Exam Preparatory Manual for Undergraduates - Pathology PDF

Clinical Pathology 367 TABLE 13.16: Thyroid function tests Test Significance Serum thyroid hormones (normal values) Thyroid stimulating hormone/thyrotrophin (TSH Increased in primary hypothyroidism, Hashimoto thyroiditis. Decreased in 0.4–5...

Clinical Pathology 367 TABLE 13.16: Thyroid function tests Test Significance Serum thyroid hormones (normal values) Thyroid stimulating hormone/thyrotrophin (TSH Increased in primary hypothyroidism, Hashimoto thyroiditis. Decreased in 0.4–5.0 µU/mL) hyperthyroidism Thyroid hormone levels: Free thyroxine (FT4) (5.4– Increased in hyperthyroidism and decreased in hypothyroidism 11.7 µg/dL), triiodothyronine (T3) (77–135 ng/dL) Thyrotrophin releasing hormone (TRH) stimulation In primary hypothyroidism an exaggerated prolonged rise of already increased test (0.4–5.0 µU/mL) TSH level is observed. In secondary hyperthyroidism (pituitary), there will be no rise in the decreased TSH level Thyroglobulin (Tg) Increased in well-differentiated thyroid carcinoma and hyperthyroidism. Decreased following total thyroidectomy or destruction of thyroid by radiation Calcitonin level Used for diagnosis of primary/recurrence of medullary carcinoma of thyroid or metastases after the removal of the primary. Increased in some paraneoplastic syndromes (e.g. carcinoma of lung), hypercalcemia of any cause and C cell hyperplasia Thyroid autoantibody tests Anti-microsomal antibody Diagnosis and monitoring of autoimmune thyroid diseases, Hashimoto Anti-thyroid peroxidase antibody (TPOAb) thyroiditis: Antimicrosomal or antithyroid peroxidase antibodies, Graves’ disease: Anti-thyroglobulin antibody (TgAb) Anti-TSH receptor antibodies TSH receptor antibody (TRAb) Radioactive iodine uptake (RAIU) Increased in Graves’ disease, toxic multinodular goiter and adenoma and early thyroiditis. Decreased in hypothyroidism, late thyroiditis Needle: Vim Silverman’s needle is used for liver biopsy. Obstructive jaundice: Liver biopsy may cause leakage of bile from liver into the peritoneum causing severe and Indications for Liver Biopsy fatal bile peritonitis. Q. Indications for liver biopsy. Massive ascites. Unexplained hepatomegaly, splenomegaly, jaundice. Patients with severe cough where diaphragm movements Cirrhosis of liver, to assess the type, etiology and activity cannot be controlled. of the disease process. Uncooperative patients. Chronic hepatitis: For identifying, grading of inflamma- Hydatid cyst liver  tory activity, staging and evaluation of the course.  These are relative contradictions. Hemangioma liver  Pyrexia of unknown origin (PUO): A liver biopsy may be helpful in the diagnosis of miliary tuberculosis, sarcoidosis or malignancy. Complications Idiopathic hemochromatosis: To determine iron stores Hemorrhage from the biopsy site. in liver. Bile peritonitis in patients with obstructive jaundice. Referred pain to shoulder from right pleura. Contraindications Q. Contraindications for liver biopsy. RENAL FUNCTION TESTS Congenital coagulation disorders, e.g. hemophilia A and B. Q. Name renal function tests. PT prolonged by more than 3 seconds over control. Urine analysis (both routine and microscopic). mebooksfree.com  368 Exam Preparatory Manual for Undergraduates—Pathology Blood chemistry: Impaired renal function causes THYROID FUNCTION TESTS elevation of end-products of protein metabolism which is known as azotemia. These include: Q. Write short essay on thyroid function tests. –– Blood urea (normal range 20–40 mg/dL). –– Blood urea nitrogen (BUN): Normal range 10–20 mg/dL. Thyroid function tests (TFTs) is a collective term for –– Creatinine (normal range 0.6–1.2 mg/dL). test used to check the function of the thyroid gland. Renal clearance tests. Various tests and their significance are mentioned in Table Concentration and dilution tests. 13.16. mebooksfree.com  6(&7,21 3 Systemic Pathology 14. Vascular Disorders 22. Male Genital Tract Disorders 15. Heart Disorders 23. Female Genital Tract Disorders 16. Lung Disorders 24. Breast Disorders 17. Oral Cavity and Salivary Gland Disorders 25. Endocrine Disorders 18. Gastrointestinal Tract Disorders 26. Skin Disorders 19. Hepatobiliary Disorders 27. Bone and Joint Disorders 20. Pancreatic Disorders 28. Central Nervous System Disorders 21. Kidney and Urinary Tract Disorders mebooksfree.com mebooksfree.com  14 &+$37(5 Vascular Disorders ARTERIOSCLEROSIS Atherosclerosis Risk in Communities Study. Risk roughly increases with the increase in number of risk factors. For Arteriosclerosis (“hardening of the arteries”) is characterized example, two factors increase risk about four-fold, and by arterial wall thickening and may be caused by: three (i.e. hyperlipidemia, hypertension, and smoking), 1. Arteriolosclerosis: It affects small arteries and arterioles. increase risk by a factor of seven. 2. Mönckeberg medial sclerosis: It is characterized by x Classification of risk factors: The risk factors may be deposition of calcium in muscular arteries seen in old broadly classified as modifiable, nonmodifiable and age (above 50 years). additional (Table 14.1). 3. Atherosclerosis: It is the most frequent and important Atherosclerosis: Major modifiable risk factors include hyperlipid- disease of intima. emia, hypertension, cigarette smoking and diabetes. Capillaries: Maximum cross-sectional surface area. Modifiable Risk Factors in Ischemic Heart Maximum blood volume present in the veins. Disease (IHD) These are four in number namely: (1) hyperlipidemia, (2) ATHEROSCLEROSIS hypertension, (3) cigarette smoking, and (4) diabetes. 1. Hyperlipidemia: Increase in the serum lipids mainly Atherosclerosis: Primarily a disease of intima characterized by cholesterol (hypercholesterolemia) is a major modifiable lesions called atheroma. Q. Write short note on risk factors for atherosclerosis. Definition: Atherosclerosis is primarily a progressive dis- TABLE 14.1: Risk factors for atherosclerosis ease of intima involving large and medium-sized elastic and muscular arteries. It is characterized by focal lipid- A. Modifiable major risk factors rich intimal lesions called atheromas (atheromatous or x Hyperlipidemia x Cigarette smoking atherosclerotic plaques). x Hypertension x Diabetes mellitus Epidemiology: Atherosclerosis is a worldwide disease seen B. Nonmodifiable (constitutional) risk factors in both developed and developing countries. x Genetic abnormalities x Increasing age The word atherosclerosis is derived from Greek for “gruel” x Family history x Male gender (atheroma) and “hardening” (sclerosis). C. Additional risk factors x Inflammation x Raised procoagulant levels x CRP level x Inadequate physical activity Risk Factors for Atherosclerosis x Hyperhomocystinemia x Stressful lifestyle x They were identified through several studies most x Metabolic syndrome x Obesity important being the Framingham Heart Study and x Lipoprotein (a) x Alcohol mebooksfree.com 372 Exam Preparatory Manual for Undergraduates—Pathology risk factor. Hypercholesterolemia can initiate atheroscle- HDL: Removes cholesterol from atheromatous plaque for disposal rotic lesion even in the absence of other risk factors. The in the liver. major components of lipids in the blood are: x Low-density lipoprotein (LDL) known as “bad Increased very low density lipoprotein (VLDL) leads to reduced cholesterol” is one of the components of serum lipid HDL. and its higher level is associated with increased risk of atherosclerosis. LDL delivers cholesterol to 2. Hypertension: It is one of the major risk factor. peripheral tissues. x Incidence of atherosclerosis increases as BP rises, x High-density lipoprotein (HDL) known as “good and this excess risk is related to both systolic and cholesterol” and its higher levels are associated with diastolic levels of blood pressure. decreased risk. x Control of hypertension with antihypertensive – HDL mobilizes cholesterol from the periphery therapy reduces the risk of myocardial infarction (including atheroma) and excretes it through bile and stroke. in liver. 3. Cigarette smoking: It is the most important avoidable – Exercise and moderate consumption of ethanol cause of atherosclerosis. raise HDL levels, whereas obesity and smoking x Atherosclerosis is more severe and extensive among lower it. smokers than in nonsmokers. This may be the x Serum cholesterol level: Normal range is 140–240 reason for the increased incidence and severity of mg/dL. Serum cholesterol is strongly related to atherosclerosis in men compared to women. There is the dietary intake of saturated fat (in the absence a strong dose-linked relationship between cigarette of genetic disorders of lipid metabolism). Risk of smoking and ischemic heart disease. Cessation of atherosclerosis increases with increasing serum smoking reduces the risk. cholesterol concentrations and lowering serum 4. Diabetes mellitus: It is a potent risk factor for athero- cholesterol concentrations reduces the risk. The risk sclerosis. of atherosclerosis can be reduced by lowering LDL or x Diabetes is associated with hypercholesterolemia o total plasma cholesterol, and/or raising serum HDL. increases the risk of atherosclerosis. The incidence This can be achieved either by dietary modification or of myocardial infarction and other atherosclerotic by treatment with cholesterol-lowering drugs. vascular diseases (strokes, gangrene of the lower – Diet which raises blood cholesterol: extremities) is more in diabetics than in nondiabetics. ◆ Diet high in cholesterol and saturated fats (e.g. egg yolks, animal fats, and butter). Transunsatu- rated fats produced by artificial hydrogenation Nonmodifiable/Constitutional Risk Factors of polyunsaturated oils (used in baked goods 1. Genetic abnormalities: Most common inherited and margarine). modifiable risk factors (hypertension, hyperlipidemia, ◆ Diet which lower blood cholesterol: Diets and diabetes mellitus) are polygenic. Mendelian low in cholesterol and/or with higher ratios of disorders, such as familial hypercholesterolemia are polyunsaturated fats. associated with atherosclerosis. ◆ Omega-3 fatty acids (high in fish and fish oils). 2. Family history: Atherosclerotic disease often runs in – Cholesterol-lowering drug: For example, statins families. Familial predisposition is usually multifactorial, lowers circulating cholesterol levels by inhibiting due to genetic, environmental and lifestyle factors. hydroxymethylglutaryl coenzyme A (HMG CoA) reductase. This is the rate-limiting enzyme in 3. Increasing age: Age is the most powerful independent involved in cholesterol biosynthesis in the liver. risk factor. Clinical manifestation of atherosclerosis is usually observed after middle age and the lesions LDL: Bad cholesterol; HDL: Good cholesterol. progressively rise with each decade. HDL: Good cholesterol removes cholesterol from atheromatous 4. Sex: Premenopausal women have lower incidence of plaque and transports to liver. From the liver, it is excreted in atherosclerosis-related diseases compared to males of the bile. the same age group. However, after menopause this sex difference disappears. This may be due to protective role Disorders associated with hypercholesterolemia of estrogen. However, hormone replacement therapy 1. Nephrotic syndrome has no role in the prevention of coronary heart disease. 2. Alcoholism 3. Hypothyroidism Achilles tendon xanthoma: Pathognomonic of familial hyper- 4. Diabetes mellitus. cholesterolemia. mebooksfree.com  Vascular Disorders 373 Additional Risk Factors A. Insudation hypothesis: According to this, the focal accumulation of lipid in a vessel wall is due to insudation 1. Inflammation: It plays a role in atherogenesis and may (transport) of plasma lipoproteins across an intact be a risk factor. endothelium. 2. C-reactive protein (CRP) level: It is a marker of systemic B. Encrustation hypothesis: This hypothesis states that inflammation and predicts the risk of atherosclerosis small mural thrombi are formed at the site of endothelial related diseases. damage. These thrombi become organized and form 3. Hyperhomocysteinemia: It is a rare autosomal recessive plaque. inborn error and results in elevated circulating homo- C. Monoclonal hypothesis: The monoclonal concept cysteineopremature and severe atherosclerosis. postulates that single clone (monoclonal) of smooth 4. Metabolic syndrome: It is associated with central muscle migrate from the underlying media into the obesity, insulin resistance and is known risk factors for intima and then proliferate. The stimulus for monoclonal atherosclerosis. proliferation may be metabolites of cholesterol. 5. Increased Lipoprotein (a) Lp(a) levels: It is an altered D. Response-to-injury hypothesis: This is the currently form of LDL and is associated with increased risk. favored hypothesis. Lp(a) has structural similarity to plasminogen. It competes with plasminogen in clots and decreases Response-to-Injury Hypothesis (Figs 14.1A to E) the ability to form and clear clots. Increased Lp(a) levels are associated with higher risk of atherosclerosis, Q. Write short note on reaction-to-injury hypothesis of athero- independent of total cholesterol or LDL levels. sclerogenesis. 6. Raised procoagulant levels: These procoagulants According to this theory, atherosclerosis develops as a include, thrombin (procoagulant and proinflammatory chronic (inflammatory and healing) response of the arterial action), platelet activation and raised fibrinogen o wall to the endothelial injury. Probably accumulation of increased risk. cholesterol crystals and free fatty acids in macrophages 7. Inadequate physical activity: Lack of exercise doubles and other cells initiate inflammation. It is thought that the risk. chronic inflammation is responsible for both the initiation and progression of atherosclerotic lesions. The sequence of 8. Stressful lifestyle: Certain personality associated with pathogenic events (Figs 14.1A to E) is as follows: competitive, stressful life (“type A” personality) is associated with an increased risk of coronary disease. 1. Endothelial injury and dysfunction: x Causes of endothelial injury/dysfunction: 9. Obesity: It is often associated with hypertension, – Hemodynamic disturbances: Plaques develop in diabetes mellitus, hypertriglyceridemia, decreased regions having disturbed blood flow such as origin HDL and physical inactivity. or ostia of vessels, branching points of vessel and 10. Alcohol consumption: It is associated with reduced along the posterior wall of the abdominal aorta. rates of coronary artery disease. – Risk factors: Hyperlipidemia, hypertension, C-reactive protein (CRP) level. toxins from cigarette smoke, and advanced glycation end products in diabetes can produce C-reactive protein: Excellent marker for disrupted atheromatous endothelial injury/dysfunction. plaque. – Others: Homocysteine, immunocomplexes, and infectious agents. Regular exercise (brisk walking, cycling or swimming for 20 minutes two or three times a week) has a protective effect. x Effect of endothelial injury or dysfunction: – Leukocyte (mainly monocyte) adhesion to Excess alcohol consumption is associated with hypertension and endothelium cerebrovascular disease. – Increased vascular permeability – Platelet adhesion and thrombosis Pathogenesis of Atherosclerosis – Movement of low-density lipoproteins (LDLs) across the endothelium into the intima. Q. Write short note on pathogenesis of atherosclerosis. 2. Migration of monocytes into the intima: There are several theories proposed for pathogenesis of x The leukocytes, which adhere at the site of endothelial atherosclerosis and few of them are: injury/dysfunction, are mainly monocytes and mebooksfree.com  374 Exam Preparatory Manual for Undergraduates—Pathology Foam cells in atherosclerosis: Lipid laden 1. Smooth muscle cells 2. Tissue macrophages 3. Blood monocytes. Pathogenesis of atherosclerosis: Pres- ently favored theory is reaction to injury hypothesis. Infection: Herpes virus, cytomegalovirus, and Chlamydia pneumoniae have been found in atheromatous plaques. These infections may be responsible for local inflammatory reaction. Risk factors in atherosclerosis: Cause endothelial injury/dysfunction and stimulate smooth muscle recruitment into the intima. Figs 14.1A to E: Various steps in response to injury hypothesis of atherogenesis. (A) Normal; (B) Endothelial injury/dysfunction with adhesion of monocytes; (C) Migration of monocytes into the arterial intima and are transformed into macrophages. They engulf lipoproteins and oxidized LDL to form foam cells; (D) Migration of smooth muscle followed by their proliferation in the intima; (E) Fully developed atheromatous plaque T lymphocytes. Accumulation of leukocytes initiates 3. Lipid accumulation in the intima: the atheroma formation. x Endothelial dysfunction also allows penetration of endothelium by lipoproteins (mainly LDL) from blood x Locally produced chemokines allows penetration oLDLs accumulate within the intima of the vessel. of the endothelial layer by monocytes and lympho- x LDL is oxidized by the action of oxygen free radicals cytes. The monocytes migrate into the intima where produced locally by monocytes/macrophages and they are transformed into macrophages. dysfunctional endothelial cells. mebooksfree.com  Vascular Disorders 375 4. Formation of foam cells and activation of macrophages: MORPHOLOGY x Macrophage engulfs lipoproteins and oxidized LDL from the extracellular space in the intima. Their Q. Write short note on fatty streak. cytoplasm becomes foamy and these cells are called Fatty Streaks: They may be the earliest or precursor lesions as foam cells. of atherosclerosis. They are found in young children (older than 10 years) as well as in adults. x Some foam cells may undergo apoptosisorelease x Gross: Multiple small (~1 mm) flat yellow lesions in the lipids o form lipid-rich center, often called the intima, which may coalesce to form long streaks 1 cm or necrotic core in atheromatous plaques. more in length. They may be mildly elevated above intima x Oxidized LDL is cytotoxic to endothelial cells and without disturbing the blood flow. smooth muscle cells and can cause endothelial x Microscopy: Consist of lipid-filled foamy macrophages in dysfunction. the intima. x Oxidized LDL causes activated macrophages which Fatty streaks may be the earliest or precursor lesions of athero- produce: sclerosis and may be seen in children. – Cytokine (e.g. TNF)—increases leukocyte adhe- sion. Atherosclerotic Plaque – Chemokines (e.g. monocyte chemotactic Q. Differences between fatty streak and atherosclerotic plaque. protein 1)—accumulation of monocytes. Q. Write short note on gross and microscopic features of – Reactive oxygen species—aggravate oxidation atherosclerosis. of LDL. – Growth factors—stimulate smooth muscle cell Q. Write short note on aortic lesions in atherosclerosis. proliferation and extracellular matrix (ECM) Gross (Fig. 14.2): synthesis. x Sites: Major vessels involved in atherosclerosis in descending 5. Migration of smooth muscle cells into the intima: order are: x Growth factor (e.g. platelet-derived growth factor) – Lower abdominal aorta (abdominal aorta more than the thoracic aorta) from activated platelets, macrophages, and endo- – Coronary arteries thelial cells causes migration of smooth muscle cells – Popliteal arteries either from the arterial media or from circulating – Internal carotid arteries precursors. – Vessels of the circle of Willis. 6. Smooth muscle cell proliferation in the intima and x Color: White to yellow. If superimposed by a thrombus o ECM production: red-brown. x Smooth muscle cells proliferate, and produce ECM x Size: Range from 0.3 to 1.5 cm in diameter. Can coalesce to (mainly collagen and proteoglycans). Many growth form larger masses. Advanced lesions are oval and range from 8 to 12 cm in diameter. factors can cause smooth muscle cell proliferation. x Shape: Irregular with well-defined borders. These includes: PDGF, fibroblast growth factor (FGF) x Distribution: Patchy (focal) and usually involve only a portion and transforming growth factor-D (TGF-D). of the involved arterial wall. On cross-section o appears as an x Smooth muscle cell may also engulf oxidized LDL eccentric lesion. and form foam cells. x Composition: Soft, yellow, grumous core of lipid covered by a white fibrous cap. 7. Lipid accumulation x Occurs both intracellularly (within macrophages and Atherosclerosis: Most common site is abdominal aorta. smooth muscle cells) and extracellularly. Atherosclerosis: Microscopy shows necrotic center covered x Extracellular lipid is derived from insudation by fibrous cap. from the vessel lumen (mainly in the presence of hypercholesterolemia) and also from necrotic foam Microscopy (Figs 14.3 and 9.1E) cells. Three main components in varying proportions in different lesions: x Cholesterol in the plaque is also due to an imbalance 1. Cells: Smooth muscle cells, macrophages, and T-cells. between influx and efflux. High-density lipoprotein 2. Extracellular matrix (ECM): Collagen, elastic fibers, and (HDL) probably transfers cholesterol from these proteoglycans. lesions and leads to its excretion by liver. 3. Lipid: Both intracellular and extracellular lipid. mebooksfree.com  376 Exam Preparatory Manual for Undergraduates—Pathology A B Figs 14.2A and B: (A) Atheromatous plaques on the intimal surface of aorta. Lower region shows thrombus over the plaque; (B) Diagrammatic gross appearance of atheromas A B C Figs 14.3A to C: Microscopy of atheromatous plaque. (A) Scanner view of coronary atherosclerosis causing more than 90% narrowing of the lumen; (B) Shows central necrotic core and superficial fibrous cap; (C) Shows junction between the vessel wall and atheromatous plaque, shoulder region and cholesterol clefts in the necrotic core These components occur in three regions: Complications of atherosclerosis: x Superficial fibrous cap: Composed of smooth muscle cells 1. Rupture and collagen. 2. Hemorrhage into the plaque x Necrotic core: It is seen deep to the fibrous cap and contains: 3. Thrombosis – Lipid: Typical atheroma contains abundant lipid, mainly 4. Embolism cholesterol and cholesterol esters, which is seen as empty 5. Aneurysm needle, shaped cleft-like spaces. 6. Calcification. – Debris from dead cells. – Foam cells (lipid-laden macrophages and smooth muscle 1. Rupture, ulceration, or erosion: Plaque protrudes into cells). the lumen and can disturb the blood floworesulting – Others: Fibrin, organized thrombus, and plasma proteins. in turbulent flow of bloodowhich can damage the x Shoulder: It is the peripheral region beneath and to the side of endotheliumocause rupture, ulceration or erosion of the cap. It is more cellular and contains macrophages, smooth the intimal surface of plaques. muscle cells, and T-cells. Neovascularization (proliferating small blood vessels): It may be 2. Hemorrhage into the plaque: It may occur due to seen at the periphery of the lesions near the shoulder. rupture of the fibrous cap of the plaque or of the thin- walled vessels formed due to neovascularization. Q. Write short note on complications of atherosclerosis. 3. Thrombosis and embolism: Ulceration/erosion/ Complicated plaques: Atherosclerotic plaques can undergo rupture of endothelial surfaceoexposes the blood to the following clinically important changes: highly thrombogenic subendothelial collagenofavors mebooksfree.com  Vascular Disorders 377 thrombus formation o can partially or completely sufficiently severe it may lead to tissue ischemia and occlude the lumen (depending on the size of the this lesion is termed as critical stenosis. lumen)olead to ischemia. The thrombus may become – The effects of vascular stenosis depend on arterial organized or fragment to form thromboemboli. supply and the metabolic demand of the affected 4. Atheroembolism: Plaque rupture o discharge tissue. In small arteries, it may reduce blood flow atherosclerotic debris into the bloodstream oresults leading to ischemic injury. In the coronary artery in atheroemboli. atherosclerotic lesion when produces a 70% decrease in luminal cross-sectional area, the patient may 5. Aneurysm formation: Atherosclerosis even though develop chest pain with exertion (stable angina; refer an intimal disease may cause pressure or ischemic Chapter 15). In other sites, diminished arterial blood atrophy of the underlying media. It may also damage the flow can cause ischemia of the bowel (mesenteric elastic tissue and cause weakening the walloresult in occlusion), sudden cardiac death, chronic ischemic aneurysmal dilationowhich may rupture. heart disease, ischemic encephalopathy, and 6. Calcification: It may occur in the central necrotic area intermittent claudication (diminished perfusion of of the plaque (dystrophic calcification). the extremities). Major clinical consequences of atherosclerosis (Fig. 14.4): 2. Acute plaque change (refer Chapter 15 page 394) 1. Myocardial infarction (heart attack) Atheromatous plaques causing myocardial infarction and 2. Cerebral infarction (stroke) other acute coronary syndromes are often asymptomatic. 3. Aortic aneurysms Acute plaque change is the sudden change/event 4. Peripheral vascular disease (gangrene of the legs). occurring in an atheromatous plaque. The composition of plaques is dynamic and it decides the risk of rupture. Stable plaque: Vulnerable plaques are more likely to undergo rupture. 1. Have thick densely collagenized fibrous cap These are plaques that have (1) necrotic centre with 2. Minimal inflammation large areas of foam cells and extracellular lipid, (2) thin 3. Negligible lipid core. fibrous caps or contain few smooth muscle cells or (3) Vulnerable plaque: have clusters of inflammatory cells. 1. Contain numerous foam cells – Mechanical strength and stability of plaque: De- 2. Abundant extracellular lipid pends mainly on the collagen in the fibrous cap. The 3. Many inflammatory cells balance between synthesis of collagen against its deg- 4. Thin fibrous cap radation decides the integrity of fibrous cap integrity. 5. Few smooth muscle cells ◆ Collagen synthesis: It is mainly by smooth muscle 6. High-risk to undergo rupture. cells and loss of these cells reduces the integrity and strength of fibrous cap. ◆ Collagen degradation: Generally inflammatory Clinicopathologic Manifestations of cells in the plaque increase in collagen degradation Atherosclerosis and reduced collagen synthesis. This reduces the mechanical strength and integrity of the fibrous cap. 1. Atherosclerotic stenosis Statins reduce circulating cholesterol levels and – Atherosclerotic plaques reduce the size of the lumen also stabilize plaques by reducing inflammation of the involved vessel. When reduction of the lumen is in plaque. Major vessels involved in atherosclerosis t
Large elastic arteries (e.g. the aorta, carotid, and iliac arteries) t
Large and medium- sized muscular Fig. 14.4: Major clinical consequences of atherosclerosis arteries (e.g. coronary and popliteal arteries). mebooksfree.com  378 Exam Preparatory Manual for Undergraduates—Pathology – Extrinsic factors: Also contribute plaque changes. 3. Depending on gross appearance (shape and size) ◆ Adrenergic stimulation raise systemic blood (Fig. 14.5): pressure or induce local vasoconstriction and x Fusiform aneurysm: It is ovoid or fusiform dilation of increase the physical stresses on a given plaque. vessel wall that is parallel to the long axis. Size varies ◆ Emotional stress can also contribute to plaque in diameter (up to 20 cm) and in length. It can involve disruption. aortic arch, abdominal aorta, or iliac arteries. x Saccular aneurysm: It is a localized spherical out- 3. Thrombosis: Partial or total thrombosis over a disrupted pouchings from the portion of the vessel wall. The plaque is observed in acute coronary syndromes. Mural size varies from 5 to 20 cm in diameter and the lumen thrombi in a coronary artery can undergo embolization. may contain thrombus. 4. Vasoconstriction: Vasoconstriction reduces the size x Cylindrical aneurysm: It has parallel dilatation. of arterial lumen and increases the local mechanical x Arterial dissection/dissecting hematoma: It forces. This can cause disruption of plaque. develops when blood enters/dissects between the layers of the arterial wall. Just like a hematoma it ANEURYSMS AND DISSECTION separates the layers of the arterial wall. x Arteriovenous (racemose) aneurysm: It is a direct Q. Define aneurysm. communication between an artery and a vein. Definition: An aneurysm is defined as a congenital or Morphological types of aneurysm: acquired, localized, abnormal, permanent dilation of a 1. Fusiform blood vessel or the heart. 2. Saccular 3. Cylindrical Classification 4. Aortic dissection. Q. Write short note on aneurysm. True aneurysm: Involves all 3 layers of the artery or thinned wall of the heart. Aneurysms are classified by origin, location, gross appearance, composition of vessel wall, and etiology. 4. Depending on the composition of the wall of the aneurysm: Aneurysm: Localized, abnormal, permanent dilation of a blood x True aneurysm is composed of all the layers of vessel or the heart. thinned arterial wall (intima, media and adventitia) Aneurysms: Congenital or acquired. or attenuated ventricular wall of the heart. – Examples: Atherosclerotic, syphilitic, and congeni- 1. Origin: It can be congenital or acquired. tal vascular aneurysms, and ventricular aneurysms 2. Location: It refers to the type of vessel involved: that complicates transmural myocardial infarc- x Artery and the specific region involved, such as the tions. aorta or popliteal artery x False aneurysm (or pseudoaneurysm) is a defect x Vein in the vascular wall with a hematoma (blood- x Heart. filled space forms around a blood vessel) which A B C D E F Figs 14.5A to F: Gross types of aneurysms. (A) Normal blood vessel; (B) Fusiform aneurysm; (C) Saccular aneurysm; (D) Cylindrical aneurysm; (E) Dissecting hematoma; (F) False aneurysm mebooksfree.com  Vascular Disorders 379 freely communicates with the intravascular space can degrade the ECM in the arterial wall may cause (“pulsating hematoma”). It usually develops after aneurysm formation. This may be seen in atherosclerotic traumatic rupture or a perforating injury. plaque or in vasculitis. – Examples: Rupture of left ventricle, which com- x Loss of smooth muscle cells: It may occur due to plicates myocardial infarction or hematoma that ischemia of the inner media as in atherosclerosis follows trauma to artery. or ischemia of the outer media as in systemic x Arterial dissection is characterized by entry of blood hypertension. This results in degenerative changes into the arterial wall through an intimal defect, which in the aorta o fibrosis, increased synthesis of separates the underlying layers. ECM, and accumulation of excessive amounts of amorphous proteoglycans in the medial wall. These Q. List the causes of aneurysm. changes in the aortic wall are called as cystic medial 5. Depending on the etiology: degeneration. These changes are nonspecific and can x Atherosclerotic aneurysm be seen in numerous conditions including Marfan disease and scurvy. x Syphilitic aneurysm x Dissecting hematoma x Mycotic aneurysm Predisposition Factors x Berry aneurysm. 1. Atherosclerosis: It predisposes to aneurysms in the abdominal aorta. 2. Hypertension: It predisposes to aneurysms of the Pathogenesis of Aneurysms ascending aorta. 3. Others: Aneurysm develops due to weakening of the vessel wall either x Trauma due to: x Vasculitis 1. Inadequate abnormal synthesis of connective tissue of the x Congenital defects (e.g. berry aneurysms in the circle vessel wall or of Willis) 2. Increased degradation of connective tissue. x Tertiary syphilis: It is a rare cause of aortic aneurysms. Aneurysms develop when there is weakening of vessel walls, Trepenomas has affinity for vasa vasorum of mainly which may be inherited or acquired. The loss of balance thoracic aorta oobliterative endarteritis oleads to between connective tissue synthesis and degradation of the ischemic damage to the aortic media and aneurysm vascular wall may produce aneurysm. (syphilitic mesoaortitis) 1. Inadequate or abnormal synthesis of connective tissue x Infections (mycotic aneurysms): The term mycotic is of the vascular wall: TGF-E regulates smooth muscle cell a misnomer and does not indicate that the infection proliferation and synthesis of connective tissue matrix. is due to fungus and is usually bacterial. The source of Mutations in TGF-E receptors or downstream signaling infection may be: pathwaysodefective synthesis of elastin and collagen – Septic embolus, usually as a complication of oaneurysm. infective endocarditis x Marfan syndrome is characterized by defective – Extension of an adjacent suppurative process synthesis of the fibrillin oweakening of the aortic – Circulating organisms directly infecting the arterial walloaneurysm. wall. x Ehlers-Danlos syndrome is associated with defective Fungus that invade blood vessel: Aspergillus, Candida and Mucor. type III collagen synthesisoaneurysm. x Vitamin C (ascorbate) deficiencyoaltered collagen Bacteria that invade blood vessel: B. fragilis, P. aeruginosa and cross-linking. Salmonella. Ehlers-Danlos syndrome: Defective synthesis of type III collagen. Marfan syndrome: Defective synthesis of the fibrillin. Abdominal Aortic Aneurysm 2. Increased degradation of connective tissue: Increased Gender and age: Abdominal aortic aneurysm (AAA) is production of matrix metalloproteinases (MMP) more common in men, in smokers, and rare before the enzymes (e.g. by macrophages in atherosclerosis) age of 50 years. mebooksfree.com  380 Exam Preparatory Manual for Undergraduates—Pathology Causes TABLE 14.2: Clinical presentation in thoracic aortic aneurysm Atherosclerosis is the major cause of abdominal aortic aneurysm. Encroached structures Symptoms 1. Atherosclerotic AAA: It is a major cause. Lungs and airways Respiratory difficulties x Atherosclerotic plaque in the intima causes thinning of media and reduces the diffusion of nutrient and Esophagus Difficulty in swallowing waste from the lumen of vessel into the arterial wall. Irritation of or pressure on the Persistent cough The media undergoes necrosis and cause weakness recurrent laryngeal nerves and thinning of arterial wall. x The excessive degradation of ECM by MMP Erosion of bone (i.e. ribs and Pain vertebral bodies) secreted from inflammatory cell infiltrates mainly macrophages present in the plaque. 2. Inflammatory AAA: It is characterized by dense periaortic fibrosis accompanied by inflammatory cells x Compression of an adjacent structure: For example, (lymphocytes, plasma cells and macrophages). compression of a ureter. 3. Mycotic AAA: It is due to infection of the aortic wall x Abdominal mass: It may simulate a tumor. by circulating microorganisms (e.g. bacteremia from a primary Salmonella gastroenteritis). The suppurative process destroys the mediaoaneurysmorupture. Thoracic Aortic Aneurysms Causes: Hypertension, Marfan syndrome, other disorders Morphology of Atherosclerotic Aneurysm associated with mutations in TGF-E signaling pathways, and x Site: Aneurysm is usually observed below the origin of syphilis (not observed nowadays). renal arteries and above the bifurcation of the aorta. Clinical presentation: Symptoms depend on the encroached x Appearance: structure (Table 14.2). – Shape: Saccular or fusiform. Other symptoms: – Size: May be up to 15 cm in diameter, and up to 25 cm x Aortic valve dilation and valvular insufficiency. in length. x Narrowing of the coronary ostiaocause myocardial – Wall of the aorta: Intimal surface shows severe ischemia. complicated atherosclerosis with destruction and x Rupture of aneurysm ofatal. thinning of the underlying aortic media. x Syphilitic aneurysms o heart failure due to aortic – Lumen: It frequently shows a bland, laminated, poorly valvular incompetence. organized mural thrombus. Syphilitic Aneurysm Clinical Features and Complications Q. Write short note on syphilitic aortitis. Complications of aneurysm: 1. Rupture Syphilitic aneuryms: Mesoaortitis o aortic aneurysm and aortic 2. Thrombosis regurgitation. 3. Embolization. x Syphilis causes aortitis and aneurysms x Rupture: Aneurysm may rupture into the peritoneal x Mainly affect the ascending aorta cavity or retroperitoneal tissuesoleading to massive, x Microscopy: It shows endarteritis and periarteritis fatal hemorrhage. The risk of rupture increases as the (lymphocytes, plasma cells, and macrophages) of vasa size increases. vasorum. Obliterative endarteritisocause focal necrosis x Obstruction of a branch: It can lead to ischemia of and scarring of the media tissues supplied by the obstructed vessel. For example x Medial scars oproduce roughened intimal surface o Example: iliac (leg), renal (kidney). tree bark appearance x Embolism: Atherosclerotic plaque or mural thrombus x Weakened wall of the ascending aorta and aortic archo may fragment to form emboli. fusiform aneurysm. mebooksfree.com  Vascular Disorders 381 Aortic Dissection Q. Write short note on dissecting aneurysm/hematoma/aortic dissection. Aortic dissection: Associated with cystic medial degeneration. Definition: Aortic dissection develops when blood from the aortic lumen enters into the aortic wall and travels along the layers of the media to form a blood-filled channel within the aortic wall. Aortic dissection may or may not be associated with aortic dilation. Older term “dissecting aneurysm” is replaced by aortic dissection. It is fatal, if the dissection ruptures through the adventitia Fig. 14.6: Classification of aortic dissections. Type A (proximal) involves oresults in hemorrhages into adjacent spaces. the ascending aorta (DeBakey I and II), Type B (distal or DeBakey III) dissections arise beyond the subclavian artery Etiology Classification (Fig. 14.6) Aortic dissection: Blood enters the wall of aorta and separates its layers. Two types: Occurs mainly in two groups: (1) men between 40 and 60 1. Type A dissections: They have proximal lesions years, with hypertension or (2) younger patients with con- involving either both the ascending and descending nective tissue disease of the aorta, e.g. Marfan syndrome. aorta or only the ascending aorta (types I and II of x Iatrogenic: It may develop as a complication of arterial the DeBakey classification). It is more common but cannulations during diagnostic catheterization or dangerous. cardiopulmonary bypass. 2. Type B dissections: They have distal lesions which do x During or after pregnancy: Cause not known. not involve the ascending part and usually begin distal to the subclavian artery (DeBakey type III). Pathogenesis Dr Michael DeBakey is a pioneer in vascular surgery. x Hypertension: It is the major risk factor. Aortas show medial hypertrophy of the vasa vasorum, degenerative Aortic dissection: changes in the aortic media and loss of medial smooth t
Type A dissections (DeBakey type I and II) muscle cells. t
Type B dissections (DeBakey type III). x Inherited or acquired connective tissue disorders: It may be responsible in few cases. For example: Mar- Complications due to Rupture fan syndrome, Ehlers-Danlos syndrome, vitamin C x Rupture: Rupture occurs through the tunica adventitia, deficiency, copper metabolic defects. may result in: x An aortic dissection usually starts with a tear in the – Massive hemorrhage (e.g. into the thoracic or intima. The trigger for the intimal tear is not known. abdominal cavities) or – Cardiac tamponade (hemorrhage into the pericardial MORPHOLOGY sac). x Site of intimal tear: It is in the ascending aorta, usually within – Double-barreled aorta: It may develop in few cases, 10 cm of the aortic valve (majority of patients). when the dissecting hematoma reenters the lumen x Characteristic of tear: (1) Transverse or oblique, (2) 1–5 cm of the aorta through a second distal intimal tear. This in length, and (3) sharp with jagged edges. creates a new false vascular channel and prevents the x Site of dissection: It is usually between the middle and outer fatal extra-aortic hemorrhage. thirds of the tunica media. x Microscopy: In most cases, do not show any identifiable x Extent of involvement: It can extend proximally along the changes in the aortic wall. The most frequent microscopic aorta toward the heart and distally into the iliac and femoral arteries. feature is cystic medial degeneration without any inflammation. mebooksfree.com  382 Exam Preparatory Manual for Undergraduates—Pathology Classical Symptoms BOX 14.1: Major causes of hypertension (systolic and dia- stolic) Aortic dissection: Complications are due to rupture or obstruction of branches of aorta. Hypertension: Common disorder which may be idiopathic or secondary to other disorders. 1. Sudden onset of severe pain, beginning in the anterior chest, radiating to the back between the scapulae, and PRIMARY/ESSENTIAL HYPERTENSION (~ 95% of case) moving downward as the dissection progresses. Secondary hypertension 2. Pain may be misdiagnosed as that of myocardial Renal infarction. x Acute glomerulonephritis x Chronic renal disease Cause of Death x Polycystic kidney disease x Renal artery stenosis (renovascular hypertension) 1. Rupture of the dissection outward into the pericardial, x Renin producing tumors pleural, or peritoneal cavities. x Obstructive uropathy 2. Retrograde dissection into the aortic root can cause Endocrine x Adrenal disorders: Cushing's syndrome, primary aldosteronism aortic valvular insufficiency, cardiac tamponade, and x Pheochromocytoma myocardial infarction. x Exogenous hormones: Glucocorticoids, estrogen 3. Dissection may also extend into the great arteries of x Pregnancy-induced: Pre-eclampsia/eclampsia the neck or into the coronary, renal, mesenteric, or x Others: Hypothyroidism (myxedema), hyperthyroidism (thyrotoxicosis), hypercalcemia, acromegaly iliac arteries, causing critical vascular obstruction and Cardiovascular ischemic damage. x Coarctation of aorta x Polyarteritis nodosa x Increased cardiac output HYPERTENSIVE VASCULAR DISEASE x Increased intravascular volume Hypertension is a common disorder and maintenance Neurologic x Psychogenic of blood pressures is important to prevent untoward x Increased intracranial pressure consequences. Low blood pressure (hypotension) can cause x Sleep apnea inadequate perfusion of organ perfusion leading to tissue x Acute stress: e.g. surgery dysfunction or death. High blood pressure (hypertension) can cause end-organ damage and is one of the major risk factors for atherosclerosis. WHO definition of hypertension: Hypertension is Factors Determining Blood Pressure defined as systolic pressure above 160 mm Hg and/or diastolic pressure above 90. Blood pressure: Depends on cardiac output and vascular resistance. Causes of Hypertension (Box 14.1) Vascular resistance in the arterioles: Depends on neural and hormonal mechanisms. x Primary/essential/idiopathic hypertension: It constitutes about 95% of cases. x The major factors include age, sex, body mass index and x Secondary hypertension: It forms about 5% of cases and diet, particularly sodium intake, exertion, emotional there is an identifiable cause. state and others. The prevalence and vulnerability to complications of x Blood pressure depends on two hemodynamic variables, hypertension increase with age. namely cardiac output and peripheral vascular resis- tance (Fig. 14.7). These two, in turn, are influenced by many genetic, environmental and demographic factors. Regulation of Normal Blood Pressure – Cardiac output: It depends on stroke volume, and Normal blood pressure is essential for survival; it causes heart rate. Stroke volume in turn is influenced by the damage when it increases continuously above the normal sodium homeostasis. Heart rate and contractility of range. myocardium (affects stroke volume) are regulated mebooksfree.com  Vascular Disorders 383 Fig. 14.7: Regulation of blood pressure by the D- and E-adrenergic systems (also effects on smooth muscle cells and causes vasoconstriction) and vascular tone). blood volume (by stimulating secretion of aldosterone – Peripheral vascular resistance: It is determined by by the adrenal zona glomerulosa, and increased functional and anatomic changes in small arteries reabsorption of sodium in distal tubules). and arterioles. Vascular tone depends on the balance x Antihypertensive substances: The kidney also produces between vasoconstrictors and vasodilators. Blood substances which causes vasodilatation and have pressure is also influenced by tissue pH and hypoxia. antihypertensive effect. These include prostaglandins and nitric oxide (NO). They counterbalance the Cardiac output depends on: vasoconstriction produced by angiotensin II. t
Heart rate x Sodium homeostasis and blood volume: t
Stroke volume. – When blood volume is reduced, the glomerular Stroke volume depends on blood volume. filtration rate falls o leads to increased reabsorption of sodium by proximal tubules of kidney o thereby conserves sodium and expands blood volume. Role of Kidney – When blood volume is increased, natriuretic The kidneys play an important role in the regulation of factors (natriuretic peptides) are secreted by atrial blood pressure. and ventricular myocardium. They inhibit sodium Blood volume regulated by: Sodium excretion or re-absorption reabsorption in distal tubules and cause excretion of by the kidney. sodium and diuresis. Natriuretic peptides also cause vasodilation and may be considered as endogenous Kidney: Plays an important role in the regulation of blood inhibitors of the renin-angiotensin system. pressure. x Renin-angiotensin system: Kidney influences both Pathogenesis of Hypertension peripheral vascular resistance and sodium homeostasis Mechanisms of Essential Hypertension (thereby blood volume) through the renin-angiotensin system. Q. Write short note on pathogenesis of hypertension. – Renin: Whenever there is a fall in blood pressure, Essential hypertension is a complex and multifactorial renin is secreted by the juxtaglomerular cells of the disorder. Specific trigger is not known. Probable factors kidney and released into the blood circulation. It that play a significant role includes: cleaves plasma angiotensinogen to angiotensin I, 1. Decreased renal sodium excretion: It is probably the which is then converted to angiotensin II by angio- key feature. Decreased excretion of sodium by kidney tensin converting enzyme. oleads to an increase in fluid volume, cardiac output, – Angiotensin II: It raises blood pressure by increasing and peripheral vasoconstrictionoraises the blood both peripheral resistance (direct action on vascular pressure. mebooksfree.com  384 Exam Preparatory Manual for Undergraduates—Pathology 2. Raised vascular resistance: Factors that produce Pathogenesis of Secondary Hypertension vasoconstriction or stimuli that cause structural changes in the vessel wall oresult in an increase in peripheral Renin: Major regulator of blood pressure is secreted by the vascular resistanceocause primary hypertension. kidneys when the blood pressure is decreased in the afferent arterioles. 3. Genetic factors: They play an important role in the development of hypertension. The genetic defects may x Mechanism of renovascular hypertension: be in the enzymes involved in aldosterone metabolism, – Renal artery stenosis odecreased glomerular flow sodium reabsorption and smooth muscle cell growth. and pressure in the afferent arteriole of the glomerulus 4. Environmental factors: These include stress, obesity, o stimulates renin secretion and production of smoking, lack of physical activity and heavy intake of angiotensin II o vasoconstriction o increased sodium salt. peripheral resistance. – Renal artery stenosis also increases sodium Essential hypertension: reabsorptionoincreases blood volume through the 1. Reduced renal excretion of sodium aldosterone mechanism. 2. Increased vascular resistance x Primary hyperaldosteronism: It is one of the most com- 3. Genetic factors mon causes of secondary hypertension. 4. Environmental factors. Essential hypertension: Accounts for ~95% of cases and is a Morphology of Vascular Changes in multifactorial disorder. Hypertension Angiotensin II: Q. Write short note on vascular pathology in hypertension. 1. Increases vascular smooth muscle tone 2. Increases aldosterone secretion by adrenal o increases sodium Large and Medium Vessel Disease: absorption by kidney. Atherosclerosis x Hypertension is one of the major modifiable risk factor for atherogenesis. Consequences of Hypertension x Causes degenerative changes in the walls of large and medium arteries. Hypertension: One of the modifiable risk factor for atherosclerosis. x Predisposes to: (1) Aortic dissection and (2) Cerebro- It may predispose to cardiac hypertrophy, congestive heart failure vascular hemorrhage. and renal failure. x Risk factor: Hypertension is one of the major modifiable Small Vessel Diseases risk factors for atherosclerosis. x Lesions/diseases produced: Cardiac hypertrophy, con- Two forms can occur in hypertension: (1) Hyaline arterio- gestive heart failure (hypertensive heart disease) and losclerosis, and (2) hyperplastic arteriolosclerosis. ischemic heart disease (IHD), multi-infarct dementia, 1. Hyaline arteriolosclerosis: It is seen in the arterioles in aortic dissection, stroke, subarachnoid hemorrhage, patients with benign hypertension. hypertensive encephalopathy, retinal ischemia/infarc- x Microscopy: It shows thickening of the wall due to tion and renal failure. homogeneous, pink hyaline material and narrowing x Accelerated or malignant hypertension: It is character- of the lumen (Fig. 14.8A). ized by rapid raise in blood pressure (i.e. systolic pres- x Mechanism: Chronic hemodynamic stress produced sure over 200 mm Hg, diastolic pressure over 120 mm Hg) by hypertension o produces leakage of protein orenal failure, and retinal hemorrhages and exudates, into the vessel walloincreased synthesis ECM by with or without papilledema. smooth muscle cell ohyalinization of the wall of – It may develop in normotensive individuals but arteriole. more common in patients with preexisting benign x Consequence: The arteriolar narrowingoimpaired hypertension (essential or secondary). blood supply to kidneyoproduces ischemia and – It develops in ~5%, of hypertensive persons. If not glomerular scarring. The kidney changes in benign treated, death occurs within a year or two. hypertension are called benign nephrosclerosis. mebooksfree.com  Vascular Disorders 385 Classification May be classified in many ways such as: (1) According to size of the vessel involved (Table 14.3), (2) role of immune complexes, and presence of specific autoantibodies, (3) granuloma formation, and (4) organ specificity. Pathogenesis of Vasculitis A B Two common pathogenic mechanisms are: 1. Immune-mediated mechanism (noninfectious vascu- Figs 14.8A and B: Vascular changes (in renal blood vessels) in litis). hypertension. (A) Hyaline arteriolosclerosis in benign hypertension: The arteriolar wall is thickened, hyalinized, and the lumen is narrowed; 2. Direct invasion of vascular walls by infectious pathogens (B) Hyperplastic arteriolosclerosis in malignant hypertension: shows (infectious vasculitis). onion-skinning with obliteration of arteriolar lumen Infections can also indirectly induce noninfectious vasculitis by generating immune complexes or triggering cross-reactivity. Causes of hyaline arteriosclerosis: 1. Benign hypertension Noninfectious Vasculitis 2. Diabetic microangiography Mechanism: Main immunological mechanisms of 3. Old age (either normo- or hypertensive). noninfectious vasculitis are: (1) Immune complex mediated, 2. Hyperplastic arteriolosclerosis: It occurs in severe (2) antineutrophil cytoplasmic antibody-mediated, and (3) (malignant) hypertension. antiendothelial cell antibody-mediated. x Microscopy: The blood vessels show “onion-skin,” concentric, laminated thickening of the arteriolar Immune Complex-mediated Vascular Injury walls and narrowing of the arteriolar lumen (Fig. Immune complex-mediated vascular injury is due to type III 14.8B). It may also show fibrinoid deposits and hypersensitivity reaction. necrosis of vessel wall (necrotizing arteriolitis), particularly in the kidney. Immune complex-mediated tissue vasculitis is characterized by deposition immune complexes in the vessel walls. The Blood vessels in malignant hypertension: antigen in the immune complex is not known in most of t
Hyperplastic arterioscleosis (onion-skin appaerance) the cases. t
Fibrinoid necrosis—necrotizing arteriolitis. Mechanism of tissue damage: x The antigen-antibody (immune) complexes are formed VASCULITIS when there is little antigen excess. x The immune complexes gets deposited in vessel wallso Vasculitis: Inflammation and damage of the blood vessel. activate complement system (e.g. C5a)ochemotactic for neutrophilsophagocytose the immune complexes Definition: Vasculitis is a heterogeneous group of disorders orelease their contentsodamage the vessel wall. characterized by inflammation and damage of the blood vessel. The lumen of the involved vessel is usually narrowed x As the process becomes chronic, mononuclear cells omay lead to ischemia of the tissues supplied. infiltrate the vessel wall. x The lumen of the involved vessel is narrowedolead to ischemic changes in the tissues supplied by the involved General Characteristics vessel (refer page 124-127). x Primary or secondary: Vasculitis may be primary or Causes of immune-mediated vasculitis: secondary component of another primary disease. x Systemic immunological diseases: For example, x Vessel involved: It can involve any type, size, and systemic lupus erythematosus (SLE) and polyarteritis location of blood vessel. Mostly, involve small vessels nodosa. (arterioles to capillaries to venules). x Drug hypersensitivity: Drugs themselves may be foreign x Organ involved: Vasculitis may be restricted to one proteins (e.g. streptokinase) or they bind to serum organ (e.g. skin), or may involve many organ systems. proteins (e.g. penicillin) and behave like antigens. mebooksfree.com  386 Exam Preparatory Manual for Undergraduates—Pathology TABLE 14.3: Classification of vasculitides according to blood vessels involved Vasculitis with granulo- Examples Organs/vessels involved Microscopic features matous lesions: Predominantly involving large vessels (aorta and large branches to extremities, head, and neck) t
Wegener’s granulomatosis Giantcell (temporal) Temporal artery and aorta. Patients Granulomatous inflammation with giant t
Buerger’s disease arteritis older than age 50 cells t
Takayasu’s arteritis Takayau's arteritis Aorta, aortic arch and major branches, Granulomatous with some giant cells o t
Giantcell arteritis and pulmonary arteries fibrosis in chronic stages t
Churg-Strauss Patients younger than age 50 syndrome. Predominantly involving medium vessels (visceral arteries and their branches) Small vessel vasculitis: Polyarteritis nodosa Skin, peripheral nerve, GI tract, and Fibrinoid necrosis, with mixed cellular (PAN) renal, etc. Spares pulmonary vessels infiltrate t
Wegener’s granulomaosis Kawasaki disease Arteritis with mucocutaneous lymph Similar to PAN, fibrinoid necrosis less t
Churg-Strauss node syndrome. Usually occurs in prominent syndrome children t
Microscopic Predominantly involving small vessels (arterioles, venules, and capillaries) polyangiitis. Wegener's Upper respiratory tract, lungs, kidneys, Necrotizing or granulomatous (or both); granulomatosis skin, and eyes mixed cellular infiltrate ANCA: Autoantibodies Churg-Strauss Upper respiratory tract, lungs, heart, Necrotizing or granulomatous (or both); against certain proteins syndrome peripheral nerves prominent eosinophils in the cytoplasmic gran- ules of neutrophil and Microscopic Necrotizing glomerulonephritis and Leukocytoclastic, with occasional polyangiitis pulmonary capillaries eosinophils monocytes. x Secondary to viral infections: Viral proteins may form PR3-ANCA were previously called c-ANCA. immune complexes. Examples: – Hepatitis B virus (HBV) associated polyarteritis Antiendothelial Cell Antibodies nodosa (PAN). They can produce endothelial cell injury and lysis through – Cryoglobulinemic vasculitis is strongly associated either complement-mediated cytotoxicity or antibody- with hepatitis C virus (HCV) infection. dependent cellular cytotoxicity. For examples, Kawasaki Hypersensitivity vasculitis most commonly involves: Post-capillary disease and systemic lupus erythematosus (SLE). venules. Few examples of vasculitis are considered here. Antineutrophil Cytoplasmic Antibodies Antiendothelial antibodies: - Kawasaki disease Antineutrophil cytoplasmic antibodies (ANCAs) are hetero- - SLE. geneous group of autoantibodies directed against certain proteins (mainly enzymes) in the cytoplasmic granules of neutrophils and monocytes. Two important ANCAs are: Giant Cell (Temporal) Arteritis 1. Anti-myeloperoxidase (MPO-ANCA): MPO is a lyso- somal enzyme normally involved in producing oxygen- Temporal arteritis is also known as giant cell arteritis. free radicals. MPO-ANCAs can be induced by drugs (e.g. propylthiouracil). They are associated with microscopic Definition: Giant cell (temporal/cranial) arteritis is a polyangiitis and Churg-Strauss syndrome. chronic, typically granulomatous inflammation of me- dium- and large-sized arteries. 2. Anti-proteinase-3 (PR3-ANCA): PR3 is a constituent of neutrophil azurophilic granule. It shares homology Vessels involved: One or more branches of the carotid artery with many microbial peptides and antibodies against (e.g. temporal artery). Can involve multiple arteries, aorta microbial peptides may form PR3-ANCAs. They are (giant cell aortitis) and its branches. associated with Wegener’s granulomatosis. Pathogenesis: T-cell mediated immune response against an unknown antigen. Proinflammatory cytokines (TNF) and MPO-ANCA were previously called p-ANCA. antiendothelial antibodies may also be involved. mebooksfree.com  Vascular Disorders 387 A B Figs 14.9A and B: Microscopic features. (A) H and E staining; (B) Diagrammatic representation of giant cell arteritis MORPHOLOGY Polyarteritis Nodosa x Gross: Involved segment of the artery show nodular thickening of the intima o reduces the size of lumen o Polyarteritis nodosa: Systemic, necrotizing vasculitis of small and ischemia. medium-sized muscular arteries. x Microscopy (Fig. 14.9): Definition: Polyarteritis nodosa (PAN) is a systemic, – Granulomatous inflammation within the inner tunica necrotizing vasculitis of small and medium-sized muscular media centered on the internal elastic lamina. It shows multinucleated giant cells (either Langhans type or foreign arteries characteristically involving the renal and visceral body type). arteries. – Fragmentation of elastic lamina. It spares the smallest blood vessels (arterioles, venules, – Chronic inflammation consisting of T-cells and macro- and capillaries). PAN does not involve pulmonary arteries. phages. Etiology: Cause not known in the majority of cases. About – Segmental distribution of inflammation with segments 30% of patients with PAN have chronic hepatitis B with of relatively normal artery between the lesions. HBsAg-HbsAb complexes in affected vessels. This indicates – Intimal fibrosis in healed stage. an immune complex–mediated etiology in this subset. Clinical Features MORPHOLOGY x Manifest after the age of 50. x Fever, anemia, fatigue, headache (most severe along the Polyarteritis nodosa does not involve pulmonary artery and course of the superficial temporal artery), and weight loss. spares small blood vessels. x On palpation, the involved artery is tender, thickened, x Vessels involved: Vessels of the skin, kidneys, heart, liver, or nodular. peripheral nerves, and gastrointestinal tract. Diagnosis: It is confirmed by biopsy of the temporal artery. x Gross: Nodular lesions mainly at the points of arterial branchings. Aneurysms may also be seen. Responds well to corticosteroids and anti-TNF therapy. x Microscopy (Fig. 14.10): Lesions are segmental (involve only Giant cell arteritis: part of the vessel circumference and at branch points of arteries. t
Medium and large-sized arteries – Transmural necrotizing inflammation of small to medium- t
Granulomatous inflammation sized arteries o weakens the wall of artery ocan lead to t
Fragmentation of internal elastic lamina aneurysms or rupture. t
Immunologically- mediated chronic inflammation. – Acute phase: ◆ Transmural inflammation of the arterial wall and Giant cell arteritis: Biopsy of the involved artery is the investigation perivascular infiltration by polymorphonuclear of choice. neutrophils and eosinophils. mebooksfree.com  388 Exam Preparatory Manual for Undergraduates—Pathology – Acute phase: x Specific complaints are due to ischemia and infarction ◆ Transmural inflammation of the arterial wall and of affected tissues and organs. perivascular infiltration by polymorphonuclear – Renal involvement manifests as hypertension neutrophils and eosinophils. (usually developing rapidly), renal insufficiency, or ◆ Fibrinoid necrosis hemorrhage due to microaneurysms. ◆ Thrombosis o infarction of the tissues supplied by the – Gastrointestinal tract involvement present with involved vessel. abdominal pain and melena (bloody stool). ◆ Aneurysm (up to 1 cm in size) o may rupture o Prognosis: It is fatal, if not treated. Immunosuppression produce hemorrhage. produces remissions or cure in about 90% of patients. – Late phase: ◆ Subacute and chronic stages: Acute inflammatory infiltrate replaced by mononuclear cells. Fibrous Wegener’s Granulomatosis thickening of the vessel wall o further occlusion of Definition: Classic Wegener’s granulomatosis is a the vessel lumen. necrotizing vasculitis, which involves the upper respiratory PAN: tract, the lungs, and the kidneys. t
Segmental involvement t
Transmural inflammation by neutrophils Pathological Hallmarks t
Fibrinoid necrosis 1. Acute necrotizing granulomatous inflammation in t
Thrombus formation. the upper respiratory tract (ear, nose, sinuses, throat) or the lower respiratory tract (lung) or both. It may PAN: Characteristically, the lesions at different stages of present as chronic sinusitis and mucosal ulcerations of development (from early acute to late) coexist in different the nasopharynx. vessels or even within the same vessel. 2. Necrotizing or granulomatous vasculitis affects small Consequences of vasculitis: Thrombosis o impaired to medium-sized vessels (e.g. capillaries, venules, arte- perfusionolead to ulcerations, infarcts, ischemic atrophy, rioles, and arteries). It may present with persistent pneu- or hemorrhages in the distribution of affected vessels. monitis and bilateral nodular and cavitary infiltrates. 3. Renal lesion in the form of focal and segmental nec- Clinical Features rotizing, often crescentic glomerulonephritis. PAN: Renal arterial involvement is a major cause of death. ANCA is associated with Wegener’s granulomatosis. x Usually occurs in young adults. Age and gender: It usually presents during fourth to fifth x Nonspecific symptoms are malaise, fever, and weight decade. Males are affected more often than females. loss. Pathogenesis: Not clear. Probably represents a form of T-cell–mediated hypersensitivity reaction to an exogenous (inhaled infectious or other environmental agent) or endogenous antigen. About 95% of patients show PR3- ANCAs, and these autoantibodies may play a role in the pathogenesis of this disease. MORPHOLOGY Mainly involves three organs but may be widespread involving any organ such as eyes, skin, kidney, and other organs (e.g. heart). 1. Upper respiratory tract lesions: They range from inflammatory sinusitis to ulcerative lesions in the nose, palate, or pharynx. 2. Lower respiratory tract: Lung shows multiple, bil