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Pathology_Robbins. Today, the main sources of exposure to mercury are contaminated fish and dental amalgams, which release mercury vapors. 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 levels may be 1 million times higher than in the surrounding water. Almost 90% of the ingested mercury is absorbed in the GI tract. The consumption of contaminated fish from the release of methyl mercury in Minamata Bay and the Agano River in Japan, and the consumption of bread containing grain treated with a methyl mercury–based fungicide in Iraq, caused widespread morbidity and many deaths.


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Pathology_Robbins. The medical disorders associated with the Minamata episode became known as “Minamata disease” and include cerebral palsy, deafness, blindness, and major CNS defects in children exposed in utero. The developing brain is extremely sensitive to methyl mercury; for this reason, the CDC in the United States has recommended that pregnant women avoid the consumption of fish known to contain mercury. Ingested mercury can injure the gut and cause ulcerations and bloody diarrhea. In the kidneys, mercury can cause acute tubular necrosis and renal failure.


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Pathology_Robbins. Arsenic salts interfere with several aspects of cellular metabolism, leading to toxicities that are most prominent in the GI tract, nervous system, skin, and heart. Arsenic was poison of choice of skilled practitioners in the Borgia http://ebooksmedicine.net and Medici families in Renaissance Italy. Today, arsenic exposure is an important health problem in many areas of the world. Arsenic is found naturally in soil and water and is used in wood preservatives, herbicides, and other agricultural products. It may be released into the environment by the mining and smelting industries. Arsenic is present in Chinese and Indian herbal medicine, and arsenic trioxide is a frontline treatment for acute promyelocytic leukemia (Chapter 6). Large concentrations of inorganic arsenic are present in ground water in countries such as Bangladesh, Chile, and China. Between 35 and 77 million people in Bangladesh drink water contaminated with arsenic, constituting one of the greatest environmental cancer


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Pathology_Robbins. water in countries such as Bangladesh, Chile, and China. Between 35 and 77 million people in Bangladesh drink water contaminated with arsenic, constituting one of the greatest environmental cancer risks yet uncovered.


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Pathology_Robbins. If ingested in large quantities, arsenic causes acute toxicity manifesting as severe abdominal pain, diarrhea; cardiac arrhythmias, shock and respiratory distress syndrome; and acute encephalopathy. GI, cardiovascular and CNS toxicity may be severe enough to cause death. These effects may be attributed to the interference with mitochondrial oxidative phosphorylation. Chronic exposure to arsenic causes hyper-pigmentation and hyperkeratosis of the skin, which may be followed by the development of basal and squamous cell carcinomas (but not melanomas). A symmetrical sensorimotor polyneuropathy can also develop. Arsenic-induced skin tumors differ from those induced by sunlight by appearing on palms and soles, and by occurring as multiple lesions. Arsenic exposure also is associated with an increased risk of lung carcinoma. The mechanisms of arsenic carcinogenesis in the skin and the lung are uncertain.


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Pathology_Robbins. Cadmium is preferentially toxic to the kidneys and the lungs through uncertain mechanisms that may involve increased production of ROS. In contrast with the metals already discussed, cadmium is a relatively modern toxic agent. It is used mainly in nickel-cadmium batteries, which generally are disposed of as household waste. Cadmium can contaminate soil and plants directly or through fertilizers and irrigation water. Food is the most important source of exposure for the general population. Excessive cadmium intake can lead to obstructive lung disease and renal toxicity, initially as tubular damage that may progress to end-stage renal disease. Cadmium exposure can also cause skeletal abnormalities associated with calcium loss. Cadmium-contaminated 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. A survey showed that 5% of persons aged 20


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Pathology_Robbins. caused a disease in postmenopausal women known as “itai-itai” (ouch-ouch), a combination of osteoporosis and osteomalacia associated with renal disease. A survey showed that 5% of persons aged 20 years and older in the U.S. population have urinary cadmium levels that, according to research data, may produce subtle kidney injury and increased calcium loss.


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Pathology_Robbins. Cadmiumfromnickel-cadmiumbatteriesandchemicalfertilizerscancontaminatesoil.Excesscadmiumcausesobstructivelungdiseaseandkidneydamage. More than 10 million occupational injuries occur annually in the United States, and approximately 65,000 people die as a consequence of occupational injuries and illnesses. Industrial exposures to toxic agents are as varied as the industries themselves. They range from merely annoying irritations of respiratory airways by formaldehyde or ammonia fumes, to lung cancers arising from exposure to asbestos, arsenic, or uranium. Human diseases associated with occupational exposures are listed in Table 8.2 . In addition to toxic metals (already discussed), other important agents that contribute to environmental diseases include the following:


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Pathology_Robbins. Table 8.2 . In addition to toxic metals (already discussed), other important agents that contribute to environmental diseases include the following: 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 CNS depression and even coma. Lower levels may cause liver and kidney toxicity. Occupational exposure of rubber workers to benzene and 1,3-butadiene increases the risk of leukemia. Benzene is oxidized to an epoxide through hepatic CYP2E1, a component of the P-450 enzyme system already mentioned. The epoxide and other metabolites disrupt progenitor cell differentiation in the bone marrow, and may lead to marrow aplasia and acute myeloid leukemia.


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Pathology_Robbins. Polycyclic hydrocarbons are released during the combustion of coal and gas, particularly at the high temperatures used in steel foundries, and also are present in tar and soot. (Pott identified soot as the cause of scrotal cancers in chimney sweeps in 1775, as mentioned in Chapter 6). Polycyclic hydrocarbons are among the most potent carcinogens, and industrial exposures have been implicated in the causation of lung and bladder cancer. Organochlorines (and halogenated organic compounds in general) are synthetic products that resist degradation and are lipophilic. Important organochlorines used http://ebooksmedicine.net Table 8.2 Human Diseases Associated With Occupational Exposures CardiovascularsystemHeartdiseaseCO,lead,solvents,cobalt,cadmium UrinarysystemToxicityMercury,lead,glycolethers,solventsBladdercancerNaphthylamines,4-aminobiphenyl,benzidine,rubberproducts HematopoieticsystemLeukemiaBenzene,radon,uranium


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Pathology_Robbins. UrinarysystemToxicityMercury,lead,glycolethers,solventsBladdercancerNaphthylamines,4-aminobiphenyl,benzidine,rubberproducts HematopoieticsystemLeukemiaBenzene,radon,uranium SkinFolliculitisandacneiformdermatosisPolychlorinatedbiphenyls,dioxins,herbicidesCancerUltravioletradiation CNS, Centralnervoussystem;CO, carbonmonoxide;DDT, dichlorodiphenyltrichloroethane;GI,gastrointestinal.DatafromLeighJP,MarkowitzSB,FahsM,etal:OccupationalinjuryandillnessintheUnitedStates:estimatesofcosts,morbidity,andmortality,Arch Intern Med 157:1557,1997;MitchellFL:Hazardouswaste.InRomWN,editor:Environmental and occupational medicine, ed2,Boston,1992,Little,Brown,pp1275;andLeviPE:Classesoftoxicchemicals.InHodgsonE,LeviPE,editors:A textbook of modern toxicology, Stamford,CT,1997,Appleton&Lange,pp229.


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Pathology_Robbins. as pesticides are DDT (dichlorodiphenyltrichloroethane) and its metabolites, and agents such as 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 population have detectable serum levels of p,p′DDE, a long-lasting DDT metabolite, including those born after the ban on DDT went into effect. PCB and TCDD also are present in the blood of most of the U.S. population. Acute DDT poisoning in humans causes neurologic toxicity. Most organochlorines are endocrine disruptors and have anti-estrogenic or anti-androgenic activity in laboratory animals, but long-term health effects in humans have not been firmly established.


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Pathology_Robbins. Nonpesticide organochlorines include polychlorinated biphenyls (PCBs) and dioxin (TCDD [2,3,7,8-tetrachlorodibenzo-p-dioxin]). Dioxins and PCBs can cause skin disorders such as folliculitis and acneiform dermatosis known as chloracne, which consists of acne, cyst formation, hyperpigmentation, and hyperkeratosis, generally around the face and behind the ears. It can be accompanied by abnormalities in the liver and CNS. Because PCBs induce the P-450 enzyme system, workers exposed to these substances may show altered drug metabolism. Environmental disasters in Japan and China in the late 1960s caused by the consumption of rice oil contaminated by PCBs poisoned about 2000 people in each episode. The primary manifestations of the disease (yusho in Japan, yu-cheng in China) were chloracne and hyperpigmentation of the skin and nails.


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Pathology_Robbins. Bisphenol A (BPA) is used in the synthesis of polycarbonate food and water containers and of epoxy resins that line almost all food bottles and cans; as a result, exposure to BPA is virtually ubiquitous in humans. BPA has long been known as a potential endocrine disruptor. Several large retrospective studies have linked elevated urinary BPA levels to heart disease in adult populations. In addition, infants who drink from BPA-containing containers may be particularly susceptible to BPA’s endocrine effects. In 2010, Canada was the first country to list BPA as a toxic substance, and the largest makers of baby bottles and “sippy” cups have stopped using BPA in the manufacturing process. The extent of the human health risks associated with BPA remains uncertain, however, and requires further study. Vinyl chloride, used in the synthesis of polyvinyl resins, can cause angiosarcoma of the liver, a rare type of liver tumor.


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Pathology_Robbins. Vinyl chloride, used in the synthesis of polyvinyl resins, can cause angiosarcoma of the liver, a rare type of liver tumor. Inhalation of mineral dusts causes chronic, nonneoplastic lung diseases called pneumoconioses. This group of disorders includes diseases induced by organic and inorganic particulates as well as chemical fume-and vapor-induced nonneoplastic lung diseases. The most common pneumoconioses are caused by exposures to coal dust (in mining of hard coal), silica (in sandblasting and stone cutting), asbestos (in mining, fabrication, and insulation work), and beryllium (in mining and fabrication). Exposure to these agents nearly always occurs in the workplace. The increased risk of cancer as a result of asbestos exposure, however, extends to family members of asbestos workers and to other persons exposed outside the workplace. Pneumoconioses and their pathogenesis are discussed in Chapter 13.


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Pathology_Robbins. Tobacco is the most common exogenous cause of human cancers, being responsible for 90% of lung cancers. The http://ebooksmedicine.net


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Pathology_Robbins. Fig. 8.6 Theeffectsofsmokingonsurvival.Thestudycomparedage-specificdeathratesforcurrentcigarettesmokerswiththoseofindividualswhoneversmokedregularly(BritishDoctorsStudy).Thedifferenceinsurvival,measuredatage75betweensmokersandnonsmokersis7.5years.(Modified from Stewart BW, Kleihues P, editors: Worldcancerreport,Lyon, 2003, IARC Press.) main culprit is cigarette smoking, but smokeless tobacco in its various forms (snuff, chewing tobacco) also is harmful to health and is an important cause of oral cancer. Not only does the use of tobacco products create personal risk, but also passive tobacco inhalation from the environment (“second-hand smoke”) can cause lung cancer in nonsmokers. From 1998 to 2007 in the United States, the incidence of smoking declined modestly, but this trend failed to continue, and approximately 20% of adults remain smokers. In recent years, China has become the world’s largest producer and consumer of cigarettes. China has approximately 350 million smokers who in


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Pathology_Robbins. continue, and approximately 20% of adults remain smokers. In recent years, China has become the world’s largest producer and consumer of cigarettes. China has approximately 350 million smokers who in aggregate consume about 33% of all cigarettes smoked worldwide. Cigarette smoking causes, worldwide, more than 4 million deaths annually, mostly from cardiovascular disease, various types of cancers, and chronic respiratory problems. It is expected that there will be 8 million tobacco-related deaths yearly by 2020, the major increase occurring in developing countries. Of people alive today, an estimated 500 million will die from tobacco-related illnesses. In the United States alone, tobacco is responsible for more than 400,000 deaths per year, with one-third of these attributable to lung cancer.


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Pathology_Robbins. Smoking is the most important cause of preventable human death. It reduces overall survival in a dose-dependent fashion. Whereas 80% of nonsmokers are alive at age 70, only about 50% of smokers survive to this age ( Fig. 8.6 ). Cessation of smoking greatly reduces the risk of death from lung cancer, and it even has an effect, albeit reduced, on people who stop smoking at age 60. Discussed Fig. 8.7 Adverseeffectsofsmoking.Themorecommonareinboldface.Cancer of oral cavity Cancer of larynx Cancer of esophagus Cancer of lung Myocardial infarction Peptic ulcer Cancer of pancreas Systemic atherosclerosis Chronic bronchitis, emphysema Cancer of bladder next are some of the agents contained in tobacco and diseases associated with tobacco consumption. Adverse effects of smoking in various organ systems are shown in Fig. 8.7 The number of potentially noxious chemicals in tobacco smoke is vast;


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Pathology_Robbins. Fig. 8.7 The number of potentially noxious chemicals in tobacco smoke is vast; Table 8.3 presents only a partial list and includes the type of injury produced by these agents. Nicotine, an alkaloid present in tobacco leaves, is not a direct cause of tobacco-related diseases, but it is highly addictive. Nicotine binds to receptors in the brain and, through the Table 8.3 Effects of Selected Tobacco Smoke Constituents NicotineGanglionicstimulationanddepression,tumorpromotion http://ebooksmedicine.net Table 8.4 Organ-Specific Carcinogens in Tobacco Smoke Lung,larynxPolycyclicaromatichydrocarbons4-(Methylnitrosoamino)-1-(3-pyridyl)1-butanone(NNK)210Polonium PancreasNNK(?) Bladder4-Aminobiphenyl,2-naphthylamine Oralcavity:smokingPolycyclicaromatichydrocarbons,NNK,NNN Oralcavity:snuffNNK,NNN,210polonium DatafromSzczesnyLB,HolbrookJH:Cigarettesmoking.InRomWH,editor:Environmental and occupational medicine, ed2,Boston,1992,Little,Brown,pp1211.


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Pathology_Robbins. Oralcavity:snuffNNK,NNN,210polonium DatafromSzczesnyLB,HolbrookJH:Cigarettesmoking.InRomWH,editor:Environmental and occupational medicine, ed2,Boston,1992,Little,Brown,pp1211. release of catecholamines, is responsible for the acute effects of smoking, such as increased heart rate and blood pressure, and increased cardiac contractility and output. The most common diseases caused by cigarette smoking involve the lung and include emphysema, chronic bronchitis, and lung cancer, all discussed in Chapter 13. The mechanisms responsible for some tobacco-induced diseases include the following: 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, increasing local elastase production and subsequent injury to lung tissue that leads to emphysema.


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Pathology_Robbins. Carcinogensis. Components of cigarette smoke, particularly polycyclic hydrocarbons and nitrosamines ( 8.4 ), are potent carcinogens in animals and probably are involved in the causation of lung carcinomas in humans (see Chapter 13). The risk of developing lung cancer is related to the intensity of exposure, frequently expressed in terms of “pack years” (e.g., one pack daily for 20 years equals 20 pack years) or in cigarettes smoked per day ( Fig. 8.8 ). In addition to lung cancers, tobacco smoke contributes to the development of cancers of the oral cavity, esophagus, pancreas, and bladder.


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Pathology_Robbins. Fig. 8.8 ). In addition to lung cancers, tobacco smoke contributes to the development of cancers of the oral cavity, esophagus, pancreas, and bladder. Table 8.4 lists organ-specific carcinogens contained in tobacco smoke. Moreover, smoking multiplies the risk of disease associated with other carcinogens; well-recognized examples are the 10-fold increased incidence of lung carcinomas in asbestos workers and uranium miners who smoke than in those who do not. The combination of tobacco (chewed or smoked) and alcohol consumption has multiplicative effects on the risks of oral, laryngeal, and esophageal cancers. An example of the carcinogenic interaction of these all-too-common vices is shown for laryngeal cancer ( Fig. 8.9


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Pathology_Robbins. Fig. 8.9 Atherosclerosis and its major complication, myocardial infarction, are strongly linked to cigarette smoking. The causal mechanisms probably relate to several factors, including increased platelet aggregation, decreased myocardial oxygen supply (because of lung disease coupled with hypoxia related to CO in cigarette smoke) accompanied by increased oxygen demand, and a decreased threshold for ventricular fibrillation. Almost one-third of all heart attacks are associated with cigarette smoking. Smoking has a multiplicative effect on risk when combined with hypertension and hypercholesterolemia. Maternal smoking increases the risk of spontaneous abortions and preterm births and results in intrauterine growth retardation (Chapter 7); however, birth weights of infants born to mothers who stopped smoking before pregnancy are normal.


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Pathology_Robbins. Fig. 8.8 Theriskoflungcancerisdeterminedbythenumberofcigarettessmoked.(Data from Stewart BW, Kleihues P, editors: Worldcancerreport,Lyon, 2003, IARC Press.)


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Pathology_Robbins. Fig. 8.9 Multiplicativeincreaseintheriskoflaryngealcancerfromtheinteractionbetweencigarettesmokingandalcoholconsumption.(Data from Stewart BW, Kleihues P, editors: Worldcancerreport, Lyon, 2003, IARC Press.) 0–40 http://ebooksmedicine.net • Passive smoke inhalation is also associated with detrimental effects. It is estimated that the relative risk of lung cancer in nonsmokers exposed to environmental smoke is about 1.3 times that in nonsmokers who are not exposed to smoke. In the United States, approximately 3000 lung cancer deaths in nonsmokers older than 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 30,000 to 60,000 cardiac deaths annually in the United States are associated with passive exposure to smoke. Children living in a household with an adult who smokes have an increased frequency of respiratory illnesses and asthma. Passive smoke


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Pathology_Robbins. the United States are associated with passive exposure to smoke. Children living in a household with an adult who smokes have an increased frequency of respiratory illnesses and asthma. Passive smoke inhalation in nonsmokers can be estimated by measuring the blood levels of cotinine, a metabolite of nicotine. In the United States, median cotinine levels in nonsmokers have decreased by more than 60% since around 2000 because of the adoption of nonsmoking policies in public places. However, passive exposure to tobacco smoke in the home remains a major public health concern, particularly for children. It is clear that the transient pleasure a puff may provide comes with a heavy long-term price.


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Pathology_Robbins. Maternalsmokingincreasestheriskofabortion,prematurebirth,andintrauterinegrowthretardation. Ethanol is consumed, at least partly, for its mood-altering properties, but when used in moderation its effects are socially acceptable and not injurious. When excessive amounts are used, alcohol can cause marked physical and psychologic damage. Here we describe the lesions that are directly associated with the abuse of alcohol.


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Pathology_Robbins. Despite all the attention given to illegal drugs, alcohol abuse is a more widespread hazard and claims many more lives. Fifty percent of adults in the Western world drink alcohol, and approximately 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. Almost 50% of these deaths result from accidents caused by drunken driving and alcohol-related homicides and suicides, and about 15% are a consequence of cirrhosis of the liver.


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Pathology_Robbins. After consumption, ethanol is absorbed unaltered in the stomach and small intestine and then distributes to all of 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 for 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 most states. For an average individual, this alcohol concentration may be reached after consumption of three standard drinks, about three (12 ounce) bottles of beer, 15 ounces of wine, or 4 to 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 develop tolerance to alcohol. They metabolize alcohol at a higher rate than normal and hence


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Pathology_Robbins. arrest, at higher levels. The rate of metabolism affects the blood alcohol level. Chronic alcoholics develop tolerance to alcohol. They metabolize alcohol at a higher rate than normal and hence show lower peak levels of alcohol than average for the same about of alcohol consumed. Most of the alcohol in the blood is metabolized to acetaldehyde in the liver by three enzyme systems: alcohol dehydrogenase; cytochrome P-450 isoenzymes; and catalase (


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Pathology_Robbins. Fig. 8.10 ). Of these, the main enzyme involved in alcohol metabolism is alcohol dehydrogenase, located in the cytosol of hepatocytes. At high blood alcohol levels, however, the microsomal ethanol-oxidizing system also plays an important role. This system involves cytochrome P-450 enzymes, particularly the CYP2E1 isoform, located in the smooth ER. Induction of P-450 enzymes by alcohol explains the increased susceptibility of alcoholics to other compounds metabolized by the same enzyme system, which include drugs (acetaminophen, cocaine), anesthetics, carcinogens, and industrial solvents. Of note, however, when alcohol is present in the blood at high concentrations, it competes with other CYP2E1 substrates and may delay the catabolism of other drugs, thereby potentiating their effects. Catalase is of minor importance, being responsible for only about 5% of alcohol metabolism. Acetaldehyde produced by these systems is in turn converted by acetaldehyde dehydrogenase to acetate, which is


Pathology_Robbins

Pathology_Robbins. is of minor importance, being responsible for only about 5% of alcohol metabolism. Acetaldehyde produced by these systems is in turn converted by acetaldehyde dehydrogenase to acetate, which is used in the mitochondrial respiratory chain.


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Pathology_Robbins. Several toxic effects result from ethanol metabolism. Listed here are only the most important of these: • Alcohol oxidation by alcohol dehydrogenase causes a decrease in nicotinamide adenine dinucleotide (NAD+) and an increase in NADH (the reduced form of NAD+). NAD+ is required for fatty acid oxidation in the liver. Its deficiency is a main cause of fat accumulation in the liver of alcoholics. The increase in the NADH/NAD+ ratio in alcoholics also causes lactic acidosis. http://ebooksmedicine.net CYP2E1ADHCATALASEMitochondriaMicrosom sCytosolP roxisom sH2O2 CH3CH2OH Ethanol NADPH + H+ NADP+, H2O NAD+ NADH + H+ NAD+ NADH + H+ + O2 CH3C Acetaldehyde Acetic acid H2O H2O O H CH3C O OH CH3CH OH OH ALDH


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Pathology_Robbins. Fig. 8.10 Metabolismofethanol:oxidationofethanoltoacetaldehydebythreedifferentroutes,andthegenerationofaceticacid.Notethatoxidationbyalcoholdehydrogenase(ADH)takesplaceinthecytosol;thecytochromeP-450systemanditsCYP2E1isoformarelocatedintheER(microsomes),andcatalaseislocatedinperoxisomes.Oxidationofacetaldehydebyaldehydedehydrogenase(ALDH)occursinmitochondria.(Data from Parkinson A: Biotransformation of xenobiotics. In Klassen CD, editor: CasarettandDoull’stoxicology:Thebasicscienceofpoisons,ed 6, New York, 2001, McGraw-Hill, pp 133.) Acetaldehyde toxicity may be responsible for some of the acute effects of alcohol. Acetaldehyde metabolism differs between populations because of genetic variation. Most notably, about 50% of Asians express a defective form of acetaldehyde dehydrogenase. After ingesting alcohol, such persons experience flushing, tachycardia, and hyperventilation owing to the accumulation of acetaldehyde.


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Pathology_Robbins. ROS generation. Metabolism of ethanol in the liver by CYP2E1 produces ROS and causes lipid peroxidation of cell membranes. Nevertheless, the precise mechanisms that account for alcohol-induced cellular injury have not been well defined. Endotoxin release. Alcohol may cause the release of endotoxin (lipopolysaccharide), a product of gram-negative bacteria, from the intestinal flora. Endotoxin stimulates the release of tumor necrosis factor (TNF) and other cytokines from circulating macrophages and from Kupffer cells in the liver, causing cell injury.


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Pathology_Robbins. Acute alcoholism exerts its effects mainly on the CNS but also may induce reversible hepatic and gastric injuries. Even with moderate intake of alcohol, multiple fat droplets accumulate in the cytoplasm of hepatocytes (fatty change or hepatic steatosis). Gastric damage occurs in the form of acute gastritis and ulceration. In the CNS, alcohol is a depressant, first affecting subcortical structures 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, GI tract, CNS, cardiovascular system, and pancreas.


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Pathology_Robbins. The liver is the main site of chronic injury. In addition to fatty change, mentioned earlier, chronic alcoholism causes alcoholic hepatitis and cirrhosis (described in Chapter 16). Cirrhosis is associated with portal hypertension and an increased risk of hepatocellular carcinoma. In the GI tract, chronic alcoholism can cause massive bleeding from gastritis, gastric ulcer, or esophageal varices (associated with cirrhosis), which may prove fatal. Neurologic effects. Thiamine deficiency is common in chronic alcoholics; the principal lesions resulting from this deficiency are peripheral neuropathies and the Wernicke-Korsakoff syndrome (see Table 8.9 and Chapter 23). Cerebral atrophy, cerebellar degeneration, and optic neuropathy may also occur. http://ebooksmedicine.net


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Pathology_Robbins. Table 8.9 and Chapter 23). Cerebral atrophy, cerebellar degeneration, and optic neuropathy may also occur. http://ebooksmedicine.net Cardiovascular effects. Alcohol has diverse effects on the cardiovascular system. Injury to the myocardium may produce dilated congestive cardiomyopathy (alcoholic cardiomyopathy), discussed in Chapter 11. Moderate amounts of alcohol (one drink per day) have been reported to increase serum levels of high-density lipoproteins (HDLs) and inhibit platelet aggregation, thus protecting against coronary artery disease. However, heavy consumption, with attendant liver injury, results in decreased levels of HDL, increasing the likelihood of heart disease. Chronic alcoholism also is associated with an increased incidence of hypertension. Pancreatitis. Excess alcohol intake increases the risk of acute and chronic pancreatitis (Chapter 16).


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Pathology_Robbins. Pancreatitis. Excess alcohol intake increases the risk of acute and chronic pancreatitis (Chapter 16). Effects on fetus. The use of ethanol during pregnancy— reportedly even in low amounts—can cause fetal alcohol syndrome. It consists of microcephaly, growth retardation and facial abnormalities in the newborn, and a reduction of mental functions in older children. It is difficult to establish the amount of alcohol consumption that can cause fetal alcohol syndrome, but consumption during the first trimester of pregnancy is particularly harmful. Carcinogenesis. Chronic alcohol consumption is associated with an increased incidence of cancers of the oral cavity, esophagus, liver, and, possibly, breast in females. The mechanisms of the carcinogenic effect are uncertain.


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Pathology_Robbins. Malnutrition. Ethanol is a substantial source of energy, but is often consumed at the expense of food (empty calories). Chronic alcoholism is thus associated with malnutrition and deficiencies, particularly of the B vitamins. Acutealcoholabusecausesdrowsinessatbloodlevelsofapproximately200mg/dL.Stuporandcomadevelopathigherlevels. Alcoholisoxidizedtoacetaldehydeintheliverprimarilybyalcoholdehydrogenase,andtoalesserextentbythecytochromeP-450system,andbycatalase.Acetaldehydeisconvertedtoacetateinmitochondriaandisusedintherespiratorychain. AlcoholoxidationbyalcoholdehydrogenasedepletesNAD,leadingtoaccumulationoffatintheliverandtometabolicacidosis. Themaineffectsofchronicalcoholismarefattyliver,alcoholichepatitis,andcirrhosis,whichleadstoportalhypertensionandincreasestheriskfordevelopmentofhepatocellularcarcinoma.


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Pathology_Robbins. Themaineffectsofchronicalcoholismarefattyliver,alcoholichepatitis,andcirrhosis,whichleadstoportalhypertensionandincreasestheriskfordevelopmentofhepatocellularcarcinoma. Chronicalcoholismcancausebleedingfromgastritisandgastriculcers,peripheralneuropathyassociatedwiththiaminedeficiency,andalcoholiccardiomyopathy,anditincreasestheriskfordevelopmentofacuteandchronicpancreatitis. Chronicalcoholismisamajorriskfactorforcancersoftheoralcavity,larynx,andesophagus.Theriskisgreatlyincreasedbyconcurrentsmokingortheuseofsmokelesstobacco. InjurybyTherapeuticDrugs:AdverseDrugReactions Adverse drug reactions (ADRs) are untoward effects of drugs that are administered in conventional therapeutic settings. These reactions are extremely common in the practice of medicine and are believed to affect 7% to 8% of patients admitted to a hospital. About 10% of such reactions prove fatal.


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Pathology_Robbins. Table 8.5 lists common pathologic findings in ADRs and the drugs most frequently involved. As can be seen, many of the drugs involved in ADRs, such as the anti-neoplastic agents, are highly potent, and the ADR is a calculated risk for the dosage assumed to achieve the maximum therapeutic effect. Commonly used drugs such as long-acting tetracyclines, which are used to treat diverse conditions, including acne, may produce localized or systemic reactions ( Fig. 8.11 ). Because they are widely used, estrogens and oral contraceptives (OCs) are discussed next in more detail. In addition, acetaminophen and aspirin, which are nonprescription drugs but are important


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Pathology_Robbins. Fig. 8.11 Adversereactiontominocycline,along-actingtetracyclinederiva-tive.(A)Diffuseblue-graypigmentationoftheforearm,secondarytomino-cyclineadministration.(B)Depositionofdrugmetabolite/iron/melaninpigmentparticlesinthedermis.(A and B, Courtesy of Dr. Zsolt Argenyi, Depart-ment of Pathology,University of Washington,Seattle,Washington.) http://ebooksmedicine.net Table 8.5 Some Common Adverse Drug Reactions and Their Agents Granulocytopenia,aplasticanemia,pancytopeniaAnti-neoplasticagents,immunosuppressives,andchloramphenicol Hemolyticanemia,thrombocytopeniaPenicillin,methyldopa,quinidine Urticaria,macules,papules,vesicles,petechiae,exfoliativedermatitis,fixedAnti-neoplasticagents,sulfonamides,hydantoins,someantibiotics,anddrugeruptions,abnormalpigmentationmanyotheragents ArrhythmiasTheophylline,hydantoins CardiomyopathyDoxorubicin,daunorubicin AcutetubularnecrosisAminoglycosideantibiotics,cyclosporine,amphotericinB


Pathology_Robbins

Pathology_Robbins. ArrhythmiasTheophylline,hydantoins CardiomyopathyDoxorubicin,daunorubicin AcutetubularnecrosisAminoglycosideantibiotics,cyclosporine,amphotericinB TubulointerstitialdiseasewithpapillarynecrosisPhenacetin,salicylates InterstitialfibrosisBusulfan,nitrofurantoin,bleomycin DiffusehepatocellulardamageHalothane,isoniazid,acetaminophen CholestasisChlorpromazine,estrogens,contraceptiveagents Lupuserythematosussyndrome(drug-inducedlupus)Hydralazine,procainamide *Featureinalmosthalfofalldrug-relateddeaths. causes of accidental or intentional overdose, merit special comment.


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Pathology_Robbins. The most common type of MHT (previously referred to as hormone replacement therapy, or HRT) consists of the administration of estrogens together with a progestogen. Because of the risk of uterine cancer, estrogen therapy alone is used only in hysterectomized women. Initially used to counteract “hot flashes” and other symptoms of menopause, early clinical studies suggested that MHT use in postmenopausal women could prevent or slow the progression of osteoporosis (Chapter 21) and reduce the likelihood of myocardial infarction. However, subsequent randomized clinical trials have produced decidedly mixed results. According to these, although MHT did reduce the number of fractures in women on treatment, it was also reported that after 5 years of treatment, combination MHT increased the risk of breast cancer (Chapter 19), stroke, and venous thromboembolism and had no effect on the incidence of coronary heart disease. But during the past few years there has been a reappraisal of the risks


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Pathology_Robbins. of breast cancer (Chapter 19), stroke, and venous thromboembolism and had no effect on the incidence of coronary heart disease. But during the past few years there has been a reappraisal of the risks and benefits of MHT. These newer analyses showed that MHT effects depend on the type of hormone therapy regimen used (combination estrogen-progestin versus estrogen alone), the age and risk factor status of the woman at the start of treatment, the duration of the treatment, and possibly the hormone dose, formulation, and route of administration. The current risk:benefit consensus can be summarized as follows:


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Pathology_Robbins. Combination estrogen-progestin increases the risk of breast cancer after a median time of 5 to 6 years. In contrast, estrogen alone in women with hysterectomy is associated with a borderline reduction in the risk of breast cancer. MHT may have a protective effect on the development of atherosclerosis and coronary disease in women younger than 60 years of age, but there is no protection in women who started MHT at an older age. These data support the notion that there may be a critical therapeutic window for MHT effects on the cardiovascular system. Protective effects in younger women depend in part on the response of estrogen receptors in healthy vascular endothelium. However, MHT should not be used for the http://ebooksmedicine.net prevention of cardiovascular disease or other chronic diseases.


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Pathology_Robbins. • MHT increases the risk of stroke and venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. The increase in VTE 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). Whether risks of VTE and stroke are lower with transdermal than oral routes of estrogen administration warrants further study. As can be appreciated from these associations, assessment of risks and benefits when considering the use of MHT in women is complex. The current feeling is that these agents have a role in the management of menopausal symptoms in early menopause but should not be used long term for chronic disease prevention.


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Pathology_Robbins. Although OCs have been used for several decades, disagreement continues about their safety and adverse effects. They nearly always contain a synthetic estradiol and a variable amount of a progestin (“combination OCs”), but a few preparations contain only progestins. Currently prescribed OCs contain a smaller amount of estrogens (less than 50 µg/day) and clearly have fewer side effects than those reported for earlier formulations. Hence, the results of epidemiologic studies must be interpreted in the context of the dosage. Nevertheless, there is reasonable evidence to support the following conclusions: Breast carcinoma: The prevailing opinion is that OCs do not cause an increase in breast cancer risk. Endometrial cancer and ovarian cancers: OCs have a protective effect against these tumors. Cervical cancer: OCs may increase the risk of cervical carcinomas in women infected with human papillomavirus.


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Pathology_Robbins. Cervical cancer: OCs may increase the risk of cervical carcinomas in women infected with human papillomavirus. Thromboembolism: Most studies indicate that OCs, including the newer low-dose (less than 50 µg of estrogen) preparations, are associated with a threefold to sixfold increased risk of venous thrombosis and pulmonary thromboembolism resulting from increased hepatic synthesis of coagulation factors. This risk may be even higher with newer “third-generation” OCs that contain synthetic progestins, particularly in women who are carriers of the factor V Leiden mutation. To put this complication into context, however, the risk of thromboembolism associated with OC use is two to six times lower than the risk of thromboembolism associated with pregnancy.


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Pathology_Robbins. Cardiovascular disease: There is considerable uncertainty about the risk of atherosclerosis and myocardial infarction in users of OCs. It seems that OCs do not increase the risk of coronary artery disease in women younger than 30 years or in older women who are nonsmokers, but the risk approximately doubles in women older than 35 years who smoke. Hepatic adenoma: There is a well-defined association between the use of OCs and this rare benign hepatic tumor, especially in older women who have used OCs for prolonged periods (Chapter 14). Obviously, the pros and cons of OCs must be viewed in the context of their wide applicability and acceptance as a form of contraception that protects against unwanted pregnancies.


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Pathology_Robbins. At therapeutic doses, acetaminophen, a widely used nonprescription analgesic and anti-pyretic, is mostly conjugated in the liver with glucuronide or sulfate. About 5% or less is metabolized to NAPQI (N-acetyl-p-benzoquinoneimine) through the hepatic P-450 system. With very large doses, however, NAPQI accumulates, leading to centriloblar hepatic necrosis. The mechanisms of injury produced by NAPQI include (1) covalent binding to hepatic proteins and (2) depletion of reduced GSH. The depletion of GSH makes the hepatocytes more susceptible to cell death caused by ROS. The window between the usual therapeutic dose (0.5 g) and the toxic dose (15 to 25 g) is large, and the drug ordinarily is very safe. Nevertheless, accidental overdoses occur in children, and suicide attempts using acetaminophen are not uncommon, particularly in the United Kingdom. In the United States, acetaminophen toxicity is causes about 50% of acute liver failure. Toxicity begins with nausea, vomiting, diarrhea, and


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Pathology_Robbins. are not uncommon, particularly in the United Kingdom. In the United States, acetaminophen toxicity is causes about 50% of acute liver failure. Toxicity begins with nausea, vomiting, diarrhea, and sometimes shock, followed in a few days by the appearance of jaundice. Overdoses of acetaminophen can be treated in early stages by the administration of N-acetylcysteine, which restores GSH. With serious overdoses, liver failure ensues, and centrilobular necrosis may extend to involve entire lobules; such patients often require liver transplantation. Some patients also show evidence of concurrent renal damage.


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Pathology_Robbins. Aspirin overdose may result from accidental ingestion in young children or suicide attempts in adults. The major untoward consequences are metabolic, with few morphologic changes. At first, respiratory alkalosis develops, followed by a metabolic acidosis that often proves fatal. Fatal doses may be as little as 2 to 4 g in children and 10 to 30 g in adults, but survival has been reported after doses five times larger.


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Pathology_Robbins. Chronic aspirin toxicity (salicylism) may develop in persons who take 3 gm or more daily (the dose used to treat chronic inflammatory conditions). Chronic salicylism is manifested by headache, dizziness, ringing in the ears (tinnitus), difficulty in hearing, 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 15), which may produce overt or covert GI bleeding and lead to gastric ulceration. A bleeding tendency may appear concurrently with chronic toxicity because aspirin irreversibly inhibits platelet cyclooxygenase and blocks the ability to make thromboxane A2, an activator of platelet aggregation (Chapter 4). Petechial hemorrhages may appear in the skin and internal viscera, and bleeding from gastric ulcerations may be exaggerated.


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Pathology_Robbins. Proprietary analgesic mixtures of aspirin and phenacetin or its active metabolite, acetaminophen, when taken throughout several years, can cause tubulointerstitial http://ebooksmedicine.net Table 8.6 Common Drugs of Abuse OpioidnarcoticsMuopioidreceptor(agonist)Heroin,hydromorphone(Dilaudid)OxycodoneMethadone(Dolophine) Phencyclidine-likedrugsNMDAglutamatereceptorchannel(antagonist)Phencyclidine(PCP)(i.e.,“angeldust”)Ketamine CB1, Cannabinoidreceptortype1;GABA, γ-aminobutyricacid;5-HT2, 5-hydroxytryptamine;NMDA, N-methyl-D-aspartate;PCP, 1-(1-phenylcyclohexyl)piperidine.DatafromHymanSE:A28-year-oldmanaddictedtococaine,JAMA 286:2586,2001. nephritis with renal papillary necrosis. This clinical entity is referred to as analgesic nephropathy (Chapter 14). 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


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Pathology_Robbins. Table 8.6 . Considered here are cocaine, opiates, and marijuana, with a brief mention of a few other drugs. In 2014, it was estimated that there were 1.5 million users of cocaine in the United States, of which approximately 15% to 20% were users of “crack” cocaine. Use is highest among adults 18 to 25 years of age, of whom 1.4% reported taking cocaine within the past month. Extracted from the leaves of the coca plant, cocaine usually is prepared as a water-soluble powder, cocaine hydrochloride, but when sold on the street it is liberally diluted with talcum powder, lactose, or other look-alikes. Crystallization of the pure alkaloid from cocaine hydrochloride yields nuggets of crack (so called because of the popping sound it makes when heated). The pharmacologic actions of cocaine and crack are identical, but crack is far more potent. Both forms can be snorted, smoked after mixing with tobacco, ingested, or injected subcutaneously or intravenously.


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Pathology_Robbins. Cocaine produces a sense of intense euphoria and mental alertness, making it one of the most addictive of all drugs. Experimental animals will press a lever more than 1000 times and will forgo food and drink to obtain the drug. In cocaine users, although physical dependence seems not to occur, the psychologic dependence is profound. Intense cravings are particularly severe in the first several months after abstinence and can recur for years. Acute overdose produces seizures, cardiac arrhythmias, and respiratory arrest. The following are the important manifestations of cocaine toxicity: Cardiovascular effects. The most serious physical effects of cocaine relate to its acute action on the cardiovascular system. Cocaine is a sympathomimetic agent (


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Pathology_Robbins. Fig. 8.12 ), 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 neurotransmitters in synapses and excessive stimulation, manifested by tachycardia, hypertension, and peripheral vasoconstriction. Cocaine also induces myocardial ischemia, the basis for which is multifactorial. It causes coronary artery vasoconstriction and promotes thrombus formation by facilitating platelet aggregation. Cigarette smoking potentiates cocaine-induced coronary vasospasm. Thus, by increasing myocardial oxygen demand by its sympathomimetic action and, at the same time, reducing coronary blood flow, cocaine often triggers myocardial ischemia, which may lead to myocardial infarction. Cocaine also can precipitate lethal arrhythmias by enhanced sympathetic activity as well as by disrupting normal ion


Pathology_Robbins

Pathology_Robbins. often triggers myocardial ischemia, which may lead to myocardial infarction. Cocaine also can 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.


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Pathology_Robbins. CNS effects. The most common CNS findings are hyperpyrexia (thought to be caused by aberrations of the dopaminergic pathways that control body temperature) and seizures. Effects on the fetus. 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 fetuses of pregnant women who are chronic drug users. http://ebooksmedicine.net Euphoria, paranoia, hyperthermia DopaminePresynaptic axon Postsynaptic dendrite


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Pathology_Robbins. http://ebooksmedicine.net Euphoria, paranoia, hyperthermia DopaminePresynaptic axon Postsynaptic dendrite Fig. 8.12 Theeffectofcocaineonneurotransmission.Thedruginhibitsreuptakeoftheneurotransmittersdopamineandnorepinephrineinthecentralandperipheralnervoussystems.Hypertension, cardiac arrhythmia, myocardial infarct, cerebral hemorrhage, and infarct Norepinephrine • Chronic cocaine use. Chronic use may cause (1) perforation of the nasal septum in snorters, (2) decrease in lung diffusing capacity in users who inhale the smoke, and (3) the development of dilated cardiomyopathy.


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Pathology_Robbins. Heroin is an addictive opioid derived from the poppy plant and is closely related to morphine. Its effects are even more harmful than those of cocaine. Nevertheless, it is estimated that almost 4 million people in the United States have used heroin at least once, and that in 2012 more than 650,000 people used the drug at some time during the year. As sold on the street, it is cut (diluted) with an agent (often talc or quinine); thus, the size of the dose not only is variable but also usually is unknown to the buyer. Heroin, along with any contaminating substances, usually is self-administered intravenously or subcutaneously. Effects are varied and include euphoria, hallucinations, somnolence, and sedation. Heroin has a wide range of adverse physical effects that can be categorized etiologically according 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, and (4) diseases


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Pathology_Robbins. according 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, and (4) diseases contracted through the sharing of needles. Some of the most important adverse effects of heroin are the following:


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Pathology_Robbins. Sudden death. Sudden death, usually related to overdose, is an ever-present risk, because drug purity generally is unknown and may range from 2% to 90%. The yearly incidence of sudden death among chronic users in the United States is estimated to be between 1% and 3%. Sudden death sometimes is due to a loss of tolerance for the drug, such as after a period of incarceration. The mechanisms of death include profound respiratory depression, arrhythmia and cardiac arrest, and pulmonary edema. Pulmonary disease. Pulmonary complications include edema, septic embolism, lung abscess, opportunistic infections, and foreign body granulomas from talc and other adulterants. Although granulomas occur principally in the lung, they also are sometimes found 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.


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Pathology_Robbins. Infections. Infectious complications are common. The 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 Staphylococcus aureus, but fungi and a multitude of other organisms have also been implicated. Viral hepatitis is the most common infection among addicts and is acquired by the sharing of dirty needles. In the United States, this practice has also led to a very high incidence of human immunodeficiency virus (HIV) infection in intravenous drug abusers.


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Pathology_Robbins. Skin lesions. Cutaneous lesions probably are the most frequent telltale sign of heroin addiction. Acute changes include abscesses, cellulitis, and ulcerations resulting from 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.


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Pathology_Robbins. Tragically, more widespread availability of prescription opiates, such as hydrocodone and oxycodone, has fueled an epidemic of opioid abuse that surpasses that associated with heroin. In 2014, it was estimated that 4.3 million Americans engaged in non-medical use of prescription opioids, and that prescription opioid overdoses led to approximately 19,000 deaths, mainly from respiratory failure. Moreover, an increasing number of heroin users start with prescription opioids, then switch to heroin because it is a substantially less expensive habit. This trend underlies a near doubling of heroin use in the United States between 2005 and 2012. Current efforts are focused on making opioid antagonists widely available to first responders, which has prevented many deaths, and tightening the use of prescription opioids to limit their potential for abuse. http://ebooksmedicine.net


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Pathology_Robbins. http://ebooksmedicine.net Marijuana, or “pot,” is the most widely used illegal drug. As of 2014 in the United States, 22.2 million people (7.0% of the population) admitted use during the previous month. Several states in the United States have legalized the “recreational” use of marijuana, and more states appear poised to follow; thus, its status as an illicit drug is undergoing reevaluation.


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Pathology_Robbins. Marijuana is made from the leaves of the Cannabis sativa plant, which contain the psychoactive substance Δ9tetrahydrocannabinol (THC). When marijuana is smoked, about 5% to 10% of the THC content is absorbed. Despite numerous studies, whether the drug includes persistent adverse physical and functional effects remains unresolved. Some of the untoward anecdotal effects may be allergic or idiosyncratic reactions or are possibly related to contaminants in the preparations, rather than to marijuana’s pharmacologic effects. On the other hand, beneficial effects of THC include its capacity to decrease intraocular pressure in glaucoma and to combat intractable nausea secondary to cancer chemotherapy.


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Pathology_Robbins. The functional and organic CNS consequences of marijuana have received great scrutiny. Marijuana use is well recognized to distort sensory perception and impair 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 the inability to judge time, speed, and distance. Among adolescents, such impairment often leads to automobile accidents. Marijuana increases the heart rate and sometimes blood pressure and it may cause angina in a person with coronary artery disease.


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Pathology_Robbins. The lungs are affected by chronic marijuana smoking; laryngitis, pharyngitis, bronchitis, cough, hoarseness, and asthmalike symptoms all have been described, along with mild but significant airway obstruction. Smoking a marijuana cigarette, compared with a tobacco cigarette, is associated with a 3-fold increase in the amount of tar inhaled and retained in the lungs, as a consequence of deeper inhalation and longer breath holding.


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Pathology_Robbins. The variety of drugs that have been tried by those seeking “new experiences” (highs, lows, “out-of-body experiences”) defies belief. These drugs include various stimulants, depressants, analgesics, and hallucinogens. Among these are PCP (1-(1-phenylcyclohexyl) piperidine), or phencyclidine, and ketamine (related anesthetic agents); lysergic acid diethylamide (LSD), the most potent hallucinogen known; “ecstasy” (3,4-methylenedioxymethamphetamine [MDMA]); and “bath salts”, synthetic cathinones that are chemically related to khat, a widely used stimulant in East Africa. Not much is known about the long-term deleterious effects of any of these agents. Acutely, LSD has unpredictable effects on mood, affect, and thought, sometimes leading to bizarre and dangerous behaviors. Chronic use of ecstasy may deplete the CNS of serotonin, potentially leading to sleep disorders, depression, anxiety, and aggressive behavior.


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Pathology_Robbins. 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 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 23). 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 ( Fig. 8.13


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Pathology_Robbins. http://ebooksmedicine.net Fig. 8.13 (A)Lacerationofthescalp:Thebridgingstrandsoffibroustissuesareevident.(B)Contusionresultingfromblunttrauma.Theskinisintact,buthemorrhageofsubcutaneousvesselshasproducedextensivediscoloration.(A and B, From the teaching collection of the Department of Pathology, University of Texas Southwestern Medical School, Dallas,Texas.)


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Pathology_Robbins. Both excess heat and excess cold are important causes of injury. Burns are all too common and are discussed first; a brief discussion of hyperthermia and hypothermia follows. In the United States, burns cause 3500 deaths per year and result in the hospitalization of more than 10 times that many persons. Many victims are children, in whom the cause of injury often is scalding by hot liquids. Fortunately, since the 1970s marked decreases have been seen in both mortality rates and the length of hospitalizations. These improvements have been achieved through better understanding of the systemic effects of massive burns and the discovery of better ways to prevent wound infection and to facilitate the healing of skin surfaces. The clinical severity of burns depends on the following important variables: Percentage of body surface involved Whether internal injuries from the inhalation of hot and toxic fumes are present


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Pathology_Robbins. The clinical severity of burns depends on the following important variables: Percentage of body surface involved Whether internal injuries from the inhalation of hot and toxic fumes are present Promptness and efficacy of therapy, especially fluid and electrolyte management and prevention or control of wound infections A full-thickness burn produces total destruction of the epidermis and dermis, including the dermal appendages that harbor cells needed for epithelial regeneration. Both thirdand fourth-degree burns are in this category. In partial-thickness burns, at least the deeper portions of the dermal appendages are spared. Partial-thickness burns include first-degree burns (epithelial involvement only) and second-degree burns (involving both the epidermis and the superficial dermis).


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Pathology_Robbins. Organ system failure resultingfromsepsis continuestobetheleadingcauseofdeathinburnedpatients.Theburnsiteisidealforthegrowthofmicroorganisms;theserumanddebrisprovidenutrients,andtheburninjurycompromisesbloodflow,blockingeffectiveinflammatoryresponses.ThemostcommonoffenderistheopportunistPseudomonas aeruginosa, butantibiotic-resistantstrainsofothercommonhospital-acquiredbacteria,suchasS. aureus andfungi,particularlyCandida spp.,alsomaybeinvolved.Furthermore,cellularandhumoraldefensesagainstinfectionsarecompromised,andbothlymphocyteandphagocytefunctionsareimpaired.Directbacteremicspreadandreleaseoftoxicsubstancessuchasendotoxinfromthelocalsitehavedireconsequences.Pneumonia orseptic shock, accompaniedbyrenal failure and/ortheacuterespiratorydistresssyndrome(ARDS)(Chapter13),arethemostcommonserioussequelae.


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Pathology_Robbins. Anotherveryimportantpathophysiologiceffectofburnsisthedevelopmentofahypermetabolicstate,withexcessheatlossandanincreasedneedfornutritionalsupport.Itisestimatedthatwhenmorethan40%ofthebodysurfaceisburned,therestingmetabolicratemayapproachtwicenormal. Prolonged exposure to elevated ambient temperatures can result in heat cramps, heat exhaustion, or heat stroke. Heat cramps result from loss of electrolytes through sweating. Cramping of voluntary muscles, usually in association with vigorous exercise, is the hallmark sign. 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 reestablished if the victim is able to rehydrate.


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Pathology_Robbins. Heat stroke is associated with high ambient temperatures and high humidity. Thermoregulatory mechanisms fail, sweating ceases, and core body temperature rises. In the clinical setting, a rectal temperature of 106°F or higher is considered a grave prognostic sign, and the mortality rate for such patients exceeds 50%. The underlying mechanism is marked generalized peripheral vasodilation with peripheral pooling of blood and a decreased effective circulating blood volume. Necrosis of the muscles and myocardium may occur. Arrhythmias, disseminated intravascular coagulation, and other systemic effects are common. Elderly people, persons with cardiovascular disease, and otherwise healthy people undergoing physical stress (such as young athletes and military recruits) are prime candidates for heat stroke.


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Pathology_Robbins. • Malignant hyperthermia, although similar sounding, is not caused by exposure to high temperatures. It is a genetic condition resulting from mutations in genes such as RYR1 that control calcium levels in skeletal muscle cells. In affected individuals, exposure to certain anesthetics during surgery may trigger a rapid rise in calcium levels in skeletal muscle, which in turn leads to muscle rigidity and increased heat production. The resulting hyperthermia has a mortality rate of approximately 80% if untreated, but this falls to less than 5% if the condition is recognized and muscle relaxants are administered promptly.


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Pathology_Robbins. Prolonged exposure to low ambient temperature leads to hypothermia. The condition is seen all too frequently in homeless alcoholics, in whom wet or inadequate clothing and dilation of superficial blood vessels, occurring as a result of the ingestion of alcohol, hasten the lowering of body temperature. At about 90°F, loss of consciousness occurs, followed by bradycardia and atrial fibrillation at lower core temperatures. Chilling or freezing of cells and tissues causes injury by two mechanisms: Direct effects probably are mediated by physical disruptions within cells and high salt concentrations incident to the crystallization of the intra-and extracellular water.


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Pathology_Robbins. Indirect effects are the result of circulatory changes, which vary depending on the rate and the duration of the temperature drop. Slowly developing, prolonged chilling may induce vasoconstriction and increased permeability, leading to edema. Such changes are typical of “trench foot.” This condition developed in soldiers who spent long periods of time in waterlogged trenches during the First World War (1914–1918), frequently causing gangrene that necessitated amputation. Alternatively, with sudden sharp drops in temperature, 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 only become evident with rewarming. If the period of ischemia is prolonged, hypoxic changes and infarction of the affected tissues (e.g., gangrene of toes or feet) may result.


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Pathology_Robbins. Electrical injuries, which may be fatal, can arise from low-voltage currents (i.e., in the home and workplace) or from high-voltage currents carried in power lines or by 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 burning depend on the amperage of the electric current and its path within the body. http://ebooksmedicine.net


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Pathology_Robbins. Voltage in the household and the 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 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 injuries are more likely to produce paralysis of medullary centers


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Pathology_Robbins. Currents generated from high-voltage sources cause similar damage; however, because of the large current flows generated, these injuries are more likely to produce paralysis of medullary centers and extensive burns. Lightning is a classic cause of high-voltage electrical injury.


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Pathology_Robbins. Radiation is energy that travels in the form of waves or high-speed particles. It has a wide range of energies that span the electromagnetic spectrum; it can be divided into nonionizing and ionizing radiation. The energy of nonionizing radiation, such as ultraviolet (UV) and infrared light, microwaves, and sound waves, can move atoms in a molecule or cause them to vibrate but is not sufficient to displace electrons from atoms. By contrast, ionizing radiation has sufficient energy to remove tightly bound electrons. Collision of these free electrons with other atoms releases additional electrons, in a reaction cascade referred to as ionization. The main sources of ionizing radiation are (1) x-rays and gamma rays, which are electromagnetic waves of very high frequencies, and (2) 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


Pathology_Robbins

Pathology_Robbins. 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. Some of the total dose of ionizing radiation received by the U.S. population is human-made, mostly originating from medical devices and radioisotopes. In fact, the exposure of patients to ionizing radiation during radiologic imaging tests roughly doubled between the early 1980s and 2006, mainly because of much more widespread use of CT scans.


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Pathology_Robbins. Ionizing radiation is indispensable in medical practice, but this application constitutes a two-edged sword. Radiation in this form is used in the treatment of cancer, in diagnostic imaging, and as therapeutic or diagnostic radioisotopes. However, it also is mutagenic, carcinogenic, and teratogenic. The following terms are used to express exposure, absorption, and dose of ionizing radiation: • Curie (Ci) represents the disintegrations per second of a spontaneously disintegrating radionuclide (radioisotope). One Ci is equal to 3.7 × 1010 disintegrations per second. Gray (Gy) is a unit that expresses the energy absorbed by a target tissue. It corresponds to the absorption of 104 ergs per gram of tissue. A centigray (cGy), which is the absorption of 100 ergs per gram of tissue, is equivalent to the exposure of tissue to 100 rads (R) (“radiation absorbed dose”). The cGy nomenclature has now replaced the rad in medical parlance.


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Pathology_Robbins. 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 the 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 provides a uniform measuring unit. 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, and the duration of the exposure, as well as other biologic factors (discussed next). The effective dose of x-rays, computed tomography (CT), and other imaging and nuclear medicine procedures are commonly expressed in millisieverts (mSv). For x-radiation, 1 mSv = 1 mGy. Main Determinants of the Biologic Effects of Ionizing Radiation


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Pathology_Robbins. 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 variables: Rate of delivery. The rate of delivery significantly modifies the biologic effect. Although the effect of radiant energy is cumulative, delivery in divided doses may allow cells to repair some of the damage in the intervals. Thus, fractional doses of radiant energy have a cumulative effect only to the extent that repair during the intervals is incomplete. Radiotherapy of tumors exploits the capability of normal cells to repair themselves and to recover more rapidly than tumor cells. 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 they are delivered to small, carefully shielded fields, whereas smaller doses delivered to larger fields may be lethal.


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Pathology_Robbins. Cell proliferation. Because ionizing radiation damages DNA, rapidly dividing cells are more vulnerable to injury than are quiescent cells. Except at extremely high doses that impair DNA transcription, DNA damage is compatible with survival in nondividing cells, such as neurons and muscle cells. However, as discussed in Chapter 6, in dividing cells DNA damage is detected by sensors that produce signals leading to the upregulation of p53, the “guardian of the genome.” p53 in turn upregulates the expression of genes that initially lead to cell-cycle arrest and, if the DNA damage is too great to repair, genes that cause cell death through apoptosis. Understandably, therefore, tissues with a high rate of cell turnover, such as gonads, bone marrow, lymphoid tissue, and the mucosa of the GI tract, are extremely vulnerable to radiation, and the injury is manifested early after exposure. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Hypoxia. The production of ROS by the radiolysis of water is the most important mechanism of DNA damage by ionizing radiation. Tissue hypoxia, such as may exist in the center of rapidly growing, poorly vascularized tumors, may thus reduce the extent of damage and the effectiveness of radiotherapy directed against tumors. Vascular damage. Damage to endothelial cells, which are moderately sensitive to radiation, may cause narrowing or occlusion of blood vessels, leading to impaired healing, fibrosis, and chronic ischemic atrophy. These changes may appear months or years after exposure. Despite the low sensitivity of brain cells to radiation, vascular damage after irradiation can lead to late manifestations of radiation injury in this tissue. The most important cellular target of ionizing radiation is DNA (


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Pathology_Robbins. Fig. 8.14 ). Damage to DNA caused by ionizing radiation that is not precisely repaired leads to mutations, which can manifest years or decades later as cancer. Ionizing radiation can cause many types of damage in DNA, including single-base damage, singleand double-strand breaks, and crosslinks between DNA and protein. In surviving cells, simple defects may be reparable by various enzyme repair systems contained in mammalian cells (see Chapter 6). These repair systems are linked to cell-cycle regulation through proteins such as ATM (ataxia-telangiectasia mutated) that initiate signal transduction after the damage, and p53, which can transiently arrest the cell cycle to allow for DNA repair or to trigger apoptosis of cells that are irreparable. However, double-strand breaks may persist without repair, or the repair of lesions may be imprecise (error prone), creating mutations. If cell-cycle checkpoints are not functioning (for instance, because of mutations in TP53), cells with abnormal


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Pathology_Robbins. repair, or the repair of lesions may be imprecise (error prone), creating mutations. If cell-cycle checkpoints are not functioning (for instance, because of mutations in TP53), cells with abnormal and unstable genomes survive


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Pathology_Robbins. Inhibition of Failed or Additional cell division aberrant repair transforming Fetus or germ cells: teratogenesis Carcinogenesis events Cell death Fig. 8.14 EffectsofionizingradiationonDNAandtheirconsequences.TheeffectsonDNAcanbedirector,mostimportant,indirect,throughfreeradicalformation. and may expand as abnormal clones to form tumors eventually. A common consequence of cancer radiotherapy is the development of fibrosis in the irradiated field ( Fig. 8.15 ). Fibrosis may occur weeks or months after irradiation, leading to the replacement of dead parenchymal cells by connective tissue and the formation of scars and adhesions (see Chapter 3). As already mentioned, ionizing radiation causes vascular damage and consequent tissue ischemia. Vascular damage, the killing of tissue stem cells by ionizing radiation, and the release of cytokines and chemokines that promote an inflammatory reaction all contribute to fibroblast activation and the development of radiation-induced fibrosis.


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Pathology_Robbins. Fig. 8.15 Vascularchangesandfibrosisofsalivaryglandsproducedbyradiationtherapyoftheneckregion.(A)Normalsalivarygland;(B)fibrosiscausedbyradiation;(C)fibrosisandvascularchangesconsistingoffibrointimalthickeningandarteriolarsclerosis.V, Vessellumen;I, thickenedintima.(A–C, Courtesy of Dr. Melissa Upton,Department of Pathology,University of Washington,Seattle,Washington.) http://ebooksmedicine.net BRAIN • Adult – resistant SKIN • Atrophy, cancerGONADS MARROW • Granulocytopenia • Anemia • Lymphopenia Fig. 8.16 Overviewofthemajormorphologicconsequencesofradiationinjury.Earlychangesoccurinhourstoweeks;latechangesoccurinmonthstoyears.ARDS, Acuterespiratorydistresssyndrome.


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Pathology_Robbins. Fig. 8.16 depicts the main consequences of radiation injury. As already mentioned, the most sensitive organs and tissues are the gonads, the hematopoietic and lymphoid systems, and the lining of the GI tract. Estimated threshold doses for the effects of acute exposure to radiation in various organs are shown in Table 8.7 . The changes in the hematopoietic and lymphoid systems, along with cancers induced by environmental or occupational exposure to ionizing radiation, are summarized as follows: • Hematopoietic and lymphoid systems. The hematopoietic and lymphoid systems are extremely susceptible to radiation injury and deserve special mention. With high Embryonic – destruction of neurons and glial cells (weeks to months) Erythema, edema (early) Dyspigmentation (weeks to months) (months to years) Interstitial fibrosis (months to years) Fibrosis of wall (late) Atrophy and fibrosis of gonads (late)


Pathology_Robbins

Pathology_Robbins. Erythema, edema (early) Dyspigmentation (weeks to months) (months to years) Interstitial fibrosis (months to years) Fibrosis of wall (late) Atrophy and fibrosis of gonads (late) Table 8.7 Estimated Threshold Doses for Acute Radiation Effects on Specific Organs 0.15 0.50 Reversibleskineffects(e.g.,Skin1.0–2.0erythema) PermanentsterilityOvaries2.5–6.0


Pathology_Robbins

Pathology_Robbins. TemporaryhairlossSkin3.0–5.0 3.5 5.0 http://ebooksmedicine.net 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 progenitors is prompt, leading to restoration of a normal lymphocyte count. Hematopoietic precursors in the bone marrow are also quite sensitive to radiant energy, which produces a dose-dependent marrow aplasia. The acute effects of marrow irradiation on peripheral blood counts reflects the kinetics of turnover of the formed elements—the granulocytes, platelets, and red cells, which have half-lives of less than 1 day, 10 days, and 120 days, respectively. After a brief rise in the circulating neutrophil count, neutropenia appears within several days. Neutrophil counts reach their nadir, often at counts


Pathology_Robbins

Pathology_Robbins. than 1 day, 10 days, and 120 days, respectively. After a brief rise in the circulating neutrophil count, neutropenia appears within several days. Neutrophil counts reach their nadir, often at counts near zero, during the second week. If the patient survives, full recovery of granulocytes may require 2 to 3 months. Thrombocytopenia appears by the end of the first week, with the platelet count nadir occurring somewhat later than that of granulocytes; recovery is similarly delayed. Anemia appears after 2 to 3 weeks and may persist for months. Understandably, higher doses of radiation produce more severe cytopenias and more prolonged periods of recovery. Very high doses kill marrow stem cells and induce permanent aplasia (aplastic anemia) marked by a failure of blood count recovery, whereas with lower doses the aplasia is transient.


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Pathology_Robbins. • Environmental exposure and cancer development. Any cell capable of division that has sustained mutations 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 100 mSv cause serious consequences, including cancer. This is documented by the increased incidence of leukemias and tumors at various sites (such as thyroid, breast, and lung) in survivors of the atomic bombings of Hiroshima and Nagasaki, the increase in thyroid cancers in survivors of the Chernobyl accident, and the development of “second cancers,” such as acute myeloid leukemia, myelodysplastic syndrome, and solid tumors, in individuals who received radiation therapy for cancers such as Hodgkin lymphoma. It is believed that the risk of secondary cancers


Pathology_Robbins

Pathology_Robbins. myeloid leukemia, myelodysplastic syndrome, and solid tumors, in individuals who received radiation therapy for cancers such as Hodgkin lymphoma. It is believed that the risk of secondary cancers following irradiation is greatest in children. This is based in part on a large-scale epidemiologic study showing that children who receive at least two CT scans have very small but measurable increased risks for leukemia and malignant brain


Pathology_Robbins

Pathology_Robbins. Table 8.8 Effects of Whole-Body Ionizing Radiation tumors, and on older studies showing that radiation therapy to the chest is particularly likely to produce breast cancers when administered to adolescent females. • Occupational exposure and cancer development. Radon is a ubiquitous product of the spontaneous decay of uranium. The carcinogenic agents are two radon decay byproducts (polonium-214 and polonium-218, or “radon daughters”), which emit alpha particles and have a short half-life. These particulates are deposited in the lung, and chronic exposure in uranium miners may give rise to lung carcinomas. Risks also are present in those 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.


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Pathology_Robbins. Exposure of large areas of the body to even small doses of radiation may have devastating effects. Dosages less than 1 Sv produce minimal or no symptoms. Greater exposures, however, cause health effects known as acute radiation syndromes, which at progressively higher doses involve the hematopoietic system, GI system, and CNS. The syndromes associated with total-body exposure to ionizing radiation are summarized in Table 8.8 RADIATIONINJURYdose levels and large exposure fields, severe lymphopedose levels and large exposure fields, severe lymphope Ionizingradiationmayinjurecellsdirectlyorindirectlybygeneratingfreeradicalsfromwaterormolecularoxygen. IonizingradiationdamagesDNA;therefore,rapidlydividingcellssuchasgermcells,andthoseinthebonemarrowandGItractareverysensitivetoradiationinjury. DNAdamagethatisnotadequatelyrepairedmayresultinmutationsthatpredisposeaffectedcellstoneoplastictransformation.


Pathology_Robbins

Pathology_Robbins. DNAdamagethatisnotadequatelyrepairedmayresultinmutationsthatpredisposeaffectedcellstoneoplastictransformation. Ionizingradiationmaycausevasculardamageandsclerosis,resultinginischemicnecrosisofparenchymalcellsandtheirreplacementbyfibroustissue. Millions of people in developing nations starve or live on the cruel edge of starvation, whereas those in the developed world, and more recently in the developing world, struggle to avoid calories and the attendant obesity or fear that what they eat may contribute to atherosclerosis and Mainsignsand—ModerateleukopeniaLeukopenia,hemorrhage,Diarrhea,fever,electrolyteAtaxia,coma,convulsions,symptoms epilation,vomitingimbalance,vomitingvomiting http://ebooksmedicine.net hypertension. So both the lack of nutrition and overnutrition are major health concerns.


Pathology_Robbins

Pathology_Robbins. A healthy diet provides (1) sufficient energy, in the form of carbohydrates, fats, and proteins, for the body’s daily metabolic needs; (2) essential (as well as nonessential) amino acids and fatty acids, used as building blocks for synthesis of structural and functional proteins and lipids; and (3) vitamins and minerals, which function as co-enzymes 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, or conditional, malnutrition, the dietary intake of nutrients is adequate, and malnutrition results from nutrient malabsorption, impaired use or storage, excess losses, or increased requirements. The causes of secondary malnutrition can be grouped into three general but overlapping categories: GI diseases, chronic wasting diseases, and acute critical illness.


Pathology_Robbins

Pathology_Robbins. Malnutrition is widespread and may be gross or subtle. Some common causes of dietary insufficiencies are listed here. Poverty. Homeless people, elderly persons, and children of the poor often suffer from severe malnutrition as well as trace nutrient deficiencies. In poor countries, poverty, together with droughts, crop failure, and livestock deaths, creates the setting for malnourishment of children and adults. Ignorance. 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 also contributes to malnutrition, as follows: (1) iron deficiency often develops in infants exclusively fed artificial milk diets; (2) polished rice used as the mainstay of a diet may lack adequate amounts of thiamine; and (3) iodine often is lacking in food and water in regions removed from the oceans, unless supplementation is provided.


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Pathology_Robbins. Chronic alcoholism. Alcoholic persons may sometimes suffer from malnutrition but are more frequently lacking in several vitamins, especially thiamine, pyridoxine, folate, and vitamin A, as a result of dietary deficiency, defective GI absorption, abnormal nutrient utilization and storage, increased metabolic needs, and an increased rate of loss. A failure to recognize thiamine deficiency in patients with chronic alcoholism may result in irreversible brain damage (e.g., Korsakoff psychosis, discussed in Chapter 23). Acute and chronic illnesses. The basal metabolic rate becomes accelerated in many illnesses (in patients with extensive burns, it may double), resulting in increased daily requirements for all nutrients. Failure to recognize these nutritional needs may delay recovery. Malnutrition is often present in patients with advanced cancer and AIDS.


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Pathology_Robbins. Self-imposed dietary restriction. Anorexia nervosa, bulimia, and less overt eating disorders affect a large population of persons who are concerned about body image or suffer from an unreasonable fear of cardiovascular disease (anorexia and bulimia are discussed in a separate section in this chapter). • Other causes. Additional causes of malnutrition include GI diseases, acquired and inherited malabsorption syndromes, specific drug therapies (which block uptake or use of particular nutrients), and total parenteral nutrition. The remainder of this section presents a general overview of nutritional disorders. Particular attention is devoted to severe acute malnutrition, anorexia nervosa and bulimia, deficiencies of vitamins and trace minerals, and obesity, with a brief consideration of the relationships of diet to atherosclerosis and cancer. Other nutrients and nutritional issues are discussed in the context of specific diseases throughout the text.


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Pathology_Robbins. The World Health Organization defines severe acute malnutrition (SAM) as a state characterized by a greatly reduced weight for height ratio that is below 3 standard deviation of WHO standards. Worldwide about 16 million children under the age of 5 years are affected by it. It is common in poor countries, where as many as 25% of children may be affected and where it is a major contributor to the high death rates among the very young. In addition to loss of life, wars also exact a heavy toll on refugees who live in abject poverty. In camps set up for refugees from Syria, as many as 20% of the children are severely or moderately malnourished.


Pathology_Robbins

Pathology_Robbins. SAM previously called protein energy malnutrition (PEM) manifests as a range of clinical syndromes, all resulting from a dietary intake of protein and calories that is inadequate to meet the body’s needs. The two ends of the spectrum of SAM are known as marasmus and kwashiorkor. It should be noted that from a functional standpoint, there are two 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. These two compartments are regulated differently, as detailed subsequently. The somatic compartment is affected more severely in marasmus and the visceral compartment is depleted more severely in kwashiorkor. Clinical assessment of undernutrition is discussed next, followed by descriptions of marasmus and kwashiorkor.


Pathology_Robbins

Pathology_Robbins. The diagnosis of SAM is obvious in its most severe forms. In mild to moderate forms, the usual approach is to compare the body weight for a given height against standard tables; other helpful parameters are fat stores, muscle mass, and levels of certain serum proteins. With a loss of fat, measured skinfold thickness (which includes skin and subcutaneous tissue) is reduced. If the somatic protein compartment is catabolized, the resultant reduction in muscle mass is reflected by reduced circumference of the midarm. Measurement of serum proteins (albumin, transferrin, and others) provides an estimate of the adequacy of the visceral protein compartment. Recent studies suggest a role for the gut microbiome in the pathogenesis of SAM. There is a substantial difference in the microbial flora of children with SAM when compared with the gut microbiome of normal children. It seems that the alterations in the microbiome are not merely the consequences of SAM but play a role in their causation.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 8.17 Childhoodmalnutrition.(A)Marasmus.Notethelossofmusclemassandsubcutaneousfat;theheadappearstobetoolargefortheemaciatedbody.(B)Kwashiorkor.Theinfantshowsgeneralizededema,seenasascitesandpuffinessoftheface,hands,andlegs.(A, From Clinic Barak, Reisebericht Kenya.) Marasmus develops when the diet is severely lacking in calories ( Fig. 8.17A ). A marasmic child suffers growth retardation and loss of muscle mass as a result of 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. Of interest, the visceral protein compartment, which presumably is more critical for survival, is depleted only marginally, so serum albumin levels are either normal or only slightly reduced.


Pathology_Robbins

Pathology_Robbins. In addition to muscle proteins, subcutaneous fat is also mobilized and used as fuel. Leptin (discussed later under “Obesity”) production is low, which may stimulate the hypothalamic-pituitary-adrenal axis to produce the 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. Anemia and manifestations of multivitamin deficiencies are present, and there is evidence of immune deficiency, particularly of T-cell–mediated immunity. Hence, concurrent infections are usually present, which impose an additional stress on an already weakened body. Kwashiorkor occurs when protein deprivation is relatively greater than the reduction in total calories ( Fig.


Pathology_Robbins

Pathology_Robbins. Kwashiorkor occurs when protein deprivation is relatively greater than the reduction in total calories ( Fig. 8.17B ). This is the most common form of SAM seen in African children who have been weaned too early and subsequently fed, almost exclusively, a carbohydrate diet (the name kwashiorkor, from the Ga language in Ghana, describes the illness in a baby that appears after the arrival of another child). The prevalence of kwashiorkor also is 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 (e.g., protein-losing enteropathies, the nephrotic syndrome, or the aftermath of extensive burns). Rare cases of kwashiorkor resulting from fad diets or replacement of milk by rice-based beverages have been reported in the United States.


Pathology_Robbins

Pathology_Robbins. In kwashiorkor, unlike in marasmus, 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. 8.17 ). The weight of children with severe kwashiorkor typically is 60% to 80% of normal. However, the true loss of weight is masked by the increased fluid retention (edema). In further contrast with marasmus, there is relative sparing of subcutaneous fat and muscle mass. The modest loss of these compartments may also be masked by edema.


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Pathology_Robbins. Children with kwashiorkor have characteristic skin lesions with alternating zones of hyperpigmentation, desquamation, and hypopigmentation, giving a “flaky paint” appearance. Hair changes include loss of color or alternating bands of pale and darker color, straightening, fine texture, and loss of firm attachment to the scalp. Other features that distinguish 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. As in marasmus, vitamin deficiencies are likely to be present, as are defects in immunity and secondary infections. In kwashiorkor, the inflammation caused by infection produces a catabolic state that aggravates the malnutrition. As already mentioned, marasmus and kwashiorkor represent two ends of a spectrum, and considerable overlap exists. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net In the United States, secondary malnutrition often develops in chronically ill, older, and bedridden patients. It is estimated that more than 50% of older residents in nursing homes in the United States are malnourished. Weight loss of more than 5% resulting from malnutrition increases the risk of mortality in nursing home patients by almost 5-fold. A particularly severe form of secondary malnutrition, called cachexia, often develops in patients with advanced cancer (Chapter 6). The wasting is all too apparent and often presages death. Although loss of appetite may partly explain it, cachexia may appear before the appetite decreases. The underlying mechanisms are complex, but appear to involve cytokines secreted by tumor cells, particularly TNF, which are released as part of the host response to advanced tumors. These factors directly stimulate the degradation of skeletal muscle proteins, and also stimulate fat mobilization from lipid stores.


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Pathology_Robbins. Thebrain ininfantswhoareborntomalnourishedmothersandwhosufferfromSAMduringthefirst1or2yearsoflifehasbeenreportedbysomeinvestigatorstoshowcerebralatrophy,areducednumberofneurons,andimpairedmyelinationofwhitematter. Manyotherchangesmaybepresent,including(1)thymicandlymphoidatrophy(moremarkedinkwashiorkorthaninmarasmus),(2)anatomicalterationsinducedbyintercurrentinfections,particularlywithendemichelminthsandotherparasites,and(3)deficienciesofotherrequirednutrientssuchasiodineandvitamins. Anorexia nervosa is a state of self-induced starvation resulting in marked weight loss; bulimia is a condition in which the patient binges on food and then induces vomiting. Bulimia is more common than anorexia nervosa and carries a better prognosis. It is estimated to occur in 1% to 2% of women and 0.1% of men, with an average age at onset of 20 years. These disorders occur primarily in previously healthy young women who have acquired an obsession with attaining or maintaining thinness.


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Pathology_Robbins. The clinical findings in anorexia nervosa generally are similar to those in SAM. In addition, effects on the endocrine system are prominent. Amenorrhea, resulting from decreased secretion of gonadotropin-releasing hormone (and consequent decreased secretion of luteinizing and follicle-stimulating hormones), is so common that its presence is almost a diagnostic feature. 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 frequent findings. Body hair may be increased but usually is fine and pale (lanugo). Bone density is decreased, most likely because of low estrogen levels, which mimics the postmenopausal acceleration of osteoporosis. As expected with severe malnutrition, anemia, lymphopenia, and hypoalbuminemia may be present. A major complication of anorexia nervosa is an increased susceptibility to cardiac arrhythmia and


Pathology_Robbins

Pathology_Robbins. As expected with severe malnutrition, anemia, lymphopenia, and hypoalbuminemia may be present. A major complication of anorexia nervosa is an increased susceptibility to cardiac arrhythmia and sudden death, both resulting from hypokalemia.


Pathology_Robbins

Pathology_Robbins. In bulimia, binge eating is the norm. Huge 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 are related to continual induced vomiting and chronic use of laxatives and diuretics. These include (1) electrolyte imbalances (hypokalemia), which predispose the patient to cardiac arrhythmias; (2) pulmonary aspiration of gastric contents; and (3) esophageal and stomach rupture. Nevertheless, there are no specific signs and symptoms for this syndrome, and the diagnosis must rely on a comprehensive psychologic assessment of the patient. Before we summarize the functions of individual vitamins and the consequence of their deficiency, some general comments are in order.