Pathology (environmental 4)

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

• In contrast to an incision, most lacerations have intact bridging blood vessels and jagged, irregular edges
• Laceration--> Blunt object
• Incision--> sharp object

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

fire or scalding, the latter being a major cause of injury in children. 

• Superficial burns (formerly known as first-degree burns) are confined to the epidermis.
• Partial thickness burns (formerly known as second-degree burns) involve injury to the dermis.  
• Full-thickness burns (formerly known as third-degree burns) extend to the subcutaneous tissue. Full-thickness burns may also involve damage to muscle tissue underneath the subcutaneous tissue (these were known formerly as fourth-degree burns)

Shock, sepsis, and respiratory insufficiency

• Particularly in burns of more than 20% of the body surface, there is a rapid (within hours) shift of body fluids into the interstitial compartments, both at the burn site and systemically, which can result in hypovolemic shock.
• Because protein from the blood is lost into interstitial tissue, generalized edema, including pulmonary edema, can be severe

excess heat loss and an increased need for nutritional support

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

Removal of the burn wound

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

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

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

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

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

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

marked generalized vasodilation, with peripheral pooling of blood and a decreased effective circulating blood volume

nitrosylation of the ryanodine receptor type 1 (RYR1) in skeletal muscle

• RYR1 is located in the sarcoplasmic reticulum and regulates the release of calcium into the cytoplasm.
• Inherited mutations in RYR1 occur in the condition called malignant hyperthermia, characterized by a rise in core body temperature and muscle contractures in response to exposure to common anesthetics. 
• RYR1 mutations may also increase the susceptibility to heat stroke
• Necrosis of the muscles (rhabdomyolysis) and myocardium may occur as a consequence of the nitrosylation of the ryanodine receptor type 1 (RYR1) in skeletal muscle

• Prolonged exposure to low ambient temperature leads to hypothermia, a condition seen all too frequently in homeless persons.
• High humidity, wet clothing, and dilation of superficial blood vessels resulting from the ingestion of alcohol hasten the lowering of body temperature

loss of consciousness/bradycardia and atrial fibrillation

• Direct effects are probably mediated by physical disruptions within cells by high salt concentrations caused by the crystallization of intra- and extracellular water.  
• Indirect effects resulting from circulatory changes, which vary depending on the rate and duration of the temperature drop. Slowly developing chilling may induce vasoconstriction and increased vascular permeability, leading to edema and hypoxia. Such changes are typical of “trench foot.” frequently causing gangrene that necessitated amputation. With sudden, persistent chilling, the vasoconstriction and increased viscosity of the blood in the local area may cause ischemic injury and degenerative changes in peripheral nerves. In this situation, the vascular injury and increased permeability with exudation become evident only after the temperature begins to return to normal. However, during the period of ischemia, hypoxic changes and infarction of the affected tissues may develop (e.g., gangrene of toes or feet).

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

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

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

acute electrical cardiac injury can result in sudden cardiac arrest due to asystole (usually with DC current or lightning) or ventricular fibrillation (AC current) 

• LV--> superficial
• HV--> deep
• Lightening-->rare

• Light: Direct CNS injury
• HV: Indirect trauma or tetanic contraction of respiratory muscles
• LV: Tetanic contractions of respiratory muscles

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

At equivalent amounts of energy, alpha particles induce heavy damage in a restricted area, whereas x-rays and gamma rays dissipate energy over a longer, deeper course, and produce considerably less damage per unit of tissue

• Curie (Ci) represents the disintegrations per second of a radionuclide (radioisotope). One Ci is equal to 3.7 × 1010 disintegrations per second. This is an expression of the amount of radiation emitted by a source.  
• Gray (Gy) is a unit that expresses the energy absorbed by the target tissue per unit mass. It corresponds to the absorption of 104 erg/gm of tissue. The centigray (cGy), which is the absorption of 100 erg/gm of tissue, is equivalent to the exposure of tissue to 100 Rads (radiation absorbed dose), abbreviated as R. The cGy terminology has now replaced R.  
• Sievert (Sv) is a unit of equivalent dose that depends on the biologic rather than the physical effects of radiation (it replaced a unit called “rem”). For the same absorbed dose, various types of radiation differ in the extent of damage they produce. The equivalent dose controls for this variation and thereby provides a uniform measure of biologic dose. The equivalent dose (expressed in Sieverts) corresponds to the absorbed dose (expressed in Grays) multiplied by the relative biologic effectiveness of the radiation. The relative biologic effectiveness depends on the type of radiation, the type and volume of the exposed tissue, the duration of the exposure, and some other biologic factors. The effective dose of x-rays in radiographs and computed tomography is commonly expressed in millisieverts (mSv). For x-radiation, 1 mSv = 1 mGy

• Rate of delivery
• Field size
• Cell proliferation
• Oxygen effects and hypoxia
• Vascular damage

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

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

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

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

True

The production of reactive oxygen species from the radiolysis of water

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

Chronic vascular injury with subintimal fibrosis occluding the lumen

vascular damage and the release of pro-inflammatory cytokines

Temporary sterility (0.15 Sv)

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

None

• Lymphocytes (major site of injury)
• Moderate granulocytopenia
• Lymphopenia
• After 1- days
• No lethality

• Bone marrow (major site)
• Cytopenia, GI, hair loss
• After 2-6 weeks
• May be lethal

• Small bowel (major site)
• Diarrhea, fever, electrolyte imbalance, vomiting
• Within 5-14 days
• Always lethal

• Brain (major site)
• Ataxia, coma, convulsions, vomiting
• Within 1-4 hour
• 100% mortality

• 1–2 Sv--> lymphocyte
• 2–10 Sv--> Bone marrow
• 10–20 Sv--> Small bowel
• >50 Sv--> Brain

• All forms of abnormal nuclear morphology may be seen. 
• Giant cells with pleomorphic nuclei or more than one nucleus may appear and persist for years after exposure.
• At extremely high doses of radiant energy, markers of cell death, such as nuclear pyknosis, and lysis appear quickly

• Cytoplasmic swelling, mitochondrial distortion, and degeneration of the endoplasmic reticulum.
• Plasma membrane breaks

The histologic constellation of cellular pleomorphism, giant-cell formation, conformational changes in nuclei, and abnormal mitotic figures

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

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

below 1 Sv

• With high dose levels and large exposure fields, severe lymphopenia may appear within hours of irradiation, along with shrinkage of the lymph nodes and spleen.
• Radiation directly destroys lymphocytes, both in the circulating blood and in tissues (nodes, spleen, thymus, gut).
• With sublethal doses of radiation, regeneration from viable precursors is prompt, leading to restoration of a normal lymphocyte count in the blood within weeks to months.

• Hematopoietic precursors in the bone marrow are also quite sensitive to radiant energy, which produces a dose-dependent marrow aplasia.
• Very high doses of radiation kill marrow stem cells and induce permanent aplasia (aplastic anemia), whereas with lower doses the aplasia is transient.
• The circulating granulocyte count may first rise but begins to fall toward the end of the first week. Levels near zero may be reached during the second week. If the patient survives, recovery of the normal granulocyte count may require 2 to 3 months. 
• Platelets are similarly affected, with the nadir of the count occurring somewhat later than that of granulocytes; recovery is similarly delayed.
• Red cell counts fall and anemia appears after 2 to 3 weeks and may persist for months.

Granulocyte/RBC

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

Chronic radiation dermatitis with atrophy of epidermis, dermal fibrosis, and telangiectasia of the subcutaneous blood vessels

double-stranded breaks (DSBs)

• Two types of mechanisms can repair DSBs in mammalian cells: homologous recombination and nonhomologous end joining (NHEJ), with NHEJ being the most common repair pathway.
• DNA repair through NHEJ often produces mutations, including short deletions or duplications, or gross chromosomal aberrations such as translocations and inversions.
• If the replication of cells containing DSBs is not stopped by cell cycle checkpoint controls, cells with chromosomal damage persist and may initiate carcinogenesis many years later.
• These abnormal cells may also have a “bystander effect,” that is, they may promote growth of non-irradiated surrounding cells through the production of growth factors and cytokines. Bystander effects are referred to as non-target effects of radiation

50 mSv

0.01, 0.15, and 10 mSv,

• Radon gas is a ubiquitous product of the spontaneous decay of uranium. Its carcinogenic effects are largely attributable to two decay products, polonium 214 and 218 (or “radon daughters”), which emit alpha particles. Polonium 214 and 218 produced from inhaled radon tend to deposit in the lung, and chronic exposure in uranium miners may give rise to lung carcinomas.
• Risks are also present in homes in which the levels of radon are very high, comparable to those found in mines. However, there is little or no evidence to suggest that radon contributes to the risk of lung cancer in the average household.

Malnutrition, also referred to as protein energy malnutrition or PEM, is a consequence of inadequate intake of proteins and calories, or deficiencies in the digestion or absorption of proteins, resulting in the loss of fat and muscle tissue, weight loss, lethargy, and generalized weakness

• In primary malnutrition, one or all of these components (energy, aa, FFA, mineral, vitamin) are missing from the diet.
• By contrast, in secondary malnutrition, the supply of nutrients is adequate, but malnutrition results from insufficient intake, malabsorption, impaired utilization or storage, excess loss, or increased need for nutrients

• Poverty
• Infections
• Acute and chronic illnesses(increased BMR)
• Chronic alcoholism
• Ignorance and failure of diet supplementation
• Self-imposed dietary restriction (eating disorders)
• GI diseases and malabsorption syndromes, genetic diseases, specific drug therapies (which block uptake or utilization of particular nutrients), and total parenteral nutrition

Alcoholic persons may sometimes suffer PEM but more frequently have deficiency of several vitamins, especially thiamine, pyridoxine, folate, and vitamin A, as a result of dietary deficiency, defective gastrointestinal absorption, abnormal nutrient utilization and storage, increased metabolic needs, and an increased rate of loss.

• iron deficiency in infants fed exclusively artificial milk diets;
• polished rice used as the mainstay of a diet may lack adequate amounts of thiamine;
• lack of iodine from food and water in regions removed from the oceans

body mass index

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

• Marasmus and kwashiorkor.
• From a functional standpoint, there are two differentially regulated protein compartments in the body: the somatic compartment, represented by proteins in skeletal muscles, and the visceral compartment, represented by protein stores in the visceral organs, primarily the liver.
• The somatic compartment is affected more severely in marasmus, and the visceral compartment is depleted more severely in kwashiorkor

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

The production of leptin is low, which may stimulate the HPA axis to produce high levels of cortisol that contribute to lipolysis.

muscle and subcutaneous fat

• Kwashiorkor occurs when protein deprivation is relatively greater than the reduction in total calories.
• This is the most common form of PEM seen in African children who have been weaned too early and subsequently fed, almost exclusively, a carbohydrate diet.
• Less severe forms may occur worldwide in persons with chronic diarrheal states in which protein is not absorbed or in those with chronic protein loss due to conditions such as protein-losing enteropathies, the nephrotic syndrome, or after extensive burns. Cases of kwashiorkor resulting from fad diets or replacement of milk by rice-based beverages have been reported in the United States
• In kwashiorkor, marked protein deprivation is associated with severe loss of the visceral protein compartment, and the resultant hypoalbuminemia gives rise to generalized or dependent edema.
• The loss of weight in these patients is masked by the increased fluid retention.
• In further contrast to marasmus, there is relative sparing of subcutaneous fat and muscle mass.
• Children with kwashiorkor have characteristic skin lesions, with alternating zones of hyperpigmentation, areas of desquamation, and hypopigmentation, giving a “flaky paint” appearance.
• Hair changes include overall loss of color or alternating bands of pale and darker hair.
• Other features that differentiate kwashiorkor from marasmus include an enlarged, fatty liver (resulting from reduced synthesis of the carrier protein component of lipoproteins), and the development of apathy, listlessness, and loss of appetite.
• Vitamin deficiencies are likely to be present, as are defects in immunity and secondary infections.

Flaky paint skin/ hair changes/ enlarged fatty liver/ edema/ hypoalbuminemia/ sparing of subQ fat and muscles/ apathy/anorexia/ listlessness/ small bowel atrophy and disaccharidase deficiency/ thymic and lymphoid atrophy

reduced synthesis of the carrier protein component of lipoproteins

Visceral protein

• Secondary PEM often develops in chronically ill, elderly, and bedridden patients.
• Weight loss of more than 5% associated with PEM increases the risk of mortality in nursing home patients by almost five-fold.
• The most obvious signs of secondary PEM include: (1) depletion of subcutaneous fat in the arms, chest wall, shoulders, or metacarpal regions; (2) wasting of the quadriceps femoris and deltoid muscles; and (3) ankle or sacral edema.
• Bedridden or hospitalized malnourished patients have an increased risk of infection, sepsis, impaired wound healing, and death after surgery

• The central anatomic changes in PEM are (1) growth failure, (2) peripheral edema in kwashiorkor, and (3) loss of body fat and atrophy of muscle, more marked in marasmus.
• The liver in kwashiorkor, but not in marasmus, is enlarged and fatty.
• In kwashiorkor (rarely in marasmus) the small bowel shows a decrease in the mitotic index in the crypts of the glands, associated with mucosal atrophy and loss of villi and microvilli. In such cases concurrent loss of small intestinal enzymes occurs, most often manifested as disaccharidase deficiency. Hence, infants with kwashiorkor initially may not respond well to full-strength, milk-based diets. With treatment, the mucosal changes are reversible.
• The bone marrow in both kwashiorkor and marasmus may be hypoplastic, mainly as a result of decreased numbers of red cell precursors. The peripheral blood commonly reveals mild to moderate anemia, which often has a multifactorial origin; nutritional deficiencies of iron, folate, and protein, as well as the suppressive effects of infection (anemia of chronic disease) may all contribute. Depending on the predominant factor, the red cells may be microcytic, normocytic, or macrocytic.
• The brain in infants who are born to malnourished mothers and who suffer PEM during the first 1 or 2 years of life has been reported by some to show cerebral atrophy, a reduced number of neurons, and impaired myelinization of white matter.
• Many other changes may be present, including (1) thymic and lymphoid atrophy (more marked in kwashiorkor than in marasmus), (2) anatomic alterations induced by intercurrent infections, particularly with all manner of endemic worms and other parasites, and (3) deficiencies of other required nutrients such as iodine and vitamins

In kwashiorkor (rarely in marasmus) the small bowel shows a decrease in the mitotic index in the crypts of the glands, associated with mucosal atrophy and loss of villi and microvilli. In such cases concurrent loss of small intestinal enzymes occurs, most often manifested as disaccharidase deficiency

decreased numbers of red cell precursors

gastrointestinal, pancreatic, and lung

. It is a highly debilitating condition characterized by extreme weight loss, fatigue, muscle atrophy, anemia, anorexia, and edema

atrophy of the diaphragm and other respiratory muscles

• Cachetic agents produced by tumors include:  •   PIF (proteolysis-inducing factor), which is a glycosylated polypeptide excreted in the urine of weight-losing patients with pancreatic, breast, colon, and other cancers  •   LMF (lipid-mobilizing factor), which increases fatty acid oxidation, and pro-inflammatory cytokines such as TNF (originally known as cachetin), interleukin-2 (IL-2), and IL-6.
• TNF and IL-6 trigger an acute-phase response from the host, increasing the secretion of C-reactive protein and fibrinogen, and decreasing plasma concentrations of albumin.
• Proteolysis-inducing factor (PIF) and pro-inflammatory cytokines cause skeletal muscle breakdown through the NFκB-induced activation of the ubiquitin proteasome pathway, leading to the degradation of myosin heavy chain.
• The induction of the ubiquitin proteasome pathway involves the production of two muscle-specific ubiquitin ligases, MuRF1 (muscle RING finger-1) and MAFBx (muscle atrophy F-box, or atroglin-1).
• More recent data also implicate alterations in the myofibrillar membrane of skeletal muscle with loss of dystrophin caused by alterations in the dystrophin-glycoprotein complex as contributors to muscle atrophy, through a mechanism similar to that which occurs in some muscular dystrophies

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

Anorexia nervosa

True

Altered serotonin metabolism

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

• In bulimia, binge eating is the norm.
• Large amounts of food, principally carbohydrates, are ingested, only to be followed by induced vomiting.
• Although menstrual irregularities are common, amenorrhea occurs in less than 50% of bulimic patients, probably because weight and gonadotropin levels are maintained near normal.
• The major medical complications relate to continual induced vomiting, and the chronic use of laxatives and diuretics. They include (1) electrolyte imbalances (hypokalemia), which predispose the patient to cardiac arrhythmias; (2) pulmonary aspiration of gastric contents; and (3) esophageal and gastric cardiac rupture.
• A recent trend in bulimic patients has been the combination of binge eating with high ingestion of alcohol. Needless to say, the combined effects of bulimia and alcoholism are devastating.

decreased secretion of gonadotropin-releasing hormone

autism spectrum disorder and intellec­tual disability (intellectual developmental disorder)

• A. Repeated regurgitation of food over a period of at least 1 month. Regurgitated food may be re-chewed, re-swallowed, or spit out.
• B. The repeated regurgitation is not attributable to an associated gastrointestinal or other medical condition (e.g., gastroesophageal reflux, pyloric stenosis).
• Previously swal­lowed food that may be partially digested is brought up into the mouth without apparent nausea, involuntary retching, or disgust. The food may be re-chewed and then ejected from the mouth or re-swallowed.
• Regurgitation in rumination disorder should be fre­quent, occurring at least several times per week, typically daily

• A. An eating or feeding disturbance (e.g., apparent lack of interest in eating or food; avoid­ance based on the sensory characteristics of food; concern about aversive conse­quences of eating) as manifested by persistent failure to meet appropriate nutritional and/or energy needs associated with one (or more) of the following:1. Significant weight loss (or failure to achieve expected weight gain or faltering growth in children).2. Significant nutritional deficiency.3. Dependence on enteral feeding or oral nutritional supplements.4. Marked interference with psychosocial functioning.
• B. The disturbance is not better explained by lack of available food or by an associated culturally sanctioned practice

• A. Restriction of energy intake relative to requirements, leading to a significantly low body weight in the context of age, sex, developmental trajectory, and physical health. Significantly low weight is defined as a weight that is less than minimally normal or, for children and adolescents, less than that minimally expected.
• B. Intense fear of gaining weight or of becoming fat, or persistent behavior that interferes with weight gain, even though at a significantly low weight.
• C. Disturbance in the way in which one’s body weight or shape is experienced, undue in­fluence of body weight or shape on self-evaluation, or persistent lack of recognition of the seriousness of the current low body weight
• Restricting type: During the last 3 months, the individual has not engaged in recurrent episodes of binge eating or purging behavior (i.e., self-induced vomiting or the misuse of laxatives, diuretics, or enemas). This subtype describes presentations in which weight loss is accomplished primarily through dieting, fasting, and/or excessive exercise.
• Binge-eating/purging type: During the last 3 months, the individual has en­gaged in recurrent episodes of binge eating or purging behavior (i.e., self-induced vomiting or the misuse of laxatives, diuretics, or enemas)

• Leukopenia
• Elevated BUN, Hypercholesterolemia LFT
• Hypo­magnesemia, hypozincemia, hypophosphatemia, and hyperamylasemia
• Self-induced vomiting may lead to metabolic alkalosis (elevated serum bicarbon­ate), hypochloremia, and hypokalemia; laxative abuse may cause a mild metabolic acidosis.
• Serum thyroxine (T4 ) levels are usually in the low-normal range; triiodothy­ronine (T3 ) levels are decreased, while reverse T3 levels are elevated. Females have low se­rum estrogen levels, whereas males have low levels of serum testosterone.
• Sinus bradycardia
• Low BMD
• reduction in resting energy ex­penditure.

• Mood and anxiety disorders
• OCD in restricting type
• Alcohol in binging/purging type

• A. Recurrent episodes of binge eating. An episode of binge eating is characterized by both of the following:1. Eating, in a discrete period of time (e.g., within any 2-hour period), an amount of food that is definitely larger than what most individuals would eat in a similar period of time under similar circumstances.2. A sense of lack of control over eating during the episode (e.g., a feeling that one cannot stop eating or control what or how much one is eating).
• B. Recurrent inappropriate compensatory behaviors in order to prevent weight gain, such as self-induced vomiting; misuse of laxatives, diuretics, or other medications; fasting; or excessive exercise.
• C. The binge eating and inappropriate compensatory behaviors both occur, on average, at least once a week for 3 months.
• D. Self-evaluation is unduly influenced by body shape and weight.
• E. The disturbance does not occur exclusively during episodes of anorexia nervosa.

• Mood
• Anxiety
• Alcohol
• Stimulant (to control weight)
• Most common personality disorder is BPD

• A. Recurrent episodes of binge eating. An episode of binge eating is characterized by both of the following:1. Eating, in a discrete period of time (e.g., within any 2-hour period), an amount of food that is definitely larger than what most people would eat in a similar period of time under similar circumstances.2. A sense of lack of control over eating during the episode (e.g., a feeling that one cannot stop eating or control what or how much one is eating).
• B. The binge-eating episodes are associated with three (or more) of the following:1. Eating much more rapidly than normal.2. Eating until feeling uncomfortably full.3. Eating large amounts of food when not feeling physically hungry.4. Eating alone because of feeling embarrassed by how much one is eating.5. Feeling disgusted with oneself, depressed, or very guilty afterward.
• C. Marked distress regarding binge eating is present.
• D. The binge eating occurs, on average, at least once a week for 3 months.
• E. The binge eating is not associated with the recurrent use of inappropriate compensa­tory behavior as in bulimia nervosa and does not occur exclusively during the course of bulimia nervosa or anorexia nervosa

• Mood
• Anxiety