Pathophysiology Examination Answers

August 31, 2017 | Author: Fırat Güllü | Category: Immunodeficiency, Immune Tolerance, T Cell, Allergy, Apoptosis
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Pathophysiology Examination Answers...


1-Causes of Cell Injury The causes of cell injury range from the external gross physical violence of an automobile accident to internal endogenous causes, such as a subtle genetic mutation causing Oxygen Deprivation. Hypoxia is a deficiency of oxygen, which causes cell injury by reducing aerobic oxidative respiration. Hypoxia is an extremely important and common cause of cell injury and cell death. Physical Agents. Physical agents capable of causing cell injury include mechanical trauma, extremes of temperature (burns and deep cold), sudden changes in atmospheric pressure, radiation, and electric shock.Chemical Agents and Drugs. The list of chemicals that may produce cell injury defies compilation. Simple chemicals such as glucose or salt in hypertonic concentrations may cause cell injury directly or by deranging electrolyte homeostasis of cells. Infectious Agents. These agents range from the submicroscopic viruses to the large tapeworms. In between are the rickettsiae, bacteria, fungi, and higher forms of parasites Immunologic Reactions. Although the immune system serves an essential function in defense against infectious pathogens, immune reactions may, in fact, cause cell injury Genetic DerangementsThe genetic injury may result in a defect as severe as the congenital malformations associated with Down syndrome, caused by a chromosomal abnormality, or as subtle as the decreased life of red blood cells caused by a single amino acid substitution in hemoglobin S in sickle cell anemia Nutritional Imbalances. Nutritional imbalances continue to be major causes of cell injury. Protein-calorie deficiencies cause an appalling number of deaths, chiefly among underprivileged populations.      

Physical Agents e.g.. trauma, thermal injury Chemical Agents e.g. poisons, environmental pollutants and drugs Nutritional Infectious Diseases caused by protozoa, bacteria, viruses Immunological mechanisms Inherited diseases- inborn errors of metabolism

Mechanisms of Cell Injury            

Two mechanisms serve as useful models: fatty change hypoxia fatty change is generally a reversible form of sublethal injury whereas the effects of hypoxia depend on the severity, duration and on the vulnerability of the cell Fatty Change Accumulation of fat in hepatocytes depends on rate of fat synthesis, catabolism and on the synthesis and export of lipoproteins. Alcohol increases triglycyeride synthesis and reduces fatty acid catabolism Malnutrition impairs protein synthesis and therefore reduces lipoprotein synthesis Hypoxia Interruption of oxidative phosphorylation within mitochondria- depletion of ATP Progressive loss of membrane functional integrity Increased cytosolic calcium 1

Cell injury results from functional and biochemical abnormalities in one or more of several essential cellular components

2-Pathophysiology of cell injury.Effects and responses. The normal cell is confined to a fairly narrow range of function and structure by its genetic programs of metabolism, differentiation, and specialization; by constraints of neighboring cells; and by the availability of metabolic substrates. It is nevertheless able to handle normal physiologic demands, maintaining a steady state called homeostasis. More severe physiologic stresses and some pathologic stimuli may bring about a number of physiologic and morphologic cellular adaptations, during which new but altered steady states are achieved, preserving the viability of the cell and modulating its function as it responds to such stimuli . The adaptive response may consist of an increase in the number of cells, called hyperplasia, or an increase in the sizes of individual cells, called hypertrophy. Conversely, atrophy is an adaptive response in which there is a decrease in the size and function of cells. If the limits of adaptive response to a stimulus are exceeded, or in certain instances when the cell is exposed to an injurious agent or stress, a sequence of events follows that is loosely termed cell injury. Cell injury is reversible up to a certain point, but if the stimulus persists or is severe enough from the beginning, the cell reaches a "point of no return" and suffers irreversible cell injury and ultimately cell death. Adaptation, reversible injury, and cell death can be considered stages of progressive impairment of the cell's normal function and structure. Cell death, the ultimate result of cell injury, is one of the most crucial events in the evolution of disease of any tissue or organ. It results from diverse causes, including ischemia(lack of blood flow), infection, toxins, and immune reactions. There are two principal patterns of cell death, necrosis and apoptosis. Necrosis is the type of cell death that occurs after such abnormal stresses as ischemia and chemical injury, and it is always pathologic. Apoptosis occurs when a cell dies through activation of an internally controlled suicide program. Cellular Adaptations of Growth and Differentiation Cells respond to increased demand and external stimulation by hyperplasia or hypertrophy, and they respond to reduced supply of nutrients and growth factors by atrophy. In some situations, cells change from one type to another, a process called metaplasia. There are numerous molecular mechanisms for cellular adaptations. Some adaptations are induced by direct stimulation of cells by factors produced by the responding cells themselves or by other cells in the environment. Others are due to activation of various cell surface receptors and downstream signaling pathways. Adaptations may be associated with the induction of new protein synthesis by the target cells, as in the response of muscle cells to increased physical demand, and the induction of cellular proliferation, as in responses of the endometrium to estrogens. Adaptations can also involve a switch by cells from producing one type of proteins to another or markedly overproducing one protein; such is the case in cells producing various types of collagens and extracellular matrix proteins in chronic inflammation and fibrosis. HYPERPLASIA Hyperplasia is an increase in the number of cells in an organ or tissue, usually resulting in increased volume of the organ or tissue. HYPERTROPHY 2

Hypertrophy refers to an increase in the size of cells, resulting in an increase in the size of the organ. Thus, the hypertrophied organ has no new cells, just larger cells.

3) Apoptosis Death of cells occurs in two ways: 1. Necrosis--(irreversible injury) changes produced by enzymatic digestion of dead cellular elements 2. Apoptosis--vital process that helps eliminate unwanted cells--an internally programmed series of events effected by dedicated gene products Mechanisms of Cell Death Mechanisms of cell death caused by different agents may vary. However, certain biochemical events are seen in the process of cell necrosis:      

ATP depletion Loss of calcium homeostasis and free cytosolic calcium Free radicals: superoxide anions, Hydroxyl radicals, hydrogen peroxide Defective membrane permeability Mitochondrial damage Cytoskeletal damage

Apoptosis This process helps to eliminate unwanted cells by an internally programmed series of events effected by dedicated gene products. It serves several vital functions and is seen under various settings.       

During development for removal of excess cells during embryogenesis To maintain cell population in tissues with high turnover of cells, such as skin, bowels. To eliminate immune cells after cytokine depletion, and autoreactive T-cells in developing thymus. To remove damaged cells by virus To eliminate cells with DNA damage by radiation, cytotoxic agents etc. Hormone-dependent involution - Endometrium, ovary, breasts etc. Cell death in tumors.

Morphology of Apoptosis     

Shrinkage of cells Condensation of nuclear chormatin peripherally under nuclear membrane Formation of apoptotic bodies by fragmentation of the cells and nuclei. The fragments remain membrane-bound and contain cell organelles with or without nuclear fragments. Phagocytosis of apoptotic bodies by adjacent healthy cells or phagocytes. Unlike necrosis, apoptosis is not accompanied by inflammatory reaction

Mechanisms of Apoptosis Apoptosis can be induced by various factors under both physiological and pathological conditions: It is an energy-dependent cascade of molecular events which include protein cleavage by a group of enzymes (caspases), protein cross-linking, DNA breakdown. Apoptosis is regulated by a large family of genes some of which are inhibitory (bcl-2) and some are stimulatory (bax).


Apoptosis goes through several complex phases. To put it simply, abnormal mitochondrial membrane permeability is a crucial event which allows escape of cytochrome-c into the cystosol which, in turn, activates proteolytic enzymes (caspases) leading to the execution of the process. The final phase is the removal of dead cell fragments by phagocytosis without inflammatory reactions.

4- Free Radicals ACCUMULATION OF OXYGEN-DERIVED FREE RADICALS (OXIDATIVE STRESS) Cells generate energy by reducing molecular oxygen to water. During this process, small amounts of partially reduced reactive oxygen forms are produced as an unavoidable by product of mitochondrial respiration by phagocytes. Free radicals are chemical species that have a single unpaired electron in an outer orbit. Energy created by this unstable configuration is released through reactions with adjacent molecules, such as inorganic or organic chemicals— proteins, lipids, carbohydrates— particularly with key molecules in membranes and nucleic acids. ■ Absorption of radiant energy ■ Enzymatic metabolism of exogenous chemicals or drugs ■ The reduction-oxidation reactions that occur during normal metabolic processes. ■ Transition metals ■ Nitric oxide ■ Lipid peroxidation of membranes ■ Oxidative modification of proteins ■ Lesions in DNA. Reactions with thymine in nuclear and mitochondrial DNA produce single-stranded breaks in DNA. This DNA damage has been implicated in cell aging and in malignant transformation of cells ■ Antioxidants either block the initiation of free radical formation or inactivate free radicals and terminate radical damage ■ As we have seen, iron and copper can catalyze the formation of reactive oxygen species ■ A series of enzymes acts as free radical-scavenging systems and break down hydrogen peroxide and superoxide anion

5- Mechanisms of cell death As stated at the beginning of the chapter, cell injury results when cells are stressed so severely that they are no longer able to adapt or when cells are exposed to inherently damaging agents. Injury may progress through a reversible stage and culminate in cell death (Fig. 1-7). An overview of the morphologic changes in cell injury is shown in .The biochemical alterations "Mechanisms of Cell Injury." These alterations may be divided into the following stages: -Reversible cell injury. Initially, injury is manifested as functional and morphologic changes that are reversible if the damaging stimulus is removed. The hallmarks of reversible injury are reduced oxidative phosphorylation, adenosine triphosphate (ATP) depletion, and cellular swelling caused by changes in ion concentrations and water influx. -Irreversible injury and cell death. With continuing damage, the injury becomes irreversible, at which time the cell cannot recover


   

Cell injury occurs when an adverse stimulus reversibly disrupts the normal complex homeostatic balance of cellular metabolism. If the stimulus is persistent or of sufficient magnitude then irreversible injury may develop. The severity of the injury may also depend on the specific properties of the cell- selective vulnerability Cell death occurs when there is an irreversible loss of integrated cellular function.

Types of Cell Death: Necrosis       

Cell death is very often a passive process, an inevitable consequence of severe perturbations of the external environment beyond the limits of homeostatic mechanisms. This type of cell death is known as necrosis. Necrosis is invariably pathological. Caused by infarction, infectious diseases, poisoning etc. Affects contiguous groups of cells Cell swelling and cell lysis accompanied by loss of cell membrane integrity and lysosomal leakage Necrosis usually precipitates an inflammatory response

Types of Cell Death: Apoptosis 

      

In contrast to the passive pathological process of necrosis, a second type of cell death is now recognised which is an active process and which may occur as a physiological regulatory mechanism. This process is known as apoptosis. May be induced by physiological influences e.g. glucocorticoids or pathological influences e.g. ionising radiation or viral infections Active process characterised by specific biochemical mechanisms- DNA fragmentation, vitronectin expression Causes deletion of individual cells in the midst of others Cell shrinkage, preservation of membrane integrity, nuclear fragmentation with dense chromatin No inflammatory response but rapid phagocytosis Apoptosis important in inflammation, neoplasia, AIDS and neurodegenerative disorders


8-Traumatic Shock “Shock” is the systemic disease that results from any process that impairs the systemic delivery of oxygen to the cells of the body, or that prevents its normal uptake and utilization. Hemorrhage with decreased cardiac output is the most common cause of shock in trauma patients (Table 1), although it is not unusual for shock to result from a combination of events. Hemorrhage, tension pneumothorax, and cardiac contusion can all coexist in the patient with chest trauma, for example, with each contributing to systemic hypoperfusion. Iatrogenic contributors to shock may include anemia following vigorous crystalloid infusion, the use of tourniquets, and the use of systemic pressor agents. Underlying medical conditions can also play a part, with myocardial ischemia


potentially contributing to decreased oxygen delivery, especially in older trauma patients. The effects of alcohol, medications, and illicit drugs may contribute to a state of hypoperfusion and may block normal compensatory mechanisms. It is important to recognize that the traumatic shock seen clinically in severely injured patients may be quite different from the induced shock seen in laboratory animals hemorrhaged under controlled conditions. Stages of Shock Traumatic shock as occurring in four stages, based on arbitrary levels of blood loss and vital signs. Better approximation of the degree of shock, based on the patient’s symptoms, response to therapy, and prognosis. In compensated traumatic shock, an increase in heart rate and vasoconstriction of nonessential and ischemia-tolerant vascular beds will allow prolonged survival and easy recovery once hemostasis is achieved and resuscitation is completed. Decompensated traumatic shock, also known as progressive shock, is a transitory state in which lack of perfusion is creating cellular damage that will produce toxic effects. Shock is still reversible at this stage. In subacute irreversible shock, the patient is resuscitated to normal vital signs but succumbs at a later time to multiple organ system failure (MOSF) as the result of tissue ischemia and reperfusion. Finally, acute irreversible shock is the condition of ongoing hemorrhage, acidosis, and coagulopathy that spirals downward to early death from exsanguination. Progression from compensated to uncompensated shock (usually due to ongoing hemorrhage) is a surgical and metabolic emergency. Successful recovery requires rapid diagnosis and control of the inciting event (i.e., hemostasis) facilitated by resuscitative therapy directed toward minimizing the overall “dose” of shock. A patient who experiences substantial blood loss and massive transfusion will experience some degree of organ system failure thereafter (i.e., edema, pulmonary dysfunction). This is due to the systemic effects of tissue ischemia. Bleeding may be controlled and vital signs may be normal or even hypernormal, but the damage has been done on the cellular level. Ischemia can persist because of “no reflow” caused by cellular swelling and microcirculatory obstruction, while effects in nonischemic organ systems such as the lungs are actually a form of reperfusion injury. The Systemic Response to Shock The stages of traumatic shock are directly related to the physiologic response to hemorrhage. The initial response is on the macrocirculatory level and is mediated by the neuroendocrine system.Decreased blood pressure leads to vasoconstriction and catecholamine release. Heart and brain blood flow is preserved, while other regional beds are constricted. Pain, hemorrhage, and cortical perception of traumatic injuries lead to the release of a number of hormones as part of the “fight or flight” response, including renin–angiotensin, vasopressin, antidiuretic hormone, growth hormone, glucagon, cortisol, epinephrine and norepinephrine.This rush of chemicals sets the stage for the microcirculatory responses that follow. On the cellular level the body responds to hemorrhage by takingup interstitial fluid, causing cells to swell.Edematous cells obstruct adjacent capillaries, resulting in the "no-reflow" phenomenon that can prevent the reversal of ischemia even in the presence of adequate macro flow. The Central Nervous System The central nervous system is exquisitely sensitive to hypoperfusion and is thus the prime trigger of the neuroendocrine response to shock, which maintains oxygen supply to the heart and brain at the expense of other tissues.Regional glucose uptake in the brain changes during shock. Cardiovascular


The heart has little capacity to function anaerobically, and is relatively preserved from ischemia during hemorrhage because of maintenance or even increase of nutrient blood flow driven by the fight or flight response. Kidney and Adrenal Glands The kidney and adrenal glands are prime responders to the neuroendocrine changes of shock, producing renin, angiotensin, aldosterone, cortisol, erythropoietin, and catecholamines.The kidney itself maintains glomerular filtration in the face of hypotension by selective vasoconstriction and concentration of blood flow in the medulla and deep cortical area. The Lung The lung is almost never the trigger of the shock syndrome because it cannot itself become ischemic. The lung is nonetheless the downstream filter for the inflammatory byproducts of the ischemic body, and is itself an active immune organ.downstream filter for the inflammatory byproducts of the ischemic body, and is itself an active immune organ. The Gut Splanchnic perfusion is very strongly controlled by the autonomic nervous system, and the gut becomes vasoconstricted early in the course of hemorrhagic shock. The intestine is one of the earliest organs affected by hypoperfusion and may be a primary trigger of MOSF(Multi-Organ System Failure) The Liver The liver has a complex microcirculation and has been demonstrated to suffer both “no reflow” and reperfusion injury during recovery from shock. Hepatic cells are also metabolically active and contribute to the inflammatory response to decompensated shock. Skeletal Muscle, Bone, and Skin Vasoconstrictive mechanisms in peripheral tissue are important to spontaneous hemostasis and tissues of the musculoskeletal system are ischemia-tolerant as long as motor function is not required. Conclusion Traumatic shock is a disease of tissue ischemia, and is characterized by a trigger that produces tissue ischemia (usually hemorrhage) and the inflammatory disease that follows. Surgical hemostasis and precision resuscitation can restore normal blood volume quickly after major trauma, but the patient can still die as a result of the systemic effects of shock. The future management of this disease will depend on a clear understanding of the effects of shock in different organ systems, the ways in which inflammatory mediators can exacerbate ongoing ischemic distress, and our ability to support multiple failing organ systems simultaneously.

9-SORU YOK 10-Pathogenic Effect Of Electric Current The passage of an electric current through the body may be without effect; may cause sudden death by disruption of neural regulatory impulses, producing, for example, cardiac arrest; or may cause thermal injury to organs interposed in the pathway of the current. Many variables are involved, but most important are the resistance of the tissues to the conductance of the electric current and the intensity of the current. The greater the resistance of tissues, the greater the heat generated. Although all tissues of the body are conductors of electricity, their resistance to flow varies inversely with their water content. Dry skin is particularly resistant, but when skin is wet or immersed in water, its resistance is greatly decreased. Thus, an electric current may cause only a surface burn of dry skin 7

but may cause death by disruption of regulatory pathways when it is transmitted through wet skin, producing, for example, ventricular fibrillation or respiratory paralysis without injury to the skin. The thermal effects of the passage of the electric current depend on its intensity. High-intensity current, such as lightning coursing along the skin, produces linear arborizing burns known as lightning marks. Sometimes intense current is conducted around the victim (so-called flashover), blasting and disrupting the clothing but doing little injury. When lightning is transmitted internally, it may produce sufficient heat and steam to explode solid organs, fracture bones, or char areas of organs. Focal hemorrhages from rupture of small vessels may be seen in the brain. Sometimes, death is preceded by violent convulsions related to brain damage. Less intense voltage may heat, coagulate, or rupture vessels and cause hemorrhages or, in solid organs such as the spleen and kidneys, cause infarctions or ruptures.

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

Effects.Cells surviving radiant energy damage show a wide range of structural changes in chromosomes, including deletions, breaks, translocations, and fragmentation. The mitotic spindle often becomes disorderly, and polyploidy and aneuploidy may be encountered. Nuclear swelling and condensation and clumping of chromatin may appear; sometimes the nuclear membrane breaks down. Apoptosis may occur. All forms of abnormal nuclear morphology may be seen. Giant cells with pleomorphic nuclei or more than one nucleus may appear and persist for years after exposure. At extremely high doses of radiant energy, markers of cell death, such as nuclear pyknosis, and lysis appear quickly. In addition to affecting DNA and nuclei, radiant energy may induce a variety of cytoplasmic changes, including cytoplasmic swelling, mitochondrial distortion, and degeneration of the endoplasmic reticulum. Plasma membrane breaks and focal defects may be seen. The histologic constellation of cellular pleomorphism, giant-cell formation, conformational changes in nuclei, and abnormal mitotic figures creates a more than passing similarity between radiation-injured cells and cancer cells, a problem that plagues the pathologist when evaluating post-irradiation tissues for the possible persistence of tumor cells.


At the light microscopic level, vascular changes and interstitial fibrosis are prominent in irradiated tissues .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.

12- SORU YOK 13- SORU YOK 14- SORU YOK 15- SORU YOK 16 -SORU YOK 17. Allergy. Essence and classification. Humorally mediated allergy. Mechanism Exposure to an antigen results in the formation of IgE. The antigen reacts with CD4+ cells, which differentiate to TH2 cells. TH2 cells release interleukin-3 (IL-3), IL-4, and IL-5. IL-5 stimulates eosinophils, and IL-4 activates IgE-producing B cells. The IgE binds to mast cells. Subsequent exposure to the same antigen results in binding of the antigen to IgE bound to mast cells, with the consequence of degranulation of the mast cells and release of mediators (e.g., histamine). The release of mediators causes increased vascular permeability, leading to edema and increased smooth muscle contraction and eventuallyto bronchoconstriction. Sequence of events in type I hypersensitivity reaction; 1. Early phase (occurs within 5–30 minutes of exposure to antigen): Characterized by vasodilation, increased vascular permeability, and increased smooth muscle contraction. The early phase is due to binding of antigen to IgE bound to mast cells, with subsequent degranulation of the mast cells and release of mediators. 2. Late phase (occurs after 2–24 hours and lasts for days): Characterized by infiltration by neutrophils, eosinophils, basophils, and monocytes, and results in mucosal damage due to release of mediators by these recruited inflammatory cells. Immediate Response Vasodilation Vascular Leakage Smooth Muscle Spasm Forms of type I hypersensitivity reactions Systemic anaphylaxis: Due to parenteral administration of antigen; for example, a bee sting or a reaction to penicillin. Local reaction: Urticaria (hives). Causes: Penicillin, angiotensin-converting enzyme (ACE) inhibitors, intravenous (IV) contrast and other drugs, proteins (e.g., insect venoms), and food. Clinical and Pathologic Manifestations An immediate hypersensitivity reaction may occur as a systemic disorder or as a local reaction. The nature of the reaction is often determined by the route of antigen exposure. Systemic (parenteral) 9

administration of protein antigens (e.g., in bee venom) or drugs (e.g., penicillin) may result in systemic anaphylaxis. Within minutes of an exposure in a sensitized host, itching, urticaria (hives), and skin erythema appear, followed in short order by profound respiratory difficulty caused by pulmonary bronchoconstriction and accentuated by hypersecretion of mucus. Laryngeal edema may exacerbate matters by causing upper airway obstruction. In addition, the musculature of the entire gastrointestinal tract may be affected, with resultant vomiting, abdominal cramps, and diarrhea. Without immediate intervention, there may be systemic vasodilation with fall in blood pressure (anaphylactic shock), and the patient may progress to circulatory collapse and death within minutes. Local reactions generally occur when the antigen is confined to a particular site, such as skin (contact, causing urticaria), gastrointestinal tract (ingestion, causing diarrhea), or lung (inhalation, causing bronchoconstriction). The common forms of skin and food allergies, hay fever, and certain forms of asthma are examples of localized allergic reactions. Susceptibility to localized type I reactions is genetically controlled, and the term atopy is used to imply familial predisposition to such localized reactions. Patients who suffer from nasobronchial allergy (including hay fever and some forms of asthma) often have a family history of similar conditions. Linkage studies have identified several chromosomal regions that are associated with susceptibility to asthma and other allergic diseases. Among the candidate genes that are present close to these chromosomal loci are genes that encode HLA molecules (which may confer immune responsiveness to particular allergens), cytokines (which may control TH2 responses), a component of the FcεRI, and ADAM33, a metalloproteinase that may be involved in tissue remodeling in the airways. Type I Clinical allergy represents IgE-mediated hypersensitivity response arising from deleterious inflammation in response to the presence of normally harmless environmental antigens. Anaphylactic or immediate hypersensitivity reactions occur after binding of antigen to IgE antibodies attached to the surface of the mast cell or basophil and result in the release of preformed and newly generated inflammatory mediators that produce the clinical manifestations. Examples of type I– mediated reactions include anaphylactic shock, allergic rhinitis, allergic asthma, and allergic drug reactions. Type II Cytotoxic reactions involve the binding of either IgG or IgM antibody to antigens covalently bound to cell membrane structures. Antigen-antibody binding activates the complement cascade and results in destruction of the cell to which the antigen is bound. Examples of tissue injury by this mechanism include immune hemolytic anemia and Rh hemolytic disease in the newborn. Another example of the type II–mediated disease process without cell death is autoimmune hyperthyroidism, a disorder in which thyroid-stimulating antibodies stimulate thyroid tissue. Type III Immune complex–mediated reactions occur when immune complexes are formed by the binding of antigens to antibodies with fixation of complement. Complement-bound immune complexes facilitate opsonization by phagocytes and ADCC. Complexes are usually cleared from the circulation in the reticuloendothelial system. However, deposition of these complexes in tissues or in vascular endothelium can produce immune complex–mediated tissue injury by leading to complement activation, anaphylatoxin generation, chemotaxis of polymorphonuclear leukocytes, mediator release and tissue injury. Cutaneous Arthus reaction, systemic serum sickness, some aspects of clinical autoimmunity, and certain features of infective endocarditis are clinical examples of type III– mediated diseases. Type IV Cell-mediated immunity is responsible for host defenses against intracellular pathogenic organisms, although abnormal regulation of this system may result in delayed-type hypersensitivity. Type IV


hypersensitivity reactions are mediated not by antibody but by antigen-specific T lymphocytes. Classic examples are tuberculin skin test reactions and contact dermatitis.

18) Cell-mediated allergy Allergies Immunologists, as well as the general public, use the term allergy in several different ways. An allergy is a harmful immune response elicited by an antigen that is not itself intrinsically harmful. Examples:  

The windblown pollen released by orchard grass has no effect on me but produces a violent attack of hay fever (known to physicians as allergic rhinitis) in my wife. She, on the other hand, can safely handle the leaves of poison ivy while if I do so, I break out in a massive skin rash a day or two later.

Antigens that trigger allergies are often called allergens. Four different immune mechanisms can result in allergic responses. 1. Immediate Hypersensitivities. These occur quickly after exposure to the allergen. They are usually mediated by antibodies of the IgE class. Examples:   

hay fever hives asthma

2. Antibody-Mediated Cytotoxicity Cell damage caused by antibodies directed against cell surface antigens. Hence a form of autoimmunity. Examples:  

Hemolytic disease of the newborn (Rh disease). Myasthenia gravis (MG)

3. Immune Complex Disorders Damage caused by the deposit in the tissues of complexes of antigen and their antibodies. Examples:  

Serum sickness Systemic lupus erythematosus (SLE)

4. Cell-Mediated Hypersensitivities These reactions are mediated by CD4+ T cells. Examples:


The rash produced following exposure to poison ivy. Because it takes a day or two for the T cells to mobilize following exposure to the antigen, these responses are called delayed-type hypersensitivities (DTH). Those, like poison ivy, that are caused by skin contact with the antigen are also known as contact sensitivities or contact dermatitis. certain autoimmune diseases, including o Type 1 diabetes mellitus o Multiple sclerosis (MS) o Rheumatoid arthritis (RA)

Immediate Hypersensitivities Local Anaphylaxis The constant region of IgE antibodies (shown in blue) has a binding site for a receptor present on the surface of basophils and their tissue-equivalent the mast cell. These cell-bound antibodies have no effect until and unless they encounter allergens (shown in red) with epitopes that can bind to their antigen-binding sites. When this occurs, the mast cells to which they are attached  

explosively discharge their granules by exocytosis. The granules contain a variety of active agents including histamine; synthesize and secrete other mediators including leukotrienes and prostaglandins.

Release of these substances into the surrounding tissue causes local anaphylaxis: swelling, redness, and itching. In effect, each IgE-sensitized mast cell is a tiny bomb that can be exploded by a particular antigen. The most common types of local anaphylaxis are:   

allergic rhinitis (hay fever) in which airborne allergens react with IgE-sensitized mast cells in the nasal mucosa and the tissues around the eyes; bronchial asthma in which the allergen reaches the lungs either by inhalation or in the blood [Further discussion of asthma]; hives (physicians call it urticaria) where the allergen usually enters the body in food.

ome people respond to environmental antigens (e.g., pollen grains, mold spores) with an unusually vigorous production of IgE antibodies. Why this is so is unclear; heredity certainly plays a role. In any case, the immune system of these people is tilted toward the production of T helper cells of the Th2 subtype. These release interleukin 4 (IL-4) and interleukin 13 (IL-13) on the B cells that they "help". These lymphokines promote class switching in the B cell causing it to synthesize IgE antibodies. An inherited predisposition to making IgE antibodies is called atopy. Atopic people are apt to have higher levels of circulating IgE (up to 12 µg/ml) than is found usually (about 0.3 µg/ml). Whereas only 20–50% of the receptors on mast cells are normally occupied by IgE, all the receptors may be occupied in atopic individuals.


Systemic Anaphylaxis Some allergens can precipitate such a massive IgE-mediated response that a life-threatening collapse of the circulatory and respiratory systems may occur. Frequent causes:   

insect (e.g., bee) stings many drugs (e.g., penicillin) a wide variety of foods. Egg white, cow's milk, and nuts are common offenders in children; in fact, some school systems in the U. S. now ban peanuts and peanut-butter sandwiches when they have a student at risk of systemic anaphylaxis from exposure to peanuts. Fish and shellfish are frequent causes of anaphylaxis in adults.

Treatment of systemic anaphylaxis centers on the quick administration of adrenaline, antihistamines, and — if shock has occurred — intravenous fluid replacement. Anti-IgE Antibodies IgE molecules bind to mast cells and basophils through their constant region. If you could block this region, you could interfere with binding — hence sensitization of — these cells. Humanized monoclonal antibodies specific for the constant region of IgE are in clinical trials. They have shown some promise against asthma and peanut allergy, but such treatment will probably have to be continued indefinitely (and will be very expensive).

19. Autoimmune response – essence and mechanism of generation. The evidence is compelling that an immune reaction to self-antigens (i.e., autoimmunity) is the cause of certain human diseases; a growing number of entities have been attributed to this process. However, in many of these disorders the proof is not definitive, and an important caveat is that the simple presence of autoreactive antibodies or T cells does not equate to autoimmune disease. For example, low-affinity antibodies and T cells reactive with self-antigens can be readily demonstrated in most otherwise healthy individuals; presumably, these antibodies and T cells are not pathogenic and are of little consequence. Moreover, similar innocuous autoantibodies to selfantigens are frequently generated following other forms of injury (e.g., ischemia) and may even serve a physiologic role in the removal of products of tissue breakdown. Thus, the presence of a multiplicity of autoantibodies accounts for many of the clinical and pathologic manifestations of SLE. Moreover, these autoantibodies can be identified within lesions by immunofluorescence and electron-microscopic techniques. In many other disorders, an autoimmune etiology is suspected but is unproven. Indeed, in some cases of apparent autoimmunity the response may be directed against an exogenous antigen, such as a microbial protein; such is the probable pathogenesis of the vasculitis in many cases of polyarteritis nodosa. Presumed autoimmune diseases range from those in which specific immune responses are directed against one particular organ or cell type and result in localized tissue damage, to multisystem diseases characterized by lesions in many organs and associated with multiple autoantibodies or cellmediated reactions against numerous self-antigens. In the systemic diseases, the lesions affect principally the connective tissue and blood vessels of the various organs involved. Thus, even though the systemic reactions are not specifically directed against constituents of connective tissue or blood vessels, the diseases are often referred to as "collagen vascular" or "connective tissue" disorders. It is obvious that autoimmunity implies loss of self-tolerance, and the question arises as to how this happens. To understand the pathogenesis of autoimmunity, it is important to first familiarize ourselves with the mechanisms of normal immunologic tolerance.


Immunological tolerance is unresponsiveness to an antigen that is induced by exposure of specific lymphocytes to that antigen. Self-tolerance refers to a lack of immune responsiveness to one's own tissue antigens. During the generation of billions of antigen receptors in developing T and B lymphocytes, it is not surprising that receptors are produced that can recognize self-antigens. Since these antigens cannot all be concealed from the immune system, there must be means of eliminating or controlling self-reactive lymphocytes. Several mechanisms work in concert to select against selfreactivity and to thus prevent immune reactions against one's own antigens. These mechanisms are broadly divided into two groups: central tolerance and peripheral tolerance.Central tolerance. This refers to deletion of self-reactive T and B lymphocytes during their maturation in central lymphoid organs (i.e., in the thymus for T cells and in the bone marrow for B cells). Many autologous (self) protein antigens are processed and presented by thymic APCs in association with self-MHC. Any developing T cell that expresses a receptor for such a self-antigen is negatively selected (deleted by apoptosis), and the resulting peripheral T-cell pool is thereby depleted of self-reactive cells. An exciting recent advance has been the identification of putative transcription factors that induce the expression of apparently peripheral tissue antigens in the thymus. One such factor is called the autoimmune regulator (AIRE); mutations in the AIRE gene are responsible for an autoimmune polyendocrine syndrome in which T cells specific for multiple self-antigens escape deletion, presumably because these self-antigens are not expressed in the thymus. Some T cells that encounter self-antigens in the thymus are not killed but differentiate into regulatory T cells. Immature B cells that recognize, with high affinity, self-antigens in the bone marrow may also die by apoptosis. Some self-reactive B cells may not be deleted but may undergo a second round of rearrangement of antigen receptor genes and express new receptors that are no longer self-reactive (a process called "receptor editing").Unfortunately, the process of deletion of self-reactive lymphocytes is far from perfect. Many self-antigens may not be present in the thymus, and hence T cells bearing receptors for such autoantigens escape into the periphery. There is similar "slippage" in the B-cell system as well, and B cells that bear receptors for a variety of self-antigens, including thyroglobulin, collagen, and DNA, can be found in healthy individuals.Peripheral tolerance. Selfreactive T cells that escape negative selection in the thymus can potentially wreak havoc unless they are deleted or effectively muzzled. Several mechanisms in the peripheral tissues that silence such potentially autoreactive T cells have been identified: Anergy: This refers to functional inactivation (rather than death) of lymphocytes induced by encounter with antigens under certain conditions. Recall that activation of T cells requires two signals: recognition of peptide antigen in association with self-MHC molecules on APCs, and a set of second costimulatory signals (e.g., via B7 molecules) provided by the APCs. If the second costimulatory signals are not delivered, or if an inhibitory receptor on the T cell (rather than the costimulatory receptor) is engaged when the cell encounters self-antigen, the T cell becomes anergic and cannot respond to the antigen. Because costimulatory molecules are not strongly expressed on most normal tissues, the encounter between autoreactive T cells and self-antigens in tissues may result in anergy. B cells can also become anergic if they encounter antigen in the absence of specific helper T cells.Suppression by regulatory T cells: The responses of T lymphocytes to self-antigens may be actively suppressed by regulatory T cells. The best-defined populations of regulatory T cells express CD25, one of the chains of the receptor for IL-2, and require IL-2 for their generation and survival. These cells also express a unique transcription factor called FoxP3, and this one protein seems to be both necessary and sufficient for the development of regulatory cells. Mutations in the FOXP3 gene are responsible for a systemic autoimmune disease called IPEX (immune dysregulation, 14

polyendocrinopathy, enteropathy, X-linked syndrome), which is associated with deficiency of regulatory T cells. The probable mechanism by which regulatory T cells control immune responses is by secreting immunosuppressive cytokines (e.g., IL-10 and TGF-β), which can dampen a variety of Tcell responses.Activation-induced cell death: Another mechanism of peripheral tolerance involves apoptosis of mature lymphocytes as a result of self-antigen recognition. T cells that are repeatedly stimulated by antigens in vitro undergo apoptosis. One mechanism of apoptosis is the death receptor Fas (a member of the TNF receptor family) being engaged by its ligand coexpressed on the same cells. The same pathway is important for the deletion of self-reactive B cells by Fas ligand expressed on helper T cells. The importance of this pathway of self-tolerance is illustrated by the discovery that mutations in the FAS gene are responsible for an autoimmune disease called the autoimmune lymphoproliferative syndrome, characterized by lymphadenopathy and multiple autoantibodies including anti-DNA. Defects in Fas and Fas ligand are also the cause of similar autoimmune diseases in mice. Mechanisms of Autoimmunity Now that we have summarized the principal mechanisms of self-tolerance, we can ask how these mechanisms might break down to give rise to pathologic autoimmunity. Unfortunately, there are no simple answers to this question, and we still do not understand the underlying causes of most human autoimmune diseases. We referred above to mutations that compromise one or another pathway of self-tolerance and cause pathologic autoimmunity. These single-gene mutations are extremely informative, and they help to establish the biologic significance of the various pathways of selftolerance. The diseases caused by such mutations are rare, however, and most autoimmune diseases cannot be explained by defects in single genes. The breakdown of self-tolerance and the development of autoimmunity are probably related to the inheritance of various susceptibility genes and changes in tissues, often induced by infections or injury, that alter the display and recognition of self-antigens. Genetic Factors in Autoimmunity There is abundant evidence that susceptibility genes play an important role in the development of autoimmune diseases. Autoimmune diseases have a tendency to run in families, and there is a greater incidence of the same disease in monozygotic than in dizygotic twins.Several autoimmune diseases are linked with the HLA locus, especially class II alleles. Two genetic polymorphisms have recently been shown to be quite strongly associated with certain autoimmune diseases. One, called PTPN22, encodes a phosphatase, and particular variants are associated with rheumatoid arthritis and several other autoimmune diseases. Another, called NOD2, encodes an intracellular receptor for microbial peptides, and certain variants or mutants of this gene are present in as many as 25% of patients with Crohn's disease in some populations. How these genes contribute to autoimmunity is not established.

20)IMMUNODEFİCİENCY STATES.PRIMARY IMMUNODEFICIENCY DISEASE Immunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. Immunodeficiency may also decrease cancer immunosurveillance. Most cases of immunodeficiency are acquired ("secondary") but some people are born with defects in their immune system, or primary immunodeficiency. Transplant patients take medications to suppress their immune system as an anti-rejection measure, as do some patients suffering from an over-active immune system. A person who has an immunodeficiency of any kind is said to be immunocompromised. An immunocompromised 15

person may be particularly vulnerable to opportunistic infections, in addition to normal infections that could affect everyone. Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function properly. To be considered a primary immunodeficiency, the cause of the immune deficiency must not be secondary in nature (i.e., caused by other disease, drug treatment, or environmental exposure to toxins). Most primary immunodeficiencies are genetic disorders; the majority are diagnosed in children under the age of one, although milder forms may not be recognized until adulthood. About 1 in 500 people is born with a primary immunodeficiency. Types of immunodeficiencies:  

a primary immunodeficiency results from a genetic or developmental defect in the immune system. a secondary or acquired immunodeficiency is a loss of immune function due to exposure to an external agent.

Primary immunodeficiences:  

may affect either adaptive or innate immune functions. categorized by the type of cells involved or the developmental stage at which the defect occurs . defects generally affect either the lymphoid or myeloid cell lineages and involve specific genes Depending on the affected component of the immune system, there will be increased susceptibility to infection by different pathogens.

Lymphoid immunodeficiencies:  

may involve B cells, T cells or both B and T cells. B cell defects range from a complete absence of B cells, plasma cells, and immunoglobulin to a selective loss of certain immunoglobulin classes. Serious B cell defects cause frequent bacterial infections due to the absence of humoral immunity. T cell defects cause frequent viral and fungal infections due to the absence of cell-mediated immunity. Humoral immunity to T-dependent antigens is also affected.

T cell immunodeficiencies: 

can affect humoral, as well as cell-mediated immunity since many antigens are T-dependent, leading to a form of SCID. Although there is some decrease in antibody levels, the main result is increased susceptibility to viral, fungal and protozoal infections. DiGeorge Syndrome (congenital thymic aplasia) is the result of a developmental defect in which children are born without a thymus or parathyroids (in some cases the thymus is not completely absent). Because few functional T cells are present, cell-mediated immunity is undetectable, although a diminished humoral response is able to deal with most common bacterial infections. However, viral, fungal and protozoal infections are often fatal. A fetal thymus transplant can provide a source of thymic hormones and an environment for T cell maturation.

B cell immunodeficiencies: 

may range from a complete absence of mature B cells, plasma cells and immunoglobulin to a selective deficiency in one class of immunoglobulin. 16

patients suffer from recurrent bacterial infections (especially by encapsulated bacteria because antibodies are critical for the opsonization and clearance of these microbes), although immunity to most viral and fungal infections is normal. X-linked agammaglobulinemia occurs in 1 in 103 to 106 males (X chromosome-linked). Pre-B cells in the bone marrow fail to differentiate into mature B cells because of a defect in a tyrosine kinase (Brutonís tyrosine kinase) that is required to couple the pre-B cell receptor to nuclear events that lead to light chain gene rearrangement and B cell maturation. These individuals have little or no circulating antibody because of arrested B cell development at the pre-B cell stage. The condition can be treated with injections of purified pooled human IgG, although sinopulmonary infections persist due to lack of secretory IgA. X-linked hyper-IgM syndrome results from a defect in the gene coding for CD40 ligand. Since CD40 on B cells must interact with CD40 ligand on T cells for B cell activation to occur, these individuals fail to respond to T-dependent antigens. The response to T-independent antigens is normal, leading to heightened IgM production. selective immunoglobulin deficiencies result when one class or subclass of antibody is missing. The most common is an IgA deficiency due to a failure of IgA-committed B cells to differentiate into plasma cells. These patients suffer frequent bacterial and viral sinopulmonary infections, and increased allergies due to excessive IgE production. Treatment is with broad-spectrum antibiotics.

Myeloid immunodeficiencies: 

congenital agranulocytosis results from decreased production of G-CSF and a failure of myeloid stem cells to differentiate into neutrophils and other granulocytes. Frequent bacterial infections are common. chronic granulomatous disease is caused by a defect in the oxidative pathway that phagocytes use to generate hydrogen peroxide. As a result phagocytes are unable to kill many types of phagocytosed bacteria, leading to excessive inflammatory responses and susceptibility to bacterial and fungal infections. Antigen processing and presentation by macrophages is also impaired. leukocyte adhesion deficiency (LAD) is caused by a failure to express the ß subunit of the adhesion molecules LFA-1, MAC-1 (CR3), and p150,90 (CR4). These adhesion molecules, which are required for cellular interactions (Table 19-2), are nearly absent from the cell membrane. Individuals with this defect exhibit impaired extravasation of neutrophils, monocytes and lymphocytes; impaired ability of CTL and NK cells to adhere to target cells; and failure of T helper cells and B cells to form conjugates. Frequent bacterial infections and impaired wound healing are major problems.

21. Immunodeficient states. Acquired immunodeficiency syndrome (AIDS). Clinical Presentation AIDS is the most common immunodeficiency disorder worldwide, and HIV infection is one of the greatest epidemics in human history. AIDS is the consequence of a chronic retroviral infection that produces severe, life-threatening CD4 helper T lymphocyte dysfunction, opportunistic infections, and malignancy. Retroviruses contain viral RNA that is transcribed by viral reverse transcriptase into double-stranded DNA, which is integrated into the host genome. Cellular activation leads to transcription of HIV gene products and viral replication. AIDS is defined by serologic evidence of HIV infection with the presence of a variety of indicator diseases associated with clinical immunodeficiency. Table 3-7 lists criteria for defining and 17

diagnosing AIDS. HIV is transmitted by exposure to infected body fluids or sexual or perinatal contact. Transmissibility of the HIV virus is related to subtype virulence, viral load, and immunologic host factors. Acute HIV infection may present as an acute, self-limited, febrile viral syndrome characterized by fatigue, pharyngitis, myalgias, rash, lymphadenopathy, and significant viremia without detectable anti-HIV antibodies. Over time, there is a progressive decline in CD4 T lymphocytes, a reversal of the normal CD4:CD8 T lymphocyte ratio, and numerous other immunologic derangements. The clinical manifestations are directly related to HIV tissue tropism and defective immune function. Development of neurologic complications, opportunistic infections, or malignancy signal marked immune deficiency. The time course for progression of the disease varies; the majority of individuals remain asymptomatic for as long as 5-10 years. Typically, up to 70% of individuals will develop AIDS after a decade of subclinical HIV infection. Pathology & Pathogenesis Chemokines (chemoattractant cytokines) regulate leukocyte trafficking to sites of inflammation and have been discovered to play a significant role in the pathogenesis of HIV disease. During the initial stages of infection and viral proliferation, virion entry and cellular infection requires binding to two coreceptors on target T lymphocytes and monocyte/macrophages. All HIV strains express the envelope protein gp120 that binds to CD4 molecules, but different viral strains display tissue “tropism” or specificity based on the coreceptor they recognize. These coreceptors belong to the chemokine receptor family. Changes in viral phenotype during the course of HIV infection may lead to changes in tropism and cytopathology at different stages of disease. Viral strains isolated in early stages of infection (eg, R5 viruses) demonstrate tropism toward macrophages. X4 strains of HIV are more commonly seen in later stages of disease. X4 viruses bind to chemokine receptor CXCR4, more broadly expressed on T cells, and are associated with syncytium formation. A small percentage of individuals possessing nonfunctional alleles for the polymorphic chemokine receptor CCR5 appear to be highly resistant to HIV infection or display delayed progression of disease. Mathematical models estimate that during HIV infection billions of virions are produced and cleared each day. The reverse transcription step of HIV replication is error prone; mutations are frequent, and even within an individual patient HIV heterogeneity develops rapidly. The development of antigenically and phenotypically distinct strains contributes to progression of disease, clinical drug resistance, and lack of efficacy of early vaccines. Cellular activation is critical for viral infectivity and reactivation of integrated proviral DNA. Although only 2% of mononuclear cells are found peripherally, lymph nodes from HIV-infected individuals can contain large amounts of virus sequestered among infected follicular dendritic cells in the germinal centers. With HIV infection there is an absolute reduction of CD4 T lymphocytes, an accompanying deficit in CD4 T lymphocyte function, and an associated increase in CD8 cytotoxic T lymphocytes (CTLs). CTL activity is initially brisk and effective at controlling viremia through elimination of virus and virus-infected cells. Ultimately, viral proliferation outpaces host responses, and HIV-induced immunosuppression leads to disease progression. Loss of viral containment occurs with diminution of CD8+ T-cell dependent cytotoxic responses, lack of adequate helper T function, accumulation of viral escape mutations, and general cytokine dysregulation detrimental to effective immune responses. In addition to the cell-mediated immune defects, B-lymphocyte function is altered such that many infected individuals have marked hypergammaglobulinemia but impaired specific antibody responses. Both anamnestic responses and those to neoantigens can be impaired. However, the role of humoral immunity in controlling viremia or slowing disease progression is unclear. The development of assays to measure viral burden (plasma HIV-RNA quantification) has led to a better understanding of HIV dynamics and has provided a tool for assessing response to therapy. It is now well recognized that viral replication continues throughout the disease, and immune deterioration occurs despite clinical latency. The risk of progression to AIDS appears correlated with 18

an individual's viral load after seroconversion. The marked decline in CD4 T lymphocyte counts characterizing HIV infectionis due to several mechanisms, including (1) direct HIV-mediated destruction of CD4 T lymphocytes, (2) autoimmune destruction of virus-infected T cells, (3) depletion by fusion and formation of multinucleated giant cells (syncytium formation), (4) toxicity of viral proteins to CD4 T lymphocytes and hematopoietic precursors, and (5) induction of apoptosis (programmed cell death). Data from several large clinical cohorts have shown that there is a direct correlation between the CD4 T-lymphocyte count number and the risk of AIDS-defining opportunistic infections. Thus, the viral load and the degree of CD4 T-lymphocyte depletion serve as important clinical indicators of immune status in HIV-infected individuals. Prophylaxis for opportunistic infections such as pneumocystis pneumonia is started when CD4 T lymphocyte counts reach the 200-250 cells/µL range. Similarly, patients with HIV infection with fewer than 50 CD4 T lymphocytes/µL are at significantly increased risk for cytomegalovirus (CMV) retinitis and Mycobacterium avium complex (MAC) infection. Cells other than CD4 T lymphocytes contribute to the pathogenesis of HIV infection. Monocytes, macrophages, and dendritic cells can be infected with HIV and facilitate transfer of virus to lymphoid tissues and immunoprivileged sites, such as the CNS. HIV-infected monocytes will also release large quantities of the acute-phase reactant cytokines, including IL-1, IL-6, and TNF, contributing to constitutional symptomatology. TNF, in particular, has been implicated in the severe wasting syndrome seen in patients with advanced disease. Clinical Manifestations The clinical manifestations of AIDS are the direct consequence of the progressive and severe immunologic deficiency induced by HIV. Patients are susceptible to a wide range of atypical or opportunistic infections with bacterial, viral, protozoal, and fungal pathogens. Common nonspecific symptoms include fever, night sweats, and weight loss. Weight loss and cachexia can be due to nausea, vomiting, anorexia, or diarrhea. They often portend a poor prognosis. The incidence of infection increases as the CD4 T lymphocyte number declines. Lung infection with Pneumocystis jiroveci is the most common opportunistic infection, affecting 75% of patients. Patients present clinically with fevers, cough, shortness of breath, and hypoxemia ranging in severity from mild to life threatening. A diagnosis of pneumocystis pneumonia can be made by substantiation of the clinical and radiographic findings with Wright-Giemsa or silver methenamine staining of induced sputum samples. A negative sputum stain does not rule out disease in patients in whom there is a strong clinical suspicion of disease, and further diagnostic maneuvers such as bronchoalveolar lavage or fiberoptic transbronchial biopsy may be required to establish the diagnosis. Complications of pneumocystis pneumonia include pneumothoraces, progressive parenchymal disease with severe respiratory insufficiency, and, most commonly, adverse reactions to the medications used for treatment and prophylaxis. For reasons that are not clear, HIV-infected patients have an unusually high rate of adverse reactions to a wide variety of antibiotics and frequently develop severe debilitating cutaneous reactions. As a consequence of chronic immune dysfunction, HIV-infected individuals are also at high risk for other pulmonary infections, including bacterial infections with S pneumoniae and H influenzae; mycobacterial infections with M tuberculosis or M avium-intracellulare (MAC); and fungal infections with C neoformans, H capsulatum, or C immitis. Clinical suspicion followed by early diagnosis of these infections should lead to aggressive treatment. The development of active tuberculosis is significantly accelerated in HIV infection as a result of compromised cellular immunity. The risk of reactivation is estimated to be 5-10% per year in HIVinfected patients compared with a lifetime risk of 10% in those without HIV. Furthermore, diagnosis may be delayed because of anergic skin responses. Extrapulmonary manifestations occur in up to 70% of HIV-infected patients with tuberculosis, and the emergence of multidrug resistance may 19

compound the problem. MAC is a less virulent pathogen than M tuberculosis, and disseminated infections usually occur only with severe clinical immunodeficiency. Symptoms are nonspecific and typically consist of fever, weight loss, anemia, and GI distress with diarrhea. The presence on physical examination of oral candidiasis (thrush) and hairy leukoplakia is highly correlated with HIV infection and portends rapid progression to AIDS. Abnormal outgrowth of Candida from normal mouth flora is the cause of persistent oral candidiasis, whereas Epstein-Barr virus is the cause of hairy leukoplakia. HIV-infected individuals with oral candidiasis are at much greater risk for esophageal candidiasis, which may present as substernal pain and dysphagia. This infection and its characteristic clinical presentation are so common that most practitioners treat with empiric oral antifungal therapy. Should the patient not respond rapidly, other explanations for the esophageal symptoms should be explored, including herpes simplex and CMV infections. Persistent diarrhea, especially when accompanied by high fevers and abdominal pain, may signal infectious enterocolitis. The list of potential pathogens in such cases is long and includes bacteria, MAC, protozoans (cryptosporidium, microsporidia, Isospora belli, Entamoeba histolytica, Giardia lamblia), and even HIV itself. HIV-associated gastropathy and malabsorption are commonly noted in these patients. Because of their reduced gastric acid concentrations, patients have an increased susceptibility to infection with Campylobacter, Salmonella, and Shigella. Skin lesions commonly associated with HIV infection are typically classified as infectious (viral, bacterial, fungal), neoplastic, or nonspecific. Herpes simplex virus (HSV) and herpes zoster virus (HZV) may cause chronic persistent or progressive lesions in patients with compromised cellular immunity. HSV commonly causes oral and perianal lesions but can be an AIDS-defining illness when involving the lung or esophagus. The risk of disseminated HSV or HZV infection and the presence of molluscum contagiosum appear to be correlated with the extent of immunoincompetence. Seborrheic dermatitis caused by Pityrosporum ovale and fungal skin infections (Candida albicans, dermatophyte species) are also commonly seen in HIV-infected patients. Staphylococcus can cause the folliculitis, furunculosis, and bullous impetigo commonly observed in HIV-infected patients, which require aggressive treatment to prevent dissemination and sepsis. Bacillary angiomatosis is a potentially fatal dermatologic disorder of tumor-like proliferating vascular endothelial cell lesions, the result of infection by Bartonella quintana or Bartonella henselae. The lesions may resemble those of Kaposi's sarcoma but respond to treatment with erythromycin or tetracycline. CNS manifestations in HIV-infected patients include infections and malignancies. Toxoplasmosis frequently presents with space-occupying lesions, causing headache, altered mental status, seizures, or focal neurologic deficits. Cryptococcal meningitis commonly manifests as headache and fever. Up to 90% of patients with cryptococcal meningitis exhibit a positive serum test for Cryptococcus neoformans antigen. HIV-associated cognitive-motor complex, or AIDS dementia complex, is the most frequently diagnosed cause of altered mental status in HIV-infected patients. Patients typically have difficulty with cognitive tasks, poor short-term memory, slowed motor function, personality changes, and waxing and waning dementia. Up to 50% of AIDS patients suffer from this disorder, perhaps caused by glial or macrophage infection by HIV resulting in destructive inflammatory changes within the CNS. The differential diagnosis can be broad, including metabolic disturbances and toxic encephalopathy resulting from drugs. Other causes of altered mental status include neurosyphilis, CMV or herpes simplex encephalitis, lymphoma, and progressive multifocal leukoencephalopathy, a progressive demyelinating disease caused by a JC papovavirus. Peripheral nervous system manifestations of HIV infection include sensory, motor, and inflammatory polyneuropathies. Almost 33% of patients with advanced HIV disease develop peripheral tingling, numbness, and pain in their extremities. These symptoms are likely to be due to loss of nerve axons from direct neuronal HIV infection. Alcoholism, thyroid disease, syphilis, vitamin B12 deficiency, drug toxicity (ddI, ddC), CMV-associated ascending polyradiculopathy, and transverse myelitis also cause peripheral neuropathies. Less commonly, HIV-infected patients can develop an inflammatory demyelinating polyneuropathy similar to Guillain-Barr© syndrome; however, unlike 20

the sensory neuropathies, this inflammatory demyelinating polyneuropathy typically presents before the onset of clinically apparent immunodeficiency. The origin of this condition is not known, although an autoimmune reaction is suspected because the disease typically responds favorably to treatment with plasmapheresis. Retinitis resulting from CMV infection is the most common cause of rapidly progressive visual loss in HIV infection. The diagnosis can be difficult to make because Toxoplasma gondii infection, microinfarction, and retinal necrosis can all cause visual loss. HIV-related malignancies commonly seen in AIDS include Kaposi's sarcoma, non-Hodgkin's lymphoma, primary CNS lymphoma, invasive cervical carcinoma, and anal squamous cell carcinoma. Impairment of immune surveillance and defense and increased exposure to oncogenic viruses appear to contribute to the development of neoplasms. Kaposi's sarcoma is the most common HIV-associated cancer. In San Francisco, 15-20% of HIVinfected homosexual men develop this tumor during the progression of their disease. Kaposi's sarcoma is uncommon in women and children for reasons that are not clear. Unlike classic Kaposi's sarcoma, which affects elderly men in the Mediterranean, the disease in HIV-infected patients may present with either localized cutaneous lesions or disseminated visceral involvement. It is often a progressive disease, and pulmonary involvement can be fatal. Histologically, the lesions of Kaposi's sarcoma consist of a mixed cell population that includes vascular endothelial cells and spindle cells within a collagen network. Human herpesvirus 8 is associated with Kaposi's sarcoma in AIDS patients. HIV itself appears to induce cytokines and growth factors that stimulate tumor cell proliferation rather than causing malignant cellular transformation. Clinically, cutaneous Kaposi's sarcoma typically presents as a purplish nodular skin lesion or painless oral lesion. Sites of visceral involvement include the lung, lymph nodes, liver, and GI tract. In the GI tract, Kaposi's sarcoma can produce chronic blood loss or acute hemorrhage. In the lung it often presents as coarse nodular infiltrates bilaterally, frequently associated with pleural effusions. These infiltrates can be difficult to distinguish from opportunistic infections. Non-Hodgkin's lymphoma is particularly aggressive in HIV-infected patients and usually indicative of significant immune compromise. The majority of these tumors are high-grade B-cell lymphomas with a predilection for dissemination. The CNS is frequently involved either as a primary site or as an extranodal site of widespread disease. Anal dysplasia and squamous cell carcinoma are also more commonly found in HIV-infected homosexual men. These tumors appear to be associated with concomitant anal or rectal infection with human papillomavirus (HPV). In HIV-infected women, the incidence of HPV-related cervical dysplasia is as high as 40%, and dysplasia can progress rapidly to invasive cervical carcinoma. Other complications of HIV-infection include arthritides, myopathy, GI syndromes, dysfunction of the adrenal and thyroid glands, hematologic cytopenias, and nephropathy. Since the disease was first described in 1981, medical knowledge of the underlying pathogenesis of AIDS has increased at a rate unprecedented in medical history. This knowledge has led to the rapid development of therapies directed at controlling HIV infection as well as the multitude of complicating opportunistic infections and cancers.

22)DISTURBANCES OF PERIPHERAL CIRCULATION.ARTERIAL HYPEREMIA Blood circulation in the area of peripheral vascular bed, but the movement of blood, ensuring the exchange water, electrolytes, gases, essential nutrients and metabolites in system of blood - tissue - blood. Peripheral arterial disease (P.A.D.) is a disease in which plaque (plak) builds up in the arteries that carry blood to your head, organs, and limbs. Plaque is made up of fat, cholesterol, calcium, fibrous tissue, and other substances in the blood.


When plaque builds up in the body's arteries, the condition is called atherosclerosis . Over time, plaque can harden and narrow the arteries. This limits the flow of oxygen-rich blood to your organs and other parts of your body.P.A.D. usually affects the arteries in the legs, but it also can affect the arteries that carry blood from your heart to your head, arms, kidneys, and stomach. PVD, also known as arteriosclerosis obliterans, is primarily the result of atherosclerosis. The atheroma consists of a core of cholesterol joined to proteins with a fibrous intravascular covering. The atherosclerotic process may gradually progress to complete occlusion of medium and large arteries. The disease typically is segmental, with significant variation from patient to patient. Vascular disease may manifest acutely when thrombi, emboli, or acute trauma compromises perfusion. Thromboses are often of an atheromatous nature and occur in the lower extremities more frequently than in the upper extremities. Multiple factors predispose patients for thrombosis. These factors include sepsis, hypotension, low cardiac output, aneurysms, aortic dissection, bypass grafts, and underlying atherosclerotic narrowing of the arterial lumen. Arterial hyperemia is the enhanced blood filling of an organ because of the reinforced blood inflowing through arterial vessels.There are the physiological and pathological arterial hyperemia. The typical example of the physiological hyperemia is work hyperemia, which develops during the reinforced organ function. Pathological arterial hyperemia is observed when the part of body or all organism exposes to the influence of unusual factors of external or internal environment –microbe toxins, chemical substances, biologically active substances etc. Аngioneurotic hyperemia is displayed in two forms – the neuroparalytic and neurotonic types. The first one arises due to paralysis of vasoconstrictor nerves, the other one – at the stimulation of vasodilatator nerves. Collateral hyperemia arises in connection with the difficulty of blood flowing in the magistral artery, the lumen of which is closed by thrombus, еmbol or is narrowed by tumor. Blood comes to the bloodless place through the collateral vessels, which reflexly expand. Hyperemia after anemia arises in the cases, when a factor, that pressed the artery, quickly liquidates. For such conditions the vessels of before bloodless organ sharply expand and become overflowed by blood what can bring about their break and bleeding. Also from the blood redistribution in the blood streem anemia of other organs appeares. The redistributory ischemia of the cerebrum can bring about the loss of consciousness. To avoid such complication, it is necessary to let the liquid out from abdominal cavity slowly.The vacate hyperemia develops in connection with the decreasing of the barometric pressure, for example into divers at their fast lifting from the depth.Arterial hyperemia is a permanent inflammation satellite.

23)VENOUS HYPEREMİA.STASIS Passive Hyperemia Passive Hyperemiais an excess of venous blood in a part. It is the result of a distention of a vein on account of some obstruction to the outflow of the blood. This can be caused by obstruction within the veins or capillaries, as by thickening of their walls, by thrombi, or by pressure from without, as from atumor. A common cause for general passivehyperemiais a lesion of the heart-valves. The circulation will continue slowly unless the venous pressure becomes as great as the arterial, when it will stop, a condition known as stasis.


A part that is the seat of passive hyperemia becomes cyanotic, swollen, edematous, cooler than normal, and its function less. The rate of blood-flow is lessened. Theedemais due to the escape of fluid from the blood. If severe, red corpuscles may escape. Following long-continued passive hyperemia the tissues will undergo afatty degenerationon account of the decreased nutrition, or evennecrosisandgangrenemay result. There may also be some increase in the amount of connective tissue. Pigmentation from escapedhemoglobinis not uncommon -brown atrophy. When stasis occurs the blood-corpuscles slowly collect in the smaller vessels, the plasma is exuded, and the cells become packed closely together. Finally, the outline of the cells cannot be seen and the vessels appear to be filled with coagulated blood. Such is not the case, as when the circulation is reestablished the corpuscles separate and move along as usual. Localanemiaor ischemia is the condition in which the part contains less than its normal amount of blood. It is most commonly due to obstruction by pressure of the flow of arterial blood into a part. This may be due to tight bandaging, pressure from a tumor, or to thrombi or emboli, or to changes in the wall of the vessel. Disturbances of the vasomotor system may bring about marked lesions. If there is a good collateral circulation the area to which the obstructed vessel goes may show very slight change. If such is not the case,infarctionmay follow. An anemic area is pale in color,temperaturelower, and functional activity decreased.

24)ISCHEMIA. INFARCTION Ischemia, is a restriction in blood supply to tissues, causing a shortage of oxygenand glucose needed for cellular metabolism Ischemia is generally caused by problems with blood vessels, with resultant damage to or dysfunction of tissue. Since oxygen is carried to tissues in the blood, insufficient blood supply causes tissue to become starved of oxygen. In the highly aerobic tissues of the heart and brain, irreversible damage to tissues can occur in as little as 3–4 minutes at body temperature. Ischemia results in tissue damage in a process known as ischemic cascade. The damage is the result of the build-up of metabolic waste products, inability to maintain cell membranes, mitochondrial damage, and eventual leakage of autolyzing proteolytic enzymes into the cell and surrounding tissues. Restoration of blood supply to ischemic tissues can cause additional damage known as reperfusion injury that can be more damaging than the initial ischemia. Reintroduction of blood flow brings oxygen back to the tissues, causing a greater production of free radicals and reactive oxygen species that damage cells. It also brings more calcium ions to the tissues causing further calcium overloading and can result in potentially fatal cardiac arrhythmias and also accelerates cellular selfdestruction. The restored blood flow also exaggerates the inflammation response of damaged tissues, causing white blood cells to destroy damaged cells that may otherwise still be viable. Cardiac ischemia Cardiac ischemia may be asymptomatic or may cause chest pain, known as angina pectoris. It occurs when the heart muscle, or myocardium, receives insufficient blood flow. This most frequently results from atherosclerosis, which is the long-term accumulation of cholesterol-rich plaques in the coronary arteries. Classification By histopathology


Infarctions are divided into 2 types according to the amount of blood present: White infarctions (anemic infarcts) affect solid organs such as the spleen and kidneys wherein the solidity of the tissue substantially limits the amount of nutrients that can flow into the area of ischemic necrosis Red infarctions (hemorrhagic infarcts), generally affect the lungs or other loose organs (testis, ovary, small intestines). The occlusionconsists more of red blood cells and fibrin strands. By localization Heart: Myocardial infarction (MI), commonly known as a heart attack, is an infarction of the heart, causing some heart cells to die. This is most commonly due to occlusion (blockage) of a coronary artery following the rupture of a vulnerable atherosclerotic plaque, which is an unstable collection of lipids and white blood cells in the wall of an artery. The resulting ischemia and oxygen shortage, if left untreated for a sufficient period of time, can cause damage or death of heart muscle tissue Causes. If the myocardial ischemia lasts for some time (even at rest [unstable angina]; tissue necrosis, i.e., myocardial infarction ,occurs within about an hour. In 85% of cases this is due to acute thrombus formation in the region of the atherosclerotic coronary stenosis. This development is promoted by – turbulence, and – atheroma rupture with collagen exposure. Both events – activate thrombocytes. Thrombosis is also encouraged through – abnormal functions of the endothelium, thus its vasodilators (NO, prostacyclin) and antithrombotic substances are not present Rare causes of MI are inflammatory vascular diseases, embolism ,severe coronary spasm, increased blood viscosity as well as a markedly raised O2 demand at rest Brain: Cerebral infarction is the ischemic kind of stroke due to a disturbance in the blood vessels supplying blood to the brain. It can be atherothrombotic or embolic.[6] Stroke caused by cerebral infarction should be distinguished from two other kinds of stroke: cerebral hemorrhage and subarachnoid hemorrhage. Cerebral infarctions vary in their severity with one third of the cases resulting in death. 

Lung: Pulmonary infarction or lung infarction

Spleen: Splenic infarction occurs when the splenic artery or one of its branches are occluded, for example by a blood clot. Although it can occur asymptomatically, the typical symptom is severe pain in the left upper quadrant of the abdomen, sometimes radiating to the left shoulder. Fever and chills develop in some cases.[7] It has to be differentiated from other causes of acute abdomen.

Limb: Limb infarction is an infarction of an arm or leg. Causes include arterial embolisms and skeletal muscle infarction as a rare complication of long standing, poorly controlled diabetes mellitus.[8] A major presentation is painful thigh or leg swelling.[8]

Bone: Infarction of bone results in avascular necrosis. Without blood, the bone tissue dies and the bone collapses.[9] If avascular necrosis involves the bones of a joint, it often leads to destruction of the joint articular surfaces

Testicle: an infarction of a testicle may be caused by testicular torsion.


Eye: an infarction can occur to the central retinal artery which supplies the retina causing sudden visual loss. 

25. Thrombosis. Pathogenesis There are three primary influences on thrombus formation (called Virchow's triad): (1) endothelial injury, (2) stasis or turbulence of blood flow, and (3) blood hypercoagulability. Endothelial Injury This is a dominant influence, since endothelial loss by itself can lead to thrombosis. It is particularly important for thrombus formation occurring in the heart or in the arterial circulation, where the normally high flow rates might otherwise hamper clotting by preventing platelet adhesion or diluting coagulation factors. Thus, thrombus formation within the cardiac chambers (e.g., after endocardial injury due to myocardial infarction), over ulcerated plaques in atherosclerotic arteries, or at sites of traumatic or inflammatory vascular injury (vasculitis) is largely a function of endothelial injury. Clearly, physical loss of endothelium leads to exposure of subendothelial ECM, adhesion of platelets, release of tissue factor, and local depletion of PGI2 and plasminogen activators. However, it is important to note that endothelium need not be denuded or physically disrupted to contribute to the development of thrombosis; any perturbation in the dynamic balance of the prothrombotic and antithrombotic activities of endothelium can influence local clotting events. Thus, dysfunctional endothelium may elaborate greater amounts of procoagulant factors (e.g., platelet adhesion molecules, tissue factor, plasminogen activator inhibitors) or may synthesize fewer anticoagulant effectors (e.g., thrombomodulin, PGI2, t-PA). Significant endothelial dysfunction (in the absence of endothelial cell loss) may occur with hypertension, turbulent flow over scarred valves, or by the action of bacterial endotoxins. Even relatively subtle influences, such as homocystinuria, hypercholesterolemia, radiation, or products absorbed from cigarette smoke, may be sources of endothelial dysfunction. Alterations in Normal Blood Flow Turbulence contributes to arterial and cardiac thrombosis by causing endothelial injury or dysfunction, as well as by forming countercurrents and local pockets of stasis; stasis is a major contributor to the development of venous thrombi. Normal blood flow is laminar, such that platelets flow centrally in the vessel lumen, separated from the endothelium by a slower moving clear zone of plasma. Stasis and turbulence therefore: Disrupt laminar flow and bring platelets into contact with the endothelium. Prevent dilution of activated clotting factors by fresh-flowing bloodRetard the inflow of clotting factor inhibitors and permit the buildup of thrombiPromote endothelial cell activation, resulting in local thrombosis, leukocyte adhesion, etc. Turbulence and stasis contribute to thrombosis in several clinical settings. Ulcerated atherosclerotic plaques not only expose subendothelial ECM but also cause turbulence. Abnormal aortic and arterial dilations, called aneurysms, create local stasis and consequently a fertile site for thrombosis. Acute myocardial infarction results in focally noncontractile myocardium; ventricular remodeling after more remote infarction can lead to aneurysm formation. In both cases cardiac mural thrombi


form more easily because of the local blood stasis. Mitral valve stenosis (e.g., after rheumatic heart disease) results in left atrial dilation. In conjunction with atrial fibrillation, a dilated atrium is a site of profound stasis and a prime location for development of thrombi. Hyperviscosity syndromes increase resistance to flow and cause small vessel stasis; the deformed red cells in sickle cell anemia cause vascular occlusions, with the resultant stasis also predisposing to thrombosis. Fate of the Thrombus If a patient survives the initial thrombosis, in the ensuing days or weeks thrombi undergo some combination of the following four events: 1 Propagation. Thrombi accumulate additional platelets and fibrin, eventually causing vessel obstruction. 2 Embolization. Thrombi dislodge or fragment and are transported elsewhere in the vasculature. 3 Dissolution. Thrombi are removed by fibrinolytic activity 4 Organization and recanalization. Thrombi induce inflammation and fibrosis (organization). These can eventually recanalize (re-establishing some degree of flow), or they can be incorporated into a thickened vessel wall. Clinical Correlations: Venous versus Arterial Thrombosis Thrombi are significant because they cause obstruction of arteries and veins and are potential sources of emboli. Which effect is most important depends on the site of thrombosis. Venous thrombi can cause congestion and edema in vascular beds distal to an obstruction, but they are most worrisome for their capacity to embolize to the lungs and cause death (see below). Conversely, while arterial thrombi can embolize and even cause downstream tissue infarction (see below), their role in vascular obstruction at critical sites (e.g., coronary and cerebral vessels) is much more significant clinically.

26)EMBOLISM Embolus is a free mass in the blood which can occlude any vessel at any time. If it occludes an artery it will lead to tissue necrosis.Embolism: an embolism occurs when an object migrates from one part of the body andcausesa blockage of a blood vessel in another part of the body. MATERIAL 1.Thromboembolism –embolism of thrombus or blood clot. 2.Fat embolism –embolism of fat droplets. 3.Air embolism (also known as a gas embolism) –embolism of air bubbles. 4.Septic embolism –embolism of pus-containing bacteria. 5.Tissue embolism –embolism of small fragments of tissue. 6.Foreign body embolism –embolism of foreign materials such as talc and other smallobjects. 7.Amniotic fluid embolism –embolism of amniotic fluid, foetal cells, hair, or other debristhat enters the mother's bloodstream via the placental bed of the uterus and triggers anallergic reaction PATHWAY 1.Anterograde 2.Retrograde 3.Paradoxica CAUSES & Pathophysiology A.Thromboembolism ,This is when a part of a blood clot (thrombus) blocks blood flow to a major organ such asthe heart or lungs. It’sthe most common type of embolism. B.Fat embolism usually occurs when 26

Endogenous :1.Thefracture of tubular bones (such as the femur), which will lead to theleakage of fat tissue within the bone marrow into ruptured vessels.2.Trauma of burns of a fatty area. Exogenous:(from sources of external origin) causes such as intravenousinjection of emulsions. C. Air embolism is usually always caused by exogenic factors. the rupture of alveoli, and inhaled air can be leaked into the blood vessels. The puncture of the subclavian vein by accident or during operation where thereis negative pressure.Air is then sucked into the veins by the negative pressure caused by thoracicexpansion during the inhalation phase of respiration.Intravenoustherapy, when air is leaked into the system (however this iatrogenicerror in modern medicine is extremely rare).

Gas embolism is a common concern for deep-sea divers because the gasesin our blood (usually nitrogen and helium) can be easily dissolved at higheramounts during the descent into deep sea. However, when the diver ascends tothe normal atmospheric pressure, the gases become insoluble, causing theformation of small bubbles in the blood. This is also known as decompressionsickness or the Bends. D.Septic embolism happens when a purulent tissue (pus-containing tissue) is dislodged fromits original focus. E.Tissue embolism is a near-equivalent to cancer metastasis, which happens when cancertissue infiltrates blood vessels, and small fragments of them are released into the blood stream. F. Foreign-body embolism happens when exogenous—and only exogenous—materials suchas talc enter the blood stream and cause occlusion or obstruction of blood circulation. G. Amniotic-fluid embolism is a rare complication of childbirth ANEMBOLISM IN AN ARTERY causes symptoms in the affected area and may includethe following:pain,numbness,tingling,coldness,mottled or pale skin,and muscular spasms (twitches)or paralysis (unable to move). AN EMBOLISM IN A VEIN doesn't always cause symptoms. However, there may be:tenderness in the calf or upper leg, which may get gradually more painful,amild fever, with the skinfeeling hot in the area where the embolism is,swelling in one leg and not the other,redness of the leg,andswollen veins. DEEP VEIN THROMBOSIS is an example of an embolism that forms in a vein in this case, ablood clot. If the blood clot breaks away, it can be carried in the bloodstream up to and through the heart,before entering one of the main arteries to the lungs. This can cause the following symptoms:chest pain,rapid heart beat,shortness of breath and fast breathing, andcoughing (sometimes bringing up blood).

27-Abnormalities of Lipid Digestion and Absorption In Gastro.... The mechanisms for lipid digestion and absorption are more complex and involve more steps than those for carbohydrate and protein. Thus, there are also more steps at which an abnormality of lipid digestion or absorption can occur. Each step in the normal process is essential: pancreatic enzyme secretion and function, bile acid secretion, emulsification, micelle formation, diffusion of lipids into 27

intestinal epithelial cells, chylomicron formation, and transfer of chylomicrons into lymph. An abnormality at any one of the steps will interfere with lipid absorption and result in steatorrhea (fat excreted in feces). 

Pancreatic insufficiency. Diseases of the exocrine pancreas (e.g., chronic pancreatitis and cystic fibrosis) result in failure to secrete adequate amounts of pancreatic enzymes, including those involved in lipid digestion, pancreatic lipase and colipase, cholesterol ester hydrolase, and phospholipase A2. For example, in the absence of pancreatic lipase, triglycerides cannot be digested to monoglycerides and free fatty acids. Undigested triglycerides are not absorbable and are excreted in feces. Acidity of duodenal contents. If the acidic chyme delivered to the duodenum is not adequately neutralized by the HCO3--containing pancreatic secretions, then pancreatic enzymes are inactivated (i.e., the pH optimum for pancreatic lipase is 6). The gastric chyme, which is delivered to the duodenum, has a pH ranging from 2 at the pylorus to 4 at the duodenal bulb. Sufficient HCO3- must be secreted in pancreatic juice to neutralize the H+ and increase the pH to the range where pancreatic enzymes function optimally. There are two reasons that all of the H+ delivered from the stomach might not be neutralized: (1) Gastric parietal cells may be secreting excessive quantities of H+, causing an overload to the duodenum; or (2) the pancreas may fail to secrete sufficient quantities of HCO3- in pancreatic juice. The first reason is illustrated by Zollinger-Ellison syndrome, in which a tumor secretes large quantities of gastrin. The elevated levels of gastrin stimulate excessive secretion of H+ by the gastric parietal cells, and this H+ is delivered to the duodenum, overwhelming the ability of pancreatic juices to neutralize it. The second reason is illustrated by disorders of the exocrine pancreas (e.g., pancreatitis) in which there is impaired HCO3- secretion (in addition to impaired enzyme secretion). Deficiency of bile salts. Deficiency of bile salts interferes with the ability to form micelles, which are necessary for solubilization of the products of lipid digestion. Ileal resection (removal of the ileum) interrupts the enterohepatic circulation of bile salts, which then are excreted in feces rather than being returned to the liver. Because the synthesis of new bile salts cannot keep pace with the fecal loss, the total bile salt pool is reduced. Bacterial overgrowth. Bacterial overgrowth reduces the effectiveness of bile salts by deconjugating them. In other words, bacterial actions remove glycine and taurine from bile salts, converting them to bile acids. Recall that at intestinal pH, bile acids are primarily in the nonionized form (since their pKs are higher than intestinal pH); the nonionized form is lipid soluble and readily absorbed by diffusion across the intestinal epithelial cells. For this reason, the bile acids are absorbed "too early" (before reaching the ileum), before micelle formation and lipid absorption is completed. Similarly, decreased pH in the intestinal lumen promotes "early" absorption of bile acids by converting them to their nonionized form. Decreased intestinal cells for absorption. In conditions such as tropical sprue, the number of intestinal epithelial cells is reduced, which reduces the microvillar surface area. Since lipid absorption across the apical membrane occurs by diffusion, which depends on surface area, lipid absorption is impaired because the surface area for absorption is decreased. Failure to synthesize apoproteins. Failure to synthesize Apo B (β-lipoprotein) causes abetalipoproteinemia. In this disease, chylomicrons either do not form or are unable to be transported out of intestinal cells into lymph. In either case, there is decreased absorption of lipids into blood and a buildup of lipid within the intestinal cells.

28. Disturbances in lipids transport. Hyperlipidemia. Fatty liver


Lipoproteins are large, mostly spherical complexes that transport lipids (triglycerides, cholesteryl esters, and fat-soluble vitamins) through body fluids (plasma, interstitial fluid, and lymph) to and from tissues.Lipids such as free fatty acids (FFAs), cholesterol, and triglycerides are hydrophobic molecules that bind protein for transport. Nonesterified FFAs travel as anions complexed to albumin. Esterified complex lipids are transported in lipoprotein particles. Lipoproteins have a hydrophobic core (cholesteryl esters and triglycerides) and an amphiphilic surface monolayer (phospholipids, unesterified cholesterol, and apolipoproteins). Proteins on the surface of lipoproteins, apolipoproteins (apo), activate enzymes and receptors that guide lipid metabolism. Ultracentrifugation separates lipoproteins into five classes based on their density: chylomicrons, very low density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). The density of a lipoprotein is determined by the amount of lipid and protein per particle. HDL is the smallest and most dense lipoprotein, whereas chylomicrons and VLDL are the largest and least dense lipoprotein particles.Most triglyceride is transported in chylomicrons or VLDL, and most cholesterol is carried as cholesteryl esters in LDL and HDL. ApoA-I, which is synthesized in the liver and intestine, is found on virtually all HDL particles. ApoA-II is the second most abundant HDL apolipoprotein. ApoB is the major structural protein of chylomicrons, VLDL, IDL, and LDL; one molecule of apoB, either apoB-48 (chylomicrons) or apoB-100 (VLDL, IDL, or LDL), is present on each lipoprotein particle. The human liver makes only apoB-100, and the intestine makes apoB-48. ApoE is present in multiple copies on chylomicrons, VLDL, and IDL and plays a critical role in the metabolism and clearance of triglyceride-rich particles. Three apolipoproteins of the C-series (apoC-I, -II, and -III) also participate in the metabolism of triglyceride-rich lipoproteins. Transport of Dietary Lipids (Exogenous Pathway): The exogenous pathway of lipoprotein metabolism permits efficient transport of dietary lipids. Dietary triglycerides are hydrolyzed by pancreatic lipases within the intestinal lumen and are emulsified with bile acids to form micelles. Dietary cholesterol and retinol are esterified (by the addition of a fatty acid) in the enterocyte to form cholesteryl esters and retinyl esters, respectively. Longer-chain fatty acids (12 carbons) are incorporated into triglycerides and packaged with apoB- 48, cholesteryl esters, retinyl esters, phospholipids, and cholesterol to form chylomicrons. Nascent chylomicrons are secreted into the intestinal lymph and delivered directly to the systemic circulation, where they are extensively processed by peripheral tissues before reaching the liver. The particles encounter lipoprotein lipase (LPL), which is anchored to proteoglycans that decorate the capillary endothelial surfaces of adipose tissue, heart, and skeletal muscle. The triglycerides of chylomicrons are hydrolyzed by LPL, and free fatty acids are released; apoC-II, which is transferred to circulating chylomicrons, acts as a cofactor for LPL in this reaction. The released free fatty acids are taken up by adjacent myocytes or adipocytes and either oxidized or reesterified and stored as triglyceride. Some free fatty acids bind albumin and are transported to other tissues, especially the liver. The chylomicron particle progressively shrinks in size as the hydrophobic core is hydrolyzed and the hydrophilic lipids (cholesterol and phospholipids) on the particle surface are transferred to HDL. The resultant smaller, more cholesterol ester–rich particles are referred to as chylomicron remnants. 29

The remnant particles are rapidly removed from the circulation by the liver in a process that requires apoE. Transport of Hepatic Lipids (Endogenous Pathway): The endogenous pathway of lipoprotein metabolism refers to the hepatic secretion and metabolism of VLDL to IDL and LDL. VLDL particles resemble chylomicrons in protein composition but contain apoB-100. The triglycerides of VLDL are derived predominantly from the esterification of long-chain fatty acids. The packaging of hepatic triglycerides with the other major components of the nascent VLDL particle (apoB-100, cholesteryl esters, phospholipids, and vitamin E) requires the action of the enzyme microsomal transfer protein (MTP). After secretion into the plasma, VLDL acquires multiple copies of apoE and apolipoproteins of the C series. The triglycerides of VLDL are hydrolyzed by LPL, especially in muscle and adipose tissue. As VLDL remnants undergo further hydrolysis, they continue to shrink in size and become IDL, which contain similar amounts of cholesterol and triglyceride. The liver removes approximately 40 to 60% of VLDL remnants and IDL by LDL receptor–mediated endocytosis via binding to apoE. The remainder of IDL is remodeled by hepatic lipase (HL) to form LDL; during this process, most of the triglyceride in the particle is hydrolyzed and all apolipoproteins except apoB-100 are transferred to other lipoproteins. The cholesterol in LDL accounts for70% of the plasma cholesterol in most individuals. Approximately 70% of circulating LDLs are cleared by LDL receptor–mediated endocytosis in the liver. ¤ Familial Hypercholesterolemia: Mutations in the gene that encodes the LDL (apo B/E) receptor results in familial hypercholesterolemia (FH). Impairment in LDL receptor synthesis or function decreases the clearance of LDL and increases circulating LDL levels. Excess LDL then enters macrophages through scavenger receptors resulting in foam cell and cholesterol plaque formation. These plaques deposit in arteries (atheroma), skin or tendons (xanthoma), eyelids (xanthelasma), and iris (corneal arcus). Homozygous form (rare): Affected individuals present early in life with elevated total cholesterol (600 to 1000 mg/dL) and LDL (550 to 950 mg/dL). Triglyceride and HDL levels are normal. They develop CHD, aortic stenosis due to atherosclerosis of the aortic root, and tendon xanthomas. These xanthomas commonly involve the Achilles tendon and present as tendonitis. If untreated, patients with HM FH typically die from myocardial infarction before age 20 years. The heterozygous (HZ) form: Partial receptor defect resulting in cells displaying half the normal number of fully functional LDL receptors. These individuals have lower elevated total cholesterol (>300 to 600 mg/dL) and LDL (250 to 500 mg/dL) levels. Premature CHD and tendon xanthomas are characteristic clinical findings. FH can be established by identifying one of the many known gene mutations in the LDL receptor or by demonstrating diminished LDL receptor function. The diagnosis of FH usually is made on the basis of clinical features. Elevated total cholesterol (>300 mg/dL) and LDL (>250 mg/dL) in an individual with personal or family history of premature CHD and tendon xanthomas identifies individuals at risk for FH. Treatment requires a low-fat ( 1200 mosmol/L) urine. Concentration and dilution of urine are in the first instance the result of processes in the thick ascending loop of Henle (pars ascendens) which transports NaCl (, red arrow) to the interstitial space of the renal medulla without water (blue arrow) being able to follow. The tubular fluid becomes hypotonic (50–100 mosmol/L) by the time it passes the ascending part, while the interstitial space becomes hypertonic.A protein-low 175

diet impairs the concentrating ability of the kidney because of reduced contribution of urea to the concentrating mechanism. Abnormalities of Glomerular Function: Reduced hydraulic conductivity or areduced filtration surface decreases the GFR.No filtration equilibrium can be achieved; as aresult of the reduced increase in, Peff ultimately rises. But this does not compensate for the reduced conductivity. Constriction of the vas afferens when systemic blood pressure remains constant reduces the filtration pressure and thus the proportion of filtered plasma water (filtration fraction = GFR/RPF). At the same time the renal blood flow and the GFR fall because of the increased resistance. Constriction of the vas efferens (!A4) raises the effective filtration pressure and thus also GFR/RPF. Simultaneously it reduces glomerular perfusion and thus GFR at any given filtration fraction. The constriction of the vas efferens (e.g., on infusion of angiotensin II) orobstruction of venous flow (e.g., by renalvein thrombosis) can thus ultimately reduce GFR. The function of the glomeruli is to produce an adequate GFR, i.e., the volume of plasma water that is controlled by the renal epithelium. The selective permeability of this filter ensures the formation of a nearly protein-free filtrate. As all of the blood flowing through the kidney must pass through the glomerular vessels, the resistance of these vessels also determines RPF. The GFR is determined by the effective filtration pressure (Peff), the hydraulic conductivity (Kf), and the filtering surface (F): GFR =Kf • F • Peff Masugi’s nephritis, caused by autoantibodies against the basement membrane, is much less common than immune complex nephritis. The local inflammation initially results in hyperemia, accumulation of neutrophils (exudative phase), and damage to the often markedly thickened basement membrane. It is common for endothelial, mesangial, or capsular epithelial cells to proliferate and ultimately for excess mesangial matrix to form (sclerosing). The glomeruli may also be damaged without any local inflammation, for example, by deposition of amyloid in amyloidosis, by a high concentration of filtrable proteins in plasma (e.g., in multiple myeloma), by high pressure in the glomerular capillaries (e.g., in arterial hypertension, renal vein thrombosis, venous back pressure in right heart failure, or hyperfiltration in diabetic nephropathy) as well as by reduced perfusion (e.g., in atherosclerosis, arteriosclerosis).İn glomerulonephritis, resistance in thevasa afferentia and efferentia is increased and the RPF is reduced despite filtration pressure usually being high. The reduced hydraulic conductivity prevents filtration equilibrium being achieved and lowers GFR. The reduced renal perfusion stimulates the release of renin which, via angiotensin and aldosterone, raises blood pressure. In addition, the development of hypertension is aided by reduced excretion of NaCl and H2O, brought about by the decrease in GFR. Selective permeability is lost by damage to the glomerular filter, thus leading to proteinuria and edema .Damage to the kidney can, for example, destroy erythropoietin-producing cells and thus result in the development of anemia. Interstitial Nephritis: The term interstitial nephritis is applied to inflammatory changes in the kidney if the inflammation does not originate in the glomeruli.Renal tissue is infiltrated by inflammatory cells (especially granulocytes) and the inflammation can lead to local destruction of renal tissue. Nephrotic syndrome : If proteinuria, hypoproteinemia, and peripheral edema occur together, this is termed nephrotic syndrome. As the lipoproteins are not filtered even if the filter is damaged, but hypoproteinemia stimulates the formation of lipoproteins in the liver, hyperlipidemia results and thus also hypercholesterolemia. It remains debatable whether a loss of glomerular lipoprotein lipase contributes to the effect.


133-Acute Renal Failure Obstruction of the urinary tract, for example,by urinary stones can stop urinary excretion, even though the kidney remainsintact—at least at first.In hemolysis and in the destruction of muscle cells (myolysis) hemoglobin or myoglobin, respectively, is filtered through the glomeruli and precipitated in the acidic tubular lumen, especially because their tubular concentration is increased by fluid absorption. The resulting leads to urine formation being interrupted. Renal function can also cease as a result of rapidly progressing renal diseases (e.g., glomerulonephritis) or toxic damage tothe kidney.Loss of blood and fluid impairs renal perfusion and glomerular filtration because in centralization of the circulation. the kidney is treated like a peripheral organ, i.e.,sympathetic activation produces renal vascular constriction via "-adrenoceptors. The result is acute ischemic renal failure. Energy deficiency impairs Na+/K+-ATPase;the resulting increase in intracellular concentration of Na+ also causes, via the 3Na+/ Ca2+ exchanger, a rise in intracellular Ca2+ concentration (!p.10,12) and thus vasoconstriction. – The ischemia promotes the release of renin both primarily and via an increased NaCl supply in the macula densa (reduced Na+ absorption in the ascending tubules) and thus the intrarenal formation of angiotensin II, which has a vasoconstrictor action. – If there is a lack of energy supply, adenosine is freed from ATP. It acts on the kidney—in contrast to the other organs—as a marked vasoconstrictor.Intravascular stasis (“sludge”) that cannot be flushed out of the network between renal medulla and cortex, even if the perfusion pressure rises. In the first three days of acute renal failure no urine (anuria) or only a little volume of poorly concentrated urine (oliguria) is excreted as a rule (oliguric phase). However, urinary volume alone is a very poor indicator of the functional capacity of the kidney in acute renal failure, because the tubular transport processes are severely restricted and the reabsorption of filtered fluid is thus reduced.Despite normal-looking urine volume, renal excretion of all those substances that must normally be excreted in the urine may be markedly impaired. In this case determination of the plasma and urine creatinine concentration provides information on the true functional state of the kidneys.Recovery after the oliguric phase will lead to a polyuric phase characterized by the gradual increase of the GFR while the reabsorption function of the epithelial nephron is still impaired (salt-losing kidney). If the renal tubules are damaged (e.g., by heavy metals), polyuric renal failure occurs as a primary response, i.e., large volumes of urine are excreted despite a markedly decreased GFR.The dangers of acute renal failure lie in the inability of the kidney to regulate the water and electrolyte balance. The main threat in the oliguric phase is hyperhydration (especially with infusion of large volumes of fluid) and hyperkalemia (especially with the simultaneous release of intracellular K+, as in burns, contusions, hemolysis, etc.). In the polyuric phase the loss of Na+, water, HCO3 and especially of K+ may be so large as to be life-threatening.

134-Chronic Renal Failure.Uremia A number of renal diseases can ultimately lead to the destruction of renal tissue.If the residual renal tissue is not in a position to adequately fulfill its tasks, the picture of renal failure evolves.Reduced renal excretion is particularly significant.The decreased GFR leads to an inversely proportional rise in the plasma level of creatinine. The plasma concentration of reabsorbed substances also rises, but less markedly, because renal tubular reabsorption is impaired in renal failure. The reabsorption of Na+ 177

and water is inhibited in renal failure by a variety of factors,such as natriuretic hormone, PTH, and vanadate. The reduced reabsorption of Na+ in the proximal tubules also directly or indirectly decreases the reabsorption of othersubstances, such as phosphate, uricacid,HCO3, Ca2+, urea, glucose, and amino acids.The reabsorption of phosphate is also inhibited by PTH. It is probably the disruption in renal water and electrolyte excretion that is responsible, at least partially, for the development of most of symptoms of chronic renal failure. Excess volume and the changed electrolyte concentrations lead to edemas, hypertension, osteomalacia, acidosis, pruritus, and arthritis, either directly or via the activation of hormones. Also, abnormalities of the excitatory cells (polyneuropathy, confusion, coma, seizures,cerebral edemas), of gastrointestinal function (nausea, peptic ulcer, diarrhea), and of blood cells (hemolysis, abnormal leukocyte function, abnormal blood clotting) are due to this.The reduced consumption of fatty acids by the kidney contributes to hyperlipidemia,while reduced gluconeogenesis favors the development of hypoglycemia..While uric acid can be precipitated at high concentrations, especially in the joints, and thus cause gout , sufficiently high concentrations of uric acid are only rarely achieved in renal failure. The role of reduced elimination of so-called uremia toxins (e.g.,acetone, 2,3-butyleneglycol, guanidinosuccinic acid, methylguanidine, indoles, phenols,aliphatic and aromatic amines, etc.) as well as of so-called middle molecules (lipids or peptides with a molecular weight of 300– 2000 Da) in producing the symptoms of renal failure remains the subject of considerable debate. High concentrations of urea can destabilize proteins and bring about cell shrinkage. But its effect is partly canceled by the cellular uptake of stabilizing osmolytes. Uremia is a clinical syndrome associated with fluid, electrolyte, and hormone imbalances and metabolic abnormalities, which develop in parallel with deterioration of renal function. The term uremia, which literally means urine in the blood, was first used by Piorry to describe the clinical condition associated with renal failure. Uremia more commonly develops with chronic renal failure (CRF) or the later stages of chronic kidney disease (CKD), but it also may occur with acute renal failure (ARF) if loss of renal function is rapid. As yet, no single uremic toxin has been identified that accounts for all of the clinical manifestations of uremia. Toxins, such as parathyroid hormone (PTH), beta2-microglobulin, polyamines, advanced glycosylation end products, and other middle molecules, are thought to contribute to the clinical syndrome. Causes : Anemia Anemia-induced fatigue is thought to be one of the major contributors to the uremic syndrome. Erythropoietin (EPO), a hormone necessary for red blood cell production in bone marrow, is produced by peritubular cells in the kidney in response to hypoxia. Coagulopathy Acidosis Hyperkalemia Calcium, parathyroid, and vitamin D abnormalities Endocrine abnormalities Cardiovascular abnormalities Cardiovascular abnormalities, including uremic pericarditis, pericardial effusions, calcium and phosphate deposition–associated worsening of underlying valvular disorders, and uremic suppression of myocardial contractility, are common in patients with CRF.[11] Left ventricular 178

hypertrophy is a common disorder found in approximately 75% of patients who have not yet undergone dialysis. Malnutrition

135-Glomerulonephritis Glomerulonephritis is a type of kidney disease in which the part of your kidneys that helps filter waste and fluids from the blood is damaged. Types : 1-Non Proliferative This is characterised by absence of increase in the number of cells (lack of hypercellularity) in the glomeruli. They usually cause nephrotic syndrome. This includes the following types: Minimal change GN (also known as Minimal Change Disease) This form of GN causes 78.4% of nephrotic syndrome in children, but only 20% in adults. As the name indicates, there are no changes visible on simple light microscopy, but on electron microscopy there is fusion of podocytes (supportive cells in the glomerulus). Immunohistochemistry staining is negative. Focal Segmental Glomerulosclerosis (FSGS) FSGS may be primary or secondary to reflux nephropathy, Alport syndrome, heroin abuse or HIV. FSGS presents as a nephrotic syndrome with varying degrees of impaired renal function (seen as a rising serum creatinine, hypertension). As the name suggests, only certain foci of glomeruli within the kidney are affected, and then only a segment of an individual glomerulus. Membranous glomerulonephritis Membranous glomerulonephritis (MGN), a relatively common type of glomerulonephritis in adults, frequently produces a mixed nephrotic and nephritic picture. Its cause is usually unknown, but may be associated with cancers of the lung and bowel, infection such as hepatitis and malaria, drugs including penicillamine, and connective tissue diseases such as systemic lupus erythematosus. Individuals with cerebral shunts are at risk of developing shunt nephritis, which frequently produces MGN. 2- Proliferative This type is characterised by increased number of cells in the glomerulus (hypercellular). Usually present as a nephritic syndrome and usually progress to end-stage renal failure (ESRF) over weeks to years (depending on type). IgA nephropathy (Berger's disease) IgA nephropathy is the most common type of glomerulonephritis in adults worldwide. It usually presents as macroscopic haematuria (visibly bloody urine). It occasionally presents as a nephrotic syndrome. It often affects young males within days (24-48hrs) after an upper respiratory tract or gastrointestinal infection. Microscopic examination of biopsy specimens shows increased number of mesangial cells with increased matrix (the 'cement' that holds everything together). Immuno-staining is positive for immunoglobulin A deposits within the matrix.

Post-infectious Post-infectious glomerulonephritis can occur after essentially any infection, but classically occurs after infection with Streptococcus pyogenes. It typically occurs 10–14 days after a skin or pharyngeal infection with this bacterium. 179

Membranoproliferative/mesangiocapillary GN:This may be primary, or secondary to SLE, viral hepatitis, or hypocomplementemia. One sees 'hypercellular and hyperlobular' glomeruli due to proliferation of both cells and the matrix within the mesangium. Usually presents with a combined nephritic-nephrotic picture, with inevitable progression to end stage renal failure. The primary form consists of two types: Type 1 (Classical and Alternative Complement activation) Type 2 (also known as Dense Deposit Disease) Alternative Complement activation only. C3 Nephritic Factor stabilizes C3 convertase, leading to Hypocomplementemia. Unlike Type 1, no IgG is detected. Rapidly progressive Glomerolonephritis(Crescentic GN) has a poor prognosis, with rapid progression to kidney failure over weeks. Steroid therapy is sometimes used.[5] Any of the above types of GN can be rapidly progressive. Additionally two further causes present as solely RPGN. One is Goodpasture syndrome, an autoimmune disease whereby antibodies are directed against basal membrane antigens found in the kidney and lungs. As well as kidney failure, patients have hemoptysis (cough up blood). The second cause is vasculitic disorders such as Wegener granulomatosis and polyarteritis. There is a lack of immune deposits on staining, but blood tests are positive for ANCA antibody. Causes, incidence, and risk factors Glomerulonephritis may be caused by specific problems with the body's immune system. Often, the precise cause of glomerulonephritis is unknown.Damage to the glomeruli causes blood and protein to be lost in the urine.The condition may develop quickly, with loss of kidney function occurring over weeks and months (called rapidly progressive glomerulonephritis).In about a quarter of people with chronic glomerulonephritis there is no history of kidney disease and the disorder first appears as chronic renal failure. The following increase your risk of developing this condition: History of cancer Blood or lymphatic system disorders Exposure to hydrocarbon solvents Infections such as strep infections, viruses, heart infections,or abscesses Diabetes Many conditions are known to cause or increase the risk for glomerulonephritis, including: Focal segmental glomerulosclerosis Goodpasture syndrome Membranoproliferative GN IgA nephropathy Lupus nephritis or Henoch-Schonlein purpura Anti-glomerular basement membrane antibody disease Blood vessel diseases such as vasculitis or polyarteritis Common symptoms of glomerulonephritis are: Blood in the urine (dark, rust-colored, or brown urine) Foamy urine Swelling (edema) of the face, eyes, ankles, feet, legs, or abdomen Symptoms that may also appear include the following:Abdominal pain Cough.


136-Nephrotic Syndrome Certain glomerular diseases virtually always produce the nephrotic syndrome. In addition, many other forms of primary and secondary. Pathophysiology. The manifestations of the nephroticsyndrome include: 1. Massive proteinuria, with the daily loss of 3.5 gm or more of protein (less in children) 2. Hypoalbuminemia, with plasma albumin levels less than 3 gm/dL 3. Generalized edema 4. Hyperlipidemia and lipiduria The various components of nephrotic syndrome bear a logical relationship to one another. The initial event is a derangement in glomerular capillary walls resulting in increased permeability to plasma proteins. It will be remembered that the glomerular capillary wall, with its endothelium, GBM, and visceral epithelial cells, acts as a size and charge barrier through which the glomerular filtrate must pass. Increased permeability resulting from either structural or physicochemical alterations allows protein to escape from the plasma into the glomerular filtrate. Massive proteinuria results. The heavy proteinuria leads to depletion of serum albumin levels below the compensatory synthetic abilities of the liver,with consequent hypoalbuminemia and a reversed albuminglobulin ratio. Increased renal catabolism of filtered albumin also contributes to the hypoalbuminemia. The generalized edema is, in turn, the consequence of the loss of colloid osmotic pressure of the blood with subsequent accumulation of fluid in the interstitial tissues. There is also sodium and water retention, which aggravates the edema. This appears to be due to several factors, including compensatory secretion of aldosterone, mediated by the hypovolemiaenhanced antidiuretic hormone secretion; stimulation of the sympathetic system; and a reduction in the secretion of natriuretic factors such as atrial peptides.The largest proportion of protein lost in the urine is albumin, but globulins are also excreted in some diseases. The ratio of low- to high-molecular-weight proteins in the urine in various cases of nephrotic syndrome is a manifestation of the selectivity of proteinuria. The genesis of the hyperlipidemia is complex. Most patients have increased blood levels of cholesterol, triglyceride, very-low-density lipoprotein, low-density lipoprotein, Lp(a) lipoprotein, and apoprotein, and there is a decrease in highdensity lipoprotein concentration in some patients. These defects seem to be due in part to increased synthesis of lipoproteins in the liver, abnormal transport of circulating lipid particles, and decreased catabolism. Lipiduria follows the hyperlipidemia because not only albumin molecules but also lipoproteins leak across the glomerular capillary wall. The lipid appears in the urine either as free fat or as oval fat bodies, representing lipoprotein resorbed by tubular epithelial cellsand then shed along with the degenerated cells.These patients are particularly vulnerable to infection, especially with staphylococci and pneumococci. This vulnerability could be related to loss of immunoglobulins or lowmolecular- weight complement components in the urine. Thrombotic and thromboerrtbolic complications are also common in nephrotic syndrome, owing in part to loss of anticoagulant factors (e.g., antithrombin III) and antiplasmin activity through the leaky glomerulus. Renal vein thrombosis, once thought to be a cause of nephrotic syndrome, is most often 181

a consequence of this hypercoagulable state. Causes. The relative frequencies of the several causes of the nephrotic syndrome vary according to age and geography. In children younger than 17 years the nephrotic syndrome is almost always caused by a lesion primary to the kidney; whereas among adults, it may often be associated with a systemic diseaseThe most frequent systemic causes of the nephrotic syndrome are diabetes, amyloidosis, and SLE. The most important of the primary glomerular lesions are minimal change disease, membranous glomerulopathy, and focal segmental glomerulosclerosis. The first is most common in children in North America, the second is most common in older adults, but focal segmental glomerulosclerosis occurs at all ages." These three lesions, as well as a fourth, less common disorder, membranoproliferative glomerulonephritis, are discussed individually in the following sections. Other primary causes, the various proliferative glomerulonephritides, frequently present as a mixed syndrome with nephrotic and nephritic features.

137-Renal Stones Stones may form at any level in the urinary tract, but most arise in the kidney. Urolithiasis is a frequent clinical problem, affecting 5% to 10% of Americans in their lifetime.?' Men are affected more often than women are, and the peak age at onset is between 20 and 30 years. Familial and hereditary predisposition to stone formation has long been known. Many of the inborn errors of metabolism, such as gout, cystinuria, and primary hyperoxaluria, provide good examples of hereditary disease characterized by excessive production and excretion of stone-forming substances. Cause and Pathogenesis. There are four main types of calculi 11 '' 1 ' (1) most stones (about 70%) are calcium containing, composed largely of calcium oxalate or calcium oxalate mixed with calcium phosphate; (2) another 15% are so-called triple stones or struvite stones, composed of magnesium ammonium phosphate; (3) 5% to 10% are uric acid stones; and (4) 1 % to 2% are made up of cystine. An organic matrix of mucoprotein, making up 1% to 5% of the stone by weight, is present in all calculi. Although there aremany causes for the initiation and propagation of stones, the most important determinant is an increased urinary concentration of the stones' constituents, such that it exceeds their solubility in urine (supersaturation). A low urine volume in some metabolically normal patients may also favor supersaturation. Calcium oxalate stones are associated in about 5% of patients with both hypercalcemia and hypercalciuria, caused by hyperparathyroidism, diffuse bone disease, sarcoidosis, and other hypercalcemic states. About 55% have hypercalciuria without hypercalcemia. This is caused by several factors, including hyperabsorption of calcium from the intestine (absorptive hypercalciuria), an intrinsic impairment in renal tubular reabsorption of calcium (renal hypercalciuria), or idiopathic fasting hypercalciuria with normal parathyroid function. Magnesium ammonium phosphate stones are formed largely after infections by urea-splitting bacteria (e.g., Proteus and some staphylococci), which convert urea to ammonia. The resultant alkaline urine causes the precipitation of magnesium ammonium phosphate salts. Uric acid stones are common in patients with hyperuricemia, such as gout, and diseases involving rapid cell turnover, such as the leukemias. However, more than half of all patients with orate calculi have neither hyperuricemia nor increased urinary excretion of uric acid. 182

Cystine stones are caused by genetic defects in the renal reabsorption of amino acids, including cystine, leading to cystinuria. Stones form at low urinary pH. It can therefore be appreciated that increased concentration of stone constituents, changes in urinary pH, decreased urine volume, and the presence of bacteria influence the formation of calculi. Morphology: Stones are unilateral in about 80% of patients. The favored sites for their formation are within the renal calyces and pelves (Fig. 20-57) and in the bladder. Clinical Course. Stones are of importance when they obstruct urinary flow or produce ulceration and bleeding. They may be present without producing any symptoms or significant renal damage. In general, smaller stones are most hazardous, because they may pass into the ureters, producing pain referred to as colic (one of the most intense forms of pain) as well as ureteral obstruction. Larger stones cannot enter the ureters and are more likely to remain silent within the renal pelvis.

138-Primary And Secondary Hyperparathyroidism.Familial hypocalciuric hypercalcemia. Primary hyperparathyroidism is one of the most common endocrine disorders, and it is an important cause of hypercalcemia. The frequency of the various parathyroid lesions underlying the hyperfunction is as follows: ■ Adenoma: 75% to 80% ■ Primary hyperplasia (diffuse or nodular): 10% to 15% ■ Parathyroid carcinoma: less than 5% Primary hyperparathyroidism is usually a disease of adults and is more common in women than in men by a ratio of nearly 3:1. Studies have begun to provide a molecular understanding of the pathogenesis of primary hyperparathyroidism. In more than 95% of cases, the disorder is caused by sporadic parathyroid adenomas or sporadic hyperplasia . Although familial syndromes are a distant second, they have provided a unique insight into the pathogenesis of primary hyperparathyroidism. The genetic syndromes associated with familial primary hyperparathyroidism include the following: ■ Multiple endocrine neoplasia-1 (MEN-1): The MEN1 gene on chromosome 1 ig13 is a tumor suppressor gene inactivated in a variety of MEN-1-related parathyroid lesions, including parathyroid adenomas and hyperplasia. ■ Multiple endocrine neoplasia-2 (MEN-2): The MEN-2 syndrome is caused by activating mutations in the tyrosine kinase receptor, RET, on chromosome IOq. Morphology. The morphologic changes seen in primary hyperparathyroidism include those in the parathyroid glands as well as those in other organs affected by elevated levels of calcium. Parathyroid adenomas are almost always solitary and, similar to the normal parathyroid glands, may lie in close proximity to the thyroid gland or in an ectopic site (e.g., the mediastinum). Clinical Cases: Primary hyperparathyroidism presents in one of two general ways: (1) It may be asymptomatic and be identified after a routine chemistry profile, or (2) patients may have the classic


clinical manifestations of primary hyperparathyroidism." Asymptomatic Hyperparathyroidism. Because serum calcium levels are routinely assessed in the work-up of most patients who need blood tests for unrelated conditions, clinically silent hyperparathyroidism is often detected early. SECONDARY HYPERPARATHYROIDISM Secondary hyperparathyroidism is caused by any condition associated with a chronic depression in the serum calcium level because low serum calcium leads to compensatory overactivity of the parathyroid glands. ; ' Renal failure is by far the most common cause of secondary hyperparathyroidism, although a number of other diseases, including inadequate dietary intake of calcium, steatorrhea, and vitamin ll deficiency, may also cause this disorder. The mechanisms by which chronic renal failure induces secondary hyperparathyroidism are complex and not fully understood. Chronic renal insufficiency is associated with decreased phosphate excretion, which in turn results in hyperphosphatemia. The elevated serum phosphate levels directly depress serum calcium levels and thereby stimulate parathyroid gland activity. In addition, loss of renal substance reduces the availability of a-1-hydroxylase necessary for the synthesis of the active form of vitamin D, which in turn reduces intestinal absorption of calcium. Morphology.The parathyroid glands in secondary hyperparathyroidism are hyperplastic.As in the case of primary hyperplasia,the degree of glandular enlargement is not neccessarily symetric. Clinical Course. The clinical features of secondary hyperparathyroidism are usually dominated by those associated with chronic renal failure. Bone abnormalities (renal osteodystrophy) and other changes associated with PTH excess are, in general, less severe than are those seen in primary hyperparathyroidism. ■ Familial hypocalciuric hypercalcemia (FHH) is an autosomal- dominant disorder characterized by enhanced parathyroid function due to decreased sensitivity to extracellular calcium. Mutations in the parathyroid calciumsensing receptor gene (CASK) on chromosome 3q are a primary cause for this disorder.'' Patients with homozygous CASR mutations present in the neonatal period with severe hyperparathyroidism. CASR mutations have not been described in sporadic parathyroid tumors.

139-Hyperparathyroidism & Pseudohypoparathyroidism. Hypoparathyroidism Hypoparathyroidism is far less common than is hyperparathyroidism. There are many possible causes of deficient PTH secretion resulting in hypoparathyroidism: ■ Surgically induced hypoparathyroidism occurs with inadvertent removal of all the parathyroid glands during thyroidectomy, excision of the parathyroid glands in the mistaken belief that they are lymph nodes during radical neck dissection for some form of malignant disease, or removal of too large a proportion of parathyroid tissue in the treatment of primary hyperparathyroidism. ■ Congenital absence of all glands, as in certain developmental abnormalities, such as thymic aplasia and cardiac defects ■ Familial hypoparathyroidism is often associated with chronic mucocutaneous candidiasis and primary adrenal insufficiency; this syndrome is known as autoimmune polyendocrine syndrome type 1 (APS1) and is caused by mutations


The syndrome typically presents in childhood with the onset of candidiasis, followed several years later by hypoparathyroidism and then adrenal insufficiency during adolescence. APS1 is discussed further in the section on adrenal glands. ■ Idiopathic hypoparathyroidism most likely represents an autoimmune disease with isolated atrophy of the glands. Sixty per cent of the patients with this disorder have autoantibodies directed against the calcium-sensing receptor (CASK) in the parathyroid gland The major clinical manifestations of hypoparathyroidism are referable to hypocalcemia and are related to the severity and chronicity of the hypocalcemia. ■ The hallmark of hypocalcemia is tetany, which is characterized by neuromuscular irritability, resulting from decreased serum ionized calcium concentration. ■ Mental status changes ■ Intracranial manifestations ■ Ocular disease results in calcification of the lens leading to cataract formation. ■ Cardiovascular manifestations ■ Dental abnormalities Pseudohypoparathyroidism In this condition, hypoparathyroidism occurs because of end-organ resistance to the actions of PTH. Indeed, serum PTH levels are normal or elevated. Central to the understanding of PTH resistance are two key concepts: (1) Gproteins,principally G„ mediate the cellular actions of PTH on hone and kidney, and (2) GNASI is a selectively imprinted gene, with tissue-specific patterns of imprinting." 1. Pseudohypoparathyroidism type IA is associated with multihormone resistance and Albright hereditary osteodystrophy (AHO), a syndrome characterized by skeletal and developmental defects. Patients with AHO often have short stature, obesity, short metacarpal and metatarsal bones, and variable mental deficits. The multihormone resistance involves three hormones (PTH, TSH, and LH/FSH), all of which activate Got-mediated pathways in target tissues. The PTH resistance is the most obvious clinical manifestation, presenting as hypocalcemia, hyperphosphatemia, and elevated circulating PTH. TSH resistance is generally mild, while LH/FSH resistance manifests as hypergonadotropic hypogonadism in females. The mutation in this disorder is inherited on the maternal allele, severely impeding the actions of PTH on the kidney in maintaining calcium homeostasis. 2. Pseudopseudohypoparathyroidism: In this disorder, the mutation is inherited on the paternal allele, and it is characterized by AHO without accompanying multihormonal resistance. As a result, serum calcium, phosphate and PTH levels are normal.

140-Osteoporosis & Osteomalacia Osteoporosis Osteoporosis is a disease characterized by increased porosity of the skeleton resulting from reduced bone mass. The associated structural changes predispose the bone to fracture. Thedisorder may be localized to a certain bone or region, as in disuse osteoporosis of a limb, or may involve the entire skeleton, as a manifestation of a metabolic bone disease. Generalized osteoporosis may be primary, or secondary to a large variety of conditions . The most common forms of osteoporosis are senile and postmenopausal osteoporosis. In these disorders, the critical loss of bone mass makes the skeleton 185

vulnerable to fractures. Pathogenesis. Peak bone mass is achieved during young adulthood. Its magnitude is determined largely by hereditary factors, especially the vitamin D receptor allele that is expressed, as well as the genes for collagen 1 A I, estrogen receptor, and insulin-like growth factor 1 and its binding protein.'Physical activity, muscle strength, diet, and hormonal state,however, all contribute. Age-related changes in bone cells and matrix have a strong impact on bone metabolism. Osteoblasts from elderly individuals have reduced replicative and biosynthetic potential when compared with osteoblasts from younger individuals." Also, proteins bound to the extracellular matrix (such as growth factors, which are mitogenic to osteoprogenitor cells and stimulate osteoblastic synthetic activity) lose their biologic potency over time. ■ Reduced physical activity increases the rate of bone loss in experimental animals and humans because mechanical forces are important stimuli for normal bone remodeling. ■ Genetic factors are also important, as noted previously.The type of vitamin D receptor molecule that is inherited accounts for approximately 75% of the maximal peak mass achieved. ■ The body 's calcium nutritional state is important. It has been shown that adolescent girls (but not boys) have insufficient calcium intake in the diet. ■ Hormonal influences. In the decade after menopause, yearly reductions in bone mass may reach up to 2% of cortical bone and 9% of cancellous bone. Morphology. The entire skeleton is affected in postmenopausal and senile osteoporosis , but certain regions tend to be more severely involved than others. In postmenopausal osteoporosis, the Osteoporotic vertebral body (right) shortened by compression fractures, compared with a normal vertebral body.The osteoporotic vertebra has a characteristic loss of horizontal trabeculae and thickened vertical trabeculae. increase in osteoclast activity affects mainly bones or portions of bones that have increased surface area, such as the cancellous compartment of vertebral bodies. Osteomalacia results from defective bone mineralisation. This is a result of a lack of one or more of the factors necessary for osteogenesis: namely, a normal extracellular concentration of calcium and phosphate and a normal pH at the site of calcification. Normal mineralisation depends on interdependent factors that supply adequate calcium and phosphate to the bones. Vitamin D maintains calcium and phosphate homeostasis through its actions on the GI tract, the kidneys, bone, and the parathyroid glands. Vitamin D is obtained from the diet, or it can be produced from a sterol precursor (7-dehydrocholesterol) in the skin following exposure to UV-B light. Sequential hydroxylation of vitamin D is required to produce the metabolically active form of vitamin D. Hydroxylation occurs first in the liver and then in the kidneys and produces vitamin D 1,25(OH). Dysfunction in any of these metabolic steps results in osteomalacia and secondary hyperparathyroidism in adults.

141- 142 Diabetis Mellitus.Pathology & Pathogenesis Diabetes mellitus (DM) is not a single disease entity, but rather agroup of metabolic disorders sharing the common underlying feature of hyperglycemia. Hyperglycemia in diabetes results from defects in insulin secretion, insulin action, or, most commonly, both. The chronic hyperglycemia and attendant


metabolic dysregulation may be associated with secondary damage in multiple organ systems, especially the kidneys, eyes, nerves, and blood vessels.

CLASSIFICATION Although all forms of diabetes mellitus share hyperglycemia as a common feature, the pathogenic processes involved in the development of hyperglycemia vary widely. The previous classification schemes of diabetes mellitus were based on the age at onset of the disease or on the mode of therapy; in contrast, the recently revised classification reflects our greater understanding of the pathogenesis of each variant."The vast majority of cases of diabetes fall into one of two broad classes: Type 1 diabetes is characterized by an absolute deficiency of insulin caused by pancreatic B-cell destruction. It accounts for approximately 10% of all cases. Type 2 diabetes is caused by a combination of peripheral resistance to insulin action and an inadequate secretory response by the pancreatic B-cells("relative insulin deficiency" ). Approximately 80% to 90% of patients have type 2 diabetes. NORMAL INSULIN PHYSIOLOGY Normal glucose homeostasis is tightly regulated by three interrelated processes: glucose production in the liver; glucose uptake and utilization by peripheral tissues, chiefly skeletal muscle; and actions of insulin and counter-regulatory hormones, including glucagon, on glucose. Insulin and glucagon have opposing regulatory effects on glucose homeostasis. During fasting states, low insulin and high glucagon levels facilitate hepatic gluconeogenesis and glycogenolysis (glycogen breakdown) while decreasing glycogen synthesis, thereby preventing hypoglycemia. Thus, fasting plasma glucose levels are determined primarily by hepatic glucose output. Following a meal, insulin levels rise and glucagon levels fall in response to the large glucose load. Insulin promotes glucose uptake and utilization in tissues (discussed later). The skeletal muscle is the major insulinresponsive site for postprandial glucose utilization, and is critical for preventing hyperglycemia and maintaining glucose homeostasis. Regulation of Insulin Release The insulin gene is expressed in the B cells of the pancreatic islets (Fig. 24–27). Preproinsulin is synthesized in the rough endoplasmic reticulum from insulin mRNA and delivered to the Golgi apparatus. There, a series of proteolytic cleavage steps generate the mature insulin and a cleavage peptide, C-peptide.Both insulin and C-peptide are then stored in secretory granules and secreted in equimolar quantities after physiologic stimulation; increasingly, C-peptide levels are being used as a clinical assay to measure endogenous insulin secretion. The most important stimulus that triggers insulin synthesis and release is glucose itself. Insulin Action and Insulin Signaling Pathways Insulin is the most potent anabolic hormone known, with multiple synthetic and growth-promoting effects. Its principal metabolic function is to increase the rate of glucose transport into certain cells in the body. PATHOGENESIS OF TYPE 1 DIABETES MELLITUS This form of diabetes results from a severe lack of insulin caused by an immunologically mediated destruction of [3 cells. Type I diabetes most commonly develops in childhood, becomes manifest at 187

puberty, and progresses with age. Since the disease can develop at any age, including late adulthood, the appellation "juvenile diabetes " is now considered obsolete.Type 1 diabetes is an autoimmune disease in which islet destruction is caused primarily by T lymphocytes reacting against as yet poorly defined 13-cell antigens. PATHOGENESIS OF TYPE 2 DIABETES MELLITUS Environmental factors, such as a sedentary life style and dietary habits, clearly play a role, as will become evident when obesity is considered. Nevertheless, genetic factors are even more important than intype 1 diabetes. PATHOGENESIS OF THE COMPLICATIONS OF DIABETES The morbidity associated with long-standing diabetes of either type results from a number of serious complications, involving both large- and medium-sized muscular arteries (macrovascular disease), as well as capillary dysfunction in target organs ( microvascular disease). Macrovascular disease causes accelerated atherosclerosis among diabetics, resulting in increased risk of myocardial infarction, stroke, and lowerextremity gangrene. The effects of microvascular disease are most profound in the retina, kidneys, and peripheral nerves, resulting in diabetic retinopathy, nephropathy, and neuropathy, respectively.

143. COMPLICATIONS IN DIABETES MELLITUS The morbidity associated with long-standing diabetes of either type results from a number of serious complications, involving both large- and medium-sized muscular arteries (macrovascular disease), as well as capillary dysfunction in target organs ( microvascular disease). Macrovascular disease causes accelerated atherosclerosis among diabetics, resulting in increased risk of myocardial infarction, stroke, and lowerextremity gangrene. The effects of microvascular disease are most profound in the retina, kidneys, and peripheral nerves, resulting in diabetic retinopathy, nephropathy, and neuropathy, respectively. Diabetes is the leading cause of blindness and end-stage renal disease in the Western hemisphere, besides contributing substantially to the incidence of cardiovascular events each year. Hence, the basis of long-term complications of diabetes is the subject of a great deal of research. Most of the available experimental and clinical evidence suggests that the complications of diabetes are a consequence of the metabolic derangements, mainly hyperglycemia. Formation of Advanced Glycation End Products. Advanced glycation end products (AGEs) are formed as a result of nonenzymatic reactions between intracellular glucose-derived dicarbonyl precursors (glyoxal, methylglyoxal, and 3-deoxyglucosone) with the amino group of both intracellular and extracellular proteins. ■ On extracellular matrix components, such as collagen or laminin, the formation of AGEs causes cross-linking between polypeptides, resulting in abnormal matrix— matrix and matrix—cell interactions. For example, crosslinking between collagen type I molecules in large vessels decreases their elasticity, which may predispose these vessels to shear stress and endothelial injury ■ Circulating plasma proteins are modified by addition of AGE residues; these proteins, in turn, bind to AGE receptors on several cell types (endothelial cells, mesangial cells,macrophages). 188

AGE residues; these proteins, in turn, bind to AGE receptors on several cell types (endothelial cells, mesangial cells, macrophages). The AGE-receptor ligation results in activation and nuclear translocation of the pleotropic transcription factor NF-KB, generating a variety of cytokines, growth factors and other pro-inflammatory molecules. AGEs also contribute to microvascular injury in diabetes.The AGE inhibitor aminoguanidine has recently been shown to retard the progression of nephropathy in type 1 diabetics. Activation of Protein Kinase C. Activation of intracellular protein kinase C (PKC) by calcium ions and the second messenger diacylglycerol (DAG) is an important signal transduction pathway in many cellular systems. Intracellular hyperglycemia can stimulate the de novo synthesis of DAG from glycolytic intermediates and hence cause activation of PKC. The downstream effects of PKC activation are numerous and include the following:" ■ Production of the proangiogenic molecule vascular endothelial growth factor ■ Increased activity of the vasoconstrictor endothelin-1 and decreased activity of the vasodilator endothelial nitric oxide synthase. ■ Production of profibrogenic molecules like transforming growth factor-B (TGF-B), leading to increased deposition of extracellular matrix and basement membrane material ■ Production of the procoagulant molecule plasminogen activator inhibitor-1 (PAI-1), leading to reduced fibrinolysis and possible vascular occlusive episodes ■ Production of pro-inflammatory cytokines by the vascular endothelium. Intracellular Hyperglycemia with Disturbances inPolyol Pathways. In some tissues that do not require insulin for glucose transport (e.g., nerves, lenses, kidneys, blood vessels), hyperglycemia leads to an increase in intracellular glucose that is then metabolized by the enzyme aldose reductase to sorbitol, a polyol, and eventually to fructose. In this process, intracellular NADPH is used as a cofactor. NADPH is also required as a cofactor by the enzyme glutathione reductase for regenerating reduced glutathione (GSH). GSH is one of the important antioxidant mechanisms in the cell (Chapter 1), and a reduction in GSH levels increases cellular susceptibility to oxidative stress."

144-Body Weight Control By The Hypothalamus .Obesity. Several regulatory circuits are considered to be responsible for regulating body weight, each governed by the hypothalamus, for example, by its ventromedial nucleus as the “satiety center” and by the lateral hypothalamus as the“eating center”. The regulatory cycle that is probably decisive in the long term is the lipostatic mechanism: the body’s fat mass is recognized on the basis of a substance that is secreted by the fat cells (probably leptin), and a feedback loop keeps this fat mass constant during changes in appetite and physical activity (!A). Thus fat, even if surgically removed, is rapidly replaced. Obesity (adiposity, excess weight) is a risk factor for hypertension, type 2 diabetes mellitus, hyperlipidemia, atherosclerosis as well as renal stones and gallstones. More than 40% excessweight is associated with a twofold risk of premature death. Obesity is partly of (poly)genetic, partly of environmental origin. Its causes are little known. Two defective genes have been discovered, one in two male mouse strains with extreme obesity and one in type 2 diabetes. If the ob[esity]-gene is 189

defective, the 16-kDa protein leptin, coded by the obgene, is absent from plasma. Injection of leptin into mice with homozygotic ob mutation counteracts the symptoms of the gene defect. Its administration to normal mice leads to weight loss. But if the db-gene has mutated, the leptin receptor in the hypothalamus (in the arcuate nucleus, among other sites) is defective. While high concentrations of leptin circulate in plasma, the hypothalamus does not respond to them. Some obese persons also have a defective leptin gene, but in most others the plasma leptin concentration is high. In this case the feedback chain after leptin must have been interrupted somewhere (!A, red X). Various possible defects have been postulated: ! Leptin can no longer overcome the blood– brain barrier (? defective transcytosis). The inhibitory effect of leptin on the secretion of neuropeptide Y (NPY) in the hypothalamus, which stimulates food intake and reduces energy consumption, is abnormal. ! Leptin does not cause the release in the hypothalamus of "-melanocortin (melanocytestimulating hormone ["-MSH]), which acts there via MCR-4 receptors and has the opposite effect of NPY.Quite recently a homozygotic leptin receptor defect was found in three very obese sisters. As they had never gone through puberty and the secretion of both somatotropin hormone and thyrotropinreleasing hormone had been reduced,it seems that leptin also plays a part in other endocrine regulatory cycles.

145- Pituitary Adenoma The most common cause of hyperpituitarism is an adenoma arising in the anterior lobe. Other, less common, causes include hyperplasia and carcinomas of the anterior pituitary, secretion of hormones by some extrapituitary tumors, and certain hypothalamic disorders. Pituitary adenomas can be functional (i.e., associated with hormone excess and clinical manifestations thereof) or silent (i.e., immunohistochemical and/or ultrastructural demonstration of hormone production at the tissue level only, without clinical symptoms of hormone excess). Both functional and silent pituitary adenomas are usually composed of a single cell type and produce a single predominant hormone, although exceptions are known to occur. Pituitary adenomas are classified on the basis of hormone(s) produced by the neoplastic cells detected by immunohistochemical stains performed on tissue sections (Table 24-1). Some pituitary adenomas can secrete two hormones (GH and prolactin being the most common combination), and rarely, pituitary adenomas are plurihormonal. Finally, pituitary adenomas may be hormone-negative, based on absence of immunohistochemical reactivity and ultra- structural demonstration of lineage-specific differentiation. Both silent and hormone-negative pituitary adenomas may cause hypopituitarism as they encroach on and destroy adjacent anterior pituitary parenchyma. Clinically diagnosed pituitary adenomas are responsible for about 10% of intracranial neoplasms; they are discovered incidentally in up to 25% of routine autopsies. In fact, using highresolution computed tomography or magnetic resonance imaging suggest that approximately 20% of "normal" adult pituitary glands harbor an incidental lesion measuring 3 mm or more in diameter, usually a silent adenoma.' Pituitary adenomas are usually found in adults, with a peak incidence from the thirties to the fifties. Most pituitary adenomas occur as isolated lesions. In about 3% of cases, however, adenomas are associated with multiple endocrine neoplasia (MEN) type 1. 190

■ The great majority of pituitary adenomas are monoclonal in origin, even those that are plurihormonal, suggesting that most arise from a single somatic cell. ■ G-protein mutations are possibly the best-characterized molecular abnormalities in pituitary adenomas. ■ Multiple endocrine neoplasia (MEN) syndrome (discussed in detail below) is a familial disorder associated with tumors and hyperplasias of multiple endocrine organs, including the pituitary. ■ Additional molecular abnormalities present in aggressive or advanced pituitary adenomas include activating mutations of the RAS oncogene and overexpression of the c-MYC oncogene, suggesting that these genetic events arelinked to disease progression.' PROLACTINOMAS Prolactinomas (lactotroph adenomas) are the most frequent type of hyperfunctioning pituitary adenoma, accounting for about 30% of all clinically recognized pituitary adenomas. These lesions range from small microadenomas to large, expansile tumors associated with substantial mass effect. GROWTH HORMONE (SOMATOTROPH CELL) ADENOMAS GH-secreting tumors are the second most common type of functioning pituitary adenoma. As we have mentioned, 40% of somatotroph cell adenomas express a mutant GTPasedeficient a-subunit of the G-protein, G,. Somatotroph cell adenomas may be quite large by the time they come to clinical attention because the manifestations of excessive GH may be subtle. CORTICOTROPH CELL ADENOMAS Corticotroph adenomas are usually small microadenomas at the time of diagnosis. These tumors are most often basophilic (densely granulated) and occasionally chromophobic (sparsely granulated). Both variants stain positively with periodic acid—Schiff (PAS) because of the presence of carbohydrate in pre-opiomelanocorticotropin (POMC), the ACTH precursor molecule; in addition, they demonstrate variable immunoreactivity for POMC and its derivatives, including ACTH and [3endorphin. OTHER ANTERIOR PITUITARY ADENOMAS Gonadotroph((LH-producing and FSH-producing) Thyrotroph (TSH-producing) Nonfunctioning pituitary adenomas

146- Hypopituitarism Hypopituitarism refers to decreased secretion of pituitary hormones, which can result from diseases of the hypothalamus or of the pituitary. Hypofunction of the anterior pituitary occurs when approximately 75% of the parenchyma is lost or absent. This may be congenital or the result of a variety of acquired abnormalities that are intrinsic to the pituitary. Most cases of hypofunction arise from destructive processes directly involving the anterior pituitary, although other mechanisms have been identified: ■ Tumors and other mass lesions: Pituitary adenomas, other benign tumors arising within the sella, primary and metastatic malignancies, and cysts can cause hypopituitarism. Any mass lesion in the sella can cause damage by exerting pressure on adjacent pituitary cells. 191

■ Pituitary surgery or radiation: Surgical excision of a pituitary adenoma may inadvertently extend to the nonadenomatous pituitary. Radiation of the pituitary, used to prevent regrowth of residual tumor after surgery, can damage the nonadenomatous pituitary. ■ Pituitary apoplexy: As has been mentioned, this is a sudden hemorrhage into the pituitary gland, often occurring into a pituitary adenoma.; ■ Ischemic necrosis of the pituitary and Sheehan syndrome:Ischemic necrosis of the anterior pituitary is an important cause of pituitary nsufficiency. Sheehan syndrome, or postpartum necrosis of the anterior pituitary, is the most common form of clinically significant ischemic necrosis of the anterior pituitary. ` During pregnancy, the anterior pituitary enlarges to almost twice its normal size. This physiologic expansion of the gland is not accompanied by an increase in blood supply from the low-pressure venous system; hence, there is relative anoxia of the pituitary. ■ Ratlike cleft cyst: These cysts, lined by ciliated cuboidal epithelium with occasional goblet cells and anterior pituitary cells, can accumulate proteinaceous fluid and expand, compromising the normal gland. ■ Empty sella syndrome: Any condition that destroys part or all of the pituitary gland, such as ablation of the pituitary by surgery or radiation, can result in an empty sella. ■ Genetic defects: Rare congenital deficiencies of one or more pituitary hormones have been recognized in children. Less frequently, disorders that interfere with the delivery of pituitary hormone—releasing factors from the hypothalamus, such as hypothalamic tumors, may also cause hypofunction of the anterior pituitary. Any disease involving the hypothalamus can alter secretion of one or more of the hypothalamic hormones that influence secretion of the corresponding pituitary hormones. Hypothalamic lesions that cause hypopituitarism include: ■ Tumors, including benign lesions that arise in the hypothalamus, such as craniopharyngiomas, and malignant tumors that metastasize to that site, such as breast and lung carcinomas. ■ Inflammatory disorders and infections, such as sarcoidosis or tuberculous meningitis, can cause deficiencies of anterior pituitary hormones and diabetes insipidus.

147-Diabetes Insipidus The clinically relevant posterior pituitary syndromes involve ADH and include diabetes insipidus and secretion of inappropriately high levels of ADH. ■ Diabetes insipidus. ADH deficiency causes diabetes insipidus, a condition characterized by excessive urination (polyuria) owing to an inability of the kidney to resorb water properly from the urine. It can result from a variety of processes, including head trauma, tumors, and inflammatory disorders of the hypothalamus and pituitary as well as surgical procedures involving these organs. The condition can also arise spontaneously, in the absence of an underlying disorder. Diabetes insipidus from ADH deficiency is designated as central to differentiate it from nephrogenic diabetes insipidus, which is a result of renal tubular unresponsiveness to circulating ADH. The clinical manifestations of the two diseases are similar and include the excretion of large volumes of dilute urine with an inappropriately low specific gravity. Serum sodium and osmolality are increased owing to excessive renal loss of free water, resulting in thirst and polydipsia. Patients who can drink water can generally compensate for urinary losses; patients who are obtunded, bedridden, or otherwise limited in their ability to obtain water may develop life-threatening dehydration.


148- Syndrome of inappropriate ADH (SIADH) secretion. ADH excess causes resorption of excessive amounts of free water, resulting in hyponatremia. The most frequent causes of SIADH include the secretion of ectopic ADH by malignant neoplasms (particularly small cell carcinomas of the lung), non-neoplastic diseases of the lung, and local injury to the hypothalamus or posterior pituitary (or both). The clinical manifestations of SIADH are dominated by hyponatremia, cerebral edema, and resultant neurologic dysfunction. Although total body water is increased, blood volume remains normal, and peripheral edema does not develop. Irreversible neurologic damage and death may occur when the rate of correction of Na+ exceeds 0.5 mEq/L/h for patients with severe hyponatremia. At this rate of correction, osmolytes that have been lost in defense against brain edema during the development of hyponatremia cannot be restored as rapidly when hyponatremia is rapidly corrected. The brain cells are thus subject to osmotic injury, a condition termed osmotic demyelination. Certain factors such as hypokalemia, severe malnutrition, and advanced liver disease predispose patients to this devastating complication.

149-Hyperthyroidism Thyrotoxicosis is a hypermetabolic state caused by elevated circulating levels of free T, and T 4 . Because it is caused most commonly by hyperfunction of the thyroid gland, it is often referred to as hyperthyroidism. However, in certain conditions the oversupply is related to either excessive release of preformed thyroid hormone (e.g., in thyroiditis) or to an extrathyroidal source, rather than hyperfunction of the gland ( Table 24-2). Thus, strictly speaking, hyperthyroidism is only Not Associated with HyperthyroidismSubacute granulomatous thyroiditis (painful)Subacute lymphocytic thyroiditis (painless) Struma ovarii (ovarian teratoma with ectopic thyroid) Factitious thyrotoxicosis (exogenous thyroxine intake) "'Associated with increased TSH; all other causes of thyrotoxicosisassociated with decreased (albeit the most common) cause of thyrotoxicosis. The terms primary and secondary hyperthyroidism are sometimes used to designate hyperthyroidism arising from an intrinsic thyroid abnormality and that arising from processes outside of the thyroid, such as a TSH-secreting pituitary tumor. With this disclaimer, we will follow the common practice of using the terms thyrotoxicosis and hyperthyroidism interchangeably. The three most common causes of thyrotoxicosis are also associated with hyperfunction of the gland and include the following: ■ Diffuse hyperplasia of the thyroid associated with Graves disease (accounts for 85% of cases) ■ Hyperfunctional multinodular goiter ■ Hyperfunctional adenoma of the thyroid Clinical Course. The clinical manifestations of hyperthyroidism are protean and include changes referable to the hypermetabolic state induced by excess thyroid hormone as well as those related to overactivity of the sympathetic nervous system (i.e., an increase in the 13-adrenergic "tone"). Excessive levels of thyroid hormone result in an increase in the basal metabolic rate. The skin of thyrotoxic patients tends to be soft, warm, and flushed because of increased blood flow and peripheral vasodilation to increase heat loss. Heat intolerance is common. Sweating is increased because of higher levels of calorigenesis. Increased basal metabolic rate also results in characteristic weight loss despite increased appetite. Cardiac manifestations are among the earliest and most consistent features of hyperthyroidism. 193

Myocardial changes, such as foci of lymphocytic and eosinophilic infiltration, mild fibrosis in the interstitium, fatty changes in myofibers, and an increase in size and number of mitochondria, have been described. In the neuromuscular system, overactivity of the sympathetic nervous system produces tremor, hyperactivity, emotional lability, anxiety, inability to concentrate, and insomnia. Ocular changes often call attention to hyperthyroidism. A wide, staring gaze and lid lag are present because of sympathetic overstimulation of the levator palpebrae superioris. However, true thyroid ophthalmopathy associated with proptosis is a feature seen only in Graves disease. In the gastrointestinal system, sympathetic hyperstimulation of the gut results in hypermotility, malabsorption, and diarrhea. The skeletal system is also affected in hyperthyroidism.Thyroid hormone stimulates bone resorption, resulting in increased porosity of cortical bone and reduced volume of trabecular bone. A diagnosis of hyperthyroidism is made using both clinical and laboratory findings. The measurement of serum TSH concentration using sensitive TSH (sTSH) assays provides the most useful single screening test for hyperthyroidism, as its levels are decreased even at the earliest stages, when the disease may still be subclinical.

150-Hypothyroidism Hypothyroidism is caused by any structural or functional derangement that interferes with the production of adequate levels of thyroid hormone. It can result from a defect anywhere in the hypothalamic-pituitary-thyroid axis. As in the case of hyperthyroidism, this disorder is divided into primary and secondary categories, depending on whether the hypothyroidism arises from an intrinsic abnormality in the thyroid or occurs as a result of pituitary disease; rarely, hypothalamic failure is a cause of tertiary hypothyroidism. Primary hypothyroidism accounts for the vast majority of cases of hypothyroidism. Primary hypothyroidism can be thyroprivic (due to absence or loss of thyroid parenchyma) or goitrous (due to enlargement of the thyroid gland under the influence of TSH). The causes of primary hypothyroidism include the following. Surgical or radiation-induced ablation of thyroid parenchyma can cause hypothyroidism. A large resection of the gland (total thyroidectomy) for the treatment of hyperthyroidism of a primary neoplasm can lead to hypothyroidism. The gland may also be ablated by radiation, whether in the form of radioiodine administered for the treatment of hyperthyroidism, or exogenous irradiation, such as external radiation therapy to the neck. Autoimmune hypothyroidism is the most common cause of goitrous hypothyroidism in iodinesufficient areas of the world. The vast majority of cases of autoimmune hypothyroidism are due to Hashimoto thyroiditis. Circulating autoantibodies, including anti–TSH receptor autoantibodies, are commonly found in Hashimoto thyroiditis.

Causes Of Hypothyroidism Primary: 194

Developmental (thyroid dysgenesis : PAX-8,TTF-2,TSH-receptor Mutations) Thyroid hormone resistance syndrome (TRb Mutations) Postablative Surgery,radioiodine therapy, or external radiation Autoimmune hypothyroidism Hashimoto thyroiditis* Iodine deficiency* Drugs(lithium,iodidesip-aminosaliycylic acid)* Congenital biosynthetic defect (dyshormonogenetic goiter) Secondary: Pituitary failure Tertiary Hypothalamic failure(rare) Associated with enlargement of thyroid ("goitrous hypothyroidism").Hashimoto thyroiditis and postablative hypothroidism account for the majority of cases.

151-Goiter Diffuse and Multinodular Goiters Enlargement of the thyroid, or goiter, is the most common manifestation of thyroid disease. Diffuse and multinodular goiters reflect impaired synthesis of thyroid hormone, most often caused by dietary iodine deficiency. Impairment of thyroid hormone synthesis leads to a compensatory rise in the serum TSH level, which, in turn, causes hypertrophy and hyperplasia of thyroid follicular cells and, ultimately, gross enlargement of the thyroid gland. The compensatory increase in functional mass of the gland is able to overcome the hormone deficiency, ensuring an euthyroid metabolic state in the vast majority of individuals. If the underlying disorder is sufficiently severe (e.g., a congenital biosynthetic defect or endemic iodine deficiency, see below), the compensatory responses may be inadequate to overcome the impairment in hormone synthesis, resulting in goitrous hypothyroidism. The degree of thyroid enlargement is proportional to the level and duration of thyroid hormone deficiency. DIFFUSE NONTOXIC (SIMPLE) GOITER Diffuse nontoxic (simple) goiter specifies a form of goiter that diffusely involves the entire gland without producing nodularity. Because the enlarged follicles are filled with colloid, the term colloid goiter has been applied to this condition.This disorder occurs in both an endemic and a sporadic distribution. Endemic goiter occurs in geographic areas where the soil, water, and food supply contain only low levels of iodine. The term endemic is used when goiters are present in more than10% of the population in a given region. Variations in the prevalence of endemic goiter in regions with similar levels of iodine deficiency point to the existence of other causative influences, particularly dietary substances,eferred to as goitrogens. Sporadic goiter occurs less frequently than does endemic goiter. There is a striking female preponderance and a peak incidence at puberty or in young adult life. Sporadic goiter can be caused by a number of conditions, including the ingestion of substances that interfere with thyroid hormone synthesis.


Clinical Course. The vast majority of patients with simple goiters are clinically euthyroid. Therefore, the clinical manifestations are primarily related to mass effects from the enlarged thyroid gland. MULTINODULAR GOITER With time, recurrent episodes of hyperplasia and involution combine to produce a more irregular enlargement of the thyroid, termed multinodular goiter. Virtually all longstanding simple goiters convert into multinodular goiters. They may be nontoxic or may induce thyrotoxicosis (toxic multinodular goiter). Multinodular goiters produce the most extreme thyroid enlargements and are more frequently mistaken for neoplastic involvement than any other form of thyroid disease. Because they derive from simple goiter, they occur in both sporadic and endemic forms, having the same female-tomale distribution and presumably the sane origins but affecting older individuals because they are late complications.

152- ADRENOCORTICAL HYPERFUNCTION (HYPERADRENALISM) - Cushing Syndrome Just as there are three basic types of corticosteroids elaborated by the adrenal cortex (glucocorticoids, mineralocorticoids, and sex steroids), so there are three distinctive hyperadrenal clinical syndromes: (1) Cushing syndrome, characterized by an excess of cortisol; (2) hyperaldosteronism; and (3) adrenogenital or virilizing syndromes caused by an excess of androgens. The clinical features of these syndromes overlapsomewhat because of the overlapping functions of some of the adrenal steroids. Hypercortisolism (Cushing Syndrome) Pathogenesis. This disorder is caused by any condition that produces an elevation in glucocorticoid levels."' There are four possible sources of excess cortisol .In clinical practice, most causes of Cushing syndrome are the result of the administration of exogenous glucocorticoids. The other three sources of the hypercortisolism call be categorized as endogenous Cushing syndrome: ■ Primary hypothalamic-pituitary diseases associated with hypersecretion of ACTH ■ Hypersecretion of cortisol by an adrenal adenoma, carcinoma, or nodular hyperplasia ■ The secretion of ectopic ACTH by a nonendocrine neoplasm Primary hypersecretion of ACTH accounts for 70% to 80% of cases of endogenous hypercortisolism. In recognition of the neurosurgeon who first published the full description of this syndrome and related it to a pituitary lesion,"' this pituitary form of Cushing syndrome is referred to as Cushing disease. The disorder affects women about five times more frequently than men, and it occurs most frequently during the twenties and thirties. In the vast majority of cases, the pituitary gland contains an ACTH-producing microadenoma that does not produce mass effects in the brain; some corticotroph tumors qualify as macroadenomas (>10 mm). In most of the remaining cases, the anterior pituitary contains areas of corticotroph cell hyperplasia without a discrete adenoma. Corticotroph cell hyperplasia may be primary or may arise secondarily from excessive stimulation of ACTH release by a hypothalamic corticotropin releasing hormone (CRH)-producing tumor. Morphology. The main lesions of Cushing syndrome are found in the pituitary and adrenal glands. The pituitary in Cushing syndrome shows changes regardless of the cause. The most common alteration, resulting from high levels of endogenous or exogenous glucocorticoids, is termed Crooke 196

hyaline change. In this condition, the normal granular, basophilic cytoplasm of the ACTH-producing cells in the anterior pituitary is replaced by homogeneous, lightly basophilic material. This alteration is the result of the accumulation of intermediate keratin filaments in the cytoplasm. The morphology of the adrenal glands depends on the cause of the hypercortisolism. The adrenals have one of the following abnormalities: (1) cortical atrophy; (2) diffuse hyperplasia; (3) nodular hyperplasia; and (4) an adenoma, rarely a carcinoma. Diffuse hyperplasia is found in 60% to 70% of cases of Cushing syndrome. Both glands are enlarged, either subtly or markedly, weighing up to 25 to 40 gm.The adrenal cortex is diffusely thickened and yellow, owing to an increase in the size and number of lipidrich cells in the zonae fasciculata and reticularis. Some degree of nodularity is common but is pronounced in nodular hyperplasia. Primary adrenocortical neoplasms causing Cushing syndrome may be malignant orbenign. Adenomas or carcinomas of the adrenal cortex as the source of cortisol secretion are not macroscopically distinctive from nonfunctioning adrenal neoplasms to be described later.

153-Adrenocortical Insufficiancy.Addison's Diseases. ADRENAL INSUFFICIENCY Adrenocortical insufficiency, or hypofunction, may be caused by either primary adrenal disease (primary hypoadrenalism) or decreased stimulation of the adrenals owing to a deficiency of ACTH (secondary hypoadrenalism). The patterns of adrenocortical insufficiency can be considered under the following headings: (1) primary acute adrenocortical insufficiency (adrenal crisis), (2) primary chronic adrenocortical insufficiency (Addison disease), and (3) secondary adrenocortical insufficiency. Primary Acute Adrenocortical Insufficiency Acute adrenal cortical insufficiency occurs in a variety of clinical settings: ■ As a crisis in patients with chronic adrenocortical insufficiency precipitated by any form of stress that requires an immediate increase in steroid output from glands incapable of responding ■ In patients maintained on exogenous corticosteroids, in whom rapid withdrawal of steroids or failure to increase steroid doses in response to an acute stress may precipitate an adrenal crisis, owing to the inability of the atrophic adrenals to produce glucocorticoid hormones ■ As a result of massive adrenal hemorrhage, which destroys the adrenal cortex sufficiently to cause acute adrenocortical insufficiency. This occurs in newborns following prolonged and difficult delivery with considerable trauma and hypoxia, leading to extensive adrenal hemorrhages beginning in the medulla and extending into the cortex. Secondary Insufficiency Hypothalamic pituitary disease Neoplasm, inflammation (sarcoidosis, tuberculosis, pyogens, fungi) Hypothalamic pituitary suppression Long-term steroid administration Steroid-producing neoplasms

Primary Chronic Adrenocortical Insufficiency (Addison Disease) In a paper published in 1855, Thomas Addison described a group of patients suffering from a constellation of symptoms, including "general languor and debility, remarkable feebleness of the heart 's action, and a peculiar change in the color of the skin" associated with disease of the 197

"suprarenal capsules" or,in more current terminology, the adrenal glands. Addison disease, or chronic adrenocortical insufficiency, is an uncommon disorder resulting from progressive destruction of the adrenal cortex. Pathogenesis. A large number of diseases may attack the adrenal cortex, including lymphomas, amyloidosis, sarcoidosis, hemochromatosis, fungal infections, and adrenal hemorrhage, but more than 90% of all cases are attributable to one of four disorders: autoimmune adrenalitis, tuberculosis, the acquired immune deficiency syndrome (AIDS), or metastatic cancers. ■ Autoinmrune polyendocrine syndrome type 1 (APSI) is also known as autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED). ■ Autoimmune polyendocrine syndrome type 2 (APS2) usually starts in early adulthood and presents as a combination of adrenal insufficiency with autoimmune thyroiditis or type I diabetes. ■ Isolated autoimmune A ddison disease presents with autoimmune destruction restricted to the adrenal glands.However, in terms of age at presentation and linkage to HLA and other susceptibility loci, isolated autoimmune adrenalitis overlaps with APS2, suggesting that the former may be a variant of the latter. Infections, particularly tuberculosis and those produced by fungi, may also cause primary chronic adrenocortical insufficiency.Tuberculous adrenalitis, which once accounted for as much as 90% of Addison disease, has become less common with the development of antituberculous agents.Histoplasma capsulatum and Coccidioides immitis may also result in chronic adrenocortical insufficiency. Patients with AIDS are at risk for developing adrenal insufficiency from several infectious (cytomegalovirus, Mycobacterium aviuinintercellulare)and noninfectious complications (Kaposi sarcoma).Metastatic neoplasms involving the adrenals are another potential cause of adrenal insufficiency. Genetic disorders of adrenal insufficiency include adrenal hypoplasia congenital (AHC) and adrenoleukodystrophy. Morphology. The anatomic changes in the adrenal glands depend on the underlying disease. Primary autoimmune adrenalitis is characterized by irregularly shrunken glands, which may be difficult to identify within the suprarenal adipose tissue. Clinical Course. Addison disease begins insidiously and does not come to attention until at least 90% of the cortex of both glands is destroyed and the levels of circulating glucocorticoids and mineralocorticoids are significantly decreased.The initial manifestations include progressive weakness and easy fatigability, which may be dismissed as nonspecific complaints. Gastrointestinal disturbances are common and include anorexia, nausea, vomiting, weight loss, and diarrhea. Secondary Adrenocortical Insufficiency Any disorder of the hypothalamus and pituitary, such as metastatic cancer, infection, infarction, or irradiation, that reduces the output of ACTH leads to a syndrome of hypoadrenalism that has many similarities to Addison disease. Analogously, prolonged administration of exogenous glucocorticoids suppresses the output of ACTH and adrenal function. With secondary disease, the hyperpigmentation of primary Addison disease is lacking because melanotropic hormone levels are low.ACTH deficiency can occur alone, but in some instances, it is only one part of panhypopituitarism, associated with multiple primary trophic hormone deficiencies. The differentiation of secondary disease from Addison disease can be confirmed with demonstration of low levels of plasma ACTH in the former. Morphology. In cases of hypoadrenalism secondary to hypothalamic or pituitary disease (secondary 198

hypoadrenalism), depending on the extent of ACTH lack, the adrenals may be moderately to markedly reduced in size. They are reduced to small, flattened structures that usually retain their yellow color owing to a small amount of residual lipid. The cortex may be reduced to a thin ribbon composed largely of zona glomerulosa. The medulla is unaffected.

154-Hyperaldosteronism.Conn's Syndrome Hyperaldosteronism is the generic term for a small group of closely related, uncommon syndromes, all characterized by chronic excess aldosterone secretion. Excessive levels of aldosterone cause sodium retention and potassium excretion, with resultant hypertension and hypokalemia. Hyperaldosteronism may be primary, or it may be a secondary event resulting from an extra-adrenal cause. Primary hyperaldosteronism indicates an autonomous overproduction of aldosterone, with resultant suppression of the renin-angiotensin system and decreased plasma renin activity. Primary hyperaldosteronism is caused by one of three mechanisms; ■ Adrenocortical neoplasm, either an aldosteroneproducing adrenocortical adenoma (the most common cause) or, rarely, an adrenocortical carcinoma. In approximately 80% of cases, primary hyperaldosteronism is caused by a solitary aldosterone-secreting adenoma, a condition referred to as Corm syndrome. This syndrome occurs most frequently in adult middle life and is more common in women than in men (2:1). Multiple adenomas may be present in an occasional patient. ■ Primary adrenocortical hyperplasia (idiopathic hyperaldosteronism), characterized by bilateral nodular hyperplasia of the adrenal glands, highly reminiscent of those found in the nodular hyperplasia of Cushing syndrome. The genetic basis of idiopathic hyperaldosteronism is not clear, although it is possibly caused by an overactivity of the aldosterone synthase gene, CY P11 NI Glucocorticoid-remediable hyperaldosteronism is an uncommon cause of primary hyperaldosteronism that is familial and genetic. In some families, it is caused by a chimeric gene resulting from fusion between CY P11BI (the 11B-hydroxylase gene) and CY P11 B2 (the aldosterone synthase gene)."_ This leads to a sustained production of hybrid steroids in addition to both cortisol and aldosterone. The activation of aldosterone secretion is under the influence of ACTH and hence is suppressible by exogenous administration of dexamethasone. In secondary hyperaldosteronism, in contrast, aldosterone release occurs in response to activation of the reninangiotensin system. It is characterized by increased levels of plasma renin and is encountered in conditions such as the following: ■ Decreased renal perfusion (arteriolar nephrosclerosis, renal artery stenosis) ■ Arterial hypovolemia and edema (congestive heart failure, cirrhosis, nephrotic syndrome) ■ Pregnancy (due to estrogen-induced increases in plasma renin substrate). Morphology. Aldosterone-producing adenomas are almost always solitary, small (
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