HUMAN DISEASE

an impairment of the normal state of a human being that interrupts or modifies its vital functions. Additional reading Lawrie Reznek, The Nature of Disease (1987), written for the general reader, discusses the nature of disease from several perspectives, including medical, legal, political, philosophical, and economic. David O. Slauson, Barry J. Cooper, and Maja M. Suter, Mechanisms of Disease: A Textbook of Comparative General Pathology, 2nd ed. (1990), written for the veterinary student but a great resource for pathologists and biomedical researchers, provides a fundamental overview of the mechanisms of diseases, often at the molecular level. Max Samter (ed.), Immunological Diseases, 4th ed., 2 vol. (1988), covers the collagen diseases. F.M. Burnet, The Natural History of Infectious Disease, 3rd ed. (1962), offers a unique view of infectious disease as an ecological and evolutionary phenomenon. Books for the general reader include June Goodfield, Quest for the Killers (1985), exploring efforts to conquer several epidemic diseases; Andrew Scott, Pirates of the Cell: The Story of Viruses from Molecule to Microbe, rev. ed. (1987); and Peter Radetsky, The Invisible Invaders: The Story of the Emerging Age of Viruses (1991). William Burrows Dante G. Scarpelli Kenneth F. Kiple (ed.), The Cambridge World History of Human Disease (1993), a reference text written for advanced undergraduates and professionals in the biomedical and social sciences, surveys the medical and geographic characteristics of human diseases worldwide throughout history. James B. Wyngaarden, Lloyd H. Smith, Jr., and J. Claude Bennett (eds.), Cecil Textbook of Medicine, 19th ed. (1992), considers all facets of human disease in depth from the modern point of view. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th ed. by Joel G. Hardman and Lee E. Limbird (1996), is a comprehensive text on drugs. T.R. Harrison, Harrison's Principles of Internal Medicine, 13th ed. edited by Kurt J. Isselbacher et al. (1994), discusses in detail the cardinal manifestations of disease under various headings. Theodore Lidz, The Person: His and Her Development Throughout the Life Cycle, rev. ed. (1976, reissued 1983), provides an excellent insight into humans, the psychological organisms. Vinay Kumar, Ramzi S. Cotran, and Stanley L. Robbins, Basic Pathology, 5th ed. (1992), clearly and succinctly presents the causes and pathogenesis of human disease with an emphasis on molecular mechanisms. Margaret W. Thompson, Roderick R. McInnes, and Huntington F. Willard, Thompson & Thompson Genetics in Medicine, 5th ed. (1991), is a well-illustrated and clearly written text on basic genetic principles and their relation to the genesis of human disease. Charles R. Scriver et al. (eds.), The Metabolic Basis of Inherited Disease, 6th ed., 2 vol. (1989), a monumental, highly technical text, provides a comprehensive presentation of the clinical, biochemical, and genetic information concerning those diseases thought to be a consequence of genetic variation. More specific in focus and perhaps less monumental (if not less technical) than the above are Roger N. Rosenberg et al. (eds.), The Molecular and Genetic Basis of Neurological Disease (1993); Aldons J. Lusis, Jerome I. Rotter, and Robert S. Sparkes (eds.), Molecular Genetics of Coronary Artery Disease (1992); and Linda L. Gallo (ed.), Cardiovascular Disease: Molecular and Cellular Mechanisms, Prevention, and Treatment (1987), which address their particular topics on cellular and molecular levels. Robert C. Gallo and Flossie Wong-Staal (eds.), Retrovirus Biology and Human Disease (1990), written for the technically advanced reader, covers various topics in retrovirology, including historical background, epidemiology, clinical features, molecular biology, immunology, and therapeutic approaches. Adrianne Bendich and C.E. Butterworth, Jr. (eds.), Micronutrients in Health and in Disease Prevention (1991), discusses evidence of a correlation between the intake of nonoptimal levels of dietary micronutrients and the development of chronic diseases; although written for the health-care professional, it is also valuable to anyone interested in the relationship between nutrition and health. Stanley L. Robbins Jonathan H. Robbins Dante G. Scarpelli Classifications of diseases 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 the United States and 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 beddead 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. Stanley L. Robbins Jonathan H. Robbins Dante G. Scarpelli 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 BC, 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. Diseases of genetic origin 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 cellsi.e., the gametes, ova and spermare 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. Diseases of neuropsychiatric origin Neurological diseases Huntington's chorea