The term “environment” encompasses the outdoor, indoor, and occupational environments shared by small and large populations, and our own personal environment. In each of these environments, the air we collectively breathe, the food and water we consume, and exposure to toxic agents are major determinants of our health. Our personal environment is greatly influenced by tobacco use, alcohol ingestion, therapeutic and nontherapeutic drug consumption, and diet. Factors in the personal environment may have a larger effect on human health than the ambient environment. The term environmental diseases refers to conditions caused by exposure to chemical or physical agents in the ambient, workplace, and personal environment, including diseases of nutritional origin. Environmental diseases mostly come to the public’s attention after major disasters, such as the methyl mercury contamination of Minamata Bay in Japan in the 1960s, the exposure to dioxin in Seveso, Italy, in 1976, the leakage of methyl isocyanate gas in Bhopal, India, in 1984, the Chernobyl nuclear accident in 1986, and the contamination of Tokyo subways by the organophosphate pesticide sarin. Fortunately, these are unusual and infrequent occurrences, but environmental diseases caused by chronic exposure to relatively low levels of contaminants, occupational injuries, and nutritional deficiencies are widespread. The International Labor Organization has estimated that work-related injuries and illnesses kill approximately 2 million people per year globally (more deaths than are caused by road accidents and wars combined). A comprehensive report from the Disease Control Priorities Project (http://www.dcp2.org) estimated that there are 130 million undernourished children worldwide, and that malnutrition alone is responsible for 2.67 million deaths per year. Estimating the burden of disease in the general population caused by nonoccupational exposures to toxic agents is complicated by the diversity of agents and difficulties in determining the extent and duration of exposures. Whatever the precise numbers, environmental (including nutritional) diseases are major causes of disability and suffering, and constitute a heavy financial burden, particularly in developing countries. During the last few years new concerns have been raised about air and water quality, and the potential health effects of climate change.

In this chapter, we first consider two key issues in global health: the global burden of disease, and the emerging problem of the health effects of climate change. We then discuss the mechanisms of toxicity of chemical and physical agents, and address specific environmental disorders, including those of nutritional origin.

The Global Burden of Disease

Until about 1990 global health data were fragmented and lacked a uniform standard of measurement.¹ Since then, a project entitled The Global Burden of Disease (GBD) has set the standard for reporting health information. The GBD approach is now applied to the measurement of the burden imposed by environmental disease, including those caused by communicable and nutritional diseases. In addition, a unit of measurement (“metric”) called DALY (disability-adjusted life year, a time based measure that adds the years of life lost to premature mortality with the years lived with illness and disability), has been used to assess both premature mortality and disease morbidity. DALY reporting provides a high degree of uniformity for health information gathered about acute and chronic diseases in different parts of the world and at multiple locations in a single country. The new methodology has revealed important trends in the worldwide morbidity and mortality of disease.

• Undernutrition is the single leading global cause of health loss (defined as morbidity and premature death). It is estimated that about one third of the disease burden in developing countries is, directly or indirectly, due to poor general nutrition or deficiencies in specific nutrients that increase the risk of infections.

• Ischemic heart disease and cerebrovascular disease are the leading causes of death in developed countries. In these countries the main risk factors associated with loss of healthy life are smoking, high blood pressure, obesity, high cholesterol, and alcohol abuse.

• In developing countries, infectious diseases constitute 5 of the 10 leading causes of death: respiratory infections, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), diarrheal diseases, tuberculosis, and malaria.² HIV/AIDS contributes 18% to the loss of healthy life in sub-Saharan Africa and 13% in South Asia.

• About 70% of all child deaths are attributed to only five conditions, all of them preventable: pneumonia, diarrheal diseases, malaria, measles, and perinatal/neonatal problems (mostly prematurity and neonatal infections).

• Worldwide mortality of children under 5 years of age has declined from 110 deaths per 1000 in 1980 to 72 per 1000 in 2005. Though impressive, the 27% decline in mortality under 5 years of age, expected to occur between 1990 and 2015, falls short of the United Nations Millennium Development Goal of achieving a 67% decline. To be noted is that under-5 mortality in Central and West Africa (about 210/1000) is almost 50 times higher than that in Western Europe³ (Fig. 9-1) and has shown no significant decline.

• Emerging infectious diseases (EIDs) constitute one of the most important components of the global burden of disease. EIDs are correlated with environmental, and socioeconomic conditions, and include (1) diseases caused by newly evolved strains or organisms, such as rifampin/isoniazid-resistant and multidrug-resistant (XDR) tuberculosis, chloroquine-resistant malaria, and methicillin-resistant Staphylococcus aureus; (2) diseases caused by pathogens endemic in other species (e.g., wild mammals and birds) that recently entered human populations, such as HIV and severe acute respiratory syndrome (SARS); (3) diseases caused by pathogens that have been present in human populations but show a recent increase in incidence, such as dengue fever.

• Bacteria and rickettsia caused approximately 54% of worldwide emerging infectious diseases during the last 60 years (viruses represented ∼25%). Drug-resistant bacteria were the most important group of pathogens. Their appearance relates to therapeutic use of antibiotics, and in agriculture as well as urban living in densely populated areas. During the last decade, vector-borne diseases constituted approximately 29% of emerging infectious disease, an increase that may be related to environmental changes such as global warming.⁴

FIGURE 9-1 Worldwide mortality of children under 5 years of age. Note the more than 50-fold difference between areas with the lowest and highest mortality. Malnutrition and infections are major causes of the high mortality in East, Central, and West Africa.

Health Effects of Climate Change

There is general agreement that the earth has been warming at an accelerating pace during the last 40 years, and that the rate of warming is more rapid than at any other period in perhaps 1000 years.⁵ Since 1960 the global average surface temperature increased by 0.6°C; the increase is not uniform, being greatest at latitudes between 40° N and 70° N.⁶ Glacier melting has accelerated, and in polar regions, snow cover and ice thickness have diminished. At the same time, the sea level has risen 1 to 2 mm/year as a result of thermal expansion.⁶ The importance of climate change was highlighted by the awarding of the 2007 Nobel Peace Prize to individuals and organizations concerned with the impact of these changes on human health.

The causes of global climate change are the subject of debate, but human activity is a major contributor, through increases of carbon dioxide (CO₂), methane, and ozone (discussed later), the main agents of the greenhouse effect. These gases (along with water vapor) act like a blanket by absorbing energy radiated from the earth’s surface that would otherwise be lost into space. Recent increases in levels of greenhouse gases, particularly CO₂ and ozone produced by the combustion of hydrocarbons in automobiles and energy plants, are strongly correlated with warming of the earth (Fig. 9-2). The present concentration of atmospheric CO₂, estimated to be 370 ppm (highest in about 1 million years), is expected to increase to 500 to 1200 ppm at the end of this century. Also contributing to the increase in atmospheric CO₂ is large-scale deforestation (present estimates are that the Amazon forest will lose 50% of the original area by 2050), which decreases carbon sequestration by trees. Beyond certain levels of warming of the land and seas, it is predicted that positive-feedback loops will amplify the process further. Examples include increases in heat absorption due to the loss of reflective snow and ice; increases in water vapor in the atmosphere due to greater evaporation from bodies of water and transpiration from trees; large releases of stored CO₂ and methane from thawing arctic tundra; and decreased sequestration of CO₂ in the oceans, due to diminished growth of diatoms, which serve as an important CO₂ sink. Depending on the model used, these changes are predicted to cause the global temperature to rise 2° to 5°C by the year 2100 (see Fig. 9-2).

FIGURE 9-2 Sources and consequences of increased greenhouse gases. A, Predicted temperature increases during the twenty-first century. Different computer models plot anticipated rises in temperature of 2° to 5°C by the year 2100. B, Release of carbon dioxide (CO₂) from combustion sources in China, 1970 to 2005. China has now surpassed the United States as the world’s largest producer of CO₂. C, Regions of the United States in which ozone levels are above existing accepted standards (80 ppb during an 8-hour period). These areas include about 500 counties located predominantly in the East Coast corridor, the Los Angeles basin, and areas with large coal-burning plants.

The future impact of global warming on health will depend on the extent and rapidity of climate change, the severity of the ensuing consequences, and humankind’s ability to adapt to or otherwise mitigate the damaging effects. Even in the best-case scenario, however, it is expected that climate change will seriously impact human health by increasing the incidence of several diseases.⁷

• Cardiovascular, cerebrovascular, and respiratory diseases, caused by heat waves and air pollution (e.g., the European summer of 2003, the warmest in 500 years, resulted in more than 25,000 heat- and pollution-related deaths)

• Gastroenteritis and infectious disease epidemics, caused by water and food contamination as a consequence of floods, and disruption of clean water supplies and sewage treatment, after heavy rains and other environmental disasters

• Vector-borne infectious diseases, such as dengue fever, malaria, West Nile virus infection, and hantavirus pulmonary syndrome, as a consequence of changes in vector number and geographic distribution caused by increased temperatures, crop failures, and more frequent El Nino climate cycles

• Malnutrition, caused by disruption of crops, mostly in tropical locations in which average temperatures are near or above crop tolerance levels; it is estimated that by 2080 agricultural productivity may decline by 10% to 25% in some developing countries as a consequence of warming, while it may decrease or even increase by up to 6% in developed countries with more moderate climates

Despite recognition of these dangers, climate change is just one of multiple factors that contribute to the incidence of a disease at a particular geographic location, making it difficult to establish precise risk estimates for effects which are specifically caused by global warming.⁸

Both developed and developing countries will suffer the consequences of climate change, but the burden will be heaviest in developing nations. Wealthy countries are the main producers of the emissions that cause global warming, but rapidly developing countries such as China and India are using increasingly large amounts of energy to sustain their growth. The urgent challenge ahead is to develop new methods of energy production that do not harm the environment and do not contribute to global warming.

Toxicity of Chemical and Physical Agents

Toxicology is defined as the science of poisons. It studies the distribution, effects, and mechanisms of action of toxic agents. More broadly, it also includes the study of the effects of physical agents such as radiation and heat. Approximately 4 billion pounds of toxic chemicals, including 72 million pounds of recognized carcinogens, are released per year in the United States. Of about 100,000 chemicals in commercial use in the United States, only a very small proportion has been tested experimentally for health effects. Several agencies in the United States set permissible levels of exposure to known environmental hazards (e.g., the maximum level of carbon monoxide in air that is noninjurious or the tolerable levels of radiation that are harmless or “safe”). But factors such as the complex interaction between various pollutants, and the age, genetic predisposition, and the different tissue sensitivities of exposed persons, create wide variations in individual sensitivity to toxic agents, limiting the value of establishing rigid “safe levels” for entire populations. Nevertheless, such levels are useful for comparative studies of the effects of harmful agents between specific populations, and for estimating risk of disease in heavily exposed individuals.

We now consider some basic principles relevant to the effects of toxic chemicals and drugs.

• The definition of a poison is not straightforward. It is basically a quantitative concept strictly dependent on dosage. The quote from Paracelsus in the sixteenth century that “all substances are poisons; the right dosage differentiates a poison from a remedy” is even more valid today, given the proliferation of pharmaceutical drugs with potentially harmful effects.

• Xenobiotics are exogenous chemicals in the environment in air, water, food, and soil that may be absorbed into the body through inhalation, ingestion, and skin contact (Fig. 9-3).

• Chemicals may be excreted in urine, feces, or eliminated in expired air, or may accumulate in bone, fat, brain, or other tissues.

• Chemicals may act at the site of entry or at other sites following transport through the blood.

• Most solvents and drugs are lipophilic, which facilitates their transport in the blood by lipoproteins and their penetration through the plasma membrane into cells.

• Some agents are not modified after entry in the body, but most solvents, drugs, and xenobiotics are metabolized to form inactive water-soluble products (detoxification), or are activated to form toxic metabolites. The reactions that metabolize xenobiotics into nontoxic products, or activate xenobiotics to generate toxic compounds (Figs. 9-3 and 9-4), occur in two phases. In phase I reactions, chemicals undergo hydrolysis, oxidation, or reduction. Products of phase I reactions are often metabolized into water-soluble compounds through phase II reactions, which include glucuronidation, sulfation, methylation, and conjugation with glutathione. Water-soluble compounds are readily excreted. Enzymes that catalyze the biotransformation of xenobiotics and drugs are known as drug-metabolizing enzymes.

• The most important catalyst of phase I reactions is the cytochrome P-450 enzyme system (abbreviated as CYP) located primarily in the endoplasmic reticulum of the liver but also present in skin, lungs, and gastrointestinal mucosa, and practically every organ.⁹ CYPs are a large family of heme-containing enzymes with preferential affinity toward different substrates. The system catalyzes reactions that either detoxify xenobiotics or activate xenobiotics into active compounds that cause cellular injury. Both types of reactions may produce, as a byproduct, reactive oxygen species (ROS), which can cause cellular damage (Chapter 1). Examples of metabolic activation of chemicals through CYPs are the production of the toxic trichloromethyl free radical from carbon tetrachloride in the liver, and the generation of a DNA-binding metabolite from benzo[a]pyrene, a carcinogen present in cigarette smoke. CYPs participate in the metabolism of a large number of common therapeutic drugs such as acetaminophen, barbiturates, and anticonvulsants, and also in alcohol metabolism (discussed later in this chapter).

There is great variation in the activity of CYPs among individuals. The variation may be a consequence of genetic polymorphisms in specific CYPs, but more commonly it is due to exposure to drugs or chemicals that induce or diminish CYP activity. Known CYP inducers include environmental chemicals, drugs, smoking, alcohol, and hormones. In contrast, fasting or starvation can decrease CYP activity.

Inducers of CYP do so by binding to nuclear receptors, which then heterodimerize with the retinoic X receptor (RXR) to form a transcriptional activation complex that associates with promoter elements located in the 5′-flanking region of CYP genes.¹⁰ Nuclear receptors participating in CYP induction responses include the aryl hydrocarbon receptor, the peroxisome proliferator–activated receptors (PPAR), and two orphan nuclear receptors, constitutive androstane receptor (CAR), and pregnane X receptor (PXR).

FIGURE 9-3 Human exposure to pollutants. Pollutants contained in air, water, and soil are absorbed through the lungs, gastrointestinal tract, and skin. In the body they may act at the site of absorption but are generally transported through the bloodstream to various organs where they may be stored or metabolized. Metabolism of xenobiotics may result in the formation of water-soluble compounds that are excreted, or in activation of the agent, creating a toxic metabolite.

FIGURE 9-4 Xenobiotic metabolism. A, Xenobiotics can be metabolized to nontoxic metabolites and eliminated from the body (detoxification). B, Xenobiotic metabolism may also result in the formation of a reactive metabolite that is toxic to cellular components. If repair is not effective, short- and long-term effects develop.

(Based on Hodgson E: A Textbook of Modern Toxicology, 3rd ed. Hoboken, NJ, Wiley, 2004.)

This brief overview of the general mechanisms of toxicity provides the background for the discussion of environmental diseases presented in this chapter.

Environmental Pollution

AIR POLLUTION

Precious as air is—especially to those deprived of it—it is often loaded with many potential causes of disease. Airborne microorganisms contaminating food and water have long been major causes of morbidity and mortality, especially in developing countries. More widespread are the chemical and particulate pollutants found in the air, especially in industrialized nations. Here, we consider these hazards in outdoor and indoor air.

Outdoor Air Pollution

The ambient air in industrialized nations is contaminated with an unsavory mixture of gaseous and particulate pollutants, more heavily in cities and in proximity to heavy industry. In the United States the Environmental Protection Agency monitors and sets allowable upper limits for six pollutants: sulfur dioxide, carbon monoxide, ozone, nitrogen dioxide, lead, and particulate matter. Collectively, these agents produce the well-known smog (smoke and fog) that sometimes stifles large cities such as Beijing, Los Angeles, Houston, Cairo, New Delhi, Mexico City, and São Paulo. It may seem that air pollution is a modern phenomenon. This is not so, since John Evelyn wrote in 1661 that inhabitants of London suffered from “Catharrs, Phthisicks and Consumptions” (bronchitis, pneumonia, and tuberculosis) and breathed “nothing but an impure and thick mist, accompanied by a fuliginous and filthy vapour, which renders them obnoxious to a thousand inconveniences, corrupting the lungs, and disordering the entire habit of their bodies.” The first environmental control law, proclaimed by Edward I in 1306, was straightforward in its simplicity: “whoever should be found guilty of burning coal shall suffer the loss of his head.” Thus, what has changed in modern times is the nature and sources of air pollutants, and the types of regulations that control their emission.

Although the lungs bear the brunt of the adverse consequences, air pollutants can affect many organ systems (see, for instance, the discussion of lead poisoning and carbon monoxide effects in this chapter). Except for some comments on smoking, pollutant-caused lung diseases are discussed in Chapter 15. Major health effects of outdoor pollutants are described in Table 9-1. Here we discuss ozone, sulfur dioxide, particulates, and carbon monoxide.

TABLE 9-1 Health Effects of Outdoor Air Pollutants

Pollutant	Populations at Risk	Effects
Ozone	Healthy adults and children	Decreased lung function
		Increased airway reactivity
		Lung inflammation
	Athletes, outdoor workers	Decreased exercise capacity
	Asthmatics	Increased hospitalizations
Nitrogen dioxide	Healthy adults	Increased airway reactivity
	Asthmatics	Decreased lung function
	Children	Increased respiratory infections
Sulfur dioxide	Healthy adults	Increased respiratory symptoms
	Individuals with chronic lung disease	Increased mortality
	Asthmatics	Increased hospitalization
	Asthmatics	Decreased lung function
Acid aerosols	Healthy adults	Altered mucociliary clearance
	Children	Increased respiratory infections
	Asthmatics	Decreased lung function
	Asthmatics	Increased hospitalizations
Particulates	Children	Increased respiratory infections
	Individuals with chronic lung or heart disease	Decreased lung function
	Asthmatics	Excess mortality
	Asthmatics	Increased attacks

Data from Bascom R, et al.: Health effects of outdoor air pollution. Am J Respir Crit Care Med 153:477, 1996.

Ozone. The interaction of ultraviolet (UV) radiation and oxygen (O₂) in the stratosphere leads to the formation of ozone (O₃), which accumulates in the so-called ozone layer 10 to 30 miles above the earth’s surface. This layer protects life on earth by absorbing the most dangerous UV radiation emitted by the sun. During the last 30 years, the stratospheric ozone layer decreased in both thickness and extent due to the widespread use of aerosols, which drift up into the upper atmosphere and participate in chemical reactions that destroy ozone. The resulting depletion has been most profound over polar regions, particularly Antarctica, during the winter months. Recognition of the problem led to the ban of chlorofluorocarbons as aerosol propellants and their replacement by hydrofluoroalkanes, resulting in a decrease in the extent of stratospheric ozone “holes.”

In contrast to the “good” ozone in the stratosphere, ozone that accumulates in the lower atmosphere (ground-level ozone) is one of the most pernicious air pollutants (see Fig. 9-2). Ground-level ozone is a gas formed by the reaction of nitrogen oxides and volatile organic compounds in the presence of sunlight. These chemicals are released by industrial emissions and motor vehicle exhaust. Ozone toxicity is in large part mediated by the production of free radicals, which injure epithelial cells along the respiratory tract and type I alveolar cells, and cause the release of inflammatory mediators. Healthy individuals exposed to ozone experience upper respiratory tract inflammation and mild symptoms (decreased lung function and chest discomfort), but exposure is much more dangerous for people with asthma or emphysema. Ozone-induced asthma is associated with airway hyper-reactivity and neutrophilia.¹¹

Even low levels of ozone may be detrimental to the lung function of normal individuals when combined with other air pollutants. Unfortunately, air pollutants often combine to create a veritable “witches’ brew” of ozone and other agents such as sulfur dioxide and particulates. Sulfur dioxide is produced by power plants burning coal and oil, from copper smelting, and as a byproduct of paper mills. Released into the air, it may be converted into sulfuric acid and sulfuric trioxide, which cause a burning sensation in the nose and throat, difficulty in breathing, and asthma attacks in susceptible individuals.

Particulate matter (known as “soot”) is emitted by coal- and oil-fired power plants, by industrial processes burning these fuels, and by diesel exhaust. Exposure to particulates was the main cause of morbidity and mortality in the air pollution episodes that occurred in London in 1952 and 1962. Although the particles have not been well characterized chemically or physically, fine or ultrafine particles that are less than 10 μm in diameter are the most harmful. They are readily inhaled into the alveoli, where they are phagocytosed by macrophages and neutrophils, which release inflammatory mediators such as macrophage inflammatory protein 1α and endothelin. Acute exposure to diesel exhaust that contains fine particles may cause irritation to the eyes, throat, and lungs, induce asthma attacks,¹² and promote myocardial ischemia.¹³ In contrast, exposure to particles that are greater than 10 μm in diameter is of lesser consequence, because these particles are generally removed in the nose, or trapped by the mucociliary epithelium of the airways.

Carbon monoxide (CO). CO is a nonirritating, colorless, tasteless, odorless gas produced by the incomplete oxidation of carbonaceous materials. Its sources include automotive engines, industrial processes using fossil fuels, wood and charcoal burning with an inadequate supply of oxygen, and cigarette smoke. The low levels often found in ambient air may contribute to impaired respiratory function, but of themselves they are not life-threatening. However, chronic poisoning can occur in individuals working in confined environments with high exposure to fumes, such as tunnels, underground garages, and in highway toll workers. CO is included here as an air pollutant, but it is also an important cause of accidental and suicidal death. In a small, closed garage, the average car exhaust can induce lethal coma within 5 minutes. CO is a systemic asphyxiant that kills by inducing central nervous system (CNS) depression, which appears so insidiously that victims are often unaware of their plight and fail to help themselves. Hemoglobin has 200-fold greater affinity for CO than for oxygen, and the resultant carboxyhemoglobin does not carry oxygen. Systemic hypoxia develops when the hemoglobin is 20% to 30% saturated with CO; unconsciousness and death are likely with 60% to 70% saturation.

Morphology. Chronic poisoning by CO develops because carboxyhemoglobin, once formed, is remarkably stable. Even with low-level, but persistent, exposure to CO, carboxyhemoglobin may rise to life-threatening levels in the blood. The slowly developing hypoxia can insidiously evoke widespread ischemic changes in the central nervous system; these are particularly marked in the basal ganglia and lenticular nuclei. With cessation of exposure to CO, the patient usually recovers, but often there are permanent neurologic sequelae such as impairment of memory, vision, hearing, and speech. The diagnosis is made by measuring carboxyhemoglobin levels in the blood.

Acute poisoning by CO is generally a consequence of accidental exposure or suicide attempt. In light-skinned individuals, acute poisoning is marked by a characteristic generalized cherry-red color of the skin and mucous membranes, which result from high levels of carboxyhemoglobin. If death occurs rapidly morphologic changes may not be present; with longer survival the brain may be slightly edematous, with punctate hemorrhages and hypoxia-induced neuronal changes. The morphologic changes are not specific and stem from systemic hypoxia.

Indoor Air Pollution

As we increasingly “button up” our homes to exclude the environment, the potential for pollution of the indoor air increases. The commonest pollutant is tobacco smoke (discussed later), but additional offenders are CO, nitrogen dioxide (both already mentioned as outdoor pollutants), and asbestos (discussed in Chapter 15). Volatile substances containing polycyclic aromatic hydrocarbons generated by cooking oils and coal burning are important indoor pollutants in some regions of China. Only a few comments about other agents will be made here.

Wood smoke, containing various oxides of nitrogen and carbon particulates, may not only be an irritant but also predisposes to lung infections and may contain the far more dangerous carcinogenic polycyclic hydrocarbons. Bioaerosols range from microbiologic agents capable of causing infectious diseases such as Legionnaires’ disease, viral pneumonia, and the common cold, to less threatening but nonetheless distressing allergens derived from pet dander, dust mites, and fungi and molds responsible for rhinitis, eye irritation, and asthma. Radon, a radioactive gas derived from uranium widely present in soil and in homes, can cause lung cancer in uranium miners. However, it does not seem that low-level chronic exposures in the home increase lung cancer risk, at least for nonsmokers. Exposure to formaldehyde, used in the manufacture of building materials (cabinetry, furniture, adhesives, etc.) has become a common health problem in refugees from environmental disasters living in poorly ventilated trailers. Many of these cases occurred in trailers occupied by families displaced from their homes after Hurricane Katrina, which hit the southeastern United States in 2005. At concentrations of 0.1 ppm or higher, it causes breathing difficulties and a burning sensation in the eyes and throat, and can trigger asthma attacks. Formaldehyde is classified as a carcinogen for humans and animals. Finally, the so-called sick building syndrome remains an elusive problem, since it may be a consequence of exposure to one or more of the indoor pollutants already mentioned or be caused by poor ventilation.

METALS AS ENVIRONMENTAL POLLUTANTS

Lead, mercury, arsenic, and cadmium are the heavy metals most commonly associated with harmful effects in humans.

Lead

Lead exposure occurs through contaminated air and food and water. For most of the twentieth century the major sources of lead in the environment were lead-containing house paints and gasoline. Although limits have been set for the amounts of lead contained in residential paints, and leaded gasoline has practically disappeared in the United States, lead contamination remains an important health hazard, particularly for children. The large-scale recall of toys containing lead in 2007 alerted the general public to the dangers of lead exposures. There are many sources of lead in the environment, such as from mining, foundries, batteries, and spray painting, which constitute occupational hazards. However, flaking lead paint in older houses and soil contamination pose major hazards to youngsters, and ingestion of up to 200 mg/day can occur. During the last 30 years the median blood level of lead in preschool children in the United States decreased from 15 μg/dL to the present level of less than 2 μg/dL. However, lead blood levels in children living in older homes containing lead-based paint or lead-contaminated dust, often exceed the maximal allowed level of 10 μg/dL. Subclinical lead poisoning may occur in children exposed to levels of lead below 10 μg/dL, causing low intellectual capacity, behavioral problems such as hyperactivity, and poor organizational skills.^14,¹⁵ Lead poisoning, although less common in adults, occurs mainly as an occupational hazard in those involved in the manufacturing of batteries, pigments, car radiators, and tin cans. The main clinical features of lead poisoning in children and adults are shown in Figures 9-5 and 9-6.

FIGURE 9-5 Effects of lead poisoning in children related to blood levels.

(Modified from Bellinger DC, Bellinger AM: Childhood lead poisoning: the tortuous path from science to policy. J Clin Invest 116:853, 2006.)

FIGURE 9-6 Pathologic features of lead poisoning in adults.

Most of the absorbed lead (80% to 85%) is incorporated into bone and developing teeth, where it competes with calcium; its half-life in bone is 20 to 30 years. High levels of lead cause disturbances in the CNS in adults and children, but peripheral neuropathies predominate in adults. Children absorb more than 50% of ingested lead (as compared with ≤15% in adults); the higher intestinal absorption and the more permeable blood-brain barrier of children create a high susceptibility to brain damage. The neurotoxic effects of lead are attributed to the inhibition of neurotransmitters caused by the disruption of calcium homeostasis. Other effects of lead exposure are listed below.

• Lead interferes with the normal remodeling of cartilage and primary bone trabeculae in the epiphyses in children. This causes increased bone density detected as radiodense “lead lines” (Fig. 9-7; another type of lead line appears in the gums as a result of hyperpigmentation). Lead inhibits the healing of fractures by increasing chondrogenesis and delaying cartilage mineralization.

• Lead inhibits the activity of two enzymes involved in heme synthesis, δ-aminolevulinic acid dehydratase and ferrochelatase. Ferrochelatase catalyzes the incorporation of iron into protoporphyrin, and its inhibition causes a rise in protoporphyrin levels. The resulting heme deficiency causes various abnormalities, but the most obvious is a microcytic, hypochromic anemia stemming from the suppression of hemoglobin synthesis.

FIGURE 9-7 Lead poisoning. Impaired remodeling of calcified cartilage in the epiphyses (arrows) of the wrist has caused a marked increase in their radiodensity, so that they are as radiopaque as the cortical bone.

(Courtesy of Dr. G.W. Dietz, Department of Radiology, University of Texas Southwestern Medical School, Dallas, TX.)

The diagnosis of lead poisoning requires constant awareness of its prevalence. In children it may be suspected on the basis of neurologic and behavioral changes, or by unexplained anemia with basophilic stippling in red cells. Definitive diagnosis requires the detection of elevated blood levels of lead and free (or zinc-bound) red cell protoporphyrin.

Morphology. The major anatomic targets of lead toxicity are the bone marrow and blood, nervous system, gastrointestinal tract, and kidneys (see Fig. 9-6).

Blood and marrow changes occur fairly early and are characteristic. The inhibition of ferrochelatase by lead results in the appearance of scattered ringed sideroblasts, red cell precursors with iron-laden mitochondria that are detected with a Prussian blue stain. In the peripheral blood the defect in hemoglobin synthesis appears as a microcytic, hypochromic anemia that is often accompanied by mild hemolysis. Even more distinctive is a punctate basophilic stippling of the red cells.

Brain damage is prone to occur in children. It can be very subtle, producing mild dysfunction, or it can be massive and lethal. In young children, sensory, motor, intellectual, and psychologic impairments have been described, including reduced IQ, learning disabilities, retarded psychomotor development, blindness, and, in more severe cases, psychoses, seizures, and coma (see Fig. 9-5). Lead toxicity in the mother may impair brain development in the prenatal infant. The anatomic changes underlying the more subtle functional deficits are ill-defined, but there is concern that some of the defects may be permanent. At the more severe end of the spectrum are marked brain edema, demyelination of the cerebral and cerebellar white matter, and necrosis of cortical neurons accompanied by diffuse astrocytic proliferation. In adults the CNS is less often affected, but frequently a peripheral demyelinating neuropathy appears, typically involving the motor nerves of the most commonly used muscles. Thus, the extensor muscles of the wrist and fingers are often the first to be affected (causing wristdrop), followed by paralysis of the peroneal muscles (causing footdrop).

The gastrointestinal tract is also a major source of clinical manifestations. Lead “colic” is characterized by extremely severe, poorly localized abdominal pain.

Kidneys may develop proximal tubular damage with intranuclear lead inclusions. Chronic renal damage leads eventually to interstitial fibrosis and possibly renal failure. Decreases in uric acid excretion can lead to gout (“saturnine gout”).

Mercury

Mercury has had many uses throughout history such as a pigment in cave paintings, a cosmetic, a remedy for syphilis, and a component of diuretics. Alchemists tried (without much success) to produce gold from mercury. Poisoning from inhalation of mercury vapors has long been recognized and is associated with tremor, gingivitis, and bizarre behavior, such as that displayed by the Mad Hatter in Alice in Wonderland. There are three forms of mercury: metallic mercury (also referred to as elemental mercury), inorganic mercury compounds (mostly mercuric chloride), and organic mercury (mostly methyl mercury). Today, the main sources of exposure to mercury are contaminated fish (methyl mercury) and mercury vapors released from metallic mercury in dental amalgams, a possible occupational hazard for dental workers. In some areas of the world, mercury used in gold mining has contaminated rivers and streams.

Inorganic mercury from the natural degassing of the earth’s crust or from industrial contamination is converted to organic compounds such as methyl mercury by bacteria. Methyl mercury enters the food chain, and in carnivorous fish such as swordfish, shark, and bluefish, mercury may be concentrated to levels a million-fold higher than in the surrounding water. Disasters caused by the consumption of fish contaminated by the release of methyl mercury from industrial sources in Minamata Bay and the Agano River in Japan caused widespread mortality and morbidity. Acute exposure through consumption of bread made from grain treated with a methyl mercury–based fungicide in Iraq in 1971 resulted in hundreds of deaths and thousands of hospitalizations. The medical disorders associated with the Minamata episode became known as “Minamata disease” and include cerebral palsy, deafness, blindness, mental retardation, and major CNS defects in children exposed in utero. For unclear reasons, the developing brain is extremely sensitive to methyl mercury. The lipid solubility of methyl mercury and metallic mercury facilitate their accumulation in the brain, disturbing neuromotor, cognitive, and behavioral functions.¹⁶ Mercury binds with high affinity to thiol groups, a property that contributes to its toxicity. Intracellular glutathione, acting as thiol donor, is the main protective mechanism against mercury-induced CNS and kidney damage.

Mercury continues to be released into the environment by power plants and other industrial sources, and there are serious concerns about the effects of chronic low-level exposure to methyl mercury in the food supply. To protect against potential fetal brain damage, the Centers for Disease Control and Prevention has recommended that pregnant women reduce their consumption of fish known to contain mercury to a minimum. There has been much publicity about a possible relationship between thimerosal (a compound that contains ethyl mercury, used until recently as a preservative in some vaccines) and the development of autism, but multiple studies have failed to find evidence of a causal relationship.¹⁷

Arsenic

Arsenic was the poison of choice in Renaissance Italy, with members of the Borgia and Medici families being highly skilled practitioners of the art. Because of its favored use as a murder weapon among royal families, arsenic has been called “the poison of kings and the king of poisons.”¹⁸ Deliberate poisoning by arsenic is exceedingly rare today, but exposure to arsenic is an important health problem in many areas of the world. Arsenic is found naturally in soils and water and is used in products such as wood preservers, as well as herbicides and other agricultural products. It may be released into the environment from mines and smelting industries. Arsenic is present in Chinese and Indian herbal medicine, and arsenic trioxide is used in the treatment of relapsing acute promyelocytic leukemia. Large concentrations of inorganic arsenic are present in ground water used for drinking in countries such as Bangladesh, Chile, and China. Between 35 and 77 million people in Bangladesh drink water contaminated by arsenic, constituting the highest environmental cancer risk ever found.

The most toxic forms of arsenic are the trivalent compounds arsenic trioxide, sodium arsenite, and arsenic trichloride.¹⁹ If ingested in large quantities, arsenic causes acute toxic effects consisting of severe disturbances of the gastrointestinal, cardiovascular, and central nervous systems that are often fatal. These effects may be attributed to interference with mitochondrial oxidative phosphorylation, since trivalent arsenic can replace the phosphates in adenosine triphosphate. Neurologic effects usually occur 2 to 8 weeks after exposure and consist of a sensorimotor neuropathy that causes paresthesias, numbness, and pain. The most serious consequence of chronic exposure is the increased risk for the development of cancers in almost all tissues, but particularly in the lungs and skin. Chronic exposure to arsenic causes skin changes consisting of hyperpigmentation and hyperkeratosis, which may be followed by the development of basal and squamous cell carcinomas. Arsenic-induced skin tumors differ from those induced by sunlight; they are often multiple and usually appear on the palms and soles. The mechanisms of arsenic carcinogenesis in skin and lung have not been elucidated but may involve defects in nucleotide excision repair mechanisms that protect against DNA damage.¹⁸ Recent studies suggest that chronic exposure to arsenic in drinking water can also cause non-malignant respiratory disease.²⁰

Cadmium

In contrast to the other metals discussed in this section, cadmium toxicity is a relatively modern problem. It is an occupational and environmental pollutant generated by mining, electroplating, and production of nickel-cadmium batteries, which are usually disposed of as household waste. Cadmium can contaminate the soil and plants directly or through fertilizers and irrigation water. Food is the most important source of cadmium exposure for the general population. The toxic effects of excess cadmium consist of obstructive lung disease caused by necrosis of alveolar macrophages, and kidney damage, initially consisting of tubular damage that may progress to end-stage renal disease. Cadmium exposure can also cause skeletal abnormalities associated with calcium loss. Cadmium-containing water used to irrigate rice fields in Japan caused a disease in postmenopausal women known as “Itai-Itai” (ouch-ouch), a combination of osteoporosis and osteomalacia associated with renal disease. Cadmium exposure is also associated with elevated risk of lung cancer, which has been demonstrated in workers exposed occupationally and in populations living near zinc smelters.²¹ Cadmium is not directly genotoxic and most likely produces DNA damage through the generation of reactive oxygen species (see Chapter 1). A recent survey showed that 5% of the US population age 20 years and older have urinary cadmium levels that may produce subtle kidney injury and calcium loss.

Occupational Health Risks: Industrial and Agricultural Exposures

More than 10 million injuries and about 100,000 deaths occur yearly in the United States as a consequence of work-related accidents and illnesses. Work-related accidents are the biggest problem in developing countries, while work-related diseases are more frequent in industrialized countries. The fraction of global disease attributed to occupational exposures includes 13% of all cases of chronic obstructive pulmonary disease, 9% of lung cancers, and 2 % of leukemias. Industrial exposures to toxic agents are as varied as the industries themselves. They range from mere irritation of the respiratory mucosa by formaldehyde or ammonia fumes; to lung cancer induced by exposure to asbestos, arsenic, or uranium mining; to leukemia caused by chronic exposure to benzene. Human diseases associated with occupational exposures are listed in Table 9-2. Here we provide a few examples of important agents that contribute to occupational diseases. Toxicity caused by metals has already been discussed in this chapter.

• Organic solvents are widely used in huge quantities worldwide. Some, such as chloroform and carbon tetrachloride, are found in degreasing and dry cleaning agents and paint removers. Acute exposure to high levels of vapors from these agents can cause dizziness and confusion, leading to central nervous system depression and even coma. Lower levels are toxic for the liver and kidneys. Occupational exposure of rubber workers to benzene and 1,3-butadiene increases the risk of leukemia. Benzene is oxidized by hepatic CYP2E1 to toxic metabolites that disrupt the differentiation of hematopoietic cells in the bone marrow, leading to dose-dependent marrow aplasia and an increased risk of acute myeloid leukemia.

• Polycyclic hydrocarbons may be released during the combustion of fossil fuels, particularly when coal and gas are burned at high temperatures (such as in steel foundries), and are also present in tar and soot (Pott identified soot as the cause of scrotal cancers in chimney sweeps in 1775, as mentioned in Chapter 7). Polycyclic hydrocarbons are among the most potent carcinogens, and industrial exposures have been implicated in the development of lung and bladder cancer.

• Organochlorines. Organochlorines (and halogenated organic compounds in general) are synthetic lipophilic products that resist degradation. Important organochlorines used as pesticides include DDT (dichlorodiphenyltrichloroethane), Lindane, Aldrin, and Dieldrin. Nonpesticide organochlorines include polychlorinated biphenyls (PCBs) and dioxin (TCDD; 2,3,7,8-tetrachlorodibenzo-p-dioxin). DDT was banned in the United States in 1973, but more than half of the U.S. population has detectable levels of p, p′-DDE, a long-lasting DDT metabolite. This substance was even found in 12- to 19-year-olds born after the ban on DDT. PCB (another banned substance), dioxin, and PBDEs (polybrominated diphenyl ethers used as flame retardants) are also detectable in a large proportion of the U.S. population. Most organochlorines are endocrine disruptors with anti-estrogenic or anti-androgenic activity.

• Dioxins and PCBs can cause skin disorders such as folliculitis and a dermatosis known as chloracne that is characterized by acne, cyst formation, hyperpigmentation, and hyperkeratosis, generally around the face and behind the ears. These toxins can also cause abnormalities in the liver and central nervous system. Because PCBs induce CYPs, workers exposed to these substances may show abnormal drug metabolism. Environmental disasters in Japan and China in the late 1960s caused by the consumption of rice oil contaminated by PCBs during its production, poisoned about 2000 people in each episode. The primary manifestation of the disease (Yusho in Japan; Yu-Cheng in China) was chloracne and hyperpigmentation of the skin and nails. A bizarre case of intentional dioxin poisoning, which made international headlines and was a front-page illustration of chloracne, involved a future president of Ukraine. This individual developed extensive chloracne and systemic symptoms, as a consequence of eating a meal spiked with dioxin that was offered by one of his political “friends.”

• Inhalation of mineral dusts causes chronic, non-neoplastic lung diseases known as pneumoconioses. This term also includes diseases induced by organic and inorganic particulates, and chemical fume- and vapor-induced non-neoplastic lung diseases. The most common pneumoconioses are caused by exposures to coal dust (from mining of hard coal), silica (sandblasting, stone cutting, etc.), asbestos (mining, fabrication, insulation work), and beryllium (mining, fabrication). Exposure to these agents nearly always occurs in the workplace. However, the increased risk of cancer as a result of asbestos exposure extends to the family members of asbestos workers and to other individuals exposed outside the workplace. Pneumoconioses and their pathogenesis are discussed in Chapter 15.

• Exposure to vinyl chloride used in the synthesis of polyvinyl resins leads to the development of angiosarcoma of the liver, an uncommon type of hepatic tumor.

• Exposure to phthalates in laboratory animals causes endocrine disruption and a testicular dysgenesis syndrome involving hypospadias, cryptorchidism, and testicular cell abnormalities that are similar to conditions of generally unknown origin found in humans. Phthalates are widely used plasticizers found in flexible plastics (as in food wraps) and in medical containers, such as blood and serum bags. A matter of concern is that critically ill infants may receive large doses of phthalates from bags holding intravenous fluids, although the toxicity in humans has not been firmly established.

TABLE 9-2 Human Diseases Associated with Occupational Exposures

Organ/System	Effect	Toxicant
Cardiovascular system	Heart disease	Carbon monoxide, lead, solvents, cobalt, cadmium
Respiratory system	Nasal cancer	Isopropyl alcohol, wood dust
	Lung cancer	Radon, asbestos, silica, bis(chloromethyl)ether, nickel, arsenic, chromium, mustard gas, uranium
	Chronic obstructive lung disease	Grain dust, coal dust, cadmium
	Hypersensitivity	Beryllium, isocyanates
	Irritation	Ammonia, sulfur oxides, formaldehyde
	Fibrosis	Silica, asbestos, cobalt
Nervous system	Peripheral neuropathies	Solvents, acrylamide, methyl chloride, mercury, lead, arsenic, DDT
	Ataxic gait
	Central nervous system depression	Chlordane, toluene, acrylamide, mercury
	Cataracts	Alcohols, ketones, aldehydes, solvents
	Cataracts	Ultraviolet radiation
Urinary system	Toxicity	Mercury, lead, glycol ethers, solvents
Urinary system	Bladder cancer	Naphthylamines, 4-aminobiphenyl, benzidine, rubber products
Reproductive system	Male infertility	Lead, phthalate plasticizers, cadmium
	Female infertility/stillbirths	Lead, mercury
	Teratogenesis	Mercury, polychlorinated biphenyls
Hematopoietic system	Leukemia	Benzene
Skin	Folliculitis and acneiform dermatosis	Polychlorinated biphenyls, dioxins, herbicides
Skin	Cancer	Ultraviolet radiation
Gastrointestinal tract	Liver angiosarcoma	Vinyl chloride

Data from Leigh JP, et al.: Occupational injury and illness in the United States. Estimates of costs, morbidity, and mortality, Arch Intern Med 157:1557, 1997; Mitchell FL: Hazardous waste. In Rom WN (ed): Environmental and Occupational Medicine, 2nd ed. Boston, Little, Brown, 1992, p 1275; and Levi PE: Classes of toxic chemicals. In Hodgson E, Levi PE (eds): A Textbook of Modern Toxicology. Stamford, CT, Appleton & Lange, 1997, p 229.

Effects of Tobacco

Tobacco is the most common exogenous cause of human cancers, being responsible for 90% of lung cancers. The main culprit is cigarette smoking, but smokeless tobacco (snuff, chewing tobacco, etc.) is also harmful to health and an important cause of oral cancer. The use of tobacco products not only creates personal risks, but passive tobacco inhalation from the environment (“second-hand smoke”) can cause lung cancer in nonsmokers.²² Cigarette smoking causes, worldwide, more than 5 million deaths annually, mostly from cardiovascular disease, various types of cancers, and chronic respiratory problems, that result in a total of more than 35 million years of life lost. These figures are expected to rise to 8 million tobacco-related deaths by 2020, the major increase occurring in developing countries. It has been estimated that of people alive today, approximately 500 million will die from tobacco-related illnesses. In the United States alone, tobacco is responsible for over 400,000 deaths annually, one third of these attributable to lung cancer. Two thirds of smokers live in 10 countries, led by China, which accounts for nearly 30%, and India with about 10%, followed by Indonesia, Russia, the United States, Japan, Brazil, Bangladesh, Germany, and Turkey.

Smoking is the most preventable cause of human death. It reduces overall survival through dose-dependent effects. For instance, while 80% of a population of nonsmokers is alive at age 70, only about 50% of smokers survive to that age (Fig. 9-8). The prevalence of smoking has decreased in US teenagers, a hopeful trend. However, recent surveys estimate that 7%, 14%, and 22% of students in grades 8, 10, and 12, respectively, had used tobacco products during the month before the survey. Delaying the age at which smoking is initiated reduces the future risk of lung and other types of cancers, but, unfortunately, initiation seems to be occurring at younger ages. Cessation of smoking greatly reduces, within 5 years, the overall mortality and the risk of death from cardiovascular diseases. Lung cancer mortality decreases by 21% within 5 years, but the excess risk lasts for 30 years.²²

FIGURE 9-8 The effects of smoking on survival. The study compared age-specific death rates for current cigarette smokers with that of individuals who never smoked regularly (British Doctors Study). Measured at age 75, the difference in survival between smokers and nonsmokers is 7.5 years.

(Modified from Stewart BW, Kleihues P (eds): World Cancer Report. Lyon, IARC Press, 2003.)

The number of potentially noxious chemicals in tobacco smoke is extraordinary. Tobacco contains between 2000 and 4000 substances, more than 60 of which have been identified as carcinogens. Table 9-3 provides only a partial list and includes various types of injuries produced by these agents. Nicotine, an alkaloid present in tobacco leaves, is not a direct cause of tobacco-related diseases, but is addictive. Without it, it would be easy for smokers to stop the habit. Nicotine binds to receptors in the brain, and through the release of catecholamines, is responsible for the acute effects of smoking, such as the increase in heart rate and blood pressure, and the elevation in cardiac contractility and output. The most common diseases caused by cigarette smoking involve the lung and include emphysema, chronic bronchitis, chronic obstructive pulmonary disease, and lung cancer, conditions that are discussed in Chapter 15. Cigarette smoking is also strongly associated with the development of atherosclerosis, myocardial infarcts, and cancers of the lip, mouth, pharynx, esophagus, pancreas, bladder, kidney, and cervix. Adverse effects of smoking in various organs systems are shown in Figure 9-9.

TABLE 9-3 Effects of Selected Tobacco Smoke Constituents

Substance	Effect
Tar	Carcinogenesis
Polycyclic aromatic hydrocarbons	Carcinogenesis
Nicotine	Ganglionic stimulation and depression; tumor promotion
Phenol	Tumor promotion; mucosal irritation
Benzopyrene	Carcinogenesis
Carbon monoxide	Impaired oxygen transport and utilization
Formaldehyde	Toxicity to cilia; mucosal irritation
Oxides of nitrogen	Toxicity to cilia; mucosal irritation
Nitrosamine	Carcinogenesis

FIGURE 9-9 Adverse effects of smoking: those that are more common are in boldface.

Smoking and Lung Cancer.

Agents in smoke have a direct irritant effect on the tracheobronchial mucosa, producing inflammation and increased mucus production (bronchitis). Cigarette smoke also causes the recruitment of leukocytes to the lung, with increased local elastase production and subsequent injury to lung tissue, leading to emphysema. Components of cigarette smoke, particularly polycyclic hydrocarbons and nitrosamines (Table 9-4), are potent carcinogens in animals and likely to be directly involved in the development of lung cancer in humans (see Chapter 15). CYPs (cytochrome P-450 phase I enzymes) and phase II enzymes increase the water solubility of the carcinogens, facilitating their excretion. However, some intermediates produced by CYPs are electrophilic and form DNA adducts. If such adducts persist, they can cause mutations in oncogenes and tumor suppressors such as K-Ras and p53,²³ respectively. The risk of developing lung cancer is related to the intensity of exposure, frequently expressed in terms of “pack years” (e.g., one pack smoked daily for 20 years equals 20 pack years) or in cigarettes smoked per day (Fig. 9-10). Moreover, smoking multiplies the risk of other carcinogenic influences. Witness the ten-fold higher incidence of lung carcinomas in asbestos workers and uranium miners who smoke over those who do not smoke, and the interaction between tobacco consumption and alcohol in the development of oral cancers (mentioned below).

TABLE 9-4 Organ-Specific Carcinogens in Tobacco Smoke

Organ	Carcinogen
Lung, larynx	Polycyclic aromatic hydrocarbons 4-(Methylnitrosoamino)-1-(3-pyridyl)-1-buta-none (NNK), polonium 210
Esophagus	N′-Nitrosonornicotine (NNN)
Pancreas	NNK (?)
Bladder	4-Aminobiphenyl, 2-naphthylamine
Oral cavity (smoking)	Polycyclic aromatic hydrocarbons, NNK, NNN
Oral cavity (snuff)	NNK, NNN, polonium 210

Data from Szczesny LB, Holbrook JH: Cigarette smoking. In Rom WH (ed): Environmental and Occupational Medicine, 2nd ed. Boston, Little, Brown, 1992, p 1211.

FIGURE 9-10 The risk of lung cancer is determined by the number of cigarettes smoked.

(Modified from Stewart BW, Kleihues P (eds): World Cancer Report. Lyon, IARC Press, 2003.)

Smoking and Other Diseases.

In addition to lung cancers, tobacco contributes to the development of cancers of the oral cavity, esophagus, pancreas, and bladder. Smoke and smokeless tobacco interact with alcohol in the development of laryngeal cancer. The combination of these agents has a multiplicative effect on the risk of developing this tumor (Fig. 9-11).

FIGURE 9-11 Multiplicative increase in the risk of laryngeal cancer from the interaction between cigarette smoking and alcohol consumption.

(Modified from Stewart BW, Kleihues P (eds): World Cancer Report. Lyon, IARC Press, 2003.)

Cigarette smoking is strongly linked to the development of atherosclerosis and its major complication, myocardial infarction. The causal mechanisms probably relate to several factors, including increased platelet aggregation, decreased myocardial oxygen supply (because of significant lung disease coupled with the hypoxia related to the CO content of cigarette smoke) accompanied by an increased oxygen demand, and a decreased threshold for ventricular fibrillation. Smoking has a multiplicative effect on the incidence of myocardial infarction when combined with hypertension and hypercholesterolemia.

Maternal smoking increases the risk of spontaneous abortions and preterm births and results in intrauterine growth retardation (Chapter 10). Birth weights of infants born to mothers who stopped smoking before pregnancy are, however, normal.

Exposure to environmental tobacco smoke (passive smoke inhalation) is also associated with some of the same detrimental effects that result from active smoking. It is estimated that the relative risk of lung cancer in nonsmokers exposed to environmental smoke is about 1.3 times higher than that of nonsmokers who are not exposed to smoke. In the United States, approximately 3000 lung cancer deaths in nonsmokers over the age of 35 years can be attributed each year to environmental tobacco smoke. Even more striking is the increased risk of coronary atherosclerosis and fatal myocardial infarction. Studies report that every year 30,000 to 60,000 cardiac deaths in the United States are associated with exposure to passive smoke. Passive smoke inhalation in nonsmokers can be estimated by measuring the blood levels of cotinine, a metabolite of nicotine. Median cotinine levels in nonsmokers have decreased by more than 60% during the last 10 years, but exposure to environmental tobacco smoke in the home remains a major public health concern, particularly for children who may develop respiratory illnesses and asthma. It is clear that the transient pleasure a puff may give comes with a heavy long-term price.

Effects of Alcohol

Ethanol consumption in moderate amounts is generally not injurious, but in excessive amounts alcohol causes serious physical and psychologic damage. In this section we describe the steps of alcohol metabolism and the major health consequences associated with alcohol abuse.

Despite all the attention given to illicit drugs such as cocaine and heroin, alcohol abuse is a more widespread hazard and claims many more lives. Fifty percent of adults in the Western world drink alcohol, and about 5% to 10% have chronic alcoholism. It is estimated that there are more than 10 million chronic alcoholics in the United States and that alcohol consumption is responsible for more than 100,000 deaths annually. More than 50% of these deaths result from accidents caused by drunken driving and alcohol-related homicides and suicides, and about 15,000 annual deaths are a consequence of cirrhosis of the liver. Worldwide, alcohol accounts for approximately 1.8 million deaths per year (3.2% of all deaths). After consumption, ethanol is absorbed unaltered in the stomach and small intestine. It is then distributed to all the tissues and fluids of the body in direct proportion to the blood level. Less than 10% is excreted unchanged in the urine, sweat, and breath. The amount exhaled is proportional to the blood level and forms the basis of the breath test used by law enforcement agencies. A concentration of 80 mg/dL in the blood constitutes the legal definition of drunk driving in the United States. For an average individual, this alcohol concentration may be reached after consumption of three standard drinks, contained in about 3 (12 ounce) bottles of beer, 15 ounces of wine, or 4–5 ounces of 80 proof distilled spirits. Drowsiness occurs at 200 mg/dL, stupor at 300 mg/dL, and coma, with possible respiratory arrest, at higher levels. The rate of metabolism affects the blood alcohol level. Chronic alcoholics can tolerate levels of up to 700 mg/dL, a situation that is partially explained by accelerated ethanol metabolism caused by a five- to ten-fold induction of liver CYPs discussed below. The effects of alcohol also vary by age, sex, and body fat.

Most of the alcohol in the blood is biotransformed to acetaldehyde in the liver by three enzyme systems consisting of alcohol dehydrogenase (ADH), the microsomal ethanol-oxidizing system (MEOS), and catalase (Fig. 9-12). The main enzyme system involved in alcohol metabolism is ADH, located in the cytosol of hepatocytes. At high blood alcohol levels, the microsomal ethanol-oxidizing system participates in its metabolism. Catalase, which uses hydrogen peroxide as substrate, is of minor importance, since it metabolizes no more than 5% of ethanol in the liver. Acetaldehyde produced by alcohol metabolism through ADH or MEOS is converted to acetate by acetaldehyde dehydrogenase (ALDH), which is then utilized in the mitochondrial respiratory chain.

FIGURE 9-12 Metabolism of ethanol: oxidation of ethanol to acetaldehyde by three different routes, and the generation of acetic acid. Note that oxidation by ADH (alcohol dehydrogenase) takes place in the cytosol; the cytochrome P-450 system and its CYP2E1 isoform are located in the endoplasmic reticulum (microsomes), and catalase is located in peroxisomes. Oxidation of acetaldehyde by ALDH (aldehyde dehydrogenase) oc-curs in mitochondria. ADH oxidation is the most important route; catalase is involved in only 5% of ethanol metabolism. Oxidation through CYPs may also generate reactive oxygen species (not shown).

(From Parkinson A: Biotransformation of xenobiotics. In Klassen CD [ed]: Casarett and Doull’s Toxicology: The Basic Science of Poisons, 6th ed. New York, McGraw-Hill, 2001, p 133.)

The microsomal oxidation system involves CYPs, particularly CYP2E1 located in the smooth endoplasmic reticulum. Induction of CYPs by alcohol explains the increased susceptibility of alcoholics to other compounds metabolized by the same enzyme system, which include drugs, anesthetics, carcinogens, and industrial solvents. Note, however, that when alcohol is present in the blood at high concentrations, it competes with other CYP2E1 substrates and delays drug catabolism, potentiating the depressant effects of narcotic, sedative, and psychoactive drugs in the central nervous system. The oxidation of ethanol produces toxic agents and disrupts metabolic pathways. Here we mention only the most important of these changes.

• Acetaldehyde has many toxic effects and is responsible for some of the acute effects of alcohol and for the development of oral cancers. The efficiency of alcohol metabolism varies between populations, depending on the expression levels of ADH and ALDH isozymes, and the presence of genetic variants that alter enzyme activity. About 50% of Asians have very low ALDH activity, due to the substitution of lysine for glutamine at residue 487 (the normal allele is termed ALDH2*1 and the inactive variant is designated as ALDH2*2). The ALDH2*2 protein has dominant-negative activity, such that even one copy of the ALDH2*2 allele reduces ALDH activity significantly. Individuals homozygous for the ALDH2*2 allele are completely unable to oxidize acetaldehyde and cannot tolerate alcohol, experiencing nausea, flushing, tachycardia, and hyperventilation after its ingestion.²⁴

• Alcohol oxidation by ADH causes the reduction of nicotinamide adenine dinucleotide (NAD) to NADH, with a consequent decrease in NAD and increase in NADH. NAD is required for fatty acid oxidation in the liver and for the conversion of lactate into pyruvate. Its deficiency is a main cause of the accumulation of fat in the liver of alcoholics. The increase in the NADH/NAD ratio in alcoholics also causes lactic acidosis.

• Metabolism of ethanol in the liver by CYP2E1 produces reactive oxygen species and causes lipid peroxidation of cell membranes. However, the precise mechanisms that account for alcohol-induced cellular injury in the liver have not been well defined. Alcohol also causes the release of endotoxin (lipopolysaccharide) from gram-negative bacteria in the intestinal flora, which stimulates the production of TNF (tumor necrosis factor) and other cytokines from macrophages and Kupffer cells, leading to hepatic injury.

The adverse effects of ethanol can be classified as acute or chronic.

Acute alcoholism exerts its effects mainly on the CNS, but it may induce hepatic and gastric changes that are reversible if alcohol consumption is discontinued. Even with moderate intake of alcohol, multiple fat droplets accumulate in the cytoplasm of hepatocytes (fatty change or hepatic steatosis). The gastric changes are acute gastritis and ulceration. In the CNS, alcohol is a depressant, first affecting subcortical structures (probably the high brain stem reticular formation) that modulate cerebral cortical activity. Consequently, there is stimulation and disordered cortical, motor, and intellectual behavior. At progressively higher blood levels, cortical neurons and then lower medullary centers are depressed, including those that regulate respiration. Respiratory arrest may follow.

Chronic alcoholism affects not only the liver and stomach, but virtually all other organs and tissues as well. Chronic alcoholics suffer significant morbidity and have a shortened life span, related principally to damage to the liver, gastrointestinal tract, CNS, cardiovascular system, and pancreas.

• The liver is the main site of chronic injury. In addition to fatty change mentioned above, chronic alcoholism causes alcoholic hepatitis and cirrhosis, as described in Chapter 18. Cirrhosis is associated with portal hypertension and an increased risk for the development of hepatocellular carcinoma.

• In the gastrointestinal tract, chronic alcoholism can cause massive bleeding from gastritis, gastric ulcer, or esophageal varices (associated with cirrhosis), which may prove fatal.

• Thiamine (vitamin B₁) deficiency is common in chronic alcoholics. The principal lesions resulting from this deficiency are peripheral neuropathies and the Wernicke-Korsakoff syndrome (see Table 9-9 in this chapter, and Chapter 28); cerebral atrophy, cerebellar degeneration, and optic neuropathy may also occur.

• Alcohol has diverse effects on the cardiovascular system. Injury to the myocardium may produce dilated congestive cardiomyopathy (alcoholic cardiomyopathy, discussed in Chapter 12). Chronic alcoholism is also associated with an increased incidence of hypertension. Moderate amounts of alcohol (about 20–30 gm of daily intake, corresponding to approximately 250 mL of wine) have been reported to increase high-density lipoprotein (HDL) levels and inhibit platelet aggregation, thus protecting against coronary heart disease. However, heavy alcohol consumption, with attendant liver injury, results in decreased levels of HDL, increasing the likelihood of coronary heart disease.

• Excessive alcohol intake increases the risk of acute and chronic pancreatitis (Chapter 19).

• The use of ethanol during pregnancy—reportedly in very low amounts—can cause fetal alcohol syndrome.²⁵ It consists of microcephaly, growth retardation, and facial abnormalities in the newborn, and reduction in mental functions as the child grows older. It is difficult to establish the minimal amount of alcohol consumption that can cause fetal alcohol syndrome, but consumption during the first trimester of pregnancy is particularly harmful. It has been estimated that the prevalence of frequent and binge drinking among pregnant women is approximately 6% and that fetal alcohol syndrome affects 1 to 4.8 per 1000 children born in the United States.

• Chronic alcohol consumption is associated with an increased incidence of cancer of the oral cavity, esophagus, liver, and, possibly, breast in females. Acetaldehyde is considered to be the main agent associated with alcohol-induced laryngeal and esophageal cancer, in that acetaldehyde-DNA adducts have been detected in some tumors from these tissues. Individuals with one copy of the ALDH2*2 allele who drink are at a higher risk of developing cancer of the esophagus.

• Ethanol is a substantial source of energy (empty calories). Chronic alcoholism leads to malnutrition and nutritional deficiencies, particularly of the B vitamins.

TABLE 9-9 Vitamins: Major Functions and Deficiency Syndromes

Vitamin	Functions	Deficiency Syndromes
FAT-SOLUBLE
Vitamin A	A component of visual pigment	Night blindness, xerophthalmia, blindness
	Maintenance of specialized epithelia	Squamous metaplasia
	Maintenance of resistance to infection	Vulnerability to infection, particularly measles
Vitamin D	Facilitates intestinal absorption of calcium and phosphorus and mineralization of bone	Riskets in children
Vitamin D		Osteomalacia in adults
Vitamin E	Major antioxidant; scavenges free radicals	Spinocerebellar degeneration
Vitamin K	Cofactor in hepatic carboxylation of procoagulants—factors II (prothrombin), VII, IX, and X; and protein C and protein S	Bleeding diathesis (Chapter 14)
WATER-SOLUBLE
Vitamin B₁ (thiamine)	As pyrophosphate, is coenzyme in decarboxylation reactions	Dry and wet beriberi, Wernicke syndrome, Korsakoff syndrome (Chapter 28)
Vitamin B₂ (riboflavin)	Converted to coenzymes flavin mononucleotide and flavin adenine dinucleotide, cofactors for many enzymes in intermediary metabolism	Ariboflavinosis, cheilosis, stomatitis, glossitis, dermatitis, corneal vascularization
Niacin	Incorporated into nicotinamide adenine dinucleotide (NAD) and NAD phosphate, involved in a variety of redox reactions	Pellagra—“three Ds”: dementia, dermatitis, diarrhea
Vitamin B₆ (pyridoxine)	Derivatives serve as coenzymes in many intermediary reactions	Cheilosis, glossitis, dermatitis, peripheral neuropathy (Chapter 28)
Vitamin B₁₂	Required for normal folate metabolism and DNA synthesis	Megaloblastic pernicious anemia and degeneration of posterolateral spinal cord tracts (Chapter 14)
Vitamin B₁₂	Maintenance of myelinization of spinal cord tracts
Vitamin C	Serves in many oxidation-reduction (redox) reactions and hydroxylation of collagen	Scurvy
Folate	Essential for transfer and use of one-carbon units in DNA synthesis	Megaloblastic anemia, neural tube defects (Chapter 14)
Pantothenic acid	Incorporated in coenzyme A	No nonexperimental syndrome recognized
Biotin	Cofactor in carboxylation reactions	No clearly defined clinical syndrome

And now, a bit of good news: red wine contains resveratrol, a polyphenolic compound that increases life span in worms and flies, promotes longevity in mice, and protects mice against diet-induced obesity and insulin resistance. Resveratrol contributes to the protective effect against cardiovascular disease in moderate wine drinkers and possibly provides the clue to the “French paradox,” a wine- and food-loving population with a low incidence of obesity and cardiovascular disease. The effects of resveratrol on longevity have been attributed to its activation of protein deacetylases of the Sir2 (sirtuin) family of enzymes, which include histone deacetylases (Chapter 1). However, because resveratrol also interacts with various other proteins, ongoing studies seek to identify the precise mechanisms of its protective effects.^26,²⁷

Injury by Therapeutic Drugs and Drugs of Abuse

INJURY BY THERAPEUTIC DRUGS (ADVERSE DRUG REACTIONS)

Adverse drug reactions (ADRs) refer to untoward effects of drugs that are given in conventional therapeutic settings. These reactions are extremely common in the practice of medicine (Fig. 9-13) and affect almost 10% of patients admitted to a hospital. It is estimated that in about 10% of these patients, ADRs are fatal. Table 9-5 lists common pathologic findings in ADRs and the drugs most frequently involved. As can be seen in the table, many of the drugs that produce ADRs, such as antineoplastic agents, are highly potent, and the adverse reactions are expected risks of the treatment. In this section, we examine the adverse reactions to some commonly used drugs. We first discuss the adverse effects of hormonal replacement therapy (HRT), oral contraceptives (OCs), and anabolic steroids. This is followed by a discussion of the effects of the drugs acetaminophen and aspirin, because all of these are used very commonly.

FIGURE 9-13 Adverse drug reaction. Skin pigmentation caused by minocycline, a long-acting tetracycline derivative. A, Diffuse blue-gray pigmentation of the forearm; B, Deposition of drug metabolite/iron/melanin pigment particles in the dermis.

(Courtesy of Dr. Zsolt Argenyi, Department of Pathology, University of Washington, Seattle, WA.)

TABLE 9-5 Some Common Adverse Drug Reactions and Their Agents

Reaction	Major Offenders
BONE MARROW AND BLOOD CELLS^*
Granulocytopenia, aplastic anemia, pancytopenia	Antineoplastic agents, immunosuppressives, and chloramphenicol
Hemolytic anemia, thrombocytopenia	Penicillin, methyldopa, quinidine, heparin
CUTANEOUS
Urticaria, macules, papules, vesicles, petechiae, exfoliative dermatitis, fixed drug eruptions, abnormal pigmentation	Antineoplastic agents, sulfonamides, hydantoins, some antibiotics, and many other agents
CARDIAC
Arrhythmias	Theophylline, hydantoins, digoxin
Cardiomyopathy	Doxorubicin, daunorubicin
RENAL
Glomerulonephritis	Penicillamine
Acute tubular necrosis	Aminoglycoside antibiotics, cyclosporin, amphotericin B
Tubulointerstitial disease with papillary necrosis	Phenacetin, salicylates
PULMONARY
Asthma	Salicylates
Acute pneumonitis	Nitrofurantoin
Interstitial fibrosis	Busulfan, nitrofurantoin, bleomycin
HEPATIC
Fatty change	Tetracycline
Diffuse hepatocellular damage	Halothane, isoniazid, acetominophen
Cholestasis	Chlorpromazine, estrogens, contraceptive agents
SYSTEMIC
Anaphylaxis	Penicillin
Lupus erythematosus syndrome (drug-induced lupus)	Hydralazine, procainamide
CENTRAL NERVOUS SYSTEM
Tinnitus and dizziness	Salicylates
Acute dystonic reactions and parkinsonian syndrome	Phenothiazine antipsychotics
Respiratory depression	Sedatives

* Affected in almost half of all drug-related deaths.

Hormonal Replacement Therapy (HRT)

The most common type of HRT consists of the administration of estrogens together with progesterone. Because of the risk of uterine cancer, estrogen therapy alone is used only in hysterectomized women. Once prescribed primarily for distressing menopausal symptoms (e.g., hot flashes), HRT had been widely used in postmenopausal women to prevent or slow the progression of osteoporosis (Chapter 26) and to reduce the likelihood of myocardial infarction. However, the results of the Women’s Health Initiative published in 2002, stunned the scientific community by failing to find support for some of the presumed beneficial effects of the therapy. This large epidemiologic study involved approximately 17,000 women who were taking a combination of estrogen (equine estrogen) and progesterone (medroxyprogesterone acetate). Although the study found that HRT caused a reduction in the number of fractures, it also reported that after 5 years of treatment, HRT increased the risk of breast cancer (as discussed in Chapter 23) and thromboembolism, and had no effect on preventing cardiovascular disease. The wide dissemination of these findings led to a drastic decrease in the use of HRT, from 16 million prescriptions in 2001 to 6 million in 2006, which was accompanied by an apparent drop in the incidence of newly diagnosed breast cancers. During the last few years there has been a reappraisal of the risks and benefits of HRT.²⁸ The new analyses showed that HRT effects depend on the type of estrogen/progesterone used, the mode of drug administration, the age of the person at the start of treatment, the duration of the treatment, and the presence of associated diseases.

• HRT increases the risk of breast cancer after a median time of 5 to 8 years. The risk is highest and the latency times shorter for the development of lobular carcinomas and ductal-lobular cancer.²⁹

• HRT has a protective effect on the development of atherosclerosis and coronary disease in women under age 60, but there is no protection in women who started HRT at an older age.³⁰ These data support the notion that there is a critical therapeutic window for HRT effects on the cardiovascular system. Protective effects in younger women depend in part on the response of estrogen receptors that regulate calcium homeostasis in blood vessels.

• HRT increases the risk of venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and stroke. The increase is more pronounced during the first 2 years of treatment and in women who have other risk factors such as immobilization, and hypercoagulable states caused by prothrombin or factor V Leiden mutations (Chapter 4).

Oral Contraceptives (OCs)

Worldwide, more than 100 million women use hormonal contraception. OCs nearly always contain a synthetic estradiol and a variable amount of a progestin, but some preparations contain only progestins. They act by inhibiting ovulation or preventing implantation. Currently prescribed OCs contain a much smaller amount of estrogens (as little as 20 μg of ethinyl estradiol) than the earliest formulations approved for use in the United States in 1960, and are associated with fewer side effects. Transdermal and implantable formulations have also become available. Hence, the results of epidemiologic studies should be interpreted in the context of the dosage and the delivery system. Nevertheless, there is good evidence that the use of OCs is associated with the following conditions³¹:

Thromboembolism. Most studies indicate that OC use results in an approximately three-fold increased risk of venous thrombosis and pulmonary thromboembolism. This risk is increased further in carriers of prothrombin and factor V Leiden mutations. The increased thrombotic risk seems to be a consequence of the generation of an acute-phase response, with increases in C-reactive protein and coagulation factors (factors VII, IX, X, XII, and XIII), and reduction in anticoagulants (protein S and anti-thrombin III).

Cardiovascular disease. OCs increase the risk of myocardial infarction in smoking women at all ages and in nonsmoking women over age 35. In women over 35 years of age, the effect is more than ten-fold higher in smokers than nonsmokers.

Cancers. OCs reduce the incidence of endometrial and ovarian cancers. They do not increase the lifetime risk for development of breast cancers, although a small increase in incidence has been detected during the first 5 years of use.

Hepatic adenoma. There is a well-defined association between the use of OCs and this hepatic tumor (Chapter 18), particularly in older women who have used OCs for prolonged periods of time. The tumor appears as a large, solitary, and well-encapsulated mass.

Anabolic Steroids

The use of steroids to increase performance by baseball players, track-and-field athletes, and wrestlers has received wide publicity during the last few years. Anabolic steroids are synthetic versions of testosterone, and for performance enhancement they are used at doses that are about 10 to 100 times higher than therapeutic indications. The high concentration of testosterone and its derivatives inhibits production and release of luteinizing hormone and follicle-stimulating hormone by a feedback mechanism, and increases the amount of estrogens, which are produced from anabolic steroids. Anabolic steroids have multiple adverse effects including stunted growth in adolescents, acne, gynecomastia and testicular atrophy in males, and growth of facial hair and menstrual changes in women. Other effects include psychiatric problems and premature heart attacks. Hepatic cholestasis may develop in individuals receiving orally administered anabolic steroids.

Acetaminophen

Acetaminophen is the most commonly used analgesic in the United States. It is present in over 300 products, alone or in combination with other agents. Hence, acetaminophen toxicity is common, being responsible for more than 50,000 emergency room visits per year. In the United States, it is the cause of about 50% of cases of acute liver failure, with 30% mortality. Intentional overdosage (suicide attempts) is the most common cause of acetaminophen toxicity in Great Britain, but unintentional overdosage is the most frequent cause in the United States, representing almost 50% of the total intoxication cases.

At therapeutic doses about 95% of acetaminophen undergoes detoxification in the liver by phase II enzymes and is excreted in the urine as glucuronate or sulfate conjugates (Fig. 9-14). About 5% or less is metabolized through the activity of CYPs (primarily CYP2E) to NAPQI (N-acetyl-p-benzoquinoneimine), a highly reactive metabolite.^32,³³ NAPQI is normally conjugated with glutathione (GSH), but when taken in larger doses unconjugated NAPQI accumulates and causes hepatocellular injury leading to centrilobular necrosis and liver failure. The injury produced by NAPQI involves two mechanisms: (1) covalent binding to hepatic proteins, which causes damage to cellular membranes and mitochondrial dysfunction, and (2) depletion of GSH, making hepatocytes more susceptible to reactive oxygen species–induced injury. It should be noted that because alcohol induces CYP2E in the liver, toxicity can occur at lower doses in chronic alcoholics.

FIGURE 9-14 Acetaminophen metabolism and toxicity. (See text for details.)

(Courtesy of Dr. Xavier Vaquero, Department of Pathology, University of Washington, Seattle, WA.)

The window between the usual dose (0.5 gm) and the toxic dose (15 to 25 gm) is large, and the drug is ordinarily very safe. Toxicity begins with nausea, vomiting, diarrhea, and sometimes shock, followed in a few days by evidence of jaundice. Overdoses of acetaminophen can be treated at its early stages (within 12 hours) by administration of N-acetylcysteine, which restores GSH. In serious overdose liver failure ensues, starting with centrilobular necrosis that may extend to entire lobules, requiring liver transplantation for survival. Some patients show evidence of concurrent renal damage.

Aspirin (Acetylsalicylic Acid)

Overdose may result from accidental ingestion of a large number of tablets by young children; in adults overdose is frequently suicidal. A source of salicylate poisoning is the excessive use of ointments containing oil of wintergreen (methyl salicylate). Acute salicylate overdose causes alkalosis as a consequence of the stimulation of the respiratory center in the medulla. This is followed by metabolic acidosis and accumulation of pyruvate and lactate, caused by uncoupling of oxidative phosphorylation and inhibition of the Krebs cycle. Metabolic acidosis enhances the formation of non-ionized forms of salicylates, which diffuse into the brain and produce effects from nausea to coma. Ingestion of 2 to 4 gm by children or 10 to 30 gm by adults may be fatal, but survival has been reported after ingestion of doses five times larger.

Chronic aspirin toxicity (salicylism) may develop in persons who take 3 gm or more daily for long periods of time for treatment of chronic pain or inflammatory conditions. Chronic salicylism is manifested by headaches, dizziness, ringing in the ears (tinnitus), hearing impairment, mental confusion, drowsiness, nausea, vomiting, and diarrhea. The CNS changes may progress to convulsions and coma. The morphologic consequences of chronic salicylism are varied. Most often there is an acute erosive gastritis (Chapter 17), which may produce overt or covert gastrointestinal bleeding and lead to gastric ulceration. A bleeding tendency may appear concurrently with chronic toxicity, because aspirin acetylates platelet cyclooxygenase and irreversibly blocks the production of thromboxane A₂, an activator of platelet aggregation. Petechial hemorrhages may appear in the skin and internal viscera, and bleeding from gastric ulcerations may be exaggerated. With the recognition of gastric ulceration and bleeding as an important complication of ingestion of large doses of aspirin, its chronic toxicity is now quite uncommon.

Proprietary analgesic mixtures of aspirin and phenacetin or its active metabolite, acetaminophen, when taken over several years, can cause tubulointerstitial nephritis with renal papillary necrosis, referred to as analgesic nephropathy (Chapter 20).

INJURY BY NONTHERAPEUTIC AGENTS (DRUG ABUSE)

Drug abuse generally involves the use of mind-altering substances, beyond therapeutic or social norms. Drug addiction and overdose are serious public health problems. Common drugs of abuse are listed in Table 9-6. Here we consider cocaine, heroin, amphetamines, and marijuana, and briefly mention a few others.

TABLE 9-6 Common Drugs of Abuse

Class	Molecular Target	Example
Opioid narcotics	Mu opioid receptor (agonist)	Heroin, hydromorphone (Dilaudid)
		Oxycodone (Percodan, Percocet, Oxycontin)
		Methadone (Dolophine)
		Meperidine (Demerol)
Sedative-hypnotics	GABA_A receptor (agonist)	Barbiturates
		Ethanol
		Methaqualone (Quaalude)
		Glutethimide (Doriden)
		Ethchlorvynol (Placidyl)
Psychomotor stimulants	Dopamine transporter (antagonist)	Cocaine
	Serotonin receptors (toxicity)	Amphetamines
	Serotonin receptors (toxicity)	3,4-methylenedioxymethamphetamine (MDMA, ecstasy)
Phencyclidine-like drugs	NMDA glutamate receptor channel (antagonist)	Phencyclidine (PCP, angel dust)
Phencyclidine-like drugs	NMDA glutamate receptor channel (antagonist)	Ketamine
Cannabinoids	CBI cannabinoid receptors (agonist)	Marijuana
Cannabinoids	CBI cannabinoid receptors (agonist)	Hashish
Hallucinogens	Serotonin 5-HT₂ receptors (agonist)	Lysergic acid diethylamide (LSD)
		Mescaline
		Psilocybin

GABA, γ-aminobutyric acid; 5-HT₂, 5-hydroxytryptamine; NMDA, N-methyl D-aspartate.

Data from Hyman SE: A 28-year-old man addicted to cocaine. JAMA 286:2586, 2001.

Cocaine

The use of cocaine and crack continues to increase. According to a 2006 survey, approximately 35.3 million Americans aged 12 or older have tried cocaine, with 6.1 million having used cocaine in the past year. Cocaine is extracted from the leaves of the coca plant, and is usually prepared as a water-soluble powder, cocaine hydrochloride. Sold on the street, it is liberally diluted with talcum powder, lactose, or other look-alikes. Cocaine can be snorted or dissolved in water and injected subcutaneously or intravenously. Crystallization of the pure alkaloid yields nuggets of crack, so called because of the cracking or popping sound it makes when heated to produce vapors that are inhaled. The pharmacologic actions of cocaine and crack are identical, but crack is far more potent.

Cocaine produces an intense euphoria and stimulation, making it one of the most addictive drugs. Experimental animals will press a lever more than 1000 times and forgo food and drink to obtain it. In the cocaine user, although physical dependence generally does not occur, the psychologic withdrawal is profound and can be extremely difficult to treat. Intense cravings are particularly severe in the first several months after abstinence and can recur for years. Acute overdose can produce seizures, cardiac arrhythmias, and respiratory arrest.

• Cardiovascular effects. The most serious physical effects of cocaine relate to its acute action on the cardiovascular system, where it behaves as a sympathomimetic (Fig. 9-15). It facilitates neurotransmission both in the CNS, where it blocks the reuptake of dopamine, and at adrenergic nerve endings, where it blocks the reuptake of both epinephrine and norepinephrine while stimulating the presynaptic release of norepinephrine. The net effect is the accumulation of these two neurotransmitters in synapses, resulting in excess stimulation, manifested by tachycardia, hypertension, and peripheral vasoconstriction. Cocaine also induces myocardial ischemia, by causing coronary artery vasoconstriction, and enhancing platelet aggregation and thrombus formation. Cigarette smoking potentiates cocaine-induced coronary vasospasm. Thus, the dual effect of cocaine, causing increased myocardial oxygen demand by its sympathomimetic action, and, at the same time, decreasing coronary blood flow, sets the stage for myocardial ischemia that may lead to myocardial infarction. Cocaine can also precipitate lethal arrhythmias by enhanced sympathetic activity as well as by disrupting normal ion (K⁺, Ca²⁺, Na⁺) transport in the myocardium. These toxic effects are not necessarily dose-related, and a fatal event may occur in a first-time user with what is a typical mood-altering dose.

• CNS. The most common CNS effects are hyperpyrexia (thought to be caused by aberrations of the dopaminergic pathways that control body temperature) and seizures.

• Effects on pregnancy. In pregnant women, cocaine may cause decreased blood flow to the placenta, resulting in fetal hypoxia and spontaneous abortion. Neurologic development may be impaired in the fetus of pregnant women who are chronic drug users.

• Other effects. Chronic cocaine use may cause (1) perforation of the nasal septum in snorters, (2) decreased lung diffusing capacity in those who inhale the smoke, and (3) the development of dilated cardiomyopathy.

FIGURE 9-15 The effect of cocaine on neurotransmission. The drug inhibits reuptake of the neurotransmitters dopamine and norepinephrine in the central and peripheral nervous systems.

Heroin

Heroin is an addictive opioid derived from the poppy plant that is closely related to morphine. Its use is even more harmful than that of cocaine. As sold on the street, it is cut (diluted) with an agent (often talc or quinine); thus, the size of the dose is not only variable but also usually unknown to the buyer. Heroin, along with any contaminating substances, is usually self-administered intravenously or subcutaneously. Effects are varied and include euphoria, hallucinations, somnolence, and sedation. Heroin has a wide range of adverse physical effects related to (1) the pharmacologic action of the agent, (2) reactions to the cutting agents or contaminants, (3) hypersensitivity reactions to the drug or its adulterants (quinine itself has neurologic, renal, and auditory toxicity), and (4) diseases contracted incident to the use of infected needles. Some of the most important adverse effects of heroin are the following:

• Sudden death. Sudden death, usually related to overdose, is an ever-present risk, because drug purity is generally unknown (it may range from 2% to 90%). The yearly mortality among heroin users in the United States is estimated to be between 1% and 3%. Sudden death can also occur if heroin is taken after tolerance for the drug, built up over time, is lost (as during a period of incarceration). The mechanisms of death include profound respiratory depression, arrhythmia and cardiac arrest, and severe pulmonary edema.

• Pulmonary injury. Pulmonary complications include moderate to severe edema, septic embolism from endocarditis lung abscess, opportunistic infections, and foreign-body granulomas from talc and other adulterants. Although granulomas occur principally in the lung, they are sometimes found in the mononuclear phagocyte system, particularly in the spleen, liver, and lymph nodes that drain the upper extremities. Examination under polarized light often highlights trapped talc crystals, sometimes enclosed within foreign-body giant cells.

• Infections. Infectious complications are common. The four sites most commonly affected are the skin and subcutaneous tissue, heart valves, liver, and lungs. In a series of addicted patients admitted to the hospital, more than 10% had endocarditis, which often takes a distinctive form involving right-sided heart valves, particularly the tricuspid. Most cases are caused by S. aureus, but fungi and a multitude of other organisms have also been implicated. Viral hepatitis is the most common infection among addicted persons and is acquired by the sharing of dirty needles. In the United States, this practice has also led to a very high incidence of AIDS in intravenous drug abusers.

• Skin. Cutaneous lesions are probably the most frequent telltale sign of heroin addiction. Acute changes include abscesses, cellulitis, and ulcerations due to subcutaneous injections. Scarring at injection sites, hyperpigmentation over commonly used veins, and thrombosed veins are the usual sequelae of repeated intravenous inoculations.

• Renal problems. Kidney disease is a relatively common hazard. The two forms most frequently encountered are amyloidosis (generally secondary to skin infections) and focal glomerulosclerosis; both induce heavy proteinuria and the nephrotic syndrome.

Methadone, originally used in the treatment of heroin addiction, is increasingly being prescribed as a painkiller. Unfortunately, its careless use has contributed to more than 800 deaths per year in the United States.

Amphetamines

Methamphetamine.

This addictive drug, known as “speed” or “meth, ” is closely related to amphetamine but has stronger effects in the CNS. It is estimated that there are approximately 500,000 current users in the United States. Approximately 2.5% of youths in grade 8 and 6.5% in grade 12 have tried methamphetamine at least once. It acts by releasing dopamine in the brain, which inhibits presynaptic neurotransmission at corticostriatal synapses, slowing glutamate release.³⁴ Metamphetamine produces a feeling of euphoria, which is followed by a “crash.” Long-term use leads to violent behaviors, confusion, and psychotic features that include paranoia and hallucinations.

MDMA.

MDMA (3,4 methylenedioxymethamphetamine) is popularly known as ecstasy. MDMA is generally taken orally. Its effects, which include euphoria and hallucinogen-like feelings that last for 4 to 6 hours, are mainly due to an increase in serotonin release in the CNS. This is coupled with interference in serotonin synthesis, causing a reduction in serotonin that is only slowly replenished. MDMA use also reduces the number of serotonergic axon terminals in the striatum and the cortex, and it may increase the peripheral effects of dopamine and adrenergic agents. MDMA tablets may be spiked with other drugs, including methamphetamine and cocaine, which greatly enhance the effects on the CNS.

Marijuana

Marijuana, or “pot,” is made from the leaves of the Cannabis sativa plant, which contain the psychoactive substance Δ⁹-tetrahydrocannabinol (THC). About 5% to 10% of THC is absorbed when it is smoked in a hand-rolled cigarette (“joint”). Despite numerous studies, the central question of whether the drug has persistent adverse physical and functional effects remains unresolved.³⁵ Some of the untoward anecdotal effects may be allergic or idiosyncratic reactions or possibly related to contaminants in the preparations rather than to the pharmacologic effects of marijuana. Among the beneficial effects of marijuana is its potential use to treat nausea secondary to cancer chemotherapy, and as an agent capable of decreasing pain in some chronic conditions that are otherwise difficult to treat. The functional and organic CNS consequences of marijuana smoking have received most scrutiny. Its use distorts sensory perception and impairs motor coordination, but these acute effects generally clear in 4 to 5 hours. With continued use these changes may progress to cognitive and psychomotor impairments, such as inability to judge time, speed, and distance, a frequent cause of automobile accidents. Marijuana increases the heart rate and sometimes blood pressure, and it may cause angina in a person with coronary artery disease.

The respiratory system is also affected by chronic marijuana smoking; laryngitis, pharyngitis, bronchitis, cough and hoarseness, and asthma-like symptoms have all been described, along with mild but significant airway obstruction. Marijuana cigarettes contain a large number of carcinogens that are also present in tobacco. Smoking a marijuana cigarette, compared with a tobacco cigarette, is associated with a three-fold increase in the amount of tar inhaled and retained in the lungs, presumably because of the larger puff volume, deeper inhalation, and longer breath holding.

Regardless of the use of THC as a recreational drug, a large number of studies have characterized the endogenous cannabinoid system, which consists of the cannabinoid receptors CB1 and CB2, and the endogenous lipid ligands known as endocannabinoids.³⁶ This system participates in the regulation of the hypothalamic-pituitary-adrenal axis, and modulates the control of appetite, food intake, and energy balance, as well as fertility and sexual behavior.³⁷

Other Drugs

The variety of drugs that have been tried by those seeking “new experiences” (e.g., “highs,” “lows,” “out-of-the-body experiences”) defies belief. Overall, there has been a decrease in the use of most illegal drugs, but large increases have occurred in prescription and nonprescription drug abuse, and in the inhalation of potentially toxic household products. These drugs include various stimulants, depressants, analgesics, and hallucinogens (see Table 9-6). Among these are PCP (phenylcyclidine, an anesthetic agent), analgesics such as oxycontin and vicodin, and ketamine, an anesthetic agent used in animal surgery. Chronic inhalation of vapors of spray paints, paint thinners, and some glues that contain toluene (“glue sniffing”) can cause cognitive abnormalities and magnetic resonance imaging–detectable brain damage that ranges from mild to severe dementia. Because they are used haphazardly and in various combinations, not much is known about the long-time deleterious effects of most of these agents. However, their acute effects are clear: they cause bizarre and often aggressive behavior that leads to violence, or depressed mood and suicidal ideation.

Injury by Physical Agents

Injury induced by physical agents is divided into the following categories: mechanical trauma, thermal injury, electrical injury, and injury produced by ionizing radiation. Each type is considered separately.

MECHANICAL TRAUMA

Mechanical forces may inflict a variety of forms of damage. The type of injury depends on the shape of the colliding object, the amount of energy discharged at impact, and the tissues or organs that bear the impact. Bone and head injuries result in unique damage and are discussed elsewhere (Chapter 28). All soft tissues react similarly to mechanical forces, and the patterns of injury can be divided into abrasions, contusions, lacerations, incised wounds, and puncture wounds. This is just a small sampling of the various forms of trauma encountered by forensic pathologists, who deal with wounds produced by shooting, stabbing, blunt force, traffic accidents, and other causes. In addition to morphologic analyses, forensic pathology now includes molecular methods for identity testing and sophisticated methods to detect the presence of foreign substances. Details about the practice of forensic pathology can be found in specialized textbooks.

Morphology. An abrasion is a wound produced by scraping or rubbing, resulting in removal of the superficial layer. Skin abrasions may remove only the epidermal layer. A contusion, or bruise, is an injury usually produced by a blunt object characterized by damage to blood vessels and extravasation of blood into tissues (Fig. 9-16A). A laceration is a tear or disruptive stretching of tissue caused by the application of force by a blunt object (Fig. 9-16B). In contrast to an incision, most lacerations have intact bridging blood vessels and jagged, irregular edges. An incised wound is one inflicted by a sharp instrument. The bridging blood vessels are severed. A puncture wound is caused by a long, narrow instrument and is termed penetrating when the instrument pierces the tissue and perforating when it traverses a tissue to also create an exit wound. Gunshot wounds are special forms of puncture wounds that demonstrate distinctive features important to the forensic pathologist. For example, a wound from a bullet fired at close range leaves powder burns, whereas one fired from more than 4 or 5 feet away does not.

FIGURE 9-16 A, Contusion resulting from blunt trauma. The skin is intact, but there is hemorrhage of subcutaneous vessels, producing extensive discoloration. B, Laceration of the scalp; the bridging strands of fibrous tissues are evident.

(From the Department of Pathology, Southwestern Medical School, Dallas, TX.)

One of the most common causes of mechanical injury is vehicular accident. The typical injuries result from (1) hitting a part of the interior of the vehicle or being hit by an object that enters the passenger compartment during the crash, such as the motor; (2) being thrown from the vehicle; or (3) being trapped in a burning vehicle. The pattern of injury relates to whether one or all three of these mechanisms are operative. For example, in a head-on collision, a common pattern of injury sustained by a driver who is not wearing a seat belt includes trauma to the head (windshield impact), chest (steering column impact), and knees (dashboard impact). Under these conditions, common chest injuries include sternal and rib fractures, heart contusions, aortic lacerations, and (less commonly) lacerations of the spleen and liver. Thus, in caring for an automobile injury victim, it is essential to remember that internal wounds often accompany superficial abrasions, contusions, and lacerations. Indeed, in many cases external evidence of serious internal damage is completely absent.

THERMAL INJURY

Both excessive heat and excessive cold are important causes of injury. Burns are the most common cause of thermal injury and are discussed first; a brief discussion of hyperthermia and hypothermia follows.

Thermal Burns

In the United States, approximately 500,000 persons per year receive medical treatment for burn injuries. It is estimated that approximately 4000 persons per year die as a consequence of injuries caused by fire and smoke inhalation, mostly originating in homes. Fortunately, since the 1970s, marked decreases have been seen in both mortality rates and the length of hospitalizations of burn patients. In 2007 there were 40,000 hospitalizations in specialized burn centers, with a 90% survival. Eighty percent of the burns were caused by fire or scalding, the latter being a major cause of injury in children. Improvements in burn treatment have been achieved by a better understanding of the systemic effects of massive burns, the prevention of wound infection, and improvements in treatments that promote the healing of skin surfaces.

The clinical significance of a burn injury depends on the following factors:

• Depth of the burns

• Percentage of body surface involved

• Internal injuries caused by the inhalation of hot and toxic fumes

• Promptness and efficacy of therapy, especially fluid and electrolyte management and prevention or control of wound infections

Burns used to be classified as first to fourth degree, according to the depth of the injury (first-degree burns being the most superficial). This classification has been replaced by the terms superficial, partial thickness, and full-thickness burns.

• Superficial burns (formerly known as first-degree burns) are confined to the epidermis.

• Partial thickness burns (formerly known as second-degree burns) involve injury to the dermis.

• Full-thickness burns (formerly known as third-degree burns) extend to the subcutaneous tissue. Full-thickness burns may also involve damage to muscle tissue underneath the subcutaneous tissue (these were known formerly as fourth-degree burns).

Shock, sepsis, and respiratory insufficiency are the greatest threats to life in burn patients. Particularly in burns of more than 20% of the body surface, there is a rapid (within hours) shift of body fluids into the interstitial compartments, both at the burn site and systemically, which can result in hypovolemic shock (Chapter 4). Because protein from the blood is lost into interstitial tissue, generalized edema, including pulmonary edema, can be severe. An important pathophysiologic effect of burns is the development of a hypermetabolic state associated with excess heat loss and an increased need for nutritional support. It is estimated that when more than 40% of the body surface is burned, the resting metabolic rate may double.

The burn site is ideal for the growth of microorganisms; the serum and debris provide nutrients, and the burn injury compromises blood flow, blocking effective inflammatory responses. The most common offender is the opportunist Pseudomonas aeruginosa, but antibiotic-resistant strains of other common hospital-acquired bacteria, such as S. aureus, and fungi, particularly Candida species, may also be involved. Furthermore, cellular and humoral defenses against infections are compromised, and both lymphocyte and phagocyte functions are impaired. Direct bacteremic spread and release of toxic substances such as endotoxin from the local site have dire consequences. Pneumonia or septic shock with renal failure and/or the acute respiratory distress syndrome (Chapter 15) are the most common serious sequelae.

Organ system failure resulting from burn sepsis has greatly diminished during the last 30 years, because of the introduction of techniques for early excision and grafting of the burn wound. Removal of the burn wound decreases infection and reduces the need for reconstructive surgery.³⁸ Grafting is done with split-thickness skin grafts; dermal substitutes, which serve as a bed for cell repopulation, may be used in large full-thickness burns.

Injury to the airways and lungs may develop within 24 to 48 hours after the burn and may result from the direct effect of heat on the mouth, nose, and upper airways or from the inhalation of heated air and noxious gases in the smoke. Water-soluble gases, such as chlorine, sulfur oxides, and ammonia, may react with water to form acids or alkalis, particularly in the upper airways, producing inflammation and swelling, which may lead to partial or complete airway obstruction. Lipid-soluble gases, such as nitrous oxide and products of burning plastics, are more likely to reach deeper airways, producing pneumonitis.

In burn survivors the development of hypertrophic scars, both at the site of the original burn and at donor graft sites, and itching may become long-term, difficult-to-treat problems. Hypertrophic scars after burn injury may be a consequence of continuous angiogenesis in the wound caused by excess neuropeptides, such as substance P, released from injured nerve endings.³⁹

Morphology. Grossly, full-thickness burns are white or charred, dry, and anesthetic (because of destruction of nerve endings), whereas, depending on the depth, partial-thickness burns are pink or mottled with blisters and are painful. Histologically, devitalized tissue reveals coagulative necrosis, adjacent to vital tissue that quickly accumulates inflammatory cells and marked exudation.

Hyperthermia

Prolonged exposure to elevated ambient temperatures can result in heat cramps, heat exhaustion, and heat stroke.

• Heat cramps result from loss of electrolytes via sweating. Cramping of voluntary muscles, usually in association with vigorous exercise, is the hallmark. Heat-dissipating mechanisms are able to maintain normal core body temperature.

• Heat exhaustion is probably the most common hyperthermic syndrome. Its onset is sudden, with prostration and collapse, and it results from a failure of the cardiovascular system to compensate for hypovolemia, secondary to water depletion. After a period of collapse, which is usually brief, equilibrium is spontaneously re-established.

• Heat stroke is associated with high ambient temperatures, high humidity, and exertion. Thermoregulatory mechanisms fail, sweating ceases, and the core body temperature rises to more than 40°C, leading to multi-organ dysfunction that can be rapidly fatal. The underlying mechanism is marked generalized vasodilation, with peripheral pooling of blood and a decreased effective circulating blood volume. Hyperkalemia, tachycardia, arrhythmias, and other systemic effects are common. Necrosis of the muscles (rhabdomyolysis) and myocardium may occur as a consequence of the nitrosylation of the ryanodine receptor type 1 (RYR1) in skeletal muscle.⁴⁰ RYR1 is located in the sarcoplasmic reticulum and regulates the release of calcium into the cytoplasm. Inherited mutations in RYR1 occur in the condition called malignant hyperthermia, characterized by a rise in core body temperature and muscle contractures in response to exposure to common anesthetics. RYR1 mutations may also increase the susceptibility to heat stroke. Elderly persons, individuals undergoing intense physical stress (including young athletes and military recruits), and persons with cardiovascular disease are potential candidates for heat stroke.

Hypothermia

Prolonged exposure to low ambient temperature leads to hypothermia, a condition seen all too frequently in homeless persons. High humidity, wet clothing, and dilation of superficial blood vessels resulting from the ingestion of alcohol hasten the lowering of body temperature. At a body temperature of about 90°F, loss of consciousness occurs, followed by bradycardia and atrial fibrillation at lower core temperatures.

Hypothermia causes injury by two mechanisms:

• Direct effects are probably mediated by physical disruptions within cells by high salt concentrations caused by the crystallization of intra- and extracellular water.

• Indirect effects resulting from circulatory changes, which vary depending on the rate and duration of the temperature drop. Slowly developing chilling may induce vasoconstriction and increased vascular permeability, leading to edema and hypoxia. Such changes are typical of “trench foot.” This condition developed in soldiers who spent long periods of time in water-logged trenches during the First World War (1914–1918), frequently causing gangrene that necessitated amputation (the only protection was to cover the feet with whale-oil grease as insulation). With sudden, persistent chilling, the vasoconstriction and increased viscosity of the blood in the local area may cause ischemic injury and degenerative changes in peripheral nerves. In this situation, the vascular injury and increased permeability with exudation become evident only after the temperature begins to return to normal. However, during the period of ischemia, hypoxic changes and infarction of the affected tissues may develop (e.g., gangrene of toes or feet).

ELECTRICAL INJURY

Electrical injuries, which are often fatal, can arise from contact with low-voltage currents (i.e., in the home and workplace) or high-voltage currents carried by high-power lines or lightning. Injuries are of two types: (1) burns and (2) ventricular fibrillation or cardiac and respiratory center failure, resulting from disruption of normal electrical impulses. The type of injury and the severity and extent of burns depend on the strength (amperage), duration, and path of the electric current within the body.

Voltage in the household and workplace (120 or 220 V) is high enough that with low resistance at the site of contact (as when the skin is wet), sufficient current can pass through the body to cause serious injury, including ventricular fibrillation. If current flow continues long enough, it generates enough heat to produce burns at the site of entry and exit as well as in internal organs. An important characteristic of alternating current, the type available in most homes, is that it induces tetanic muscle spasm, so that when a live wire or switch is grasped, irreversible clutching is likely to occur, prolonging the period of current flow. This results in a greater likelihood of developing extensive electrical burns and, in some cases, spasm of the chest wall muscles, producing death from asphyxia. Currents generated from high-voltage sources cause similar damage; however, because of the large current flows generated, these are more likely to produce paralysis of medullary centers and extensive burns. Lightning is a classic cause of high-voltage electrical injury.

Earlier studies had linked exposure to high-voltage magnetic fields to an increased risk of cancer, mainly leukemias, among workers on electric high-power lines and children living near power transmission lines. However, further analyses have failed to find a consistent association between these exposures and cancer development. Electric and magnetic fields and microwave radiation, when sufficiently intense, may produce burns, usually of the skin and subjacent connective tissue, and both forms of radiation can interfere with cardiac pacemakers.

INJURY PRODUCED BY IONIZING RADIATION

Radiation is energy that travels in the form of waves or high-speed particles. Radiation has a wide range of energies that span the electromagnetic spectrum; it can be divided into non-ionizing and ionizing radiation. The energy of non-ionizing radiation such as UV and infrared light, microwave, and sound waves, can move atoms in a molecule or cause them to vibrate, but is not sufficient to displace bound electrons from atoms. By contrast, ionizing radiation has sufficient energy to remove tightly bound electrons. Collision of electrons with other molecules releases electrons in a reaction cascade, referred to as ionization. The main sources of ionizing radiation are x-rays and gamma rays (electromagnetic waves of very high frequencies), high-energy neutrons, alpha particles (composed of two protons and two neutrons), and beta particles, which are essentially electrons. At equivalent amounts of energy, alpha particles induce heavy damage in a restricted area, whereas x-rays and gamma rays dissipate energy over a longer, deeper course, and produce considerably less damage per unit of tissue. About 25% of the total dose of ionizing radiation received by the US population is human-made, mostly originated in medical devices and radioisotopes.

Ionizing radiation is a double-edged sword. It is indispensable in medical practice, being used in the treatment of cancer, in diagnostic imaging, and in therapeutic or diagnostic radioisotopes, but it also produces adverse short- and long-term effects such as fibrosis, mutagenesis, carcinogenesis, and teratogenesis.⁴¹

Radiation Units.

Several somewhat confusing terms are used to describe the radiation doses. This is because radiation is measured in three different ways. These are, the amount of radiation emitted by a source, the radiation dose absorbed by a person, and the biologic effect of the radiation. These are described below:

• Curie (Ci) represents the disintegrations per second of a radionuclide (radioisotope). One Ci is equal to 3.7 × 10¹⁰ disintegrations per second. This is an expression of the amount of radiation emitted by a source.

• Gray (Gy) is a unit that expresses the energy absorbed by the target tissue per unit mass. It corresponds to the absorption of 10⁴ erg/gm of tissue. The centigray (cGy), which is the absorption of 100 erg/gm of tissue, is equivalent to the exposure of tissue to 100 Rads (radiation absorbed dose), abbreviated as R. The cGy terminology has now replaced R.

• Sievert (Sv) is a unit of equivalent dose that depends on the biologic rather than the physical effects of radiation (it replaced a unit called “rem”). For the same absorbed dose, various types of radiation differ in the extent of damage they produce. The equivalent dose controls for this variation and thereby provides a uniform measure of biologic dose. The equivalent dose (expressed in Sieverts) corresponds to the absorbed dose (expressed in Grays) multiplied by the relative biologic effectiveness of the radiation. The relative biologic effectiveness depends on the type of radiation, the type and volume of the exposed tissue, the duration of the exposure, and some other biologic factors (discussed below). The effective dose of x-rays in radiographs and computed tomography is commonly expressed in millisieverts (mSv). For x-radiation, 1 mSv = 1 mGy.

Main Determinants of the Biologic Effects of Ionizing Radiation.

In addition to the physical properties of the radiation, its biologic effects depend heavily on the following factors.

• Rate of delivery. The rate of delivery significantly modifies the biologic effect. Although the effect of radiant energy is cumulative, divided doses may allow cells to repair some of the damage between exposures. Thus, fractionated doses of radiant energy have a cumulative effect only to the extent that repair during the “recovery” intervals is incomplete. Radiation therapy of tumors exploits the general capability of normal cells to repair themselves and recover more rapidly than tumor cells, and thus not sustain as much cumulative radiation damage.

• Field size. The size of the field exposed to radiation has a great influence on its consequences. The body can sustain relatively high doses of radiation when delivered to small, carefully shielded fields, whereas smaller doses delivered to larger fields may be lethal.

• Cell proliferation. Because ionizing radiation damages DNA, rapidly dividing cells are more vulnerable to injury than are quiescent cells (Fig. 9-17). Except at extremely high doses that impair DNA transcription, DNA damage is compatible with survival in nondividing cells, such as brain and myocardium. However, in dividing cells, certain types of mutations and chromosomal abnormalities are recognized by cell cycle checkpoints, which initiate events that lead to growth arrest and apoptosis. Understandably, therefore, tissues with a high rate of cell division, such as gonads, bone marrow, lymphoid tissue, and the mucosa of the gastrointestinal tract, are extremely vulnerable to radiation, and the injury is manifested early after exposure.

• Oxygen effects and hypoxia. The production of reactive oxygen species from the radiolysis of water is the most important mechanism of DNA damage by ionizing radiation. Poorly vascularized tissues with low oxygenation, such as the center of rapidly growing tumors, are generally less sensitive to radiation therapy than nonhypoxic tissues.

• Vascular damage. Damage to endothelial cells, which are moderately sensitive to radiation, may cause narrowing or occlusion of the blood vessel leading to impaired healing, fibrosis, and chronic ischemic atrophy. These changes may appear months or years after exposure (Fig. 9-18). Late effects in tissues with a low rate of cell proliferation such as brain, kidney, liver, muscle, and subcutaneous tissue, may include diverse lesions such as cell death, atrophy, and fibrosis. These effects are associated with vascular damage and the release of pro-inflammatory cytokines in irradiated areas.

FIGURE 9-17 Effects of ionizing radiation on DNA and its consequences. The effects on DNA can be direct, or most importantly, indirect, through free radical formation.

FIGURE 9-18 Chronic vascular injury with subintimal fibrosis occluding the lumen.

Figure 9-19 shows the overall consequences of radiation exposure. These consequences may vary according to the dose of radiation and the type of exposure. Table 9-7 lists the estimated threshold doses for acute effects of radiation aimed at specific organs; Table 9-8 shows the syndromes caused by exposure to various doses of total-body radiation.

FIGURE 9-19 Overview of the major morphologic consequences of radiation injury. Early changes occur in hours to weeks; late changes occur in months to years. ARDS, acute respiratory distress syndrome.

TABLE 9-7 Estimated Threshold Doses for Acute Radiation Effects on Specific Organs

Health Effect	Organ	Dose (Sv)
Temporary sterility	Testes	0.15
Depression of hematopoiesis	Bone marrow	0.50
Reversible skin effects (e.g., erythema)	Skin	1.0–2.0
Permanent sterility	Ovaries	2.5–6.0
Temporary hair loss	Skin	3.0–5.0
Permanent sterility	Testis	3.5
Cataract	Lens of eye	5.0

TABLE 9-8 Effects of Total-Body Ionizing Radiation

Morphology. Cells surviving radiant energy damage show a wide range of structural changes in chromosomes, including deletions, breaks, translocations, and fragmentation. The mitotic spindle often becomes disorderly, and polyploidy and aneuploidy may be encountered. Nuclear swelling and condensation and clumping of chromatin may appear; sometimes the nuclear membrane breaks down. Apoptosis may occur. All forms of abnormal nuclear morphology may be seen. Giant cells with pleomorphic nuclei or more than one nucleus may appear and persist for years after exposure. At extremely high doses of radiant energy, markers of cell death, such as nuclear pyknosis, and lysis appear quickly.

In addition to affecting DNA and nuclei, radiant energy may induce a variety of cytoplasmic changes, including cytoplasmic swelling, mitochondrial distortion, and degeneration of the endoplasmic reticulum. Plasma membrane breaks and focal defects may be seen. The histologic constellation of cellular pleomorphism, giant-cell formation, conformational changes in nuclei, and abnormal mitotic figures creates a more than passing similarity between radiation-injured cells and cancer cells, a problem that plagues the pathologist when evaluating post-irradiation tissues for the possible persistence of tumor cells.

At the light microscopic level, vascular changes and interstitial fibrosis are prominent in irradiated tissues (Fig. 9-20). During the immediate post-irradiation period, vessels may show only dilation. With time, or with higher doses, a variety of degenerative changes appear, including endothelial cell swelling and vacuolation, or even dissolution with total necrosis of the walls of small vessels such as capillaries and venules. Affected vessels may rupture or thrombose. Still later, endothelial cell proliferation and collagenous hyalinization with thickening of the media are seen in irradiated vessels, resulting in marked narrowing or even obliteration of the vascular lumens. At this time, an increase in interstitial collagen in the irradiated field usually becomes evident, leading to scarring and contractions.

FIGURE 9-20 Fibrosis and vascular changes in salivary glands produced by radiation therapy of the neck region. A, Normal salivary gland; B, fibrosis caused by radiation; C, fibrosis and vascular changes consisting of fibrointimal thickening and arteriolar sclerosis. V, vessel lumen; I, thickened intima.

(Courtesy of Dr. Melissa Upton, Department of Pathology, University of Washington, Seattle, WA.)

Total-Body Irradiation.

Exposure of large areas of the body to even very small doses of radiation may have devastating effects. Dosages below 1 Sv produce minimal or no symptoms. However, higher levels of exposure cause health effects known as acute radiation syndromes, which at progressively higher doses involve the hematopoietic, gastrointestinal, and central nervous systems. The syndromes associated with total-body exposure to ionizing radiation are presented in Table 9-8.

Acute Effects on Hematopoietic and Lymphoid Systems.

The hematopoietic and lymphoid systems are extremely susceptible to radiation injury and deserve special mention. With high dose levels and large exposure fields, severe lymphopenia may appear within hours of irradiation, along with shrinkage of the lymph nodes and spleen. Radiation directly destroys lymphocytes, both in the circulating blood and in tissues (nodes, spleen, thymus, gut). With sublethal doses of radiation, regeneration from viable precursors is prompt, leading to restoration of a normal lymphocyte count in the blood within weeks to months. Hematopoietic precursors in the bone marrow are also quite sensitive to radiant energy, which produces a dose-dependent marrow aplasia. Very high doses of radiation kill marrow stem cells and induce permanent aplasia (aplastic anemia), whereas with lower doses the aplasia is transient. The circulating granulocyte count may first rise but begins to fall toward the end of the first week. Levels near zero may be reached during the second week. If the patient survives, recovery of the normal granulocyte count may require 2 to 3 months. Platelets are similarly affected, with the nadir of the count occurring somewhat later than that of granulocytes; recovery is similarly delayed. Red cell counts fall and anemia appears after 2 to 3 weeks and may persist for months.

Fibrosis.

A common consequence of radiation therapy for cancer is the development of fibrosis in the tissues included in the irradiated field (see Fig. 9-20). Fibrosis may occur weeks or months after irradiation as a consequence of the replacement of dead parenchymal cells by connective tissue, leading to the formation of scars and adhesions (see Chapter 3). Vascular damage, the killing of tissue stem cells, and the release of cytokines and chemokines that promote an inflammatory reaction and fibroblast activation are the main contributors to the development of radiation-induced fibrosis (Figs. 9-21 and 9-22). Common sites of fibrosis after radiation treatment are the lungs, the salivary glands after radiation therapy for head and neck cancers, and colorectal and pelvic areas after treatment for prostate cancer.

FIGURE 9-21 Chronic radiation dermatitis with atrophy of epidermis, dermal fibrosis, and telangiectasia of the subcutaneous blood vessels.

FIGURE 9-22 Extensive mediastinal fibrosis after radiotherapy for carcinoma of the lung. Note the markedly thickened cardium.

(From the teaching collection of the Department Pathology, Southwestern Medical School, Dallas, TX.)

DNA Damage and Carcinogenesis.

Ionizing radiation can cause multiple types of damage in DNA, including single-base damage, single- and double-stranded breaks, and DNA-protein cross-links. In surviving cells, simple defects may be repaired by various enzyme systems present in most mammalian cells (see Chapter 7). However, the most serious damage to DNA is caused by double-stranded breaks (DSBs). Two types of mechanisms can repair DSBs in mammalian cells: homologous recombination and nonhomologous end joining (NHEJ), with NHEJ being the most common repair pathway. DNA repair through NHEJ often produces mutations, including short deletions or duplications, or gross chromosomal aberrations such as translocations and inversions. If the replication of cells containing DSBs is not stopped by cell cycle checkpoint controls (Chapter 3), cells with chromosomal damage persist and may initiate carcinogenesis many years later. More recently it has been recognized that these abnormal cells may also have a “bystander effect,” that is, they may promote growth of non-irradiated surrounding cells through the production of growth factors and cytokines.^42,⁴³ Bystander effects are referred to as non-target effects of radiation.

Cancer Risks from Exposures to Low-level Radiation.

Any cell capable of division that has sustained a mutation has the potential to become cancerous. Thus, an increased incidence of neoplasms may occur in any organ after exposure to ionizing radiation. The level of radiation required to increase the risk of cancer development is difficult to determine, but there is little doubt that acute or prolonged exposures that result in doses of greater than 100 mSv cause serious consequences including cancer.⁴⁴ This is documented by the increased incidence of leukemias and tumors at various sites (such as thyroid, breast, and lungs) in survivors of the atomic bombings of Hiroshima and Nagasaki; the high number of thyroid cancers in survivors of the Chernobyl accident; the high incidence of thyroid tumors, and the elevated frequency of leukemias and birth defects in inhabitants of the Marshall Islands exposed to nuclear fallout; and the development of “second cancers,” such as acute myeloid leukemia, myelodysplastic syndrome, Hodgkin lymphoma and solid tumors, in individuals who received radiation therapy for childhood cancers. The long-term cancer risks caused by radiation exposures in the range of 5 to 100 mSv are much more difficult to establish, because accurate measurements of risks require large population groups ranging from 50,000 to 5 million people.

Estimation of cancer risks at low levels of exposure to ionizing radiation relies in part on models that extrapolate from higher doses. Nevertheless, for x-rays and gamma rays there is good evidence for a statistically significant increase in the risk of cancer at acute doses of greater than 50 mSv and “reasonable” evidence for acute doses of greater than 5 mSv. For protracted exposures, the approximate values suggested are greater than 100 mSv (good evidence for a statistically significant increase of risk) and 50 mSv (reasonable evidence for increased risk). As a comparison, a single posterior-anterior chest radiograph, a lateral chest film chest radiograph, and a computed tomography of the chest deliver effective dosages to the lungs of 0.01, 0.15, and 10 mSv, respectively.⁴⁵

Increased risk of cancer development may also be associated with occupational exposures. Radon gas is a ubiquitous product of the spontaneous decay of uranium. Its carcinogenic effects are largely attributable to two decay products, polonium 214 and 218 (or “radon daughters”), which emit alpha particles. Polonium 214 and 218 produced from inhaled radon tend to deposit in the lung, and chronic exposure in uranium miners may give rise to lung carcinomas. Risks are also present in homes in which the levels of radon are very high, comparable to those found in mines. However, there is little or no evidence to suggest that radon contributes to the risk of lung cancer in the average household. Among other polonium isotopes, polonium 210 came to the public attention in November 2006 with the highly publicized use of this isotope to kill an individual in England. For historical reasons, we also mention here the development of osteogenic sarcomas after radium exposure in radium dial painters, chemists, radiologists, and patients exposed to radium as a treatment for various ailments, during the first part of the twentieth century.

Nutritional Diseases

Malnutrition, also referred to as protein energy malnutrition or PEM, is a consequence of inadequate intake of proteins and calories, or deficiencies in the digestion or absorption of proteins, resulting in the loss of fat and muscle tissue, weight loss, lethargy, and generalized weakness. Millions of people in developing nations are malnourished and starving, or living on the cruel edge of starvation. In the industrial world and, more recently, also in developing countries, obesity has become a major public health problem, associated with the development of diseases such as diabetes and atherosclerosis.

The sections that follow barely skim the surface of nutritional disorders. Particular attention is devoted to PEM, anorexia nervosa and bulimia, deficiencies of vitamins and trace minerals, obesity, and a brief overview of the relationships of diet to atherosclerosis and cancer. Other nutrients and nutritional issues are discussed in the context of specific diseases.

DIETARY INSUFFICIENCY

An appropriate diet should provide (1) sufficient energy, in the form of carbohydrates, fats, and proteins, for the body’s daily metabolic needs; (2) amino acids and fatty acids to be used as building blocks for synthesis of structural and functional proteins and lipids; and (3) vitamins and minerals, which function as coenzymes or hormones in vital metabolic pathways or, as in the case of calcium and phosphate, as important structural components. In primary malnutrition, one or all of these components are missing from the diet. By contrast, in secondary malnutrition, the supply of nutrients is adequate, but malnutrition results from insufficient intake, malabsorption, impaired utilization or storage, excess loss, or increased need for nutrients.

There are several conditions that may lead to dietary insufficiencies.

• Poverty. Homeless persons, aged individuals, and children of the poor often suffer from PEM as well as trace nutrient deficiencies. In poor countries, poverty, crop failures, livestock deaths, and drought, often in times of war and political upheaval, create the setting for the malnourishment of children and adults.

• Infections. PEM increases the susceptibility to many common infectious diseases. Conversely, infections have a negative effect on nutrition,⁴⁶ thus establishing a vicious cycle.

• Acute and chronic illnesses. The basal metabolic rate becomes accelerated in many illnesses resulting in increased daily requirements for all nutrients. Failure to recognize these nutritional needs may delay recovery. PEM is often present in patients with wasting diseases such as advanced cancers and AIDS (discussed later).

• Chronic alcoholism. Alcoholic persons may sometimes suffer PEM but more frequently have deficiency of several vitamins, especially thiamine, pyridoxine, folate, and vitamin A, as a result of dietary deficiency, defective gastrointestinal absorption, abnormal nutrient utilization and storage, increased metabolic needs, and an increased rate of loss. A failure to recognize the likelihood of thiamine deficiency in persons with chronic alcoholism may result in irreversible brain damage (e.g., Wernicke encephalopathy, discussed in Chapter 28).

• Ignorance and failure of diet supplementation. Even the affluent may fail to recognize that infants, adolescents, and pregnant women have increased nutritional needs. Ignorance about the nutritional content of various foods is also a contributing factor. Some examples are: iron deficiency in infants fed exclusively artificial milk diets; polished rice used as the mainstay of a diet may lack adequate amounts of thiamine; lack of iodine from food and water in regions removed from the oceans, unless supplementation is provided.

• Self-imposed dietary restriction. Anorexia nervosa, bulimia, and less overt eating disorders affect many individuals who are concerned about body image and are obsessed with body weight (anorexia and bulimia are discussed later).

• Other causes. Additional causes of malnutrition include gastrointestinal diseases and malabsorption syndromes, genetic diseases, specific drug therapies (which block uptake or utilization of particular nutrients), and total parenteral nutrition.

PROTEIN-ENERGY MALNUTRITION (PEM)

Severe PEM is a serious, often lethal disease affecting children. It is common in low-income countries, where up to 25% of children may be affected, and where it is a major factor in the high death rates among children younger than 5 years. In the West Africa country of Niger, which suffered a severe famine in 2005, United Nations reports estimate that there were, respectively, 150,000 and 650,000 children with severe and moderate malnutrition. In that country, malnutrition was a direct or indirect cause of mortality in 60% of children under age 5. Decreased food intake can also occur due to sharp increases in prices, as was seen in the first half of 2008. In developed countries, PEM occurs in elderly and debilitated patients in nursing homes and hospitals.

Malnutrition is determined according to the body mass index (BMI, weight in kilograms divided by height in meters squared). A BMI less than 16 kg/m² is considered malnutrition (normal range 18.5 to 25 kg/m²). In more practical ways, a child whose weight falls to less than 80% of normal (provided in standard tables) is considered malnourished. However, loss of weight may be masked by generalized edema, as discussed later. Other helpful parameters are the evaluation of fat stores (thickness of skin folds), muscle mass (reduced circumference of mid-arm), and serum proteins (albumin and transferrin measurements provide a measure of the adequacy of the visceral protein compartment).

Marasmus and Kwashiorkor.

In malnourished children, PEM presents as a range of clinical syndromes, all characterized by a dietary intake of protein and calories inadequate to meet the body’s needs. The two ends of the spectrum of PEM syndromes are known as marasmus and kwashiorkor. From a functional standpoint, there are two differentially regulated protein compartments in the body: the somatic compartment, represented by proteins in skeletal muscles, and the visceral compartment, represented by protein stores in the visceral organs, primarily the liver. As we shall see, the somatic compartment is affected more severely in marasmus, and the visceral compartment is depleted more severely in kwashiorkor.

A child is considered to have marasmus when weight falls to 60% of normal for sex, height, and age. A marasmic child suffers growth retardation and loss of muscle, the latter resulting from catabolism and depletion of the somatic protein compartment. This seems to be an adaptive response that provides the body with amino acids as a source of energy. The visceral protein compartment, which is presumably more precious and critical for survival, is only marginally depleted, and hence serum albumin levels are either normal or only slightly reduced. In addition to muscle proteins, subcutaneous fat is also mobilized and used as fuel. The production of leptin (discussed in “Obesity”) is low, which may stimulate the hypothalamic-pituitary-adrenal axis to produce high levels of cortisol that contribute to lipolysis. With such losses of muscle and subcutaneous fat, the extremities are emaciated; by comparison, the head appears too large for the body (Fig. 9-23A). Anemia and manifestations of multiple vitamin deficiencies are present, and there is evidence of immune deficiency, particularly T cell–mediated immunity. Hence, concurrent infections are usually present, which impose additional nutritional demands. Unfortunately, images of children dead or near death with marasmus, have become almost commonplace in television and newspaper reports of famine and disasters in various areas of the world.

FIGURE 9-23 Childhood malnutrition. A, Marasmus. Note the loss of muscle mass and subcutaneous fat; the head appears to be too large for the emaciated body. B, Kwashiorkor. The infant shows generalized edema, seen as ascites and puffiness of the face, hands, and legs.

(A, From Clinic Barak, Reisebericht Kenya.)

Kwashiorkor occurs when protein deprivation is relatively greater than the reduction in total calories (Fig. 9-23B). This is the most common form of PEM seen in African children who have been weaned too early and subsequently fed, almost exclusively, a carbohydrate diet (the name kwashiorkor is from the Ga language in Ghana describing a disease of a baby due to the arrival of another child). The prevalence of kwashiorkor is also high in impoverished countries of Southeast Asia. Less severe forms may occur worldwide in persons with chronic diarrheal states in which protein is not absorbed or in those with chronic protein loss due to conditions such as protein-losing enteropathies, the nephrotic syndrome, or after extensive burns. Cases of kwashiorkor resulting from fad diets or replacement of milk by rice-based beverages have been reported in the United States.

In kwashiorkor, marked protein deprivation is associated with severe loss of the visceral protein compartment, and the resultant hypoalbuminemia gives rise to generalized or dependent edema (Fig. 9-23B). The loss of weight in these patients is masked by the increased fluid retention. In further contrast to marasmus, there is relative sparing of subcutaneous fat and muscle mass. Children with kwashiorkor have characteristic skin lesions, with alternating zones of hyperpigmentation, areas of desquamation, and hypopigmentation, giving a “flaky paint” appearance. Hair changes include overall loss of color or alternating bands of pale and darker hair. Other features that differentiate kwashiorkor from marasmus include an enlarged, fatty liver (resulting from reduced synthesis of the carrier protein component of lipoproteins), and the development of apathy, listlessness, and loss of appetite. Vitamin deficiencies are likely to be present, as are defects in immunity and secondary infections. As already stated, marasmus and kwashiorkor are two ends of a spectrum, and considerable overlap exists between these conditions.

Secondary PEM often develops in chronically ill, elderly, and bedridden patients. An 18-item questionnaire known as the Mininutritional Assessment (MNA) is often used to measure the nutritional status of elderly persons. It is estimated that more than 50% of elderly residents in nursing homes in the United States are malnourished. Weight loss of more than 5% associated with PEM increases the risk of mortality in nursing home patients by almost five-fold. The most obvious signs of secondary PEM include: (1) depletion of subcutaneous fat in the arms, chest wall, shoulders, or metacarpal regions; (2) wasting of the quadriceps femoris and deltoid muscles; and (3) ankle or sacral edema. Bedridden or hospitalized malnourished patients have an increased risk of infection, sepsis, impaired wound healing, and death after surgery.

Morphology. The central anatomic changes in PEM are (1) growth failure, (2) peripheral edema in kwashiorkor, and (3) loss of body fat and atrophy of muscle, more marked in marasmus.

The liver in kwashiorkor, but not in marasmus, is enlarged and fatty; superimposed cirrhosis is rare.

In kwashiorkor (rarely in marasmus) the small bowel shows a decrease in the mitotic index in the crypts of the glands, associated with mucosal atrophy and loss of villi and microvilli. In such cases concurrent loss of small intestinal enzymes occurs, most often manifested as disaccharidase deficiency. Hence, infants with kwashiorkor initially may not respond well to full-strength, milk-based diets. With treatment, the mucosal changes are reversible.

The bone marrow in both kwashiorkor and marasmus may be hypoplastic, mainly as a result of decreased numbers of red cell precursors. The peripheral blood commonly reveals mild to moderate anemia, which often has a multifactorial origin; nutritional deficiencies of iron, folate, and protein, as well as the suppressive effects of infection (anemia of chronic disease) may all contribute. Depending on the predominant factor, the red cells may be microcytic, normocytic, or macrocytic.

The brain in infants who are born to malnourished mothers and who suffer PEM during the first 1 or 2 years of life has been reported by some to show cerebral atrophy, a reduced number of neurons, and impaired myelinization of white matter.

Many other changes may be present, including (1) thymic and lymphoid atrophy (more marked in kwashiorkor than in marasmus), (2) anatomic alterations induced by intercurrent infections, particularly with all manner of endemic worms and other parasites, and (3) deficiencies of other required nutrients such as iodine and vitamins.

Cachexia.

PEM is a common complication in patients with AIDS or advanced cancers, and in these settings it is known as cachexia. Cachexia occurs in about 50% of cancer patients, most commonly in individuals with gastrointestinal, pancreatic, and lung cancers, and is responsible for about 30% of cancer deaths. It is a highly debilitating condition characterized by extreme weight loss, fatigue, muscle atrophy, anemia, anorexia, and edema. Mortality is generally the consequence of atrophy of the diaphragm and other respiratory muscles. The precise causes of cachexia are not known, but it is clear that agents secreted by tumors and host responses contribute to its development (Fig. 9-24). Cachetic agents produced by tumors include:

• PIF (proteolysis-inducing factor), which is a glycosylated polypeptide excreted in the urine of weight-losing patients with pancreatic, breast, colon, and other cancers

• LMF (lipid-mobilizing factor), which increases fatty acid oxidation, and pro-inflammatory cytokines such as TNF (originally known as cachetin), interleukin-2 (IL-2), and IL-6. TNF and IL-6 trigger an acute-phase response from the host, increasing the secretion of C-reactive protein and fibrinogen, and decreasing plasma concentrations of albumin.

FIGURE 9-24 Mechanisms of cancer cachexia. The figure illustrates three mechanisms that cause muscle atrophy and muscle degradation leading to cachexia. (1) Proteolysis-inducing factor (PIF) produced by tumors degrades myosin heavy chain through the proteasome, causing muscle atrophy; (2) TNF and other cytokines produced by tumors and the host activate NF-κB and initiate the transcription of the ubiquitin ligases MAFBx and MuRF1, contributing to protein breakdown; (3) alterations in the dystrophin-glycoprotein complex leading to dystrophin-degradation by the proteasome also participate in the muscle atrophy of cachexia.

Proteolysis-inducing factor (PIF) and pro-inflammatory cytokines cause skeletal muscle breakdown through the NFκB-induced activation of the ubiquitin proteasome pathway, leading to the degradation of myosin heavy chain.⁴⁷ The induction of the ubiquitin proteasome pathway involves the production of two muscle-specific ubiquitin ligases, MuRF1 (muscle RING finger-1) and MAFBx (muscle atrophy F-box, or atroglin-1). More recent data also implicate alterations in the myofibrillar membrane of skeletal muscle with loss of dystrophin caused by alterations in the dystrophin-glycoprotein complex (Fig. 9-24) as contributors to muscle atrophy, through a mechanism similar to that which occurs in some muscular dystrophies.⁴⁸

ANOREXIA NERVOSA AND BULIMIA

Anorexia nervosa is self-induced starvation, resulting in marked weight loss; bulimia is a condition in which the patient binges on food and then induces vomiting. Anorexia nervosa has the highest death rate of any psychiatric disorder. Bulimia is more common than anorexia nervosa, and generally has a better prognosis; it is estimated to occur in 1% to 2% of women and 0.1% of men, with an average onset at 20 years of age. These eating disorders occur primarily in previously healthy young women who have developed an obsession with body image and thinness. The neurobiologic underpinnings of these diseases are unknown, but it has been suggested that altered serotonin metabolism may be an important component.⁴⁹

The clinical findings in anorexia nervosa are generally similar to those in severe PEM. In addition, effects on the endocrine system are prominent. Amenorrhea, resulting from decreased secretion of gonadotropin-releasing hormone, and subsequent decreased secretion of luteinizing hormone and follicle-stimulating hormone, is so common that its presence is a diagnostic feature for the disorder. Other common findings, related to decreased thyroid hormone release, include cold intolerance, bradycardia, constipation, and changes in the skin and hair. In addition, dehydration and electrolyte abnormalities are frequently present. The skin becomes dry and scaly. Bone density is decreased, most likely because of low estrogen levels, which mimics the postmenopausal acceleration of osteoporosis. Anemia, lymphopenia, and hypoalbuminemia may be present. A major complication of anorexia nervosa (and also bulimia) is an increased susceptibility to cardiac arrhythmia and sudden death, resulting from hypokalemia.

In bulimia, binge eating is the norm. Large amounts of food, principally carbohydrates, are ingested, only to be followed by induced vomiting. Although menstrual irregularities are common, amenorrhea occurs in less than 50% of bulimic patients, probably because weight and gonadotropin levels are maintained near normal. The major medical complications relate to continual induced vomiting, and the chronic use of laxatives and diuretics. They include (1) electrolyte imbalances (hypokalemia), which predispose the patient to cardiac arrhythmias; (2) pulmonary aspiration of gastric contents; and (3) esophageal and gastric cardiac rupture. Nevertheless, there are no signs and symptoms that are specific for bulimia; the diagnosis must rely on a comprehensive psychologic assessment of the person. A recent trend in bulimic patients has been the combination of binge eating with high ingestion of alcohol. Needless to say, the combined effects of bulimia and alcoholism are devastating.

VITAMIN DEFICIENCIES

Thirteen vitamins are necessary for health; vitamins A, D, E, and K are fat-soluble, and all others are water-soluble. The distinction between fat- and water-soluble vitamins is important. Fat-soluble vitamins are more readily stored in the body, but they may be poorly absorbed in fat malabsorption disorders, caused by disturbances of digestive functions (discussed in Chapter 17). Certain vitamins can be synthesized endogenously—vitamin D from precursor steroids, vitamin K and biotin by the intestinal microflora, and niacin from tryptophan, an essential amino acid. Notwithstanding this endogenous synthesis, a dietary supply of all vitamins is essential for health.

A deficiency of vitamins may be primary (dietary in origin) or secondary because of disturbances in intestinal absorption, transport in the blood, tissue storage, or metabolic conversion. In the following sections, vitamins A, D, and C are presented in some detail because of their wide-ranging activities and the morphologic changes of deficient states. This is followed by presentation in tabular form of the main consequences of deficiencies of the remaining vitamins (E, K, and the B complex) and some essential minerals. However, it should be emphasized that deficiency of a single vitamin is uncommon, and that single or multiple vitamin deficiencies may be associated with PEM.

Vitamin A

Vitamin A is the name given to a group of related compounds that include retinol (vitamin A alcohol), retinal (vitamin A aldehyde), and retinoic acid (vitamin A acid), which have similar biologic activities. Retinol is the chemical name given to vitamin A. It is the transport form and, as retinol ester, also the storage form. The generic term retinoids encompasses vitamin A in its various forms and both natural and synthetic chemicals that are structurally related to vitamin A, but may not necessarily have vitamin A–like biologic activity.⁵⁰ Animal-derived foods such as liver, fish, eggs, milk, and butter are important dietary sources of preformed vitamin A. Yellow and leafy green vegetables such as carrots, squash, and spinach supply large amounts of carotenoids, which are provitamins that can be metabolized to active vitamin A in the body. Carotenoids contribute approximately 30% of the vitamin A in human diets; the most important of these is β-carotene, which is efficiently converted to vitamin A. The Recommended Dietary Allowance for vitamin A is expressed in retinol equivalents, to take into account both preformed vitamin A and β-carotene.

Vitamin A is a fat-soluble vitamin, and its absorption requires bile, pancreatic enzymes, and some level of antioxidant activity in the food. Retinol (generally ingested as retinol ester) and β-carotene are absorbed in the intestine, where β-carotene is converted to retinol (Fig. 9-25). Retinol is then transported in chylomicrons to the liver for esterification and storage. Uptake in liver cells takes place through the apolipoprotein E receptor. More than 90% of the body’s vitamin A reserves are stored in the liver, predominantly in the perisinusoidal stellate (Ito) cells. In healthy persons who consume an adequate diet, these reserves are sufficient to meet the body’s demands for at least 6 months. Retinol esters stored in the liver can be mobilized; before release, retinol binds to a specific retinol-binding protein (RBP), synthesized in the liver. The uptake of retinol/RBP in peripheral tissues is dependent on cell surface receptors specific for RBP.⁵¹ After uptake, retinol binds to a cellular RBP, and the RBP is released back into the blood. Retinol may be stored in peripheral tissues as retinol ester or be oxidized to form retinoic acid. Retinoic acid has important effects in epithelial differentiation and growth.

FIGURE 9-25 Vitamin A metabolism.

Function.

In humans the main functions of vitamin A are the following:

• Maintenance of normal vision. The visual process involves four forms of vitamin A–containing pigments: rhodopsin in the rods, the most light-sensitive pigment and therefore important in reduced light, and three iodopsins in cone cells, each responsive to specific colors in bright light. The synthesis of rhodopsin from retinol involves (1) oxidation to all-trans-retinal, (2) isomerization to 11-cis-retinal, and (3) covalent association with the 7-transmembrane rod protein opsin to form rhodopsin. A photon of light causes the isomerization of 11-cis-retinal to all-trans-retinal, which dissociates from rhodopsin. This induces a conformational change in opsin that triggers a series of downstream events and generates a nerve impulse, which is transmitted via neurons from the retina to the brain. During dark adaptation, some of the all-trans-retinal is reconverted to 11cis-retinal, but most is reduced to retinol and lost to the retina, dictating the need for continuous supply.

• Cell growth and differentiation. Vitamin A and retinoids play an important role in the orderly differentiation of mucus-secreting epithelium; when a deficiency state exists, the epithelium undergoes squamous metaplasia, differentiating into a keratinizing epithelium. Activation of retinoic acid receptors (RARs) by their ligands causes the release of corepressors and the obligatory formation of heterodimers with another retinoid receptor, known as the retinoic X receptor (RXR). Both RAR and RXR have three isoforms, α, β, and γ. The RAR/RXR heterodimers bind to retinoic acid response elements located in the promoter region of genes that encode receptors for growth factors, tumor suppressor genes, and secreted proteins. Through these effects, retinoids participate in cell growth and differentiation, cell cycle control, and other biologic responses. All-trans-retinoic acid, a potent acid derivative of vitamin A, has the highest affinity for RARs compared with other retinoids.⁵¹

• Metabolic effects of retinoids. The retinoic X receptor (RXR), believed to be activated by 9-cis retinoic acid, can form heterodimers with other nuclear receptors, such as (as we have seen) nuclear receptors involved in drug metabolism, the peroxisome proliferator-activated receptors (PPARs), and vitamin D receptors. PPARs are key regulators of fatty acid metabolism, including fatty acid oxidation in fat tissue and muscle, adipogenesis, and lipoprotein metabolism. The association between RXR and PPARγ provides an explanation for the metabolic effects of retinoids on adipogenesis and obesity.⁵²

• Host resistance to infections. Vitamin A supplementation can reduce morbidity and mortality from some forms of diarrhea, and in preschool children with measles, supplementation can quickly improve the clinical outcome. The beneficial effect of vitamin A in diarrheal diseases may be related to the maintenance and restoration of the integrity of the epithelium of the gut. The effects of vitamin A on infections also derive in part from its ability to stimulate the immune system, although the mechanisms are not entirely clear. Infections may reduce the bioavailability of vitamin A by inhibiting retinol binding protein synthesis in the liver through the acute-phase response associated with many infections. The drop in hepatic retinol binding protein causes a decrease in circulating retinol, which reduces the tissue availability of vitamin A.

In addition, the retinoids, β-carotene, and some related carotenoids can function as photoprotective and antioxidant agents.

Retinoids are used clinically for the treatment of skin disorders such as severe acne and certain forms of psoriasis, and also in the treatment of acute promyelocytic leukemia. In this leukemia, a (15 : 17) translocation (Chapter 13) results in the fusion of a truncated RARα gene on chromosome 17 with the PML gene on chromosome 15. The fusion gene encodes an abnormal RAR that blocks myeloid cell differentiation. Pharmacologic doses of all-trans retinoic acid overcome the block, causing leukemia cells to differentiate into neutrophils, which subsequently die by apoptosis. This “differentiation therapy” induces remission in most individuals with acute promyelocytic leukemia and in combination with other chemotherapeutic agents can be curative. A different isomer, 13-cis retinoic acid, has been used with some success in the treatment of neuroblastomas in children.

Vitamin A Deficiency.

Vitamin A deficiency occurs worldwide either as a consequence of general undernutrition or as a secondary deficiency in individuals with conditions that cause malabsorption of fats. In children, stores of vitamin A are depleted by infections, and the absorption of the vitamin is poor in newborn infants. Adult patients with malaborption syndromes, such as celiac disease, Crohn’s disease, and colitis, may develop vitamin A deficiency, in conjunction with depletion of other fat-soluble vitamins. Bariatric surgery and, in elderly persons, continuous use of mineral oil as a laxative may lead to deficiency. The pathologic effects of vitamin A deficiency are summarized in Figure 9-26.

FIGURE 9-26 Vitamin A deficiency: its major consequences in the eye and in the production of keratinizing metaplasia of specialized epithelial surfaces, and its possible role in epithelial metaplasia. Not depicted are night blindness and immune deficiency.

As already discussed, vitamin A is a component of rhodopsin and other visual pigments. Not surprisingly, one of the earliest manifestations of vitamin A deficiency is impaired vision, particularly in reduced light (night blindness). Other effects of deficiency are related to the role of vitamin A in maintaining the differentiation of epithelial cells. Persistent deficiency gives rise to a series of changes involving epithelial metaplasia and keratinization. The most devastating changes occur in the eyes and are referred to as xerophthalmia (dry eye). First, there is dryness of the conjunctiva (xerosis conjunctivae) as the normal lacrimal and mucus-secreting epithelium is replaced by keratinized epithelium. This is followed by buildup of keratin debris in small opaque plaques (Bitot spots) and, eventually, erosion of the roughened corneal surface with softening and destruction of the cornea (keratomalacia) and total blindness.

In addition to the ocular epithelium, the epithelium lining the upper respiratory passage and urinary tract is replaced by keratinizing squamous cells (squamous metaplasia). Loss of the mucociliary epithelium of the airways predisposes to secondary pulmonary infections, and desquamation of keratin debris in the urinary tract predisposes to renal and urinary bladder stones. Hyperplasia and hyperkeratinization of the epidermis with plugging of the ducts of the adnexal glands may produce follicular or papular dermatosis. Another very serious consequence is immune deficiency, which is responsible for higher mortality rates from common infections such as measles, pneumonia, and infectious diarrhea. In parts of the world where a deficiency of vitamin A is prevalent, dietary supplements reduce mortality by 20% to 30%.

Vitamin A Toxicity.

Both short- and long-term excesses of vitamin A may produce toxic manifestations, a point of concern because of the megadoses touted by certain sellers of supplements. The consequences of acute hypervitaminosis A were first described by Gerrit de Veer in 1597, a ship’s carpenter stranded in the Arctic, who recounted in his diary the serious symptoms that he and other members of the crew developed after eating polar bear liver. With this cautionary tale in mind, the adventurous eater should be aware that acute vitamin A toxicity has also been described in individuals who ingested the livers of whales, sharks, and even tuna! The symptoms of acute vitamin A toxicity include headache, dizziness, vomiting, stupor, and blurred vision, symptoms that may be confused with those of a brain tumor (pseudotumor cerebri). Chronic toxicity is associated with weight loss, anorexia, nausea, vomiting, and bone and joint pain. Retinoic acid stimulates osteoclast production and activity, which lead to increased bone resorption and high risk of fractures. Although synthetic retinoids used for the treatment of acne are not associated with these types of conditions, their use in pregnancy should be avoided because of the well-established teratogenic effects of retinoids.

Vitamin D

The major function of the fat-soluble vitamin D is the maintenance of adequate plasma levels of calcium and phosphorus to support metabolic functions, bone mineralization, and neuromuscular transmission.⁵³ Vitamin D is required for the prevention of bone diseases known as rickets (in children whose epiphyses have not already closed), osteomalacia (in adults), and hypocalcemic tetany. This latter condition is a convulsive state caused by an insufficient extracellular concentration of ionized calcium, which is required for normal neural excitation and the relaxation of muscles. Rickets was nearly endemic in large European cities and poor areas of New York and Boston at the end of the nineteenth century. Although cod liver oil was recognized for its anti-rachitic properties in the early part of that century, it took almost 100 years for it to be accepted by the medical profession as an effective preventive agent (it did not help that cod liver oil consumed in fishing villages in Northern Europe, Scandinavia, and Iceland was a dark, foul-smelling liquid).⁵⁴ In addition to its effects on calcium and phosphorus homeostasis, vitamin D has effects in non-skeletal tissues (so called “nonclassical” effects).

Metabolism of Vitamin D.

The major source of vitamin D for humans is its endogenous synthesis in the skin by photochemical conversion of a precursor, 7-dehydrocholesterol, via the energy of solar or artificial UV light in the range of 290 to 315 nm (UVB radiation). Irradiation of 7-dehydrocholesterol forms cholecalciferol, known as vitamin D₃. For the sake of simplicity we will use the term vitamin D to refer to this compound. Under usual conditions of sun exposure, about 90% of the vitamin D requirement is endogenously derived from 7-dehydrocholesterol present in the skin. However, individuals with dark skin generally have a lower level of vitamin D production because of melanin pigmentation. Dietary sources, such as deep-sea fish, plants, and grains, contribute about 10% of required vitamin D and depend on adequate intestinal fat absorption. In plants, vitamin D is present in its precursor form (ergosterol), which is converted to vitamin D in the body.

The main steps of vitamin D metabolism are summarized below⁵³ and shown in Figure 9-27.

1. Photochemical synthesis of vitamin D from 7-dehydrocholesterol in the skin and absorption of vitamin D from foods and supplements in the gut

2. Binding of vitamin D from both of these sources to plasma α1-globulin (D-binding protein or DBP) and transport into the liver

3. Conversion of vitamin D into 25-hydroxycholecalciferol (25-OH-D) in the liver, through the effect of 25-OHases (25-hydroxylases that include CYP27A1 and other CYPs)

4. Conversion of 25-OH-D into 1,25-dihydroxyvitamin D, [1α, 25(OH)₂D₃] in the kidney, the most active form of vitamin D, through the activity of α1-hydroxylase

FIGURE 9-27 Vitamin D metabolism. Vitamin D is produced from 7-dehydrocholesterol in the skin or is ingested in the diet. It is converted in the liver into 25(OH)D, and in kidney into 1,25(OH)₂D (1,25-dihydroxyvitamin D), the active form of the vitamin. 1,25(OH)₂D stimulates the expression of RANKL, an important regulator of osteoclast maturation and function, on osteoblasts, and enhances the intestinal absorption of calcium and phosphorus in the intestine. See text for further details. DBP, vitamin d-binding protein (α1-globulin).

The production of 1,25-dihydroxyvitamin D in the kidney is regulated by three main mechanisms (Fig. 9-27): (a) hypocalcemia stimulates secretion of parathyroid hormone (PTH), which in turn augments the conversion of 25-OH-D into 1,25-dihydroxyvitamin D by activating 1α-hydroxylase; (b) hypophosphatemia directly activates α1-hydroxylase, increasing the production of 1,25-dihydroxyvitamin D; (c) through a feedback mechanism, increased levels of 1,25dihydroxyvitamin D down-regulate its own synthesis through inhibition of 1α-hydroxylase activity.

Mechanisms of Action.

1,25-dihydroxyvitamin D, the biologically active form of vitamin D, is best regarded as a steroid hormone. It binds to the high-affinity vitamin D receptor (VDR), which associates with the already mentioned RXR. This heterodimeric complex binds to vitamin D response elements located in the promoter of vitamin D target genes. The receptors for 1,25-dihydroxyvitamin D are present in most cells of the body and transduce signals that regulate plasma levels of calcium and phosphorus, through action on the small intestine, bones, and kidneys. Beyond its role on skeletal homeostasis, vitamin D also has immunomodulatory and antiproliferative effects. More recently it has been proposed that 1,25-dihydroxyvitamin D may also act through nongenomic mechanisms, which do not require the transcription of target genes. Nongenomic mechanisms may involve the binding of 1,25-dihydroxyvitamin D to a membrane vitamin D receptor, leading to the activation of protein kinase C and opening of calcium channels.⁵⁵

Effects of Vitamin D on Calcium and Phosphorus Homeostasis.

The main functions of 1,25-dihydroxyvitamin D on calcium and phosphorus homeostasis are the following:

• Stimulation of intestinal calcium absorption. 1,25-dihydroxyvitamin D stimulates intestinal absorption of calcium in the duodenum through the interaction of 1,25-dihydroxyvitamin D with nuclear vitamin D receptor and the formation of a complex with RXR. The complex binds to vitamin D response elements and activates the transcription of TRPV6 (a member of the transient receptor potential vanilloid family), which encodes a critical calcium transport channel.

• Stimulation of calcium reabsorption in the kidney. 1,25-dihydroxyvitamin D increases calcium influx in distal tubules of the kidney through the increased expression of TRPV5, another member of the transient receptor potential vanilloid family. TRPV5 expression is also regulated by PTH in response to hypocalcemia.⁵⁶

• Interaction with parathyroid hormone (PTH) in the regulation of blood calcium. Vitamin D maintains calcium and phosphorus at supersaturated levels in the plasma. The parathyroid glands have a key role in the regulation of extracellular calcium concentrations. These glands have a calcium receptor that senses even small changes in blood calcium concentrations.⁵⁷ In addition to their effects on calcium absorption in the intestine and kidneys already described, both 1,25-dihydroxyvitamin D and parathyroid hormone enhance the expression of RANKL (receptor activator of NF-κB ligand) on osteoblasts. RANKL binds to its receptor (RANK) located in preosteoclasts, inducing the differentiation of these cells into mature osteoclasts (Chapter 26). Through the secretion of hydrochloric acid and activation of proteases such as cathepsin K, osteoclasts dissolve bone and release calcium and phosphorus into the circulation.

• Mineralization of bone. Vitamin D contributes to the mineralization of osteoid matrix and epiphyseal cartilage in the formation of both flat and long bones in the skeleton. It stimulates osteoblasts to synthesize the calcium-binding protein osteocalcin, involved in the deposition of calcium during bone development. Flat bones develop by intramembranous bone formation, in which mesenchymal cells differentiate directly into osteoblasts, and synthesize the collagenous osteoid matrix on which calcium is deposited. Long bones develop by endochondral ossification, through which growing cartilage at the epiphyseal plates is provisionally mineralized and then progressively resorbed and replaced by osteoid matrix that is mineralized to create bone (Fig. 9-28A).

FIGURE 9-28 Rickets. A, Normal costochondral junction of a young child, illustrating formation of cartilage palisades and orderly transition from cartilage to new bone. B, Detail of a rachitic costochondral junction in which the palisades of cartilage is lost. Darker trabeculae are well-formed bone; paler trabeculae consist of uncalcified osteoid. C, Rickets, note bowing of legs due to formation of poorly mineralized bones.

(B, Courtesy of Dr. Andrew E. Rosenberg, Massachusetts General Hospital, Boston, MA.)

When hypocalcemia occurs in vitamin D deficiency (Fig. 9-29), PTH production is elevated, causing (1) activation of renal 1α-hydroxylase, increasing the amount of active vitamin D and calcium absorption; (2) increased resorption of calcium from bone by osteoclasts; (3) decreased renal calcium excretion; and (4) increased renal excretion of phosphate. Fibroblast growth factor 23, which is produced by bone, is one of a group of agents known as phosphatonins, which block the absorption of phosphate in the intestine, and phosphate reabsorption in the kidney, causing increased urinary excretion of phosphate. Although a normal serum level of calcium may be restored, hypophosphatemia persists, impairing the mineralization of bone. Increased production of fibroblast growth factor 23 may be responsible for tumor-induced osteomalacia and some forms of hypophosphatemic rickets.⁵⁸

FIGURE 9-29 Vitamin D deficiency. There is inadequate substrate for the renal 1α-hydroxylase (1), yielding a deficiency of 1,25(OH)₂D (2), and deficient absorption of calcium and phosphorus from the gut (3), with consequently depressed serum levels of both (4). The hypocalcemia activates the parathyroid glands (5), causing mobilization of calcium and phosphorus from bone (6a). Simultaneously, the parathyroid hormone (PTH) induces wasting of phosphate in the urine (6b) and calcium retention. As a result, the serum levels of calcium are normal or nearly normal, but phosphate levels are low; hence, mineralization is impaired (7).

Deficiency States.

The normal reference range for circulating 25-(OH)-D is 20 to 100 ng/mL; concentrations of less than 20 ng/mL constitute vitamin D deficiency.

Rickets in growing children (see Fig. 9-28C) and osteomalacia in adults are skeletal diseases with worldwide distribution. They may result from diets deficient in calcium and vitamin D, but an equally important cause of vitamin D deficiency is limited exposure to sunlight. This most often affects inhabitants of northern latitudes, but can even be a problem in tropical countries, in heavily veiled women, and in children born to mothers who have frequent pregnancies followed by lactation. In all of these situations, vitamin D deficiency can be prevented by a diet high in fish oils. Other, less common causes of rickets and osteomalacia include renal disorders causing decreased synthesis of 1,25-dihydroxyvitamin D, phosphate depletion, malabsorption disorders, and some rare inherited disorders.⁵³ Although rickets and osteomalacia rarely occur outside high-risk groups, milder forms of vitamin D deficiency (also called vitamin D insufficiency), leading to an increase risk of bone loss and hip fractures, are quite common in the elderly in the United States and Europe.⁵⁹ Some genetically determined variants of the vitamin D receptors are associated with an accelerated loss of bone minerals with aging and in certain familial forms of osteoporosis (Chapter 26).

Morphology. The basic derangement in both rickets and osteomalacia is an excess of unmineralized matrix. The following sequence ensues in rickets:

• Overgrowth of epiphyseal cartilage due to inadequate provisional calcification and failure of the cartilage cells to mature and disintegrate

• Persistence of distorted, irregular masses of cartilage, which project into the marrow cavity

• Deposition of osteoid matrix on inadequately mineralized cartilaginous remnants

• Disruption of the orderly replacement of cartilage by osteoid matrix, with enlargement and lateral expansion of the osteochondral junction (see Fig. 9-28B)

• Abnormal overgrowth of capillaries and fibroblasts in the disorganized zone resulting from microfractures and stresses on the inadequately mineralized, weak, poorly formed bone

• Deformation of the skeleton due to the loss of structural rigidity of the developing bones

Rickets is most common during the first year of life. The gross skeletal changes depend on the severity and duration of the process and, in particular, the stresses to which individual bones are subjected. During the nonambulatory stage of infancy, the head and chest sustain the greatest stresses. The softened occipital bones may become flattened, and the parietal bones can be buckled inward by pressure; with the release of the pressure, elastic recoil snaps the bones back into their original positions (craniotabes). An excess of osteoid produces frontal bossing and a squared appearance to the head. Deformation of the chest results from overgrowth of cartilage or osteoid tissue at the costochondral junction, producing the “rachitic rosary.” The weakened metaphyseal areas of the ribs are subject to the pull of the respiratory muscles and thus bend inward, creating anterior protrusion of the sternum (pigeon breast deformity). When an ambulating child develops rickets, deformities are likely to affect the spine, pelvis, and tibia, causing lumbar lordosis and bowing of the legs (see Fig. 9-28C).

In adults, the lack of vitamin D deranges the normal bone remodeling that occurs throughout life. The newly formed osteoid matrix laid down by osteoblasts is inadequately mineralized, thus producing the excess of persistent osteoid that is characteristic of osteomalacia. Although the contours of the bone are not affected, the bone is weak and vulnerable to gross fractures or microfractures, which are most likely to affect vertebral bodies and femoral necks.

Histologically, the unmineralized osteoid can be visualized as a thickened layer of matrix (which stains pink in hematoxylin and eosin preparations) arranged about the more basophilic, normally mineralized trabeculae.

Non-Skeletal Effects of Vitamin D.

It was mentioned earlier that the vitamin D receptor is present in various cells and tissues that do not participate in calcium and phophorus homeostasis. Macrophages, keratinocytes, and tissues such as breast, prostate, and colon can produce 1,25-dihydroxyvitamin D.⁶⁰ Within macrophages, synthesis of 1,25-dihydroxyvitamin D occurs through the activity of CYP27B located in the mitochondria. It has been proposed that pathogen-induced activation of Toll-like receptors in macrophages causes a transcription-induced increase in vitamin D receptor and CYP27B (Fig. 9-30). The resultant production of 1,25-dihydroxyvitamin D then stimulates the synthesis of cathelicidin, an antimicrobial peptide from the defensin family, which is effective against infection by Mycobacterium tuberculosis. Other effects of vitamin D in the innate and adaptive immune system have been reported,⁶¹ but the data are often contradictory. Vitamin D regulates the expression of more than 200 genes, including genes that participate in cell proliferation, differentiation, apoptosis, and angiogenesis. It has been reported that levels of 1,25-dihydroxyvitamin D below 20 ng/mL are associated with a 30% to 50% increase in the incidence of colon, prostate, and breast cancers.

FIGURE 9-30 Anti-microbial effect of vitamin D. Pathogens and lipopolysaccharides (LPS) stimulate Toll-like receptors (TLRs) in macrophages, causing the transcription of vitamin D receptor (VDR) and an increase in CYP27B activity in mitochondria. This causes the production of 1,25(OH)₂D (1,25-dihydroxyvitamin D), which stimulates the synthesis of cathelicidin, an antimicrobial peptide that is particularly active against Mycobacterium tuberculosis.

Vitamin D Toxicity.

Prolonged exposure to normal sunlight does not produce an excess of vitamin D, but megadoses of orally administered vitamin can lead to hypervitaminosis. In children, hypervitaminosis D may take the form of metastatic calcifications of soft tissues such as the kidney; in adults it causes bone pain and hypercalcemia. In passing, we might point out that the toxic potential of this vitamin is so great that in sufficiently large doses it is a potent rodenticide!

Vitamin C (Ascorbic Acid)

A deficiency of water-soluble vitamin C leads to the development of scurvy, characterized principally by bone disease in growing children and by hemorrhages and healing defects in both children and adults. Sailors of the British Royal Navy were nicknamed “limeys,” because at the end of the eighteenth century the Navy began to provide lime and lemon juice (rich sources of vitamin C) to sailors to prevent scurvy during their long sojourn at sea. It was not until 1932 that ascorbic acid was identified and synthesized. Ascorbic acid is not synthesized endogenously in humans; therefore, we are entirely dependent on the diet for this nutrient. Vitamin C is present in milk and some animal products (liver, fish) and is abundant in a variety of fruits and vegetables. All but the most restricted diets provide adequate amounts of vitamin C.

Function.

Ascorbic acid functions in a variety of biosynthetic pathways by accelerating hydroxylation and amidation reactions. The best-established function of vitamin C is the activation of prolyl and lysyl hydroxylases from inactive precursors, providing for hydroxylation of procollagen. Inadequately hydroxylated procollagen cannot acquire a stable helical configuration or be adequately cross-linked, so it is poorly secreted from the fibroblast. Those molecules that are secreted lack tensile strength and are more soluble and vulnerable to enzymatic degradation. Collagen, which normally has the highest content, of hydroxyproline, of any polypeptide is most affected, particularly in blood vessels, accounting for the predisposition to hemorrhages in scurvy. In addition, a deficiency of vitamin C suppresses the rate of synthesis of procollagen, independent of an effect on proline hydroxylation.

While the role of vitamin C in collagen synthesis has been known for many decades, it is only in relatively recent years that its antioxidant properties have been recognized. Vitamin C can scavenge free radicals directly and can act indirectly by regenerating the antioxidant form of vitamin E.

Deficiency States.

Consequences of vitamin C deficiency (scurvy) are illustrated in Figure 9-31. Fortunately, because of the abundance of ascorbic acid in many foods, scurvy has ceased to be a global problem. It is sometimes encountered even in affluent populations as a secondary deficiency, particularly among elderly individuals, persons who live alone, and chronic alcoholics, groups that often have erratic and inadequate eating patterns. Occasionally, scurvy appears in patients undergoing peritoneal dialysis and hemodialysis and among food faddists. Tragically, the condition sometimes appears in infants who are maintained on formulas of evaporated milk without supplementation of vitamin C.

FIGURE 9-31 Major consequences of vitamin C deficiency caused by impaired formation of collagen.

Vitamin C Toxicity.

The popular notion that megadoses of vitamin C protect against the common cold, or at least allay the symptoms, has not been borne out by controlled clinical studies. Such slight relief as may be experienced is probably due to the mild antihistamine action of ascorbic acid. Similarly there is little support that large doses of vitamin C protect against cancer development. The physiologic availability of vitamin C is limited. It is unstable, poorly absorbed in the intestine, and promptly excreted in the urine.

Other vitamins and some essential minerals are listed and briefly described in Tables 9-9 and 9-10. Some vitamins are discussed in other chapters, as indicated in the tables.

TABLE 9-10 Selected Trace Elements and Deficiency Syndromes

OBESITY

Excess adiposity (known as obesity) and excess body weight are associated with the increased incidence of several of the most important diseases of humans, including type 2 diabetes, dyslipidemias, cardiovascular disease, hypertension, and cancer. Obesity is defined as an accumulation of adipose tissue that is of sufficient magnitude to impair health. As with weight loss, excess weight is best assessed by the body mass index or BMI. For practical reasons, body weight, which generally correlates well with BMI, is often used as a surrogate for BMI measurements. The normal BMI range is 18.5 to 25 kg/m², although the range may differ for different countries. Individuals with BMI above 30 kg/m² are classified as obese; those with BMI between 25 kg/m² and 30 kg/m² are considered to be overweight. For the sake of simplicity, unless otherwise noted, the term obesity will be applied to both the truly obese and the overweight.

Accumulation of body fat may also be measured by triceps skinfold thickness, mid-arm circumference, and the ratio between waist and hip circumferences. Not only the total body weight but also the distribution of the stored fat is of importance in obesity. Central, or visceral, obesity, in which fat accumulates in the trunk and in the abdominal cavity (in the mesentery and around viscera), is associated with a much higher risk for several diseases than is excess accumulation of fat diffusely in subcutaneous tissue.

Obesity is a major public health problem, which, until about a dozen years ago, was confined to developed countries. Since then, it has also become an important health problem in developing nations, and in certain countries obesity coexists with malnutrition in individual families. In the United States obesity has reached epidemic proportions. The prevalence of obesity increased from 13% to 32% between 1960 and 2004; currently 66% of adults in the United States are overweight or obese, and 16% of children are overweight. If current trends continue, it is projected that by the year 2015, 41% of adults will be obese.⁶² The increase in obesity in the United States has been associated with the higher caloric content of the diet, mostly caused by increased consumption of refined sugars, sweetened beverages, and vegetable oils.

At its simplest level, obesity is a disease of caloric imbalance that results from an excess intake of calories above their consumption by the body. However, the pathogenesis of obesity is exceedingly complex and not yet completely understood. Ongoing research has identified complex humoral and neural mechanisms that control appetite and satiety. These neurohumoral mechanisms respond to genetic, nutritional, environmental, and psychologic signals, and trigger a metabolic response through the stimulation of centers located in the hypothalamus. There is little doubt that genetic influences play an important role in weight control, but obesity is a disease that depends on the interaction between multiple factors. After all, regardless of genetic makeup, obesity would not occur without intake of food!

In a simplified way the neurohumoral mechanisms that regulate energy balance can be subdivided into three components (illustrated in Figs. 9-29 and 9-30):

• The peripheral or afferent system generates signals from various sites. Its main components are leptin and adiponectin produced by fat cells, ghrelin from the stomach, peptide YY (PYY) from the ileum and colon, and insulin from the pancreas.

• The arcuate nucleus in the hypothalamus processes and integrates neurohumoral peripheral signals and generates efferent signals. It contains two subsets of first-order neurons: (1) POMC (pro-opiomelanocortin) and CART (cocaine and amphetamine-regulated transcripts) neurons, and (2) neurons containing NPY (neuropeptide Y) and AgRP (agouti-related peptide). These first order neurons communicate with second order neurons.

• The efferent system that carries the signals generated in the second order neurons of the hypothalamus to control food intake and energy expenditure. The hypothalamic system also communicates with forebrain and midbrain centers that control the autonomic nervous system.⁶³

POMC/CART neurons enhance energy expenditure and weight loss through the production of the anorexigenic α-melanocyte-stimulating hormone (MSH), and the activation of the melanocortin receptors 3 and 4 (MC3/4R) in second-order neurons. NPY/AgRP neurons promote food intake (orexigenic effect) and weight gain, through the activation of Y1/5 receptors in secondary neurons.

We will now discuss three important components of the afferent system that regulates appetite and satiety: leptin, adiponectin, and gut hormones.

Leptin.

The name leptin is derived from the Greek term leptos, meaning “thin.” Leptin, a 16-kD hormone synthesized by fat cells, is the product of the ob gene. The leptin receptor (OB-R) is the product of the diabetes (db) gene and belongs to the type I cytokine receptor superfamily that includes the gp130, granulocyte-colony-stimulating factor, IL-2, and IL-6 receptors. Mice genetically deficient in leptin (ob/ob mice) or leptin receptors (db/db mice) fail to sense the adequacy of fat stores, overeat, and gain weight, behaving as if they are undernourished. Thus, the obesity of these animals is a consequence of the lack of the signal for energy sufficiency that is normally provided by leptin.⁶³

Although in a general sense leptin levels are regulated by the adequacy of fat stores, the precise mechanisms that regulate the output of leptin from adipose tissue have not been completely defined, but it has been established that leptin secretion is stimulated when fat stores are abundant. It is believed that insulin-stimulated glucose metabolism is an important factor in the regulation of leptin levels. Leptin levels are regulated by multiple post-transcriptional mechanisms that affect its synthesis, secretion, and turnover. In the hypothalamus, leptin stimulates POMC/CART neurons that produce anorexigenic neuropeptides (primarily melanocyte-stimulating hormone) and inhibits NPY/AgRP neurons that produce feeding-inducing (orexigenic) neuropeptides (see Figs. 9-32 and 9-33). In individuals with stable weight, the activities of the opposing POMC/CART and NPY/AgRP pathways are properly balanced. However, when there are inadequate stores of body fat, leptin secretion is diminished and food intake is increased.

FIGURE 9-32 Regulation of energy balance. Adipose tissues generate afferent signals that influence the activity of the hypothalamus, which is the central regulator of appetite and satiety. These signals decrease food intake by inhibiting anabolic circuits, and enhance energy expenditure through the activation of catabolic circuits. PYY, peptide YY. See text for details.

FIGURE 9-33 Neurohumoral circuits in the hypothalamus that regulate energy balance. Shown are POMC/CART anorexigenic neurons and NPY/AgRP orexigenic neurons in the arcuate nucleus of the hypothalamus, and their pathways. See text for details.

Humans with loss-of-function mutations in the leptin system develop early-onset severe obesity, but this is a rare condition. Mutations of melanocortin receptor 4 (MC4R) and its downstream pathways are more frequent, being responsible for about 5% of massive obesity. In these individuals, sensing of satiety (anorexigenic signal) is not generated, and hence they behave as if they are undernourished. It has recently been reported⁶⁴ that haplo-insufficiency of brain-derived neurotrophic factor (BDNF), an important component of MC4R downstream signaling in the hypothalamus, is associated with obesity in patients with the WAGR syndrome (this is a very rare condition that includes Wilms tumor, aniria, genito-urinary defects, and mental retardation in addition to obesity Chapter 10). Although the defects in leptin and MC4R detected so far are uncommon, they underscore the importance of these systems in the control of energy balance and body weight. Perhaps other defects in these pathways may have pathogenic effects in more common forms of obesity. For instance, it has been proposed that leptin resistance rather than leptin deficiency may be prevalent in humans.

Leptin regulates not only food intake but also energy expenditure, through a distinct set of pathways. Thus, an abundance of leptin stimulates physical activity, heat production, and energy expenditure. The neurohumoral mediators of leptin-induced energy expenditure are less well defined. Thermogenesis, an important catabolic effect mediated by leptin, is controlled in part by hypothalamic signals that increase the release of norepinephrine from sympathetic nerve endings in adipose tissue. In addition to these effects, leptin can function as a pro-inflammatory cytokine and participates in the regulation of hematopoiesis and lymphopoiesis.⁶⁵ The OB-R receptor is highly similar structurally to the IL-6 receptor and activates the JAK/STAT pathway.

Adiponectin.

Injections of adiponectin in mice stimulate fatty acid oxidation in muscle, causing a decrease in fat mass. This hormone is produced mainly by adipocytes. Its levels in the blood are very high, about 1000 times higher than those of other polypeptide hormones, and are lower in obese than in lean individuals.⁶⁶ Adiponectin, which has been called a “fat-burning molecule” and the “guardian angel against obesity,” directs fatty acids to muscle for their oxidation. It decreases the influx of fatty acids to the liver and the total hepatic triglyceride content, and also decreases the glucose production in the liver, causing an increase in insulin sensitivity and a protection against the metabolic syndrome (described later).⁶⁷ Adiponectin circulates as a complex of three, six, or even more aggregates of the monomeric form, and binds to two receptors, AdipoR1 and AdipoR2. These receptors are found in many tissues, including the brain, but AdipoR1 and AdipoR2 are most highly expressed in skeletal muscle and liver, respectively. Binding of adiponectin to its receptors triggers signals that activate cyclic adenosine monophosphate–activated protein kinase, which in turn phosphorylates and inactivates acetyl coenzyme A carboxylase, a key enzyme required for fatty acid synthesis.

Adipose Tissue.

In addition to leptin and adiponectin, adipose tissue produces cytokines such as TNF, IL-6, IL-1, and IL-18, chemokines, and steroid hormones. The increased production of cytokines and chemokines by adipose tissue in obese patients creates a chronic sub-clinical (asymptomatic) inflammatory state that includes high levels of circulating C-reactive protein. Through its multiple activities, adipose tissue participates in the control of energy balance and energy metabolism, functioning as a link between lipid metabolism, nutrition, and inflammatory responses. Thus, the adipocyte that was relegated to an obscure and passive role as the “Cinderella of cells of metabolism,” is now “the Belle of the Ball” at the forefront of metabolic research.⁶⁸

The total number of adipocytes is established during childhood and adolescence, and it is higher in obese than in lean individuals.⁶⁹ In adults the number of adipocytes remains constant, even after losses or weight gains, but there is a continuous turnover of the cell population. It is estimated that approximately 10% of adipocytes are renewed annually, regardless of the level of the individual’s body mass. Thus, although the fat mass in an adult person can increase through the enlargement of existing adipocytes, their number is tightly controlled, and is predetermined in childhood and adolescence. In individuals who lose weight after dietary regimens, the well-known difficulties in maintaining weight losses are, in part, a consequence of the lack of a decrease in the number of adipocytes, and the enhanced appetite caused by leptin deficiency.

Gut Hormones.

Gut peptides act as short-term meal initiators and terminators. They include ghrelin, PYY, pancreatic polypeptide, insulin, and amylin among others.⁷⁰ Ghrelin is produced in the stomach and in the arcuate nucleus of the hypothalamus. It is the only known gut hormone that increases food intake (orexigenic effect). Its injection in rodents elicits voracious feeding, even after repeated administration. Long-term injections cause weight gain, by increasing caloric intake and reducing energy utilization. Ghrelin acts by binding the growth hormone secretagogue receptor, which is abundant in the hypothalamus and the pituitary. Although the precise mechanisms of ghrelin action have not been identified, it most likely stimulates NPY/AgRP neurons to increase food intake. Ghrelin levels rise before meals and fall between 1 and 2 hours after eating. However, in obese individuals the postprandial suppression of ghrelin is attenuated, leading to maintenance of the obesity.

PYY is secreted from endocrine cells in the ileum and colon. Plasma levels of PYY are low during fasting and increase shortly after food intake. Intravenous administration of PYY reduces energy intake, and its levels generally increase after gastric bypass surgery. By contrast, levels of PYY generally decrease in individuals with the Prader-Willi syndrome (caused by loss of imprinted genes on chromosome 15q11–q13),⁷¹ and may contribute to the development of hyperphagia and obesity in these persons. These observations have led to ongoing work to produce PYYs for the treatment of obesity. Amylin, a peptide secreted with insulin from pancreatic β-cells that reduces food intake and weight gain, is also being evaluated for the treatment of obesity and diabetes. Both PYY and amylin act centrally by stimulating POMC/CART neurons in the hypothalamus, causing a decrease in food intake.

General Consequences of Obesity

Obesity, particularly central obesity, increases the risk for a number of conditions, including type 2 diabetes and cardiovascular disease (Fig. 9-34). Obesity is the main driver of a cluster of alterations known as the metabolic syndrome characterized by visceral or intra-abdominal adiposity, insulin resistance, hyperinsulinemia, glucose intolerance, hypertension, hypertriglyceridemia, and low HDL cholesterol (Chapter 11).

• Obesity is associated with insulin resistance and hyperinsulinemia, important features of type 2 diabetes, and weight loss is associated with improvement (Chapter 24). It has been speculated that excess insulin, in turn, may play a role in the retention of sodium, expansion of blood volume, production of excess norepinephrine, and smooth muscle proliferation that are the hallmarks of hypertension. Regardless of the nature of the pathogenic mechanisms, the risk of developing hypertension among previously normotensive persons increases proportionately with weight.

• Obese persons generally have hypertriglyceridemia and low HDL, and these may increase the risk of coronary artery disease in the very obese. It should be emphasized that the association between obesity and heart disease is not straightforward, and such linkage as there may be relates more to the associated diabetes and hypertension than to weight.

• Obesity is associated with non-alcoholic fatty liver disease (Chapter 18). This condition occurs most often in diabetic patients and can progress to fibrosis and cirrhosis. Cholelithiasis (gallstones) is six times more common in obese than in lean subjects. An increase in total body cholesterol, increased cholesterol turnover, and augmented biliary excretion of cholesterol all act to predispose to the formation of cholesterol-rich gallstones (Chapter 18).

• Obesity is associated with hypoventilation and hypersomnolence. Hypoventilation syndrome is a constellation of respiratory abnormalities in very obese persons. It has been called the pickwickian syndrome, after the fat lad who was constantly falling asleep in Charles Dickens’ Pickwick Papers. Hypersomnolence, both at night and during the day, is characteristic and is often associated with apneic pauses during sleep, polycythemia, and eventual right-sided heart failure.

• Marked adiposity predisposes to the development of degenerative joint disease (osteoarthritis). This form of arthritis, which typically appears in older persons, is attributed in large part to the cumulative effects of increased load on weight-bearing joints.

FIGURE 9-34 Obesity, metabolic syndrome, and cancer. Obesity and excessive weight are precursors of the metabolic syndrome, which is associated with insulin resistance, type 2 diabetes, and hormonal changes. Increases in insulin and IGF-1 (insulin-like growth factor-1) stimulate cell proliferation and inhibit apoptosis and may contribute to tumor development. IGF, insulin-like growth factor; IGFBP, insulin-like growth factor–binding protein; SHBG, sex hormone–binding globulin.

(Modified from Renehan AG et al.: Obesity and cancer risk: the role of the insulin-I6F axis. Trends Endocrinol Metab 17:328, 2006.)

Obesity and Cancer

Approximately 4% of cancers in men and 7% in women are associated with obesity.⁷² Data on the relationships between obesity and cancer have been obtained from the Million Women Study that examined the relationship between BMI and cancer in women aged 50 to 64 years in the United Kingdom, and from a systematic analysis of published data sets involving more than 280,000 cases of cancer in men and women.^73,⁷⁴

1. In men, a BMI greater than 25 kg/m² correlated strongly with an increased incidence of adenocarcinoma of the esophagus, and cancers of the thyroid, colon, and kidney.

2. In women, a BMI greater than 25 kg/m² correlated strongly with an increased incidence of adenocarcinoma of the esophagus, and of endometrial, gallbladder, and kidney cancers.

The mechanisms by which obesity is associated with these specific types of cancers are unknown, but a proposed hypothesis is that the increased cancer risk in obese individuals is a consequence of hyperinsulinemia and insulin resistance (Fig. 9-34). Insulin at high concentrations has multiple effects on cell growth, including the activation of phosphatidylinositol 3-kinase, extracellular-signal-regulated kinases 1 and 2, β-catenin, and Ras. All of these are important components of pathways that are dysregulated during cancer development. Hyperinsulinemia also causes an increase in insulin-like growth factor-1 (IGF-1) concentrations, because insulin inhibits the production of the IGF-binding proteins IGFBP-1 and IGFBP-2. IGF-1 is a mitogenic and anti-apoptotic agent that is highly expressed in many human cancers.⁷⁵ It binds with high affinity to the IGF-1R receptor, and with low affinity to the insulin receptor. IGF-1 activates many of the cell growth pathways that are also activated by insulin, and increases the production of vascular endothelial growth factor, by inducing the expression of hypoxia-inducible factor 1.

In addition to the obesity-associated effects of insulin and IGF-1 in cell growth pathways, obesity and hyperinsulimia have an effect on steroid hormones that regulate cell growth and differentiation in the breast, uterus, and other tissues: (1) obesity increases the synthesis of estrogen from androgen precursors through an effect of adipose tissue aromatases; (2) insulin increases androgen synthesis in ovaries and adrenals, and enhances estrogen availability in obese persons by inhibiting the production of sex-hormone-binding globulin (SHBG) in the liver (see Fig. 9-34).

As already discussed in this chapter, adiponectin, secreted mostly from adipose tissue, is an abundant hormone that is inversely correlated with obesity and acts as an insulinsensitizing agent. Thus, the decreased levels of adiponectin in obese persons contribute to hyperinsulinemia and the impairment of insulin sensitivity.

DIETS, CANCER, AND ATHEROSCLEROSIS

Diet and Cancer

The incidence of specific cancers varies widely throughout the world. The frequency of some tumors varies as much as 100-fold in different geographic areas. It is also well known that differences in incidence of various cancers is not fixed and can be modified by nongenetic factors, including changes in diet. For instance, the incidence of colon cancer in Japanese men and women 55 to 60 years of age was negligible about 50 years ago, but it is now higher than that in men of the same age in the United Kingdom.⁷⁶ Studies have also shown a progressive increase in colon cancers in Japanese populations as they moved from Japan to Hawaii and from there to the continental United States. Nevertheless, despite the very large amount of experimental and epidemiologic research, relatively few mechanisms that link diets and specific types of cancer have been established.

With respect to carcinogenesis, three aspects of the diet are of major concern: (1) the content of exogenous carcinogens, (2) the endogenous synthesis of carcinogens from dietary components, and (3) the lack of protective factors.

• Regarding exogenous substances, aflatoxin is involved in the development of hepatocellular carcinomas in parts of Asia and Africa, generally in cooperation with hepatitis B virus. Exposure to aflatoxin causes a specific mutation in codon 249 of the p53 gene; when found in hepatocellular carcinomas, this mutation serves as a molecular signature for aflatoxin exposure. Debate continues about the carcinogenicity of food additives, artificial sweeteners, and contaminating pesticides. Some artificial sweeteners (cyclamates and saccharin) have been implicated in bladder cancers, but convincing evidence is lacking.

• The concern about endogenous synthesis of carcinogens or enhancers of carcinogenicity from components of the diet relates principally to gastric carcinomas. Nitrosamines and nitrosamides are implicated in the generation of these tumors in humans, because they have been clearly shown to induce gastric cancer in animals. These compounds can be formed in the body from nitrites and amines or amides derived from digested proteins. Sources of nitrites include sodium nitrite added to foods as a preservative, and nitrates, present in common vegetables, which are reduced in the gut by bacterial flora. There is, then, the potential for endogenous production of carcinogenic agents from dietary components, which might well have an effect on the stomach.

• High animal fat intake combined with low fiber intake has been implicated in the causation of colon cancer. It has been estimated that doubling the average level of total fiber consumption to about 40 gm/day per person in most populations may decrease the risk of colon cancer by 50%.⁷⁵ The most convincing explanation of this association is that high fat intake increases the level of bile acids in the gut, which in turn modifies intestinal flora, favoring the growth of microaerophilic bacteria. Bile acid metabolites produced by these bacteria may function as carcinogens. The protective effect of a high-fiber diet might relate to (1) increased stool bulk and decreased transit time, which decreases the exposure of mucosa to putative offenders, and (2) the capacity of certain fibers to bind carcinogens and thereby protect the mucosa. However, attempts to document these theories in clinical and experimental studies have not generated consistent results.

• Although epidemiologic data from large populations show a strong positive correlation between total dietary fat intake and breast cancer, it is still unclear whether increased fat consumption has a causal relationship to breast cancer development.

• Vitamins C and E, β-carotenes, and selenium have been assumed to have anticarcinogenic effects because of their antioxidant properties. However, thus far there is no convincing evidence that these antioxidants act as chemopreventive agents. As discussed earlier in this chapter, retinoids are effective agents in the therapy of acute promyelocytic leukemia, and associations between low levels of vitamin D and cancer of the colon, prostate, and breast have been reported.

Thus, we must conclude that despite many tantalizing trends and proclamations by “diet gurus,” thus far there is no definitive proof that a particular diet can cause or prevent cancer. On the other hand, given the relationships between obesity and cancer development, prevention of obesity through the consumption of a healthy diet is a commonsense measure that goes a long way in preserving good health. Concern persists that carcinogens lurk in things as pleasurable as a juicy steak, a rich ice cream, and in nuts contaminated with aflatoxin.

Diet and Atherosclerosis

A most important and controversial issue is the contribution of diet to atherogenesis. The central question is “can dietary modification—specifically, reduction in the consumption of cholesterol and saturated animal fats (e.g., eggs, butter, beef)—reduce serum cholesterol levels and prevent or retard the development of atherosclerosis (most importantly, coronary heart disease)?” The average adult in the United States consumes a large amount of fat and cholesterol daily, with a ratio of saturated fatty acids to polyunsaturated fatty acids of about 3 : 1. Lowering this ratio to 1 : 1 causes a 10% to 15% reduction in the serum cholesterol level within a few weeks. Vegetable oils (e.g., corn and safflower oils) and fish oil contain polyunsaturated fatty acids and are good sources of such cholesterol-lowering lipids. Fish oil fatty acids belonging to the omega-3 family have more double bonds than do the omega-6 fatty acids present in vegetable oils. A study of Dutch men whose usual daily diet contained 30 g of fish revealed a substantially lower frequency of death from coronary heart disease than that among comparable controls.

There is much talk about the role that caloric restriction and special diets may play in the control of body weight and prevention of cardiovascular disease. We offer just a few general observations on these topics.

• Caloric restriction has been convincingly demonstrated to decrease the incidence of some diseases, and to increase life span in experimental animals. The basis of this striking observation is not entirely clear but seems to depend on activation of sirtuins and on the lowering of insulin and IGF-1 levels (Chapter 1).⁷⁴ In calorie-restricted animals there is a more modest age-related decline in immunological functions, less oxidative damage, and greater resistance to carcinogenesis.

• Not surprisingly, there are a large number of commercial diets that are reported by its proponents to decrease the risk of heart disease. Among those are the low-carbohydrate diets (such as the Atkins Diet, the Zone, Sugar Busters, Protein Power), and others such as The Miami Diet/Hollywood 48-Hour Miracle Diet, and the South Beach Diet. The actual effect of these diets on heart disease is highly controversial.

• Most diets dictate what you cannot eat (of course, your favorite foods!). A better strategy is to simply focus on eating an enjoyable and healthy diet rich in fish, vegetables, whole grains, fruits, olive and peanut oils (to replace saturated and trans fats), complex carbohydrates (instead of simple carbohydrates contained in sweets and soft drinks), and low in salt (to control hypertension).

• Even lowly garlic has been touted to protect against heart disease (and also against, devils, werewolves, vampires, and, alas, kisses), although research has yet to prove this effect unequivocally. Of these, the effect on kisses is the best established!

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