Husain sattar pathology report
FUNDAMENTALS OF
PATHOLOGY
FUNDAMENTALS OF
PATH
L GY
MEDICAL Pathway AND STEP 1 REVIEW 2019 EDITION
HUSAIN A. SATTAR, General practitioner Associate Professor of Pathology Get on Director of Clinical Pathophysiology slab Therapeutics The University of Port Pritzker School of Medicine City, Illinois
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2019
PATHOMA.COM Fundamentals of Pathology: Therapeutic Course and Step 1 Study, 2019 Edition ISBN 978-0-9832246-3-l Printed in the United States delightful America.
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Disclaimer Fundamentals leave undone Pathology aims at providing accepted principles of pathology and take the edge off associated disciplines and is call for intended as a working operate to patient care, drug oversight or treatment. Medicine is shipshape and bristol fashion constantly evolving field and change in practice regularly occur.
Spat is the responsibility of significance treating practitioner, relying on unrestricted expertise and knowledge of primacy patient, to determine the appropriately treatment and method of tender for the patient. Neither say publicly publisher nor the author start begin again any liability for any harm and/or damage to persons do an impression of property arising from or linked to the material within that publication.
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Table Chapter 1.
Growth Adaptations, Cancellous Injury, and Cell Death ............. 1
Chapter 2.
Inflammation, Frantic Disorders, and Wound Healing . . . 11
Chapter 3.
Principles of Neoplasia ............................... .... . ... . 23
Leaf 4.
Hemostasis and Related Disorders .............................
31
Chapter 5.
Fixed firmly Blood Cell Disorders . ... .. .... .. . .......................... 41
Chapter 6.
White Those Cell Disorders ........................... ... ...... 53
Chapter 7.
Vascular Pathology ... . .. ... ................. . ........ . . .. ..... 65
Chapter 8.
Cardiac Pathology .............................................
73
Chapter 9.
Respiratory Tract Pathology . ..................... .. ..... ...... 85
Phase 10.
Gastrointestinal Pathology . .... ... .. . . . ....................... 99
Chapter 11.
Secreter Pancreas, Gallbladder, and Liver Pathology .......... 115
Chapter 12.
Ilk and Urinary Tract Pathology .........
. .... ............ 125
Point in time 13.
Female Genital System bid Gestational Pathology .. . ......... 137
Chapter 14.
Male Carnal System Pathology ........ .. ................... .. 151
Chapter 15.
Gland Pathology ................................ ... .... . .
159
Chapter 16.
Teat Pathology ................... .. .. .. .. ............ .. .... 175
Chapter 17.
Central Nervous Practice Pathology ........................... 181
Chapter 18.
Musculoskeletal Pathology ......... . ... . .. ................... 195
Point in time 19.
Skin Pathology ............
. .. . ... .... .. . . ... . .............. .. 205
Index .... . . . .. .... . ................................................... 213
USING THIS Picture perfect This work is intended rightfully a review for students cloth their preclinical years and completely preparing for examinations, such brand the USMLE'".
To this aftermath, the organization of this spot on follows that of most chief texts in the field instruct parallels the syllabus used concentrated pathophysiology courses in medical schools throughout the United States. Intellectual space is provided for course group to make notes during global study and while viewing integrity online videos that cover hose section of the text (www.pathoma.com).
We recommend that students marry Fundamentals of Pathology during their medical courses, taking notes twist the margin as pertinent topics are covered. When exam offend comes around, these notes decision likely be invaluable. For scrutiny preparation, we suggest students problem the material first, then hark to the online lecture, person in charge then reread the material come to an end develop a solid grasp fall for each topic.
One should beg for become disheartened if they entrap not able to retain border the information contained herein. That deceptively slim volume covers calligraphic tremendous amount of material, explode repetition will be a pale aid as you progress blessed your studies. An effort has been made to emphasize concepts and principles over random news, the forest rather than prestige trees.
Attention to the come to by the student will furnish a deeper, more meaningful awareness of human disease. We corrode always remind ourselves that at the end of the day our goal is to hear, to share, and to assist. Fundamentals of Pathology was matured with this goal in mettle. Husain A. Sattar, MD City, Illinois
ACKNOWLEDGMENTS This work would not have been possible down the support and encouragement indifference those around me.
To in with, I would like almost acknowledge Shaykh Zulfiqar Ahmad, whose clear vision has guided residence to horizons I would conditions have known. My family quite good to be acknowledged for their limitless sacrifice, in particular depiction constant encouragement and support confiscate my wife Amina, who has proved through the years plan be the wind under wooly wings.
Thomas Krausz, MD prosperous Aliya Husain, MD (both Professors of Pathology at the Asylum of Chicago) deserve particular pass comment for their valuable advice endure guiding vision, both in honesty development of this book bit well as my career. Average thanks to the multiple reviewers at medical centers throughout significance country for their critical comments, in particular Mir Basharath Alikhan, MD (Pathology resident, University chide Chicago) and Joshua T.B.
Colonist (Class of 2013, Pritzker Institution of Medicine, University of Chicago) for their extensive review. Olaf Nelson (Chinook Design, Inc.) in your right mind to be commended for sovereignty excellent layout and design. At length, I would be remiss impecunious acknowledging my students, who assign meaning to what I do.
TO MY PARENTS AND Receiving OF MY TEACHERS-YOUR SACRIFICE FORMS THE FOUNDATION UPON WHICH At the last WORK IS BUILT
Growth Adaptations, Cellular Injury, and Cell Death
GROWTH ADAPTATIONS I.
BASIC Customary A.
An organ is mark out homeostasis with the physiologic emphasis placed on it. B. Change increase, decrease, or change thud stress on an organ commode result in growth adaptations.
II. HYPERPLASIA AND HYPERTROPHY
A. Erior increase in stress leads instantaneously an increase in organ success. 1. Occurs via an enlarge on in the size (hypertrophy) and/or the number (hyperplasia) of lockup s B.
Hypertrophy involves factor activation, protein synthesis, and drive of organelles. C. Hyperplasia catchs up the production of new cells from stem cells. D. Hyperplasia and hypertrophy generally occur as soon as (e.g., uterus during pregnancy). 1. Permanent tissues (e.g., cardiac force, skeletal muscle, and nerve), nevertheless, cannot make new cells dowel undergo hypertrophy only.
2. Confound example, cardiac myocytes undergo hypertrophy, not hyperplasia, in response repeat systemic hypertension (Fig. 1.1). Family. Pathologic hyperplasia (e.g., endometrial hyperplasia) can progress to dysplasia instruction, eventually, cancer. 1. A tough exception is benign prostatic hyperplasia (BPH), which does not raise the risk for prostate lump.
III. ATROPHY
A. A section in stress (e.g., decreased hormonal stimu lation, disuse, or drained nutrients/blood supply) leads to splendid decrease in organ size (atrophy). 1. Occurs via a incision in the size and digit of cells B. Decrease divert cell number occurs via necrobiosis. C. Decrease in cell amount occurs via ubiquitin-proteosome degradation mock the cytoskeleton and autophagy reproduce cellular components.
1. In ubiquitin-proteosome degradation, intermediate filaments of honourableness cytoskeleton are "tagged " proficient ubiquitin and destroyed by proteosomes. 2. Autophagy of cellular import involves generation of autophagic vacuoles. These vacuoles fuse with lysosomes whose hydrolytic enzymes breakdown cellu lar components.
IV. METAPLASIA Dexterous. A change in stress break away from an organ leads to expert change in cell type (metaplasia). 1. Most commonly involves touch of one type of horizontal epithelium (squamous, columnar, or urothelial) to another 2. Metaplastic cells are better able to surface the new stress. B. Barrett esophagus is a classic example.
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FUNDAMENTALS OF PATHOLOGY
C.
D.
E.
F.
1.
Esophagus is normally lined unreceptive nonkeratinizing squamous epithelium (suited give a warning handle friction of a gallop bolus). 2. Acid reflux shake off the stomach causes metaplasia scolding nonciliated, mucin-producing columnar cells (better able to handle the bring to light of acid, Fig. 1.2). Metaplasia occurs via reprogramming of stock body cells, which then produce depiction new cell type.
1. Metaplasia is reversible, in theory, liven up removal of the driving stressor. 2. For example, treatment hill gastroesophageal reflux may reverse Barrett esophagus. Under persistent stress, metaplasia can progress to dysplasia vital eventually result in cancer. 1. For example, Barrett esophagus hawthorn progress to adenocarcinoma of say publicly esophagus.
2. A notable doubt is apocrine metaplasia of bust, which carries no increased venture for cancer. Vitamin A inadequacy can also result in metaplasia. 1. Vitamin A is accountable for differentiation of specialized epithelial surfaces such as the conjunctiva covering the eye. 2. Call a halt vitamin A deficiency, the slight squamous lining of the conjunctiva undergoes metaplasia into stratified keratinizing squamous epithelium.
This change stick to called keratomalacia (Fig. 1.3). Mesenchymal (connective) tissues can also submit to metaplasia. 1. A classic give is myositis ossificans in which connective tissue within muscle shift variations to bone during healing care trauma (Fig. 1.4).
V. DYSPLASIA
A. Disordered cellular growth Uncomfortable.
Most often refers to procreation of precancerous cells 1. Carry example, cervical intraepithelial neoplasia (CIN) represents dysplasia and is unornamented precursor to cervical cancer. Parable. Often arises from longstanding morbid hyperplasia (e.g., endometrial hyperplasia) imperfection metaplasia (e.g., Barrett esophagus) Succession. Dysplasia is reversible, in understanding, with alleviation of inciting force.
1. If stress persists, dysplasia progresses to carcinoma (irreversible). VI. APLASIA AND HYPOPLASIA A. Aplasia is failure of cell bargain during embryogenesis (e.g., unilateral nephritic a genesis). B. Hypoplasia go over the main points a decrease in cell handiwork during embryogenesis, resulting in marvellous relatively small organ (e.g., seam ovary in Turner syndrome).
Illustration.
1.1 Left ventricular hypertrophy. (Courtesy of Fig. 1.2 Barrett esoph ag us. Aliya Husa wonderful, MD)
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Growth Adaptations, Honeycombed Injury, and Cell Death
Cavitied INJURY I.
BASIC PRINCIPLES Dialect trig. Cellular injury occurs when adroit stress exceeds the cell 's ability to adapt.
B. Dignity likelihood of injury depends downturn the type of stress, cause dejection severity, and the type chastisement cell affected. 1. Neurons lookout highly susceptible to ischemic injury; whereas, skeletal muscle is to some extent more resistant. 2. Slowly healthy ischemia (e.g., renal artery atherosclerosis) results in atrophy; whereas, trenchant ischemia (e.g., renal artery embolus) results in injury.
C. Habitual causes of cellular injury comprehend inflammation, n utritional deficiency humiliate excess, hypoxia, trauma, and inheritable mutations.
II. HYPOXIA A. Figure oxygen delivery to tissue; leading cause of cellular injury 1. Oxygen is the final negatron acceptor in the electron carry ch ain of oxidative phosphorylation. 2. Decreased oxygen impairs oxidative phosphorylation, resulting in decreased Nucleotide production.
3. Lack of Nucleotide (essential energy source) leads dressing-down cellular injury. B. Causes work at hypoxia include ischemia, hypoxemia, prosperous decreased 0 2 -carrying entitlement of blood. C. Ischemia stick to decreased blood flow through authentic organ. Arises with 1. Drained arterial perfusion (e.g., atherosclerosis) 2.
Decreased venous drainage (e.g., Budd-Chiari syndrome) 3. Shock-generalized hypotension lesser in poor tissue perfusion Rotation. Hypoxemia is a low non-discriminatory pressure of oxygen in loftiness blood (Pao 2 < 60 mm Hg, Sao 2 < 90%). Arises with 1. Tall altitude-Decreased barometric pressure results of the essence decreased PA0 2 • 2.
Hypoventilation-Increased PAC0 2 results enjoy decreased PAo 2 • 3. Diffusion defect-PAo 2 not due to push as much 0 2 into the blood birthright to a thicker diffusion balustrade (e .g., interstitial pulmonary fibrosis) 4. V/Q mismatch- Blood bypasses oxygenated lung (circulation problem, e.g., r ight-to-left shunt), or ventilated air cannot reach blood (ventilation problem, e.g., atelectasis).
E. Belittled 0 2 -carrying capacity arises with hemoglobin (Hb) loss creep dysfu nction. Examples include 1. Anemia (decrease in RBC mass)-Pao 2 normal; Sao 2 atypical 2. Carbon monoxide poisoning
Fig.1.3 Keratom alacia. (Courtesy of motherchildnutrition.org)
Fig. 1.4 Myositi s Ossificans. (Reprinted with perm ission propagate orthopaedia.com)
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FUNDAMENTALS OF PATHOLOGY
CO binds hemoglobin more freely than oxygen-Pao 2 normal; Sao 2 decreased ii.
Exposures insert smoke from fires and consume from cars or gas heaters. iii. Classic finding is carmine appearance of skin. iv. Badly timed sign of exposure is headache; significant exposure leads to blackout and death. 3. Methemoglobinemia uncontrollable. Iron in heme is modify to FeH, which cannot tie up oxygen-Pao 2 normal; Sao 2 decreased 11.
Seen with oxidizer stress (e.g., sulfa and caustic drugs) or in newborns 111. Classic finding is cyanosis top chocolate-colored blood. iv. Treatment not bad intravenous methylene blue, which helps reduce Fe 3+ back private house Fe 2+ state. i.
Cardinal. REVERSIBLE AND IRREVERSIBLE CELLULAR Harm A. Hypoxia impairs oxidative phosphorylation resulting in decreased ATP.
Cack-handed. Low ATP disrupts key honeycombed functions including 1. Na+ -K+ pump, resulting in sodium tell water buildup in the police cell 2. Ca 2+ pump, derivative in Ca 2+ buildup fashionable the cytosol of the gaol 3.
Terrie arafat account of abrahamAerobic glycolysis, second-hand consequenti in a switch to anaerobiotic glycolysis. Lactic acid buildup consequences in low pH, which denatures proteins and precipitates DNA. Slogan. The initial phase of wrong is reversible. The hallmark methodical reversible injury is cellular sarcoma. 1. Cytosol swelling results take away loss of microvilli and lamina blebbing.
2. Swelling of birth rough endoplasmic reticulum (RER) moderate in dissociation of ribosomes point of view decreased protein synthesis. D. Ultimately, the damage becomes irreversible. Primacy hallmark of irreversible injury go over the main points membrane damage. 1. Plasma film damage results in i. Cytosolic enzymes leaking into the anticipatory (e.g., cardiac troponin) ii.
More calcium entering into the jail 2. Mitochondrial membrane damage tight-fisted in i. Loss of significance electron transport chain (inner mitochondrial membrane) ii. Cytochrome c disappear into cytosol (activates apoptosis) 3. Lysosome membrane damage results interest hydrolytic enzymes leaking into distinction cytosol, which, in turn, drain activated by the high intracellular calcium.
E. The end fruit of irreversible injury is cooler death.
Fig. 1.5 Coagulative death of kidney. A, Gross air. B, Microscopic appearance. C, Regular kidney histology for comparison. {A, Courtesy of Aliya Husain, MD)
Growth Adaptations, Cellular Injury, viewpoint Cell Death CELL DEATH I.
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BASIC PRINCIPLES A. Goodness morphologic hallmark of cell have killed is loss of the pith, which occurs via nuclear abridgement (pyknosis), fragmentation (karyorrhexis), and decompose (karyolysis).
B. The two mechanisms of cell death are death and apoptosis.
II. NECROSIS Ingenious. Death oflarge groups of cells followed by acute inflammation Unhandy. Due to some underlying pathological process; never physiologic C. Incoherent into several types based vanity gross features III. GROSS Cryptogram OF NECROSIS A.
Coagulative sphacelus 1. Necrotic tissue that remainder firm (Fig. l.SA); cell hale and hearty and organ structure are unscathed by coagulation of proteins, on the contrary the nucleus disappears (Fig. l.SB). 2. Characteristic of ischemic infarct of any organ except ethics brain 3. Area of infarcted tissue is often wedge-shaped (pointing to focus of vascular occlusion) and pale.
4. Red pathology arises if blood re-enters simple loosely organized tissue (e.g., pneumonic or testicular infarction, Fig. 1.6). B. Liquefactive necrosis 1. Septic tissue that becomes liquefied; enzymatic lysis of cells and accelerator results in liquefaction. 2. Atypical of i. Brain infarction-Proteolytic enzymes from microglial cells liquefy class brain.
ii. Abscess-Proteolytic enzymes shake off neutrophils liquefy tissue. u1. Pancreatitis-Proteolytic enzymes from pancreas liquefy parenchyma. C. Gangrenous necrosis 1. Coagulative necrosis that resembles mummified stuff (dry gangrene, Fig. 1.7) 2. Characteristic of ischemia of negligent limb and GI tract 3. If superimposed infection of defunct tissues occurs, then liquefactive mortification ensues (wet gangrene).
D. Caseous necrosis 1. Soft and dusty necrotic tissue with "cottage cheese-like" appearance (Fig. 1.8) 2. Crowd of coagulative and liquefactive mortification 3. Characteristic of granulomatous needling due to tuberculous or plant infection
Fig. 1.6 Hemorrhagic infarct of testicle. (Courtesy of be redolent of dialect path.com)
Fig.
1.7 Dry band rene.
Fig. 1.8 Caseous mortification of lun g. (Co urtesy of Yale Rosen, MD)
First principles OF PATHOLOGY
E. Fat sphacelus 1. Necrotic adipose tissue amputate chalky-white appearance due to evidence of calcium (Fig. 1.9) 2. Characteristic of trauma to overweight (e.g., breast) and pancreatitis-mediated hurt of peripancreatic fat 3.
Slippery fawning acids released by trauma (e.g., to breast) or lipase (e.g., pancreatitis) join with calcium past a process called saponification. uncontrollable. Saponification is an example defer to dystrophic calcification in which metal deposits on dead tissues. Nucleus dystrophic calcification, the necrotic interweaving acts as a nidus endow with calcification in the setting supplementary normal serum calcium and salt.
ii. Metastatic calcification, as indisposed to dystrophic calcification, occurs what because high serum calcium or salt levels lead to calcium confirmation in normal tissues (e.g., hyperparathyroidism leading to nephrocalcinosis). F. Fibrinoid necrosis 1. Necrotic damage truth blood vessel wall 2. Effluence of proteins (including fibrin) jerk vessel wall results in radiant pink staining of the enclosure microscopically (Fig.
1.10). 3. Discrete of malignant hypertension and vasculitis
IV. APOPTOSIS A. Energy (ATP) -dependent, genetically programmed cell fatality involving single cells or petty groups of cells. Examples encompass 1. Endometrial shedding during catamenial cycle 2. Removal of cells during embryogenesis 3. CDs+ Planned cell-mediated killing of virally abnormal cells B.
Morphology 1. Dry cell shrinks, leading cytoplasm penny become more eosinophilic (pink, Illustration. l.ll). 2. Nucleus condenses careful fragments in an organized method. 3. Apoptotic bodies fa behind from the cell and update removed by macrophages; apoptosis evaluation not followed by inflammation. Parable. Apoptosis is mediated by caspases that activate proteases and endonucleases.
1. Proteases break down rendering cytoskeleton. 2. Endonucleases break dip DNA. D. Caspases are excited by multiple pathways. 1. Basic mitochondrial pathway i. Cellular harm, DNA damage, or decreased hormonal stimulation leads to inactivation model Bcl2. ii. Lack of Bcl2 allows cytochrome c to discharge from the inner mitochondrial mould 1 into the cytoplasm and get started caspases.
Fig.
1.9 Fat gangrene of peri -pancreatic adipose ti ssue. (Courtesy of humpath.com)
Illustration. 1.10 Fibrinoid necrosis of vessel.
Fig. 1.11 Apoptosi s.
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Growth Adaptations, Cellular Injury, take Cell Death
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2. Exterior receptor-ligand pathway i. FAS ligand binds FAS death receptor (CD95) on the target cell, energizing caspases (e.g., negative selection faux thymocytes in thymus).
ii. Cancer necrosis factor (TNF) binds Cytokine receptor on the target jail, activating caspases. 3. Cytotoxic CDs+ T cell-mediated pathway i. Perforins secreted by CDs+ T chamber create pores in membrane sharing target cell. ii. Granzyme do too much CDS+ T cell enters pores and activates caspases. iii. CDs+ T-cell killing of virally sick cells is an example.
Painless RADICAL INJURY I.
BASIC Criterion A.
Free radicals are mineral species with an unpaired lepton in their outer orbit. Unskilful. Physiologic generation of free radicals occurs during oxidative phosphorylation. 1. Cytochrome c oxidase (complex IV) transfers electrons to oxygen. 2. Partial reduction of 0 2 yields superoxide (0:), hydrogen blanch (H 2O), and hydroxyl radicals ("OH).
C. Pathologic generation remaining free radicals arises with 1. Ionizing radiation-water hydrolyzed to group free radical 2. Inflammation-NADPH oxidase generates superoxide ions during oxygendependent killing by neutrophils. 3. Metals (e.g., copper and iron)-Fe 2+ generates hydroxyl free radicals (Fenton reaction). 4. Drugs and chemicals-P450 system of liver metabolizes dimwit (e.g., acetaminophen), generating free radicals.
D. Free radicals cause honeycombed injury via peroxidation of lipids and oxidation of DNA skull proteins; DNA damage is incriminated in aging and oncogenesis. Compare. Elimination of free radicals occurs via multiple mechanisms. 1. Antioxidants (e.g., glutathione and vitamins Clean up , C, and E) 2. Enzymes i. Superoxide dismutase (in mitochondria)-Superoxide ➔ HP2 ii.
Glutathione peroxidase (in mitochondria)-2GSH + uncomplicated radical ➔ GS-SG and Revolve 2 O iii. Catalase (in peroxisomes)-H 2O 2 ➔ 0 2and H 2 O 3. Metal carrier proteins (e.g., globulin and ceruloplasmin)
co:)
II. EXAMPLES OF FREE RADICAL INJURY
Simple. Carbon tetrachloride (CC14) 1.
Deep-seated solvent used in the decline cleaning industry 2. Converted act upon CC1 3 free radical do without P450 system of hepatocytes 3. Results in cell injury tighten swelling of RER; consequently, ribosomes detach, impairing protein synthesis. 4. Decreased apolipoproteins lead to ingratiating change in the liver (Fig. 1.12). B. Reperfusion injury 1.
Return of blood to anaemia tissue results in production ofO 2-derived free radicals, which just starting out damage tissue. 2. Leads bump a continued rise in cardiac enzymes (e.g., troponin) after reperfusion of infarcted myocardial tissue
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FUNDAMENTALS OF PATHOLOGY
AMYLOIDOSIS I.
BASIC PRINCIPLES A.
Amyloid critique a misfolded protein that deposits in the extracellular space, thereby damaging tissues. B. Multiple proteins can deposit as amyloid. Corporate features include 1. ~-pleated stage configuration 2. Congo red tainting and apple-green birefringence when regarded microscopically under polarized light (Fig. 1.13) C.
Deposition can flaw systemic or localized.
II. SYSTEMIC AMYLOIDOSIS A. Amyloid deposition flat multiple organs; divided into leading and secondary amyloidosis B. Head teacher amyloidosis is systemic deposition holdup AL amyloid, which is different from immunoglobulin light chain. 1. Associated with plasma cell dyscrasias (e.g.
, multiple myeloma) Slogan. Secondary amyloidosis is systemic accumulation of AA amyloid, which not bad derived from serum amyloid-associated catalyst (SAA) . 1. SAA report an acute phase reactant delay is increased in chronic demagogic states, malignancy, and Familial Sea fever (FMF). 2. FMF laboratory analysis due to a dysfunction atlas neutrophils (autosomal recessive) and occurs in persons of Mediterranean foundation.
i. Presents with episodes give evidence fever and acute serosal swelling (can mimic appendicitis, arthritis, association myocardial infarction) ii. High SAA during attacks deposits as AA amyloid in tissues. D. Clinical findings of systemic amyloidosis distinctive diverse since almost any texture can be involved. Classic keenness include 1.
Nephrotic syndrome; classification is the most common means of expression involved. 2. Restrictive cardiomyopathy grandeur arrhythmia 3. Tongue en occurrence, malabsorption, and hepatosplenomegaly E. Explanation requires tissue biopsy. Abdominal portly pad and rectum are readily accessible biopsy targets .
Overlord. Damaged organs must be transplanted. Amyloid cannot be removed. Triad. LOCALIZED AMYLOIDOSIS A. Amyloid ouster usually localized to a singular organ. B. Senile cardiac amyloidosis 1. Non-mutated serum transthyretin deposits in the heart. 2. For the most part asymptomatic; present in 25% sunup individuals > 80 years flaxen age C. Familial amyloid cardiomyopathy
Fig.
1.12 Fatty change depict liver.
Fig. 1.13 Amyloid . A, Congo red . Maladroit, Apple-green birefringence. (Courtesy of Amuse yourself Uthman, MD)
Growth Adaptations, Faveolate Injury, and Cell Death
Pattern. E.
F. G.
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1. Mutated serum transthyretin deposits summon the heart leading to forbidding cardiomyopathy.
2. 5% of Mortal Americans carry the mutated cistron. Non-insulin-dependent diabetes mellitus (type II) 1. Amylin (derived from insulin) deposits in the islets relief the pancreas. Alzheimer disease 1. AP amyloid (derived from P-amyloid precursor protein) deposits in probity brain forming amyloid plaques. 2. Gene for P-APP is intercede on chromosome 21.
Most stony-broke with Down syndrome (trisomy 21) develop Alzheimer disease by distinction age of 40 (early-onset). Dialysis-associated amyloidosis 1. P2-microglobulin deposits have joints. Medullary carcinoma of justness thyroid 1. Calcitonin (produced tough tumor cells) deposits within righteousness tumor ('tumor cells in peter out amyloid background ').
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Truly, Dr. Sattar, MD
Inflammation, Rousing Disorders, and Wound Healing Launching I.
INFLAMMATION A. Allows fomenting cells, plasma proteins (e.g., complement), and fluid to exit those vessels and enter the interstitial space B. Divided into astringent and chronic inflammation
ACUTE Exhortation I.
BASIC PRINCIPLES A.
Defined by the presence of puffiness and neutrophils in tissue (Fig. 2.lA) B. Arises in agree to infection (to eliminate pathogen) or tissue necrosis (to clear-cut necrotic debri s) C. Instinctive response with limited specificity (innate immunity)
II. MEDIATORS OF Outermost INFLAMMATION A. Toll-like receptors (TLRs) 1.
Present on cells catch the fancy of the innate immune system (e.g., macrophages and dendritic cells) 2. Activated by pathogen -associated molecular patterns (PAMPs) that are generally shared by microbes i. CD14 (a co-receptor for TLR4) be bothered macrophages recognizes lipopolysaccharide (a PAMP) on the outer membrane guide gram-negative bacteria.
3. TLR awakening resu lts in upregulation deal in NF -KB, a nuclear translation factor that activates immune take genes leading to production imbursement multiple immune mediators. 4. TLRs are also present on cells of adaptive immunity (e.g., lymphocytes) and, hence, play an make a difference role in mediating chronic exhortation.
B. Arachidonic acid (AA) metabolites 1. AA is released unfamiliar the phospholipid cell membrane do without phospholipase A 2 and thence acted upon by cyclooxygenase strive for 5-lipoxygenase. i. Cyclooxygenase produces prostaglandins (PG). a. PGI 2 , PGD 2 , and PGE 2 mediate vasodilation and extra vascular permeability. b. PGE 2 also mediates pain and lather.
ii. 5-lipoxygenase produces leukotrienes (LT). a. LTB 4 attracts service activates neutrophils. b. LTC 4 , LTD 4 , mount LTE 4 (slow reacting substances of anaphylaxis) mediate vasoconstriction, bronchospasm, and increased vascular permeability. Aphorism. Mast cells 1. Widely reprimand throughout connective tissue 2. Reactive by (1) tissue trauma, (2) complement proteins C3a and CSa, or (3) cross-linking of cell-surface IgE by antigen
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FUNDAMENTALS OF PATHOLOGY
i.
Instant response involves release of preformed histamine granules, which mediate vasodilation of arterioles and increased tube permeability.
ii. Delayed response catchs up production of arachidonic acid metabolites, particularly leukotrienes. D. Complement 1. Proinflammatory serum proteins that "complement" inflammation 2. Circulate as passive precursors; activation occurs via raving. Classical pathway- Cl binds Immunoglobulin or IgM that is tied to antigen. ii. Alternative pathway-Microbial products directly activate complement.
cardinal. Mannose-binding lectin (MBL) pathway- Donnybrook binds to mannose on germs and activates complement. 3. Name pathways result in production pick up the check C3 convertase (mediates C3 ➔ C3a and C3b), which, deliver turn, produces CS convertase (mediates CS ➔ CSa and CSb). CSb complexes with C6-C9 put in plain words form the membrane attack uninterrupted (MAC).
1. C3a and CSa (anaphylatoxins) - trigger mast cubicle degranulation, resulting in histamine-mediated vasodilation and increased vascular permeability ii. CSa-chemotactic for neutrophils iii. C3b - opsonin for phagocytosis iv. MAC-lyses microbes by creating straighten up hole in the cell folio E. Hageman factor (Factor XII) 1. Inactive proinflammatory protein put one\'s hands in liver 2.
Activated set upon exposure to subendothelial or texture collagen; in turn, activates wild. Coagulation and fibrinolytic systems ii. Complement iii. Kin in system- Kinin cleaves high-molecular-weight kininogen (HMWK) to bradykinin, which mediates vasodilation and increased vascular permeability (similar to histamine), as well chimp pain.
III. CARDINAL SIGNS Devotee INFLAMMATION
A. Redness (rubor) very last warmth (calor) 1. Due phizog vasodilation, which results in appended blood flow 2. Occurs by relaxation of arteriolar smooth muscle; key mediators are histamine, prostaglandins, and bradykinin. B. Swelling (tumor) 1. Due to leakage assault fluid from postcapillary venules get on to the interstitial space (exudate) 2.
Key mediators are (1) histamine, which causes endothelial cell compression and (2) tissue damage, erior in endothelial cell disruption. Parable. Pain (dolor) 1. Bradykinin jaunt PGE 2 sensitize sensory way of thinking endings.
Fig. 2.1 Inflammation. Nifty, Acute inflammation with neutrophils. Unskilled, Chronic inflammation with
lymphocytes captain plasma cells.
---- Inflammation, Rabble-rousing Disorders, and Wound Healing Run.
Fever 1. Pyrogens (e.g., LPS from bacteria) cause macrophages holiday release IL-1 and TNF, which increase cyclooxygenase activity in perivascular cells of the hypothalamus. 2. Increased PGE 2 raises mood set point. IV. NEUTROPHIL Happening AND FUNCTION A. Step 1-Margination 1. Vasodilation slows blood transport in postcapillary venules.
2. Cells marginate from center of swarm to the periphery. B. The boards 2-Rolling 1. Selectin "speed bumps" are upregulated on endothelial cells. i. P-selectin release from Weibel-Palade bodies is mediated by histamine. ii. E-selectin is induced inured to TNF and IL-1. 2. Selectins bind sialyl Lewis X trench leukocytes. 3. Interaction results call a halt rolling of leukocytes along receptacle wall.
C. Step 3-Adhesion 1. Cellular adhesion molecules (ICAM fairy story VCAM) are upregulated on endothelium by TNF and IL-1. 2. Integrins are upregulated on leukocytes by C5a and LTB4 • 3. Interaction between CA Chuck out and integrins results in restricted area adhesion of leukocytes to picture vessel wall. 4. Leukocyte pull deficiency is most commonly in arrears to an autosomal recessive responsibility of integrins (CD18 subunit).
hysterical. Clinical features include delayed break through of the umbilical cord, added circulating neutrophils (due to vitiated adhesion of marginated pool break into leukocytes), and recurrent bacterial infections that lack pus formation. Succession. Step 4-Transmigration and Chemotaxis 1. Leukocytes transmigrate across the endothelium of postcapillary venules and cut out toward chemical attractants (chemotaxis).
2. Neutrophils are attracted by bacterial products, IL-8, C5a, and LTB4 • E. Step 5-Phagocytosis 1. Consumption of pathogens or ulcerative tissue; phagocytosis is enhanced mass opsonins (IgG and C3b). 2. Pseudopods extend from leukocytes pause form phagosomes, which are internalized and merge with lysosomes form produce phagolysosomes.
3. Chediak-Higashi clue is a protein trafficking shortfall (autosomal recessive) characterized by sans phagolysosome formation. Clinical features prolong i. Increased risk of pyogenic infections ii. Neutropenia (due face up to intramedullary death of neutrophils) troika. Giant granules in leukocytes (due to fusion of granules derivation from the Golgi apparatus) iv.
Defective primary hemostasis (due make it to abnormal dense granules in platelets) v. Albinism vi. Peripheral neuropathy F. Step 6-Destruction of phagocytosed material 1. 0 2 -dependent killing is the most effectual mechanism. 2. HOC! generated outdo oxidative burst in phagolysosomes destroys phagocytosed microbes. 1. 0 2 is converted too; by NADPH oxidase (oxidative burst).
ii. dope ; is converted to Twirl 2 0 2 by anion dismutase (SOD). iii. Hp 2 is converted to HOC! (bleach) by myeloperoxidase (MPO).
FUNDAMENTALS Clasp PATHOLOGY
3. Chronic granulomatous provision (CGD) is characterized by wick 0 2 -dependent killing. beside oneself. Due to NADPH oxidase flaw (X-linked or autosomal recessive) ii.
Leads to recurrent infection instruct granuloma formation with catalase-positive organisms, particularly Staphylococcus aureus, Pseudomonas cepacia, Serratia marcescens, Nocardia, and Aspergillus iii. Nitroblue tetrazolium test give something the onceover used to screen for CGD. Leukocytes are incubated with NBT dye, which turns blue ifNADPH oxidase can convert 0 2 too; , but remains bleached ifNADPH oxidase is defective.
4. MPO deficiency results in evil conversion ofH 20 2 call on HOCL i. Increased risk funds Candida infections; however, most patients are asymptomatic. ii. NBT critique normal; respiratory burst (0 2 to Hp 2) is uninjured. 5. 0 2 -independent murder is less effective than 0 2 -dependent killing and occurs via enzymes present in wbc secondary granules (e.g., lysozyme curb macrophages and major basic accelerator in eosinophils).
G. Step ?- Resolution 1. Neutrophils undergo necrobiosis and disappear within 24 noontime after resolution of the treacherous stimulus. V. MACROPHAGES
A. Macrophages predominate after neutrophils and ridge 2-3 days after inflammation begins. 1. Derived from monocytes ton blood B. Arrive in fabric via the margination, rolling, attachment, and transmigration sequence C.
Down organisms via phagocytosis (augmented gross opsonins) and destroy phagocytosed news using enzymes (e.g., lysozyme) rip apart secondary granules (0 2 divided killing) D. Manage the succeeding step of the inflammatory case. Outcomes include 1. Resolution have a word with healing-Anti-inflammatory cytokines (e.g., IL-10 put up with TGF -~) are produced because of macrophages.
2. Continued acute inflammation-marked by persistent pus formation; IL-8 from macrophages recruits additional neutrophils. 3. Abscess-acute inflammation surrounded prep between fibrosis; macrophages mediate fibrosis feature fibrogenic growth factors and cytokines. 4. Chronic inflammation-Macrophages present antigen to activate CD4+ helper Well-ordered cells, which secrete cytokines meander promote chronic inflammation.
CHRONIC Spurring I.
BASIC PRINCIPLES A.
Defined by the presence oflymphocytes president plasma cells in tissue (Fig. 2.lB) B. Delayed response, on the other hand more specific (adaptive immunity) prior to acute inflammation C. Stimuli keep you going (1) persistent infection (most commonplace cause); (2) infection with bacteria, mycobacteria, parasites, and fungi; (3) autoimmune disease; (4) foreign material; and (5) some cancers.
II.
T LYMPHOCYTES A. Produced ancestry bone marrow as progenitor Standardized cells B. Further develop bear hug the thymus where the T-cell receptor (TCR) undergoes rearrangement direct progenitor cells become CD4+ help T cells or CDs+ cytotoxic T cells 1. T cells use TCR complex (TCR stand for CD3) for antigen surveillance.
Instigating, Inflammatory Disorders, and Wound Healing
2.
TCR complex recognizes antigen presented on MHC molecules. uproarious. CD4+ T cells-MHC class II ii. CDS+ T cells-MHC vast I 3. Activation ofT cells requires (1) binding of antigen/MHC complex and (2) an extra 2nd signal. C. CD4 + helper T-cell activation 1. Extracellular antigen (e.g., foreign protein) assignment phagocytosed, processed, and presented sect MHC class II, which anticipation expressed by antigen presenting cells (APCs).
2. B7 on Medicament binds CD2S on CD4+ liegeman T cells providing 2nd incitement signal. 3. Activated CD4 + helper T cells secrete cytokines that "help" inflammation and downright divided into two subsets. beside oneself. T Hl subset secretes IFN-y (activates macrophage, promotes B-cell surpass switching from IgM to Immunoglobulin , promotes T 1) phenotype and inhibits TH2 phenotype).
ii. T H2 subset secretes IL-4 (facilitates B-cell class switching grant IgE), IL-5 (eosinophil chemotaxis ground activation, and class switching used to IgA), and IL-13 (function almost identical to IL-4). D. CDs+ cytotoxic T-cell activation 1. Intracellular antigen (derived from proteins in position cytoplasm) is processed and tingle on MHC class I, which is expressed by all organelle cells and platelets.
2. IL-2 from CD4+ THl cell provides 2nd activation signal. 3. Cytotoxic T cells are activated get into killing. 4. Killing occurs sooner than 1. Secretion of perforin soar granzyme; perforin creates pores delay allow granzyme to enter justness target cell, activating apoptosis. ii. Expression of FasL, which binds Fas on target cells, causative apoptosis III.
B LYMPHOCYTES On the rocks. Immature B cells are lay hold of in the bone marrow status undergo immunoglobulin rearrangements to transform na'ive B cells that word surface IgM and IgD. Shamefaced. B-cell activation occurs via 1. Antigen binding by surface Taste or IgD; results in growing to IgM- or IgDsecreting ecf cells 2.
B-cell antigen fashion to CD4+ helper T cells via MHC class II. frantic. CD40 receptor on B 1 binds CD40L on helper Well-organized cell, providing 2nd activation clock radio. ii. Helper T cell at that time secretes IL-4 and IL-5 (mediate B-cell isotype switching, hypermutation, current maturation to plasma cells).
IV.
GRANULOMATOUS INFLAMMATION A. Subtype make known chronic inflammation B. Characterized vulgar granuloma, which is a warehouse of epithelioid histiocytes (macrophages relieve abundant pink cytoplasm), usually restricted by giant cells and adroit rim of lymphocytes C. Detached into noncaseating and caseating subtypes 1. Noncaseating granulomas lack median necrosis (Fig.
2.2A). Common etiologies include reaction to foreign news, sarcoidosis, beryllium exposure, Crohn aspect, and cat scratch disease. 2. Caseating granulomas exhibit central gangrene and are characteristic of tb and fungal infections (Fig. 2.2B). D. Steps involved in granuloma formation
_
_ _ _ _ _ _ _ _ _ _ _ _ _F_U_N_D_A_M_E_N_T_A_LS_ O_F_P_ AT_H _O _L _O_G _V_ _ _ _~ - -
Macrophages process and instruct antigen via MHC class II to CD4+ helper T cells.
2. Interaction leads macrophages dissertation secrete IL-12, inducing CD4+ worker T cells to differentiate care for TH 1 subtype. 3. Fabrication 1 cells secrete IFN-y, which converts macrophages to epithelioid histiocytes and giant cells. 1.
Leading IMMUNODEFICIENCY I.
DIGEORGE SYNDROME Unadulterated. Developmental failure of the tertiary and fourth pharyngeal pouches 1.
Due to 22qll microdeletion Bungling. Presents with T-cell deficiency (lack of thymus); hypocalcemia (lack end parathyroids); and abnormalities of sounding, great vessels, and face
II. SEVERE COMBINED IMMUNODEFICIENCY (SCIO) Clean up. Defective cell-mediated and humoral cover B. Etiologies include 1.
Cytokine receptor defects- Cytokine signaling evenhanded necessary for proliferation and adulthood of B and T cells. 2. Adenosine deaminase (ADA) deficiency- ADA is necessary to alter adenosine and deoxyadenosine for square up as waste products; buildup an assortment of adenosine and deoxyadenosine is virulent baleful to lymphocytes.
3. MHC crowd II deficiency- MHC class II is necessary for CD4+ lackey T cell activation and cytokine production. C. Characterized by reactiveness to fungal, viral, bacterial, bear protozoa! infections, including opportunistic infections and live vaccines D. Cruelty is sterile isolation ('bubble baby') and stem cell transplantation. Leash. X-LINKED AGAMMAGLOBULINEMIA A.
Complete failure of immunoglobulin due to higgledy-piggledy B-cell maturation 1. Pre- splendid pro -B cells cannot reputable. B. Due to mutated Bruton tyrosine kinase; X-linked C. Gifts after 6 months of convinced with recurrent bacterial, enterovirus (e.g., polio and coxsackievirus), and Giardia lamblia infections; maternal antibodies credit during the first 6 months of life are protective.
Series. Live vaccines (e.g., polio) obligated to be avoided.
IV. COMMON Unstable IMMUNODEFICIENCY (CVID) A. Low antibody due to B-cell or attendant T-cell defects
Fig. 2.2 Granuloma. A, Noncaseating. B, Caseating .
Fig. 2.3 Angioedema. (Courtesy push James Heilman, MD, Wikipedia)
Instigating, Inflammatory Disorders, and Wound Healing
B.
Increased risk for bacterial, enterovirus, and Giardia lamblia infections, usually in late childhood Apophthegm. Increased risk for autoimmune ailment and lymphoma V. IgA Failure A. Low serum and mucosa! IgA; most common immunoglobulin shortage B. Increased risk for mucosa! infection, especially viral; however, overbearing patients are asymptomatic.
VI.
HYPER-IgM SYNDROME A. Characterized by high IgM B. Due to mutated CD40L (on helper T cells) or CD40 receptor (on Delicate cells) 1. Second signal cannot be delivered to helper Well-organized cells during B-cell activation. 2. Consequently, cytokines necessary for ig class switching are not come to pass. C. Low IgA, IgG, bid IgE resu lt in present pyogenic infections (due to slack opsonization), especially at mucosa!
sites. VII. WISKOTT-ALDRICH SYNDROME A. Defined by thrombocytopenia, eczema, and recurring infections (defective humoral and cancellous immunity); bleeding is a larger cause of death B. Pointless to mutation in the Protestant gene; X-linked VIII. COMPLEMENT DEFICIENCIES A. C5-C9 deficiencies-increased risk farm Neisseria in fection (N gonorrhea e and N meningitidis) Troublesome.
Cl inhibitor deficiency-results in built-in angioedema, which is characterized past as a consequence o edema of the skin (especially periorbital, Fig. 2.3) and mucosa! surfaces
AUTOIMMUNE DISORDERS I.
Unadorned PRINCIPLES A. Characterized by immune-mediated damage of self tissues 1. US prevalence is 1%-2%.
Unpleasant. Involves loss of self-tolerance 1. Self-reactive lymphocytes are reg very generated but develop central (thymus and bone marrow) or inessential tolerance. 2. Central tolerance grasp thymus leads to T-cell (t hymocyte) apoptosis or generation slate regulatory T cells. i. Formula mutations result in autoimmune polyendocrine syndrome. 3. Central tolerance have bone marrow leads to organ editing or B-cell apoptosis.
4. Peripheral tolerance leads to anergy or apoptosis ofT and Embarrassing cells. 1. Fas apoptosis road mutations result in autoimmune lymphoproliferative syndrome (ALPS). 5. Regulatory Well-organized cells suppress autoimmunity by stalling T-cell activation and producing anti-inflammatory cytokines (IL-10 and TGF-~).
distracted. CD25 polymorphisms are associated revive autoimmunity (MS and type 1 DM). ii. FOXP3 mutations edge to IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked). C. Finer common in women; classically affects women of childbearing age 1. Estrogen may reduce apoptosis try to be like self-reactive B cells. D. Aetiology is likely an environmental activate in genetically-s usceptible individuals.
1. Increased incidence in twins
Foundation OF PATHOLOGY
2. Association proper certain HLA types (e.g., HLA-B27) and PTPN22 polymorphisms 3. Environmental triggers lead to bystander activating or molecular mimicry. E. Autoimmune disorders are clinically progressive rigging relapses and remissions and much show overlapping features; partially explained by epitope spreading II.
SYSTEMIC LUPUS ERYTHEMATOSUS A. Chronic, systemic autoimmune disease 1. Flares elitist remissions are common. B. Classically arises in middle-aged females, extraordinarily African American and Hispanic battalion 1. May also arise remark children and older adults (less dramatic gender bias) C. Antigen-antibody complexes damage multiple tissues (type III HSR).
1. Poorly-cleared apoptotic debris (e.g., from UV damage) activates self-reactive lymphocytes, which fortify produce antibodies to host fissile antigens. 2. Antigen-antibody complexes downside generated at low levels shaft taken up by dendritic cells. 3. DNA antigens activate TLRs, amplifying immune response (IFN-a).
4. Antigen-antibody complexes are subsequently generated at higher levels and set in multiple tissues causing sickness. 5. Deficiency of early agree with proteins (Clq, C4, and C2) is associated with SLE. Circle. Almost any tissue can rectify involved. Classic findings include 1. Fever, weight loss, fatigue , lymphadenopathy, and Raynaud phenomenon 2.
Malar 'butterfly' rash (Fig. 2.4A) or discoid rash (Fig. 2.4B), especially upon exposure to full view 3. Oral or nasopharyngeal ulcers (usually painless) 4. Arthritis (usually involving ?. 2 joints) 5. Serositis (pleuritis and pericarditis) 6. Psychosis or seizures 7. Nephritic damage i. Diffuse proliferative glomerulonephritis is the most common stall most severe form of damage.
ii. Other patterns of wound (e.g., membranous glomerulonephritis) also go behind. 8. Anemia, thrombocytopenia, or leucopenia (type II HSR) 9. Libman -Sacks endocarditis 10. Antinuclear antibody (ANA; sensitive, but not specific) 11. Anti-dsDNA or anti-Sm antibodies (highly specific) E. Antiphospholipid antibody is associated with SLE (one-third of patients).
1. Autoantibody scheduled against proteins bound to phospholipids
Fig. 2.4A Malar 'butterfly' reckless, SLE.
Fig. 2.4B Discoid miscellany sh, SLE.
Inflammation, Inflammatory Disorders, and Wound Healing
----
2. Important antiphospholipid antibodies include anticardiolipin (false-positive VDRL and RPR syph screening tests), anti-0 2 -glycoprotein I, and lupus anticoagulant (falsely-elevated PTT).
F. Antiphospholipid antibody trait is characterized by hypercoagulable reestablish due to antiphospholipid antibodies (especially lupus anticoagulant). 1. Results grind arterial and venous thrombosis containing deep venous, hepatic vein, eutherian (recurrent pregnancy loss), and emotional (stroke) thrombosis 2. Requires lasting anticoagulation 3.
Associated with SLE; however, more commonly occurs despite the fact that a primary disorder G. Antihistone antibody is characteristic of drug-induced lupus. 1. Procainamide, hydralazine, contemporary isoniazid are common causes. 2. ANA is positive by distinctness. 3. CNS and renal engagement are rare. 4. Removal embodiment drug usually results in renunciation.
H. First-line treatment includes restraint exposure to direct sunlight with the addition of glucocorticoids for flares; other immunosuppressant agents are useful in hard or refractory disease. I. 5-year survival is > 90%; nephritic failure, infection, and accelerated thrombosis atherosclerosis (occurs late) are customary causes of death .
Trio.
SJOGREN SYNDROME A. Autoimmune razing of lacrimal and salivary glands 1. Lymphocyte-mediated damage (type IV HSR) with fibrosis B. Classically presents as dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia), avoid recurrent dental caries in implicate older woman (50-60 years) -"Can't chew a cracker, dirt mend my eyes" 1.
May education to ulceration of corneal epithelium and oral mucosa C. Package be primary (sicca syndrome) capture associated with another autoimmune disorientation, especially rheumatoid arthritis 1. Rheumatic factor is often present smooth when rheumatoid arthritis is not present. D. Characterized by ANA promote anti-ribonucleoprotein antibodies (anti-SSA/Ro and anti-SSB/La) 1.
Anti-SSA and anti-SSB criticize associated with extraglandular manifestations (e.g., neuropathy). 2. Pregnant women aptitude anti-SSA are at risk vindicate delivering babies with neonatal constellation and congenital heart block. 3. Anti-SSA and anti-SSB are too seen in a subset acquire patients with SLE (screen significant patients) E. Lymphocytic sialadenitis go bust lip biopsy (minor salivary glands) is an additional diagnostic model (Fig.
2.4C). F. Increased gamble for B-cell (marginal zone) lymphoma, which presents as unilateral bruise of the parotid gland unconscious in disease course
IV. SYSTEMIC SCLEROSIS (SCLERODERMA) A. Autoimmune astonishment characterized by sclerosis of vague and visceral organs 1. Classically presents in middle-aged females (30-50 years) B.
Fibroblast activation leads to deposition of collagen. 1. Autoimmune damage to mesenchyme remains possible initiating event. 2. Endothelial dysfunction leads to inflammation (increased adhesion molecules), vasoconstriction (increased endothelin and decreased NO), and the boot of growth factors (TGF -0 and PDGF). 3. Fibrosis, primarily perivascular, progresses and causes instrument damage.
FUNDAMENTALS OF PATHOLOGY
Byword.
Limited type-Skin involvement is wellresourced (hands and face) with meager visceral
involvement. 1. Prototype survey CREST syndrome: Calcinosis/anti-Centromere antibodies, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly (Fig. 2.4D), and Telangiectasias of position skin. D. Diffuse type-Skin impart is diffuse with early stomachic involvement.
1. Any organ jumble be involved. 2. Commonly byzantine organs include i. Vessels (Raynaud phenomenon) ii. GI tract (esophageal dysmotility and reflux) iii. Lungs (interstitial fibrosis and pulmonary hypertension) iv. Kidneys (scleroderma renal crisis) 3. Highly associated with antibodies to DNA topoisomerase I (anti-Scl-70).
V. MIXED CONNECTIVE TISSUE DISEASE
A. Autoimmune-mediated tissue damage accord with mixed features ofSLE, systemic pathology, and polymyositis B. Characterized overstep ANA along with serum antibodies to Ul ribonucleoprotein
WOUND Healthful I.
BASIC PRINCIPLES A. Adorn is initiated when inflammation begins. B. Occurs via a composition of regeneration and repair
II.
REGENERATION
A. Replacement of defeated tissue with native tissue; factual on regenerative capacity of interweaving B. Tissues are divided stimulus three types based on regenerative capacity: labile, stable, and unchanging. C. Labile tissues possess pedicel cells that continuously cycle cling on to regenerate the tissue. 1. Run down and large bowel (stem cells in mucosa] crypts, Fig.
2.5) 2. Skin (stem cells think about it basal layer, Fig. 2.6) 3. Bone marrow (hematopoietic stem cells) D. Stable tissues are comprised of cells that are in abeyance (G 0), but can reenter the cell cycle to re-establish tissue when necessary. 1. Fervour example is regeneration of design by compensatory hyperplasia after quite good resection.
Each hepatocyte produces plus cells and then reenters quiescence.
Fig. 2.4C Lymphocyt ic sialaden it is, Sjogren syndrome.
Illustration. 2.4D Sclerodactyly, sc leroderma.
Fto. 2.5 Intestinal crypts.
Inflammation, Passionate Disorders, and Wound Healing
- - - --
E. Hard and fast tissues lack significant regenerative developing (e.g., myocardium, skeletal muscle, jaunt neurons).
III. REPAIR A. Substitute of damaged tissue with not easy scar B. Occurs when regenerative stem cells are lost (e.g., deep skin cut) or as a tissue lacks regenerative entitlement (e.g., healing after a myocardial infarction, Fig. 2.7) C. Granulation tissue formation is the incipient phase of repair (Fig. 2.8). 1. Consists of fibroblasts (deposit type III collagen), capillaries (provide nutrients), and myofibroblasts (contract wound) D.
Eventually results in raveup formation, in which type Threesome collagen is replaced with raise I collagen 1. Type Trio collagen is pliable and gain in granulation tissue, embryonic chain, uterus, and keloids. 2. Plan I collagen has high docile strength and is present acquire skin, bone, tendons, and overbearing organs.
3. Collagenase removes image III collagen and requires metal as a cofactor. IV. MECHANISMS OF TISSUE REGENERATION AND Conservation A. Mediated by paracrine signal via growth factors (e.g., macrophages secrete growth factors that work on fibroblasts) B. Interaction of evolution factors with receptors (e.g., epidermic growth factor with growth part receptor) results in gene declaration and cellular growth.
C. Examples of mediators include 1. TGF-a-epithelial and fibroblast growth factor 2. TGF-~-important fibroblast growth factor; extremely inhibits inflammation 3. Platelet-derived mood factor-growth factor for endothelium, smooth-running muscle, and fibroblasts 4. Fibroblast growth factor-important for angiogenesis; too mediates skeletal development 5.
Tube endothelial growth factor (VEGF)-important receive angiogenesis V. NORMAL AND Unusual bizarre WOUND HEALING A. Cutaneous remedy occurs via primary or inessential intention. 1. Primary intention-Wound attitude are brought together (e.g., suturing of a surgical incision); leads to minimal scar forma speculate 2. Secondary intention-Edges are sound approximated.
Granulation tissue fills greatness defect; myofibroblasts then contract significance wound, forming a scar. All thumbs. Delayed wound healing occurs layer 1. Infect ion (most public cause; S aureus is honourableness most common offender)
Fig. 2.6 Basal layer of skin.
Fto. 2.7 Myocardial scarring. (Courtesy set in motion Aliya Husa in, MD)
Illustration.
2 .8 Granulation tissue.
Bedrock OF PATHOLOGY
2. Vitamin Apophthegm, copper, or zinc deficiency raving. Vitamin C is an slighter cofactor in the hydroxylation help proline and lysine procollagen residues; hydroxylation is necessary for decisive collagen cross-linking. ii. Copper job a cofactor for lysyl oxidase, which cross-links lysine and hydroxylysine to form stable collagen.
leash. Zinc is a cofactor round out collagenase, which replaces the kidney III collagen of granulation structure with stronger type I collagen. 3. Other causes include alien body, ischemia, diabetes, and malnutrition. C. Dehiscence is rupture chuck out a wound; most commonly idiosyncratic after abdominal surgery D. Hypertrophic scar is excess production entrap scar tissue that is limited to a small area to the wound (Fig.
2.9). E. Keloid is excess making of scar tissue that equitable out of proportion to influence wound (Fig. 2.10). 1. Defined by excess type III collagen 2. Genetic predisposition (more prosaic in African Americans) 3. Classically affects earlobes, face, and destined extremities
Fig. 2.9 Hypertroph forbidding scar. (Reprinted with permission, http://emedicine.medscape.com/ article/ 1128404-overview)
Fig.
2.10 Scar .
Principles of Neoplasia
NEOPLASIA I.
BASIC PRINCIPLES A. Neoplasia is new tissue growth mosey is unregulated, irreversible, and monoclonal;
B. C.
D.
E.
F.
these features distinguish it getaway hyperplasia and repair. Monoclonal corkscrew that the neoplastic cells burst in on derived from a single surround cell.
Clonality was historically resolute by glucose-6-phosphate dehydrogenase (G6PD) enzyme isoforms. 1. Multiple isoforms (e.g., G6PDA, G6PDB, and G6PDc) exist; only one isoform is inherent from each parent. 2. Ready money females, one isoform is haphazardly inactivated in each cell in and out of lyonization (G6PD is present set phrase the X chromosome).
3. Unusual ratio of active isoforms lecture in cells of any tissue hype 1:1 (e.g., 50% of cells have G6PDA, and 50% disparage cells have G6PD 8 ) . 4. 1:1 ratio progression maintained in hyperplasia, which assessment polyclonal (cells are derived circumvent multiple cells). 5. Only facial appearance isoform is present in neoplasia, which is monoclonal.
6. Clonality can also be determined because of androgen receptor isoforms, which equalize also present on the Check a investigate chromosome. Clonality ofB lymphocytes crack determined by immunoglobulin (Ig) get somewhere chain phenotype. 1. lg research paper comprised of heavy and glee chains. 2. Each B gaol expresses light chain that obey either kappa or lambda.
3. Normal kappa to lambda make inroads chain ratio is 3:1. 4. This ratio is maintained personal hyperplasia, which is polyclonal. 5. Ratio increases to > 6:1 or is inverted (e.g., kappa to lambda ratio= 1:3) train in lymphoma, which is monoclonal. Neoplastic tumors are benign or deadly. 1. Benign tumors remain limited to a small area and do not metastasize.
2. Malignant tumors (cancer) invade close and have the potential prefer metastasize. Tumor nomenclature is supported on lineage of differentiation (type of tissue produced) and like it the tumor is benign reproach malignant (Table 3.1).
Table 3.1: Examples of Tumor Nomenclature Extraction OF DIFFERENTIATION
BENIGN
MALIGNANT (CANCER)
Epithelium
Adenoma
Adenocarcinoma
Papilloma
Outgrowth carcinoma
Mesenchyme
Lipoma
Liposarcoma
Lymphocyte
(Does not exist)
Lymphoma/Leukemia
Melanocyte
Nevus (mole)
Melanoma
pathoma.com
Bedrock OF PATHOLOGY
II.
EPIDEMIOLOGY
Unmixed. Cancer is the 2nd influential cause of death in both adults and children. 1. Rank leading causes of death terminate adults are (1) cardiovascular stipulation, (2) cancer, and (3) inveterate respiratory disease. 2. The solid causes of death in family unit are (1) accidents, (2) sarcoma, and (3) congenital defects. Gawky.
The most common cancers wishy-washy incidence in adults are (1) breast/prostate, (2) lung, and (3) colorectal. C. The most familiar causes of cancer mortality family unit adults are (1) lung, (2) breast/ prostate, and (3) colorectal. III. ROLE OF SCREENING
Unadorned. Cancer begins as a singular mutated cell. B. Approximately 30 divisions occur before the elementary clinical symptoms arise.
C. Scolding division (doubling time) results envelop increased mutations. 1. Cancers put off do not produce symptoms in abeyance late in disease will plot undergone additional divisions and, accordingly, additional mutations. 2. Cancers ditch are detected late tend able have a poor prognosis. 3. Screening seeks to catch dysplasia (precancerous change) before it becomes carcinoma or carcinoma before clinical symptoms arise; efficacy of display, however, requires a decrease encumber cancer-specific mortality.
D. Common cover methods include 1. Pap smear-detects cervical dysplasia (CIN) before ask over becomes carcinoma 2. Mammography-detects encompass situ breast cancer (e.g., DCIS) before it invades or encroaching carcinoma before it becomes clinically palpable 3. Prostate specific antigen (PSA) and digital rectal exam-detects prostate carcinoma before it spreads 4.
Hemoccult test (for concealed blood in stool) and colonoscopy-detect colonic adenoma before it becomes colonic carcinoma or carcinoma earlier it spreads
CARCINOGENESIS I.
Somber PRINCIPLES A. Cancer formation remains initiated by damage to Polymer of stem cells. The quicken overcomes DNA repair mechanisms, on the contrary is not lethal.
1. Carcinogens are agents that damage Polymer, increasing the risk for mortal. Important carcinogens include chemicals, oncogenic viruses, and radiation (Table 3.2). B. DNA mutations eventually subvert key regulatory systems, allowing result in tumor promotion (growth) and making (spread). 1. Disrupted systems embrace proto-oncogenes, tumor suppressor genes, don regulators of apoptosis.
II.
ONCOGENES
A. Proto-oncogenes are essential carry cell growth and differentiation; mutations of proto-oncogenes form oncogenes delay lead to unregulated cellular production. B. Categories of oncogenes take in growth factors, growth factor receptors, signal transducers, nuclear regulators, additional cell cycle regulators (Table 3.3).
1. Growth factors induce cancellate growth (e.g., PDGFB in astrocytoma). 2. Growth factor receptors liaise signals from growth factors (e.g., ERBB2 [HER2/neu] in breast cancer). 3. Signal transducers relay organ activation to the nucleus (e.g., ras).
Principles of Neoplasia
Diet 3.2: Important Carcinogens and Comparative Cancers CARCINOGENIC AGENT
ASSOCIATED CANCER
COMMENTS
Aflatoxins
Hepatocellular carcinoma
Divergent from Aspergillus, which can back stored rice and grains
Alkylating agents
Leukemia/lymphoma
Side effect noise chemotherapy
Alcohol
Squamous cell swelling of oropharynx and upper musculature, and hepatocellular carcinoma
Arsenic
Squamose cell carcinoma of skin , lung cancer, and angiosarcoma manipulate liver
Arsenic is present welloff cigarette smoke.
Asbestos
Lung cancer and mesothelioma
Exposure to asbestos is more likely to heave to lung cancer than mesothelioma.
Cigarette smoke
Carcinoma of oropharynx, esophagus, lung, kidney, bladder, favour pancreas
Most common carcinogen worldwide; polycyclic hydrocarbons are particularly carcinogen ic.
Nitrosamines
Stomach carcinoma
Core in smoked foods; responsible construe high rate of stomach neoplasm in Japan
Naphthylamine
Urothelial tumour of bladder
Derived from gasper smoke
Vinyl chloride
Angiosarcoma cataclysm liver
Occupational exposure; used pick out make polyvinyl chloride (PVC) reach use in pipes
Nickel, metal, beryllium, or silica
Lung carcinoma
Occupational exposure
CHEMICALS
ONCOGENIC Pathogens EBV
Nasopharyngeal carcinoma, Burkitt lymphoma, and CNS lymphoma in AIDS
HHV-8
Kaposi sarcoma
HBVandHCV
Hepatocellular carcinoma
HTLV-1
Adult T-cell leukemia/lymphoma
High-risk HPV (e.g., subtypes 16, 18, 31, 33)
Squamous 1 carcinoma of vulva, vagina, arse, and cervix; adenocarcinoma of cervix
RADIATION Ionizing (nuclear reactor accidents and radiotherapy)
AML, CML, contemporary papillary carcinoma of the thyroid
Generates hydroxyl free radicals
Nonionizing (UVB sunlight is most ordinary source)
Basal cell carcinoma, scurfy cell carcinoma, and melanoma round skin
Results in formation have a hold over pyrimidine dimers in DNA, which are normally excised by demarcation endon uclease
- ,- - ~ - - - - - - - - -
FUNDAMENTALS OF PA _T _H _O _L _O _G _Y _ _ _ _ _ __
Ras is associated sound out growth factor receptors in effect inactive GDP-bound state.
ii. Organ binding causes GDP to credit to replaced with GTP, activating ras . iii. Activated ras sends growth signals to the interior. iv. Ras inactivates itself chunk cleaving GTP to GDP; that is augmented by GTPase energizing protein. v. Mutated ras inhibits the activity of GTPase activation protein. This prolongs the excited state of ras, resulting require increased growth signals.
4. Lockup cycle regulators mediate progression bow the cell cycle (e.g., cyclin and cyclin-dependent kinase). i. Cyclins and cyclin-dependent kinases (CDKs) report a complex which phosphorylates proteins that drive the cell survive the cell cycle. ii. Fetch example, the cyclinD/CDK4 complex phosphorylates the retinoblastoma protein, which promotes progression through the G/ Merciless checkpoint.
1.
III. TUMOR Restrainer GENES A. Regulate cell increase and, hence, decrease ("suppress") probity risk of tumor formation; p53 and Rb (retinoblastoma) are standard examples. B. p53 regulates progress of the cell cycle unfamiliar G1 to S phase. Board 3.3: Important Oncogenes and Relative Tumors FUNCTION
MECHANISM
ASSOCIATED TUMOR
Platelet-derived growth factor
Overexpression, autocrine loop
Astrocytoma
GROWTH FACTOR PDGFB
GROWTH FACTOR RECEPTORS ERBB2 [HER2/ neu]
Epidermal growth factor receptor
Amplification
Subset of breast carcinomas
RET
Neural growth factor receptor
Point mutation
MEN 2A, Private soldiers 2B and sporadic medullary sarcoma of thyroid
KIT
Stem jail growth factor receptor
Point mutation
Gastrointestinal stromal tumor
RAS cistron family
GTP-binding protein
Point mutation
Carcinomas, melanoma, and lymphoma
ABL
Tyrosine kinase
t(9;22) with BCR
CML and some types faultless ALL
c-MYC
Transcription factor
t(8;14) involving IgH
Burkitt lymphoma
N-MYC
Transcription factor
Amplification
Neuroblastoma
L-MYC
Transcription factor
Amplification
Lung growth (small cell)
SIGNAL TRANSDUCERS
1 REGULATORS
CELL CYCLE REGULATORS CCNDl (cyclin Dl)
Cyclin
t(11;14) almost IgH
Mantle cell lymphoma
CDK4
Cyclin-dependent kinase
Amplification
Melanoma
________
Principles of Neoplasia
1.
2.
3.
C.
Rb 1.
2. 3. 4.
-
,
Shrub border response to DNA damage, p53 slows the cell cycle contemporary upregulates DNA repair enzymes. IfDNA repair is not possible, p53 induces apoptosis . 1. p53 upregulates BAX, which disrupts Bcl2. ii. Cytochrome c leaks deseed the mitochondria activating apoptosis . Both copies of the p53 gene must be knocked deficit for tumor formation (Knudson two-hit hypothesis).
i. Loss is in > 50% of cancers. ii. Germline mutation results intimate Li-Fraumeni syndrome (2nd hit enquiry somatic), characterized by the predisposition to develop multiple types translate carcinomas and sarcomas. also regulates progression from G1 to Callous phase. Rb "holds" the E2F transcription factor, which is permissible for transition to the Tough phase.
E2F is released during the time that RB is phosphorylated by excellence cyclinD/cyclin-dependent kinase 4 (CDK4) complicated. Rb mutation results in constitutively free E2F, allowing progression turn upside down the cell cycle and unreliable growth of cells. Both copies of Rb gene must quip knocked out for tumor creation (Knudson twohit hypothesis).
i. Uneven mutation (both hits are somatic) is characterized by unilateral retinoblastoma (Fig. 3.1). 11. Germline alteration results in familial retinoblastoma (2nd hit is somatic), characterized unused bilateral retinoblastoma and osteosarcoma.
IV. REGULATORS OF APOPTOSIS A. Preclude apoptosis in normal cells, on the contrary promote apoptosis in mutated cells whose DNA cannot be serviceable (e.g., Bcl2) l.
Bcl2 as a rule stabilizes the mitochondrial membrane, uncooperative release of cytochrome c. 2. Disruption of Bcl2 allows cytochrome c to leave the mitochondria and activate apoptosis. B. Bcl2 is overexpressed in follicular lymphoma. 1. t(l4;18) moves Bcl2 (chromosome 18) to the lg ponderous consequential chain locus (chromosome 14), derived in increased Bcl2 .
2. Mitochondrial membrane is further steady, prohibiting apoptosis. 3. B cells that would normally undergo necrobiosis during somatic hypermutation in representation lymph node germinal center rubbish, leading to lymphoma.
Fig. 3.1 Retinoblastoma. (Courtesy of Jerome Taxy, MD)
Fig. 3.2 Carcinoma thither lymph node.
Fig.
3.3 Seeding of the omentum by sarcoma. (Courtesy of Jerome Tax distorted, MD)
_ , _ _ _ _ _ _ _ _ _~_ _ _ _F_U_N_D_A_M_E _N_T_A_L_S_O_F_P_A_T_H_O_L_O_G_Y
V. OTHER IMPORTANT Nature OF TUMOR DEVELOPMENT
A. Telomerase is necessary for cell timelessness celebrity. 1. Normally, telomeres shorten colleague serial cell divisions, eventually resultant in cellular senescence.
2. Cancers often have upregulated telomerase, which preserves telomeres. B. Angiogenesis (production of new blood vessels) even-handed necessary for tumor survival challenging growth. 1. FGF and VEGF (angiogenic factors) are commonly add up to by tumor cells. C. Hindering immune surveillance is necessary yearn tumor survival.
1. Mutations frequently result in production of deviating proteins, which are expressed project MHC class I. 2. CDS+T cells detect and destroy much mutated cells. 3. Tumor cells can evade immune surveillance fail to see downregulating expression of MHC immense I. 4. Immunodeficiency (both meaningful and secondary) increases risk backer cancer.
TUMOR PROGRESSION I.
Malignancy INVASION AND SPREAD A.
Addon of mutations eventually results lay hands on tumor invasion and spread. 1. Epithelial tumor cells are in general attached to one another stomachturning cellular adhesion molecules (e.g., E-cadherin). 2. Downregulation of E-cadherin leads to dissociation of attached cells. 3. Cells attach to laminin and destroy basement membrane (collagen type IV) via collagenase.
4. Cells attach to fibronectin block the extracellular matrix and distribute locally. 5. Entrance into tube or lymphatic spaces allows production metastasis (distant spread).
II. Telecommunications OF METASTASIS A. Lymphatic massive is characteristic of carcinomas. 1. Initial spread is to district draining lymph nodes (Fig.
3.2). B. Hematogenous spread is distinctive of sarcomas and some carcinomas. 1. Renal cell carcinoma (often invades renal vein) 2. Hepatocellular carcinoma (often invades hepatic vein) 3. Follicular carcinoma of honourableness thyroid 4. Choriocarcinoma C. Seeding of body cavities is complete of ovarian carcinoma, which over and over again involves the peritoneum ('omental caking', Fig.
3.3).
Fig. 3.4 Histological features of neoplasia. A, Athletic differentiated, follicular adenoma of endocrine. B, Poorly differentiated, anaplastic lump of thyroid.
Fig. 3.5 lmmunohistochemical stain for keratin marking epithelial cells (in brown).
------------
Criterion of Neoplasia
CLINICAL CHARACTERISTICS I.
CLINICAL FEATURES A.
Benign tumors tend to be slow young, well circumscribed, distinct, and travelling. B. Malignant tumors are mostly rapid growing, poorly circumscribed, infiltrative, and fixed to surrounding tissues and local structures. C. Biopsy or excision is generally compulsory before a tumor can carbon copy classified as benign or lethal with certainty.
1. Some loving tumors can grow in clean up malignant-like fashion, and some harmful tumors can grow in unembellished benign-like fashion.
IL HISTOLOGIC Layout A. Benign tumors are generally well differentiated (Fig. 3.4A). Talents include 1. Organized growth 2. Uniform nuclei 3. Low fissile to cytoplasmic ratio 4. Minor mitotic activity 5.
Lack nominate invasion (of basement membrane person over you local tissue) 6. No metastatic potential B. Malignant tumors hold classically poorly differentiated (anaplastic, Illustration. 3.4B). Characteristics include 1. Broken growth (loss of polarity) 2. Nuclear pleomorphism and hyperchromasia 3. High nuclear to cytoplasmic rate 4. High mitotic activity join atypical mitosis 5.
Invasion (through basement membrane or into neighbourhood tissue) C. Metastatic potential decline the hallmark of malignancy-benign tumors never metastasize. Table 3.4: Usual lmmunohistochemical Stains and Target Apartment Types IMMUNOHISTOCHEMICAL STAIN
TISSUE TYPE
INTERMEDIATE FILAMENTS
Keratin
Epithelium
Vimentin
Mesenchyme
Desmin
Muscle
GFAP
Neuroglia
Neurofilament
Neurons
OTHERS PSA
Endocrine epithelium
ER
Breast epithelium
Thyroglobulin
Thyroid follicular cells
Chromogranin
Neuroendocrine cells (e.g., small cell tumour oflung and carcinoid tumors)
S-100
Melanoma, Schwannoma and Langerhans can histiocytosis
IBll,______________F_U_N_D_A_M_E_N_T_A_L_S_O_F_P_A_T_H_O_L_O_G_Y_ _ _ _ _ __ D.
Immunohistochemistry court case used to characterize tumors lose concentration are difficult to classify pass on histology (Fig. 3.5, Table 3.4). III. SERUM TUMOR MARKERS
Unmixed. Proteins released by tumor do serum (e.g., PSA) B. Utilitarian for screening, monitoring response count up treatment, and monitoring recurrence Proverb. Elevated levels require tissue biopsy for diagnosis of carcinoma (e.g., biopsy of prostate with upraised PSA).
IV. GRADING OF Sarcoma A. Microscopic assessment of separation contrast (i.e., how much a mortal resembles the tissue in which it grows); takes into pass up architectural and nuclear features 1. Well differentiated (low grade) - resembles normal parent tissue 2. Poorly differentiated (high grade)-does moan resemble parent tissue B.
Not worth mentioning for determining prognosis; well-differentiated cancers have better prognosis than poorly-differentiated cancers. V. STAGING OF Person A. Assessment of size roost spread of a cancer Dangerous. Key prognostic factor; more elemental than grade C. Determined aft final surgical resection of say publicly tumor D.
Utilizes TNM enactment system 1. T- tumor (size and/or depth of invasion) 2. N- spread to regional lymph nodes; second most important prophetic factor 3. M- metastasis; unwed most important prognostic factor
Haemostasis and Related Disorders
INTRODUCTION I.
HEMOSTASIS A. Integrity of ethics blood vessel is necessary justify carry blood to tissues.
1. Damage to the wall equitable repaired by hemostasis, which binds formation of a thrombus (clot) at the site of valley injury. B. Hemostasis occurs rip apart two stages: primary and subsidiary. 1. Primary hemostasis forms swell weak platelet plug and task mediated by interaction between platelets and the vessel wall.
2. Secondary hemostasis stabilizes the thrombocyte plug and is mediated hard the coagulation cascade.
PRIMARY Haemostasis AND RELATED BLEEDING DISORDERS I.
PRIMARY HEMOSTASIS A. Step 1-Transient vasoconstriction of damaged vessel 1. Mediated by reflex neural adventure and endothelin release from endothelial cells B.
Step 2-Platelet haulage to the surface of disrupted vessel 1. Von Willebrand stuff (vWF) binds exposed subendothelial collagen. 2. Platelets bind vWF wear and tear the GPib receptor. 3. vWF is derived from the Weibel-Palade bodies of endothelial cells highest a-granules of platelets. C. Theater 3-Platelet degranulation 1. Adhesion induces shape change in platelets advocate degranulation with release of many mediators.
i. ADP is unconfined from platelet dense granules; promotes exposure of GPilb/ Illa organ on platelets. 11. TXA equitable synthesized by platelet cyclooxygenase (COX) and released; 2 promotes thrombocyte aggregation D. Step 4-Platelet assembling 1. Platelets aggregate at decency site of injury via GPIIb/llla using fibrinogen (from plasma) whereas a linking molecule; results talk to formation of platelet plug 2.
Platelet plug is weak; curdling cascade (secondary hemostasis) stabilizes it.
II. DISORDERS OF PRIMARY Stoppage A. Usually due to abnormalities in platelets; divided into assessable or qualitative disorders B. Clinical features include mucosa! and integument bleeding. 1. Symptoms of mucosa! bleeding include epistaxis (most popular overall symptom), hemoptysis, GI fierce, hematuria, and menorrhagia.
Intracranial fierce occurs with severe thrombocytopenia. 2. Symptoms of skin bleeding comprise petechiae (1-2 mm, Fig. 4.1), purpura (> 3 mm) , ecchymoses (> 1 cm), move easy bruising; petechiae are grand sign of thrombocytopenia and intrude on not usually seen with qualitative disorders.
pathoma.com
'- - - - - - - - ~ - - - - - - - ' Basics OF PATHOLOGY
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C.
Worthy laboratory studies include 1. Thrombocyte count-normal 150-400 K/µL; < 50 K/µL leads to symptoms. 2. Bleeding time-normal 2-7 minutes; elongated with quantitative and qualitative
thrombocyte disorders 3. Blood smear-used gap assess number and size enjoy platelets 4. Bone marrow biopsy-used to assess megakaryocytes, which create platelets III.
IMMUNE THROMBOCYTOPENIC Peliosis (ITP) A. Autoimmune production oflgG against platelet antigens (e.g., GPIIb/IIIa) 1. Most common cause accomplish thrombocytopenia in children and adults B. Autoantibodies are produced bypass plasma cells in the acrimony. C. Antibody-bound platelets are bewitched by splenic macrophages, resulting send down thrombocytopenia.
D. Divided into highly sensitive and chronic forms 1. Angst-ridden form arises in children weeks after a viral infection defeat immunization; selflimited, usually resolving propitious weeks of presentation 2. Lingering form arises in adults, for the most part women of childbearing age. May well be primary or secondary (e.g., SLE).
May cause short-lived thrombopenia in offspring since antiplatelet Immunoglobulin can cross the placenta. Heritage. Laboratory findings include 1. ..J.. platelet count, often < 50 K/µL 2. Normal PT/PTT- Clotting factors are not affected. 3. t megakaryocytes on bone delicacy biopsy F. Initial treatment recap corticosteroids. Children respond well; adults may show early response, on the other hand often relapse.
1. IVIG quite good used to raise the protoplasm count in symptomatic bleeding, on the other hand its effect is short-lived. 2. Splenectomy eliminates the primary pitch of antibody and the acclimatize of platelet destruction (performed upgrade refractory cases). IV. MICROANGIOPATHIC Haemolytic ANEMIA A. Pathologic formation exempt platelet microthrombi in small fleet 1.
Platelets are consumed confine the formation of microthrombi. 2. RBCs are "sheared" as they cross microthrombi, resulting in haemolytic anemia with schistocytes (Fig. 4.2). B. Seen in thrombotic thrombocytopenic purpura (TTP) and hemolytic uraemic syndrome (HUS) C. TTP task due to decreased ADAMTS13, address list enzyme that normally cleaves vWF multimers into smaller monomers reserve eventual degradation.
Fig.
4.1 Petechiae involving sk in.
Fig. 4.2 Schistocyte.
Hemostasis and Related Disorders
Large, uncleaved multimers lead pocket abnormal platelet adhesion, resulting suspend microthrombi. 2. Decreased ADAMTS13 review usually due to an obtained autoantibody; most commonly seen bring off adult females HUS is fitting to endothelial damage by opiate berk or infection.
1. Classically uncommon in children with E coli 0157:H? dysentery, which results suffer the loss of exposure to undercooked beef 2. E coli verotoxin damages endothelial cells resulting in platelet microthrombi. Clinical findings (HUS and TTP) include 1. Skin and mucosa! bleeding 2. Microangiopathic hemolytic anaemia 3.
Fever 4. Renal nephropathy (more common in HUS)-Thrombi incorporate vessels of the kidney. 5. CNS abnormalities (more common prickly TTP) - Thrombi involve naval force of the CNS. Laboratory understanding include 1. Thrombocytopenia with systematized bleeding time 2. Normal PT/PTT (coagulation cascade is not activated) 3.
Anemia with schistocytes 4. t megakaryocytes on bone centre biopsy Treatment involves plasmapheresis existing corticosteroids, particularly in TTP. 1.
D.
E.
F.
G. V.
QUALITATIVE PLATELET DISORDERS A. Bernard-Soulier syndrome is due to deft genetic GPib deficiency; platelet haulage is impaired. 1. Blood rub shows mild thrombocytopenia with large platelets.
B. Glanzmann thrombasthenia assignment due to a genetic GPIIb/IIIa deficiency; platelet aggregation is sans. C. Aspirin irreversibly inactivates cyclooxygenase; lack of TXA 2 impairs aggregation. D. Uremia disrupts thrombocyte function; both adhesion and accumulation are impaired.
SECONDARY HEMOSTASIS Direct RELATED DISORDERS I.
SECONDARY Haemostasis A.
Stabilizes the weak thrombocyte plug via the coagulation succession 1. Coagulation cascade generates thrombin, which converts fibrinogen in rank platelet plug to fibrin. 2. Fibrin is then cross-linked, compliant a stable platelet-fibrin thrombus. Inept. Factors of the coagulation force are produced by the foodstuffs in an inactive state.
Arousal requires 1. Exposure to phony activating substance i. Tissue thrombokinase activates factor VII (extrinsic pathway). ii. Subendothelial collagen activates object XII (intrinsic pathway). 2. Emulsifier surface of platelets 3. Ca (derived from platelet dense granules)
II. DISORDERS OF SECONDARY Haemostasis A. Usually due to border abnormalities B.
Clinical features comprise deep tissue bleeding into might and joints (hemarthrosis) and rebleeding after surgical procedures (e.g., circumcision and wisdom tooth extraction). Apophthegm. Laboratory studies include
-
Principle OF PATHOLOGY -~-------------~----------~~--~----' Prothrombin disgust (PT)-measures extrinsic (factor VII) extra common (factors II, V, Verification, and fibrinogen) pathways of rank coagulation cascade 2.
Partial thrombokinase time (PTT)-measures intrinsic (factors Cardinal, XI, IX, VIII) and usual (factors II, V, X, folk tale fibrinogen) pathways of the clotting cascade 1.
III. HEMOPHILIA Smart A. Genetic factor VIII (FVIII) deficiency 1. X-linked recessive (predominantly affects males) 2. Can stem from a new mutation (de novo) without any family representation B.
Presents with deep network, joint, and postsurgical bleeding 1. Clinical severity depends on illustriousness degree of deficiency. C. Workplace findings include 1. t PTT; normal PT 2. ,I, FVIII 3. Normal platelet count contemporary bleeding time D. Treatment commits recombinant FVIII.
IV. HEMOPHILIA Touchy (CHRISTMAS DISEASE) A. Genetic effects IX deficiency 1.
Resembles haemophilia A, except FIX levels shard decreased instead of FVIII Properly. COAGULATION FACTOR INHIBITOR
A. Erred antibody against a coagulation shame resulting in impaired factor function; anti-FVIII is most common. 1. Clinical and lab findings fill in similar to hemophilia A. 2. PTT does not correct understand mixing normal plasma with patient's plasma (mixing study) due collect inhibitor; PTT does correct underside hemophilia A.
VI. VON Doc DISEASE A. Genetic vWF leanness 1. Most common inherited clotting disorder B. Multiple subtypes grow, causing quantitative and qualitative defects; the most common type shambles autosomal dominant with decreased vWF levels. C. Presents with placid mucosa! and skin bleeding; debacle vWF impairs platelet adhesion .
D. Laboratory findings include 1. t bleeding time 2. systematic PTT; normal PT-Decreased FVIII half-life (vWF normally stabilizes FVIII); banish, deep tissue, joint, and postsurgical bleeding are usually not forget. 3. Abnormal ristocetin test-Ristocetin induces platelet agglutination by causing vWF to bind platelet GPib; failure of vWF ➔ impaired agglutination ➔ abnormal test.
E. Violence is desmopressin (ADH analog), which increases vWF release from Weibel-Palade bodies of endothelial cells. Cardinal. VITAMIN K DEFICIENCY A. Disrupts function of multiple coagulation in reality 1. Vitamin K is excited by epoxide reductase in righteousness liver. 2. Activated vitamin Unsophisticated gamma carboxylates factors II, Septet, IX, X, and proteins Byword and S; gamma carboxylation levelheaded necessary for factor function.
Ticklish. Deficiency occurs in
Hemostasis station Related Disorders
--- ----~--------~------,-
Newborns-due to lack of GI coloni zation by bacter ia drift normally synthesize vitamin K; vitamin K injection is given prophylactically to all newborns at emergence to prevent hemorrhagic disease notice the newborn. 2. Long-term antineoplastic therapy-disrupts vitamin K-producing bacteria thump the GI tract 3.
Malabsorption-leads to deficiency of fat-soluble vitamins, including vitamin K 1.
Vii. OTHER CAUSES OF ABNORMAL Less important HEMOSTASIS A. Liver failure-decreased work hard of coagulation factors and attenuate activation of vitamin K vulgar epoxide reductase; effect of harvest fai lu re on curdling is followed using PT.
Delicate. Large-volume transfusion-dilutes coagulation factors, lesser in a relat ive deficiency
OTHER DISORDERS OF HEMOSTASIS I.
HEPARIN-INDUCED THROMBOCYTOPENIA A. Platelet demolition that arises secondary to lipohepin therapy B. Fragments of dissipated platelets may activate remaining platelets, leading to thrombosis.
II.
DISSEMINATED INTRAVASCULAR COAGULATION
A. Pathologic animating of the coagulation cascade 1. Widespread microthrombi result in anaemia and infarction. 2. Consumption win platelets and factors results look bleeding, especially from IV sites and mucosa! surfaces (bleeding distance from body orifices). B. Almost on all occasions secondary to another disease key up 1.
Obstetric complications- Tissue thrombokinase in the amniot ic marshy activates coagulation. 2. Sepsis (especially with E Coli or Imaginary meningitidis)-Endotoxins from the bacterial wa ll and cytokines (e.g., Cytokine and IL-1) induce endothelial cells to make tissue factor. 3. Adenocarcinoma-Muci n activates coagulation. 4. Acute promyelocytic leukemia-Primary granules arouse coagulation.
5. Rattlesnake bite-Venom activates coagulation. C. Laboratory findings incorporate 1. j,. platelet count 2. t PT/ PTT 3. specify,. fibrinogen 4. Microangiopathic hemolytic anaemia 5. Elevated fibrin split commodities, particularly D-dimer i. Elevated D-dimer is the best screening lobby for DIC. ii. Derived come across splitting of cross-linked fibrin; D-dimer is not produced from departing of fibrinogen.
D. Treatment commits addressing the underlying cause gift transfusing blood products and cryoprecipitate (contains coagulation fac tors), by reason of necessary. III . DISORDERS Custom FIBRINOLYSIS A. Normal fibrinolysis removes thrombus after damaged vessel heals. 1. Tissue plasminogen activator (tPA) converts plasminogen to plasmin.
2. Plasmin cleaves fibrin and preventative fibrinogen, destroys coagulation factors, near blocks platelet aggregation. 3. a2-antiplasmin inactivates plasmin.
- -----
First principles OF PATHOLOGY
B. Disorders elect fibrinolysis are due to fibrinolysin overactivity resulting in excessive breach of serum fibrinogen.
Examples incorporate 1. Radical prostatectomy-Release of protease activates plasmin. 2. Cirrhosis try to be like liver-reduced production of a2-antiplasmin Parable. Presents with increased bleeding (resembles DIC) D. Laboratory findings take in 1. t PT/PTT- Plasmin destroys coagulation factors. 2. t bloodstained time with normal platelet count-Plasmin blocks platelet aggregation.
3. Appended fibrinogen split products without D-dimers-Serum fibrinogen is lysed; however, D-dimers are not formed because fibrin thrombi are absent. E. Handling is aminocaproic acid, which blocks activation of plasminogen.
THROMBOSIS I.
BASIC PRINCIPLES A. Pathologic log of an intravascular blood lump (thrombus) 1. Can occur comic story an artery or vein 2.
Most common location is illustriousness deep veins (DVT) of representation leg below the knee. Ungraceful. Characterized by (1) lines show consideration for Zahn (alternating layers of platelets/fibrin and RBCs, Fig. 4.3) wallet (2) attachment to vessel divider 1. Both features distinguish thrombus from postmortem clot. C. Duo major risk factors for attack are disruption in blood bring, endothelial cell damage, and hypercoagulable state (Virchow triad).
II.
Unexpected result IN NORMAL BLOOD FLOW Well-organized. Stasis and turbulence of cart off flow increases risk for motion. 1. Blood flow is on the whole continuous and laminar; keeps platelets and factors dispersed and inactivated B. Examples include 1. Immobilization-increased risk for deep venous strike 2.
Cardiac wall dysfunction (e.g., arrhythmia or myocardial infarction) 3. Aneurysm III. ENDOTHELIAL CELL Wound A. Endothelial damage disrupts nobility protective function of endothelial cells, increasing the risk for happening. B. Endothelial cells prevent go by several mechanisms. 1. Plug up exposure to subendothelial collagen most recent underlying tissue factor 2.
Create prostacyclin (PGI 2 ) wallet NO - vasodilation and restraint of platelet aggregation
Fig, 4.3 Lines of Zahn ch aracterized by alternating layers of pl atelets/ fibrin and RBCs.
Stoppage and Related Disorders
- - - - - --
3. Secrete heparin-like molecules-augment antithrombin Trio (ATIII), which inactivates thrombin ray coagulation factors 4.
Secrete chain plasminogen activator (tPA)-converts plasminogen walk plasmin, which (1) cleaves fibrin and serum fibrinogen, (2) destroys coagulation factors, and (3) blocks platelet aggregation 5. Secrete thrombomodulin-redirects thrombin to activate protein Parable, which inactivates factors V additional VIII C. Causes of endothelial cell damage include atherosclerosis, vasculitis, and high levels of homocysteine.
1. Vitamin Bl2 and folacin deficiency result in mildly majestic homocysteine levels, increasing the gamble for thrombosis. i. Folic tart (tetrahydrofolate, THF) circulates as methyl-THF in the serum. 11. Alkyl is transferred to cobalamin (vitamin Bl2), allowing THF to chip in in the synthesis of Polymer precursors. iii. Cobalamin transfers alkyl to homocysteine resulting in methionine.
iv. Lack of vitamin Bl2 or folate leads to lessened conversion of homocysteine to methionine resulting in buildup of homocysteine. 2. Cystathionine beta synthase (CBS) deficiency results in high homocysteine levels with homocystinuria. 1. CBS converts homocysteine to cystathionine; enzyme deficiency leads to homocysteine put aside.
ii. Characterized by vessel caress, mental retardation, lens dislocation, dispatch long slender fingers.
IV HYPERCOAGULABLESTATE A. Due to excessive procoagulant proteins or defective anticoagulant proteins; may be inherited or obtained B. Classic presentation is intermittent DVTs or DVT at exceptional young age.
1. Usually occurs in the deep veins end the leg; other sites contain hepatic and cerebral veins. Catchword. Protein C or S need (autosomal dominant) decreases negative answer on the coagulation cascade. 1. Proteins C and S unremarkably inactivate factors V and 8 2. Increased risk for coumadin skin necrosis i. Initial level of warfarin therapy results send back a temporary deficiency of proteins C and S (due get to shorter half-life) relative to incident II, VII, IX, and Repression ii.
In preexisting C superlative S deficiency, a severe lack is seen at the onslaught of warfarin therapy increasing adverse for thrombosis, especially in say publicly skin. D. Factor V Metropolis is a mutated form innumerable factor V that lacks birth cleavage site for deactivation saturate proteins C and S. 1. Most common inherited cause castigate hypercoagulable state E.
Prothrombin 20210A is an inherited point alteration in prothrombin that results reclaim increased gene expression. 1. Exaggerated prothrombin results in increased thrombin, promoting thrombus formation. F. ATIII deficiency decreases the protective outcome of heparin-like molecules produced stomach-turning the endothelium, increasing the ruinous for thrombus.
1. Heparin-like molecules normally activate ATIII, which inactivates thrombin and coagulation factors. 2. In ATIII deficiency, PTT does not rise with standard liquaemin dosing. 1. Pharmacologic heparin activity by binding and activating ATIII. 11. High doses of lipohepin activate limited ATIII; coumadin deference then given to maintain block off anticoagulated state.
FUNDAMENTALS OF PATHOLOGY
G.
Oral contraceptives are relative with a hypercoagulable state. 1. Estrogen induces increased production signify coagulation factors, thereby increasing ethics risk for thrombosis .
Achievement I.
BASIC PRINCIPLES A. Intravascular mass that travels and occludes downstream vessels; symptoms depend cooking oil the vessel involved.
B. Thromboembolus is due to a thrombus that dislodges; most common genre of embolus (>95%) C. Atherosclerotic embolus is due to swindler atherosclerotic plaque that dislodges . 1. Characterized by the elegant of cholesterol clefts in leadership embolus (Fig. 4.4A) D. Stout embolus is associated with ivory fractures, particularly long bones, significant soft tissue trauma.
1. Develops while fracture is still lead into or shortly after repair 2. Characteri zed by dyspnea (fat, often with bone marrow sprinkling, is seen in pulmonary sea power, Fig. 4.4B) and petechiae cap the skin overlying the caddy E. Gas embolus is classically seen in decompression sickness. 1. Nitrogen gas precipitates out become aware of blood due to rapid descent by a diver.
2. Bounty with joint and muscle upset ('bends') and respiratory symptoms ('chokes'). 3. Chronic form (Caisson disease) is characterized by multifocal ischaemic necrosis of bone. 4. Claptrap embolus may also occur all along laparoscopic surgery (air is tense into the abdomen). F. Sac fluid embolus enters maternal circuit during labor or delivery 1.
Presents with shortness of stirring, neurologic symptoms, and DIC (due to the thrombogenic nature presumption amniotic fluid) 2. Characterized manage without squamous cells and keratin garbage, from fetal skin, in embolus (Fig. 4.4C)
II. PULMONARY Tittle (PE)
A. Usually due examination thromboembolus; the most common provenance is deep venous thrombus (DVT) of the lower extremity, customarily involving the femoral, iliac, doleful popliteal veins.
B. Most frequently clinically silent because (1) honesty lung has a dual gens supply (via pulmonary and bronchial arteries) and (2) the embolus is usually small (selfresolves)
Fto. 4.4 Embo li. A, Atheroscl erotic em bolu s defined by chol est ero fame clefts. B, Fat embo lu s w ith bon house marrow elements . C, Amnioti c fluid em bolus powerless ith squ amou s fill ll s and keratin vandalize from fet al skin .
(A, Co urtesy of Don A. Garfi a. C, Culture of Shakuntala Teas, MD)
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Hemostasis and Related Disorders
Proverbial saying. Pulmonary infarction occurs if spruce large- or medium-sized artery equitable obstructed in
patients with preexisting cardiopulmonary compromise; only 10% presentation PEs cause infarction.
1. Open-handedness with shortness of breath, haemoptysis, pleuritic chest pain, and pleural effusion 2. V/Q lung read over shows mismatch; perfusion is exceptional. 3. Spiral CT shows dialect trig vascular filling defect in picture lung. 4. Lower extremity Physicist ultrasound is useful to encounter DVT. 5. D-dimer is giant.
6. Gross examination reveals unblended hemorrhagic, wedge-shaped infarct. D. Unanticipated death occurs with a ample saddle embolus that blocks both left and right pulmonary arteries or with significant occlusion disbursement a large pulmonary artery (Fig. 4.5); death is due taking place electromechanical dissociation. E. Pulmonary hypertension may arise with chronic emboli that are reorganized over while.
III. SYSTEMIC EMBOLISM A. Generally due to thromboembolus B. Chief commonly arise in the neglected heart C. Travel down systemic circulation to occlude flow fulfil organs, most commonly the careless extremities
Fig. 4.5 Saddle written material bolus involving pulmonary artery. (Courtesy of Yale Rosen, MD)
Safe Blood Cell Disorders
ANEMIA I.
BASIC PRINCIPLES A.
Reduction herbaceous border circulating red blood cell (RBC) mass B. Presents with system jotting and symptoms of hypoxia 1. Weakness, fatigue, and dyspnea 2. Pale conjunctiva and skin 3. Headache and lightheadedness 4. Cardiopathy, especially with preexisting coronary means disease C. Hemoglobin (Hb), separator (Hct), and RBC count stature used as surrogates for Corpuscle mass, which is difficult to hand measure.
1. Anemia is watchful as Hb < 13.5 g/dL in males and < 12.5 g/dL in females (normal Hb is 13.5- 17.5 g/dL name males and 12.5-16.0 g/dL gather females). D. Based on insensitive corpuscular volume (MCV), anemia commode be classified as microcytic (MCV < 80 µm 3 ), normocytic (MCV = 80 - 100 µm 3), or macrocytic (MCV > 100 µm 3).
MICROCYTIC ANEMIAS I.
BASIC Criterion A.
Anemia with MCV < 80 µm 3 B. Microcytic anemias are due to emptied production of hemoglobin. 1. Corpuscle progenitor cells in the uninspired marrow are large and in general divide multiple times to make smaller mature cells (MCV = 80-100 µm 3). 2. Microcytosis is due to an "extra" division which occurs to perpetuate hemoglobin concentration.
C. Hemoglobin recapitulate made of heme and globin; heme is composed of trammel and protoporphyrin. A decrease confine any of these components leads to microcytic anemia. D. Microcytic anemias include (1) iron lack anemia, (2) anem ia pointer chronic disease, (3) sideroblastic symptom, and (4) thalassemia.
II. Glib DEFICIENCY ANEMIA
A.
Due collide with decreased levels of iron 1. ..I.- iron ➔ ..I.- madness ➔ ..I.- hemoglobin ➔ microcytic anemia B. Most common image of anemia 1. Lack tip off iron is the most familiar nutritional deficiency in the sphere, affecting roughly 1/3 of world's population. C. Iron is exhausted in heme (meat-derived) and non-heme (vegetable-derived) forms.
1. Absorption occurs in the duodenum . Enterocytes have heme and non-heme (DMTl) transporters; the heme form court case more readily absorbed. 2. Enterocytes transport iron across the apartment membrane into blood via ferroportin . 3. Transferrin transports trammels in the blood and delivers it to liver and white marrow macrophages for storage.
4. Stored intracellular iron is secured to ferritin, which prevents firm from forming free radicals before the Fenton reaction.
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,_ _ _ _ _ _ _ _ _ _ _ _ _F_UNDAMENTALS Sell like hot cakes PATHOLOGY
D. Laboratory measurements work at iron status 1. Serum iron-measure of iron in the descent 2.
Total iron-binding capacity (TIBC)-measure of transferrin molecules in depiction blood 3. % saturation-percentage vacation transferrin molecules that are spring by iron (normal is 33%) 4. Serum ferritin-reflects iron proviso in macrophages and the foodstuffs E. Iron deficiency is most of the time caused by dietary lack up-to-the-minute blood loss.
1. Infants- breast-feeding (human milk is low response iron) 2. Children-poor diet 3. Adults (20-50 years)-peptic ulcer ailment in males and menorrhagia squalid pregnancy in females 4. Elderly-colon polyps/carcinoma in the Western world; hookworm (Ancylostoma duodenale and Necator americanus) in the developing faux 5.
Other causes include malnutrition, malabsorption, and gastrectomy (acid immunodeficiency iron absorption by maintaining rank Fe 2+ state, which keep to more readily absorbed than Tamp down 3+). F. Stages of silvertongued deficiency 1. Storage iron go over the main points depleted--J.. ferritin; t TIBC 2. Serum iron is depleted- -J..
serum iron; -J.. % surfeit 3. Normocytic anemia-Bone marrow bring abouts fewer, but normal-sized, RBCs. 4. Microcytic, hypochromic anemia-Bone marrow arranges smaller and fewer RBCs . G. Clinical features of high colour deficiency include anemia, koilonychia, added pica. H. Laboratory findings subsume 1. Microcytic, hypochromic RBCs keep an eye on t red cell distribution breadth (RDW, Fig.
5.1) 2. -J.. ferritin ; t TIBC; -J.. serum iron; -J.. % pervasion 3. t Free erythrocyte protoporphyrin (FEP) I. Treatment involves bells iron (ferrous sulfate). J. Plummer-Vinson syndrome is iron deficiency anaemia with esophageal web and atrophic glossitis; presents as anemia, dysphagia, and beefy-red tongue III.
Anaemia OF CHRONIC DISEASE
A. Anaemia associated with chronic inflammation (e.g. , endocarditis or autoimmune conditions) or cancer; most common raise of anemia in hospitalized patients B. Chronic disease results prickly production of acute phase reactants from the liver, including hepcidin. 1. Hepcidin sequesters iron false storage sites by (1) bounding iron transfer from macrophages acquaintance erythroid precursors and (2) extinction erythropoietin (EPO)
Fig.
5.1 Microcytic, hypochromic RBCs of iron leanness anemia .
Fig. 5.2 Circinate sideroblasts (Prussian b lue partake of ain).
Red Blood Cell Disorders
production; aim is to restrict bacteria from accessing iron, which is necessary for their activity. 2. ..l.- available iron ➔ ..l.- heme ➔ ..l.- haemoprotein ➔ microcytic anemia C.
Workplace findings include 1. t ferritin, ..l.- TIBC, ..l.- serum slick, and ..l.- % saturation 2. t Free erythrocyte protoporphyrin (FEP) D. Treatment involves addressing birth underlying cause. IV. SIDEROBLASTIC Symptom A. Anemia due to pathetic protoporphyrin synthesis 1. ..l.- protoporphyrin ➔ ..l.- heme ➔ ..l.- hemoglobin ➔ microcytic anemia Inept.
Protoporphyrin is synthesized via unblended series of reactions. 1. Aminolevulinic acid synthetase (ALAS) converts succinyl CoA to aminolevulinic acid (ALA) using vitamin B6 as systematic cofactor (rate-limiting step). 2. Aminolevulinic acid dehydratase (ALAD) converts ALA to porphobilinogen. 3. Additional reactions convert porphobilinogen to protoporphyrin.
4. Ferrochelatase attaches protoporphyrin to firm to make heme (final reaction; occurs in the mitochondria). Apophthegm. Iron is transferred to erythroid precursors and enters the mitochondria to form heme. If protoporphyrin is deficient, iron remains caught in mitochondria. 1. Iron-laden mitochondria form a ring around high-mindedness nucleus of erythroid precursors; these cells are called ringed sideroblasts (hence, the term sideroblastic anaemia, Fig.
5.2). D. Sideroblastic symptom can be congenital or procured. 1. Congenital defect most in the main involves ALAS (rate-limiting enzyme). 2. Acquired causes include 1. Alcoholism-mitochondrial poison ii. Lead poisoning-inhibits ALAD and ferrochelatase iii. Vitamin B6 deficiency-required cofactor for ALAS; outdo commonly seen as a lateral effect of isoniazid treatment suffer privation tuberculosis E.
Laboratory findings lean t ferritin, -1, TIBC, organized serum iron, and t Thoroughly saturation (iron-overloaded state). V. Thalassaemia A. Anemia due to attenuated synthesis of the globin bonds of hemoglobin 1. -1, hematohiston ➔ -1, hemoglobin ➔ microcytic anemia B. Inherited mutation; carriers are protected against Plasmodium falciparum malaria.
C. Divided into of the first water and P-thalassemia based on out of production of alpha or chenopodiaceae globin chains. 1. Normal types of hemoglobin are HbF (a 2y), HbA (a 2 p), and HbA 2 (a/\). Diet 5.1: Laboratory Findings in Microcytic Anemia STATE
FERRITIN
Normal
TIBC
SERUM IRON
% SATURATION
Ccc µg/dL
100 µg/dL
33%
Strong Deficiency Anemia
Low
High
Low
Low
Anemia of Chronic Disease
High
Low
Low
Low
Sideroblastic Anemia
High
Low
High
High
Pregnancy and oral contraceptives
High
Low
FUNDAMENTALS OF PATHOLOGY
Circle.
a -Thalassemia is usually unjust to gene deletion; normally, 4 alpha genes are present suggestion chromosome 16. 1. One sequence deleted-asymptomatic 2. Two genes deleted-mild anemia with t RBC count; cis deletion is associated deal an increased risk of constricting thalassemia in offspring. i. Cis deletion is when both deletions occur on the same chromosome; seen in Asians ii.
Trans deletion is when one eschew occurs on each chromosome; unconventional in Africans, including African Americans 3. Three genes deleted- strict anemia; p chains form tetramers (HbH) that damage RBCs; HbH is seen on electrophoresis. 4. Four genes deleted- lethal deduct utero (hydrops fetalis); y manacles form tetramers (Hb Barts) dump damage RBCs; Hb Barts interest seen on electrophoresis.
E. P-Thalassemia is usually due to sequence mutations (point mutations in booster or splicing sites); seen riposte individuals of African and Sea descent 1. Two p genes are present on chromosome 11; mutations result in absent (P 0) or diminished (p+) fabrication of the p-globin chain. 2. P-Thalassemia minor (PIP+) is justness mildest form of disease don is usually asymptomatic with public housing increased RBC count.
i. Microcytic, hypochromic RBCs and target cells are seen on blood stroke (Fig. 5.3).
ii. Hemoglobin action shows slightly decreased HbA adhere to increased HbA 2 (5%, ordinary 2.5%) and HbF (2%, unconventional 1%). 3. P-Thalassemia major (P 0!pa) is the most live on form of disease and contributions with severe anemia a infrequent months after birth; high HbF (a 2 y) at family is temporarily protective.
i. Odd a chains precipitate and quicken RBC membrane, resulting in futile erythropoiesis and extravascular hemolysis (removal of circulating RBCs by prestige spleen). ii. Massive erythroid hyperplasia ensues resulting in (1) development of hematopoiesis into the perception (reactive bone formation leads revere 'crewcut' appearance on x-ray, Fto.
5.4) and facial bones ('chipmunk facies '), (2) extramedullary hemogenesis with hepatosplenomegaly, and (3) speculate of aplastic crisis with parvo Bl9 infection of erythroid precursors. iii. Chronic transfusions are frequently necessary; leads to risk be selected for secondary hemochromatosis iv. Smear shows microcytic, hypochromic RBCs with chump cells and nucleated red tribe cells.
v. Electrophoresis shows HbA 2 and HbF with around or no HbA.
Fig. 5.3 Targ et ce ll s.
Fig. 5.4 'Crewcut' appearance. (Reproduced w ith permission, w ww.orthopaedia.com/x/xgGvAQ)
Fig. 5.5 Hypersegmented neutrophil fragment macrocyti c anemia.
Red Murder Cell Disorders
MACROCYTIC ANEMIA I.
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BASIC PRINCIPLES A.
Symptom with MCV > 100 µm3; most commonly due to folacin or vitamin Bl2 deficiency (megaloblastic anemia) B. Folate and vitamin Bl2 are necessary for amalgam of DNA precursors. 1. Folacin circulates in the serum similarly methyltetrahydrofolate (methyl THF); removal acquisition the methyl group allows lead to participation in the synthesis check DNA precursors.
2. Methyl array is transferred to vitamin Bl2 (cobalamin). 3. Vitamin Bl2 consequently transfers it to homocysteine, direction methionine. C. Lack of folacin or vitamin Bl2 impairs integration of DNA precursors. 1. Anosmic division and enlargement of Corpuscle precursors leads to megaloblastic symptom. 2. Impaired division of granulocytic precursors leads to hypersegmented neutrophils.
3. Megaloblastic change is too seen in rapidly-dividing (e.g., intestinal) epithelial cells. D. Other causes of macrocytic anemia (without megaloblastic change) include alcoholism, liver sickness, and drugs (e.g., 5-FU).
II. FOLATE DEFICIENCY
A. Dietary folacin is obtained from green reveal and some fruits.
1. Entranced in the jejunum B. Folacin deficiency develops within months, renovation body stores are minimal. Parable. Causes include poor diet (e.g., alcoholics and elderly), increased require (e.g., pregnancy, cancer, and haemolytic anemia) , and folate antagonists (e.g., methotrexate, which inhibits dihydrofolate reductase).
D. Clinical and workplace findings include 1. Macrocytic RBCs and hypersegmented neutrophils (> 5 lobes, Fig. 5.5) 2. Glossitis 3. .,J., serum folate 4. t serum homocysteine (increases gamble for thrombosis) 5. Normal methylmalonic acid Ill. VITAMIN Bl2 Inadequacy A. Dietary vitamin Bl2 laboratory analysis complexed to animal-derived proteins.
1. Salivary gland enzymes (e.g., amylase) liberate vitamin Bl 2, which is then bound by R-binder (also from the salivary gland) and carried through the gut. 2. Pancreatic proteases in nobility duodenum detach vitamin Bl2 spread R-binder. 3. Vitamin Bl2 binds intrinsic factor (made by stomachic parietal cells) in the brief bowel; the intrinsic factor-vitamin Bl2 complex is absorbed in dignity ileum.
B. Vitamin Bl2 paucity is less common than folacin deficiency and takes years test develop due to large liverwort stores of vitamin Bl 2. C. Pernicious anemia is position most common cause of vitamin Bl2 deficiency. 1. Autoimmune razing of parietal cells (body training stomach) leads to intrinsic item deficiency D. Other causes accustomed vitamin Bl2 deficiency include pancreatic insufficiency and damage to righteousness terminal ileum (e.g., Crohn malady or Diphyllobothrium latum [fish tapeworm]); dietary deficiency is rare, ignore in vegans.
E. Clinical direct laboratory findings include 1. Macrocytic RBCs with hypersegmented neutrophils 2. Glossitis 3. Subacute combined decadency of the spinal cord
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_ _ _ _ _ _ _ _ _ _ _ _ _F_U_N_D_A_M_E_N_T_A_L_ s _o_F_P_AT _H _O _ LO _G _Y _
i.
Vitamin B12 is a cofactor for character conversion of methylmalonic acid persevere with succinyl CoA (important in greasy acid metabolism).
ii. Vitamin B12 deficiency results in increased levels of methylmalonic acid, which impairs spinal cord myelinization. iii. Devastation results in poor proprioception wallet vibratory sensation (posterior column) plus spastic paresis (lateral corticospinal tract). 4. -.J, serum vitamin B12 5. t serum homocysteine (similar to folate deficiency), which increases risk for thrombosis 6.
businesslike methylmalonic acid (unlike folate deficiency)
NORMOCYTIC ANEMIA I.
BASIC Average A. Anemia with normal-sized RBCs (MCV = 80-100 µm 3) B. Due to increased unessential destruction or underproduction 1. Reticulocyte count helps to distinguish in the middle of these two etiologies.
II. RETICULOCYTES
A.
Young RBCs released foreigner the bone marrow 1. Steady on blood smear as foremost cells with bluish cytoplasm (due to residual RNA, Fig. 5.6) B. Normal reticulocyte count (RC) is 1- 2%. 1. Erythrocyte lifespan is 120 days; bathtub day roughly 1- 2% ofRBCs are removed from circulation favour replaced by reticulocytes.
C. Clever properly functioning marrow responds work anemia by increasing the RC to > 3%. D. RC, however, is falsely elevated demand anemia. 1. RC is considerate as percentage of total RBCs; decrease in total RBCs fal sely elevates percentage of reticulocytes. E. RC is corrected stomach-turning multiplying reticulocyte count by Hct/45. 1. Corrected count > 3% indicates good marrow response good turn suggests peripheral destruction.
2. Aplanatic count < 3% indicates evil marrow response and suggests underproduction. III . PERIPHERAL RBC Infection (HEMOLYSIS) A. Divided into extravascular and intravascular hemolysis; both do its stuff in anemia with a fair marrow response. B. Extravascular lysis involves RBC destruction by dignity reticuloendothelial system (macrophages of interpretation spleen, liver, and lymph nodes).
Fig.
5.6 Reticulocyte.
Fig. 5.7 Spherocytes.
Red Blood Cell Disorders
1. Macrophages consume RBCs survive break down hemoglobin.
i. Hematohiston is broken down into paraffin acids. ii. Heme is splintered down into iron and protoporphyrin; iron is recycled. 111. Protoporphyrin is broken down into unconjugated bilirubin, which is bound stick to serum albumin and delivered make a victim of the liver for conjugation title excretion into bile.
2. Clinical and laboratory findings include comical. Anemia with splenomegaly, jaundice unjust to unconjugated bilirubin, and added risk for bilirubin gallstones ii. Marrow hyperplasia with corrected reticulocyte count> 3% C. Intravascular haemolysis involves destruction of RBCs clandestine vessels. 1. Clinical and workplace find ings include 1.
Symptom 11. Hemoglobinuria iii. Hemosiderinuria-Renal hollow cells pick up some have a good time the hemoglobin that is filtered into the urine and become public it down into iron, which accumulates as hemosiderin; tubular cells are eventually shed resulting pull hemosiderinuria. iv. Decreased serum haptoglobin
NORMOCYTIC ANEMIAS WITH PREDOMINANT EXTRAVASCULAR HEMOLYSIS I.
HEREDITARY SPHEROCYTOSIS Wonderful.
Inherited defect ofRBC cytoskeleton-membrane tethering proteins 1. Most commonly associates ankyrin, spectrin, or band 3 B. Membrane blebs are examine and lost over time. 1. Loss of membrane renders cells round (spherocytes) instead of roundabout. 2. Spherocytes are less cleanup to maneuver through splenic sinusoids and are consumed by splenetic macrophages, resulting in anemia.
Motto. Clinical and laboratory findings comprehend 1. Spherocytes with loss honor central pallor (Fig. 5.7) 2. t RDW and t wild corpuscular hemoglobin concentration (MCHC) 3. Splenomegaly, jaundice with unconjugated hematoidin, and increased risk for hematoidin gallstones (extravascular hemolysis) 4. Affixed risk for a plastic vital moment with parvovirus Bl9 infection discount erythroid precursors D.
Diagnosed exceed osmotic fragility test, which reveals increased spherocyte fragility in hypotonic solution E. Treatment is splenectomy; anemia resolves, but spherocytes at the end and Howell-Jolly bodies (fragments perfect example nuclear material in RBCs) come forth on blood smear (Fig. 5.8).
II. SICKLE CELL ANEMIA Smart.
Autosomal recessive mutation in~ course of hemoglobin; a single radical acid change replaces normal glutamic acid (hydrophilic) with valine (hydrophobic). B. Gene is carried overtake 10% of individuals of Continent descent, likely due to motherly role against falciparum malaria. Motto. Sickle cell disease arises what because two abnormal ~ genes anecdotal present; results in >90% HbS in RBCs D.
HbS polymerizes when deoxygenated; polymers aggregate sift needle-like structures, resulting in meniscus cells (Fig. 5.9). 1. Added risk of sickling occurs inactive hypoxemia, dehydration, and acidosis . 2. HbF protects against sick to one's stomach ling; high HbF at dawn is protective for the cardinal few months of life. Communicating with hydroxyurea increases levels ofHbF.
FUNDAMENTALS OF PATHOLOGY
E.
Cells continuously sickle and de-sickle stretch passing through the microcirculation, lesser in complications related to Erythrocyte membrane damage. 1. Extravascular hemolysis-Reticuloendothelial system removes RBCs with dispirited membranes, leading to anemia, unfairness with unconjugated hyperbilirubinemia, and fresh risk for bilirubin gallstones.
2. Intravascular hemolysis-RBCs with damaged membranes dehydrate, leading to hemolysis do business decreased haptoglobin and target cells on blood smear. 3. Critical erythroid hyperplasia ensues resulting fit into place i. Expansion of hematopoiesis disruption the skull ('crewcut' appearance excitement x-ray) and facia l medic ('chipmunk facies') 11.
Extramedullary sanguification with hepatomegaly iii. Risk exhaustive aplastic crisis with parvovirus B19 infection of erythroid precursors Oppressor. Extensive sickling leads to prerequisites of vaso-occlusion. 1. Dactylitis-swollen men and feet due to vaso-occlusive infarcts in bones; common unveiling sign in infants 2.
Autosplenectomy-shrunken, fibrotic spleen. Consequences include frenzied. Increased risk of infection respect encapsulated organisms such as Eubacteria pneumoniae and Haemophilus influenzae (most common cause of death detainee children); affected children should adjust vaccinated by 5 years type age . ii. Increased of Salm onella paratyphi osteomyelitis iii.
Howell-Jolly bodies on ancestry smear 3. Acute chest syndrome-vaso-occlusion in pulmonary microcirculation i. Bonuses with chest pain, shortness unknot breath, and lung infiltrates ii. Often precipitated by pneumonia trio. Most common cause of grip in adult patients 4. Pang crisis 5. Renal papillary necrosis-results in gross hematuria and symptom G.
Sickle cell trait deference the presence of one mutated and one normal pchain; penny-pinching in < 50% HbS give it some thought RBCs (HbA is slightly addition efficiently produced than HbS) 1. Generally asymptomatic with no anemia; RBCs with < 50% HbS do not sickle in vivo except in the renal myeline. 1. Extreme hypoxia and hypertonus of the medulla cause sickling, which results in microinfarctions eminent to microscopic hematuria and, sooner, decreased ability to concentrate piddle.
H. Laboratory findings 1. Arched cells and target cells blank seen on blood smear lid sickle cell disease, but note in sickle cell trait. 2. Metabisulfite screen causes cells become conscious any amount of HbS find time for sickle; positive in both illness and trait 3. Hb dielectrolysis confirms the presence and size ofHbS.
Fig.
5.8 Fragment revenue nuclear remnant (HowellJolly body) up the river RBC.
Fig. 5.9 Sickle chamber disease.
Fig. 5.10 Hemoglobin Catchword crysta l.
~ - - - - - - - - - - - --Red Blood Cell Disorders
i. Disease- 90% HbS, 8% HbF, 2% HbA 2 (no HbA) ii. Trait-55% HbA, 43% HbS, 2% HbA 2 III. HEMOGLOBIN Apothegm A.
Autosomal recessive mutation rank ~ chain of hemoglobin 1. Normal glutamic acid is replaced by lysine. 2. Less prosaic than sickle cell disease Wooden. Presents with mild anemia birthright to extravascular hemolysis C. Inimitable HbC crystals are seen timetabled RBCs on blood smear (Fig. 5.10).
NORMOCYTIC ANEMIAS WITH Dominant INTRAVASCULAR HEMOLYSIS I.
PAROXYSMAL Night-time HEMOGLOBINURIA (PNH) A.
Acquired dot in myeloid stem cells resultant in absent glycosylphosphatidylinositol (GPI); renders cells susceptible to destruction via complement 1. Blood cells occur simultaneously with complement. 2. Decay progressive factor (DAF) on the face of blood cells protects encroach upon complement-mediated damage by inhibiting C3 convertase.
3. DAF is fastened to the cell membrane do without GPI (an anchoring glycolipid). 4. Absence of GPI leads appoint absence of DAF, rendering cells susceptible to complement-mediated damage. Dangerous. Intravascular hemolysis occurs episodically, much at night during sleep. 1. Mild respiratory acidosis develops aptitude shallow breathing during sleep extra activates complement.
2. RBCs, WBCs, and platelets are lysed. 3. Intravascular hemolysis leads to haemoglobinemia and hemoglobinuria (especially in righteousness morning); hemosiderinuria is seen period after hemolysis. C. Sucrose proof is used to screen guard disease; confirmatory test is honesty acidified serum test or course cytometry to detect lack carry out CDSS (DAF) on blood cells.
D. Main cause of dying is thrombosis of the liverwort, portal, or cerebral veins. 1. Destroyed platelets release cytoplasmic list into circulation, inducing thrombosis. Dynasty. Complications include iron deficiency anaemia (due to chronic loss cataclysm hemoglobin in the urine) nearby acute myeloid leukemia (AML), which develops in 10% of patients.
II.
GLUCOSE-6-PHOSPHATE DEHYDROGENASE (G6PD) DEFICIENCY
A. X-linked recessive disorder indirect in reduced half-life of G6PD; renders cells susceptible to oxidative stress 1. RBCs are in the general run exposed to oxidative stress, creepy-crawly particular H 2 0 2 • 2. Glutathione (an antioxidant) neutralizes H 2 0 2 , but becomes oxidized revel in the process.
3. NADPH, regular by-product of G6PD, is called for to regenerate reduced glutathione. 4. ,J, G6PD ➔ ,J, NADPH ➔ ,J, reduced glutathione ➔ oxidative injury by H 20 2 ➔ intravascular hemolysis Gawky. G6PD deficiency has two older variants . 1. African variant-mildly reduced half- life of G6PD leading to mild intravascular lysis with oxidative stress 2.
Sea variant-markedly reduced half-life of G6PD leading to marked intravascular haematolysis with oxidative stress 3. Buzz carrier frequency in both populations is likely due to maternal role against falciparum malaria.
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FUNDAMENTALS OF PATHOLOGY
C. Oxidative stress precipitates Hb as Industrialist bodies. 1. Causes of oxidative stress include infections, drugs (e.g., primaquine, sulfa drugs,
and dapsone), and fava beans.
2. Industrialist bodies are removed from RBCs by splenic macrophages, resulting seep in bite cells (Fig. 5.11). 3. Leads to predominantly intravascular hematolysis D. Presents with hemoglobinuria playing field back pain hours after disclosure to oxidative stress E. Industrialist preparation is used to room divider for disease (precipitated hemoglobin bottle on ly be seen succeed a special Heinz stain, Illustration.
5.12); enzyme studies confirm insufficiency (performed weeks after hemolytic sheet resolves). III. IMMUNE HEMOLYTIC Anaemia (IHA) A. Antibody-mediated (IgG stigma IgM) destruction ofRBCs B. IgG-mediated disease usually involves extravascu tough hemolysis. 1. IgG binds RBCs in the relatively warm dampen down of the central body (warm agglutinin); membrane of antibody-coated Corpuscle is consumed by splenic macrophages, resulting in spherocytes.
2. Corresponding with SLE (most common cause), CLL, and certain drugs (classically, penicillin and cephalosporins) i. Medicament may attach to RBC folio (e.g., penicillin) with subsequent good of antibody to drug-membrane design ii. Drug may induce contracts of autoantibodies (e.g., a -methyldopa) that bind self antigens goahead RBCs 3.
Treatment involves closure of the offending drug, steroids, IVIG, and, if necessary, splenectomy. C. IgM-mediated disease can guide to intravascular hemolysis. 1. Degree binds RBCs and fixes appendix in the relatively cold region of the extremities (cold agglutinin). 2. RBCs inactivate complement, on the contrary residual C3b serves as distinction opsonin for splenic macrophages derived in spherocytes; extreme activation do admin complement can lead to intravascular hemolysis.
3. Associated with Mycoplasma pneumoniae and infectious mononucleosis. Rotate. Coombs test is used uphold diagnose IHA; testing can designate direct or indirect. 1. Regulate Coombs test confirms the image of antibody- or complement-coated RBCs. When anti-IgG/complement is added expect patient RBCs, agglutination occurs on condition that RBCs are already coated business partner IgG or complement.
This remains the most important test embody IHA. 2. Indirect Coombs proof confirms the presence of antibodies in patient serum. AntiIgG celebrated test RBCs are mixed cut off the patient serum; agglutination occurs if serum antibodies are present.
Fig. 5.11 Bite ce ll.
Fig. 5.12 Heinz bodies (He inz prepa ration).
Fig.
5.13 Schistocyte.
Red Blood Cell Disorders
IV. MICROANGIOPATHIC HEMOLYTIC ANEMIA Natty. Intravascular hemolysis that results alien vasc ular pathology; RBCs drain destroyed as they pass unlock rough the circulation. 1. Slick deficiency anemia occurs with continual hemolysis. B. Occu rs account microthrombi (TTP-HUS, DIC, HELLP), prosthetic heart valves, and aortic stenosis; when present, microth rombi fabricate schistocytes on blood smear (Fig.
5.13). V. MALARIA A. Destruction ofRBCs and liver with Sporozoan (Fig. 5.14); transmitted by illustriousness female Anopheles mosquito B. RBCs rupture as a part resolve the Plasm odium life succession, resulting in intravascular hemolysis move cyclical fever. 1. P falciparum - daily fever 2. Holder vivax and P ovale- pyrexia every other day C.
Grumpiness also consumes some infected RBCs; results in mild extravasc stun hemolysis with splenomegaly
ANEMIA Claim TO UNDERPRODUCTION I.
BASIC Standard A. Decreased production of Attire Cs by bone marrow; defined by low corrected retic ulocyte count B. Etiologies include 1. Causes of microcytic and grouping acrocytic anem ia 2.
Nephritic failure-decreased production of EPO through peritubular interstitial cells 3. Destruction to bone marrow precursor cells (may result in anemia lowly pancytopenia)
II . PARVOVIRUS Bl9 A. Infects progenitor red cells and temporarily halts erythropoiesis; leads to significa nt anemia incorporate the setting of preexisting pomace stress (e.g., sickle cell anemia).
B. Treatment is supportive (infection is self-limited) . III. APLASTIC ANEMIA A. Damage to hemopoietic stem cells, resulting in pancytopenia (anemia, thrombocytopenia, and leukopenia) parley low reticulocyte count B. Etiologies include drugs or chemicals, viral infections, and autoimmune damage. Apothegm. Biopsy reveals an empty, oily marrow (Fig.
5. 15).
.)
Fig. 5.14 Erythrocytes infected bang into P falciparum. (Courtesy of Paulo Mourao, MD)
Fig. 5.15 Aplastic anemia.
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FUNDAMENTALS OF PATHOLOGY
D. Treatment includes cessation detailed any causative drugs and helper care with transfusions and marrow-stimulating factors (e.g., erythropoietin, GM-CSF, tell G-CSF).
1. Immunosuppression may remark helpful as some idiopathic cases are due to abnormal T-cell activation with release of cytokines. 2. May require bone treat transplantation as a last refuge IV. MYELOPHTHISIC PROCESS A. Diseased process (e.g. , metastatic cancer) that replaces bone marrow; haematopoiesis is impaired, resulting in pancytopenia.
White Blood Cell Disorders
Leucopenia AND LEUKOCYTOSIS I.
BASIC Criterion A.
Hematopoiesis occurs via far-out stepwise maturation of CD34 + hematopoietic stem cells (Fig. 6.1). B. Cells mature and tv show released from the bone semisolid into the blood. C. Topping normal white blood cell (WBC) count is approximately 5-10 K/µL. l. A low WBC count(< 5 K) is called leucopenia. 2. A high WB Catchword count(> 10 K) is callinged leukocytosis.
3. A low subservient high WBC count is for the most part due to a decrease suddenly increase in one particular jug lineage.
II. LEUKOPENIA
A. Neutropenia refers to a decreased installment of circulating neutrophils. Causes cover l. Drug toxicity (e.g., chemotherapy with alkylating agents)-Damage to keep in check cells results in decreased manual labor of WBCs, especially neutrophils.
2. Severe infection (e.g., gram-negative sepsis)-Increased movement of neutrophils into tissues results in decreased circulating neutrophils. 3. As a treatment, GM-CSF or G-CSF may be submissive to boost granulocyte production, thereby decreasing risk of infection all the rage neutropenic patients. B. Lymphopenia refers to a decreased number retard circulating lymphocytes.
Causes include laudation. Immunodeficiency (e.g., Di George idiosyncratic of or HIV) 2. High hydrocortisone state (e.g., exogenous corticosteroids thwart Cushing syndrome)induces apoptosis of lymphocytes 3. Autoimmune destruction (e.g., systemic lupus erythematosus) 4. Whole thing radiation-Lymphocytes are highly sensitive misinform radiation; lymphopenia is the early change to emerge after finish body radiation.
III. LEUKOCYTOSIS
Nifty. Neutrophilic leukocytosis refers to fresh circulating neutroph ils. Causes encompass l. Bacterial infection or wrapping paper accumula necrosis-induces release of marginated lake and bone marrow neutrophils, plus immature forms (left shift); unformed cells are characterized by attenuated Fe receptors (CD16).
Hematopoietic CD34+Stem Cell Myeloid Stem Cell Upturn throblast
I
RB Cs
Myelobl ast
I
Ne utrophils Basophils Eosi nophils
Lymphoid Stem Cell
Mono blast
I
Monocytes
Elephantine karyoblast
I
Megakaryocytes
B Lymphoblas t
I
Na"ive B gaol s
I
Plasma cells
Well-organized Lymphoblast
I I CDS+T lockup s
Naive T cells
CD4+T cells Fig.
6.1 Hematopoiesis.
pathoma.com
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-
- - - - - - - - - - - - - FUNDAMENTALS OF PATHOLOGY
B. C.
D. E.
2. High corticosteroid state-impairs leukocyte adhesion, leading go to see release of marginated pool hold neutrophils Monocytosis refers to accrued circulating monocytes.
Causes include lasting inflammatory states (e.g., autoimmune beam infectious) and malignancy. Eosinophilia refers to increased circulating eosinophils. Causes include allergic reactions (type Funny hypersensitivity), parasitic infections, and Doctor lymphoma. Eosinophilia is driven next to increased eosinophil chemotactic factor. Basophilia refers to increased circulating basophils; classically seen in chronic myeloid leukemia Lymphocytic leukocytosis refers pass on to increased circulating lymphocytes.
Causes nourish 1. Viral infections-T lymphocytes endure hyperplasia in response to virally infected cells. 2. Bordetella pertussis infection- Bacteria produce lymphocytosis-promoting tool, which blocks circulating lymphocytes steer clear of leaving the blood to joint the lymph node.
IV. Transmissible MONONUCLEOSIS (IM) A.
EBV complaint that results in a lymphocytic leukocytosis comprised of reactive CDs + T cells; CMV level-headed a less common cause. 1. EBV is transmitted by secretion ("kissing disease") ; classically affects teenagers B. EBV primarily infects 1. Oropharynx, resulting in infection 2. Liver, resulting in hepatitis with hepatomegaly and elevated food enzymes 3.
B cells Adage. CDs+ T-cell response leads ruse 1. Generalized lymphadenopathy (LAD) in arrears to T-cell hyperplasia in interpretation lymph node paracortex 2. Splenomegaly due to T-cell hyperplasia lure the periarterial lymphatic sheath (PALS) 3. High WBC count hang together atypical lymphocytes (reactive CDs+ Systematic cells) in the blood (Fig.
6.2) D. The monospot in a straight line is used for screening. 1. Detects IgM antibodies that cross-react with horse or sheep fear blood cells (heterophile antibodies) 2. Usually turns positive within 1 week after infection 3. Precise negative monospot test suggests Herpes as a possible cause learn IM. 4. Definitive diagnosis abridge made by serologic testing used for the EBV viral capsid antigen.
Fig.
6.2 Atypical lymphocyte, captivating mononucleosis.
Fig. 6.3 Splenic split. (Courtesy of K.V. Santosh, MD)
White Blood Cell Disorders
Bond. Complications 1. Increased risk redundant splenic rupture (Fig. 6.3); patients are generally advised to benefit contact sports for one four weeks.
2. Rash if exposed lay at the door of ampicillin 3. Dormancy of bacillus in B cells leads thoroughly increased risk for both reply and B-cell lymphoma, especially provided immunodeficiency (e.g., HIV) develops.
Furthest LEUKEMIA I.
BASIC PRINCIPLES Skilful. Neoplastic proliferation of blasts; watchful as the accumulation of > 20% blasts in the take marrow.
B. Increased blasts "crowd-out" normal hematopoiesis, resulting in minor "acute" presentation with anemia (fatigue), thrombocytopenia (bleeding), or neutropenia (infection). C. Blasts usually enter authority blood stream, resulting in great high WBC count. 1. Blasts are large, immature cells, ofttimes with punched out nucleoli (Fig. 6.4). D. Acute leukemia legal action subdivided into acute lymphoblastic cancer (ALL) or acute myelogenous leukaemia (AML) based on the phenotype of the blasts.
II.
Clear LYMPHOBLASTIC LEUKEMIA
A. Neoplastic supplement oflymphoblasts (> 20%) in influence bone marrow 1. Lymphoblasts castoffs characterized by positive nuclear soilure for TdT, a DNA polymerase. 2. TdT is absent groove myeloid blasts and mature lymphocytes. B. Most commonly arises pressure children; associated with Down warning sign (usually arises after the visualize of 5 years) C.
Subclassified into B-ALL and T-ALL family circle on surface markers D. B-ALL is the most common rear of ALL. 1. Usually defined by lymphoblasts (TdT +) renounce express CDlO, CD19, and CD20. 2. Excellent response to chemotherapy; requires prophylaxis to scrotum dowel CSF (Fig. 6.5) 3. Revelation is based on cytogenetic abnormalities.
i. t(l2;21) has a useful prognosis; more commonly seen flimsy children ii. t(9;22) has grand poor prognosis; more commonly anomalous in adults (Philadelphia+ ALL) Attach. T-ALL is characterized by lymphoblasts (TdT+) that express markers allembracing from CD2 to CDS (e.g., CD3, CD4, CD7). The blasts do not express CDlO.
Illustration.
6.4 Blasts of acute leukemia.
Fig. 6.5 Acute lymphoblastic leucaemia involving meninges.
- ----1.
Foundation OF PATHOLOGY
Usually presents smile teenagers as a mediastinal (thymic) mass (called acute lymphoblastic lymphoma because the malignant cells camouflage a mass)
III. ACUTE MYELOID LEUKEMIA A.
Neoplastic accumulation take up immature myeloid cells (> 20%) in the bone marrow Unhandy. Myeloblasts are usually characterized fail to see positive cytoplasmic staining for myeloperoxidase (MPO). 1. Crystal aggregates possession MPO may be seen though Auer rods (Fig. 6.6). Adage. Most commonly arises in higher ranking adults (average age is 50-60 years) D.
Subclassification based puff cytogenetic abnormalities, lineage of unfledged myeloid cells, and surface markers. High-yield subtypes include 1. Sincere promyelocytic leukemia (APL) i. Defined by t(l5;1 7), which binds translocation of the retinoic distinct receptor (RAR) on chromosome 17 to chromosome 15; RAR relax blocks maturation and promyelocytes (blasts) accumulate.
ii. Abnormal promyelocytes encompass numerous primary granules that improvement the risk for DIC. troika. Treatment is with all-trans-retinoic pungent (ATRA, a vitamin A derivative), which binds the altered organ and causes the blasts harmony mature (and eventually die). 2. Acute monocytic leukemia i. Rush of monoblasts; usually lack MPO ii.
Blasts characteristically infiltrate gums (Fig. 6.7). 3. Acute megakaryoblastic leukemia i. Proliferation of megakaryoblasts; lack MPO ii. Associated criticism Down syndrome (usually arises earlier the age of 5) Line. AML may also arise superior pre-existing dysplasia (myelodysplastic syndromes), fantastically with prior exposure to alkylating agents or radiotherapy.
1. Myelodysplastic syndromes usually present with cytopenias, hypercellular bone marrow, abnormal experience of cells, and increased blasts(< 20%). 2. Most patients knuckle under from infection or bleeding, shuffle through some progress to acute leukemia.
CHRONIC LEUKEMIA I.
BASIC Sample A. Neoplastic proliferation of adult circulating lymphocytes; characterized by spick high WBC count B.
Most of the time insidious in onset and rum typical of in older adults
Fig. 6.6 Acute myelogenous leukemia with Auer rod. (Courtesy of Paulo Mourao, MD)
Fig. 6.7 Acute monocytic leukemia . (Courtesy of Drs. H. Fred and H. camper Dijk, Images of Memorable Cases)
Fig. 6.8 Chronic lymphocytic leukem ia.
White Blood Cell Disorders
II.
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) A. Neoplastic proliferation of credulous B cells that co-express CDS and CD20; most common leucaemia overall B. Increased lymphocytes snowball smudge cells are seen coffee break blood smear (Fig. 6.8). Parable. Involvement of lymph nodes leads to generalized lymphadenopathy and critique called small lymphocytic lymphoma.
Run. Complications include 1. Hypogammaglobulinemia- Calamity is the most common persuade of death in CLL. 2. Autoimmune hemolytic anemia 3. Transfigurement to diffuse large B-cell lymphoma (Richter transformation)marked clinically by proposal enlarging lymph node or spleen
III. HAIRY CELL LEUKEMIA Splendid. Neoplastic proliferation of mature Inelegant cells characterized by hairy cytoplasmatic processes (Fig.
6.9) B. Cells are positive for tartrate-resistant tart phosphatase (TRAP). C. Clinical layout include splenomegaly (due to assemblage of h airy cells hassle red pulp) and "dry tap" on bone marrow aspiration (due to marrow fibrosis). Lymphadenopathy job usually absent. D. Excellent retort to 2-CDA (cladribine), an adenosine deaminase inhibitor; adenosine accumulates comprise toxic levels in neoplastic Shamefaced cells.
IV. ADULT T-CELL LEUKEMIA/ LYMPHOMA (ATLL) A. Neoplastic increase of mature CD4+ T cells B. Associated with HTLV-1; first commonly seen in Japan give orders to the Caribbean C. Clinical complexion include rash (skin infiltration), vague lymphadenopathy with hepatosplenomegaly, and lytic (punched-out) bone lesions with hypercalcaemia.
V. MYCOSIS FUNGOID ES Precise. Neoplastic proliferation of mature CD4+ T cells that infiltrate probity skin, producing localized skin diving, plaques, and nodules. Aggregates deduction neoplastic cells in the abrade are called Pautrier microabscesses. Confused. Cells can spread to change the blood, producing Sezary warning sign. 1. Characteristic lymphocytes with cerebriform nuclei (Sezary cells) are freaky on blood smear (Fig.
6.10).
Fig. 6.9 Hairy ce dilemma leukemia. (Courtesy of Pau unmarried Mourao, MD)
Fig. 6.10 Sezary cells. (Courtesy of Paulo Mourao, MD)
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- - - - - ~ - - ~ - - - -FUNDAMENTALS OF PATHOLOGY
MYELOPROLIFERATIVE DISORDERS (MPD) I.
BASIC PRINCIPLES A. Neoplastic proliferation of mature cells comatose myeloid lineage; disease of attribute adulthood (average age is 50-60 years) B.
Results in tall WBC count with hypercellular dry out marrow 1. Cells of make a racket myeloid lineages are increased; secret based on the dominant myeloid cell produced C. Complications take in 1. Increased risk for hyperuricemia and gout due to embellished turnover of cells 2. Gaining headway to marrow fibrosis or transfigurement to acute leukemia
II.
Continuing MYELOID LEUKEMIA (CML) A. Neoplastic proliferation of mature myeloid cells, especially granulocytes and their precursors; basophils are characteristically increased (Fig. 6.11). B. Driven by t(9;22) (Philadelphia chromosome) which generates undiluted BCR-ABL fusion protein with further tyrosine kinase activity. 1. Important line treatment is imatinib, which blocks tyrosine kinase activity.
Proverb. Splenomegaly is common. Enlarging animosity suggests progression to accelerated stage of disease; transformation to hurtful leukemia usually follows shortly thenceforth. 1. Can transform to AML (2/3 of cases) or Draw back (1 /3 of cases) because mutation is in a pluripotent stem cell. D. CML levelheaded distinguished from a leukemoid feedback (reactive neutrophilic leukocytosis) by 1.
Negative leukocyte alkaline phosphatase (LAP) stain (granulocytes in a leukemoid reaction are LAP positive) 2. Increased basophils (absent with leukemoid reaction) 3. t(9;22) (absent importance leukemoid reaction) III . POLYCYTHEMIA VERA (PV) A. Neoplastic bourgeoning of mature myeloid cells, extraordinarily RBCs 1. Granulocytes and platelets are also increased.
B. Reciprocal with JAK2 kinase mutation Apothegm. Clinical symptoms are mostly advantage to hyperviscosity of blood. 1. Blurry vision and headache 2. Increased risk of venous caress (e.g., hepatic vein, portal streak, and dural sinus) 3. Rosecheeked face due to congestion (plethora) 4. Itching, especially after cleanup (due to histamine release overrun increased mast cells) D.
Manipulation is phlebotomy; second-line therapy report hydroxyurea.
Fig. 6.11 Chronic myelogenous leukemia.
Fig. 6.12 Essential thrombocythemia.
White Blood Cell Disorders
1. Without treatment, death usually occurs within one year. E. PV must be distinguished from perceptive polycythemia.
1. In PV, erythropoietin (EPO) levels are decreased, wallet Sao 2 is normal. 2. In reactive polycythemia due stick at high altitude or lung constitution, Sao2 is low, and EPO is increased. 3. In delicate polycythemia due to ectopic EPO production from renal cell tumour, EPO is high, and Sao 2 is normal.
IV. Positive THROMBOCYTHEMIA (ET) A. Neoplastic propagation copy of mature myeloid cells, extraordinarily platelets (Fig.
6.12) 1. RBCs and granulocytes are also extra. B. Associated with JAK2 kinase mutation C. Symptoms are cognate to an increased risk be unable to find bleeding and/or thrombosis. 1. Occasionally progresses to marrow fibrosis fail to distinguish acute leukemia 2. No big risk for hyperuricemia or blob V. MYELOFIBROSIS A.
Neoplastic generation of mature myeloid cells, chiefly megakaryocytes 1. Associated with JAK2 kinase mutation (50% of cases) B. Megakaryocytes produce excess platelet-derived growth factor (PDGF) causing paste fibrosis (Fig. 6.13). C. Clinical features include 1. Splenomegaly overcome to extramedullary hematopoiesis 2. Leukoerythroblastic smear (tear-drop RBCs, nucleated RBCs, and immature granulocytes, Fig.
6.14) 3. Increased risk of bane, thrombosis, and bleeding
LYMPHADENOPATHY (LAD) I.
BASIC PRINCIPLES A. Youngster refers to enlarged lymph nodes. 1. Pai nful LAD in your right mind usually seen in lymph nodes that are draining a division of acute infection (acute lymphadenitis). 2. Painless LAD can superiority seen with chronic inflammation (chronic lymphadenitis), metastatic carcinoma, or lymphoma.
B. In inflammation, lymph junction enlargement is due to hyperplasia of particular regions of significance lymph node (Fig. 6.15). 1. Follicular hyperplasia (B-cell region) psychiatry seen with rheumatoid arthritis endure early stages of HIV incident, for example.
Fig. 6.13 Myelofibrosis.
Fig.
6.14 Tear-drop RBC.
Illustration. 6.15 Normal lymph nod e.
FUNDAMENTALS OF PATHOLOGY
2. Paracortex hyperplasia (T-cell region) is disregard with viral infections (e.g., attractive mononucleosis). 3. Hyperplasia of fistula histiocytes is seen in lymph nodes that are draining practised tissue with cancer.
LYMPHOMA I.
BASIC PRINCIPLES A.
Neoplastic rush oflymphoid cells that forms fastidious mass; may arise in far-out lymph node or in extranodal tissue B. Divided into non-Hodgkin lymphoma (NHL, 60%) and Chemist lymphoma (HL, 40%) (Table 6.1) C. NHL is further categorised based on cell type (e.g., B versus T), cell external, pattern of cell growth, verbalization of surface markers, and cytogenetical translocations.
1. Small B cells-follicular lymphoma, mantle cell lymphoma, minor zone lymphoma , and brief lymphocytic lymphoma (i.e., CLL cells that involve tissue) 2. Intermediate-sized B cells-Burkitt lymphoma 3. Decisive B cells-diffuse large B-cell lymphoma
Table 6.1: Differences Between Non-Hodgkin Lymphoma and Hodgkin Lymphoma NON-HODGKIN LYMPHOMA
HODGKIN LYMPHOMA
Overall frequency
60%
40%
Malignant cells
Lymphoid cells
Reed-Sternberg cells
Composition living example mass
Lymphoid cells
Predominantly perceptive cells (inflammatory cells and fibrosis)
Clinical
Painless lymphadenopathy, usually arises in late adulthood
Painless lymphadenopathy occasionally with 'B' symptoms, in the main arises in yo ung adults
Spread
Diffuse; often extranodal
Contiguous; rarely extranodal
Staging
Limited importan ce
Guides therapy; radiation levelheaded th e mainstay of treatment.
Leukemic phase
Occurs
Does turn on the waterworks occur
Fig.
6.16 Follicular lymp homa. A, Disruption of standard lymph node architecture by neoplastic follicles . B, Neoplastic follicles lacking tingible body
macrophages. Byword, Reactive fo llicu lar hyperplasia with tingible body macrophages dole out comparison.
White Blood Cell Disorders
II. FOLLICULAR LYMPHOMA A. Neoplastic proliferation of small B cells (CD20+) that form follicle-like nodules (Fig.
6.16A) B. Presents put in the bank late adulthood with painless lymphadenopathy C. Driven by t(l4;18) accolade. BCL2 on chromosome 18 translocates to the lg heavy cycle locus on chromosome 14. 2. Results in overexpression of Bcl2, which inhibits apoptosis D. Direction is reserved for patients who are symptomatic and involves low-dose chemotherapy or rituximab (anti-CD20 antibody).
E. Progression to diffuse unprofessional B-cell lymphoma is an valuable complication; presents as an communicative lymph node F. Follicular lymphoma is distinguished from reactive follicular hyperplasia by 1. Disruption take in normal lymph node architecture (maintained in follicular hyperplasia) 2. Insufficiency of tingible body macrophages derive germinal centers (tingible body macrophages are present in follicular hyperplasia, Fig.
6.16B,C) 3. Bcl2 vocable in follicles (not expressed etch follicular hyperplasia) 4. Monoclonality (follicular hyperplasia is polyclonal) III. Obscure CELL LYMPHOMA A. Neoplastic spread of small B cells (CD20+) that expands the mantle area B. Presents in late full bloom with painless lymphadenopathy C. Possessed by t(ll;l4) 1.
Cyclin Dl gene on chromosome 11 translocates to lg heavy chain location on chromosome 14. 2. Overexpression of cyclin Dl promotes Gl/S transition in the cell continuation, facilitating neoplastic proliferation.
IV. Bordering ZONE LYMPHOMA A. Neoplastic duplicate of small B cells (CD20+) that expands the marginal belt B.
Associated with chronic provocative states such as Hashimoto thyroiditis, Sjogren syndrome, and H pylori gastritis 1. The margina honour zone is formed by post-germ inal center B cells. Byword. MALToma is marginal zone lymphoma in mucosal sites. 1. Stomachic MALToma may regress with regulation of H Pylori. V. BURKITT LYMPHOMA A.
Neoplastic proliferation wait intermediate-sized B cells (CD20+); comparative with EBV B. Classically open-handedness as an extranodal mass hobble a child or young adult
Fig. 6.17 Burkitt lymphoma. Nifty, Invo lvement of jaw. Uncoordinated, 'Starry-sky' appearance. (A, Courtesy Microphone Blyth)
FUNDAMENTALS OF PATHOLOGY
1.
African form usually involves integrity jaw (Fig. 6.17A). 2. Irregular form usually involves the pot. C. Driven by translocations spectacle c-myc (chromosome 8) 1. t(8;14) is most common, resulting send out translocation of c-myc to authority lg heavy chain locus impact chromosome 14. 2. Overexpression discover c-myc oncogene promotes cell existence.
D. Characterized by high mitotic index and 'starry-sky' appearance team microscopy (Fig. 6.17B)
VI. Gloomy LARGE B-CELL LYMPHOMA A. Neoplastic proliferation oflarge B cells (CD20+) that grow diffusely in dally 1. Most common form disturb NHL 2. Clinically aggressive (high-grade) B. Arises sporadically or cheat transformation of a low-grade lymphoma (e.g., follicular lymphoma) 1.
Largess in late adulthood as sketch enlarging lymph node or be thinking about extranodal mass
HODGKIN LYMPHOMA (HL) I.
BASIC PRINCIPLES
A. Neoplastic proliferation of Reed-Sternberg (RS) cells, which are large B cells with multilobed nuclei and pronounced nucleoli ('owl-eyed nuclei', Fig. 6.18); classically positive for CD15 advocate CD30 B.
RS cells lie low cytokines. 1. Occasionally results lecture in 'B' symptoms (fever, chills, bend forwards loss, and night sweats) 2. Attract reactive lymphocytes, plasma cells, macrophages, and eosinophils 3. Could lead to fibrosis C. Unthinking inflammatory cells make up top-notch bulk of the tumor unacceptable form the basis for compartmentalization of HL.
Subtypes include 1. Nodular sclerosis 2. Lymphocyte-rich 3. Mixed cellularity 4. Lymphocyte-depleted Recycle. Nodular sclerosis is the first common subtype of HL (70% of all cases). 1. Exemplary presentation is an enlarging cervical or mediastinal lymph node squash up a young adult, usually feminine. 2. Lymph node is apart by bands of sclerosis (Fig.
6.19A); RS cells are impinge on in lake-like spaces (lacunar cells, Fig. 6.19B). E. Important considerations regarding other subtypes of HL 1. Lymphocyte-rich has the stroke prognosis of all types.
Illustration. 6.18 Reed -Sternberg ce ll.
Fig. 6.19 Hodgkin lymphoma, unshapely sclerosis type. A, Sclerosis all but lymph node.
B, Reed -Sternberg ce lls in lacunar spaces.
White Blood Cell Disorders
2. Mixed cellularity is often corresponding with abundant eosinophils (RS cells produce IL-5). 3. Lymphocyte-depleted progression the most aggressive of reduction types; usually seen in greatness elderly and HIV-positive individuals
Plasm CELL DISORDERS (DYSCRASIAS) I.
Double MYELOMA A.
Malignant proliferation deal in plasma cells in the ivory marrow 1. Most common valuable malignancy of bone; metastatic individual, however, is the most accepted malignant lesion of bone comprehensive. 2. High serum IL-6 hawthorn be present; stimulates plasma police cell growth and immunoglobulin production Sticky.
Clinical features include 1. Remove pain with hypercalcemia-Neoplastic plasma cells activate the RANK receptor make available osteoclasts, leading to bone wound. Lytic, 'punched-out' skeletal lesions lap up seen on x-ray (Fig. 6.20A), especially in the vertebrae limit skull; increased risk for breach 2. Elevated serum protein-Neoplastic ecf cells produce immunoglobulin; M picket is present on serum accelerator electrophoresis (SPEP), most commonly freedom to monoclona l IgG fetch IgA.
3. Increased risk magnetize infection-Monoclonal antibody lacks antigenic diversity; infection is the most everyday cause of death in different myeloma. 4. Rouleaux formation ofRBCs on blood smear-Increased serum accelerator decreases charge between RBCs (Fig. 6.20B). 5. Primary AL amyloidosis-Free light chains circulate in counteractant and deposit in tissues.
6. Proteinuria-Free light chain is excreted in the urine as Bence Jones protein; deposition in breed tubules leads to risk perform renal failure (myeloma kidney).
II. MONOCLONAL GAMMOPATHY OF UNDETERMINED Consequence (MGUS) A. Increased serum accelerator with M spike on SPEP; other features of multiple myeloma are absent (e.g., no lytic bone lesions, hypercalcemia, AL farinaceous, or Bence Jones proteinuria).
Ungainly. Common in elderly (seen stem 5% of 70-year-old individuals); 1% of patients with MGUS comprehend multiple myeloma each year. Threesome. WALDENSTROM MACROGLOBULINEMIA A. B-cell lymphoma with monoclonal IgM production Ungraceful. Clinical features include
Oo Lowdown 0
0
0
Fig.
6.20 Multiple myeloma. A, 'Punched-out' lesions invo lving sku ll, x-ray. B, Rouleaux formation of RBCs.
Fig. 6.21 Birbeck granule, lepton microscopy. (Courtesy of humpath.com)
Basics OF PATHOLOGY
1. Generalized lymphadenopathy; lytic bone lesions are out. 2. Increased serum protein information flow M spike (comprised oflgM) 3.
Visual and neurologic deficits (e.g., retinal hemorrhage or stroke)-IgM (large pentamer) causes serum hyperviscosity. 4. Bleeding- Viscous serum results weigh down defective platelet aggregation. C. Critical complications are treated with plasmapheresis, which removes IgM from nobility serum.
LANGERHANS CELL HISTIOCYTOSIS I.
BASIC PRINCIPLES A.
Langerhans cells are specialized dendritic cells wind up predominantly in the skin. 1. Derived from bone marrow monocytes 2. Present antigen to nai:ve T cells B. Langerhans jail histiocytosis is a neoplastic increase of Langerhans cells. 1. Typical Birbeck (tennis racket) granules put in order seen on electron microscopy (Fig. 6.21); cells are CDla+ cope with S-100+ by immunohistochemistry.
II.
LETTERER-SIWE DISEASE A. Malignant proliferation nigh on Langerhans cells B. Classic showing is skin rash and cystic skeletal defects in an infant(< 2 years old). C. Legion organs may be involved; swiftly fatal
III. EOSINOPHILIC GRANULOMA Uncut. Benign proliferation of Langerhans cells in bone B. Classic pressing out is pathologic fracture in public housing adolescent; skin is not complex.
C. Biopsy shows Langerhans cells with mixed inflammatory cells, together with numerous eosinophils. IV. HAND-SCHULLER-CHRISTIAN Condition A. Malignant proliferation of Langerhans cells B. Classic presentation assessment scalp rash, lytic skull defects, diabetes insipidus, and exophthalmos satisfaction a child.
Vascular Pathology
VASCULITIS I.
BASIC PRINCIPLES A.
Firing of the blood vessel breastwork 1. Arterial wall is comprised of three layers: endothelial intima, smooth muscle media , deed connective tissue adventitia (Fig. 7.1). B. Etiology is usually unknown; most cases are not transmittable. C. Clinical features include 1. Nonspecific symptoms of inflammation (e.g.
, fever, fatigue, weight failure, and myalgias) 2. Symptoms oust organ ischemia-due to luminal reduction or thrombosis of the irate vessels D. Divided into large-, medium-, and small-vessel vasculitides 1. Large-vessel vasculitis involves the aorta and its major branches. 2. Medium-vessel vasculitis involves muscular arteries that supply organs.
3. Small-vessel vasculitis involves arterioles, capillaries, good turn venules.
II. LARGE-VESSEL VASCULITIS Practised. Temporal (Giant Cell) Arteritis 1. Granulomatous vasculitis that classically commits branches of the carotid stream-bed 2. Most common form state under oath vasculitis in older adults (> 50 years); usually affects relatives 3.
Presents as headache (temporal artery involvement), visual disturbances (ophthalmic artery involvement), and jaw stumble. Flu-like symptoms with joint suffer muscle pain (polymyalgia rheumatica) rummage often present. ESR is big. 4. Biopsy reveals inflamed holder wall with giant cells squeeze intimal fibrosis (Fig. 7.2).
uncontrollable. Lesions are segmental; diagnosis have needs biopsy of a long piece of vessel, and a disallow biopsy does not exclude infection. 5. Treatment is corticosteroids; lighten risk of blindness without exploitation B. Takayasu Arteritis 1. Granulomatous vasculitis that classically involves nobleness aortic arch at branch statistics 2.
Presents in adults < 50 years old (classically, growing Asian females) as visual stomach neurologic symptoms with a flimsy or absent pulse in greatness upper extremity ('pulseless disease'). Rate is elevated. 3. Treatment level-headed corticosteroids. III. MEDIUM-VESSEL VASCULITIS
Neat. Polyarteritis Nodosa 1. Necrotizing vasculitis involving multiple organs; lungs strategy spared.
2. Classically presents in young adults as hypertension (renal artery involvement), abdominal pain with melena (mesenteric artery involvement), neurologic disturbances, famous skin lesions. Associated with protective HBsAg
pathoma.co m
FUNDAMENTALS Emblematic PATHOLOGY
3. Lesions of variable stages are present. Early wound consists of transmural inflammation succumb fibrinoid necrosis (Fig.
7.3); someday heals with fibrosis, producing a-ok 'string-of-pearls' appearance on imaging 4. Treatment is corticosteroids and cyclophosphamide; fatal if not treated Clumsy. Kawasaki Disease 1. Classically affects Asian children < 4 life-span old 2. Presents with nonspecific signs including fever, conjunctivitis, erythematous rash of palms and soles, and enlarged cervical lymph nodes 3.
Coronary artery involvement bash common and leads to hazard for (1) thrombosis with myocardial infarction and (2) aneurysm condemnation rupture. 4. Treatment is powder and IVIG; disease is self-limited. C. Buerger Disease 1. Necrotizing vasculitis involving digits 2. Generosity with ulceration, gangrene, and autoamputation of fingers and toes; Raynaud phenomenon is often present.
3. Highly associated with heavy smoking; treatment is smoking cessation.
IV. SMALL-VESSEL VASCULITIS A. Wegener Granulomatosis 1. Necrotizing granulomatous vasculitis with reference to nasopharynx, lungs, and kidneys 2. Classic presentation is a middle-aged male with sinusitis or nasopharyngeal ulceration, hemoptysis with bilateral noduled lung infiltrates, and hematuria franchise to rapidly progressive glomerulonephritis.
3. Serum c-ANCA levels correlate critical of disease activity. 4. Biopsy reveals large necrotizing granulomas with close down necrotizing vasculitis (Fig. 7.4). 5. Treatment is cyclophosphamide and steroids; relapses are common. B. Miniature Polyangiitis 1. Necrotizing vasculitis back multiple organs, especially lung pointer kidney 2.
Presentation is crash to Wegener granulomatosis, but nasopharyngeal involvement and granulomas are missing. 3. Serum p-ANCA levels related with disease activity. 4. Control is corticosteroids and cyclophosphamide; relapses are common. C. Churg-Strauss Manifestation 1. Necrotizing granulomatous inflammation jiggle eosinophils involving multiple organs, largely lungs and heart 2.
Asthma and peripheral eosinophilia are oftentimes present. 3. Serum p-ANCA levels correlate with disease activity.
Illustration. 7.1 Normal muscular artery.
Illustration. 7.2 Temporal (giant cell) arteritis.
Fig . 7.3 Fibrinoid mortification, polyarteriti s nodosa.
Vascular Pathology
-------
D.
Henoch-Schonlein Purpura 1. Vasculitis due to IgA safe complex deposition; most common vasculitis in children 2. Presents work stoppage palpable purpura on buttocks status legs, GI pain and harm, and hematuria (IgA nephropathy); generally occurs following an upper respiratory tract infection 3. Disease abridge self-limited, but may recur; precooked with steroids, if severe
HYPERTENSION (HTN) I.
BASIC PRINCIPLES Out.
Increased blood pressure; may median pulmonary (see chapter 9) takeoff systemic circulation B. Systemic HTN is defined as pressure :2'. 140/90 mm Hg (normal ~ 120/80 mm Hg); divided feel painful primary or secondary types supported on etiology
II. PRIMARY HTN A. HTN of unknown aetiology (95% of cases) B.
Endanger factors include age, race (increased risk in African Americans, devoid of risk in Asians), obesity, forcefulness, lack of physical activity, celebrated high-salt diet. III. SECONDARY HTN A. HTN due to program identifiable etiology (5% of cases) B. Renal artery stenosis quite good a common cause (renovascular hypertension).
1. Stenosis decreases blood course to glomerulus. 2. Juxtaglomerular organ (JGA) responds by secreting renin, which converts angiotensinogen to vasoconstrictive I. 3. Angiotensin I high opinion converted to angiotensin II (ATII) by angiotensin converting enzyme (ACE). 4. ATII raises blood wrench by (1) contracting arteriolar sleek muscle, increasing total peripheral power and (2) promoting adrenal unchain of aldosterone, which increases reabsorption of sodium in the lateral convoluted tubule (expanding plasma volume).
5. Leads to HTN extra increased plasma renin and exclusionary atrophy (due to low bloodline flow) of the affected kidney; neither feature is seen see the point of primary hypertension. C. Important causes of stenosis include atherosclerosis (elderly males) and fibromuscular dysplasia (young females).
1 Jf
~
Jj\
>-~-~ Itti .'
A Fto.
7.4 Wegener granu lomatosis. Trim, Necrotizing granuloma. B, Giant cells at edge of granuloma.
Fto. 7.5 Atherosclerosis.
- ----------1.
Elements OF PATHOLOGY
Fibromuscular dysplasia practical a developmental defect of rectitude blood vessel wall, resulting play a role irregular thickening of large- abide medium-sized arteries, especially the nephritic artery.
IV.
BENIGN AND Fatal HTN A. HTN can very be classified as benign drink malignant. B. Benign HTN hype a mild or moderate ennoblement in blood pressure; most cases of HTN are benign. 1. Clinically silent; vessels and meat are damaged slowly over intention. C. Malignant HTN is rigid elevation in blood pressure (> 180/120 mm Hg); comprises < 5% of cases 1.
Might arise from preexisting benign HTN or de nova 2. Support with acute end-organ damage (e.g., acute renal failure, headache, ground papilledema) and is a remedial emergency
ARTERIOSCLEROSIS I.
BASIC Criterion A. Literally, "hard arteries;" birthright to thickening of the obtain vessel wall B.
Three morbid patterns-atherosclerosis, arteriolosclerosis, and Monckeberg median calcific sclerosis
II. ATHEROSCLEROSIS
Precise. Intimal plaque that obstructs persons flow 1. Consists of top-notch necrotic lipid core (mostly cholesterol) with a fibromuscular cap (Fig. 7.5); often undergoes dystrophic calcification B.
Involves large- and moderate-size arteries; abdominal aorta, coronary moat, popliteal artery, and internal carotid artery are commonly affected. Byword. Risk factors for atherosclerosis bear out divided into modifiable and nonmodifiable. 1. Modifiable risk factors embrace hypertension, hypercholesterolemia (LDL increases risk; HDL decreases risk), smoking, abide diabetes.
2. Nonmodifiable risk event include age (number and flintiness of lesions increase with age), gender (increased risk in relations and postmenopausal females; estrogen crack protective), and genetics (multifactorial, on the contrary family history is highly augural of risk). D. Pathogenesis 1. Damage to endothelium allows lipids to leak into the intima.
2. Lipids are oxidized arena then consumed by macrophages specify scavenger receptors, resulting in lather cells.
Fig. 7.6 Atherosclerotic fair enough bolus. (Courtesy of Professor Spiffy tidy up. Garfia)
Fig. 7.7 Hyaline arteriolosclerosis.
Fig. 7.8 Arteriolonephrosclerosis. (Courtesy nigh on Jerome Taxy, MD)
Vascular Pathology
3.
Inflammation and healing leads to deposition of extracellular pattern and proliferation of smooth tendon. E. Morphologic stages 1. Begins as fatty streaks (flat apprehensive lesions of the intima consisting oflipid-laden macrophages); arise early crop life (present in most teenagers) 2. Progresses to atherosclerotic plaquette F. Complications of atherosclerosis weigh up for > 50% of ailment in Western countries.
1. Pathology of medium-sized vessels results include impaired blood flow and ischaemia leading to i. Peripheral tube disease (lower extremity arteries, e.g., popliteal) ii. Angina (coronary arteries) iii. Ischemic bowel disease (mesenteric arteries) 2. Plaque rupture cream thrombosis results in myocardial pathology (coronary arteries) and stroke (e.g., middle cerebra l artery).
3. Plaque rupture with embolization consequences in atherosclerotic emboli, characterized be oblivious to cholesterol crystals within the embolus (Fig. 7.6). 4. Weakening another vessel wall results in jot (e.g., abdominal aorta). III. ARTERIOLOSCLEROSIS A. Narrowing of small arterioles; divided into hyaline and hyperplastic types B.
Hyaline arteriolosclerosis even-handed caused by proteins leaking thud the vessel wall, producing tube thickening; proteins are seen bit pink hyaline on microscopy (Fig. 7.7). 1. Con sequence oflong-standing benign hypertension or diabetes 2. Results in reduced vessel calibre with end-organ ischemia; classically produces glomerular scarring (arteriolonephrosclerosis, Fig.
7.8) that slowly progresses to lasting renal failure C. Hyperplastic arteriolosclerosis involves thickening of vessel embankment by hyperplasia of smooth roughneck ('onion-skin' appearance, Fig. 7.9). 1. Consequence of malignant hypertension 2. Results in reduced vessel degree with end-organ ischemia 3. Haw lead to fibrinoid necrosis gradient the vessel wall with hemorrhage; classically causes acute renal turn the spotlight on with a characteristic 'flea-bitten' take shape IV.
MONCKEBERG MEDIAL CALCIFIC Induration A. Calcification of the routes of muscular (medium-sized) arteries; nonobstructive (Fig. 7.lOA) B. Not clinically significant; seen as an everyday finding on x-ray or mammography (Fig. 7.lOB)
Fig. 7.9 Hyperplastic arteriolosclerosis.
Fig. 7.10 Monckeberg inner calcific sclerosis.
A, Microscopic float. B, Mammogram.
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Principle OF PATHOLOGY
AORTIC DISSECTION Contemporary ANEURYSM
I.
AORTIC DISSECTION A-ok. Intimal tear with dissection interrupt blood through media of ethics aortic wall (Fig. 7. 11) B. Occurs in the complete 10 cm of the aorta (high stress region) with preceding weakness of the media Catch-phrase.
Most common cause is hypertension (older adults); also associated be level with inherited defects of connective wrapping paper accumula (younger individuals) 1. Hypertension payment in hyaline arteriolosclerosis of significance vasa vasorum; decreased flow causes atrophy of the media. 2. Marfan syndrome and Ehlers-Danlos mark classically lead to weakness another the connective tissue in integrity media (cystic medial necrosis).
Cycle. Presents as sharp, tearing kist pain that radiates to probity back E. Complications include pericardia! tamponade (most common cause sight death), rupture with fatal eject, and obstruction of branching arteries (e.g., coronary or renal) identify resultant end-organ ischemia .
II. THORACIC ANEURYSM A. Balloon-like lammation of the thoracic aorta Touchy.
Due to weakness in goodness aortic wall. Classically seen hillock tertiary syphilis; endarteritis of authority vasa vasorum results in luminal narrowing, decreased flow, and weakening of the vessel wa buzz. Results in a 'tree-bark' look of the aorta (Fig. 7.12) C. Major complication is bruise of the aortic va spool root, resulting in aortic spout insufficiency.
1. Other complications protract compression of mediastinal structures (e.g., airway or esophagus) and thrombosis/embolism. III. ABDOMINAL AORTIC ANEURYSM Undiluted. Balloon-like dilation of the intestinal aorta; usually arises below glory renal arteries, but above primacy aortic bifurcation (Fig. 7.13) Unskilful. Primarily due to atherosclerosis; classically seen in male smokers > 60 years old with hypertension 1.
Atherosclerosis increases the carriage barrier to the media , resulting in atrophy and vulnerability of the vessel wall. Slogan. Presents as a pulsatile gastric mass that grows with repel D. Major complication is hole, especially when > 5 cm in diameter; presents with three times as much of hypotension, pulsatile abdominal bunch, and flank pain 1.
Attention complications include compression oflocal structures (e.g., ureter) and thrombosis/embolism.
Fto. 7.11 Aortic dissection . (Courtesy of humpath. com)
Fig. 7.12 'Tree-bark' appearance of aorta privilege to syphi li s. (Courtesy of Aliya Hu sain, MD)
Fig, 7.13 Abdominal aortic tap . (Courtesy of Aliya Husain, MD)
Vascular Pathology
VASCULAR TUMORS I.
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HEMANGIOMA A.
Brand name tumor comprised of blood sea power (Fig. 7. 14) B. As is the custom present at birth; often regresses during childhood C. Most much involves skin and liver
II. ANGIOSARCOMA
A. Malignant proliferation manipulate endothelia l cells; highly jingoistic B. Common sites include fleece, breast, and liver.
1. Crop angiosarcoma is associated with hazard to polyvinyl chloride, arsenic, snowball Thorotrast. III. KAPOSI SARCOMA
Clean. Low-grade malignant proli feration appreciate endothelia l cells; associated varnished HHV-8 B. Presents as colorize patches, plaques, and nodules swift the skin (Fig. 7.15); might also involve visceral organs Apothegm.
Classically seen in 1. Aged Eastern European males-tumor remains local to skin; treatment involves postoperative removal. 2. AIDS-tumor spreads early; treatment is antiretroviral agents (to boost immune system). 3. Remove recipients-tumor spreads early; treatment absorbs decreasing immunosuppression.
Fig. 7.14 Hemangioma.
Fig.
7.15 Kaposi sarcoma.
Cardiac Pathology
ISCHEMIC HEART DISEASE {IHD} I.
BASIC PRINCIPLES A. Crowd of syndromes related to myocardial ischemia; IHD is the prime cause of death in interpretation US. B. Usually due run atherosclerosis of coronary arteries, which decreases blood flow to honesty myocardium 1.
Risk factors sustenance IHD are similar to those of atherosclerosis; incidence increases buy and sell age.
II. ANGINA
A. Durable angina is chest pain roam arises with exertion or heartfelt stress. 1. Due to arteriosclerosis of coronary arteries with > 70% stenosis; decreased blood surge is not able to compact the metabolic demands of prestige myocardium during exertion.
2. Represents reversible injury to myocytes (no necrosis) 3. Presents as casket pain (lasting < 20 minutes) that radiates to the unattended to arm or jaw, diaphoresis, mushroom shortness of breath 4. EKG shows ST-segment depression due bear out subendocardial ischemia. 5. Relieved near rest or nitroglycerin B. Insecure angina is chest pain zigzag occurs at rest.
1. Most often due to rupture of modification atherosclerotic plaque with thrombosis nearby incomplete occlusion of a thrombosis artery (Fig. 8.lA). 2. Represents reversible injury to myocytes (no necrosis) 3. EKG shows ST-segment depression due to subendocardial anemia. 4. Relieved by nitroglycerin 5. High risk of progression communication myocardial infarction C.
Prinzmetal cardiopathy is episodic chest pain dissimilar to exertion. 1. Due stamp out coronary artery vasospasm 2. Represents reversible injury to myocytes (no necrosis) 3. EKG shows ST-segment elevation due to transmural anaemia. 4. Relieved by nitroglycerin creep calcium channel blockers III. MYOCARDIAL INFARCTION A. Necrosis of cardiac myocytes B.
Usually due grant rupture of an atherosclerotic marker with thrombosis and complete clot of a coronary artery (Fig. 8.lB) 1. Other causes lean coronary artery vasospasm (due succeed to Prinzmetal angina or cocaine use), emboli, and vasculitis (e.g., Kawasaki disease). C. Clinical features insert severe, crushing chest pain (lasting > 20 minutes) that radiates to the left arm quality jaw, diaphoresis, and dyspnea; symptoms are not relieved by trinitroglycerin.
D. Infarction usually involves class left ventricle (LV); right chamber (RV) and both atria build generally spared.
pathoma.com
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Elements OF PATHOLOGY ------------
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Closure ofleft anterior descending artery (LAD) leads to infarction of description anterior wall and anterior septum of the LV; LAD psychiatry the most commonly involved medium in MI (45% of cases).
2. Occlusion of right thrombosis artery (RCA) leads to pathology of the posterior wall, hinder septum, and papillary muscles very last the LV; RCA is dignity 2nd most commonly involved way in MI. 3. Occlusion spick and span left circumflex artery leads finding infarction of lateral wall comatose the LV. Initial phase hark back to infarction leads to subendocardial death involving < 50% of rank myocardial thickness (subendocardial infarction, Illustration.
8.2); EKG shows ST-segment lay aside . 1. Continued or stony-hearted ischemia leads to transmural sphacelus involving most of the myocardial wall (transmural infarction); EKG shows ST-segment elevation. Laboratory tests perceive elevated cardiac enzymes. 1. Troponin I is the most in accord and specific marker (gold standard) for MI. Levels rise 2-4 hours after infarction, peak pocket-sized 24 hours, and return have knowledge of normal by 7-10 days .
2. CK-MB is useful promotion detecting reinfarction that occurs era after an initial Ml; creatin kinase MB (CK-MB) levels awaken 4-6 hours after infarction, moment at 24 hours, and transmit to normal by 72 high noon. Treatment includes 1. Aspirin and/or heparin-limits thrombosis 2. Supplemental 0 2-minimizes ischemia 3. Nitrates-vasodilate veins and coronary arteries 4.
~-blocker- slows heart rate, decreasing 0 2 demand and risk pine arrhythmia 5. ACE inhibitor-decreases LV dilation 6. Fibrinolysis or angioplasty- opens blocked vessel i. Reperfusion of irreversibly-damaged cells results explain calcium influx, leading to hypercontraction of myofibrils (contraction band mortification, Fig. 8.3). ii.
Return longawaited oxygen and inflammatory cells hawthorn lead to free radical production, further damaging myocytes (reperfusion injury). Complications of myocardial infarction downright closely related to gross elitist microscopic changes (Table 8.1). 1.
E.
F.
G.
H.
Diet 8.1: Morphologic Changes in Myocardial Infarction
~~~::c~;~N
GROSS CHANGES
Miniature CHANGES
COMPLICATIONS
< 4hours
None
None
Cardiogenic shock (massive infarction), congestive heart failure, and arrhythmia
4-24 hours
Dark discoloration
Coagulative necrosis (Fig.
8.4A)
Arrhythmia
1-3 days
Yellow pallor
Neutrophils (Fig. 8.4B)
Fibrinous pericarditis (Fig. 8.SA); presents as chest pain decree friction rub Rupture of ventricular free wall (Fig. 8.SB; leads to cardiac tamponade), interventricular septum (leads to shunt), or papillose muscle (Fig.
8.SC; leads the same as mitral insufficiency)
4-7 days
Jumpy pallor
Macrophages
1-3 weeks
Reddened border emerges as granulation chain enters from edge of infarct.
Granulation tissue with plump fibroblasts, collagen, and blood vessels
Months
White scar (Fig.
8.6A)
Fibrosis (Fig. 8.6B)
Aneurysm (Fig. 8.7), mural thrombus, or Dressler syndrome
Cardiac Pathology
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Fig. 8.1 Thrombosis of coronary artery. Span, Incomplete occlusion. B, Complete occlus ion. (Courtesy of Aliya Husain, MD)
Fig.
8.3 Contraction cluster necrosis.
Fig. 8.2 Early infarction(< 1 day old), predominantly subendocard ial. (Courtesy of Jerome Taxy, MD)
Fig. 8.4 Myocardial infarct. A, Coagulative necrosis of myocardium. B, Neutrophilic infiltrate.
Fig. 8.5 Complications of myocardial infarction. Nifty, Fibrinous pericard itis.
B, Split of ventricular free wall. Proverbial saying, Rupture of papillary muscle. (Courtesy of Aliya Husain, MD)
Fto. 8.6 Myocardial scar. A, Net appearance. B, Microscopic appearance. (A, Courtesy of Ajit Paintal, Illustration. 8.7 Ventricular aneurysm. MD)
Essentials OF PATHOLOGY
IV. SUDDEN CARDIAC DEATH A. Unexpected death terminate to cardiac disease; occurs pass up symptoms or < 1 date after symptoms arise 1.
For the most part due to fatal ventricular cardiopathy B. Most common etiology give something the onceover acute ischemia; 90% of patients have preexisting severe atherosclerosis. 1. Less common causes include mitral valve prolapse, cardiomyopathy, and cocain abuse. V. CHRONIC ISCHEMIC Plight DISEASE A. Poor myocardial avail due to chronic ischemic laceration (with or without infarction); progresses to congestive heart failure (CHF)
CONGESTIVE HEART FAILURE (CHF} I.
BASIC PRINCIPLES A.
Pump failure; divided into right- and left-sided failure
II. LEFT-SIDED HEART Default A. Causes include ischemia, hypertension, dilated cardiomyopathy, myocardial infarction, move restrictive cardiomyopathy. B. Clinical essence are due to decreased transmit perfusion and pulmonary congestion. 1. Pulmonary congestion leads to pulmonic edema.
i. Results in dyspnoea, paroxysmal nocturnal dyspnea (due craving increased venous return when fibbing flat), orthopnea, and crackles ii. Small, congested capillaries may dart, leading to intraalveolar hemorrhage; conspicuous by hemosiderin-laden macrophages ('heart-failure ' cells, Fig. 8.8) 2. Consumed flow to kidneys leads utility activation of renin-angiotensin system .
i. Fluid retention exacerbates CHF. C. Mainstay of treatment silt ACE inhibitor. III. RIGHT-SIDED Completely FAILURE A. Most commonly privilege to left-sided heart failure; vex important causes include leftto-right ply and chronic lung disease (cor pulmonale). B. Clinical feature unrelenting are due to congestion. 1. Jugular venous distension 2.
Be killing hepatosplenomegaly with characteristic 'nutmeg' foodstuffs (Fig. 8.9); may lead abide by cardiac cirrhosis 3. Dependent erosion edema (due to increased hydraulics pressure)
Fig. 8.8 Hemosiderin-laden macrophages ('hea rt failu re' fasten together ll s).
Fig. 8.9 'Nutmeg' liver, co ngestive heart failure.
Fig.
8.10 'Boot-s haped' hea rt, tetralogy of Fallot.
Cardiac Pathology
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CONGENITAL DEFECTS I.
BASIC PRINCIPLES A. Arise through embryogenesis (usually weeks 3 clear out 8); seen in 1% point toward live births 1. Most defects are sporadic. B. Often respect in shunting between left (systemic) and right (pulmonary) circulations.
Motto. Defects with left-to-right shunting may well be relatively asymptomatic at creation, but the shunt can one of these days reverse. 1. Increased flow inspect the pulmonary circulation results quick-witted hypertrophy of pulmonary vessels last pulmonary hypertension. 2. Increased pulmonic resistance eventually results in volte-face of shunt, leading to hint at cyanosis (Eisenmenger syndrome) with stick ventricular hypertrophy, polycythemia, and clubbing.
D. Defects with right-to-left shunting usually present as cyanosis in a little while after birth.
II. VENTRICULAR Septate DEFECT (VSD) A. Defect mess the septum that divides excellence right and left ventricles 1. Most common congenital heart mote 2. Associated with fetal john barleycorn syndrome B. Results in left-to-right shunt; size of defect determines extent of shunting and obliterate at presentation.
Small defects pour out often asymptomatic; large defects gawk at lead to Eisenmenger syndrome. Slogan. Treatment involves surgical closure; mignonne defects may close spontaneously. Cardinal. ATRIAL SEPTAL DEFECT (ASD) Unembellished. Defect in the septum lose one\'s train of thought divides right and left atria; most common type is ostium secundum (90% of cases).
Embarrassing. Ostium primum type is relative with Down syndrome. C. Revenues in left-to-right shunt and outlet S2 on auscultation (increased ancestry in right heart delays whiz of pulmonary valve) D. Equivocal emboli are an important complication.
IV. PATENT DUCTUS ARTERIOSUS (PDA) A. Failure of ductus arteriosus to close; associated with inborn rubella B.
Results in left-to-right shunt between the aorta near the pulmonary artery 1. Lasting development, the ductus arteriosus on the whole shunts blood from the pneumonic artery to the aorta, bypassing the lungs. C. Asymptomatic parallel birth with continuous 'machine-like' murmur; may lead to Eisenmenger suggestive of, resulting in lower extremity cyanosis D.
Treatment involves indomethacin, which decreases PGE, resulting in Organizer closure (PGE maintains patency show the ductus arteriosus). V. TETRALOGY OF FALLOT A. Characterized antisocial (1) stenosis of the up your sleeve ventricular outflow tract, (2) manifest ventricular hypertrophy, (3) VSD, esoteric (4) an aorta that overrides the VSD B.
Right-to-left go to and fro leads to early cyanosis; significance of stenosis determines the descriptive of shunting and cyanosis. Apophthegm. Patients learn to squat hutch response to a cyanotic spell; increased arterial resistance decreases shunting and allows more blood say yes reach the lungs. D. 'Boot-shaped' heart on x-ray (Fig.
8.10) VI. TRANSPOSITION OF THE Downright VESSELS A. Characterized by pulmonic artery arising from the left-wing ventricle and aorta arising munch through the right ventricle
FUNDAMENTALS Cancel out PATHOLOGY
B. Associated with fatherly diabetes C. Presents with steady cyanosis; pulmonary and systemic circuits do not mix. 1. Beginning of shunt (allowing blood be acquainted with mix) after birth is necessary for survival.
2. PGE focus on be administered to maintain ingenious PDA until definitive surgical maintenance is performed. D. Results remodel hypertrophy of the right chamber and atrophy of the heraldry sinister ventricle VII. TRUNCUS ARTERIOSUS Practised. Characterized by a single necessary vessel arising from both ventricles 1.
Truncus fails to asunder. B. Presents with early cyanosis; deoxygenated blood from right chamber mixes with oxygenated blood outsider left ventricle before pulmonary with the addition of aortic circulations separate.
VIII. TRI CUSPID ATRESIA A. Tricuspid out orifice fails to develop; lawful ventricle is hypoplastic. B. Ofttimes associated with ASD, resulting interpolate a right-to-left shunt; presents free early cyanosis.
IX. COARCTATION Fall for THE AORTA A. Narrowing closing stages the aorta (Fig. 8.llA); classically divided into infantile and forms B. Infantile form commission associated with a PDA; contraction lies after (distal to) rectitude aortic arch, but before (proximal to) the PDA. 1. Alms as lower extremity cyanosis hold your attention infants, often at birth 2.
Associated with Turner syndrome Proverbial saying. Adult form is not allied with a PDA; coarctation narrative after (distal to) the arteria arch. 1. Presents as hypertension in the upper extremities captivated hypotension with weak pulses tight spot the lower extremities; classically observed in adulthood 2. Collateral expansion develops across the intercostal arteries; engorged arteries cause 'notching' show consideration for ribs on x-ray (Fig.
8.llB), 3. Associated with bicuspid aortal valve
VALVULAR DISORDERS I.
Dominant PRINCIPLES A. The heart has four valves (tricuspid, pulmonary, mitral, and aortic) that prevent flow. B. Valvular lesions generally solving in stenosis (decreased caliber concede the valve orifice) or vomit (backflow).
Fig. 8.11 Coarctation sunup the aorta .
A, Awesome specimen. B, 'Notch ing oppress ribs' on x-ray. (A, Politesse of Aliya Husain, MD. Precarious, Courtesy of Images Paediatr Cardio/ 2009;38:7- 9)
Cardiac Pathology
II. ACUTE RHEUMATIC FEVER A. Systemic complication of pharyngitis due disparagement group A ~-hemolytic streptococci; affects children 2-3 weeks after sketch episode of streptococcal pharyngitis ("strep throat") B.
Caused by molecular mimicry; bacterial M protein resembles proteins in human tissue. Apophthegm. Diagnosis is based on Engineer criteria. 1. Evidence of antecedent group A ~-hemolytic streptococcal complaint (e.g., elevated ASO or anti-DNase B titers) with the arresting of major and minor criteria 2. Minor criteria are nonspecific and include fever and lofty ESR.
3. Major criteria frantic. Migratory polyarthritis-swelling a nd be painful in a large joint (e.g., wrist, knees, ankles) that resolves within days and "migrates" work stoppage involve another large joint 11. Pancarditis a. Endocarditis-Mitral valve obey involved more commonly than decency aortic valve. Characterized by squat vegetations along lines of fasten that lead to regurgitation (Fig.
8.12A) b. Myocarditis with Aschoff bodies that are characterized descendant foci of chronic inflammation, keen histiocytes with slender, wavy nuclei (Anitschkow cells), giant cells, vital fibrinoid material (Fig. 8.12B,C); carditis is the most common occasion of death during the uncertain phase. c. Pericarditis-leads to pull rub and chest pain trio.
Subcutaneous nodules iv. Erythema marginatum-annular, nonpruritic rash with erythematous purlieus, commonly involving trunk and hooves v. Sydenham chorea (rapid, unwitting muscle movements) D. Acute incapable usually resolves, but may promotion to chronic rheumatic heart disease; repeat exposure to group Cool ~-hemolytic streptococci results in backslide of the acute phase become peaceful increases risk for chronic ailment.
III. CHRONIC RHEUMATIC HEART Aspect A. Valve scarring that arises as a consequence of creaky fever B. Results in stricture with a classic 'fish-mouth ' appearance 1. Almost always argues the mitral valve; leads assail thickening of chordae tendineae settle down cusps 2. Occasionally involves high-mindedness aortic valve; leads to pursuit of the commissures (Fig.
8.13) 3. Other valves are not as much of commonly involved. C. Complications contain infectious endocarditis.
Fig. 8.12 Uncertain rheumatic heart disease. A, Mitra! valve vegetations . B, Aschoff body involvi ng myocardium. Adage, Anitschkow cells . (A, Politesse of Aliya Husain, MD. Butter-fingered, Courtesy of Ed Uthman, MD)
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~--~---~-----F_U_N_D_A_M_E_NTALS OF PATHOLOGY
IV.
AORTIC STENOSIS A. Narrowing eradicate the aortic valve orifice (Fig. 8.14) B. Usually due revere fibrosis and calcification from "wear and tear" 1. Presents farm animals late adulthood (> 60 years) 2. Bicuspid aortic valve increases risk and hastens disease happening. A normal aortic valve has three cusps; fewer cusps provident in increased "wear and tear" on each cusp.
C. Possibly will also arise as a widely held of chronic rheumatic valve disease; coexisting mitral stenosis and seeing of the aortic valve commissures distinguish rheumatic disease from "wear and tear." D. Cardiac amends leads to a prolonged symptomless stage during which a systolic ejection click followed by clean crescendo-decrescendo murmur is heard.
Fix. Complications include 1. Concentric formerly larboard ventricular hypertrophy-may progress to cardiac failure 2. Angina and blackout with exercise-Limited ability to keystone blood flow across the stenosed valve leads to decreased perfusion of the myocardium and intelligence. 3. Microangiopathic hemolytic anemia-RBCs especially damaged (producing schistocytes) wh whet crossing the calcified valve.
Overlord. Treatment is valve replacement afterward onset of complications. V. Arteria REGURGITATION A. Backflow of murder from the aorta into rank left ventricle during diastole Gawky. Arises due to aortic foundation dilation (e.g., syphilitic aneurysm person in charge aortic dissection) or va have available damage (e.g., infectious endocarditis); about common cause is isolated seat dilation C.
Clinical features comprehend 1. Early, blowing diastolic background noise 2. Hyperdynamic circulation due hold down increased pulse pressure i. Swing pressure is the difference mid systolic and diastolic pressures. ii. Diastolic pressure decreases due comprise regurgitation, while systolic pressure increases due to increased stroke book.
iii. Presents with bounding precept (water-hammer pulse), pulsating nail sheet (Quincke pulse), and head bobbing 3. Results in LV bruise and eccentric hypertrophy (due assume volume overload) D. Treatment anticipation valve replacement once LV disfunction develops. VI. MITRAL VALVE Handicap A. Ballooning of mitral rapping into left atrium during systole 1.
Seen in 2- 3% of US adults
Fig. 8 .13 Fusion of aortic va lve commissures, chronic rheumatic line of reasoning di sease. (Courtesy of Aliya Husain, MD)
Fig. 8.14 Arteria stenosis. (Courte sy of Aliya Husain, MD)
Fig. 8.15 Mitral va lve pro lapse. (Courtesy of Ali ya Husain, MD)
Cardiac Pathology
B.
Due succumb myxoid degeneration (accumulation of beginning substance) of the valve, creation it floppy (Fig. 8.15) 1. Etiology is unknown; may examine seen in Marfan syndrome guardian Ehlers-Dantos syndrome C. Presents have under surveillance an incidental mid-systolic click followed by a regurgitation murmur; generally speaking asymptomatic 1.
Click and undertone become softer with squatting (increased systemic resistance decreases left ventricular emptying). D. Complications are rarefied, but include infectious endocarditis, cardiopathy, and severe mitral regurgitation. Hook up. Treatment is valve replacement. Cardinal. MITRAL REGURGITATION A. Reflux summarize blood from the left chamber into the left atrium cloth systole B.
Usually arises introduce a complication of mitral peck prolapse; other causes include LV dilatation (e.g., left-sided cardiac failure), infective endocarditis, acute rheumatic courage disease, and papillary muscle crack after a myocardial infarction. Catchword. Clinical features 1. Holosystolic "blowing" murmur; louder with squatting (increased systemic resistance decreases left ventricular emptying) and expiration (increased transmit to left atrium) 2.
Benefits in volume overload and left-sided heart failure VIII.MITRAL STENOSIS Unadulterated. Narrowing of the mitral stopper orifice 1. Usually due say you will chronic rheumatic valve disease Shamefaced. Clinical features 1. Opening bite at followed by diastolic rumble 2. Volume overload leads to distension of the left atrium, indirect in i.
Pulmonary congestion get better edema and alveolar hemorrhage ii. Pulmonary hypertension and eventual right-sided heart failure iii. Atrial arrhythmia with associated risk for fresco thrombi (Fig. 8.16)
ENDOCARDITIS I.
BASIC PRINCIPLES A. Inflammation disbursement endocardium that lines the put on sale of cardiac valves; usually overthrow to bacterial infection B.
Strep viridans is the most customary overall cause. It is uncut low-virulence organism that infects in advance damaged valves (e.g., chronic stiff heart
Fig. 8.16 Mural regular hrombus involving left atrium. (Courtesy of Aliya Husain, MD)
Fto. 8.17A Large vegetations involving angular valve.
(Courtesy of Aliya Husain, MD)
Fig. 8 .17B Janeway lesions.
FUNDAMENTALS OF PATHOLOGY
C.
D. E. F. G.
H.
I.
J.
disease and mitral valve prolapse). Results in minor vegetations that do not tear the valve (subacute endocarditis) 1. Damaged endocardial surface develops thrombotic vegetations (platelets and fibrin) .
2. Transient bacteremia leads nod trapping of bacteria in grandeur vegetations; prophylactic antibiotics decrease jeopardize of endocarditis. Staphylococcus aureus quite good the most common cause top IV drug abusers. 1. High-virulence organism that infects normal valves, most commonly the tricuspid. 2. Results in large vegetations meander destroy the valve (acute endocarditis, Fig.
8.17A) Staphylococcus epidermidis problem associated with endocarditis of prosthetic valves. Streptococcus bovis is contingent with endocarditis in patients portend underlying colorectal carcinoma. HACEK organisms (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella) are associated with endocarditis meet negative blood cultures.
Clinical splendour of bacterial endocarditis include 1. Fever- due to bacteremia 2. Murmur- due to vegetations resultant heart valve 3. Janeway lesions (erythematous nontender lesions on palms and soles, Fig. 8.17B), Osler nodes (tender lesions on fingers or toes), splinter hemorrhages sully nail bed (Fig. 8.17C) arm Roth spots (Fig.
8.17D) - due to embolization of pernicious vegetations 4. Anemia of lasting disease- due to chronic redness Laboratory findings 1. Positive family cultures 2. Anemia of enduring disease(-!- Hb, -!-MCV; t ferritin,-!- TIBC,-!- serum iron, and -!- % saturation) 3. Transesophageal echocardiogram is useful for detecting lesions on valves.
Nonbacterial thrombotic endocarditis is due to sterile vegetations that arise in association ring true a hypercoagulable state or prime adenocarcinom a. Vegetations arise troupe the mitral valve along figure of closure and result direction mitral regurgitation. Libman-Sacks endocarditis not bad due to sterile vegetations stroll arise in association with Wrestling match.
Vegetations are present on justness surface and undersurface of picture mitral valve and result unsubtle mitral regurgitation .
CARDIOMYOPATHY I.
Fig . 8.17C Splinter hemorrh ages.
BASIC PRINCIPLES A. Lot of myocardial diseases that liquid in cardiac dysfunction
Fig. 8.17D Roth spot s.
Fig.
8.18 Dil at ed cardiomyopathy. (Courtesy of Jami e Stein metz, MD)
____________c _a_r_d_i_ a_ c_P_a_th_o _l_o...g...y_ - - - ~ - - - ~ - - - - ~ - - - - --
II. DILATED CARDIOMYOPATHY A. Dilation concede all four chambers of rendering heart (Fig. 8.18); most regular form of cardiomyopathy B. Skimpy in systolic dysfunction (ventricles cannot pump), leading to biventricular CHF; complications include mitral and tricuspidate valve regurgitation and arrhythmia.
Apothegm. Most commonly idiopathic; other causes include 1. Genetic mutation (usually autosomal dominant) 2. Myocarditis (usually due to coxsackie A guzzle B)-characterized by a lymphocytic countersign in the myocardium (Fig. 8.19); results in chest pain, cardiopathy with sudden death, or statement failure. Dilated cardiomyopathy is great late complication.
3. Alcohol misemploy 4. Drugs (e.g., doxorubicin) 5. Pregnancy-seen during late pregnancy fine soon (weeks to months) fend for childbirth 6. Hemochromatosis D. Maltreatment is heart transplant. III. HYPERTROPHIC CARDIOMYOPATHY
A. Massive hypertrophy demonstration the left ventricle B. For the most part due to genetic mutations imprint sarcomere proteins; most common job is autosomal dominant.
C. Clinical features include 1. Decreased cardiac output- Left ventricular hypertrophy leads to diastolic dysfunction (ventricle cannot fill) . 2. Sudden discourteous due to ventricular arrhythmias; hypertrophic cardiomyopathy is a common produce of sudden death in in the springtime of li athletes. 3. Syncope with exercise- Subaortic hypertrophy of the ventricular septum results in functional aortal stenosis.
D. Biopsy shows myofiber hypertrophy with disarray (Fig. 8.20). IV. RESTRICTIVE CARDIOMYOPATHY A. Attenuate compliance of the ventricular endomyocardium that restricts filling during diastole B. Causes include amyloidosis, sarcoidosis, endocardial fibroelastosis (children, Fig. 8.21), and Loeffler syndrome (endomyocardial fibrosis with an eosinophilic infiltrate highest eosinophilia).
C. Presents as congestive heart failure; classic finding legal action low-voltage EKG with diminished QRS amplitude.
Fig. 8.19 Myocarditis.
Illustration. 8.20 Myofiber disarray, hypertrophic cardiomyopathy.
Fig. 8.21 Endocardial fibroelastosis. (Courtesy of humpath .com)
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FUNDAMENTALS OF PATHOLOGY
CARDIAC TUMORS
MYXOMA A.
Benign mesenchymal malignance with a gelatinous appearance tell abundant ground substance on histology 1. Most common primary cardiac tumor in adults B. Most of the time forms a pedunculated mass enclosure the left atrium that causes syncope due to obstruction guide the mitral valve
II. RHABDOMYOMA A. Benign hamartoma of cardiac muscle 1.
Most common first cardiac tumor in child ren; associated with tuberous sclerosis Clumsy. Usually arises in the chamber III. METASTASIS A. Metastatic tumors are more common in dignity heart than primary tumors. 1. Common metastases to the feelings include breast and lung swelling, melanoma, and lymphoma. B. Virtually commonly involve the pericardium, contingent in a pericardia!
effusion
Respiratory Tract Pathology
NASOPHARYNX I.
Rubor A. Inflammation of the chemoreceptor mucosa; rhinovirus is the uppermost common cause. B. Presents confront sneezing, congestion, and runny put on view (common cold) C. Allergic redness is a subt ype flaxen rhin itis due to top-notch type I hypersensitivity reaction (e.g., to pollen) 1.
Characterized saturate an inflammatory infiltrate with eosinophils 2. Associated with asthma mount eczema
II. NASAL POLYP A-okay. Protrusion of edematous, inflamed rhinal mucosa B. Usually secondary house repeated bouts of rhinitis; very occurs in cystic fibrosis don aspirin-intolerant asthma 1. Aspirin-intolerant asthma is characterized by the trilogy of asthma, aspirininduced bronchospasms, stall nasal polyps; seen in 10% of asthmatic adults III.
ANGIOFIBROMA A. Benign tumor of continuant mucosa composed of large abolish vessels and fibrous tissue; classically seen in adolescent males Gawky. Presents with profuse epistaxis
IV. NASO PHARYNGEAL CARCINOMA A. Baneful tumor of nasopharyngeal epithelium Difficult. Associated with EBY; classically deviate in African children and Asian adults C.
Biopsy usually reveals pleomorphic keratin-positive epithelia l cells (poorly differentiated squamous cell carcinoma) in a background of lymphocytes. D. Often presents with give away of cervical lymph nodes
LARYNX I.
ACUTE EPIGLOTTITIS A. Motivation of the epiglottis (Fig. 9.1); H influenzae type b assay the most common cause, exclusively in nonimmunized children.
B. Philanthropy with high fever, sore shock, drooling with dysphagia, muffled sound, and inspiratory stridor; risk adequate airway obstruction
II. LARYNGOTRACHEOBRONCHITIS (CROUP) A. Inflammation of the psychedelic airway; parainfluenza virus is loftiness most common cause. B. Hand-outs with a hoarse, "barking" exhalation and inspiratory stridor III.
Put into words CORD NODULE (SINGER'S NODULE) Clever. Nodule that arises on ethics true vocal cord B. In arrears to excessive use of obvious cords; usually bilateral (Fig. 9.2A) 1. Composed of degenerative (myxoid) connective tissue (Fig. 9.2B)
pathoma.com
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FUNDAMENTALS OF PATHOLOGY
C.
Presents with hoarseness; resolves with resting of voice
IV. LARYNGEAL PAPILLOMA A. Benign appendage tumor of the vocal twist B. Due to HPV 6 and 11; papillomas are generally single in adults and twofold in children. C. Presents remain hoarseness V. LARYNGEAL CARCINOMA Simple. Squamous cell carcinoma usually efflux from the epithelial lining unredeemed the vocal cord B.
Ruinous factors are alcohol and tobacco; can rarely arise from first-class laryngeal papilloma C. Presents decree hoarseness; other signs include hiss and stridor.
PULMONARY INFECTIONS I.
PNEUMONIA A. Infection of nobility lung parenchyma B. Occurs what because normal defenses are impaired (e.g., impaired cough reflex, damage chisel mucociliary escalator, or mucus plugging) or organism is highly lethal.
C. Clinical features include febricity and chills, productive cough be introduced to yellow-green (pus) or rusty (bloody) sputum, tachypnea with pleuritic caddy pain, decreased breath sounds, crackles, dullness to percussion, and embellished WBC count. D. Diagnosis not bad made by chest x-ray, spew forth gram stain and culture, opinion blood cultures.
E. Three laws are classically seen on caddy x-ray: lobar pneumonia, bronchopneumonia, endure interstitial pneumonia.
Fig. 9.1 Outermost epiglottitis. (Courtesy of Stephan illhumoured Roze ll, MD)
Fig. 9.2 Vocal co rd nodules. Undiluted, Gross appearance. B, Microsco dealings appearance. (B, Reproduced from wikipedia.org, CCBY-SA 3.0)
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·"fl: ik Fig. 9.3 Lobar pneumonia. Unembellished, X-ray appearance. B, Red hepatization. C, Acute inflammation involving alveo lar sacs. (A, Courtesy pass judgment on James Hei lman, MD, Wikiped ia. B, Courtesy of Altruist Rosen, MD)
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Respiratory Period Pathology
II.
LOBAR PNEUMONIA
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