Pathology_Robbins

Pathology_Robbins. Before we summarize the functions of individual vitamins and the consequence of their deficiency, some general comments are in order. Thirteen vitamins are necessary for health; four—A, D, E, and K—are fat-soluble and the remainder are water-soluble. The distinction between fatand water-soluble vitamins is important; although the former are more readily stored in the body, they may be poorly absorbed in fat malabsorption disorders, caused by disturbances of digestive functions (discussed in Chapter 15). Certain vitamins can be synthesized endogenously—vitamin D from precursor steroids, vitamin K and biotin by the intestinal microflora, and niacin from tryptophan, an essential amino acid. Notwithstanding this endogenous synthesis, a dietary supply of all vitamins is essential for health. Deficiency of a single vitamin is uncommon, and singleor multiple-vitamin deficiencies may accompany concurrent SAM.


Pathology_Robbins

Pathology_Robbins. Deficiency of a single vitamin is uncommon, and singleor multiple-vitamin deficiencies may accompany concurrent SAM. In the following sections, vitamins A, D, and C are presented in some detail because of their wide-ranging functions and the morphologic changes of deficient states. This is followed by a summary in tabular form of the main consequences of deficiencies of the remaining vitamins—E, K, and the B complex—and some essential minerals. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. The major functions of vitamin A are maintenance of normal vision, regulation of cell growth and differentiation, and regulation of lipid metabolism. Vitamin A is a generic name for a group of related fat-soluble compounds that include retinol, retinal, and retinoic acid, which have similar biologic activities. Retinol is the chemical name for vitamin A. It is the transport form and, as retinol ester, also the storage form. A widely used term, retinoids, refers to both natural and synthetic chemicals that are structurally related to vitamin A but may not necessarily have vitamin A activity. Animal-derived foods such as liver, fish, eggs, milk, and butter are important dietary sources of preformed vitamin A. Yellow and leafy green vegetables such as carrots, squash, and spinach supply large amounts of carotenoids, many of which are provitamins that are metabolized to active vitamin A in the body. Carotenoids contribute approximately 30% of the vitamin A in human diets; the most


Pathology_Robbins

Pathology_Robbins. large amounts of carotenoids, many of which are provitamins that are metabolized to active vitamin A in the body. Carotenoids contribute approximately 30% of the vitamin A in human diets; the most important of these is β-carotene, which is efficiently converted to vitamin A. The recommended dietary allowance for vitamin A is expressed in retinol equivalents, to take into account both preformed vitamin A and β-carotene.


Pathology_Robbins

Pathology_Robbins. Vitamin A is a fat-soluble vitamin, and its absorption requires bile, pancreatic enzymes, and some level of antioxidant activity in the food. Retinol (generally ingested as retinol ester) and β-carotene are absorbed through the intestinal wall, where β-carotene is converted to retinol (


Pathology_Robbins

Pathology_Robbins. Fig. 8.18 ). Retinol is then transported in chylomicrons, where it is taken up into liver cells through the apolipoprotein E receptor. More than 90% of the body’s vitamin A reserves are stored in the liver, predominantly in the perisinusoidal stellate (Ito) cells. In healthy persons who consume an adequate diet, these reserves are sufficient to support the body’s needs for at least 6 months. Retinol esters stored in the liver can be mobilized; before release, retinol binds to a specific retinol-binding protein (RBP), synthesized in the liver. The uptake of retinol and RBP in peripheral tissues is dependent on cell surface RBP receptors. After uptake by cells, retinol is released, and the RBP is recycled back into the blood. Retinol may be stored in peripheral tissues as retinyl ester or may be oxidized to form retinoic acid.


Pathology_Robbins

Pathology_Robbins. Function. In humans, the best-defined functions of vitamin A are the following: • Maintaining normal vision in reduced light. The visual process involves four forms of vitamin A–containing pigments: rhodopsin, located in rod cells, the most light-sensitive pigment and therefore important in reduced light; and three iodopsins, located in cone cells, each responsive to a specific color in bright light. The synthesis of rhodopsin from retinol involves (1) oxidation to all-trans-retinal, (2) isomerization to 11-cis-retinal, and (3) interaction with opsin to form rhodopsin. A photon of light causes the isomerization of 11-cis-retinal to alltrans-retinal, and a sequence of configuration changes (preformed vitamin A) (carotenes, pro-vitamin A) Fig. 8.18 Vitamin A metabolism.


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Pathology_Robbins. Fig. 8.18 Vitamin A metabolism. in rhodopsin, which produce a visual signal. In the process, a nerve impulse is generated (by changes in membrane potential) and transmitted by means of neurons from the retina to the brain. During dark adaptation, some of the all-trans-retinal is reconverted to 11-cis-retinal, but most is reduced to retinol and lost to the retina, explaining the need for a continuous supply of retinol.


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


Pathology_Robbins

Pathology_Robbins. retinoids regulate cell growth and differentiation, cell-cycle control, and other biologic responses. All-trans-retinoic acid, a potent acid derivative of vitamin A, has the highest affinity for RARs compared with other retinoids.


Pathology_Robbins

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


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Pathology_Robbins. Enhancing immunity to infections. Vitamin A supplementation can reduce morbidity and mortality rates for some forms of diarrhea. Similarly, supplementation in preschool children with measles, particularly those who are malnourished, can reduce mortality and complications of the disease, including eye damage and blindness. The effects of vitamin A on infections probably derive in part from its ability to stimulate the immune system through unclear mechanisms. Infections may reduce the bioavailability of vitamin A, possibly by inducing the acute phase response, which appears to inhibit RBP synthesis in the liver. The drop in hepatic RBP causes a decrease in circulating retinol, which reduces the tissue availability of vitamin A. The beneficial effect of vitamin A in diarrheal diseases may be related to the maintenance and restoration of the integrity of the epithelium of the gut.


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Pathology_Robbins. In addition, the retinoids, β-carotene, and some related carotenoids can function as photoprotective and antioxidant agents. Retinoids have broad biologic effects, including effects on embryonic development, cellular differentiation and proliferation, and lipid metabolism. Retinoids are used clinically to treat skin disorders such as severe acne and certain forms of psoriasis, and also to treat acute promyelocytic leukemia. As discussed in Chapter 6, all-trans-retinoic acid induces the differentiation and subsequent apoptosis of acute promyelocytic leukemia cells through its ability to bind to a PML-RARα fusion protein that characterizes this form of cancer.


Pathology_Robbins

Pathology_Robbins. Deficiency States. Vitamin A deficiency occurs worldwide as a consequence of either poor nutrition or fat malabsorption. In children, stores of vitamin A are depleted by infections, and the absorption of the vitamin is poor in newborn infants. In adults, vitamin A deficiency, in conjunction with depletion of other fat-soluble vitamins, may develop in patients with malabsorption syndromes, such as celiac disease, Crohn disease, and colitis. Bariatric surgery and the continuous use of mineral oil laxatives also may lead to deficiency. The multiple effects of vitamin A deficiency are as follows: As was already discussed, vitamin A is a component of rhodopsin and other visual pigments. Not surprisingly, one of the earliest manifestations of vitamin A deficiency is impaired vision, particularly in reduced light (night blindness). Other effects of vitamin A deficiency are related to its role in maintaining the differentiation of epithelial cells (


Pathology_Robbins

Pathology_Robbins. Other effects of vitamin A deficiency are related to its role in maintaining the differentiation of epithelial cells ( Fig. 8.19 ). Persistent deficiency gives rise to a series of changes involving epithelial metaplasia and keratization. The most devastating changes occur in the eyes and result in the clinical entity referred to as xerophthalmia (dry eye). First, there is dryness of the conjunctiva (xerosis conjunctivae) as the normal lachrymal and Bitot spots Corneal ulcer Keratomalacia Advanced metaplasia Increased cancer? Fig. 8.19 Vitamin A deficiency: major consequences in the eye and in the production of keratinizing metaplasia of specialized epithelial surfaces, and its possible role in epithelial metaplasia. Not depicted are night blindness and immune deficiency.


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Pathology_Robbins. mucus-secreting epithelium are replaced by keratinized epithelium. This is followed by a buildup of keratin debris in small opaque plaques (Bitot spots) and, eventually, the erosion of the roughened corneal surface, leading to softening and destruction of the cornea (keratomalacia) and total blindness. Vitamin A deficiency also leads to replacement of the epithelium lining the upper respiratory passage and urinary tract by keratinizing squamous cells (squamous metaplasia). Loss of the mucociliary epithelium of the airways predisposes affected patients to pulmonary infections, and desquamation of keratin debris in the urinary tract predisposes to renal and bladder stones. Hyperplasia and hyperkeratinization of the epidermis with plugging of the ducts of the adnexal glands may produce follicular or papular dermatosis.


Pathology_Robbins

Pathology_Robbins. Another serious consequence of the lack of vitamin A is immune deficiency. This impairment of immunity leads to higher mortality rates from common infections such as measles, pneumonia, and infectious diarrhea. In parts of the world with a high prevalence of vitamin A deficiency, dietary supplements reduce mortality rates for infectious disorders by 20% to 30%.


Pathology_Robbins

Pathology_Robbins. Vitamin A Toxicity. Both shortand long-term excesses of vitamin A may produce toxic manifestations—a point of concern because of the megadoses being touted by certain sellers of supplements. The consequences of acute hypervitaminosis A were first described in 1597 by Gerrit de Veer, a ship’s carpenter stranded in the Arctic, who recounted in his diary the serious symptoms that he and other crew members developed after eating polar bear liver. With this cautionary tale in mind, the adventurous eater should note that acute vitamin A toxicity also has been described in “hepatoaficionados” who feasted on the livers of whales, sharks, and even tuna!


Pathology_Robbins

Pathology_Robbins. The signs and symptoms of acute toxicity include headache, dizziness, vomiting, stupor, and blurred vision—all of which may be confused with those of a brain tumor. Chronic toxicity is associated with weight loss, anorexia, nausea, vomiting, and bone and joint pain. Retinoic acid stimulates the production and function of osteoclasts, leading to increased bone resorption and a consequent high risk of fractures. Although synthetic retinoids used for the treatment of acne are not associated with these complications, their use in pregnancy must be avoided because of the well-established teratogenic effect of retinoids.


Pathology_Robbins

Pathology_Robbins. The major function of the fat-soluble vitamin D is the maintenance of adequate plasma levels of calcium and phosphorus to support metabolic functions, bone mineralization, and neuromuscular transmission. In this capacity, the vitamin is required for the prevention of bone diseases known as rickets (in children whose epiphyses have not already closed), osteomalacia (in adults), and hypocalcemic tetany. With respect to tetany, vitamin D maintains the correct concentration of ionized calcium in the extracellular fluid compartment. When deficiency develops, the drop in ionized calcium in the extracellular fluid results in continuous excitation of muscle (tetany). It should be noted, however, that any reduction in the level of serum calcium is rapidly corrected by excess secretion of parathyroid hormone. Hence tetany is quite uncommon. Our attention here is focused on the function of vitamin D in the regulation of serum calcium levels.


Pathology_Robbins

Pathology_Robbins. Metabolism. The major source of vitamin D for humans is its endogenous synthesis in the skin by photochemical conversion of a precursor, 7-dehydrocholesterol, powered by the energy of solar or artificial UV light. Irradiation of this compound forms cholecalciferol, known as vitamin D3; in the following discussion, for the sake of simplicity, the term vitamin D is used to refer to this compound. Under usual conditions of sun exposure, approximately 90% of the vitamin D needed is endogenously derived from 7-dehydrocholesterol present in the skin. However, blacks may have a lower level of vitamin D production in the skin because of melanin pigmentation (perhaps a small price to pay for protection against UV-induced cancers). The small remainder comes from dietary sources, such as deep-sea fish, plants, and grains. In plant sources, vitamin D is present in a precursor form, ergosterol, which is converted to vitamin D in the body. The metabolism of vitamin D can be outlined as follows (


Pathology_Robbins

Pathology_Robbins. The metabolism of vitamin D can be outlined as follows ( Fig. 8.20): 1. Absorption of vitamin D along with other fats in the gut or synthesis from precursors in the skin 2. Binding to plasma α1-globulin (vitamin D–binding protein) and transport to liver 3. Conversion to 25-hydroxyvitamin D (25-OH-D) by 25-hydroxylase in the liver 4. Conversion of 25-OH-D to 1,25-dihydroxyvitamin D [1,25-(OH)2-D] (biologically the most active form of vitamin D) by α1-hydroxylase in the kidney Renal production of 1,25-(OH)2-D is regulated by three mechanisms: Hypocalcemia stimulates secretion of parathyroid hormone (PTH), which in turn augments the conversion of 25-OH-D to 1,25-(OH)2-D by activating α1-hydroxylase. Hypophosphatemia directly activates α1-hydroxylase, thereby increasing the formation of 1,25(OH)2-D.


Pathology_Robbins

Pathology_Robbins. Hypophosphatemia directly activates α1-hydroxylase, thereby increasing the formation of 1,25(OH)2-D. In a feedback loop, increased levels of 1,25-(OH)2-D downregulate the synthesis of this metabolite by inhibiting the action of α1-hydroxylase (decreases in 1,25(OH)2-D have the opposite effect). Functions. Like retinoids and steroid hormones, 1,25(OH)2-D acts by binding to a high-affinity nuclear receptor that in turn binds to regulatory DNA sequences, thereby inducing transcription of specific target genes. The receptors for 1,25-(OH)2-D are present in most nucleated cells of the body, and they transduce signals that result in various biologic activities, beyond those involved in calcium and phosphorus homeostasis. Nevertheless, the best-understood functions of vitamin D relate to the maintenance of normal plasma levels of calcium and phosphorus, through action on the intestines, bones, and kidneys ( Fig. 8.20


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Pathology_Robbins. Fig. 8.20 The active form of vitamin D: • Stimulates intestinal absorption of calcium through upregulation of calcium transport, in enterocytes http://ebooksmedicine.net 1,25 (OH)2D Ca Ca P P Ultraviolet irradiation of 7-dehydrocholesterol in skin Vitamin D in bloodSmall intestine absorption of dietary sources Normal serum levels of Ca A (normocalcemia) and P Ca and P absorption Serum Ca and P Serum Ca x P product Poor bone mineralization 1,25 (OH)2D PTHPTH Mobilization of Ca and P ˜-1-hydroxylase Ca CaP P P P 2 7 3 6a 6b 4 5


Pathology_Robbins

Pathology_Robbins. Ca and P absorption Serum Ca and P Serum Ca x P product Poor bone mineralization 1,25 (OH)2D PTHPTH Mobilization of Ca and P ˜-1-hydroxylase Ca CaP P P P 2 7 3 6a 6b 4 5 Fig. 8.20 (A)NormalvitaminDmetabolism.(B)VitaminDdeficiency.Thereisinadequatesubstratefortherenalhydroxylase(1),yieldingadeficiencyof1,25-(OH)2D(2),anddeficientabsorptionofcalciumandphosphorusfromthegut(3),withconsequentdepressedserumlevelsofboth(4).Thehypocalcemiaactivatestheparathyroidglands(5),causingmobilizationofcalciumandphosphorusfrombone(6a).Simultaneously,parathyroidhormone(PTH)induceswastingofphosphateintheurine(6b) andcalciumretention.Consequently,theserumlevelsofcalciumarenormalornearlynormal,butthephosphateislow;hence,mineralizationisimpaired(7). Stimulates calcium resorption in renal distal tubules.


Pathology_Robbins

Pathology_Robbins. Stimulates calcium resorption in renal distal tubules. Collaborates with PTH to regulate blood calcium. This occurs in part through upregulation of RANK ligand on osteoblasts, which in turn activates RANK receptors on osteoclast precursors. RANK activation produces signals that increase osteoclast differentiation and bone resorptive activities (Chapter 21). Promotes the mineralization of bone. Vitamin D is needed for the mineralization of osteoid matrix and epiphyseal cartilage during the formation of flat and long bones. It stimulates osteoblasts to synthesize the calcium-binding protein osteocalcin, which promotes calcium deposition.


Pathology_Robbins

Pathology_Robbins. Of note, effects of vitamin D on bone depend on the plasma levels of calcium: On the one hand, in hypocalcemic states 1,25-(OH)2-D together with PTH increases the resorption of calcium and phosphorus from bone to support blood levels. On the other hand, in normocalcemic states, vitamin D is required for calcium deposition in epiphyseal cartilage and osteoid matrix.


Pathology_Robbins

Pathology_Robbins. Vitamin D deficiency causes rickets in growing children and osteomalacia in adults; these skeletal diseases have worldwide distribution. They may result from diets deficient in calcium and vitamin D, but probably more important is limited exposure to sunlight (for instance, in heavily veiled women; children born to mothers who have frequent pregnancies followed by lactation, which leads to vitamin D deficiency; and inhabitants of northern climates with scant sunlight). Other, less common causes of rickets and osteomalacia include renal disorders causing decreased synthesis of 1,25-(OH)2-D or phosphate depletion, and malabsorption disorders. Although rickets and osteomalacia rarely occur outside high-risk groups, milder forms of vitamin D deficiency (also called vitamin D insufficiency) leading to bone loss and hip fractures are common among elderly persons. Studies also suggest that vitamin D may be important for preventing demineralization of bones. It appears that certain


Pathology_Robbins

Pathology_Robbins. leading to bone loss and hip fractures are common among elderly persons. Studies also suggest that vitamin D may be important for preventing demineralization of bones. It appears that certain genetically determined variants of the vitamin D receptor are associated with an accelerated loss of bone minerals with aging and certain familial forms of osteoporosis (Chapter 21).


Pathology_Robbins

Pathology_Robbins. Whatever the basis, a deficiency of vitamin D tends to cause hypocalcemia. This in turn stimulates PTH production, which (1) activates renal α1-hydroxylase, increasing the amount of active vitamin D and calcium absorption; (2) mobilizes calcium from bone; (3) decreases renal calcium excretion; and (4) increases renal excretion of phosphate. Thus, the serum level of calcium is restored to near normal, but hypophosphatemia persists, so mineralization of bone is impaired or there is high bone turnover.


Pathology_Robbins

Pathology_Robbins. An understanding of the morphologic changes in rickets and osteomalacia is facilitated by a brief summary of normal bone development and maintenance. The development of flat bones in the skeleton involves intramembranous ossification, whereas the formation of long tubular bones proceeds by endochondral ossification. With intra-membranous bone formation, mesenchymal cells differentiate directly into osteoblasts, which synthesize the collagenous osteoid matrix on which calcium is deposited. By contrast, with endochondral ossification, growing cartilage at the epiphyseal plates is provisionally mineralized and then progressively resorbed and replaced by osteoid matrix, which undergoes mineralization to create bone ( Fig. 8.21A MORPHOLOGYThe basic derangement in both rickets and osteomalacia is an excess of unmineralized bone matrix. Thechangesthatoccurinthegrowingbonesofchildrenwithrickets,however,arecomplicatedbyinadequateprovisionalcalcification http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 8.21 Rickets.(A)Normalcostochondraljunctionofayoungchild.Notecartilagepalisadeformationandorderlytransitionfromcartilagetonewbone. (B)Rachiticcostochondraljunctioninwhichthepalisadeofcartilageisabsent.Darkertrabeculaearewell-formedbone;palertrabeculaeconsistofuncalcifiedosteoid.(C)Notebowingoflegsasaconsequenceoftheformationofpoorlymineralizedboneinachildwithrickets.(B, Courtesy of Dr. Andrew E. Rosenberg, Massachusetts General Hospital, Boston, Massachusetts.) ofepiphysealcartilage,derangingendochondralbonegrowth.Thefollowingsequenceensuesinrickets: Persistenceofdistorted,irregularmassesofcartilage,manyofwhichprojectintothemarrowcavity Disruptionoftheorderlyreplacementofcartilagebyosteoidmatrix,withenlargementandlateralexpansionoftheosteochondraljunction( Fig.8.21B Abnormalovergrowthofcapillariesandfibroblastsinthedisorganizedzoneresultingfrommicrofracturesandstressesontheinadequatelymineralized,weak,poorlyformedbone


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. breast deformity). TheinwardpullatthemarginofthediaphragmcreatestheHarrison groove, girdlingthethoraciccavityatthelowermarginoftheribcage.Thepelvismaybecomedeformed.Whenanambulatingchilddevelopsrickets,deformitiesarelikelytoaffectthespine,pelvis,andlongbones(e.g.,tibia),causing,mostnotably,lumbar lordosis andbowing of the legs (


Pathology_Robbins

Pathology_Robbins. Nonskeletal Effects of Vitamin D. As mentioned earlier, the vitamin D receptor is present in various cells and tissues that do not participate in calcium and phosphorus homeostasis. In addition, macrophages, keratinocytes, and tissues such as breast, prostate, and colon can produce 1,25-dihydroxyvitamin D. It appears that pathogen-induced activation of Toll-like receptors in macrophages causes increased expression of vitamin D receptor as well as increased local synthesis of 1,25-dihydroxyvitamin D. This causes activation of vitamin-D-dependent gene expression in macrophages and other neighboring immune cells. The net effect of these changes on the immune response remains to be determined. It appears that in some patients with tuberculosis, vitamin D supplements increase lymphocyte counts and enhance the clearance of Mycobacterium tuberculosis. It has also been reported that low levels http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Inadequate synthesis Impaired wound healing Periosteum and joints of osteoid Fig. 8.22 Major consequences of impaired formation of collagen caused by vitamin C deficiency. of 1,25-dihydroxyvitamin D (<20 ng/mL) are associated with a 30% to 50% increase in the incidence of colon, prostate, and breast cancers, but whether or not vitamin D supplementation can reduce cancer risk has not been firmly established. Toxicity. Prolonged exposure to sunlight may cause sunburns but it does not produce an excess of vitamin D, but megadoses of orally administered vitamin can lead to hypervitaminosis. In children, hypervitaminosis D may take the form of metastatic calcifications of soft tissues such as the kidney; in adults, it causes bone pain and hypercalcemia. As a point of some interest, the toxic potential of this vitamin is so great that in sufficiently large doses it is a potent rodenticide!


Pathology_Robbins

Pathology_Robbins. A deficiency of water-soluble vitamin C leads to the development of scurvy, characterized principally by bone disease in growing children and by hemorrhages and healing defects in both children and adults. Sailors of the British Royal Navy were nicknamed “limeys” because at the end of the 18th century the Navy began to provide lime and lemon juice to them to prevent scurvy during their long sojourns at sea. It was not until 1932 that ascorbic acid was identified and synthesized. Unlike vitamin D, ascorbic acid is not synthesized endogenously in humans, who therefore are entirely dependent on the diet for this nutrient. Vitamin C is present in milk and some animal products (liver, fish) and is abundant in a variety of fruits and vegetables. All but the most restricted diets provide adequate amounts of vitamin C.


Pathology_Robbins

Pathology_Robbins. Function. Ascorbic acid acts in a variety of biosynthetic pathways by accelerating hydroxylation and amidation reactions. The most clearly established function of vitamin C is the activation of prolyl and lysyl hydroxy-lases from inactive precursors, allowing for hydroxylation of procollagen. Inadequately hydroxylated procollagen cannot acquire a stable helical configuration or be adequately crosslinked, so it is poorly secreted from the fibroblasts. Those molecules that are secreted lack tensile strength, are more soluble, and are more vulnerable to enzymatic degradation. Collagen, which normally has the highest content of hydroxyproline, is most affected, particularly in blood vessels, accounting for the predisposition to hemorrhages in scurvy. In addition, a deficiency of vitamin C suppresses the synthesis of collagen polypeptides, independent of effects on proline hydroxylation. Vitamin C also has anti-oxidant properties. These include an ability to scavenge free radicals directly


Pathology_Robbins

Pathology_Robbins. the synthesis of collagen polypeptides, independent of effects on proline hydroxylation. Vitamin C also has anti-oxidant properties. These include an ability to scavenge free radicals directly and the participation in metabolic reactions that regenerate the anti-oxidant form of vitamin E.


Pathology_Robbins

Pathology_Robbins. Deficiency States. Consequences of vitamin C deficiency are illustrated in Fig. 8.22 . Fortunately, because of the abundance of ascorbic acid in foods, scurvy has ceased to be a global problem. It is sometimes encountered in affluent populations as a secondary deficiency, particularly among elderly persons, people who live alone, and chronic alcoholics—groups often characterized by erratic and inadequate eating patterns. Occasionally, scurvy appears in patients undergoing peritoneal dialysis and hemodialysis and among food faddists. Toxicity. The popular notion that megadoses of vitamin C protect against the common cold or at least allay the symptoms has not been borne out by controlled clinical studies. Such slight relief as may be experienced probably is a result of the mild antihistamine action of ascorbic acid. The large excess of vitamin C is promptly excreted in the urine but may cause uricosuria and increased absorption of iron, with the potential for iron overload.


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Pathology_Robbins. Other vitamins and some essential minerals are listed and briefly described in Tables 8.9 and 8.10 . Folic acid and vitamin B12 are discussed in Chapter 12. VitaminKCofactorinhepaticcarboxylationofprocoagulants—factorsIIBleedingdiathesis(prothrombin),VII,IX,andX;andproteinCandproteinS VitaminB1(thiamine)Aspyrophosphate,iscoenzymeindecarboxylationreactionsDryandwetberiberi,Wernickesyndrome,Korsakoffsyndrome VitaminB6(pyridoxine)DerivativesserveascoenzymesinmanyintermediaryCheilosis,glossitis,dermatitis,peripheralreactionsneuropathy Essentialfortransferanduseofone-carbonunitsinDNAMegaloblasticanemia,neuraltubedefectssynthesis *SeealsoChapter12. Table 8.10 Selected Trace Elements and Deficiency Syndromes http://ebooksmedicine.net PrimarySAMisacommoncauseofchildhooddeathsinpoorcountries.ThetwomainprimarySAMsyndromesaremarasmusandkwashiorkor.SecondarySAMoccursinthechronicallyillandinpatientswithadvancedcancer(asaresultofcachexia).


Pathology_Robbins

Pathology_Robbins. Excess adiposity (obesity) and excess body weight are associated with increased incidence of several of the most important diseases of humans, including type 2 diabetes, dyslipidemias, cardiovascular disease, hypertension, and cancer. It is a major public health problem in developed countries and an emerging health problem in developing nations, such as India. In the United States, obesity has reached epidemic proportions. The prevalence of obesity increased from 13% to 34% between 1960 and 2008, and as of 2015, 68.6% of Americans between 20 and 75 years of age were overweight as were 17% of the children. Globally, the World Health Organization (WHO) estimates that in 2015, 700 million adults were obese. The causes of this epidemic are complex but undoubtedly are related to societal changes in diet and levels of physical activity. Obesity is defined as a state of increased body weight, caused by adipose tissue accumulation, that is of sufficient magnitude to produce adverse health


Pathology_Robbins

Pathology_Robbins. in diet and levels of physical activity. Obesity is defined as a state of increased body weight, caused by adipose tissue accumulation, that is of sufficient magnitude to produce adverse health effects. How does one measure fat accumulation? Several high-tech methods have been devised, but for practical purposes the body mass index (BMI) is most commonly used. BMI is calculated as (weight in kilograms)/(height in meters)2, or kg/m2.


Pathology_Robbins

Pathology_Robbins. The BMI is closely correlated with body fat. BMIs in the range 18.5 to 25 kg/m2 are considered normal, whereas BMIs between 25 and 30 kg/m2 identify the overweight, and BMIs greater than 30 kg/m2, the obese. It is generally agreed that a BMI greater than 30 kg/m2 imparts a health risk. In the following discussion, for the sake of simplicity, the term obesity is applied to both the overweight and the truly obese. The untoward effects of obesity are related not only to the total body weight but also to the distribution of the stored fat. Central, or visceral, obesity, in which fat accumulates in the trunk and in the abdominal cavity (in the mesentery and around viscera), is associated with a much higher risk for several diseases than is a condition of excess accumulation of fat in a diffuse distribution in subcutaneous tissue.


Pathology_Robbins

Pathology_Robbins. The etiology of obesity is complex and incompletely understood. Involved are genetic, environmental, and psychologic factors. However, simply put, obesity is a disorder of energy balance. The two sides of the energy equation, intake and expenditure, are finely regulated by neural and hormonal mechanisms, so that body weight is maintained within a narrow range for many years. Apparently, this fine balance is controlled by an internal set point, or “lipostat,” that senses the quantity of energy stores (adipose tissue) and appropriately regulates food intake as well as energy expenditure. Several “obesity genes” have been identified. As might be expected, they encode the molecular components of the physiologic system that regulates energy balance. A key player in energy homeostasis is the LEP gene and its product, leptin. This unique member of the cytokine family, secreted by adipocytes, regulates both sides of the energy equation—intake of food and expenditure of energy. As discussed


Pathology_Robbins

Pathology_Robbins. LEP gene and its product, leptin. This unique member of the cytokine family, secreted by adipocytes, regulates both sides of the energy equation—intake of food and expenditure of energy. As discussed later, the net effect of leptin is to reduce food intake and to enhance the expenditure of energy.


Pathology_Robbins

Pathology_Robbins. In a simplified way, the neurohumoral mechanisms that regulate energy balance and body weight may be divided into three components ( Fig. 8.23 The peripheral or afferent system generates signals from various sites. Its main components are leptin and adiponectin produced by fat cells, insulin from the pancreas, ghrelin from the stomach, and peptide YY from the ileum and colon. Leptin reduces food intake and is discussed in further detail later. Ghrelin secretion stimulates appetite, and it may function as a “meal-initiating” signal. Peptide YY, which is released postprandially by endocrine cells in the ileum and colon, is a satiety signal. The arcuate nucleus in the hypothalamus, processes and integrates the peripheral signals and generates new signals that are transmitted by (1) POMC (proopiomelanocortin) and CART (cocaine-and amphetamine-regulated transcript) neurons; and (2) NPY (neuropeptide Y) and AgRP (agouti-related peptide) neurons.


Pathology_Robbins

Pathology_Robbins. The efferent system, which consists of hypothalamic neurons regulated by the arcuate nucleus, is organized along two pathways, anabolic and catabolic, which control food intake and energy expenditure, respectively. POMC/CART neurons activate efferent neurons that enhance energy expenditure and weight loss through the production of molecules such as α-melanocyte stimulating hormone (MSH) that reduce food intake (anorexigenic effect). MSH signals through melanocortin receptor (MC4R). By contrast NPY/AgRP neurons activate efferent neurons that promote food intake (orexigenic effect) and weight gain. Signals transmitted by efferent neurons also communicate with forebrain and midbrain centers that control the autonomic nervous system. Discussed next are two important components of the afferent system that regulate appetite and satiety: leptin and gut hormones, and adiponectin that regulates fat consumption. http://ebooksmedicine.net


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Pathology_Robbins. Leptin is secreted by fat cells, and its output is regulated by the adequacy of fat stores. BMI and body fat stores are directly related to leptin secretion. With abundant adipose tissue, leptin secretion is stimulated, and the hormone crosses the blood–brain barrier and travels to the hypothalamus, where it reduces food intake by stimulating POMC/ CART neurons and inhibiting NPY/AgRP neurons. The opposite sequence of events occurs when there are inadequate stores of body fat: Leptin secretion is diminished and food intake is increased. In persons of stable weight, the activities of these pathways are balanced. Leptin also increases energy expenditure by stimulating physical activity, energy expenditure, and thermogenesis, and these may be the most important catabolic effects mediated by leptin through the hypothalamus. Although the effects of leptin on food intake and energy expenditure can be readily demonstrated in nonobese mice and humans, the anorexigenic response of leptin is


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Pathology_Robbins. leptin through the hypothalamus. Although the effects of leptin on food intake and energy expenditure can be readily demonstrated in nonobese mice and humans, the anorexigenic response of leptin is blunted in states of obesity despite high levels of circulating leptin. Such leptin resistance in obese mice can be bypassed by intraventricular injection of leptin. In keeping with this observation, injections of leptin in obese humans fail to affect food intake and energy expenditure, dashing initial enthusiasm of leptin therapy for obesity.


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Pathology_Robbins. In rodents and humans, loss-of-function mutations affecting components of the leptin pathway give rise to massive obesity. Mice with mutations that disable the leptin gene or its receptor fail to sense the adequacy of fat stores, so they behave as if they are undernourished, eating ravenously. As in mice, mutations of the leptin gene or receptor in humans, although rare, may cause massive obesity. More common are mutations in the melanocortin receptor-4 gene (MC4R), found in 4% to 5% of patients with massive obesity. As mentioned earlier, MSH sends satiety signals by binding to this receptor. These monogenic traits underscore the importance of the leptin pathway in the control of body weight, and it is possible that more common types of defects in this pathway will be discovered in the obese. In closing it should be mentioned that, like leptin, insulin also exerts anorexigenic responses. However, the mechanism of this effect of insulin is less clear, and most of the evidence suggests


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Pathology_Robbins. In closing it should be mentioned that, like leptin, insulin also exerts anorexigenic responses. However, the mechanism of this effect of insulin is less clear, and most of the evidence suggests the primacy of leptin in the regulation of adiposity.


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Pathology_Robbins. Adiponectin, produced in the adipose tissue, has been called a “fat-burning molecule” and the “guardian angel against obesity.” It directs fatty acids to muscle for their oxidation. It decreases the influx of fatty acids to the liver and the total hepatic triglyceride content. It also decreases glucose production in the liver, causing an increase in insulin sensitivity and protecting against the metabolic syndrome. In addition to its metabolic effects, adiponectin has anti-diabetic, anti-inflammatory, anti-atherogenic, anti-proliferative, and cardioprotective effects. Its serum levels are lower in obese than in lean individuals. These effects contribute to obesity-associated insulin resistance, type 2 diabetes, nonalcoholic fatty liver disease (Chapter 14), and possibly increased risk of certain cancers, discussed later.


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Pathology_Robbins. In addition to leptin and adiponectin, adipose tissue produces other mediators, such as cytokines, chemokines, and steroid hormones, which allow adipose tissue to function as a link between lipid metabolism, nutrition, and inflammatory responses. The total number of adipocytes is established by the time of adolescence and is higher in people who were obese as children, providing another reason for concern about childhood obesity. Although in adults approximately 10% of adipocytes turn over annually, the number of adipocytes remains constant, regardless of individual body mass. Diets fail in part because the loss of fat from adipocytes causes leptin levels to fall, stimulating the appetite and diminishing energy expenditure.


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Pathology_Robbins. Gut hormones are rapidly acting initiators and terminators of volitional eating. Prototypical examples are ghrelin and peptide YY (PYY). Ghrelin is produced in the stomach and the arcuate nucleus of the hypothalamus. It increases food intake, acting most likely by stimulating the NPY/AgRP neurons in the hypothalamus. Ghrelin levels normally rise before meals and fall 1 to 2 hours afterward, but this drop is attenuated in obese persons. Ghrelin levels are lower in obese individuals as compared to those with normal weight, and they increase with a reduction in obesity. Interestingly, the rise in ghrelin levels is much reduced in individuals in whom gastric bypass surgery is performed for the treatment of obesity, suggesting that the beneficial effects of such surgery may be in part due to a reduced surface of gastric mucosa that is exposed to food.


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Pathology_Robbins. PYY is secreted from endocrine cells in the ileum and colon in response to the consumption of food. It decreases appetite and augments a sense of fullness (satiety). It acts, presumably, by stimulating POMC/CART neurons in the hypothalamus, thereby decreasing food intake. PYY also reduces the rate of gastric emptying and intestinal motility (“ilea brake”), all of which contribute to satiety. PYY levels are reduced with obesity and may be of therapeutic value in the treatment of those who are overweight or obese. The Role of Gut Microbiome


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Pathology_Robbins. The Role of Gut Microbiome An interesting series of observations suggest that the gut microbiome may be involved in the development of obesity. In support of this notion is the finding that the profiles of gut microbiota differ between genetically obese mice and their lean littermates. The microbiome of genetically obese mice can harvest much more energy from food as compared to that of lean mice. Colonization of the gut of germfree mice by microbiota from obese mice (but not microbiota from lean mice) is associated with increased body weight. The relevance of these models to human obesity is tantalizing but remains to be proven. Clinical Consequences of Obesity


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Pathology_Robbins. Clinical Consequences of Obesity Obesity, particularly central obesity, is a known risk factor for a number of conditions, including type 2 diabetes, cardiovascular disease, and cancer. Central obesity also stands at the center of a cluster of alterations known as the metabolic syndrome, characterized by abnormalities of glucose and lipid metabolism coupled with hypertension and evidence of a systemic proinflammatory state. This seems to be caused by the inflammasome response to free fatty acids and excess levels of lipids in cells and tissue. The inflammasome stimulates secretion of IL-1, which induces insulin resistance. The following associations are worthy of note:


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Pathology_Robbins. Obesity is associated with insulin resistance and hyperinsulinemia, important features of type 2 diabetes (Chapter 20). Excess insulin, in turn, may play a role in the retention of sodium, expansion of blood volume, production of excess norepinephrine, and smooth muscle proliferation that are the hallmarks of hypertension. Whatever the mechanism, the risk of developing hypertension among previously normotensive persons increases proportionately with weight. Obese persons generally have hypertriglyceridemia and low HDL cholesterol levels, factors that increase the risk of coronary artery disease. The association between obesity and heart disease is not straightforward, however, and such linkage as there is relates more to the associated diabetes and hypertension than to weight per se. http://ebooksmedicine.net Nonalcoholic fatty liver disease is commonly associated with obesity and type 2 diabetes. It can progress to fibrosis and cirrhosis (Chapter 16).


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Pathology_Robbins. http://ebooksmedicine.net Nonalcoholic fatty liver disease is commonly associated with obesity and type 2 diabetes. It can progress to fibrosis and cirrhosis (Chapter 16). Cholelithiasis (gallstones) is six times more common in obese than in lean subjects. The mechanism is mainly an increase in total body cholesterol, increased cholesterol turnover, and augmented biliary excretion of cholesterol in the bile, which in turn predisposes affected persons to the formation of cholesterol-rich gallstones (Chapter 16). Hypoventilation syndrome is a constellation of respiratory abnormalities in very obese persons. It has been called the pickwickian syndrome, after the fat lad who was constantly falling asleep in Charles Dickens’ The Pickwick Papers. Hypersomnolence, both at night and during the day, is characteristic and is often associated with apneic pauses during sleep (sleep apnea), polycythemia, and eventual right-sided heart failure.


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Pathology_Robbins. Marked adiposity is a predisposing factor for the development of degenerative joint disease (osteoarthritis). This form of arthritis, which typically appears in older persons, is attributed in large part to the cumulative effects of wear and tear on joints. The greater the body burden of fat, the greater the trauma to joints with the passage of time. Markers of inflammation, such as C-reactive protein (CRP) and proinflammatory cytokines like TNF, are often elevated in obese persons. The basis for the inflammation is uncertain; both a direct proinflammatory effect of excess circulating lipids and increased release of cytokines from fat-laden adipocytes have been proposed. Whatever the cause, it is thought that chronic inflammation may contribute to many of the complications of obesity, including insulin resistance, metabolic abnormalities, thrombosis, cardiovascular disease, and cancer.


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Pathology_Robbins. There is an increased incidence of certain cancers in the overweight, including cancers of the esophagus, thyroid, colon, and kidney in men and cancers of the esophagus, endometrium, gallbladder, and kidney in women. Overall, obesity is associated with approximately 20% of cancer deaths in women and 14% of deaths in men. The underlying mechanisms are unknown and are likely to be multiple. Elevated insulin levels. Insulin resistance leads to hyperinsulinemia, which includes multiple effects that may directly or indirectly contribute to cancer. For example, hyperinsulinemia causes a rise in levels of free insulin-like growth factor-1 (IGF-1). IGF-1 is a mitogen, and its receptor, IGFR-1, is highly expressed in many human cancers. IGFR-1 activates the RAS and PI3K/AKT pathways, which promote the growth of both normal and neoplastic cells (Chapter 6).


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Pathology_Robbins. Obesity has effects on steroid hormones that regulate cell growth and differentiation in the breast, uterus, and other tissues. Specifically, obesity increases the synthesis of estrogen from androgen precursors, increases androgen synthesis in ovaries and adrenals, and enhances estrogen availability in obese persons by inhibiting the production of sex-hormone–binding globulin (SHBG) in the liver. As discussed earlier, adiponectin secretion from adipose tissue is reduced in obese individuals. Adiponectin suppresses cell proliferation and promotes apoptosis. It also counteracts the actions of p53 and p21. In obese individuals these anti-neoplastic actions of adiponectin may be compromised. • The proinflammatory state that is associated with obesity may itself be carcinogenic, through mechanisms discussed in Chapter 6.


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Pathology_Robbins. • The proinflammatory state that is associated with obesity may itself be carcinogenic, through mechanisms discussed in Chapter 6. Obesityisadisorderofenergyregulation.Itincreasestheriskforanumberofimportantconditionssuchasinsulinresistance,type2diabetes,hypertension,andhypertriglyceridemia,whichareassociatedwiththedevelopmentofcoronaryarterydisease. Theregulationofenergybalanceisverycomplex.Ithasthreemaincomponents:(1)afferentsignals,providedmostlybyinsulin,leptin,ghrelin,andpeptideYY;(2)thecentralhypothalamicsystem,whichintegratesafferentsignalsandtriggerstheefferentsignals;and(3)efferentsignals,whichcontrolenergybalance. Leptinplaysakeyroleinenergybalance.Itsoutputfromadiposetissuesisregulatedbytheabundanceoffatstores.LeptinbindingtoitsreceptorsinthehypothalamusreducesfoodintakebystimulatingPOMC/CARTneuronsandinhibitingNPY/AgRPneurons.


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Pathology_Robbins. Inadditiontodiabetesandcardiovasculardisease,obesityalsoisassociatedwithincreasedriskforcertaincancers,nonalcoholicfattyliverdisease,andgallstones. The problems of underand overnutrition, as well as specific nutrient deficiencies, have been discussed; however, the composition of the diet, even in the absence of any of these problems, may make a significant contribution to the causation and progression of a number of diseases. A few examples suffice here.


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Pathology_Robbins. Currently, one of the most important and controversial issues is the contribution of diet to atherogenesis. The central question is whether dietary modification— specifically, reduction in the consumption of foods high in cholesterol and saturated animal fats (e.g., eggs, butter, beef)—can reduce serum cholesterol levels and prevent or retard the development of atherosclerosis (of most importance, coronary heart disease) in those with no previous episode of cardiovascular disease. This is called “primary prevention”. We know some but not all the answers. The average adult in the United States consumes a large amount of fat and cholesterol daily, with a ratio of saturated fatty acids to polyunsaturated fatty acids of about 3:1. Lowering the level of saturates to the level of the polyunsaturates causes a 10% to 15% reduction in serum cholesterol within a few weeks. Vegetable oils (e.g., corn and safflower oils) and fish oils contain polyunsaturated fatty acids and are good sources of


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Pathology_Robbins. causes a 10% to 15% reduction in serum cholesterol within a few weeks. Vegetable oils (e.g., corn and safflower oils) and fish oils contain polyunsaturated fatty acids and are good sources of such cholesterol-lowering lipids. Fish oil fatty acids belonging to the omega-3, or n-3, family have more double bonds than do the omega-6, or n-6, fatty acids found in vegetable oils. A corollary of this idea is that supplementation of diet with fish oils might protect against atherosclerosis. One study of Dutch men whose usual daily diet contained 30 g of fish showed a substantially lower frequency of death from coronary heart disease than that among comparable control subjects. However, other studies have shown that omega-3 fatty acid supplements do not reduce the risk of cardiovascular diseases, suggesting that yet unknown components of fish may be required for cardioprotection.


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Pathology_Robbins. http://ebooksmedicine.net Other specific effects of diet on disease have been recognized: Restricting sodium intake reduces hypertension. Dietary fiber, or roughage, resulting in increased fecal bulk, is thought by some investigators to provide a preventive effect against diverticulosis of the colon. Caloric restriction has been convincingly demonstrated to increase life span in experimental animals, including monkeys. The basis for this striking observation is not clear (Chapter 2). Even lowly garlic has been touted to protect against heart disease (and also, alas, against kisses—and the devil), although research has yet to prove this effect unequivocally. With respect to carcinogenesis, three aspects of the diet are of concern: (1) the content of exogenous carcinogens, (2) the endogenous synthesis of carcinogens from dietary components, and (3) the lack of protective factors.


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Pathology_Robbins. • An example of an exogenous carcinogen is aflatoxin, which is an important factor in the development of hepatocellular carcinomas in parts of Asia and Africa. Exposure to aflatoxin causes a specific mutation (codon 249) in the TP53 gene in tumor cells. The mutation can be used as a molecular signature for aflatoxin exposure in epidemiologic studies.


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


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Pathology_Robbins. High animal fat intake combined with low fiber intake has been implicated in the causation of colon cancer. The most convincing explanation for this association is as follows: High fat intake increases the level of bile acids in the gut, which in turn modifies intestinal flora, favoring the growth of microaerophilic bacteria. The bile acids or bile acid metabolites produced by these bacteria might serve as carcinogens or promoters. The protective effect of a high-fiber diet might relate to (1) increased stool bulk and decreased transit time, which decreases the exposure of mucosa to putative offenders, and (2) the capacity of certain fibers to bind carcinogens and thereby protect the mucosa. Attempts to document these theories in clinical and experimental studies have, on the whole, led to contradictory results.


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Pathology_Robbins. • Vitamins C and E, β-carotenes, and selenium have been assumed to have anti-carcinogenic effects because of their anti-oxidant properties. To date, however, no convincing evidence has emerged to show that these antioxidants act as chemopreventive agents. As already mentioned, retinoic acid promotes epithelial differentiation and is believed to reverse squamous metaplasia. Thus, despite many tantalizing trends and proclamations by “diet gurus,” to date there is no definite proof that diet in general can cause or protect against cancer. Nonetheless, concern persists that carcinogens lurk in things as pleasurable as a juicy steak and rich ice cream. Bellinger DC: Lead, Pediatrics 113:1016, 2004. [An excellent overview of the subject.] Boffetta P, Hecht S, Gray N, et al: Smokeless tobacco and cancer, Lancet Oncol 9:667, 2009. [A review of cancer risks associated with smokeless tobacco worldwide.]


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Pathology_Robbins. Boffetta P, Hecht S, Gray N, et al: Smokeless tobacco and cancer, Lancet Oncol 9:667, 2009. [A review of cancer risks associated with smokeless tobacco worldwide.] Casals-Casas C, Desvergne B: Endocrine disruptors: from endocrine to metabolic disruption, Annu Rev Phys 73:135, 2011. [An update discussing the scope and possible consequences of human exposure to this class of chemical.] Global Burden of Disease Study 2010: Lancet, epublished December 13, 2012. [An entire issue of this journal devoted to a detailed summary of the latest global disease data from the GBD project.] Graham C, Mullen A, Whelan K: Obesity and gastrointestinal microbiota: a review of associations and mechanisms, Nutr Rev 73:376, 2016. [A review of the emerging data on the role of the microbiome in obesity.] Gregor MF, Hotamisligil GS: Inflammatory mechanisms in obesity, Annu Rev Immunol 29:445, 2011. [A concise discussion of current views of the proinflammatory state associated with obesity.]


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Pathology_Robbins. Gregor MF, Hotamisligil GS: Inflammatory mechanisms in obesity, Annu Rev Immunol 29:445, 2011. [A concise discussion of current views of the proinflammatory state associated with obesity.] Hanna-Attisha M, LaChance J, Sadler RC, et al: Elevated blood lead levels in children associated with the Flint drinking water crisis: a spatial analysis of risk and public health response, Am J Public Health 106:283, 2016. [An article that discusses public health issues resulting from water pollution with lead in Flint, Michigan, USA.] Hollick MF: Vitamin D deficiency, N Engl J Med 357:266, 2007. [A comprehensive review of vitamin D deficiency.] McCreanor J, Cullinan P, Nieuwenhuijsen MJ, et al: Respiratory effects of exposure to diesel traffic in persons with asthma, N Engl J Med 357:2348, 2007. [A paper discussing the danger of particulates in diesel exhaust to patients with asthma.]


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Pathology_Robbins. Matthew JD, Forsythe AV, Brady Z, et al: Cancer risk in 680,000 people exposed to computed tomography scans in childhood or adolescence: data linkage study of 11 million Australians, BMJ 346:f2360, 2013. [A paper showing that children who have undergone CT scans have a 24% increased risk of cancer, adding to accruing evidence that CT scans increase the risk of secondary cancers in children and adolescents.] Manson JE, Hsia J, Johnson KC, et al: Estrogen plus progestin and the risk of coronary heart disease, N Engl J Med 349:523, 2003. [A landmark study from the Women’s Health Initiative.] Nigro E, Scudiero O, Monaco ML, et al: New insights into adiponectin role in obesity and obesity-related diseases, Biomed Res Int 2014:658913, 2014. doi: 10.1155/2014/658913. Epub July 7, 2014. [Role of adiponectin in fat utilization and other systemic effects.]


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Pathology_Robbins. Pope CA, Ezzati M, Dockery DW: Fine-particulate air pollution and life expectancy in the United States, N Engl J Med 360:376, 2009. [A http://ebooksmedicine.net paper correlating increases in life expectancy in major U.S. cities with decreases in fine-particulate air pollution.] Ravdin PM, Cronin KA, Howlader N, et al: The decrease in breast cancer incidence in 2003 in the United States, N Engl J Med 356:1670, 2007. [A paper documenting the decrease in breast cancer that followed its linkage to menopausal hormone therapy.] Rice KM, Walker EM Jr, Wu M, et al: Environmental mercury and its toxic effects, J Prev Med Public Health 47:74, 2014. [Mercury toxicity review.] Roberts DL, Dive C, Renehan AG: Biological mechanisms linking obesity and cancer risk: new perspectives, Annu Rev Med 61:301, 2010. [A discussion of the possible interactions between obesity and cancer.]


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Pathology_Robbins. Seitz HK, Stickel F: Molecular mechanisms of alcohol-mediated carcinogenesis, Nat Rev Cancer 7:599, 2007. [A review of the multifactorial effects of alcohol that may contribute to cancer development.] Tang X-H, Gudas LJ: Retinoids, retinoic acid receptors, and cancer, Annu Rev Pathol 6:345, 2011. [A review of the role of retinoids in cancer, with a focus on solid tumors.] van der Klaauw AA, Farooqi IS: The hunger genes: pathways to obesity, Cell 161:119, 2015. [A succinct review of the afferent pathways to obesity.] Wilson J, Enriori PJ: A talk between fat tissue, gut, pancreas, and brain to control body weight, Mol Cell Endocrinol 418:108, 2015. [Excellent discussion of the various afferent pathways in obesity.] http://ebooksmedicine.net studentconsult.com General Pathology of Infectious Diseases Categories of Infectious Agents Routes of Entry of Microbes Spread and Dissemination of Microbes Within the Body Transmission of Microbes Mechanisms of Viral Injury


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Pathology_Robbins. Categories of Infectious Agents Routes of Entry of Microbes Spread and Dissemination of Microbes Within the Body Transmission of Microbes Mechanisms of Viral Injury Mechanisms of Bacterial Injury Injurious Effects of Host Immune Responses Humans are prey to thousands of infectious agents ranging from submicroscopic viruses to several meters long tape worms. This chapter reviews the general principles of the pathogenesis of infectious disease and describes the characteristic histopathologic changes caused by different types of microbes. Infections that involve specific organs are discussed in other chapters of this book.


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Pathology_Robbins. Infectious diseases are an important health problem in the United States and worldwide despite the availability of effective vaccines and antibiotics for many types of infections. Influenza and pneumonia combined are the eighth leading cause of death in the United States. In low-income countries, limited access to healthcare, unsanitary living conditions, and malnutrition contribute to a massive burden of infectious diseases. Lower-respiratory infections, HIV/AIDS, and diarrheal diseases are the top three causes of death in developing countries, and malaria and tuberculosis are among the top ten. Infectious diseases are particularly important causes of death among children, older adults, individuals with chronic debilitating diseases and inherited or acquired immunodeficiency states (e.g., AIDS), and in patients receiving immunosuppressive drugs.


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Pathology_Robbins. Infectious agents belong to a wide range of classes and vary greatly in size, ranging from prion protein aggregates of under 20 nm to tapeworms 10 meters in length ( Table 9.1


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Pathology_Robbins. Table 9.1 Prions are composed of abnormal forms of a host protein termed prion protein (PrP). These agents cause transmissible spongiform encephalopathies, including kuru (associated with human cannibalism), hereditary or sporadic Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (BSE) (better known as mad cow disease), and variant Creutzfeldt-Jakob disease (vCJD) (probably transmitted to humans through consumption of meat from BSE-infected cattle). PrP is found normally in neurons. Diseases occur when the PrP undergoes a conformational change that confers resistance to proteases. The protease-resistant PrP promotes conversion of the normal protease-sensitive PrP to the abnormal form, explaining the transmissable nature of these diseases. CJD can be transmitted from person to person iatrogenically, by surgery, organ transplantation, or blood transfusion. These diseases are discussed in detail in Chapter 23.


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Pathology_Robbins. Viruses are obligate intracellular parasites that depend on the host cell’s metabolic machinery for their replication. They consist of a nucleic acid genome surrounded by a protein coat (called a capsid) that is sometimes encased in a lipid membrane. Viruses are classified by their nucleic acid genome (DNA or RNA, but not both), the shape of the capsid (icosahedral or helical), the presence or absence of a lipid envelope, their mode of replication, their preferred cell type for replication (called tropism), or the type of http://ebooksmedicine.net Table 9.1 Classes of Human Pathogens pathology they cause. Some viral components and particles aggregate within infected cells and form characteristic inclusion bodies, which may be seen with the light microscope and are useful for diagnosis (


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Pathology_Robbins. Fig. 9.1 ). For example, cytomegalovirus (CMV)-infected cells are enlarged and show a large eosinophilic nuclear inclusion and smaller basophilic cytoplasmic inclusions; herpesviruses form a large nuclear inclusion surrounded by a clear halo; and both smallpox and rabies viruses form characteristic cytoplasmic inclusions. However, many viruses (e.g., poliovirus) do not produce inclusions. Accounting for a large share of human infections, viruses can cause disease in several ways (


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Pathology_Robbins. Table 9.2 ). Many viruses cause transient illnesses (e.g., colds, influenza). Other viruses are not eliminated from the body and persist within cells of the host for years, either continuing to multiply (e.g., chronic infection with hepatitis B virus [HBV]) or survive in some latent nonreplicating form, with the potential to be reactivated later. For example, herpes zoster virus, the cause of chickenpox, can enter dorsal root ganglia and establish latency at the site, with periodic reactivation at later times to cause shingles, a painful skin condition. Some viruses are involved in transformation of a host cell into a benign or malignant tumor (e.g., human papillomavirus [HPV]-induced benign warts and cervical carcinoma). Different species of viruses can produce the same clinical picture (e.g., adenovirus and rhinovirus causing upper respiratory infection); conversely, a single virus can cause different clinical manifestations depending on the age or immune status of the host (e.g.,


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Pathology_Robbins. (e.g., adenovirus and rhinovirus causing upper respiratory infection); conversely, a single virus can cause different clinical manifestations depending on the age or immune status of the host (e.g., CMV causing congenital neurologic damage or gastroenteritis in the immunocompromised).


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Pathology_Robbins. Bacteria are prokaryotes, meaning that they have a cell membrane but lack membrane-bound nuclei and other membrane-enclosed organelles. Most bacteria are bounded by a cell wall consisting of peptidoglycan, a polymer of long sugar chains linked by peptide bridges surrounding the cell membrane. There are two common forms of cell wall structure: a thick wall that retains crystal-violet stain (gram-positive bacteria) and a thin cell wall surrounded by an outer membrane (gram-negative bacteria) ( Fig. 9.2 ). Bacteria are classified by Gram staining (positive or negative), shape (spherical, called cocci, or rod-shaped, called bacilli) (


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Pathology_Robbins. Fig. 9.2 ). Bacteria are classified by Gram staining (positive or negative), shape (spherical, called cocci, or rod-shaped, called bacilli) ( Fig. 9.3 ), and their requirement for oxygen (aerobic or anaerobic). Motile bacteria have flagella, long helical filaments extending from the cell surface that rotate and move the bacteria. Some bacteria possess pili, another kind of surface projection that can attach bacteria to host cells or extracellular matrix. Bacteria synthesize their own DNA, RNA, and proteins, but they depend on the host for favorable growth conditions. Many bacteria remain extracellular when they grow in the host, while


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Pathology_Robbins. Fig. 9.1 Examplesofviralinclusions.(A)Cytomegalovirusinfectioninthelung.Infectedcellsshowdistinctnuclear(long arrow) andill-definedcytoplasmic(short arrows) inclusions.(B)Varicella-zostervirusinfectionintheskin.Herpessimplexvirusandvaricella-zostervirusbothcausecharacteristiccytopathologicchanges,includingfusionofepithelialcells,whichproducesmultinucleatecellswithmoldingofnucleitooneanother(long arrow), andeosinophilichaloednuclearinclusions(short arrow). (C)HepatitisBviralinfectioninliver.Inchronicinfections,infectedhepatocytesshowdiffusegranular(“ground-glass”)cytoplasm,reflectingaccumulatedhepatitisBsurfaceantigen(HBsAg). http://ebooksmedicine.net Table 9.2 Selected Human Viral Diseases and Their Pathogens AIDS, Acquiredimmunodeficiencysyndrome;HIV, humanimmunodeficiencyvirus.


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Pathology_Robbins. http://ebooksmedicine.net Table 9.2 Selected Human Viral Diseases and Their Pathogens AIDS, Acquiredimmunodeficiencysyndrome;HIV, humanimmunodeficiencyvirus. others can survive and replicate both outside and inside of host cells (facultative intracellular bacteria such as mycobacteria), and some grow only inside host cells (obligate intracellular bacteria, such as rickettsia). Bacteria cause a range of infections from common pharyngitis and urinary tract infections to rare diseases such as leprosy (


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Pathology_Robbins. Table 9.3 ). Chlamydia and Rickettsia are obligate intracellular bacteria that replicate inside membrane-bound vacuoles in epithelial and endothelial cells, respectively. These bacteria get most or all of their energy source, ATP, from the host cell. Chlamydia trachomatis is a frequent infectious cause of female sterility (by scarring and narrowing of the fallopian tubes) and blindness (by chronic inflammation of the conjunctiva that eventually causes scarring and opacification of the cornea). Rickettsiae injure the endothelial cells in which they grow, causing a hemorrhagic vasculitis, often visible as a rash, but they also may injure the central nervous system (CNS), with potentially fatal outcome, as in Rocky Mountain spotted fever and epidemic typhus. Rickettsiae are transmitted by arthropod vectors, including lice (in epidemic typhus), ticks (in Rocky Mountain spotted fever and ehrlichiosis), and mites (in scrub typhus).


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Pathology_Robbins. Mycoplasma and the related genus Ureaplasma are unique among extracellular bacterial pathogens in that they do not have a cell wall. These are the tiniest free-living organisms known (125 to 300 nm). Fungi are eukaryotes with thick cell walls composed of complex carbohydrates such as beta-glucans, chitin, and mannosylated glycoproteins. Calcofluor-white, a Immune-evasion protein (e.g., M protein) (e.g., protein F) Teichoic acid Fig. 9.2 Moleculesonthesurfaceofgram-negativeandgram-positivebacteriainvolvedinthepathogenesisofinfection. http://ebooksmedicine.net Table 9.3 Selected Human Bacterial Diseases and Their Pathogens ActinomycetalinfectionsNocardia asteroides complex Pulmonarydisease,brainabscessActinomyces israelii Headandneckabscess


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Pathology_Robbins. Fig. 9.3 Bacterialmorphologies.Thebacteriaareindicatedbyarrows.(A)Gramstainpreparationofsputumfromapatientwithpneumonia.Gram-positive,elongatedcocciinpairsandshortchains(Streptococcus pneumoniae) andaneutrophilareevident.(B)Gramstainpreparationofabronchoalveolarlavagespecimenshowinggram-negativeintracellularrodstypicalofmembersofEnterobacteriaceae suchasKlebsiella pneumoniae or Escherichia coli. (C)SilverstainpreparationofbraintissuefromapatientwithLymediseasemeningoencephalitis.Twohelicalspirochetes(Borrelia burgdorferi) areshown(arrows). (A),(B),and(C)areatdifferentmagnifications.(Aand C,Courtesy of Dr. Kenneth Van Horn, Focus Diagnostics, Cypress, California. B,Courtesy of Dr. Karen Krisher, Clinical Microbiology Institute,Wilsonville, Oregon.) http://ebooksmedicine.net fluorescent stain that binds chitin, provides a useful way to identify fungi in patient specimens. Assays for betaglucans in blood are used to diagnose disseminated fungal infections. Fungi can grow either as


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Pathology_Robbins. stain that binds chitin, provides a useful way to identify fungi in patient specimens. Assays for betaglucans in blood are used to diagnose disseminated fungal infections. Fungi can grow either as rounded yeast cells or as slender, filamentous hyphae. An important distinguishing characteristic is whether hyphae are septate (with cell walls separating individual cells) or aseptate. Some of the most important pathogenic fungi exhibit thermal dimorphism; that is, they grow as hyphal forms at room temperature but as yeast forms at body temperature. Fungi may produce sexual spores or, more commonly, asexual spores called conidia. The latter are produced on specialized structures or fruiting bodies arising along the hyphal filament.


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Pathology_Robbins. Fungi may cause superficial or deep infections. Superficial infections involve the skin, hair, and nails. Fungal species that cause superficial infections are called dermatophytes. Infection of the skin is called tinea; thus, tinea pedis is “athlete’s foot” and tinea capitis is scalp ringworm. Certain fungi invade the subcutaneous tissue, causing abscesses or granulomas. Chronic infections, often in the foot, are called mycetomas. Deep fungal infections can spread systemically and invade tissues, destroying vital organs in immunocompromised hosts, but usually resolve or remain latent in otherwise normal hosts. Fungi are divided into endemic and opportunistic species. Endemic fungi are invasive species that are usually limited to particular geographic regions (e.g., Coccidioides in the southwestern United States, Histoplasma in the Ohio River Valley).


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Pathology_Robbins. Endemic fungi are invasive species that are usually limited to particular geographic regions (e.g., Coccidioides in the southwestern United States, Histoplasma in the Ohio River Valley). Opportunistic fungi (e.g., Candida, Aspergillus, Mucor, Cryptococcus), by contrast, are ubiquitous organisms that either colonize individuals or are encountered from environmental sources but do not cause severe disease in healthy individuals. In immunodeficient individuals, opportunistic fungi give rise to life-threatening invasive infections characterized by vascular occlusion, hemorrhage, and tissue necrosis, with little or no inflammatory response ( Fig. 9.4 ). Patients with AIDS are very susceptible to infection with the opportunistic fungus Pneumocystis jiroveci (previously called Pneumocystis carinii).


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Pathology_Robbins. Protozoa are single-celled eukaryotes that are major causes of disease and death in developing countries. Protozoa can replicate intracellularly within a variety of cells (e.g., Plasmodium in red cells, Leishmania in macrophages) or extracellularly in the urogenital system, intestine, or blood. Trichomonas vaginalis organisms are sexually transmitted flagellated protozoal parasites that often colonize the vagina and male urethra. The most prevalent pathogenic intestinal protozoans, Entamoeba histolytica and Giardia lamblia, are ingested as nonmotile cysts in contaminated food or water and become motile trophozoites that attach to intestinal epithelial cells. Bloodborne protozoa (e.g., Plasmodium, Trypanosoma, Leishmania) are transmitted by insect vectors, in which they replicate before being passed to new human hosts. Toxoplasma gondii is acquired either through contact with oocyst-shedding cats or by eating cyst-ridden, undercooked meat.


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Pathology_Robbins. Fig. 9.4 MeningealbloodvesselswithangioinvasiveMucor species.Notetheirregularwidthandnearright-anglebranchingofthehyphae(arrow). (Courtesy of Dr. Dan Milner, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts.)


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Pathology_Robbins. Parasitic worms are highly differentiated multicellular organisms. Their life cycles are complex; most alternate between sexual reproduction in the definitive host and asexual multiplication in an intermediate host or vector. Thus, depending on the species, humans may harbor adult worms (e.g., Ascaris lumbricoides), immature stages (e.g., Toxocara canis), or asexual larval forms (e.g., Echinococcus spp.). Once adult worms take up residence in humans, they usually do not multiply but they produce eggs or larvae that typically are passed in stool. Often, the severity of disease is proportional to the number of infecting organisms. For example, a burden of 10 hookworms is associated with mild or no clinical disease, whereas 1000 hookworms consume enough blood to cause severe anemia. In some helminthic infections, such as schistosomiasis, disease is caused by inflammatory responses to the eggs or larvae rather than the adult worms. Helminths comprise three groups:


Pathology_Robbins

Pathology_Robbins. Helminths comprise three groups: Roundworms (nematodes) are circular in cross-section and nonsegmented. Intestinal nematodes include A. lumbricoides, Strongyloides stercoralis, and hookworms. Nematodes that invade tissues include the filariae, such as Wuchereria bancrofti and Trichinella spiralis ( Fig. 9.5 Tapeworms (cestodes) have a head (scolex) and a ribbon of multiple flat segments (proglottids). They adsorb nutrition through their tegument and do not have a digestive tract. They include the fish, beef, and pork tapeworms that make their home in the human intestine. The larvae that develop after ingestion of eggs of certain tapeworms can cause cystic disease within tissues (Echinoccus granulosus larvae cause hydatid cysts; pork tapeworm larvae produce cysts called cysticerci in many organs). Flukes (trematodes) are leaf-shaped flatworms with prominent suckers that are used to attach to the host. They include liver and lung flukes and schistosomes. http://ebooksmedicine.net


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Pathology_Robbins. Flukes (trematodes) are leaf-shaped flatworms with prominent suckers that are used to attach to the host. They include liver and lung flukes and schistosomes. http://ebooksmedicine.net Fig. 9.5 CoiledTrichinella spiralis larvawithinaskeletalmusclecell. Ectoparasites are insects (e.g., lice, bedbugs, fleas) or arachnids (e.g., mites, ticks, spiders) that cause disease by biting or by attaching to and living on or in the skin. Infestation of the skin by arthropods is characterized by itching and excoriations, such as pediculosis caused by lice attached to hairs, or scabies caused by mites burrowing into the stratum corneum. At the site of bites, mouth parts may be found associated with a mixed infiltrate of lymphocytes, macrophages, and eosinophils. Arthropods also can serve as vectors for other pathogens, such as Borrelia burgdorferi, the agent of Lyme disease, which is transmitted by deer ticks.


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Pathology_Robbins. The microbiome is the diverse microbial population of bacteria, fungi, and viruses found in or on the human body (e.g., in the intestinal tract, skin, upper airway, and vagina). While most of these organisms do not harm the healthy host, a few cause diseases such as skin and soft-tissue infections (Staphylococcus aureus and Streptococcus pyogenes), acne (Propionibacterium acnes), and tooth decay (Streptococcus mitus). The microbiome has important roles in normal health and development. In the intestinal tract, the normal flora are responsible for absorption of digested foods, for maintaining the integrity of the epithelium and the normal functioning of the intestinal immune system, and for competitively inhibiting invasion and colonization by potentially pathogenic microbes. The gut microbiome is also emerging as a regulator of nutritional status.


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Pathology_Robbins. New techniques of bacterial identification relying on ribosomal RNA sequencing have dramatically improved our understanding of the microbiome: In healthy individuals, the microbiome is very diverse. For example, there are estimated to be over 1000 species of bacteria in the normal intestinal flora of an individual. In a healthy person, a part of the bacterial population at various body sites is relatively stable over time, but may be altered by diet and environment. The diversity of bacteria is greatest in the oral cavity and the stool, intermediate on the skin, and least in the vagina. The bacterial microbiomes at various body sites are partially similar in different individuals. Dysbiosis refers to changes in composition of the microbiome that are associated with disease. These changes may result from therapies or various pathophysiologic conditions, including the following:


Pathology_Robbins

Pathology_Robbins. Use of some antibiotics is an important risk factor for intestinal infections caused by toxin-producing Clostridium difficile. These antibiotics kill or inhibit normal commensal bacteria, allowing overgrowth of C. difficile. Restoration of the microbiome by duodenal infusion of stool containing commensal flora from healthy donors successfully treats C. difficile infection in many individuals who have relapsed after antibiotic therapy. The microbiome in the stool of obese individuals is less diverse than that of lean individuals, and the proportions of bacterial phyla differ as well. The proportions of these phyla in obese individuals who change their diet and lose weight shifts to resemble that of lean individuals. Experimental animals gain more weight when colonized with bacterial populations associated with a high-fat diet than when colonized with bacterial populations associated with a normal diet.


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Pathology_Robbins. The intestinal bacterial populations in individuals with inflammatory bowel disease are altered, with reduced diversity and changes in the proportions of bacterial phyla, compared to individuals without inflammatory bowel disease. Interestingly, inflammatory bowel disease also is associated with changes in the viral populations in stool. The specific roles of different viruses and bacteria in gastrointestinal dysbiosis is an area of very active investigation. There are several methods for identifying microorganisms in tissue and body fluids: Culture. Bacterial and fungal cultures remain essential for diagnostic testing, in conjunction with additional methods, but culture of viruses has been replaced to a great extent by alternative methods.


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Pathology_Robbins. Histology. Some infectious agents can be seen in hematoxylin and eosin (H&E)–stained sections (e.g., the inclusion bodies formed by CMV and herpes simplex virus (HSV); bacterial clumps, which usually stain blue; Candida and Mucor among the fungi; most protozoans; all helminths). Many infectious agents, however, are better visualized by special stains that identify organisms on the basis of particular characteristics of their cell wall or coat—Gram, acid-fast, silver, mucicarmine, and Giemsa stains—or after labeling with specific antibodies ( Table 9.4 ). Organisms are usually best visualized at the advancing edge of a lesion rather than at its center, particularly if there is necrosis. Serology. Acute infections can be diagnosed serologically by detecting pathogen-specific antibodies in the serum. The presence of specific immunoglobulin M (IgM) antibody shortly after the onset of symptoms is often diagnostic. Alternatively, specific antibody titers http://ebooksmedicine.net


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Pathology_Robbins. Table 9.4 Techniques for Identifying Infectious Agents Acid-faststainMycobacteria,nocardiae(modified) SilverstainFungi,legionellae,Pneumocystis Periodicacid–SchiffstainFungi,amebae GiemsastainLeishmaniae,Plasmodium Proteomicmethods/massBacteria,mycobacteria,fungispectrometry can be measured early (“acute”) and again at 4 to 6 weeks (“convalescent”) after infection; a 4-fold rise in titer usually is considered diagnostic. Assays for serum antibodies are very useful for the diagnosis of viral hepatitis. Antibodies that are not pathogen-specific are produced by patients with syphilis or infectious mononucleosis, and assays for these cross-reacting antibodies are used in diagnosis.


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Pathology_Robbins. Molecular diagnostics. Nucleic acid amplification techniques, such as polymerase chain reaction (PCR) and transcription-mediated amplification, are used for diagnosis of gonorrhea, chlamydial infection, tuberculosis, and herpes encephalitis. Molecular assays are much more sensitive than conventional testing for some pathogens. PCR testing of cerebrospinal fluid (CSF) for HSV encephalitis has a sensitivity of about 80%, whereas viral culture of CSF has a sensitivity of less than 10%. Similarly, nucleic acid tests for genital Chlamydia detect 10% to 30% more cases than conventional Chlamydia culture does. For other infections, such as gonorrhea, the sensitivity of nucleic acid testing is similar to that of culture. Quantitative PCR for BK virus, CMV, and Epstein-Barr virus (EBV) is used to assess viral loads in transplant recipients. Molecular panels for detection of 20 or more pathogens are now routinely used to diagnose respiratory bacterial and viral infections, as well as


Pathology_Robbins

Pathology_Robbins. used to assess viral loads in transplant recipients. Molecular panels for detection of 20 or more pathogens are now routinely used to diagnose respiratory bacterial and viral infections, as well as gastrointestinal bacterial, viral and parasitic infections. Quantitative assays for viral nucleic acids are used to guide the medical management of patients infected with human immunodeficiency virus (HIV), HBV, and hepatitis C virus (HCV). Next-generation sequencing, with or without initial PCR amplification, is being used for the detection of novel or rare pathogens, and for epidemiologic investigations.


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Pathology_Robbins. Proteomics. Mass spectrometry can be used to identify microorganisms based on protein content and has been introduced into routine clinical laboratories. It has the advantage of rapid identification of the bacterial species but is not useful for antibiotic sensitivity. That still requires culture. A surprising number of new infectious agents continue to be discovered, and there are several reasons for this: • Some pathogens were discovered due to improved methods of detection, although they have likely been present in humans for centuries. For example, Helicobacter pylori, which causes gastritis and peptic ulcer disease, was only discovered in the 1980s. More recently, a new cause of leprosy was discovered, Mycobacterium lepromatosis. This agent, identified by sequencing bacterial DNA from biopsy material of patients who died of leprosy, is a close relative of the previously known Mycobacterium leprae.


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Pathology_Robbins. Mycobacterium leprae. Animals are a source of new pathogens that infect humans. Two coronaviruses that cause severe respiratory tract infections in humans, Middle East respiratory syndrome coronavirus (MERS CoV) and the severe acute respiratory syndrome (SARS) virus, likely spread to humans from animals and were first detected in 2003 and 2012, respectively. Other examples of pathogens that emerged in humans after being transmitted from animals include HIV and B. burgdorferi. Microorganisms can acquire genes that enhance virulence or overcome host defense. In 2011, almost 4000 individuals in Germany were infected with a new strain of highly virulent shiga-toxin producing Escherichia coli that spread in sprout seeds. The new strain was derived from a different type of E. coli that acquired a gene for the shiga-toxin from a bacteriophage.


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Pathology_Robbins. Other pathogens have become much more common because of immunosuppression caused by AIDS, or therapy to prevent transplant rejection or treat cancers (e.g., human herpes virus 8, Mycobacterium avium complex, P. jirovecii).


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Pathology_Robbins. Additional clinical syndromes may be recognized after the pathogen has been known for some time, possibly due to new contributing factors. Although Zika virus was discovered in 1947 in Uganda, very few human cases were reported for many years, until the virus more recently spread through additional countries, expanding the range from Africa, Asia, and the Pacific to the Americas, causing newly recognized clinical cases. The virus is contracted primarily via the Aedes species mosquito but also via sexual transmission and possibly blood transfusion. Although many individuals infected have no or mild nonspecific symptoms, infection may be associated with Guillain-Barre syndrome, a form of rapid-onset muscle weakness caused by immune system damage to the nervous system. Infection with Zika virus during pregnancy is associated with birth defects, including microcephaly. Many more congenital cases were diagnosed in the 2015 outbreak beginning in Brazil compared to earlier outbreaks,


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Pathology_Robbins. Zika virus during pregnancy is associated with birth defects, including microcephaly. Many more congenital cases were diagnosed in the 2015 outbreak beginning in Brazil compared to earlier outbreaks, creating a Public Health Emergency of International Concern. Further investigation is ongoing to determine if other variables may be contributing to the CNS effects such as genetics, co-infections, immunity from past infections, or yet to be defined environmental factors.


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Pathology_Robbins. http://ebooksmedicine.net Several factors contribute to the emergence of infectious diseases: Human behavior affects the spread and demographics of infections. AIDS was first recognized in the United States as predominantly a disease of homosexual men and drug abusers, but heterosexual transmission is now more common. In sub-Saharan Africa, the area of the world with the highest number of AIDS cases, it is predominantly a heterosexual disease. The Ebola virus epidemic of 2014 spread to more countries than previous Ebola outbreaks due in part to the frequent movement of people across borders in West Africa, as well as burial practices that involved contact with the bodies of the deceased. SARS, mentioned earlier, spread very quickly to 24 countries due to human air travel before it was contained.


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Pathology_Robbins. Changes in the environment occasionally increase the incidence of infectious diseases. Regrowth of forests in the eastern United States with cessation of farming has led to massive increases in deer and mice, which carry the ticks that transmit Lyme disease, babesiosis, and ehrlichiosis. Global warming also has had an impact on the spread of infections. For example, the mosquitoes that carry Dengue fever and Zika viruses, which used to be confined to the U.S.-Mexican border, are now found in more than half of the states. Chikungunya virus transmitted by mosquitoes, which causes fever and joint pain that can be severe for some, was first seen in the Americas in 2013, and transmission of Dengue and Zika viruses has recently been reported in Florida.


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Pathology_Robbins. Infectious diseases that are common in one geographic area may be introduced into a new area due to increased travel or movement of infected animals, invertebrates, or birds. For example, West Nile virus has been common in Europe, Asia, and Africa for years but was first described in the United States in 1999, possibly transported by an infected mosquito or bird. Highly pathogenic H5 influenza viruses, which have led to death of some patients in Asia, have spread throughout the world during the last 2 decades in bird populations, due to their natural migration and transport of domestic birds.


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Pathology_Robbins. Pathogens adapt rapidly to selective pressures exerted by widespread use of antibiotics. Antibiotic resistance has developed and is now common in Mycobacterium tuberculosis, Neisseria gonorrhoeae, Klebsiella pneumoniae, and S. aureus. Similarly, development of drug-resistant parasites has dramatically increased the morbidity and mortality associated with Plasmodium falciparum infection in Asia, Africa, and Latin America. Sadly, the anthrax attacks in the United States in 2001 transformed the theoretical threat of bioterrorism into reality. The Centers for Disease Control and Prevention (CDC) has evaluated the danger microorganisms pose as weapons on the basis of the efficiency with which disease can be transmitted, how difficult the microorganisms are to produce and distribute, what can be done to defend against them, and the extent to which they are likely to Table 9.5 Potential Agents of Bioterrorism Anthrax:Bacillus anthracis Botulism:Clostridium botulinum toxin


Pathology_Robbins

Pathology_Robbins. Table 9.5 Potential Agents of Bioterrorism Anthrax:Bacillus anthracis Botulism:Clostridium botulinum toxin Plague:Yersinia pestis Smallpox:Variola major virus Tularemia:Francisella tularensis Viralhemorrhagicfevers:Ebola,Marburg,Lassa,others Brucellosis:Brucella spp. Foodsafetythreats:Salmonella spp.,Escherichia coli O157:H7,Shigella, others Glanders:Burkholderia mallei Melioidosis:Burkholderia pseudomallei Psittacosis:Chlamydia psittaci Qfever:Coxiella burnetii Typhusfever:Rickettsia prowazekii Mosquito-borneencephalitisviruses:Venezuelanequineencephalitis,Easternequineencephalitis,Westernequineencephalitis,others Watersafetythreats:Vibrio cholerae, Cryptosporidium parvum, others Emerginginfectiousdiseasethreats:Nipahvirus,hantavirus,others http:// emergency.cdc.gov alarm the public and produce widespread fear. Based on these criteria, the CDC has ranked bioweapons into three categories, designated A, B, and C ( Table 9.5


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Pathology_Robbins. Table 9.5 The agents in the highest-risk category A can be readily disseminated or transmitted from person to person, typically cause diseases that carry a high mortality rate with potential for major public health impact, may cause pandemics leading to widespread panic and social disruption, and are likely to require special action for public health preparedness. For example, the smallpox virus is a category A agent because of its high transmissibility, case mortality rates of 30% or greater, and the lack of effective therapy. Smallpox readily spreads from person to person, mainly through respiratory secretions and by direct contact with virus in skin lesions. Since routine smallpox vaccination ended in the United States in 1972, immunity has waned, leaving the population highly susceptible. Concern that smallpox could be used for bioterrorism has led to reinstitution of vaccination for some medical and military personnel.


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Pathology_Robbins. Category B agents are less easy to disseminate, cause disease associated with moderate morbidity but low mortality, and require specific diagnostic and disease surveillance. Many of these agents can be spread in food or water. Category C agents include emerging pathogens that could be engineered for mass dissemination because of ease of availability, production, and dissemination; the potential for high morbidity and mortality; and great impact on health. http://ebooksmedicine.net Microbes can enter the host through several body surfaces and, once in the host, can disseminate by different routes.


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Pathology_Robbins. http://ebooksmedicine.net Microbes can enter the host through several body surfaces and, once in the host, can disseminate by different routes. Microbes can enter the host through breaches in the skin, by inhalation or ingestion, or by sexual transmission. The first defenses against infection are intact skin and mucosal surfaces, which provide physical barriers and produce anti-microbial substances. In general, respiratory, gastrointestinal, or genitourinary tract infections that occur in otherwise healthy individuals are caused by relatively virulent microorganisms that are capable of damaging or penetrating intact epithelial barriers. By contrast, most skin infections in healthy individuals are caused by less virulent organisms that breach the skin through damaged sites ( Table 9.6


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Pathology_Robbins. Table 9.6 The dense, keratinized outer layer of skin is a natural barrier to infection; furthermore, the low pH of the skin (less than 5.5) combined with the presence of fatty acids inhibit growth of microorganisms other than the normal bacteria and fungi. Included among these normal flora are potential opportunists, such as S. aureus and Candida albicans. Cutaneous infections are typically acquired by entry of microbes through breaks in the skin, including wounds


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Pathology_Robbins. Table 9.6 Routes of Microbial Infection or surgical incisions (Staphylococci), burns (Pseudomonas aeruginosa), and diabetic and pressure-related foot sores (multibacterial infections). Intravenous catheters in hospitalized patients provide portals for local or systemic infection. Needle sticks can expose the recipient to infected blood and transmit HBV, HCV, or HIV. Some pathogens penetrate the skin via an insect or animal bite. Bites by fleas, ticks, mosquitoes, mites, and lice break the skin and transmit arboviruses (causes of yellow fever and encephalitis), bacteria (plague, Lyme disease, Rocky Mountain spotted fever), protozoa (malaria, leishmaniasis), and helminths (filariasis). Animal bites can lead to infections with bacteria, such as Pasteurella, or viruses, such as rabies. Only a few microorganisms are able to cross the skin barrier directly. For example, Schistosoma larvae released from freshwater snails penetrate swimmers’ skin by releasing enzymes that dissolve the


Pathology_Robbins

Pathology_Robbins. Only a few microorganisms are able to cross the skin barrier directly. For example, Schistosoma larvae released from freshwater snails penetrate swimmers’ skin by releasing enzymes that dissolve the extracellular matrix, traversing unbroken skin. Similarly, certain fungi (dermatophytes) can infect intact stratum corneum of the skin, hair, and nails.


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Pathology_Robbins. Gastrointestinal pathogens are transmitted by food or drink contaminated with fecal material. When hygiene fails, as may occur with natural disasters such as floods and earthquakes, diarrheal disease becomes rampant. Acidic gastric secretions are important defenses and are lethal for many gastrointestinal pathogens. Healthy volunteers do not become infected by Vibrio cholerae unless they are fed 1011 organisms, but neutralizing the stomach acid reduces the infectious dose by 10,000-fold. By contrast, some Basis for Failure of Local Pathogen/Disease Site Major Local Defense(s) Defense (Examples) http://ebooksmedicine.net ingested agents, such as Shigella and Giardia cysts, are relatively resistant to gastric acid, so fewer than 100 organisms can cause illness.


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Pathology_Robbins. Other normal defenses within the gastrointestinal tract include (1) the layer of viscous mucus covering the intestinal epithelium, (2) lytic pancreatic enzymes and bile detergents, (3) mucosal anti-microbial peptides called defensins, (4) normal flora, and (5) secreted IgA antibodies. IgA antibodies are made by plasma cells located in mucosa-associated lymphoid tissue (MALT). These lymphoid aggregates are covered by a single layer of specialized epithelial cells called M cells, which are important for transport of antigens to MALT. Numerous gut pathogens use M cells to enter the host from the intestinal lumen, including poliovirus, enteropathic E. coli, V. cholerae, Salmonella enterica serotype Typhi, and Shigella flexneri.


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Pathology_Robbins. Infection via the gastrointestinal tract occurs when local defenses are weakened or the organisms develop strategies to overcome these defenses. Host defenses are weakened by low gastric acidity, by antibiotics that alter the normal bacterial flora (e.g., in pseudomembranous colitis due to C. difficile), or when there is stalled peristalsis or mechanical obstruction. Viruses that can enter the body through the intestinal tract (e.g., hepatitis A, rotavirus) are those that lack envelopes, because enveloped viruses are inactivated by bile and digestive enzymes. Enteropathogenic bacteria cause gastrointestinal disease in several ways: Toxin production in food. S. aureus and Bacillus cereus can contaminate and grow in food, where they release powerful enterotoxins that, when ingested, cause food poisoning without any bacterial growth in the gut.