Patho 2

Chapter 5

Two categories of genes expressed in cells 1.“housekeeping” -for normal function of a cell 2.genes that determine the differentiating characteristics of a particular cell type

+Changes in the Cell >ATROPHY >Decrease in work demands or adverse environmental conditions >smaller or decrease in size and a lower and more efficient level of functioning that is compatible with survival >workload of a cell declinesoxygen consumption and protein synthesis decrease decrease in the number and size of their organelles and other structures (mitochondria, myofilaments, and endoplasmic reticulum) 5 General causes 1.disuse- reduction in skeletal muscle use; ex: muscles of extremities that have been encased in plaster casts atrophy is adaptive and reversible, muscle size is restored after the cast is removed and muscle use is resumed 2.denervation- form of disuse atrophy that occurs in the muscles of paralyzed limbs 3.loss of endocrine stimulation- produces a form of disuse atrophy; ex: loss of estrogen stimulation during menopause results in atrophic changes in the reproductive organs 4.inadequate nutrition-as a means of survival 5.ischemia or decreased blood flow-as a means of survival

>HYPERTROPHY >increase in cell size and with it an increase in the amount of functioning tissue mass >increased workload (cardiac and skeletal muscle tissue) >achieve equilibrium between demand and functional capacity >may be normal physiologic or abnormal pathologic conditions >exercise (physiologic) >result of disease conditions which may be adaptive or compensatory (pathologic) >thickening of the urinary bladder from long-continued obstruction of urinary outflow and the myocardial hypertrophy that results from valvular heart disease or hypertension(adaptive) > enlargement of a remaining organ or tissue after a portion has been surgically removed or rendered inactive (compensatory) >signal for hypertrophy : may be related to ATP depletion, mechanical forces (stretching of the muscle fibers) activation of cell degradation products, or hormonal factors >limiting factors: related to limitations in blood flow

>HYPERPLASIA >increase in the number of cells in an organ or tissue >occurs in tissues with cells that are capable of mitotic division (epidermis, intestinal epithelium, and glandular tissue) >nerve, skeletal, and cardiac muscle cells do not divide no capacity for hyperplastic growth

> two common types (physiologic hyperplasia): hormonal and compensatory >Breast and uterine enlargement during pregnancy that results from estrogen stimulation (physiologic hyperplasia) >regeneration of the liver that occurs after partial hepatectomy (compensatory hyperplasia) >response of connective tissue in wound healing (proliferating fibroblasts and blood vessels contribute to wound repair) >hypertrophy and hyperplasia may occur together and are often triggered by the same mechanism (ex: pregnant uterus undergoes both hypertrophy and hyperplasia as the result of estrogen stimulation) >Nonphysiologic hyperplasia: excessive hormonal stimulation or the effects of growth factors on target tissues (excessive estrogen production: endometrial hyperplasia and abnormal menstrual bleeding; action of androgens : benign prostatic hyperplasia, which is a common disorder of men older than 50 years of age >Skin warts: hyperplasia caused by growth factors produced by certain viruses (papillomaviruses)

>METAPLASIA >reversible >one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type > reprogramming of undifferentiated stem cells that are present in the tissue undergoing the metaplastic changes >conversion of cell types never oversteps the boundaries of the primary groups of tissue >ex: adaptive substitution of stratified squamous epithelial cells for the ciliated columnar epithelial cells in the trachea and large airways of a habitual cigarette smoker >may lead to cancerous transformation of the metaplastic epithelium

>DYSPLASIA >deranged cell growth of a specific tissue that results in cells that vary in size, shape, and organization >associated with chronic irritation or inflammation >dysplasia is abnormal >adaptive (potentially reversible after the irritating cause has been removed) >precursor of cancer

>INTRACELLULAR ACCUMULATIONS > buildup of substances that cells cannot immediately use or dispose of >accumulation in the cytoplasm (lysosomes) or in the nucleus > substances can be grouped into three categories: 1.normal body substances (lipids, proteins, carbohydrates, melanin, and bilirubin) that present in abnormally large amounts 2.abnormal endogenous products(those resulting from inborn errors of metabolism) 3 exogenous products (environmental agents and pigments that cannot be broken down by the cell) may accumulate transiently or permanently; may be harmless or cases >can result from genetic disorders

>replaced with an abnormal one; or an enzyme may be missing so that accumulations happen >von Gierke’s disease- large amounts of glycogen accumulate in the liver and kidneys because of a deficiency of the enzyme glucose-6-phosphatase. (glycogen cannot be broken down to form glucose); leads not only to an accumulation of glycogen but also to a reduction in blood glucose levels >Tay-Sachs disease- abnormal lipids accumulate in the brain and other tissues, causing motor and mental deterioration >Pigments- colored substances that may accumulate in cells >Icterus (jaundice)- yellow discoloration of tissue due to the retention of bilirubin, an endogenous bile pigment; may result from increased bilirubin production from red blood cell destruction, obstruction of bile passage into the intestine, or toxic diseases that affect the liver’s ability to remove bilirubin from the blood >Lipofuscin- yellow-brown pigment that results from the accumulation of the indigestible residues produced during normal turnover of cell structures; referred to as the wear-and-tear pigment > carbon in the form of coal dust (exogebous pigment); may cause serious lung disease; formation of a blue lead line along the margins of the gum is one of the diagnostic features of lead poisoning >Tattoos- insoluble pigments introduced into the skin, where they are engulfed by macrophages and persist for a lifetime

>PATHOLOGIC CALCIFICATIONS > abnormal tissue deposition of calcium salts, together with smaller amounts of iron, magnesium, and other minerals >known as dystrophic calcification when it occurs in dead or dying tissue and as metastatic calcification when it occurs in normal tissue

Dystrophic Calcification

>macroscopic deposition of calcium salts in injured tissue > deposits that range from gritty sandlike grains to firm, hard, rock material > intracellular or extracellular formation of crystalline calcium phosphate (derived from the bodies of dead or dying cells as well as from the circulation and interstitial fluid) >commonly seen in atheromatous lesions of advanced atherosclerosis, areas of injury in the aorta and large blood vessels, and damaged heart valves >occurs in injured tissues

Metastatic Calcification >occurs in normal tissues as the result of increased serum calcium levels (hypercalcemia) > major causes of hypercalcemia are hyperparathyroidism, either primary or secondary to phosphate retention in renal failure; increased mobilization of calcium from bone, as in Paget disease, cancer with metastatic bone lesions, or immobilization; and vitamin D intoxication.

+Cell Injury and Death

>usually reversible up to a certain point, after which irreversible cell injury and death occur >ongoing processes, and in the healthy state, they are balanced by cell renewal.

CAUSES OF CELL INJURY

>Five categories: 1.injury from physical agents 2.radiation injury 3.chemical injury 4.injury from biologic agents 5.injury from nutritional imbalances.

Injury From Physical Agents

>due to environmental exposure, occupational and transportation accidents, and physical violence and assault

Mechanical Forces > result of body impact with another object >split and tear tissue, fracture bones, injure blood vessels, and disrupt blood flow

Extremes of Temperature. >low-intensity heat (43 to 46 C)- induces vascular injury, accelerates cell metabolism, inactivates temperature-sensitive enzymes, and disruptes the cell membrane >more intense heat- coagulation of blood vessels and tissue proteins occurs >cold- increases blood viscosity and induces vasoconstriction by direct action on blood vessels and through reflex activity of the sympathetic nervous system; decrease in blood flow may lead to hypoxic tissue injury, depending on the degree and duration of cold exposure; ice crystal formation and vasoconstriction; capillary stasis and arteriolar and capillary thrombosis; edema results from increased capillary permeability

Electrical Injuries

>extensive tissue injury and disruption of neural and cardiac impulse >mainly determined by its voltage, the type of current its amperage, the resistance of the intervening tissue, the pathway of the current, and the duration of exposure >alternating current (AC) is usually more dangerous than direct current (DC) because it causes violent muscle contractions, preventing the person from releasing the electrical source >body acts as a conductor of the electrical current ;exits to another conductor, such as the moisture on the ground or a piece of metal the person is holding >resistance to the flow of current in electrical circuits transforms electrical energy into heat >much of the tissue damage produced is caused by heat production in tissues that have the highest electrical resistance (greatest to the least in bone, fat, tendons, skin, muscles, blood, and nerves) >most severe tissue injury usually occurs at the skin sites where the current enters and leaves the body >thick, dry skin is more resistant to the flow of electricity than thin, wet skin > the greater the skin resistance, the greater is the amount of local skin burn; less the resistance, the greater are the deep and systemic effects

Radiation Injury >radiation energy above the ultraviolet (UV) range is called ionizing radiation (photons have enough energy to knock electrons off atoms and molecules)

>nonionizing radiation- radiation energy at frequencies below that of visible light >UV radiation - portion of the spectrum of electromagnetic radiation just above the visible range; contains increasingly energetic rays that are powerful enough to disrupt intracellular bonds and cause sunburn

Ionizing Radiation.

>directly hitting the target molecules in the cell, or by producing free radicals that interact with critical cell components >can immediately kill cells, interrupt cell replication, or cause a variety of genetic mutations, which may or may not be lethal >can result in increased risk for the development of various types of cancers (skin cancers, leukemia, osteogenic sarcomas, and lung cancer) >cell’s initial response to radiation injury: swelling, disruption of the mitochondria and other organelles, alterations in the cell membrane, and marked changes in the nucleus > later or with higher levels of radiation: destructive changes occur in small blood vessels such as the capillaries and venules >Acute reversible necrosis is represented by such disorders as radiation cystitis, dermatitis, and diarrhea from enteritis > chronic effects: fibrosis and scarring of tissues and organs in the irradiated area

Ultraviolet Radiation. >causes sunburn and increases the risk for skin cancers >degree of risk: type of UV rays, the intensity of exposure, and the amount of protective melanin pigment in the skin >caused by reactive oxygen species and by damage to melanin-producing processes in the skin >xeroderma pigmentosum- a disease where an enzyme needed to repair sunlight-induced DNA damage is lacking; characterized by extreme photosensitivity and a 2000-fold increased risk for skin cancer in sun-exposed skin

Nonionizing Radiation.

>includes infrared light, ultrasound, microwaves, and laser energy >causes vibration and rotation of atoms and molecules which are is eventually converted to thermal energy >injury is mainly thermal and, because of the deep penetration of the infrared or microwave rays, tends to involve dermal and subcutaneous tissue injury

Chemical Injury

>can injure the cell membrane and other cell structures, block enzymatic pathways, coagulate cell proteins, and disrupt the osmotic and ionic balance of the cell

Drugs. >capable of directly or indirectly damaging tissues >Ethyl alcohol can harm the gastric mucosa, liver, developing fetus, and other organs >Antineoplastic (anticancer) and immunosuppressant drugs can directly injure cells > Acetaminophen (over-the counter analgesic drug) -detoxified in the liver, where small amounts of the drug are converted to a highly toxic metabolite

Lead Toxicity. >particularly toxic metal >Small amounts accumulate to reach toxic levels >sources: flaking paint, lead-contaminated dust and soil, leadcontaminated root vegetables, lead water pipes or soldered joints, pottery glazes, and newsprint >absorbed through the gastrointestinal tract or the lungs into the blood >deficiency in calcium, iron, or zinc increases lead absorption. In children, most lead is absorbed through the lungs >crosses the placenta, exposing the fetus to levels of lead that are comparable with those of the mother >stored in bone and eliminated by the kidneys >bone deposits serve as a repository from which blood levels are maintained >related to its multiple biochemical effects >has the ability to inactivate enzymes, compete with calcium for incorporation into bone, and interfere with nerve transmission and brain development > major targets are the red blood cells, the gastrointestinal tract, the kidneys, and the nervous system >Anemia is a cardinal sign of lead toxicity (microscopic and hypochromic, resembling those seen in irondeficiency anemia) > gastrointestinal tract is the main source of symptoms in the adult (“lead colic,” a severe and poorly localized form of acute abdominal pain) >lead line formed by precipitated lead sulfite may appear along the gingival margins >renal failure, hypertension > demyelination of cerebral and cerebellar white matter and death of cortical cells (lower IQ levels and poorer classroom performance in children; acute encephalopathy in adult- persistent vomiting, ataxia, seizures, papilledema, impaired consciousness, and coma) >Screening : capillary blood obtained from a finger stick to measure free erythrocyte protoporphyrin (EP)elevated levels of EP result from the inhibition by lead of the enzymes required for heme synthesis in red blood cells; reflects the effects of iron deficiency, a condition that increases lead absorption >Treatment : removal of the lead source and, in cases of severe toxicity, administration of a chelating agent

Injury From Biologic Agents

> able to replicate and can continue to produce their injurious effects > range from submicroscopic viruses to the larger parasites >injure cells by diverse mechanisms >Viruses enter the cell and become incorporated into its DNA synthetic machinery >Certain bacteria elaborate exotoxins that interfere with cellular production of ATP; Other bacteria (gramnegative bacilli), release endotoxins that cause cell injury and increased capillary permeability

Injury From Nutritional Imbalances

>Obesity and diets high in saturated fats are thought to predispose persons to atherosclerosis >Dietary deficiencies can occur in the form of starvation, in which there is a deficiency of all nutrients

and vitamins, or because of a selective deficiency of a single nutrient or vitamin >protein and calorie deficiencies that occur with starvation cause widespread tissue damage.

>MECHANISMS OF CELL INJURY Free Radical Injury

>reactive chemical species- free radical > final common pathway for tissue damage by many injurious agents > outer electron orbits are filled with paired electrons moving in opposite directions to balance their spins >highly reactive chemical species arising from an atom that has a single unpaired electron in an outer orbit >can establish chain reactions, sometimes thousands of events long, as the molecules they react with in turn form free radicals >Uncontrolled free radical production causes damage to cell membranes, cross-linking of cell proteins, inactivation of enzyme systems, or damage to the nucleic acids that make up DNA >Molecular oxygen (O2), with its two unpaired outer electrons, is the main source of free radicals. >three types of effects: 1. lipid peroxidation 2. oxidative modification of proteins 3. DNA effects >loss of membrane integrity > interrupt vital processes throughout the cell > DNA damage: single-stranded breaks in DNA, modification of base pairs, and cross-links between strands >aging and malignant transformation of cells > protection against free radicals: vitamins E and C

Hypoxic Cell Injury >Hypoxia deprives the cell of oxygen and interrupts oxidative metabolism and the generation of ATP > Well-differentiated cells (heart, brain, and kidneys), require large amounts of oxygen to provide energy for their special functions >Brain cells (permanent damage after 4 to 6 minutes of oxygen deprivation) > result from an inadequate amount of oxygen in the air, respiratory disease, ischemia, anemia, edema, or inability of the cells to use oxygen > Ischemia - impaired oxygen delivery and impaired removal of metabolic end products such as lactic acid; commonly affects blood flow through small numbers of blood vessels and produces local tissue injury >pure hypoxia- affects the oxygen content of the blood and affects all of the cells in the body >also serves as the ultimate cause of cell death in other injuries >causes a power failure in the cell, with widespread effects on the cell’s functional and structural components >as oxygen tension falls, oxidative metabolism ceases, and the cell reverts to anaerobic metabolism, using its limited glycogen stores in an attempt to maintain vital cell functions > earliest effects of reduced ATP is acute cellular swelling caused by failure of the energy-dependent sodium/potassium (Na/K)-ATPase membrane pump, which extrudes sodium from and returns potassium to the

cell (intracellular potassium levels decrease, and sodium and water accumulate in the cell) >oxygen supply is not restored: continued loss of essential enzymes, proteins, and ribonucleic acid through the hyperpermeable membrane of the cell >Leakage of intracellular enzymes through the permeable cell membrane into the extracellular fluid is used as an important clinical indicator of cell injury and death (enzymes enter the blood and can be measured by laboratory tests)

Impaired Calcium Homeostasis

>Calcium - messenger for the release of many intracellular enzymes > low intracellular levels are maintained by energydependent membrane-associated calcium/magnesium (Ca2/Mg2)-ATPase exchange systems >Ischemia and certain toxins lead to an increase in cytosolic calcium >increased calcium level activates phospholipases (responsible for damaging the cell membrane), proteases (damage the cytoskeleton and membrane proteins), ATPases (break down ATP and hasten its depletion), and endonucleases (fragment chromatin)

>REVERSIBLE CELL INJURY AND CELL DEATH Reversible Cell Injury > does not result in cell death > Two patterns under the microscope: cellular swelling and fatty change 1. Cellular swelling - impairment of the energydependent Na/K-ATPase membrane pump 2. Fatty changes- intracellular accumulation of fat; small vacuoles of fat disperse throughout the cytoplasm; although it is reversible, it usually indicates severe injury; liver, where most fats are synthesized and metabolized, is particularly susceptible to fatty change

Programmed Cell Death (Apoptosis)

>controlled cell destruction; normal cell deletion and renewal (blood cells that undergo constant renewal from progenitor cells in the bone marrow are removed by apoptotic cell death) >Apoptosis, from Greek apo for “apart” and ptosis for “fallen,” means fallen apart >equated with cell suicide >eliminates cells that are worn out, have been produced in excess, have developed improperly, or have genetic damage >provides the space needed for cell replacement >controlled autodigestion of cell components >Cells initiate their own death through the activation of endogenous enzymes >results in cell shrinkage brought about by disruption of the cytoskeleton, condensation of the cytoplasmic organelles, disruption and clumping of nuclear DNA, and a distinctive wrinkling of the cell membrane >Membrane changes signal surrounding phagocytic cells to engulf the apoptotic cell parts and complete the degradation process > responsible for several normal physiologic processes, including programmed destruction of cells during embryonic development, hormonedependent involution of tissues, death of immune cells, cell death by

cytotoxic T cells, and cell death in proliferating cell populations >allows for the next stage of organ development >occurs in the hormone-dependent involution of endometrial cells during the menstrual cycle and in the regression of breast tissue after weaning from breastfeeding >suppression of apoptosis may be a determinant in the growth of cancers >involved in the cell death associated with certain viral infections, and in cell death caused by a variety of injurious agents >involved in neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS)

Necrosis > cell death in an organ or tissue that is still part of a living person > involves unregulated enzymatic digestion of cell components, loss of cell membrane integrity with uncontrolled release of the products of cell death into the intracellular space, and initiation of the inflammatory response >often interferes with cell replacement and tissue regeneration >there are marked changes in the appearance of the cytoplasmic contents and the nucleus > cell can undergo liquefaction (i.e., liquefaction necrosis); it can be transformed to a gray, firm mass (i.e., coagulation necrosis); or it can be converted to a cheesy material by infiltration of fatlike substances (i.e., caseous necrosis) >Liquefaction necrosis- some of the cells die but their catalytic enzymes are not destroyed (softening of the center of an abscess with discharge of its contents) -Coagulation necrosis- acidosis develops and denatures the enzymatic and structural proteins of the cell (infarcted areas) -Infarction- an artery supplying an organ or part of the body becomes occluded and no other source of blood supply exists; shape is conical -Caseous necrosis -dead cells persist indefinitely as soft, cheeselike debris (center of tuberculosis granulomas, or tubercles); thought to result from immune mechanisms

Gangrene.

> considerable mass of tissue undergoes necrosis >classified as dry or moist >dry gangrene- part becomes dry and shrinks, the skin wrinkles, and its color changes to dark brown or black -spread is slow, and its symptoms are not as marked as those of wet gangrene -produces a line of inflammatory reaction (i.e., line of demarcation) between the dead tissue of the gangrenous area and the healthy tissue -usually results from interference with arterial blood supply to a part without interference with venous return and is a form of coagulation necrosis - role confined almost exclusively to the extremities >moist or wet gangrene- area is cold, swollen, and pulseless -skin is moist, black, and under tension

- blebs form on the surface, liquefaction occurs, and a foul odor is caused by bacterial action -no line of demarcation -spread of tissue damage is rapid - systemic symptoms are usually severe, and death may occur unless the condition can be arrested -primarily results from interference with venous return from the part -bacterial invasion plays an important -may affect the internal organs or the extremities >Gas gangrene is a special type of gangrene that results from infection of devitalized tissues by one of several Clostridium bacteria (Clostridium perfringens) -widespread in nature, particularly in soil; gas gangrene is prone to occur in trauma and compound fractures in which dirt and debris are embedded in skin of healthy persons -bubbles of hydrogen sulfide gas that form in the muscle -Amputation may be required to prevent spreading infection involving a limb -Hyperbaric oxygen therapy has been used, but clinical data supporting its efficacy have not been rigorously assessed

> positive feedback mechanisms- interjects instability rather than stability into a system; produces a cycle in which the initiating stimulus produces more of the same

+Stress and Adaptation >THE STRESS RESPONSE

Chapter 9 >CONSTANCY OF THE INTERNAL ENVIRONMENT 1. Constancy in an open system requires mechanisms that act to maintain this constancy 2. Steady-state conditions require that any tendency toward change automatically meets with factors that resist change (increase in blood sugar results in thirst as the body attempts to dilute the concentration of sugar in the extracellular fluid) 3. The regulating system that determines the homeostatic state consists of a number of cooperating mechanisms acting simultaneously or successively 4. Homeostasis does not occur by chance, but is the result of organized self-government.

>multicellular organism is able to survive only as long as the composition of the internal environment is compatible with the survival needs of the individual cells > homeostasis according to Cannon, was achieved through a purposeful maintenance of a stable internal environment maintained by coordinated physiologic processes that oppose change above the set point, the feedback mechanism causes it to decrease

>CONTROL SYSTEMS

> physiologic control systems-regulate body function -consists of a collection of interconnected components that function to keep a physical or chemical parameter of the body relatively constant - composed of a sensor that detects a change, an integrator/comparator that sums and compares incoming data with a set point, and an effector system that returns the sensed function to within the range of the set point. -biochemical messengers that exist in our brain serve to control nerve activity, regulate information flow, and, ultimately, influence behavior - function in producing the emotional reactions to stressors

Feedback Systems >negative feedback mechanisms- function in a manner similar to the thermostat on a heating system; opposing mechanism

> Hans Selye -first to describe a group of specific anatomic changes that occurred in rats that were exposed to a variety of different experimental stimuli > these changes were manifestations of the body’s attempt to adapt to stimuli >stress- “a state manifested by a specific syndrome of the body developed in response to any stimuli that made an intense systemic demand on it.” >noticed that patients with diverse disease conditions had many signs and symptoms in common; referred to this as the “syndrome of just being sick.” > noted that a triad of adrenal enlargement, thymic atrophy, and gastric ulcer appeared in rats he was using for his studies > assumed that the hypothalamic-pituitary-adrenal (HPA) axis played a pivotal role in the development of this response >labeled the response to stressors as the general adaptation syndrome (GAS): general- effect was a general systemic reaction, adaptive -response was in reaction to a stressor, syndrome -physical manifestations were coordinated and dependent on each other >GAS involves three stages: the alarm stage, the resistance stage, and exhaustion stage >alarm stage- generalized stimulation of the sympathetic nervous system and the HPA axis -release of catecholamines and cortisol >resistance stage- body selects the most effective and economic channels of defense -the increased cortisol levels present during the first stage drop because they are no longer needed >exhaustion stage - stressor is prolonged or overwhelms the ability of the body to defend itself ensues - resources are depleted and signs of “wear and tear” or systemic damage appear > stressors - events or environmental agents responsible for initiating the stress response -endogenous (arising from within the body) -exogenous (arising from outside the body) > two factors to determine the nature of the stress response: -properties of the stressor -conditioning of the person being stressed >eustress (mild, brief, and controllable periods of stress) and distress (severe, protracted, and uncontrolled situations of psychological and physical distress) > conditioning factors- different responses in different persons or in the same person at different times, indicating the influence of the adaptive capacity of the person - internal (e.g., genetic predisposition, age, sex) - external (e.g., exposure to environmental agents, life experiences, dietary factors, level of social support

Neuroendocrine–Immune Interactions

> integrate signals received along neurosensory pathways and from circulating mediators that are carried in the bloodstream >(under normal circumstances)- they are not around long enough to cause damage to vital tissues >(stress response is hyperactive)- physiologic and behavioral changes induced by the response can themselves become a threat to homeostasis >(hypoactive stress response) -person may be more susceptible to diseases associated with overactivity of the immune response

Neuroendocrine Responses

>relies on communication along neuronal pathways of the cerebral cortex, the limbic system, the thalamus, the hypothalamus, the pituitary gland, and the reticular activating system >cerebral cortex- involved with vigilance, cognition, and focused attention >limbic system- emotional components (e.g., fear, excitement, rage, anger) of the stress response > thalamus- relay center and is important in receiving, sorting out, and distributing sensory input > hypothalamus- coordinates the responses of the endocrine system and the autonomic nervous system (ANS) >RAS- modulates mental alertness, ANS activity, and skeletal muscle tone, using input from other neural structures( musculoskeletal tension that occurs during the stress response – increased activity of the RAS)

Locus Ceruleus. >are in brain stem >central to the neural component of the neuroendocrine response to stress >densely populated with neurons that produce norepinephrine (NE) and is thought to be the central integrating site for the ANS response to stressful stimuli >has afferent pathways to the hypothalamus, the limbic system, the hippocampus, and the cerebral cortex > fight-or-flight response - sympathetic nervous system manifestation of the stress reaction -most rapid of the stress responses and represents the basic survival response of our primitive ancestors - increases attention and arousal and thus probably intensifies memory - heart and respiratory rates increase, the hands and feet become moist, the pupils dilate, the mouth becomes dry, and the activity of the gastrointestinal tract decreases

Corticotropin-releasing Factor.

>central to the endocrine component of the neuroendocrine response to stress >small peptide hormone found in the hypothalamus and in extrahypothalamic structures (limbic system and the brain stem) > important endocrine regulator of pituitary and adrenal activity > it is also a neurotransmitter involved in ANS activity, metabolism, and behavior >induces the secretion of the adrenocorticotropic hormone (ACTH) from the anterior pituitary gland through the hypothalamus; ACTH  adrenal gland  glucocorticoid hormones  direct or indirect physiologic effects that mediate the stress response,

enhance the action of other stress hormones, or suppress other components of the stress system >cortisol acts both as a mediator of the stress response and an inhibitor of the stress response such that overactivation does not occur -maintains blood glucose levels by antagonizing the effects of insulin and enhances the effect of catecholamines on the cardiovascular system -suppresses osteoblast activity, hematopoiesis, protein and collagen synthesis, and immune responses

Other Hormones.

>growth hormone-initially elevated at the onset of stress -prolonged presence of cortisol leads to suppression of growth hormone, somatomedin C, and other growth factors, exerting a chronically inhibitory effect on growth. In addition >somatostatin- increases; inhibits growth hormone secretion > thyroid-stimulating hormone (decreased); inhibition of conversion of thyroxine (T4) to the more biologically active triiodothyronine (T3) in peripheral tissues >Antidiuretic hormone (ADH) - hypotensive stress or stress due to fluid volume loss - also called vasopressin -increases water retention by the kidneys, produces vasoconstriction of blood vessels, and appears to synergize the capacity of CRF to increase the release of ACTH >reproductive hormones- inhibited - anovulation and amenorrhea in women - decreased spermatogenesis and decreased levels of testosterone in men

Immune Responses > the hallmark of the stress response is endocrine– immune interactions (i.e., increased corticosteroid production and atrophy of the thymus) that are known to suppress the immune response >exact stress mechanism unknown; varies from person to person -genetic endowment -environmental factors > immune and neuroendocrine systems share common signal pathways (i.e., messenger molecules and receptors) >hormones and neuropeptides can alter the function of immune cells > immune system and its mediators can modulate neuroendocrine function -receptors are the first route for neuro endocrine regulation -second possible route for neuroendocrine regulation of immune function is through the sympathetic nervous system and the release of catecholamines >stress hormones differentially stimulate the proliferation of subtypes of T lymphocyte helper cells

Coping and Adaptation to Stress

>according to René Dubos- “adaptability is found throughout life and is perhaps the one attribute that distinguishes most clearly the world of life from the world of inanimate matter. >attempt to respond adaptively, each in its own unique and most suitable manner

> social responses -modify their environments, their habits, or both to achieve a way of life that is best suited to their needs

Adaptation

>Human beings usually have alternative mechanisms for adapting and have the ability to control many aspects of their environment > modern technology creates new challenges for adaptation and provides new sources of stress >baroreflex-mediated rise in heart rate occurs when a person moves from the recumbent to the standing position

Factors Affecting the Ability to Adapt >Adaptation- successfully created a new balance between the stressor and the ability to deal with it > coping strategies or coping mechanisms - means used to attain this balance > Coping mechanisms- emotional and behavioral responses used to manage threats to our physiologic and psychological homeostasis >According to Lazarus “how we cope with stressful events depends on how we perceive and interpret the event”

Physiologic and Anatomic Reserve.

>trained athlete is able to increase cardiac output sixfold to sevenfold during exercise > safety margin for adaptation of most body systems is considerably greater than that needed for normal activities. -red blood cells carry more oxygen than the tissues can use - liver and fat cells store excess nutrients -bone tissue stores calcium in excess of that needed for normal neuromuscular function >physiologic reserve - ability of body systems to increase their function given the need to adapt -both organs are not needed to ensure the continued existence and maintenance of the internal environment (kxo nga lang ma-ooverdo ung isang organ like in kidney db?)

Time. >Adaptation is most efficient when changes occur gradually rather than suddenly

Genetic Endowment. >Adaptation affected by the availability of adaptive responses and flexibility in selecting the most appropriate and economical response >greater the number of available responses, the more effective is the capacity to adapt > Genetic endowment- ensure that the systems that are essential to adaptation function adequately

Age. > capacity to adapt is decreased at the extremes of age

Health Status. >Physical and mental health status determines physiologic and psychological reserves and is a strong determinant of the ability to adapt -severe emotional stress often produces disruption of physiologic function and limits the ability to make appropriate choices related to long-term adaptive needs

Nutrition.

>deficiencies or excesses of any of these nutrients can alter a person’s health status and impair the ability to adapt > nutrition – works in enzyme function, immune response, and wound healing >dietary excess: obesity and alcohol abuse -Obesity -predisposes to a number of health problems, including atherosclerosis and hypertension -Alcohol- acutely affects brain function and, with long-term use, can seriously impair the function of the liver, brain, and other vital structures

Sleep–Wake Cycles. >Sleep – restorative function in which energy is

restored and tissues are regenerated -occurs in a cyclic manner, alternating with periods of wakefulness and increased energy use > Biologic rhythms- works in adaptation to stress, development of illness, and response to medical treatment. >circadian, from the Latin circa (about) and dies (day)describes these 24-hour diurnal rhythms >two most common manifestations of an alteration in the sleep–wake cycle: insomnia and sleep deprivation or increased somnolence

Hardiness. > hardiness describes a personality characteristic that includes a sense of having control over the environment, a sense of having a purpose in life, and an ability to conceptualize stressors as a challenge rather than a threat

Psychosocial Factors. >social environment- resource that modulates the relation between stress and health >social support has direct and indirect positive effects on health status and serves as a buffer or modifier of the physical and psychosocial effects of stress >Persons with ample social networks are not as likely to experience many types of stress, such as being homeless or being lonely > may live longer and have a lower incidence of somatic illness >Close relationships with others can involve positive effects as well as the potential for conflict and may, in some situations, leave the person less able to cope with life stressors

+Disorders of the Stress Response >EFFECTS OF ACUTE STRESS

> fight-or-flight response > pounding headache, cold and moist skin, a stiff neck —are all part of the acute stress response >(Centrally)-facilitation of neural pathways mediating arousal, alertness, vigilance, cognition, and focused attention as well as appropriate aggression. >result from either psychologically or physiologically threatening events >Increased alertness and cognitive functioning enables rapid processing of information and arrival at the most appropriate solution to the threatening situation

>persons with limited coping abilities- acute stress response may be detrimental >healthy individuals- acute stress response can redirect attention from behaviors that promote health >ill person- can interrupt compliance with medication regimens and exercise programs

>EFFECTS OF CHRONIC STRESS

>function can be altered in several ways: component of the system fails; neural and hormonal connections among the components of the system are dysfunctional; original stimulus for the activation of the system is prolonged or of such magnitude that it overwhelms the ability of the system to respond appropriately > system may become overactive or underactive. >can result from chronic illnesses as well as contribute to the development of long-term health problems > National Institute for Occupational Safety and Health declared stress a hazard of the workplace >higher stress was correlated with a decreased immune response

>POST-TRAUMATIC STRESS DISORDER

> (PTSD)- chronic activation of the stress response as a result of experiencing a potentially life-threatening event > formerly called battle fatigue or shell shock - first characterized in men and women returning from combat > events have influenced and will continue to influence the development of PTSD in a substantial number of people >characterized by a constellation of symptoms that are experienced as states of intrusion, avoidance, and hyperarousal >Intrusion- occurrence of “flashbacks”during waking hours or nightmares in which the past traumatic event is relived, often in vivid and frightening detail >Avoidance- emotional numbing that accompanies this disorder and disrupts important personal relationships -depression is commonly a part of the clinical picture - Survivor guilt also may be a product of traumatic situations in which the person survived the disaster but loved ones did not >Hyperarousal- presence of increased irritability, difficulty in concentration, an exaggerated startle reflex, and increased vigilance and concern over safety > memory problems, sleep disturbances, and excessive anxiety are commonly experienced > three types of symptoms must be present together for at least 1 month, and the disorder must have caused clinically significant distress or impairment in social, occupational, and other areas of functioning in order to be diagnosed as PTSD >chronic PTSD - increased levels of norepinephrine and increased activity of 2-adrenergic receptors (intrusive and somatic symptoms of the disorder) >alterations in two brain structures (the amygdala and hippocampus). -involved in fear responses -hippocampus- memory processes

-neuroanatomic basis for the intrusive recollections and other cognitive problems that characterize PSTD >decreased cortisol levels, increased sensitivity of cortisol receptors, and an enhanced negative feedback inhibition of cortisol release with the dexamethasone suppression test - Dexamethasone- synthetic glucocorticoid that mimics the effects of cortisol and directly inhibits the action of CRF and ACTH > (patients with major depression)-decreased sensitivity of glucocorticoid receptors, a high plasma level of cortisol, and a decreased dexamethasone suppression >patients who present with symptoms of depression, anxiety, and alcohol or drug abuse may in fact be suffering from PTSD > person with PTSD should not be made to feel responsible for the disorder or that it is evidence of a so-called character flaw

>TREATMENT AND RESEARCH OF STRESS DISORDERS Treatment

> directed toward helping people avoid coping behaviors that impose a risk to their health and providing them with alternative stress-reducing strategies

Relaxation. >four elements are integral to the various relaxation techniques 1. repetitive mental device 2. passive attitude 3. decreased mental tonus 4. quiet environment >progressive muscle relaxation is another method of relieving tension >tension could be defined physiologically as the inappropriate contraction of muscle fibers

Imagery.

>scene visualization- person is asked to sit back, close the eyes, and concentrate on a scene narrated by the therapist >all five senses are involved: the person attempts to see, feel, hear, and taste aspects of the visual experience

Music Therapy. > used for both its physiologic and psychological effects > involves listening to selected pieces of music as a means of ameliorating anxiety or stress, reducing pain, decreasing feelings of loneliness and isolation, buffering noise, and facilitating expression of emotion >Music- has three components: 1. rhythm- order in the movement of the music - most dynamic aspect of music - particular pieces of music often are selected because they harmonize with body rhythms 2. melody--created by the musical pitch and distance (or interval) between the musical tone -contributes to the listener’s emotional response to the music 3. harmony- results from the way pitches are blended together, with the

combination of sounds described as consonant or dissonant by the listener

Massage Therapies. >Massage- manipulation of the soft tissues of the body to promote relaxation and relief of muscle tension. >gentle stroking along the length of a muscle (effleurage) >application of pressure across the width of a muscle (pétrissage) > deep massage movements applied by a circular motion of the thumbs or fingertips (friction) > squeezing across the width of a muscle (kneading) > use of light slaps or chopping actions (hacking)

Biofeedback. >Biofeedback- technique in which an individual

learns to control physiologic functioning >electronic monitoring of one or more physiologic responses to stress with immediate feedback of the specific response to the person undergoing treatment >Several types of responses are used: electromyographic (EMG), electrothermal, and electrodermal (EDR) - EMG response involves the measurement of electrical potentials from muscles, usually the forearm extensor or frontalis -EDR sensors measure conductivity of skin (usually the hands) in response to anxiety

Research

> focused on personal reports of the stress situation and the physiologic responses to stress > fewer methods are available for measuring the physiologic responses to stress in humans because much of the research in the field of stress has been accomplished using animal models -reasons: -First, the human experience of stress varies among individuals based on previous life experiences and availability of adaptive resources; therefore, it is difficult to find a stimulus that produces equivalent stress in all subjects in a study -Second, suitable methods for measuring the components of the stress response in humans are limited - many measurement methods, such as venipuncture, can introduce additional stress to the experimental condition

Chapter 59

>Arthritis- more than 100 rheumatic diseases - affects persons in all age groups and is the second leading cause of disability in the United States - cannot be cured yet much can be done to control its progress The common use of the term arthritis oversimplifies -diverse conditions share inflammation of the joint as a prominent or accompanying symptom

+Systemic Autoimmune Rheumatic Diseases >RHEUMATOID ARTHRITIS >Rheumatoid arthritis (RA)- systemic inflammatory disease that affects 0.3% to 1.5% of the population, with women affected two to three times more frequently than men >prevalence increases with age > peak incidence among women is between the ages of 40 and 60 years, with the onset at 30 to 50 years of age

Etiology and Pathogenesis

> chronic systemic inflammatory disease with bilateral involvement of diarthrodial joints > genetic predisposition-activation of a T-cell–mediated response to an immunologic trigger, such as a microbial agent - increased frequency of the disease among first-degree relatives and monozygotic twins -certain HLA-DR molecules may predispose to RA by their capacity to bind arthritogenic antigens, which in turn activate helper T cells and initiate the disease >development of joint inflammation that is immunologically mediated -aberrant immune response that leads to synovial inflammation and destruction of the joint architecture > disease is initiated by the activation of helper T cells, release of cytokines, and antibody formation

> rheumatoid factor (RF)- autologous (selfproduced) antibody that reacts with a fragment of immunoglobulin G (IgG) to form immune complexes - found in the blood, synovial fluid, and synovial membrane of affected individuals >neutrophils and macrophages phagocytize the immune complexes  release lysosomal enzymes  destructive changes in the joint cartilage; inflammatory process progresses, the synovial cells and subsynovial tissues undergo reactive hyperplasia >Vasodilation and increased blood flow cause warmth and redness > joint swelling that occurs is the result of the increased capillary permeability >development of an extensive network of new blood vessels in the synovial membrane advancement of the rheumatoid synovitis destructive vascular granulation tissue(pannus) extends from the synovium to involve the “bare area,” a region of unprotected bone at the junction between cartilage and subchondral bone >PANNUS - feature of RA that differentiates it from other forms of inflammatory arthritis -have a destructive effect on the adjacent cartilage and bone -develops between the joint margins, leading to reduced joint motion and the possibility of eventual ankylosis

Clinical Manifestations

>insidious onset; systemic manifestations (fatigue, anorexia, weight loss, and generalized aching and stiffness) > may involve only a few joints for brief durations, or it may become relentlessly progressive and debilitating >may not response to therapy

Joint Manifestations. >symmetric and polyarticular >diarthrodial joint can be involved. > joint pain and stiffness that lasts 30 minutes and frequently for several hours >limitation of joint motion (pain-early; fibrosis- later) > most frequently affected joints: - initially : fingers, hands, wrists, knees, and feet - Later, other diarthrodial joints -spinal involvement : cervical region -hands: bilateral and symmetric involvement of the proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints in the early stages; the distal interphalangeal (DIP) joints rarely are affected -PIP : spindle-shaped appearance (inflammation of the PIP joints); subluxation and instability of the joint and in limitation of movement; Swelling and thickening of the synovium (muscle and tendon imbalances develop, and mechanical forces applied to the joints through daily activities produce joint deformities) -MCP : extensor tendons can slip to the ulnar side of the metacarpal head( ulnar deviation of the finger); subluxation when this deformity is present - a swan neck deformity- hyperextension of the PIP joint and partial flexion of the DIP joint

- boutonnière deformity -flexion of the PIP joint with hyperextension of the DIP joint >knee is one of the most commonly affected -swelling -bulge sign- milking fluid from the lateral to the medial side of the patella >joint contractures, instability, and genu valgus (knock-knee) deformity > Baker’s cyst - popliteal area behind the knee; enlargement of the bursa; does not cause symptoms unless the cyst ruptures >metatarsophalangeal joints: subluxation, hallux valgus, and hammer toe deformities >Neck discomfort > long-standing disease can lead to neurologic complications (occipital headaches, muscle weakness, and numbness and tingling in the upper extremities)

Extraarticular Manifestations.

>complaints of fatigue, weakness, anorexia, weight loss, and low-grade fever when the disease is active > erythrocyte sedimentation rate (ESR)( elevated during inflammatory processes) >Anemia associated with a low serum iron level or low iron-binding (usually is resistant to iron therapy) >Rheumatoid nodules - granulomatous lesions that develop around small blood vessels - may be tender or nontender, movable or immovable, and small or large - found over pressure points (extensor surfaces of the ulna) > ischemic areas in the nail fold and digital pulp that appear as brown spots > Ulcerations in the lower extremities, particularly around the malleolar areas > neuropathy may be the only symptom of vasculitis > eye lesions (episcleritis and scleritis), hematologic abnormalities, pulmonary disease, cardiac complications, infection, and Felty’s syndrome (i.e., leukopenia with or without splenomegaly).

Diagnosis and Treatment >history, physical examination, and laboratory tests Criteria for Classification of Rheumatoid Arthritis

Four or more of the following conditions must be present to establish a diagnosis of rheumatoid arthritis: 1. Morning stiffness for at least 1 hour and present for at least 6 weeks 2. Simultaneous swelling of three or more joints for at least 6 weeks 3. Swelling of wrist, metacarpophalangeal, or proximal interphalangeal joints for 6 or more weeks 4. Symmetric joint swelling for 6 or more weeks 5. Rheumatoid nodules 6. Serum rheumatoid factor identified by a method that is positive in less than 5% of normal subjects 7. Radiographic changes typical of rheumatoid arthritis on hand or wrist radiographs.

> inflammation, swelling, tenderness, and possibly warmth and reduced motion > joints : soft, spongy feeling because of the synovial thickening and inflammation >body movements may be guarded to prevent pain >a person can have RA without the presence of RF > Anti-CPP antibodies (very early in RA)

>Radiologic findings also are not diagnostic (joint erosions often are not seen on radiographic images in the early stages of the disorder) >Synovial fluid analysis (cloudy appearance, the white blood cell count is elevated as a result of inflammation, and the complement components are decreased) >Treatment Goals : reduce pain, minimize stiffness and swelling, maintain mobility, and become an informed health care consumer -rest, therapeutic exercises, and medications - physical rest reduces joint stress - emotional rest: muscles relax, and discomfort is reduced -therapeutic exercises: maintaining joint motion and muscle strength; Isometric (muscletensing) exercises - strengthen muscles - Aerobic exercise and strengthening exercises can be an important component of the treatment regimen of selected patients - proper posture, positioning, body mechanics, and the use of supportive shoes can provide further comfort >Pharmacologic therapy: reduce pain, decrease inflammation, maintain or restore joint function, and prevent bone and cartilage destruction -Early treatment is based on the theory that Tcell–dependent pathways, which manifest early in the inflammatory process, are more responsive to treatment than later in the process, when disease progression may be controlled by activated fibroblasts and macrophages -NSAIDs- inhibit the production of prostaglandins, which have a damaging effect on joint structures -COX-2 inhibitors have been shown to inhibit inflammatory processes, but do not inhibit the protective prostaglandin synthesis in the gastrointestinal tract -Methotrexate has become the drug of choice because of its potency, and it is relatively fast acting compared with the slower-acting DMARDs; interferes with purine metabolism, leading to the release of adenosine, a potent antiinflammatory compound >Surgery -Synovectomy – reduce pain and joint damage when synovitis does not respond to medical treatment -tenosynovectomy (i.e., repair of damaged tendons) of the hand to release nerve entrapments. -Total joint replacements (i.e., arthroplasty) may be indicated to reduce pain and increase motion - Arthrodesis (i.e., joint fusion) is indicated only in extreme cases when there is so much soft tissue damage and scarring or infection that a replacement is impossible

>SYSTEMIC LUPUS ERYTHEMATOSUS

> chronic inflammatory disease that can affect virtually any organ system, including the musculoskeletal system >chronic autoimmune disorder characterized by production of a wide array of autoantibodies against nuclear and cytoplasmic cell components > often described as the great imitator because it can affect almost any organ system, including the joints of the musculoskeletal system, the skin, kidneys, lungs, nervous system, and the heart

Etiology and Pathogenesis

> formation of autoantibodies and immune complexes >B-cell hyperreactivity and increased production of antibodies against self (i.e., autoantibodies) and nonself antigens -B cells are polyclonal, each producing a different type of antibody - autoantibodies can directly damage tissues or combine with corresponding antigens to form tissuedamaging immune complexes >development of autoantibodies can result from a combination of factors, including genetic, hormonal, immunologic, and environmental factors -Genetic predisposition -occurrence of familial cases especially among identical twins - imbalance in sex hormone levels; may lead to heightened helper Tcell and weakened suppressor T-cell immune responses, which could lead to the development of autoantibodies -Androgens- protect against the development of SLE -estrogens- favor its development -environmental triggers: ultraviolet (UV) light, chemicals (e.g., drugs, hair dyes), some foods, and infectious agents

Clinical Manifestations

> called the great imitator > has the capacity for affecting many different body systems, including the musculoskeletal system, the skin, the cardiovascular system, the lungs, the kidneys, the central nervous system (CNS), and the red blood cells and platelets >onset may be acute or insidious > characterized by exacerbations and remissions. >Arthralgias and arthritis(early symptoms) > joint pain >polyarthritis of SLE initially can be confused with other forms of arthritis, especially rheumatoid arthritis, because of the symmetric arthropathy > radiologic examination: articular destruction rarely is found >Ligaments, tendons, and the joint capsule may be involved >Flexion contractures, hyperextension of the interphalangeal joint, and subluxation of the carpometacarpal joint contribute to the deformity and subsequent loss of function in the hands >musculoskeletal manifestations : tenosynovitis, rupture of the intrapatellar and Achilles tendons, and avascular necrosis, frequently of the femoral head >Skin manifestations: 1. acute- -classic malar or “butterfly” rash on the nose and cheeks - may be associated with other skin lesions, such as hives or livedo reticularis and fingertip lesions, such as periungual erythema, nail fold infarcts, and splinter hemorrhages 2. subacute 3. chronic >Hair loss >Sun sensitivity >Renal involvement ; glomerulonephritis, mesangial, focal proliferative, diffuse proliferative, and membranous - Interstitial nephritis

- Nephrotic syndrome causes proteinuria with resultant edema in the legs, abdomen, and around the eyes -Renal failure (Kidney biopsy is the best determinant of renal damage and the extent of treatment needed) >Pulmonary involvement: pleural effusions or pleuritis -also include acute pneumonitis, pulmonary hemorrhage, chronic interstitial lung disease, and pulmonary embolism >Cardiac Manifestations: Pericarditis often accompanied by pleural effusions - Myocarditis; Congenital heart block can occur in infants of mothers with lupus who have a specific type of ANA (anti-Ro) in their serum -Hypertension may be associated with lupus nephritis and long-term corticosteroid use - Ischemic heart disease -Infective carditis is rare but can occur with valvular lesions >CNS Manifestations: acute vasculitis that impedes blood flow, causing strokes or hemorrhage; an immune response involving antineuronal antibodies that attack nerve cells; or production of antiphospholipid antibodies that damage blood vessels and cause blood clots in the brain -Seizures -Psychotic symptoms (depression, unnatural euphoria, decreased cognitive functioning, confusion, and altered levels of consciousness) >Hematologic disorders : hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia -Lymphadenopathy; plaquelike lesions on the head, scalp, and neck (first appear as red, swollen patches of skin, and later there can be scarring, depigmentation, and plugging of hair follicles) >Subacute cutaneous lupus erythematosus (SCLE) - less severe form of lupus - skin lesions in this condition may resemble psoriasis - found in sun-exposed areas such as the face, chest, upper back, and arms -mild systemic problems, which usually are limited to joint and muscle pains. - low incidence of lupus nephritis

Diagnosis and Treatment

>Diagnosis: complete history, physical examination, and analysis of blood work >immunofluorescence test for ANA >high ANA levels >anti-DNA antibody test is more specific >moderate to severe anemia, thrombocytopenia, and leukocytosis or leukopenia >Treatment : managing the acute and chronic symptoms of the disease -goals: preventing progressive loss of organ function, reducing the possibility of exacerbations, minimizing disability from the disease process, and preventing complications from medication therapy -NSAID(can control fever, arthritis, and mild pleuritis) - antimalarial drug (e.g., hydroxychloroquine) may be the next medication considered to treat cutaneous and musculoskeletal manifestations of SLE

-Corticosteroids -Immunosuppressive drugs

>SYSTEMIC SCLEROSIS

> sometimes called scleroderma >autoimmune disease of connective tissue >excessive collagen deposition in the skin and internal organs such as the lungs, gastrointestinal tract, heart, and kidneys >skin is thickened through fibrosis, with an accompanying fixation of subdermal structures, including the sheaths or fascia covering tendons and muscles >affects women four times as frequently as men > evidence of both humoral and cellular immune system abnormalities >Scleroderma presents as two distinct clinical entities: 1. diffuse or generalized - skin changes in diffuse scleroderma also involve the trunk and proximal extremities - severe and progressive disease of the skin and the early onset of organ involvement -stone facies due to tightening of the facial skin with restricted motion of the mouth -Involvement of the esophagus leads to hypomotility and difficulty swallowing -Malabsorption may develop -Pulmonary involvement leads to dyspnea and eventually respiratory failure -Vascular involvement of the kidneys is responsible for malignant hypertension and progressive renal insufficiency - Cardiac problems (pericarditis, heart block, and myocardial fibrosis) 2. limited or CREST variant - CREST syndrome- hardening of the skin (scleroderma) is limited to the hands and face - calcinosis (i.e., calcium deposits in the subcutaneous tissue that erupt through the skin), Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly (localized scleroderma of the fingers), and telangiectasia -development of polyarthritis and Raynaud’s phenomenon, a vascular disorder characterized by reversible vasospasm of the arteries supplying the fingers > Treatment: symptomatic and supportive - use of angiotensinconverting enzyme (ACE) inhibitors in renal involvement

>POLYMYOSITIS AND DERMATOMYOSITIS

> chronic inflammatory myopathies >pathogenesis is multifactorial and includes cellular and humoral immune mechanisms >Systemic manifestations ; cardiac and pulmonary complications > symmetric proximal muscle weakness and occasional muscle pain and tenderness >Treatment: control inflammation and prevent longterm damage to muscles, joints, and internal organs -Corticosteroids

+Arthritis Associated With Spondylitis >SERONEGATIVE

SPONDYLOARTHROPATHIES >spondyloarthropathies - interrelated group of multisystem inflammatory disorders that primarily affect the axial skeleton, particularly the spine. >Sacroiliitis is a pathologic hallmark of the disorders > seronegative spondyloarthropathies- there is an absence of the RF

Ankylosing Spondylitis

> chronic, systemic inflammatory disease of the joints of the axial skeleton manifested by pain and progressive stiffening of the spine >manifestations begin in late adolescence or early adulthood and are slightly more common in men than in women >evolves more slowly and is less severe in women > produces an inflammatory erosion of the sites where tendons and ligaments attach to bone > begins with bilateral involvement of the sacroiliac joints and then moves to the smaller joints of the posterior elements of the spine > vertebrae take on a squared appearance and bone bridges fuse one vertebral body to the next across the intervertebral discs

Etiology and Pathogenesis. >presence of mononuclear cells in acutely involved tissue suggests an immune response > genetic and environmental factors play a role in the pathogenesis of the disease > HLA-B27 antigen remains one of the best-known examples of an association between a disease and a hereditary marker normal population >molecular mimicry- autoimmune reaction to an antigenic determinant site in the host’s tissues may occur as a consequence of an immunologic response to an identical or closely related antigen of a foreign agent, usually an infectious agent25 Clinical Manifestations. T > low back pain, which may be persistent or intermittent. The pain, which becomes worse when resting, particularly when lying in bed (may be blamed on muscle strain or spasm from physical activity) >Lumbosacral pain (discomfort in the buttocks and hip areas) >pain can radiate to the thigh in a manner similar to that of sciatic pain >prolonged stiffness in the morning and after periods of rest >Mild physical activity or a hot shower helps reduce pain and stiffness >Walking or exercise may be needed to provide comfort >Loss of motion in the spinal column is characteristic of the disease >Loss of lumbar lordosis followed by kyphosis of the thoracic spine and extension of the neck which makes it difficult for the patient to look ahead and to maintain balance while walking >spine fused in the flexed position is the end result in severe ankylosing spondylitis >X-ray films show a rigid, bamboo-like spine > heart and lungs are constricted in the chest cavity > degeneration and destruction of the hips >Systemic features: weight loss, fever, and fatigue >Osteoporosis can occur, especially in the spine >fusion of the costovertebral joints can lead to reduced lung volume

Diagnosis and Treatment.

>Diagnosis : history, physical examination, and x-ray examination > methods to assess mobility and detect sacroiliitis - pressure on the sacroiliac joints with the person in a forward-bending position to elicit pain and muscle spasm -measurement of the distance between the tips of fingers and the floor in a bent-over position with straight knees - modified Schöber’s test in which contralateral flexion of the back is measured >Measurement of chest expansion- indirect indicator of thoracic involvement, which usually occurs late in the disease course. >Laboratory findings: elevated ESR; mild normocytic normochromic anemia > Early disease, x-ray images may be negative (vertebrae normally are concave on the anterior border) >Treatment: controlling pain and maintaining mobility by suppressing inflammation -proper posture and positioning - sleeping in a supine position on a firm mattress and using one small pillow or no pillow; bed board to add firmness - therapeutic exercises in maintaining motion in peripheral joints and in the spine -muscle-strengthening exercises for extensor muscle groups -Heat applications or a shower or bath may be beneficial before exercise to improve ease of movement -Swimming is an excellent general conditioning exercise that avoids joint stress and enhances muscle tone - Immobilizing joints is not recommended. -Maintaining ideal weight reduces the stress on weight-bearing joints -Smoking should be discouraged (exacerbates respiratory problems) >Pharmacologic treatment: NSAIDs to reduce inflammation, relieve pain, and reduce muscle spasm -Phenylbutazone is highly effective(limited to persons with severe disease in whom other agents have failed because of potential bone marrow suppression with long-term use) -anti–TNF- agents- efficacious in the treatment

Reactive Arthropathies

> sterile inflammatory joint disorders that are distant in time and place from the initial inciting infective process >infecting agents cannot be cultured and are not viable once having reached the joints >Commonly recognized forms of reactive arthritis include those involving Chlamydia pneumoniae infection and Pseudomonas >others: Chlamydia trachomatis, Salmonella, Shigella, Yersinia, Campylobacter, and Streptococcus > observed in persons with acquired immunodeficiency syndrome (AIDS) > immune response to HIV infection is selective and largely spares the natural killer cells, which may be critical in the pathogenesis of these conditions >may also result from the presence of a foreign substance in the joint tissue, as in silicone implants in

the small joints of the hand or feet or after exposure to industrial gases and oils >when the pathogens cannot be isolated, even though there has been a preceding infection, the diagnosis of reactive arthritis is made >Reactive arthritis may follow a self-limited course > treatment is largely symptomatic - NSAIDs -Short antibiotic courses at this time are not effective

Reiter’s Syndrome.

> a clinical manifestation of reactive arthritis that may be accompanied by extraarticular symptoms such as uveitis, bowel inflammation, and carditis. >develops in a genetically susceptible host after a bacterial infection due to Chlamydia trachomatis in the genitourinary tract or Salmonella, Shigella, Yersinia, or Campylobacter in the gastrointestinal tract > first rheumatic disease to be recognized in association with HIV infection. >Symptoms may precede any overt signs of HIV disease >Treatment with agents such as methotrexate and azathioprine may further suppress the immune response and provoke a full expression of AIDS

Enteropathic Arthritis. >associated with an inflammatory bowel disease > intestinal disease is directly >most are classified among the spondyloarthropathies > cases in which the arthritis is associated with inflammatory bowel disease (i.e., ulcerative colitis and Crohn’s disease), the reactive arthritides triggered by enterogenic bacteria, some of the undifferentiated spondyloarthropathies, Whipple’s disease, and reactions after intestinal bypass surgery >no direct relation between the activity of the bowel disease and the degree of arthritis activity

Psoriatic Arthritis

> seronegative inflammatory arthropathy that occurs with psoriasis >heterogeneous disease with features of the spondyloarthropathies in some persons, rheumatoid arthritis in others >Genetic, environmental, and immunologic factors >T-cell–mediated immune responses also seem to play an important role in the skin and joint manifestations of the disease >the arthritis can antedate detectable skin rash >definitive diagnosis of psoriatic arthritis cannot be made without evidence of skin or nail changes typical of psoriasis >five subgroups 1. oligoarticular or asymmetric 2. spondyloarthropathy 3. polyarticular or symmetric 4. distal interphalangeal 5. arthritis mutilans in which there is osteolysis with telescoping of the fingers and toes >more than one disease is associated with psoriasis, or various clinical responses to a common cause > elevated serum level of uric acid > slowly progressive, but has a more favorable prognosis than rheumatoid arthritis > Suppression of the skin disease may be important in helping control the arthritis

>affected joints are surprisingly functional and only minimally symptomatic

+Osteoarthritis Syndrome > referred to as “wear-and-tear” arthritis > slowly destructive disorder of the articular cartilage > pathogenesis of osteoarthritis includes the progressive disruption of the smooth surface of the articular cartilage with development of surface cracks that deepen to involve the subchondral bone; followed by complete erosion of the articular cartilage with exposure of ivory-like polished subchondral bone, dislodgment of fragments of free-floating osteocartilaginous bodies, development of bone cysts, and formation of abnormal bony spurs at the joint margins. > formerly called degenerative joint disease > most prevalent form of arthritis >primary idiopathic disorder - localized or generalized >secondary disorder- has a known underlying cause such as congenital or acquired defects of joint structures, trauma, metabolic disorders, or inflammatory diseases > joint pain, stiffness, limitation of motion, and in some cases joint instability and deformity.

>EPIDEMIOLOGY AND RISK FACTORS

>age and >Men are affected more commonly at a younger age than women, but the rate of women affected exceeds that of men by middle age >Heredity > Bone mass may also influence the risk for developing OA >thinner subchondral bone mass may provide a greater shock-absorbing function than denser bone, allowing less direct trauma to the cartilage >Obesity is a particular risk factor for OA of the knee in -Excess fat may have a direct metabolic effect on cartilage beyond the effects of excess joint stress

>PATHOGENESIS

>Articular cartilage serves as a remarkably smooth weight-bearing surface; transmits the load down to the bone, dissipating the mechanical stress - extracellular matrix is composed of water, proteoglycans, collagen, and ground substance -collagen molecules provide form and tensile strength > adult bone: articular cartilage is not static; it undergoes turnover, and its “worn out” matrix components are continually degraded and replaced >health of the chondrocytes determines joint integrity >characterized by significant changes in both the composition and mechanical properties of cartilage > earliest structural changes in OA include enlargement and reorganization of the chondrocytes in the superficial part of the articular cartilage accompanied by edematous changes in the cartilaginous matrix, principally the intermediate layer >portions of the articular cartilage eventually become completely eroded, and the exposed surface of the subchondral bone becomes thickened and polished to ivory-like consistency (eburnation)

> presence of free-floating osteocartilaginous bodies (“joint mice”) that enter the joint cavity > Sclerosis, or formation of new bone and cysts, usually occurs at the joint margins forming abnormal bony outgrowths called osteophytes, or spurs >the changes in the synovium that occur in OA are not as pronounced, nor do they occur as early >Immobilization also can produce degenerative changes in articular cartilage(result from loss of the pumping action of lubrication that occurs with joint movement) >slow and gradual remobilization may be important in preventing cartilage injury

>CLINICAL MANIFESTATIONS

>may occur suddenly or insidiously >pain : aching and may be somewhat difficult to localize > worsens with use or activity and is relieved by rest >later stages: night pain may be experienced during rest -Crepitus and grinding may be evident when the joint is moved - even minimal activity may cause pain because of the limited range of motion resulting from intraarticular and periarticular structural damage > affected joints are the hips, knees, lumbar and cervical vertebrae, proximal and distal joints of the hand, the first carpometacarpal joint, and the first metatarsophalangeal joints of the feet >single joint or several may be affected >other bones which are not initially affected may be damaged too > limitations of joint motion and joint instability >Joint enlargement usually results from new bone formation; the joint feels hard, in contrast to the soft, spongy feeling characteristic of the joint in rheumatoid arthritis

>DIAGNOSIS AND TREATMENT

> Diagnosis: history and physical examination, x-ray studies, and laboratory findings that exclude other diseases >Radiologic changes: medial joint space narrowing, followed by subchondral bony sclerosis, formation of spikes on the tibial eminence, and osteophytes. > laboratory studies usually are normal >ESR may be slightly elevated in generalized OA or erosive inflammatory variations of the disease > inflammation is present: slight increase in the blood cell count > synovial fluid usually is normal >Treatment:: no cure; treatment includes physical rehabilitative, pharmacologic, and surgical measures - improving the supporting structures of the joint and strengthening opposing muscle groups involved in cushioning weight-bearing forces - balance of rest and exercise, use of splints to protect and rest the joint, use of heat and cold to relieve pain and muscle spasm, and adjusting the activities of daily living - weight reduction (when weight-bearing surfaces are involved) and the use of a cane or walker if the hips and knees are involved. -Muscle strengthening exercises may help protect the joint and decrease pain

>Oral medications: reducing inflammation or providing analgesia > NSAID > COX-2–inhibiting >Intraarticular corticosteroid injections may be used when other treatment measures have been unsuccessful in adequately relieving symptoms >Viscosupplementation- based on the hypothesis that joint lubrication is abnormal in OA >Surgery is considered when the person is having severe pain and joint function is severely reduced - arthroscopic lavage and débridement, bunion resections, osteotomies to change alignment of the knee and hip joints, and decompression of the spinal roots in osteoarthritic vertebral stenosis -Total hip replacements -total knee replacements- less consistent results -Joint replacement for the first carpometacarpal joint -Arthrodesis is used in advanced disease to reduce pain; however, this results in loss of motion

+Metabolic Diseases Associated With Rheumatic States >CRYSTAL-INDUCED ARTHROPATHIES

>crystal deposition in joints produces arthritis > uric acid crystals are found in the joint cavity in gout > pseudogout or chondrocalcinosis -calcium pyrophosphate dihydrate crystals are found in the joints

Gout > group of diseases known as the gout syndrome > includes acute gouty arthritis with recurrent attacks of severe articular and periarticular inflammation; tophi or the accumulation of crystalline deposits in articular surfaces, bones, soft tissue, and cartilage; gouty nephropathy or renal impairment; and uric acid kidney stones >primary gout- cases in which the cause of the disorder is unknown or an inborn error in metabolism and is characterized primarily by hyperuricemia and gout -may be a consequence of enzyme defects - results in an overproduction of uric acid; inadequate elimination of uric acid by the kidney; or a combination of the two -disease of men > secondary gout- cause of the hyperuricemia is known; gout is not the main disorder -hyperuricemia may be caused by increased breakdown in the production of nucleic acids, as occurs with rapid tumor cell lysis during treatment for lymphoma or leukemia -result from chronic renal disease >Asymptomatic hyperuricemia - laboratory finding; not a disease

Pathogenesis.

> elevation of the serum uric acid levels >Two pathways involved in purine synthesis 1. de novo pathway in which purines are synthesized from nonpurine precursors

2. salvage pathway in which purine bases are recaptured from the breakdown of nucleic acids derived from exogenous (dietary) or endogenous sources >attack of gout occurs when monosodium urate crystals precipitate in the joint and initiate an inflammatory response >crystal deposition usually occurs in peripheral areas of the body where the temperatures are cooler than other parts of the body >prolonged hyperuricemia crystals and microtophi accumulate in the synovial lining cells and in the joint cartilage >repeated attacks lead to chronic arthritis and the formation of the large, hard nodules (tophi) >chronic tophaceous gou- more frequent and prolonged attacks, which often are polyarticular

Clinical Manifestations. > monoarticular and usually affects the first

metatarsophalangeal joint >Acute gout often begins at night -precipitated by excessive exercise, certain medications, foods, alcohol, or dieting - pain typically is abrupt, and redness and swelling are observed -pain may be severe enough to be aggravated even by the weight of a bed sheet > intercritical gout - early stages after the initial attack has subsided, the person is asymptomatic, and joint abnormalities are not evident > it may be months or years before another attack >attacks recur with increased frequency, joint changes occur and become permanent

Diagnosis and Treatment Diagnosis.

> presence of hyperuricemia cannot be equated with gout > definitive diagnosis: monosodium urate crystals are in the synovial fluid or in tissue sections of tophaceous deposits >Synovial fluid analysis > measures to determine whether the disorder is related to overproduction or to underexcretion of uric acid ( measurement of serum uric acid levels and collection of a 24-hour urine sample for determination of urate excretion in the urine) Treatment.

>termination and prevention of the acute attacks of gouty arthritis and the correction of hyperuricemia, with consequent inhibition of further precipitation of sodium urate and absorption of urate crystal deposits already in the tissues > NSAIDs > Colchicine produces its antiinflammatory effects by inhibition of leukocyte migration and phagocytosis >Phenylbutazone usually is effective but is used only on a short-term basis because long-term use can cause bone marrow suppression >corticosteroid drugs are not recommended for treatment of gout unless all other medications have proved unsuccessful of urate and increase its excretion in the urine. > changes in lifestyle may be needed, such as maintenance of ideal weight, moderation in alcohol consumption, and avoidance of purine-rich foods (e.g.,

liver, kidney, sardines, anchovies, and sweetbreads) particularly by patients with excessive tophaceous deposits

+Rheumatic Diseases in Children and the Elderly >RHEUMATIC DISEASES IN CHILDREN Juvenile Rheumatoid Arthritis

> characterized by synovitis and can influence epiphyseal growth by stimulating growth of the affected side > Generalized stunted growth also may occur >daily intermittent high fever, which usually is accompanied by a rash, generalized lymphadenopathy, hepatosplenomegaly, leukocytosis, and anemia >infections, heart disease, and adrenal insufficiency may cause death. > pauciarticular arthritis- affects no more than four joints -affects two distinct groups - first group generally consists of girls younger than 6 years of age with chronic uveitis -second group, characterized by late-onset arthritis, is made up mostly of boys >polyarticular onset disease- affects five or more joints during the first 6 months of the disease - more closely resembles the adult form of the disease -Rheumatoid factor sometimes is present and may indicate a more active disease process -Systemic features: low-grade fever, weight loss, malaise, anemia, stunted growth, slight organomegaly (e.g., hepatosplenomegaly), and adenopathy >NSAIDs are the first-line drugs used >Second-line agents are low-dose methotrexate and, less often, sulfasalazine

Systemic Lupus Erythematosus > similar to those in adults > extent of renal involvement, which is more common and more severe in children >Infectious complications are the most common cause of death >fever, malaise, anorexia, and weight loss are present >endocrine abnormalities: Cushing’s syndrome from long-term corticosteroid use and autoimmune thyroiditis >Adolescents: menstrual disturbances >Corticosteroids: cause stunting of growth and necrosis of femoral heads and other joints >Rest periods should be balanced with exercise

Juvenile Dermatomyositis

> an inflammatory myopathy primarily involving skin and muscle and associated with a characteristic rash >Symmetric proximal muscle weakness, elevated muscle enzymes, evidence of vasculitis, and electromyographic changes confirming an inflammatory myopathy > Periorbital edema, erythema, and eyelid telangiectasia are common. >calcifications appear at pressure points or sites of previous trauma >treated primarily with corticosteroids to reduce inflammation >calcium-sufficient diet, and vitamin D therapy.

Juvenile Spondyloarthropathies

> associated with ulcerative colitis and regional enteritis > spondyloarthritis- manifests in peripheral joints first, mimicking pauciarticular JRA, with no evidence of sacroiliac or spine involvement for months to years after onset > physical therapy, education, and attention to school and growth and development issues >Medication :salicylates or other NSAIDs

>RHEUMATIC DISEASES IN THE ELDERLY

> pain, stiffness, muscle weakness and gait disturbance >elderly cope less well with mild to moderately severe disease that in younger persons is less likely to lead to serious disability for the same degree of impairment > increased incidence of false-positive test results for rheumatoid factor and ANA in the elderly population with or without rheumatic disease because older persons are better producers of autoantibodies than younger persons >One form of rheumatic disease that has a predilection for the elderly is polymyalgia rheumatica

Rheumatoid Arthritis > Seropositive patients are more likely to have had an acute onset with systemic features and higher disease activity usually follows a mild course - rheumatoid arthritis in the elderly is a broad disorder that includes a number of distinct subsets with characteristic manifestations, courses, and outcomes

Systemic Lupus Erythematosus

> accompanied less frequently by renal involvement >pleurisy, pericarditis, arthritis, and symptoms closely resembling polymyalgia rheumatica are more common than in younger patients >(elderly) -closely resemble those of drug-induced SLE, leading to speculation that the syndrome may result from one of the multiple drugs that are taken by many elderly patients

Osteoarthritis >most common form of arthritis among the elderly >greatest cause of disability and limitation of activity in older populations >begins at a very young age, expressing itself in the elderly only after a long period of latency

Crystal-Induced Arthropathies Gout. >increased involvement of joints after years of continued hyperuricemia. >High serum urate levels rarely occur in women before menopause >Gouty attacks in elderly women may be precipitated by the use of diuretics.

Pseudogout.

>osteoarthritis develops with associated cartilage degeneration and the shedding of calcium pyrophosphate crystals into the joint cavity which may produce a low-grade chronic inflammation—chronic pseudogout syndrome >accumulation of calcium pyrophosphate and related crystalline deposits in articular cartilage >may be asymptomatic >presence of the crystals may contribute to more rapid cartilage deterioration

> may coexist with severe osteoarthritis

Polymyalgia Rheumatica

> aching and morning stiffness in the cervical regions and shoulder and pelvic girdle areas >common syndrome of older patients, rarely occurring before 50 years of age and usually after 60 years of age > onset can be abrupt, with the patient going to bed feeling well and awakening with pain and stiffness in the neck, shoulders, and hips. >Diagnosis: pain and stiffness persisting for at least 1 month and an elevated ESR; respond dramatically to a small dose of prednisone, a corticosteroid; biopsies: muscles are normal but a nonspecific inflammation affecting the synovial tissue is present >may also have giant cell arteritis (i.e., temporal arteritis), frequently with involvement of the ophthalmic arteries -blindness can ensue quickly without treatment

Localized Musculoskeletal Disorders >known collectively as impingement syndromes - shoulder: rotator cuff rides against the acromion - Tennis elbow, humeral epicondylitis, fibrositis or fibromyalgia and Dupuytren’s contracture

Management of Rheumatic Diseases in the Elderly > splints, walking aids, muscle-building exercise, and local heat >muscle-strengthening and stretching exercises >Rest- cornerstone of conservative therapy; hazardous in the elderly, who can rapidly lose muscle strength >NSAIDs may be less well tolerated by the elderly, and their side effects are more likely to be serious (bleeding from the gastrointestinal tract ,renal insufficiency, cognitive dysfunction, manifested by forgetfulness, inability to concentrate, sleeplessness, paranoid ideation, and depression) >Joint arthroplasty > no contraindication to surgical treatment of arthritis >more sedentary activity level of the elderly makes them even better candidates for joint replacement because they put less stress and demand on the new joint CHART 59-3