects of ionizing radiation).
Viruses have been shown to cause mutations in human cells when the cells are grown in tissue culture, but there is no clear evidence that viral infections can cause genetic injury in humans. Instead, current evidence suggests that the oncogenic viruses implicated in some human cancers facilitate genetic mutations rather than cause them directly.
The induction of DNA mutations in cells by drugs and chemicals is complex. It involves metabolism of the drug by detoxification enzymes into reactive intermediates that damage DNA. The mutations that remain are those not removed by DNA repair enzymes. In contrast to viruses, drugs and chemicals have been shown to cause mutations not only in human cells in culture but also in a living host.
Diseases can be spread across a wide spectrum, with predominantly genetic diseases at one extreme of the spectrum and diseases of largely environmental origin at the other. In the genetic part of the spectrum are diseases such as Turner’s syndrome; in the environmental part are infectious diseases and chemical poisoning. Between these two extremes lie most human diseases—those with both genetic and environmental causative influences that are significant. Indeed, even at the very extreme ends of the spectrum both factors play some role. The genetic constitution dictates in part the host’s response to environmental challenges. Similarly, environmental factors play significant roles in the manifestation of genetically induced disease. Sickle cell anemia, for example, an inherited disease characterized by abnormal red blood cells and hemoglobin, is seriously exacerbated by low levels of oxygen in the air.
Furthermore, there are many disorders in which there is a familial tendency to develop the disease but no formal pattern of inheritance has been delineated. Many forms of cancer, high blood pressure, arthritis, and obesity, for example, seem to have a familial tendency. Although the exact roles of environmental and genetic factors are unknown in all these diseases, it is strongly felt that both factors contribute to the disease process.
A poison is any substance that can cause illness or death when ingested in small quantities. This definition excludes the multitude of substances that cause damage if ingested in large quantities. For example, even oxygen and glucose, so crucial to life, are toxic to cells when administered at high concentrations.
There are several considerations to keep in mind when one discusses poisoning. The first of these, as already suggested, is the degree of toxicity. A substance with a very high toxicity (such as cyanide) need be taken only in minute amounts to cause serious harm or death.
A second consideration is the mechanism by which a poison operates. Each poison acts at particular sites in the cell that are critical for the maintenance of homeostasis. These sites include the genome, whose expression dictates cell structure and function, and the cell membrane, which regulates ion transport, energy metabolism, and synthesis of vital proteins. Each poison also has a characteristic ability to cause damage at particular sites within the body, such as the liver, kidneys, or central nervous system.
A third factor is the body’s ability to eliminate the substance. Some chemicals, rapidly excreted in the urine, must act quickly while they remain transiently in the body. Others are poorly eliminated, and, because of this, a chronic ingestion of nontoxic amounts leads to a build-up in the body that can reach toxic levels. Lead poisoning is a good example of this phenomenon.
The route of entry is also important. Many substances are harmless when eaten but become deadly if injected into a vein. There are chemicals and drugs that are highly reactive and interact directly with an important cellular component to cause cell injury or death. Other chemicals or drugs that are not toxic per se become so following their metabolic conversion to toxic intermediates by the host. Similarly, the chemical form of a substance affects its action on the body. Metallic mercury, as found in thermometers, is harmlessly excreted, whereas the chloride salt of the same substance is deadly.
Finally, the condition of the host, the recipient of the poison, is an important consideration. A dose of aspirin (acetylsalicylic acid) that is harmless to an adult may be poisonous to an infant. Similarly, an elderly person’s tolerance of a substance may be much lower than that of a healthy young adult.
A wide variety of poisons exist, among which a few stand out as being the most commonly encountered in medical practice. Some are of relatively low toxicity but are important because of their widespread use. Many physicians consider aspirin the most dangerous poison because of its commonplace use and abuse and because it is the leading cause of poisoning in children. In the following paragraphs three groups of agents will be presented: (1) organic chemicals, (2) inorganic chemicals, and (3) drugs.
Among the organic chemicals commonly encountered in instances of poisoning are two forms of alcohol, ethyl alcohol (ethanol) and methyl alcohol (methanol). Ethyl alcohol is the form found in most alcoholic beverages. Methyl alcohol, or wood alcohol, is used for a variety of household purposes.
Acute ethyl alcohol poisoning is encountered after ingestion of large quantities over a relatively short time. The alcohol is quickly absorbed from the gastrointestinal tract, and high blood levels can be achieved in a remarkably short time. Ethyl alcohol acts principally as a central-nervous-system depressant and, fortunately, stupor usually results before fatal doses can be reached. The difference in blood levels between intoxication and fatal stupor is very slight, however, and death may result with the ingestion of large quantities of alcohol from depression of the respiratory centre in the brain.
Methyl alcohol is usually ingested either by accident or with suicidal intent. Once inside the body it is metabolized to formic acid, an extremely toxic substance that selects the nerves in the eye as its target. Without treatment, blindness results. Methyl alcohol also can affect the brain tissue itself.
Carbon monoxide is a non irritating, inert gas without colour, taste, or odour. A poison responsible for a large number of accidental and suicidal deaths, it is one of the chemical products of any combustion of organic material. Inhalation of a 1 percent concentration can be fatal within 10 to 20 minutes. Carbon monoxide acts as an internal asphyxiant causing oxygen starvation of tissues. It should be noted that exposure to even low concentrations can result in the slow accumulation of this poison over hours, days, or weeks, leading very gradually to toxic or fatal levels.
The inorganic chemicals most commonly responsible for poisonings are cyanide, mercury, arsenic, and lead. While the last three often appear in chemical forms that are quite harmless, it is the soluble salts of the substances that are poisons.
Cyanide is a dangerous substance in any form. It may occur in the form of hydrocyanic gas or as solid compounds such as potassium cyanide. It is one of the most lethal poisons known; an amount of 0.2 gram (0.007 ounce) administered to a 70-kilogram (154-pound) human causes death within minutes. Like carbon monoxide, it acts as a cellular asphyxiant.
Mercury in the pure metallic form is rather harmless, but the salt of the same substance, notably mercuric chloride, is a deadly poison. As little as 0.1 gram is enough to cause damage to body tissues, and 2 grams can cause death in a 70-kilogram person. This agent causes extensive tissue damage wherever high concentrations of the poison are encountered. When the substance is swallowed, the stomach represents the portal of entry. The mercuric chloride is partially absorbed into the blood, and this portion is excreted through the urine. The remainder affects organs in the digestive tract, principally the stomach and the colon, and the kidneys. Mercuric salts cause death of cells by precipitating the proteins within the cells, a form of cell injury called coagulative necrosis. With careful treatment, affected persons survive with full recovery. Chronic ingestion of smaller amounts of mercuric salts, as is seen in some industrial settings, can result in disease involving the mouth, skin, and nervous system.
Arsenic is contained in many items used around the house. Both odourless and tasteless compounds of arsenic are found in some rat poisons, plant sprays, paints, and other household preparations. Many of these household staples are ingested accidentally by children. Principally affected by arsenic are the blood vessels and the central nervous system; vascular collapse and depression of the central nervous system can be followed by coma and death within hours after ingestion.
The soluble salts of inorganic lead are also strong systemic poisons. They may accumulate within the body over a long period until toxic levels are reached and cell damage ensues. These salts were at one time commonly found in paints, and lead poisoning was frequently seen in children who chewed on their painted cribs or woodwork. Legislation in many countries has outlawed the use of lead-base paints for infants’ furniture. Other forms of poisoning are incurred through industrial exposure and ingestion of water from lead pipes. Lead poisoning damages red blood cells and leads to hemolysis (rupturing of red blood cells) with resulting anemia. In the brain, lead accumulation causes the degeneration of nerve cells. This produces such manifestations as mental depression, psychoses, convulsions, and even coma and death. If an early fatality does not occur, the lead is slowly excreted and complete recovery may be anticipated.
Drugs are another important cause of poisoning. It is a pharmacological principle that, for any therapeutic gain derived from a drug, a price is paid. There are few drugs used today that have no side effects (i.e., effects unintended when the drug is administered). Although these side effects may be harmless and inconsequential, certain drugs have side effects that are potent. Similarly, a drug may be useful in a certain dose range but harmful when larger doses are taken. Morphine, for example, is an excellent drug for the control of severe pain, but it can depress respiration, and too much of it can cause death. All drugs are, therefore, potentially harmful.
Barbiturates and salicylates are the major drugs commonly found to cause serious illness from over ingestion. Barbiturates affect the central nervous system almost exclusively. With toxic levels, the vital centres located within the midbrain are depressed; this leads to profound coma, depression of respiration, oxygen starvation of the tissues, and even shock. The identification of barbiturate poisoning relies almost exclusively on finding the substance in the blood or urine, because there is little anatomic change in tissues. Treatment is directed toward getting the drug out of the system as quickly as possible, either by inducing copious urinary excretion of the drug or by the use of the artificial kidney—a process called hemodialysis.
Aspirin, or acetylsalicylic acid, is a drug that deserves special mention because it is such a common household item and often within the reach of small children. Approximately 10 to 30 grams of aspirin can be fatal in adults, and much smaller amounts can be fatal in children. (A single aspirin tablet of standard size contains approximately one-third gram.) There are many signs and symptoms associated with salicylate poisoning, including headaches, drowsiness, dyspepsia, nausea, vomiting, sweating, and thirst. Salicylate poisoning is an acute medical emergency. Rigorous medical treatment is demanded, and use of the artificial kidney is often required.
Physical injuries include those caused by mechanical trauma, heat and cold, electrical discharges, changes in pressure, and radiation. Mechanical trauma is an injury to any portion of the body from a blow, crush, cut, or penetrating wound. The complications of mechanical trauma are usually related to fracture, hemorrhage, and infection. They do not necessarily have to appear immediately after occurrence of the injury. Slow internal bleeding may remain masked for days and lead to an eventual emergency. Similarly, wound infection and even systemic infection are rarely detectable until many days after the damage. All significant mechanical injuries must therefore be kept under observation for days or even weeks.
Among physical injuries are injuries caused by cold or heat. Prolonged exposure of tissue to freezing temperatures causes tissue damage known as frostbite. Several factors predispose to frostbite, such as malnutrition leading to a loss of the fatty layer under the skin, lack of adequate clothing, and any type of insufficiency of the peripheral blood vessels, all of which increase the loss of body heat.
When the entire body is exposed to low temperatures over a long period, the result can be alarming. At first blood is diverted from the skin to deeper areas of the body, resulting in anoxia (lack of oxygen) and damage to the skin and the tissues under the skin, including the walls of the small vessels. This damage to the small blood vessels leads to swelling of the tissues beneath the skin as fluid seeps out of the vessels.
When the exposure is prolonged, it leads eventually to cooling of the blood itself. Once this has occurred, the results are catastrophic. All the vital organs become affected, and death usually ensues.
Burns may be divided into three categories depending on severity. A first-degree burn is the least destructive and affects the most superficial layer of skin, the epidermis. Sunburn is an example of a first-degree burn. The symptoms are pain and some swelling. A second-degree burn is a deeper and hence more severe injury. It is characterized by blistering and often considerable edema (swelling). A third-degree burn is extremely serious; the entire thickness of the skin is destroyed, along with deeper structures such as muscles. Because the nerve endings are destroyed in such burns, the wound is surprisingly painless in the areas of worst involvement.
The outlook in burn injuries is dependent on the age of the victim and the percent of total body area affected. Loss of fluid and electrolytes and infection associated with loss of skin provide the major causes of burn mortality.
The injurious effects of an electrical current passing through the body are determined by its voltage, its amperage, and the resistance of the tissues in the pathway of the current. It must be emphasized that exposure to electricity can be harmful only if there is a contact point of entry and a discharge point through which the current leaves the body. If the body is well insulated against such passage, at the point of either entry or discharge, no current flows and no injury results. The voltage of current refers to its electromotive force, the amperage to its intensity. With high-voltage discharges, such as are encountered when an individual is struck by lightning, the major effect is to disrupt nervous impulses; death is usually caused by interruption of the regulatory impulses of the heart. In low-voltage currents, such as are more likely to be encountered in accidental exposure to house or industrial currents, death is more often due to the stimulation of nerve pathways that cause sustained contractions of muscles and may in this way block respiration. If the electrical shock does not produce immediate death, serious illness may result from the damage incurred by organs in the pathway of the electrical current passing through the body.
Physical injuries from pressure change are of two general types: (1) blast injury and (2) the effects of too-rapid changes in the atmospheric pressure in the environment. Blast injuries may be transmitted through air or water; their effect depends on the area of the body exposed to the blast. If it is an air blast, the entire body is subject to the strong wave of compression, which is followed immediately by a wave of lowered pressure. In effect the body is first violently squeezed and then suddenly over expanded as the pressure waves move beyond the body. The chest or abdomen may suffer injuries from the compression, but it is the negative pressure following the wave that induces most of the damage, since overexpansion leads to rupture of the lungs and of other internal organs, particularly the intestines. If the blast injury is transmitted through water, the victim is usually floating, and only that part of the body underwater is exposed. An individual floating on the surface of the water may simply be popped out of the water like a cork and totally escape injury.
Decompression sickness is a disease caused by a too-rapid reduction in atmospheric pressure. Underwater divers, pilots of unpressurized aircraft, and persons who work underwater or below the surface of the Earth are subject to this disorder. As the atmospheric pressure lessens, dissolved gases in the tissues come out of solution. If this occurs slowly, the gases diffuse into the bloodstream and are eventually expelled from the body; if this occurs too quickly, bubbles will form in the tissues and blood. The oxygen in these bubbles is rapidly dissolved, but the nitrogen, which is a significant component of air, is less soluble and persists as bubbles of gas that block small blood vessels. Affected individuals suffer excruciating pain, principally in the muscles, which causes them to bend over in agony—hence the term “bends” used to describe this disorder.
Radiation can result in both beneficial and dangerous biological effects. There are basically two forms of radiation: particulate, composed of very fast-moving particles (alpha and beta particles, neutrons, and deuterons), and electromagnetic radiation such as gamma rays and X rays. From a biological point of view, the most important attribute of radiant energy is its ability to cause ionization—to form positively or negatively charged particles in the body tissues that it encounters, thereby altering and, in some cases, damaging the chemical composition of the cells. DNA is highly susceptible to ionizing radiation. Cells and tissues may therefore die because of damage to enzymes, because of the inability of the cell to survive with a defective complement of DNA, or because cells are unable to divide. The cell is most susceptible to irradiation during the process of division. The severity of radiation injury is dependent on the penetrability of the radiation, the area of the body exposed to radiation, and the duration of exposure, variables that determine the total amount of radiant energy absorbed.
When the radiation exposure is confined to a part of the body and is delivered in divided doses, a frequent practice in the treatment of cancer, its effect depends on the vulnerability of the cell types in the body to this form of energy. Some cells, such as those that divide actively, are particularly sensitive to radiation. In this category are the cells of the bone marrow, spleen, lymph nodes, sex glands, and lining of the stomach and intestines. In contrast, permanently non dividing cells of the body such as nerve and muscle cells are resistant to radiation. The goal of radiation therapy of tumours is to deliver a dosage to the tumours that is sufficient to destroy the cancer cells without too severely injuring the normal cells in the pathway of the radiation. Obviously, when an internal cancer is treated, the skin, underlying fat, muscles, and nearby organs are unavoidably exposed to the radiation. The possibility of delivering effective doses of radiation to the unwanted cancer depends on the ability of the normal cells to withstand the radiation. However, as is the case in drug therapy, radiation treatment is a two-edged sword with both positive and negative aspects.
Finally, there are probable deleterious effects of radiation in producing congenital malformations, certain leukaemia’s, and possibly some genetic disorders (see radiation: Biologic effects of ionizing radiation).
The immune system protects against infectious disease, but it may also at times cause disease. Disorders of the immune system fall into two broad categories: (1) those that arise when some aspect of the host’s immune mechanism fails to prevent infection (immune deficiencies) and (2) those that occur when the immune response is directed at an inappropriate antigen, such as a noninfectious agent in an allergic reaction, the body’s own antigens in an autoimmune response, or the cells of a transplanted organ in graft rejection.
The immune system may fail to function for many reasons. Many immunodeficiency disorders are caused by a genetic defect in some component of the system and thus usually manifest early in life. Some deficiencies, however, are acquired through the action of infectious agents such as viruses, through the action of immunosuppressive agents used to treat various medical conditions, and through the effects of certain disease processes such as cancer. Both inherited and acquired immune deficiencies suppress one or many aspects of the immune response, rendering the affected individual unable to resist infection unless treated by administration of immunoglobulins or by bone marrow transplant.
Inherited immune disorders undermine the immune response in a variety of ways: B lymphocytes may be unable to produce antibodies, phagocytes may be unable to digest microbes, or specific complement components may not be produced. Severe combined immunodeficiency (SCID), a condition that arises from several different genetic defects, disrupts the functioning of both the humoral and cell-mediated immune responses.
Acquired immune deficiency syndrome (AIDS) is caused by infection with the human immunodeficiency virus (HIV), which destroys a certain type of T lymphocyte, the helper T cell. An infected individual is susceptible to a variety of infectious organisms, including those called opportunistic pathogens, which may live benignly in the human body and cause disease only when the immune system is suppressed. Certain diseases such as Kaposi’s sarcoma and Pneumocystis carinii pneumonia, which until recently were rarely encountered by clinicians, have become prevalent in the AIDS population and are often the cause of mortality.
The immune system may react to any foreign substance, and consequently it can respond to innocuous materials in the same way that it responds to infectious agents. If the foreign material poses no threat to the individual, an immune response is unnecessary, but it nevertheless may ensue. This misplaced response is called an allergy, or hypersensitivity, and the foreign material is referred to as an allergen. Common allergens include pollen, dust, bee venom, and various foods such as shellfish. What causes one person and not another to develop an allergy is not completely understood.
An allergic response occurs in the following manner. On first exposure to the allergen, the person becomes sensitized to it—that is, develops antibodies and specific T cells to the allergen. An allergic reaction does not usually accompany this initial event. When reexposure occurs, however, symptoms of the allergic response appear. These symptoms range from the mild response of sneezing and a runny nose to the sometimes life-threatening reaction of anaphylaxis, or anaphylactic shock, symptoms of which include vascular collapse and potentially fatal respiratory distress.
Allergic reactions exhibit different symptoms depending on which immune mechanisms are responsible. On the basis of this criterion, they can be categorized into four types, the first three of which involve antibodies and occur in a matter of minutes or hours. Type I hypersensitivity, which occurs immediately after the sensitized person comes in contact again with the allergen, is responsible for most common allergies. The allergen reacts with antibodies attached to the surface of either of two types of cells: mast cells, which are scattered throughout the supporting tissues of the body, and basophilic leukocytes (white blood cells that stain readily with basic dyes), which circulate in the blood. The cells release various substances such as histamine, which causes dilation of blood vessels and contraction of smooth muscles in the bronchial airways, characteristic symptoms of asthma and anaphylaxis. In type II, or cytotoxic, reactions, antibodies are not bound to cells, as in the type I reaction, but circulate freely and interact with cell-bound antigens in the same way that antibodies bind to cells containing infectious agents. Complement is usually activated, leading to cell destruction.
A special class of type II hypersensitivity involves an immune response to certain “self” proteins (antigens that belong to the host) on the surface of cells, a mechanism that underlies autoimmune disorders such as autoimmune hemolytic anemia (see below Autoimmune disorders). Type III, or immune-complex, reactions are directed against soluble antigens. Circulating antibodies combine with antigens, usually not bound to the cell surface, to form an immune complex, which is deposited in tissues or the walls of blood vessels. The complex attracts complement, to which polymorphonuclear leukocytes are drawn. These cells then release powerful enzymes that cause inflammation and vessel damage. Immune complexes also form in autoimmune disorders such as rheumatoid arthritis. Type IV hypersensitivity, unlike the other reactions, does not involve antibodies but instead is mediated by T cells. In these reactions, also called delayed-type because they arise in a matter of days rather than minutes or hours, T cells either activate a local inflammatory reaction, which can cause extensive tissue damage, or they kill tissue cells directly. Chronic inflammation characteristic of many autoimmune disorders, such as chronic thyroiditis, results from this reaction. With the exception of the type I response, all responses are seen in both allergies and autoimmune disorders.
Immune responses can be mounted against proteins that belong to the host, giving rise to autoimmune diseases. Although the immune system naturally generates antibodies to its own cells, mechanisms exist to keep this activity in check. Two mechanisms that prevent the immune system from mounting an attack against the host’s own tissues have been identified. The first involves the elimination of self-reactive lymphocytes during their development and maturation in the thymus, a lymphoid organ in the chest. Self-reactive lymphocytes present in these cell populations are destroyed when they encounter the self-antigen to which they react. Because this protective selection process is not highly efficient, some self-reactive lymphocytes survive, exit the thymus, and enter the blood and tissues. Outside the thymus a second line of defense against immune self-destruction is afforded in which self-reactive lymphocytes lose their ability to react to self-antigens when they are encountered in blood and tissues. This state is referred to as immunologic ignorance. Autoimmune diseases arise when this mechanism fails and self-reactive lymphocytes are activated by self-antigens in the host’s own tissues, often with devastating effects. Systemic lupus erythematosus, thyroiditis, insulin-dependent diabetes mellitus, and rheumatoid arthritis are examples of this type of disorder.
Transplantation of organs and cells from one individual to another has become an important medical treatment. As are other forms of therapy, it is accompanied by certain risks. Each individual’s cells have a spectrum of genetically determined cell surface protein antigens, the major histocompatibility complex (MHC) antigens, or human leukocyte antigens as they are referred to in humans. MHC antigens determine a person’s tissue type just as red blood cell antigens determine blood type. There are two classes of MHC antigens: class I molecules, encoded by three genes, and class II molecules, encoded by four possible sets of genes. Each of these genes has many alternative forms, and thus the probability of any two individuals—aside from siblings, especially identical twins—having the same form of each gene is extremely small. Even parents will have different tissue antigens from their children.
These differences in tissue antigens pose an obstacle to transplantation because it is highly likely that foreign donor tissue will introduce antigens in the recipient that will trigger an immune response leading to tissue death and rejection. However, by careful matching of the MHC type of donor and recipient, rejection can be diminished or avoided. Because perfect matching is possible only between identical twins or very close relatives, many transplants occur between less closely matched tissue types, and success is achieved with the administration of powerful immunosuppressive drugs.
Biotic agents include life-forms that range in size from the smallest virus, measuring approximately 20 nanometres (0.000 000 8 inch) in diameter, to tapeworms that achieve lengths of 10 metres (33 feet). These agents are commonly grouped as viruses, rickettsiae, bacteria, fungi, and parasites. The disease that these organisms cause is only incidental to their struggle for survival. Most of these agents do not require a human host for their life cycles. Many survive readily in soil, water, or lower animal species and are harmless to humans. Other living organisms, which require the temperature range of endothermic (warm-blooded) animals, may flourish on the skin or in the secretions of fluids of the mouth or intestinal tract but do not invade tissue or cause disease under normal conditions. Thus there is a distinction to be made between infection and disease.
All animals are infected with biotic agents. Those agents that do not cause disease are termed nonpathogenic, or commensal. Those that invade and cause disease are termed pathogenic. Streptococcus viridans bacteria, for example, are found in the throats of more than 90 percent of healthy persons. In this area they are not considered pathogenic. The same organism cultured from the bloodstream, however, is highly pathogenic and usually indicates the presence of the disease subacute bacterial endocarditis (chronic bacterial invasion of the valves of the heart). In order for such nonpathogenic agents to achieve pathogenicity, they obviously must overcome the defenses of the host. Most biotic agents require a portal of entry through the intact skin or mucosal linings of the body. They must be present in sufficient number to escape the phagocytes. They must be capable of surviving the inflammatory and immune response. Ultimately, to induce disease, they must have sufficient virulence and invasiveness to cause significant tissue injury.
Invasiveness is the capability of penetrating and spreading throughout tissues. Remarkably, little is known of the factors that condition it. In a few instances enzymes produced by biotic agents have been identified that are capable of breaking down the integrity of the supporting tissues of the body, thereby preparing a pathway for the spread of the organism.
Only very few bacteria release such enzymes, however, and there are marked differences in invasiveness to be found among the various types of bacteria. The organism that causes diphtheria (Corynebacterium diphtheriae), for example, is capable of invading only the surface cells of the mouth and throat. The disease that results is caused by the production of a powerful exotoxin (a chemical substance produced by the organism and released into the surrounding tissues) that is absorbed into the bloodstream from the local infection within the throat. This exotoxin causes major damage in the heart and the nervous system. The diphtheria bacillus, therefore, is an example of a serious infection in which the organism has low invasiveness. In contrast, the bacterium that causes syphilis (Treponema pallidum) has a high degree of invasiveness. It is one of the rare biotic agents that are capable of penetrating intact skin and mucosal linings of the body.
The invasiveness of viruses undoubtedly is facilitated by their extremely small size, but, because of this size, the exact mechanism is difficult to study. In the case of fungi and parasites, the invasiveness is related to the life cycle of the organism. The formation of tiny spores by fungi and the smaller reproductive forms of the parasites provide vehicles by which infection may be drawn into the lungs or may pass through tiny defects in the skin or mucosal linings of the various openings and tracts of the body.
In general, virulence is the degree of toxicity or the injury-producing potential of a microorganism. The words virulence and pathogenicity are often used interchangeably. The virulence of bacteria usually relates to their capability of producing a powerful exotoxin or endotoxin. Invasiveness also adds to an organism’s virulence by permitting it to spread.
Up to this point, diseases caused by biotic agents have been considered in terms of the role of the invader. Equally important is the role of the host, the individual who contracts the disease. Any infectious disease is a test between the invader and the defender. Virulent organisms may be capable of inducing serious illness even in the most robust. The converse is perhaps more important. The weak host is prey to many forms of biotic infection, even those of low virulence and invasiveness. Some of the more important of the many factors that condition the level of resistance to biotic infection in the individual are age, with infancy and old age being times of maximum vulnerability; poor nutrition; genetic disorders and immunosuppressive agents, such as the human immunodeficiency virus, that compromise the immunologic system; and metabolic disorders such as diabetes that increase vulnerability to infectious agents.
Therapeutic agents, paradoxically, also have become important factors in predisposing to disease of biotic origin and indeed in altering the incidence patterns of infectious disease. The drugs that are principally involved include those used to suppress the immune response, as well as the host of antimicrobial and antibiotic agents now employed in the treatment of infectious disease. Immunosuppressive drugs are used to block the immune response in patients about to receive an organ transplant and in the treatment of the autoimmune diseases, but such treatment renders the patient vulnerable to attack by biotic agents. Indeed, these immunologically compromised persons become susceptible to organisms of extremely low virulence.
Antimicrobial drugs also have drawbacks as well as benefits. A patient suffering from a streptococcal disease, for example, may appropriately be treated with penicillin. Certain strains of staphylococci, however, are resistant to penicillin. Although the streptococcal organisms, as well as other commensals, may be eradicated by the antibiotic, the resistant staphylococci begin to proliferate, possibly because the competition with other bacteria for nutrients and food supply has been removed. In this noncompetitive situation they may cause disease. More powerful antibiotics may destroy all bacteria, including staphylococci, but permit the unrestrained proliferation of fungi and other agents of low virulence that are nonetheless resistant to the antibiotic. Thus antibiotics have changed the entire frequency pattern of biotic disease. Organisms that have proved to be more resistant to antibiotics have become the more common causes of serious clinical infection. For this reason certain forms of drug-resistant bacteria that include Escherichia coli, Aerobacter aerogenes, Pseudomonas aeruginosa, and strains of Proteus as well as fungi have emerged as the important biotic causes of death.
Of the many existing viruses, a few are of great importance as causes of human sickness. They are responsible for such diseases as smallpox, poliomyelitis, encephalitis, influenza, yellow fever, measles, and mumps and such minor disorders as warts and the common cold.
Viruses may survive for some time in the soil, in water, or in milk, but they cannot multiply unless they invade or parasitize living cells. Certain viruses proliferate within the host cells and accumulate in sufficient number to cause rupture and death of the cells. Others multiply within the cell body and compete with the host for nutrition or vital constituents of the cell’s metabolism. Both types of viruses are said to be cytotoxic.
Viral agents, particularly those capable of producing tumours in humans and lower animals, flourish within cells and stimulate the cells to active growth. These viruses are referred to as oncogenic (tumour-producing). The number of oncogenic viruses that cause tumours in lower animals is large. In humans, several DNA viruses and one RNA virus have been implicated strongly in the induction of a variety of tumours.
Most viral infections occur in childhood. This age distribution has been explained on immunologic grounds. Viruses usually induce a firm and enduring immunity. On first exposure to a virus, children may or may not contract the disease, depending on their resistance, the size of the infective dose of virus, and many other variables. Those who contract the disease, as well as those who resist the infection, develop a permanent immunity to any further exposure. By either pathway, as children grow older they progressively gather protection against viral infections. Consequently, the incidence of these infections falls in adulthood and later life. The frequency of common colds is explained on the grounds that a host of different viral agents all induce similar respiratory infections, and, while a single attack confers immunity against the specific causative agent, it provides no protection against the rest.
Viral diseases are resistant to antibiotics and other antimicrobial agents. This point is made because of a distressing tendency among individuals to take penicillin or another antibiotic for a common cold.
Human rickettsial diseases are caused by microorganisms that fall between viruses and bacteria in size. These minute agents are barely visible under the ordinary light microscope. Like viruses, they multiply only within the cells of susceptible hosts. They are found in nature in a variety of ticks and lice and, when transmitted to humans by the bite of one of these arthropods, usually cause acute febrile (fever-producing) illnesses, most of which are characterized by skin rashes. Rocky Mountain spotted fever, a systemic rickettsial infection, invades and kills the cells lining blood vessels and causes hemorrhagic, inflammation, blood clots, and extensive tissue death; if untreated, it is fatal in about 20 to 30 percent of cases.
The diseases produced by bacteria are the most common of infectious biotic diseases. They range from trivial skin infections to such devastating disorders as bubonic plague and tuberculosis. Various types of pneumonia; infections of the cerebrospinal fluid (meningitis), the liver, and the kidneys; and the sexually transmitted diseases syphilis and gonorrhea are all forms of bacterial infection.
All bacteria induce disease by one of three methods: (1) the production of an exotoxin, a harmful chemical substance that is secreted or excreted by the bacterium (as in food poisoning caused by Clostridium botulinum), (2) the elaboration of an endotoxin, a harmful chemical substance that is liberated only after disintegration of the micro-organism (as in typhoid, caused by Salmonella typhi), or (3) the induction of sensitivity within the host to antigenic properties of the bacterial organism (as in tuberculosis, after sensitization to Mycobacterium tuberculosis).
Diseases caused by fungi and parasites are relatively uncommon in developed countries. Fungal infections, also known as mycotic infections, may affect the skin surfaces or the internal organs of the body. The superficial mycotic infections are generally not serious and include such well-known disorders as athlete’s foot (tinea pedis), caused by the dermatophyte Trichophyton. Deep mycotic infections such as histoplasmosis and candidiasis are potentially life-threatening.
Other parasites that attack humans range in size from unicellular organisms such as Entamoeba histolytica to such multicellular forms as tapeworms and roundworms. Most parasitic infestations are encountered in the less-developed areas of the world where sanitation is not optimal. Indeed, parasitic infestations constitute major causes of death in regions of Central and South America, Africa, India, and Asia. (For additional information about diseases of biotic origin.)
The growth of cells in the body is a closely controlled function, which, together with limited and regulated expression of various genes, gives rise to the many different tissues that constitute the whole organism. For the most part, control of cell growth persists throughout life except for episodic instances such as healing of an injured tissue. In this situation the growth of a localized group of cells is accelerated to reconstitute the tissue to its previous state of normal structure and function, following which tightly regulated growth resumes. Such areas of increased cell growth are referred to as hyperplasias; they consist of expanded numbers of normal-appearing cells and, depending on the duration of growth, can result in an enlargement of tissues and organs. In general, hyperplasias arise to meet special needs of the body and subside once these needs are met. Hyperplasias are the result of the sustained impact over time of stimulatory influences together with a loss of growth-inhibitory factors that are normally found within or around cells. As long as the loss of inhibition of cell growth is temporary, the capacity for enhanced cell proliferation when necessary has obvious advantages. However, if cells permanently lose their ability to respond to growth-inhibitory factors, their growth becomes irrepressible, and cancer may result.
Diseases arising from uncontrolled cell growth and behaviour collectively constitute the second most common cause of human death (the most common cause being heart disease). Cancers, the most important form of abnormal growth and behaviour, were responsible for approximately 538,000 deaths, or almost one-fourth of all deaths, in the United States in 1994. The significance of this incidence is placed in proper perspective by a consideration of the following facts. While cancer arises at all stages of life, its incidence (number of cases) increases with age, reaching a peak between 55 and 74 years. This fact, together with the increasing longevity of the general population and improved diagnostic modalities that enable clinicians to detect cancers with greater frequency, tempers the notion that the incidence of cancer is increasing.
In addition to cancers—malignant tumours that may eventually kill the host—there are benign tumours that rarely produce serious disease. The two types of tumours are collectively referred to as neoplasms (new growths), and their study is known as oncology. Tumours are referred to as malignant or benign based on the structural and functional properties of their component cells and their biological behaviour. The cells and tissues of malignant tumours differ from the tissues from which they arise. They exhibit more rapid growth and altered structure and function, including stimulation of new blood vessel growth (angiogenesis) and a capacity to invade adjacent normal tissues, enter the blood vascular system, and spread (metastasize) to distant sites. The properties of malignant tumour cells serve to enhance and support their proliferation and extension throughout the body tissues and organs, eventually leading to death of the host. In contrast, the cells and tissues of benign tumours tend to grow more slowly and in general closely resemble their normal tissues of origin. When the structure and function of benign tumour cells are morphologically and functionally indistinguishable from those of normal cells, their growth as a tumour mass is the sole feature indicative of their neoplastic nature. It is hoped that a greater understanding of malignant cell growth and behaviour will lead to the development of novel cancer therapies based on tumour cell biology that will complement or replace the current treatments of surgical extirpation (complete excision), chemotherapy, and radiation.
Epidemiological studies of the worldwide incidence of cancers have identified striking differences among countries and population groups. For example, the incidence of and death rates for skin cancer are much higher in Australia and New Zealand than in the Scandinavian countries—presumably because of the marked differences between these two regions in total annual hours of exposure to sunlight. The importance of environmental influences is highlighted by comparing the incidence of and death rates for cancers among populations in different geographic regions. For example, prostate and colon cancer rates in Japanese persons living in Japan differ from the rates in Japanese persons who have emigrated to the United States, the rates of their offspring born in California, and the rates of long-term white residents of that state. These rates are much lower among Japanese living in Japan than they are in white Californians. However, the rates for each type of tumour among first-generation Japanese immigrants are intermediate between the rates in Japan and those in California, suggesting that environmental and cultural factors may play a more important role than genetic ones.
The irreversibility of the structural and behavioral changes of cancer cells has long been recognized and has favoured the postulate that they are probably due to permanent genetic alterations. This postulate remained speculative until the discovery in 1979 that oncogenes (cancer-causing genes) are derived from proto-oncogenes (normal growth-regulatory cellular genes). When proto-oncogenes become mutated or deregulated, they are converted to oncogenes, which are capable of causing the malignant transformation of cells, including those of humans. Cellular proto-oncogenes code for proteins involved in cell regulation, such as growth factors, their receptors, and transmembrane signal transducers. Thus, changes in the structure of proto-oncogenes and their conversion to oncogenes results in the synthesis of abnormal proteins that are incapable of carrying out their usual growth-regulatory functions. In identifying the genes involved in the development of cancer, researchers discovered a group of cellular genes—tumour-suppressor, or suppressor, genes—whose protein products normally negatively regulate cell growth by suppressing cell proliferation, thus counterbalancing the growth-stimulatory effects of proteins synthesized by proto-oncogenes. Genetic analyses of various animal and human cancers have demonstrated that, in the majority, alterations of oncogenes and suppressor genes were often simultaneously present. These analyses suggest that multiple genetic alterations involving growth-stimulatory and growth-inhibitory genes are required for the induction of malignancy. Such discoveries have ushered in a new era in cancer biology and may well lead to the eventual control, cure, and prevention of malignant diseases.
The many causes of cancer include intrinsic factors, such as heredity, and extrinsic factors, such as environment and lifestyle. Hereditary causes of cancer are less common and are due to the inheritance of a single mutant gene that greatly increases the risk of developing a malignant tumour. Such cancers include (1) a childhood tumour of the eye, retinoblastoma, and a bone tumour, osteosarcoma, both of which involve the loss of a tumour suppressor gene, and (2) familial adenomatous polyposis, in which all patients develop colon cancer by age 50. The most common types of cancer that occur sporadically, such as cancers of the breast, ovary, colon, and pancreas, also have been documented to occur in familial forms. The children in such families appear to have a two- to threefold increased risk of developing a particular tumour, but the transmission pattern is unclear. A still rarer hereditary cause of cancer is an inherited deficiency in the ability to repair DNA. Patients with this defect (known as xeroderma pigmentosum) are particularly sensitive to sunlight and develop skin cancer during early adolescence because of unrepaired mutations induced by ultraviolet (UV) light.
Although the environment contains many agents that can cause cancer in humans, the extent to which they contribute to the human disease is often difficult to assess. For example, the link between tobacco smoking and lung cancer is clear; however, little is known about the cause of cancer of the prostate, the most common form of cancer in males, despite the fact that many factors—including age, race, male hormone, increased consumption of dietary fat, and a genetic basis—have been implicated.
Three categories of carcinogens (chemical or physical agents that mutate DNA) that induce cancer in experimental animals and humans have been identified in the environment: (1) chemicals, (2) radiant energy, and (3) oncogenic viruses.
Chemicals capable of causing cancer arise from a variety of sources. These include certain synthetic chemicals used in industry, some natural compounds formed during the curing and burning of tobacco, compounds formed during the cooking of meat, and chemicals present in certain plants and molds. Two categories have been identified, those capable of causing DNA damage and mutations directly (genotoxic, or direct-acting, carcinogens) and those that require prior metabolic activation by cells of the host to be converted to mutagens (epigenic, or indirect-acting, carcinogens). In the industrial countries much progress has been made in significantly decreasing and preventing exposure to chemical carcinogens in the workplace. However, exposure to carcinogens as a consequence of cultural practices, such as tobacco smoking and the cooking and consumption of meats, is difficult if not impossible to control or eradicate.
Sustained exposure to two forms of radiant energy—namely, UV light and ionizing radiation—is carcinogenic for humans. Repeated and sustained exposure to UV rays emanating from the Sun causes mutations of DNA that ultimately are capable of inducing three different types of skin cancer. As one would expect, the incidence of UV-induced skin cancer is high among farmers, sailors, and sunbathing enthusiasts. The degree of risk depends on the extent of exposure and the amount of melanin pigment in the skin, which absorbs UV rays. Dark-skinned individuals are protected by the high content of melanin in their skin; in contrast, fair-skinned persons and albinos have very little or no protective melanin pigment in their skin.
The carcinogenic effects of ionizing radiation first became apparent from the results of inappropriate exposure of early uranium ore miners and of physicians who first used X-ray machines for diagnostic purposes and were unaware of the health hazards. The devastating complications that resulted are rare today because of stricter indications for the use of radiation therapy, careful focusing of radiation beams, and effective shielding of adjacent normal tissues. However, the risks of exposure to ionizing radiation have been reemphasized from time to time by the appearance of neoplastic disease following radiation therapy and following the release of enormous amounts of radiation into the environment, as occurred from atomic bombing of Hiroshima and Nagasaki in Japan and the accident at the Chernobyl nuclear power station in Ukraine.
Reactive forms of carcinogenic chemicals and, in the case of ionizing radiation, reactive forms of oxygen damage DNA directly. If repair of damaged DNA is slow, error-prone, or not accomplished at all and cell replication occurs, the damage is amplified and becomes a permanent (fixed) mutation.
In recent years certain DNA viruses have been strongly implicated as causal agents for a variety of cancers in humans. These include human papillomavirus (HPV) as a cause of genital cancers in both sexes worldwide, the Epstein-Barr virus (EBV) for childhood lymphoma in Africa and cancer of the nose and throat in Asia and Africa, and the hepatitis viruses B and C that cause liver cancer worldwide with the highest incidence in Asia and Africa. However, at present only one type of human cancer, the rare adult T-cell leukemia, has been solidly linked to infection with an RNA virus, the human T-cell leukemia virus (HTLV-1). While much experimental and clinical evidence supports the carcinogenic role of the above-mentioned viruses in humans, additional research suggests that other factors also may be required. Observations that support the multifactorial nature of viral carcinogenesis include the continuous but not neoplastic growth of human cells infected in culture with HPV, the restricted geographic distribution of cancers induced by EBV, and the lack of either an oncoprotein (protein product produced by an oncogene) for HBV or evidence of consistent integration of the virus near a proto-oncogene encoding for a growth-regulatory protein. Thus far, oncogenic viruses have not been shown to induce DNA mutations directly in human cells; rather, their contribution seems to lie in promoting and hastening the process of mutation. (For greater detail on how viruses contribute to the induction of cancer, see the articles cancer and virus.)
The term metabolism encompasses all the chemical reactions vital to the growth and maintenance of the body. Defects in metabolism are found in almost every disease condition. Most are secondary; i.e., they result from some other basic disorder (infection, kidney disease, or heart disease, for example). In a few primary metabolic disorders, small genetic mutations lead to structural alterations of specific proteins that disrupt protein function and are responsible for the disease state. At this point, another group of primary metabolic disorders—those associated with hormonal defects—will be touched on.
Hormones are large organic molecules secreted in small amounts by specific cells in the various endocrine (ductless) glands. These secretions are carried by the blood to distant sites (target organs), where they bind to specific receptors on target cells and act to regulate specific chemical reactions.
All endocrine disease stems from either an overproduction (hyperfunction) or underproduction (hypofunction) of some hormone-secreting endocrine gland. There are relatively few causes of hormone overproduction. In general, overproduction results from hyperplasia, an increase in the number of cells (in this case, hormone-secreting cells) in a specific endocrine gland. It can also be caused by neoplasia, the growth of a tumour in an endocrine gland. Although most endocrine tumours are benign, the resulting hypersecretion of hormone can have far-reaching effects. For example, the pituitary gland, tucked into the base of the skull, produces many hormones that have far-ranging effects, mostly controlling the function of the other endocrine glands, such as the thyroid, adrenals, ovaries, and testes. Acromegaly, characterized by the enlargement of many skeletal parts, is a rare endocrine disease caused by excess secretion of pituitary growth hormone in the adult. An example of hormone overproduction because of hyperplasia is hyperthyroidism, the disease produced by an excess of thyroid hormone. It is characterized by a rapid pulse, increased sweating, weight loss, heat intolerance, and frequent disturbances in the heart rhythm. Cushing’s syndrome, an exception to the generalization that hypersecretion of hormones is due to either neoplasia or hyperplasia, results from an overproduction of the adrenal steroid hormones (such as cortisol). Although the disease is occasionally caused by tumours or by hyperplasia of the adrenals, in most instances it is not. It has been suggested that the disease results from excessive adrenocorticotropic hormone (ACTH) from the pituitary; in rare cases when the level of ACTH is not elevated, it is thought that autoantibodies to ACTH receptors cause the hyperplasia.
Underproduction of hormone is most often the result of destruction of hormone-secreting cells. This destruction may be caused by infection, infarction (tissue death due to loss of blood supply), or obliteration of endocrine glands by cancer. Underproduction of hormone also may result from failure of the gland to undergo normal fetal development, or it may be a feature of an autoimmune disease (as in juvenile diabetes mellitus).
Treatment of endocrine disease involves either hormone supplementation, in the case of hypofunction, or, in cases of hyperfunction, destruction of endocrine gland tissue by surgery or radiation.
Diseases of nutrition include the effects of undernutrition, prevalent in less-developed areas but present even in affluent societies, and the effects of nutritional excess.
Obesity, perhaps the most important nutritional disease in the United States and Europe, results usually from excessive caloric intake, although emotional, genetic, and endocrine factors may be present.
Obesity predisposes one toward several serious disorders, including a state of chronic oxygen deficiency called the hypoventilation syndrome; high blood pressure; and atherosclerosis, a degenerative condition of the blood vessels that is discussed further below.
Excessive intake of certain vitamins, especially vitamins A and D, can also produce disease. Vitamins A and D are both fat-soluble and tend to accumulate to toxic levels in the bodily tissues when taken in excessive quantities. Vitamin C and the B vitamins, soluble in water, are more easily metabolized or excreted and, therefore, rarely accumulate to toxic levels.
Nutritional deficiencies may take the form of inadequacies of (1) total caloric intake, (2) protein intake, or (3) certain essential nutrients such as the vitamins and, more rarely, specific amino acids (components of proteins) and fatty acids.
Protein-calorie malnutrition remains prevalent in certain areas. It has been estimated that about two-thirds of the world’s population has less than enough food to eat. Not only is the quantity inadequate but the quality of the food is nutritionally deficient and usually lacks protein. In deprived areas malnutrition has its greatest impact on the young. Deaths from protein-calorie malnutrition result from the failure of the child to thrive, with progressive weight loss and weakness, which in turn can lead to infection and disease, usually some form of gastrointestinal bacterial or parasitic disorder. In other circumstances adequate calories may be available, but a deficiency of protein induces a disorder known as kwashiorkor.
Vitamin deficiencies, the most important forms of selective malnutrition, may arise in a variety of ways, the most common and the most important being an improper, inadequate diet. When the total caloric intake is inadequate, vitamin deficiencies may also occur, but in these circumstances the more profound lack of calories and proteins masks the lack of vitamins.
Vitamin deficiencies may also be encountered despite a diet that is apparently adequate nutritionally. One source of such a deficiency, called secondary, is interference with absorption of the vitamin. Pernicious anemia is a classic example of this phenomenon. This disorder results from an autoimmune response to intrinsic factor, a substance normally found in the stomach lining with which vitamin B12 must form a complex to be absorbed. (Vitamin B12 is necessary for red cells to form properly.) The basis of pernicious anemia, then, is a lack of absorption of vitamin B12. The absence of certain digestive enzymes, as is found in pancreatic disease, can lead to the inability to digest and absorb fats and the fat-soluble vitamins (A, D, E, and K). Impaired uptake of vitamins may be encountered in gastrointestinal diseases. Some of these diseases reduce the absorptive function of the bowel. Similarly, diseases associated with severe, prolonged vomiting may interfere with adequate absorption.
Avitaminosis (vitamin lack) may be encountered when there are increased losses of vitamins such as occur with chronic severe diarrhea or excessive sweating or when there are increased requirements for vitamins during periods of rapid growth, especially during childhood and pregnancy. Fever and the endocrine disorder hyperthyroidism are two additional examples of conditions that require higher than the usual levels of vitamin intake. Unless the diet is adjusted to the increased requirements, deficiencies may develop. Lastly, artificial manipulation of the body and its natural metabolic pathways, as by certain surgical procedures or the administration of various drugs, can lead to avitaminoses. (Diseases involving deficiencies of particular vitamins are discussed in.
Diseases of neuropsychiatric origin afflict large segments of the population. For example, a total of about 2.8 million persons in the United States suffer from three major psychiatric diseases—schizophrenia, major depression, and mania—and three major neurological disorders—Alzheimer’s disease, Huntington’s chorea, and Parkinson’s disease. These six conditions will be briefly reviewed here. More in-depth coverage is found in the articles mental disorder and nervous system disease.
The key function of the nervous system is to collect information about the body and its external environment, process the information, and coordinate the body’s responses to that information. This complex function depends on each nerve cell (neuron) receiving signals from other neurons and transmitting this input to still other neurons. This critical input and output of communication (signaling) between neurons is mediated by chemical transmitter molecules (neurotransmitters). Neurotransmitters are synthesized by nerve cells and released from one cell to another across a narrow gap between the two neurons known as the synapse. Eight different major neurotransmitters and a large number of neuropeptide molecules (which serve to modulate the effects of neurotransmitters) have been identified. Different types of nerve cells respond to different neurotransmitters and neuropeptides. Chemical signaling between nerve cells is rapid and precise and can occur over long distances. The precision is due to receptor molecules, which are activated following their recognition and binding of specific neurotransmitters. In some types of nerves the synapses do not possess receptors, in which case interneuronal communication is achieved by electrical transmission. In many neuropsychiatric diseases alterations in the levels of transmitter substances appear to play a major role in pathogenesis.
Mental illnesses affect the very fabric of human nature, robbing it of its various facets of personality, purposeful behaviour, abstract thinking, creativity, emotion, and mood. Those suffering from mental disorders exhibit a spectrum of symptoms depending on the severity of their disease. These diseases include obsessive-compulsive personality disorder, dementia, schizophrenia, major depression, and manic disorders.
Schizophrenia in its severe form is a catastrophic mental illness that begins in adolescence or early adult life. It is relatively common, occurring in about 1 percent of the general population worldwide. Because the incidence of schizophrenia among parents, children, and siblings of patients with the disease is increased to 15 percent, it is believed that heredity plays an important role in the genesis of the disease. However, other studies suggest that nongenetic factors are also influential. The biochemical basis of the disease may be an excess of the neurotransmitter substance dopamine, as high levels of dopamine and its metabolites, as well as increased dopamine receptors, are found in the brains of persons with schizophrenia. Further evidence for this hypothesis is that the drugs most effective in treating the disease are those that have a high capacity to block dopamine receptors.
Pathological disturbances of mood, ranging from severe depression to manic behaviour, are common forms of mental illnesses. Severe depression is characterized by despondency, diminished interest in most or all activities, weight fluctuation not due to dieting, disruption in sleep patterns, psychomotor agitation or retardation, feelings of worthlessness, excessive quiet, and recurrent thoughts of death or suicide. Manic behaviour involves a period in which an expansive, elevated, or irritable mood persists abnormally. During this episode symptoms such as increased talkativeness, distractibility, decreased need for sleep, inflated self-esteem, and excessive involvement in pleasurable yet risky activities may be present. Major depression is associated with decreased brain levels of the neurotransmitters norepinephrine and serotonin, and the most effective therapy consists of drugs that inhibit the breakdown of these compounds. The neurochemical alterations in mania are less clearly understood, but it is well established that drugs effective in the treatment of mania are those that antagonize dopamine and serotonin. The mechanism responsible for the therapeutic efficacy of lithium for the treatment of mania is not yet clear. Although mood disorders have a familial background, the evidence for a genetic component is not convincing.
The three neurological diseases considered in this section—Alzheimer’s disease, Huntington’s chorea, and Parkinson’s disease—are age-related, and to varying degrees they manifest as deterioration of mental function that involves the loss of memory and of acquired intellectual skills. This deterioration is referred to as dementia. Because dementia can result from many causes, other features of each disease must be present before a definitive diagnosis can be made.
Alzheimer’s disease is the most common form of dementia, being responsible for about two-thirds of the cases of dementia in patients over 60 years of age. Women are affected twice as often as men. More rarely there are familial forms of the disease that have an early onset affecting individuals in the fourth and fifth decades of life. Alzheimer’s disease is insidious in onset. Early manifestations include memory loss, temporary confusion, restlessness, poor judgment, and lethargy. A failure to retain new information and a deterioration of social relationships often ensue. In some patients paranoia and delusions, which worsen during the night, are the first symptoms of the disease. Whatever the onset, the last stages are characterized by intellectual vacuity and loss of control over all body functions.
The brains of patients with Alzheimer’s disease are characterized by the loss of neurons, which, as the disease progresses, becomes severe and leads to decreased brain size and weight. Because nerve cells synthesize the neurotransmitters necessary for interneuronal communication, it is not surprising that Alzheimer’s disease is associated with diminished levels of neurotransmitters, including acetylcholine, norepinephrine, and serotonin, as well as modulatory neuropeptide molecules that transmit signals between nerve cells. Two other characteristic tissue lesions found in the cerebral cortex of patients with Alzheimer’s disease are neuritic plaques and neurofibrillary tangles. Neuritic plaques are deposits of neuron fragments surrounding a core of amyloid β-protein. Neurofibrillary tangles are twisted fibres of the protein tau found within neurons.
A variety of genetic factors have been identified in the different forms of Alzheimer’s disease. The rare cases of the early familial forms of the disease are linked to three different genetic defects found on three different chromosomes—chromosomes 1, 14, and 21. Another gene on chromosome 19 is believed to play a part in the more common late-onset cases. The gene on chromosome 21 was the first to be identified. (This finding is significant because an abnormality in chromosome 21—an extra copy—is found in patients with Down syndrome, virtually all of whom develop Alzheimer’s disease if they live to age 35.) The defective gene on chromosome 21 normally codes for amyloid precursor protein. A defect in this gene is thought to result in abnormal cleavage of the protein that increases the production and deposition of amyloid β-protein. This gene, however, is linked to only 2 to 3 percent of all early familial cases of the disease. The majority of patients with early-onset disease—70 to 80 percent—have the genetic mutation on chromosome 14, and another group of patients have a defective gene on chromosome 1. The gene on chromosome 19 codes for apolipoprotein E, a protein involved in cholesterol transport and metabolism. Three forms, or alleles, of the gene exist. The presence of one form—ApoE4—in an individual’s genome seems to increase the deposition of amyloid β-protein in the brain and may also increase the number of neurofibrillary tangles.
Huntington’s chorea occurs at the rate of about 5 per 100,000 individuals. It affects both sexes equally and usually becomes manifest in the fourth decade of life. The disorder is characterized by uncontrolled movements (chorea), dementia, and death within 20 years after onset. The symptoms worsen until the patient becomes totally incapacitated and bedridden. Huntington’s chorea is a hereditary disease passed on as an Autosomal dominant trait (see above Diseases of genetic origin). Because of its highly regular familial inheritance, the disease is often traceable to the original carriers who introduced the defective gene. For example, British immigrants to colonial America in the 17th century are believed to be responsible for almost all cases of Huntington’s chorea in the eastern United States, and an English sailor is thought to have introduced the defective gene into Venezuela almost 200 years ago. The recent localization of the Huntington’s chorea gene to chromosome 4 and its cloning will allow identification of the gene product, insight into the mechanism responsible for the disease, and perhaps effective treatment. It will also permit the disease to be diagnosed in fetuses as well as in children before the onset of symptoms.
Parkinson’s disease is a motor disorder characterized by the onset of a “pill rolling” rhythmic tremor, muscle rigidity, difficulty and slowness in movement, and stooped posture. As the disease progresses, the face of the patient becomes expressionless, the rate of swallowing is reduced, leading to drooling, and depression and dementia increase. The prevalence of Parkinson’s disease is estimated to be about 160 per 100,000 persons in the general population, with about 16 to 19 new cases per 100,000 appearing each year. Men are slightly more affected than women, and there are no apparent racial differences. The disease appears typically in the sixth and seventh decades, although occasionally it can begin as early as the third decade. Parkinson’s disease has no known cause. A marked decrease in the level of dopamine, a major neurotransmitter, has been noted in the brains of patients with Parkinson’s disease, and this change has been attributed to the loss of so-called dopaminergic neurons that normally synthesize and use dopamine to communicate with other neurons in parts of the brain that regulate motor function. This information has opened a new approach to the treatment of the disease—namely, administration of the metabolic precursor to dopamine (L-dopa) that can be converted by the body to dopamine. Although initially beneficial in causing a significant remission of symptoms, L-dopa frequently is effective for only 5 to 10 years, and serious side effects accompany treatment. Cotreatment with an inhibitor of the enzyme that breaks down L-dopa and thus allows the substance to remain in the brain longer has yielded an effective therapy, which allows many patients to live reasonably normal lives. Nevertheless, although treatment may slow the progress of the disease, it does not alter its course. This suggests that factors other than variation in neurotransmitter levels are responsible for the disease.
The process of aging begins at the time of conception. Throughout life the body undergoes a series of changes that can be considered as manifestations of aging. During the first half of life these changes are generally referred to as maturation, during the last half of life as progressive senescence. Visual acuity, sensitivity of hearing, and muscular vigour begin to deteriorate after the third decade of life. These changes, although they may begin at different ages and progress at differing rates, are universal among all individuals and must therefore be considered as the normal aging process. A critical question remains unanswered concerning the cause of the intrinsic retrogressive changes in cell and organ structure and function that occur throughout the aging process. Are these changes genetically determined, or are they a result of accumulated sublethal injuries that the cell sustains from exposure to noxious environmental factors over time? Or perhaps both elements act in concert to effect the changes that occur as life progresses.
It is extremely difficult to draw a sharp line between the deleterious effects of normal aging and the deleterious effects of the diseases of aging. The diseases most commonly manifested in the elderly are disorders of the heart, blood vessels, and joints. The heart disease of the elderly is related to the generalized vascular disease known as arteriosclerosis, which frequently attacks the major coronary arteries of the heart. Arteriosclerosis and arthritis will therefore be briefly touched upon here. More extended discussions may be found in cardiovascular disease and in joint disease. These problems and other aspects of aging are also considered in human aging.
Arteriosclerosis is not a specific disease. The term is applied to all diseases that cause hardening of the arteries. Several minor processes can induce hardening of the arteries, but the overwhelming preponderance of cases of arteriosclerosis are caused by atherosclerosis. This disorder, which eventually affects all individuals to varying degrees, begins relatively early in life in most persons. There are great variations, however, in the severity of this disease among individuals and among racial, national, and ethnic populations. These differences depend on the presence or absence of risk factors such as diet, hypertension, tobacco smoking, diabetes, obesity, family history, and stress.
Atherosclerosis is characterized by the deposition of fats (cholesterol and other complex lipids) in the linings (intima) of the arteries. It is accompanied by cell injury, cell death, and scarring and sometimes produces total obstruction of an artery. Atherosclerosis has a predilection for the aorta, the major artery of the body, and the arteries of the heart, brain, and legs. Atherosclerosis of the arteries of the heart (the coronaries) causes myocardial infarction, otherwise known as heart attack.
When atherosclerosis narrows but does not totally block the coronary arteries, the heart also is injured by lack of adequate blood supply and nutrition and becomes progressively smaller and weaker; even though this disease is not as life-threatening as a heart attack, it nonetheless frequently causes heart failure, an inability of the heart to deliver an adequate supply of blood to the tissues. Atherosclerosis of the arteries of the brain is the usual cause of stroke. When the arteries to the legs become affected in this way, gangrene may develop.
Arthritis, probably the second most common and distressing disease among the elderly, is a disease of the joints. It causes considerable pain, discomfort, and lack of mobility and so makes life burdensome. Moreover, arthritic individuals are more subject to other illnesses. Degenerative arthritis (osteoarthritis) is common to all elderly people to a lesser or greater degree. Osteoarthritis usually begins in the fourth decade of life and slowly progresses with increasing age. Coinciding with the characteristic degeneration of the joints are changes involving the bone itself. The bone of elderly persons is known to be less dense and more brittle; it tends, therefore, to fracture more easily. It also heals with greater difficulty.
There are many subtle changes that occur with the normal aging process. These may include degenerative changes in the brain, leading to impaired mental ability and even senility. As this damage is usually accompanied by atherosclerosis of the arteries of the brain, it is difficult to know how much of the change is the result of impaired blood flow and how much is related to normal aging. Finally, but of no less significance, is the general decline in the body’s ability to defend itself against disease. Thus elderly persons are more susceptible to infections, trauma, and a number of other bodily defects. Simple, uncomplicated pneumonia, which might be easily tolerated by the young, healthy adult, may be fatal for an elderly, weakened person.
Classifications of diseases become extremely important in the compilation of statistics on causes of illness (morbidity) and causes of death (mortality). It is obviously important to know what kinds of illness and disease are prevalent in an area and how these prevalence rates vary with time. Classifying diseases made it apparent, for example, that the frequency of lung cancer was entering a period of alarming increase in the mid-20th century. Once a rare form of cancer, it had become the single most important form of cancer in males. With this knowledge a search was instituted for possible causes of this increased prevalence. It was concluded that the occurrence of lung cancer was closely associated with cigarette smoking. Classification of disease had helped to ferret out an important, frequently causal, relationship.
The most widely used classifications of disease are (1) topographic, by bodily region or system, (2) anatomic, by organ or tissue, (3) physiological, by function or effect, (4) pathological, by the nature of the disease process, (5) etiologic (causal), (6) juristic, by speed of advent of death, (7) epidemiological, and (8) statistical. Any single disease may fall within several of these classifications.
In the topographic classification, diseases are subdivided into such categories as gastrointestinal disease, vascular disease, abdominal disease, and chest disease. Various specializations within medicine follow such topographic or systemic divisions, so that there are physicians who are essentially vascular surgeons, for example, or clinicians who are specialized in gastrointestinal disease. Similarly, some physicians have become specialized in chest disease and concentrate principally on diseases of the heart and lungs.
In the anatomic classification, disease is categorized by the specific organ or tissue affected; hence, heart disease, liver disease, and lung disease. Medical specialties such as cardiology are restricted to diseases of a single organ, in this case the heart. Such a classification has its greatest use in identifying the various kinds of disease that affect a particular organ. The heart is a good example to consider. By the segregation of cardiac disease it has been made apparent that heart disease is now the most important cause of death in most other industrialized nations. Moreover, it has become apparent that disease caused by atherosclerosis of the coronary arteries is by far the most important form of heart disease. In making a diagnosis of cardiac disease in an elderly patient, the cardiologist must first determine whether this disease of the coronary arteries is responsible for the heart’s failure to function normally.
The physiological classification of disease is based on the underlying functional derangement produced by a specific disorder. Included in this classification are such designations as respiratory and metabolic disease. Respiratory diseases are those that interfere with the intake and expulsion of air and the exchange of oxygen for carbon dioxide in the lungs. Metabolic diseases are those in which disturbances of the body’s chemical processes are a basic feature. Diabetes and gout are examples.
The pathological classification of disease considers the nature of the disease process. Neoplastic and inflammatory disease are examples. Neoplastic disease includes the whole range of tumours, particularly cancers, and their effect on human beings.
The etiologic classification of disease is based on the cause, when known. This classification is particularly important and useful in the consideration of biotic disease. On this basis disease might be classified as staphylococcal or rickettsial or fungal, to cite only a few instances. It is important to know, for example, what kinds of disease staphylococci produce in human beings. It is well known that they cause skin infections and pneumonia, but it is also important to note how often they cause meningitis, abscesses in the liver, and kidney infections. The sexually transmitted diseases syphilis and gonorrhea are further examples of diseases classified by etiology.
The juristic basis of the classification of disease is concerned with the legal circumstances in which death occurs. It is principally involved with sudden death, the cause of which is not clearly evident. Thus, on a juristic basis some deaths and diseases are classified as medical-legal and fall within the jurisdiction of coroners and medical examiners. A person living alone is found dead in bed—dead of natural causes or killed? Had the person who dropped dead on the street been given some poison that took a short time to act? Much less dramatic, but perhaps more common, are disease and death caused by exposure of the individual to some unrecognized danger to health in working or living conditions. Could the illness or disease be attributable to fumes or dusts in a factory? These are examples of the many types of disease and death that fall properly in this classification.
The epidemiological classification of disease deals with the incidence, distribution, and control of disorders in a population. To use the example of typhoid, a disease spread through contaminated food and water, it first becomes important to establish that the disease observed is truly caused by Salmonella typhi, the typhoid organism. Once the diagnosis is established, it is obviously important to know the number of cases, whether the cases were scattered over the course of a year or occurred within a short period, and what the geographic distribution is. It is critically important that the precise address and activities of the patients be established. Two widely separated locations within the same city might be found to have clusters of cases of typhoid all arising virtually simultaneously. It might be found that each of these clusters revolved about a family unit including cousins, grandparents, aunts and uncles, and friends, suggesting that in some way personal relationships might be important. Further investigation might disclose that all the infected persons had dined at one time or at short intervals in a specific home. It might further be found that the person who had prepared the meal had recently visited some rural area and had suffered a mild attack of the disease and was now spreading it to family and friends by unknowing contamination of food. This hypothetical case suggests the importance of the etiologic, as well as the epidemiological, classification of disease.
Epidemiology is one of the important sciences in the study of nutritional and biotic diseases around the world. The United Nations supports, in part, the World Health Organization, whose chief function is the worldwide investigation of the distribution of disease. In the course of this investigation, many observations have been made that help to explain the cause and provide approaches to the control of many diseases.
The statistical basis of classification of disease employs analysis of the incidence (the numbers of new cases of a specific disease that occur during a certain period) and the prevalence rate (number of cases of a disease in existence at a certain time) of diseases. If, for example, a disease has an incidence rate of 100 cases per year in a given locale and, on the average, the affected persons live three years with the disease, it is obvious that the prevalence of the disease is 300. Statistical classification is an additional important tool in the study of possible causes of disease. These studies, as well as epidemiological, nutritional, and pathological analyses, have made it clear, for example, that diet is an important consideration in the possible causation of atherosclerosis. The statistical analyses drew attention to the role of high levels of fats and carbohydrates in the diet in the possible causation of atherosclerosis. The analyses further drew attention to the fact that certain populations that do not eat large quantities of animal fats and subsist largely on vegetable oils and fish have a much lower incidence of atherosclerosis. Thus, statistical surveys are of great importance in the study of human disease.