Carcinogenic agents
Chemicals
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.
Radiant energy
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.
Viruses
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.)
Diseases of metabolic-endocrine origin
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 (see Endocrine Systems).
Diseases of nutrition
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.
Diseases 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.
Diseases of nutritional deficiency
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 nutrition: Deficiency diseases: Vitamins.)
Diseases of neuropsychiatric origin
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.
