Rapid Review Pathology PDF 4th Edition

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Full details and terms of use are available upon registration, and access will be subject to your acceptance of these terms of use. For technical assistance: email [email protected] call 800-401-9962 (inside the US) / call +1-314-995-3200 (outside the US) ii  Rapid Review Series Series Editor Edward F. Goljan, MD BEHAVIORAL SCIENCE, SECOND EDITION Vivian M. Stevens, PhD; Susan K. Redwood, PhD; Jackie L. Neel, DO; Richard H. Bost, PhD; Nancy W. Van Winkle, PhD; Michael H. Pollak, PhD BIOCHEMISTRY, THIRD EDITION John W. Pelley, PhD; Edward F. Goljan, MD GROSS AND DEVELOPMENTAL ANATOMY, THIRD EDITION N. Anthony Moore, PhD; William A. Roy, PhD, PT HISTOLOGY AND CELL BIOLOGY, SECOND EDITION E. Robert Burns, PhD; M. Donald Cave, PhD MICROBIOLOGY AND IMMUNOLOGY, THIRD EDITION Ken S. Rosenthal, PhD; Michael J. Tan, MD NEUROSCIENCE James A. Weyhenmeyer, PhD; Eve A. Gallman, PhD PATHOLOGY, FOURTH EDITION Edward F. Goljan, MD PHARMACOLOGY, THIRD EDITION Thomas L. Pazdernik, PhD; Laszlo Kerecsen, MD PHYSIOLOGY, SECOND EDITION Thomas A. Brown, MD USMLE STEP 2 Michael W. Lawlor, MD, PhD USMLE STEP 3 David Rolston, MD; Craig Nielsen, MD RAPID REVIEW PATHOLOGY FOURTH EDITION EDWARD F. GOLJAN, MD Professor Department of Pathology Oklahoma State University Center for Health Sciences College of Osteopathic Medicine Tulsa, Oklahoma 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 RAPID REVIEW PATHOLOGY, FOURTH EDITION 978-0-323-08787-2 Copyright © 2014 by Saunders, an imprint of Elsevier Inc. Copyright © 2011, 2007, 2004 by Mosby, Inc., an affiliate of Elsevier Inc. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data Goljan, Edward F. Rapid review pathology / Edward F. Goljan.—Ed. 4.    p. ; cm.—(Rapid review series) Pathology Includes bibliographical references and index. ISBN 978-0-323-08787-2 (pbk. : alk. paper) I. Title. II. Title: Pathology. III. Series: Rapid review series. [DNLM: 1. Pathology—Examination Questions. 2. Pathology—Outlines. QZ 18.2] 616.07—dc23 2012042909 Senior Content Strategist: James Merritt Content Developmental Specialist: Christine Abshire Publishing Services Manager: Jeff Patterson Senior Project Manager: Tracey Schriefer Design Direction: Steven Stave Working together to grow libraries in developing countries Printed in the United States of America. www.elsevier.com | www.bookaid.org | www.sabre.org Last digit is the print number: 9 8 7 6 5 4 3 2 1 To all our grandchildren—Austin, Bailey, Colby, Dylan, Gabriel, Phin, Rigney, Sofia, and those great-grandchildren yet to come—thank you for keeping us “young at heart.” —Nannie and Poppie  Preface Writing a new edition of a book always provides an opportunity to improve upon previous editions. This fourth edition of Rapid Review Pathology reflects these improvements thanks to many discussions I have had over the past 4 years with my colleagues in the basic sciences and my students, and comments from students in other medical schools. The most substantial changes in this new edition include a new chapter entitled “Diagnostic Testing,” more images, updated management of key diseases, more integration with the basic and clinical sciences, and more tables to summarize information, particularly in microbiology. To users of the last edition of the book (Rapid Review Pathology Revised Reprint, Third Edition), a list of corrections and additions is available on your Student Consult page in the electronic version of Rapid Review Pathology, under the Extras tab. For instructions on how to activate your Student Consult version, see the PIN page on the inside front cover of your book and go to www.studentconsult.com to activate your PIN. Edward F. Goljan, MD vi  Acknowledgments The fourth edition of Rapid Review Pathology has been extensively revised to provide students with even more high-yield information and photographs than in previous editions. Many of the photographs are grouped together in collages to provide students with an opportunity to quickly review infectious diseases, dermatology, hematology, endocrinology, and many other key areas. In addition, the emphasis on margin notes and increased content in the summary tables provides the student with a “rapid review” of high-yield material for pathology examinations and USMLE and COMLEX Step 1 and 2 examinations. As in previous editions, I especially want to thank Ivan Damjanov, MD, PhD, whose many excellent photographs have been utilized throughout the book. I highly recommend his recently published Elsevier book, Pathophysiology, as a companion text to the Rapid Review Pathology text for providing students with an even greater understanding of patho- physiologic processes in disease. I also thank Edward Klatt, MD, who graciously allowed the use of so many of his excellent images from Robbins and Cotran Atlas of Pathology, a resource that I also highly recommend as a source of high-quality images and supplemen- tary learning. Special thanks to Nicole DiCicco and Christine Abshire from Elsevier, who kept track of all the major changes in the third edition and helped facilitate the early publication of the book. Special thanks also to Karlis Sloka, DO, valued friend and teacher, whose under- standing of disease processes helped me throughout the entire writing of the new edition. I want to thank Jim Merritt, Senior Content Strategist of Medical Education, who is the inspiration and primary energy behind the entire Rapid Review Series. Thanks Jim for a job well done! Finally, I would like to thank the myriad of medical students who have sent me e-mails with encouraging words on how the book has helped them not only perform well on boards, but also become better doctors. In particular, I would like to thank Gabriel Tonkin, who sent me referenced and updated material on numerous subjects that I used throughout the writing of the fourth edition. Edward F. Goljan, MD “Poppie” vii This page intentionally left blank  Contents CHAPTER 1 Diagnostic Testing   1 CHAPTER 2 Cell Injury   8 CHAPTER 3 Inflammation and Repair   36 CHAPTER 4 Immunopathology   56 CHAPTER 5 Water, Electrolyte, Acid-Base, and Hemodynamic Disorders   93 CHAPTER 6 Genetic and Developmental Disorders   126 CHAPTER 7 Environmental Pathology   158 CHAPTER 8 Nutritional Disorders   174 CHAPTER 9 Neoplasia   195 CHAPTER 10 Vascular Disorders   215 CHAPTER 11 Heart Disorders   239 CHAPTER 12 Red Blood Cell Disorders   279 CHAPTER 13 White Blood Cell Disorders   318 CHAPTER 14 Lymphoid Tissue Disorders   334 CHAPTER 15 Hemostasis Disorders   351 CHAPTER 16 Immunohematology Disorders   367 CHAPTER 17 Upper and Lower Respiratory Disorders   377 CHAPTER 18 Gastrointestinal Disorders   419 CHAPTER 19 Hepatobiliary and Pancreatic Disorders   467 CHAPTER 20 Kidney Disorders   500 CHAPTER 21 Lower Urinary Tract and Male Reproductive Disorders   528 ix x   Contents CHAPTER 22 Female Reproductive Disorders and Breast Disorders   547 CHAPTER 23 Endocrine Disorders   588 CHAPTER 24 Musculoskeletal and Soft Tissue Disorders   630 CHAPTER 25 Skin Disorders   659 CHAPTER 26 Nervous System and Special Sensory Disorders   690 APPENDIX Formulas for Calculations of Acid-Base Disorders   732 Index   734  CHAPTER 1 Diagnostic Testing Purpose of Laboratory Tests, 1 Creating Highly Sensitive and Specific Tests, 3 Operating Characteristics of Laboratory Tests, 2 Variables Affecting Laboratory Test Results, 3 Predictive Value of Positive and Negative Test Results, 2 I. Purpose of Laboratory Tests A. Screen for disease 1. General criteria for screening a. Effective therapy that is safe and inexpensive must be available. b. Disease must have a high enough prevalence to justify the expense. Criteria for screening c. Disease should be detectable before symptoms surface in the patient. test: ↑sensitivity and d. Test must not have many false positives (people misclassified as having disease). prevalence; cost- e. Test must have extremely high sensitivity. effective; treatable 2. Examples of screening tests a. Newborn screening for inborn errors of metabolism Examples—phenylketonuria, galactosemia, congenital hypothyroidism, and maple syrup urine disease b. Adult screening tests Cervical Pap: overall (1) Mammography for breast cancer best screening test for (2) Cervical Papanicolaou (Pap) smear for cervical cancer cancer (3) Screen for human papillomavirus DNA (4) Colonoscopy to detect/remove precancerous polyps (5) Fecal occult blood testing to detect colon cancer (6) Prostate-specific antigen (PSA) to detect prostate cancer Currently, there is debate over the usefulness of this test. (7) Bone densitometry scans to detect osteoporosis in women (8) Fasting lipid profiles to evaluate coronary artery risk Includes total cholesterol, high-density–lipoprotein cholesterol, low-density lipoprotein, and total triglyceride (9) Fasting blood glucose or 2-hour oral glucose tolerance test to screen for diabetes mellitus c. Screening people with symptoms of a disease Example—serum antinuclear antibody test to rule out autoimmune disease B. Confirm disease; examples: 1. Anti-Smith and double-stranded DNA antibodies to confirm systemic lupus erythematosus 2. Chest x-ray to confirm pneumonia 3. Urine culture to confirm a urinary tract infection 4. Serum troponins I and T to confirm an acute myocardial infarction (AMI) Confirm disease: serum 5. Tissue biopsy to confirm cancer troponins to diagnose 6. Fluorescent treponemal antibody absorption test to confirm syphilis AMI C. Monitor disease status; examples: 1. Hemoglobin (Hb) AIc to evaluate long-term glycemic control in diabetics 2. International normalized ratio (INR) to monitor warfarin therapy (anticoagulation) 3. Therapeutic drug monitoring to ensure drug levels are in the optimal range Monitor disease: HbA1c, 4. Pulse oximeter to monitor oxygen saturation during anesthesia, asthmatic attacks INR, pulse oximeter 1  2   Rapid Review Pathology Test result Disease No disease + Test True positive(TP) False positive (FP) – Test False negative (FN) True negative (TN) 1-1: People with disease either have true positive (TP) or false negative (FN) test results. People without disease either have true negative (TN) or false positive (FP) test results. II. Operating Characteristics of Laboratory Tests A. Terms for test results for people with a specific disease (Fig. 1-1) 1. True positive (TP) Definition—number of people with a specific disease who have a positive test result Test results in people 2. False negative (FN) with disease: TP and FN Definition—number of people with a specific disease who have a negative test result B. Terms for test results for people without disease (see Fig. 1-1) 1. True negative (TN) Test results in people Definition—number of people without disease who have a negative test result without disease: TN 2. False positive (FP) and FP Definition—number of people without disease who have a positive test result C. Sensitivity of a test 1. Sensitivity of a test is obtained by performing the test on people that are known to have the specific disease for which the test is intended (e.g., systemic lupus erythematosus [SLE]). Sensitivity = TP ÷ (TP + 2. Definition—likelihood that a person with disease will have a positive test result FN); “positivity” in 3. Formula for calculating sensitivity is TP ÷ (TP + FN). disease The FN rate determines the test’s sensitivity. 4. Usefulness of a test with 100% sensitivity (no FNs) a. Normal test result excludes disease (must be a TN). Test with 100% b. Positive test result includes all people with disease. sensitivity: normal result (1) Positive test result does not confirm disease. TN; positive result TP (2) Positive test result could be a TP or a FP. or FP c. Tests with 100% sensitivity are primarily used to screen for disease. D. Specificity of a test 1. Specificity of a test is obtained by performing the test on people who do not have the specific disease for which the test is intended. Control group should include people of various ages and both sexes, and those who have diseases that are closely related to the disease for which the test is intended. Specificity = TN ÷ (TN + 2. Definition—likelihood that a person without disease will have a negative test result FP); “negativity” in 3. Formula for calculating specificity is TN ÷ (TN + FP). health FP rate determines the test’s specificity. 4. Usefulness for a test with 100% specificity (no FPs) Test with 100% specificity: positive test a. Positive test result confirms disease (must be a TP). TP; negative test TN b. Negative test result does not exclude disease, because a test result could be a TN or a FN. or FN E. Comments on using tests with high sensitivity and specificity 1. When a test with 100% sensitivity (or close to it) returns negative (normal) on a patient on Usefulness of test with one or more occasion, the disease can be excluded from the differential list. 100% sensitivity: For example, if the serum antinuclear antibody (ANA) test returns negative on more than exclude disease when one occasion, the diagnosis of SLE can be excluded. test returns normal 2. When a test with 100% sensitivity returns positive on a patient, a test with 100% specificity (or close to it) should be used to decide if the test result was a TP or a FP. Usefulness of test with a. For example if the serum ANA returns positive in a patient who is suspected of having 100% specificity: distinguish TP from FP SLE, the serum anti-Smith (Sm) and anti–double-stranded DNA test should be used test result because they both have extremely high specificity for diagnosing SLE. b. If either or both tests return positive, the patient has SLE. c. If both tests consistently return negative, the patient most likely does not have SLE but some other closely related disease. III. Predictive Value of Positive and Negative Test Results A. Predictive value of a negative test result (PV−) 1. Definition—likelihood that a negative test result is a TN rather than a FN 2. Formula for calculating PV− is TN ÷ (TN + FN). PV− best reflects the true FN rate of a test.  Diagnostic Testing   3 Prevalence of disease PV– PV+ Low prevalence of disease Increases (TN > FN) Decreases (FP > TP) High prevalence of disease Decreases (FN > TN) Increases (TP > FP) 1-2: Note that in a low prevalence situation (e.g., ambulatory population), the PV− increases, while the PV+ decreases. The reverse occurs in a high prevalence situation (e.g., cardiac clinic) in that the PV− decreases and the PV+ increases. 3. Tests with 100% sensitivity (no FNs) always have a PV− of 100%. Sensitivity 100% → Disease is excluded from the differential list. PV− 100% → excludes B. Predictive value of a positive test result (PV+) disease 1. Definition—likelihood that a positive test result is a TP rather than a FP 2. Formula for calculating PV+ is TP ÷ (TP + FP). PV+ best reflects the true FP rate of a test. Specificity 100% → 3. Tests with 100% specificity (no FPs) always have a PV+ of 100%. PV+ 100% → confirms Disease is confirmed. disease C. Effect of prevalence on PV− and PV+ 1. Definition—total number of people with disease in the population under study Prevalence: total # Population includes people with disease and people without disease. people with disease in a 2. To calculate prevalence, people with disease are in the numerator (TP + FN) and people population with disease (TP + FN) and without disease (TN + FP) are in the denominator. Prevalence: (TP + FN) ÷ (TP + FN) ÷ (TP + FN + TN + FP) (TP + FN + TN + FP) 3. Low prevalence of disease (e.g., ambulatory population) (Figs. 1-2 and 1-3) a. PV− increases because more TNs are present than FNs. ↓Prevalence of disease: b. PV+ decreases because more FPs are present than TPs. ↑PV−, ↓PV+ 4. High prevalence of disease (e.g., cardiac clinic) (see Figs. 1-2 and 1-3) a. PV− decreases because more FNs are present than TNs. ↑Prevalence of disease: b. PV+ increases because more TPs are present than FPs. ↓PV−, ↑PV+ IV. Creating Highly Sensitive and Specific Tests A. Ideal test (Fig. 1-4A) 1. Ideal test has 100% sensitivity (PV− 100%) and 100% specificity (PV+ 100%). 2. Note in the schematic that there are no FNs or FPs, because there is no overlap between the normal and disease population. Serum troponins: 3. Ideal test is nonexistent; however, there are some tests that have very high sensitivity and ↑sensitivity and specificity that come close to being the ideal test (e.g., serum levels of troponins I and T in specificity; screen/ diagnosing an AMI). confirm AMI 4. Most normal ranges (reference intervals) do not distinguish the normal from the disease population (see Fig. 1-4B and C). Note that there is an overlap between the normal and the disease population in parts B and C of Figure 1-4. B. Establishing a test with 100% sensitivity and PV− (see Fig. 1-4B) 1. To establish a test with 100% sensitivity and PV−, set the cutoff point for the reference interval at the beginning of the disease curve (A). ↑Sensitivity/PV−: put a. Note that this creates a test with 100% sensitivity and 100% PV−, because there are no cutoff point at the FNs within the newly established reference interval (0 to A). beginning of the disease b. Test can now be used to screen for disease. curve; no FNs 2. Note that by increasing sensitivity there is always a corresponding decrease in the specificity and PV+ due to a greater number of FPs. C. Establishing a test with 100% specificity and PV+ (see Fig. 1-4C) 1. To establish a test with 100% specificity/PV+, set the upper cutoff point for the reference interval at the end of the normal curve (B). ↑Specificity/PV+: put a. Note that this creates a test with 100% specificity and 100% PV+, because there are no cutoff point at the end FPs outside the reference interval (0 to B). of the normal curve; b. Test can now be used to confirm disease. no FPs 2. Note that by increasing specificity there is always a corresponding decrease in sensitivity and PV−, due to a greater number of FNs. V. Variables Affecting Laboratory Test Results A. Premature newborns 1. Variable hemoglobin (Hb) concentration depending on the gestational age  4   Rapid Review Pathology A. Effect of low prevalence of systemic lupus erythematosus (SLE) on PV– and PV+ Sensitivity of serum ANA for SLE 100% Specificity of serum ANA for SLE 80% Prevalence of SLE is 1% Population under study 1000 10 True positive (TP) Number of people with SLE = 1000 x 0.01 = 10 x 100% sensitivity 0 False negative (FN) 792 True negative (TN) Number of people without SLE = 990 x 80% specificity 198 False positive (FP) SLE Control group Positive test result 10 TP 198 FP Negative test result 0 FN 792 TN Total number 10 990 PV+ = 10 (TP) ÷ [10 (TP) + 198 (FP)] = ~ 5% (100 – 5 = 95% FP rate) PV– = 792 (TN) ÷ [792 (TN) + 0 (FN)] = 100% (100 – 0 = 100% FN rate) B. Effect of high prevalence of systemic lupus erythematosus (SLE) on PV– and PV+ Sensitivity of serum ANA for SLE 100% Specificity of serum ANA for SLE 80% Prevalence of SLE is 50% Population under study 1000 500 True positive (TP) Number of people with SLE = 1000 x 0.50 = 500 x 100% sensitivity 0 False negative (FN) 400 True negative (TN) Number of people without SLE = 500 x 80% specificity 100 False positive (FP) SLE Control group Positive test result 500 TP 100 FP Negative test result 0 FN 400 TN Total number 500 500 PV+ = 500 (TP) ÷ [500 (TP) + 100 (FP)] = ~ 83% (100 – 83 = 17% FP rate) PV– = 400 (TN) ÷ [400 (TN) + 0 (FN)] = 100% (100 – 0 = 100% FN rate) 1-3: Note how the PV− remained the same in both prevalence situations because of the 100% sensitivity of the serum antinuclear antibody (ANA) for systemic lupus erythematosus (SLE). However, the PV+ significantly changed, going from a low prevalence of SLE (~5%) to a high prevalence of SLE (~83%). Anemia prematurity: 2. Anemia in prematurity is due to: loss of iron from a. Iron deficiency, related to loss of the daily supply of iron from the mother’s iron stores mother; blood loss from b. Blood loss from excessive venipunctures in the premature newborn venipuncture B. Newborns 1. Newborns have higher normal ranges for Hb, Hct, and RBC counts than do infants and children. 2. HbF (2α/2γ globin chains) shifts the OBC to the left causing the release of EPO. EPO causes an increase in Hb, Hct, and the RBC count. 3. Over the ensuing 8 to 12 weeks after birth, the Hb drops from 16.8 g/dL (range 14−20 g/dL) to 11 g/dL (this is called physiologic anemia).  Diagnostic Testing   5 1-4: Establishing tests with 100% sensitivity and A specificity. Schematic A shows an ideal test with Normal Disease 100% sensitivity (100% PV−) and 100% specificity Number of (100% PV+) when the normal range is 0 to A. Test people TN TP results below the A cutoff point are all true nega- tives (TN), whereas those beyond the A cutoff point TN TN TP TP are all true positives (TP). Schematic B shows a test 0 with 100% sensitivity (100% PV−) when the upper A cutoff point is at A. Note that as sensitivity increases, the specificity and PV+ decrease because of an 100% sensitivity 100% specificity increase in false positives (FP). Schematic C shows a PV– 100% PV+ 100% test with 100% specificity (100% PV+) when the upper cutoff point is at B. Note that as specificity increases, the sensitivity and PV− decrease because B of an increase in false negatives (FN). PV−, Predic- Normal Disease tive value of a negative test result; PV+, predictive Number of value of a positive test result. (From Goljan E, Sloka people K: Rapid Review Laboratory Testing in Clinical Medicine, TN Philadelphia, Mosby Elsevier, 2008, p 5, Fig. 1-3.) FP TP TP TN TN FP TP TP 0 A B 100% sensitivity PV– 100% C Normal Disease Number of people TP TN FN TN TN TN FN TP TP 0 A B 100% specificity PV+ 100% Fetal RBCs containing HbF are destroyed by splenic macrophages. The unconjugated bilirubin derived from the initial destruction of fetal RBCs is responsible for physiologic jaundice of the newborn, which occurs ~3 days after birth. 4. HbF–containing cells are replaced by RBCs containing HbA (>97%), HbA2 (2.0%), and Newborns: ↑HbF → left HbF (1%). shift OBC → ↑EPO → 5. Immunoglobulin (Ig) synthesis ↑Hb, Hct, and RBC production a. Synthesis of IgM begins shortly after birth. b. Newborns lack IgM isohemagglutinins (natural antibodies against blood groups) in their plasma. For example, blood group A newborns lack anti-B IgM isohemagglutinin in their plasma. Newborns: lack IgM at Clinical correlation: Newborns with an increase in cord blood IgM may have an underlying birth; ↑cord blood IgM congenital infection (e.g., cytomegalovirus, rubella). Their blood should be screened for antibodies indicates congenital against the common congenital infections. infection 6. IgG antibodies in newborns are of maternal origin. a. Newborns begin synthesizing IgG 2-3 months after birth. b. Adult levels of IgG are achieved by age 6 to 10 years. Clinical correlation: A mother with a positive test for human immunodeficiency virus (e.g., IgG Newborns normally antibodies against the glycoprotein gp120) transplacentally transfers IgG antibodies to the fetus. synthesize both IgM This does not mean that the child is infected by the virus. and IgG after birth  6   Rapid Review Pathology C. Children 1. When compared to an adult, children have higher serum alkaline phosphatase (ALP) levels. a. This is due to increased bone growth in children and release of ALP from osteoblasts. b. ALP removes the phosphate from pyrophosphate, which normally inhibits bone mineralization. 2. When compared to an adult, children have higher serum phosphorus levels. For normal mineralization of bone to occur, phosphorus is required to drive calcium into bone; hence, the higher phosphorus levels in children. 3. When compared to an adult, children have a lower Hb concentration (11.5 g/dL; anemia the circulating pool. circulating pool (1) Circulating pool is located in the central axial stream of blood flowing through small blood vessels. Neutrophil distribution: (2) In a complete blood cell count (CBC), the circulating pool is counted and evaluated altered by activating/ inactivating adhesion in a peripheral blood smear. molecules c. Neutrophil distribution in these pools can be altered by activating or inactivating neutrophil adhesion molecules (see later). 2. Margination of neutrophils a. In AI, RBCs aggregate into rouleaux (“stacks of coins”) in the venules. Caused by fibrinogen released from the liver  38   Rapid Review Pathology 3-4: Acute inflammation. Histologic section of lung in bronchopneumonia showing sheets of neutrophils with multilobed nuclei. The pink staining material in between the neutrophils is an exudate, which is protein- and cell-rich fluid that is characteristic of AI. (From Damjanov I: Pathology for the Health-Related Professions, 2nd ed, Philadelphia, Saunders, 2000, p 182, Fig. 8-8.) b. Rouleau mechanically forces neutrophils out of the central axial stream and pushes them to the periphery (called margination). Margination: neutrophils Caution: margination of neutrophils is not the same as the marginating pool of pushed to periphery neutrophils. Selectins: carbohydrate- 3. Rolling of neutrophils binding adhesion a. Rolling occurs in venules and is due to expression of selectin adhesion molecules on molecules neutrophils and venular endothelial cells. b. Selectins are carbohydrate-binding adhesion molecules. L-selectin: selectin c. L-Selectin is located on leukocytes (e.g., neutrophils), whereas E-selectin and P-selectin ligand on leukocytes are located on the surface of venular endothelial cells. E-selectin: selectin (1) P-selectin is produced in the Weibel-Palade bodies in venular endothelial cells. molecule on endothelial (2) Weibel-Palade bodies are the “glue factory” of endothelial cells, because they cells synthesize P-selectin, an adhesion molecule for leukocytes, and von Willebrand factor, the adhesion molecule of the platelet (refer to Chapter 15). P-selectin: derived from d. Interleukin-1 (IL-1) and tumor necrosis factor (TNF) stimulate the expression of selectin Weibel-Palade bodies in ligands on the surface of neutrophils (L-selectin) and the expression of selectin molecules endothelial cells on the surface of venular endothelial cells (E-selectin, P-selectin; Fig. 3-5). Weibel-Palade bodies: e. Binding of circulating neutrophils to E-selectin and P-selectin on venular endothelial “glue factory” in cells is weak and transient, causing them to “roll” (bind−detach, bind−detach) along the endothelial cells; surface. selectins 4. Firm adhesion in venules is due to neutrophil expression of β2-integrins and venular endothelial cell expression of integrin adhesion molecules (ligands). Selectins activated by IL-1 and TNF a. Activation of neutrophil β2-integrin (CD11a:CD18) adhesion molecules (1) β2-integrins are located on neutrophils and interact with corresponding ligands on Selectin adhesion: venular endothelial cells (see later; see Fig. 3-5). “rolling” (bind−detach) (2) β2-Integrins on neutrophils are activated by C5a and leukotriene B4 (LTB4). of neutrophils (3) Catecholamines and corticosteroids inhibit activation of these neutrophil adhesion molecules. β2-Integrins: firm adhesion of neutrophils; (a) Inhibition of neutrophil β2-integrins, leads to an increase in the peripheral blood activated by C5a/LTB4 neutrophil count (called neutrophilic leukocytosis). (b) This occurs because the normal marginating pool becomes part of the circulating Catecholamines and pool, since they can no longer adhere to venular endothelium. corticosteroids (4) Endotoxins enhance activation of neutrophil β2-integrins. inactivate neutrophil (a) Enhanced activation of neutrophil β2-integrins causes the total circulating β2-integrins: produces neutrophilic leukocytosis neutrophil count to decrease (called neutropenia). (b) This occurs because the normal circulating neutrophil pool becomes part of the Endotoxins activate marginating neutrophil pool. neutrophil β2-integrins: b. Activation of endothelial cell integrin adhesion molecules (ligands) produces neutropenia (1) IL-1 and TNF activate intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) on venular endothelial cells. ICAM/VCAM: (2) Activated ICAM ligands bind to activated β2-integrins on neutrophils causing them endothelial cell integrin adhesion molecules to firmly adhere to venular endothelium. (ligands); activated by (3) Activated VCAM ligands firmly bind to activated β1-integrins on eosinophils, IL-1/TNF monocytes, and lymphocytes.  Inflammation and Repair   39 Integrin Migration activation by Stable Rolling through chemokines adhesion endothelium Leukocyte Integrin (low-affinity state) Integrin (high- Selectin ligand affinity state) Chemokine PECAM-1 (CD31) Selectin Proteo- Integrin glycan ligand Chemokines Cytokines (TNF, IL-1) Macrophage with microbes Fibrin and fibronectin (extracellular matrix) 3-5: The sequence of events in the migration of blood leukocytes to sites of infection. At sites of infection, macrophages and dendritic cells that have encountered microbes produce cytokines (e.g., tumor necrosis factor [TNF] and interleukin-1 [IL-1]) that activate the endothelial cells of nearby venules to produce selectins, ligands for integrins, and chemokines. Selectins mediate weak tethering and rolling of blood neutrophils on the endo- thelium; integrins mediate firm adhesion of neutrophils; and, chemokines activate the neutrophils and stimulate their migration through the endothelium to the site of infection. Blood monocytes and activated T lymphocytes use the same mechanisms to migrate to sites of infection. PECAM-1, Platelet-endothelial cell adhesion molecule-1. (From Abbas A, Lichtman A: Basic Immunology Updated Edition: Function and Disorders of the Immune System, 3rd ed, Philadelphia, Saunders Elsevier, 2010, p 30, Fig. 2-7.) c. Leukocyte adhesion deficiency (LAD) disorders (1) Autosomal recessive inheritance pattern (2) LAD type 1 is a deficiency of β2-integrin (CD11a:CD18). Delayed separation of CD stands for cluster of designation. umbilical cord: LAD due (3) LAD type 2 is a deficiency of an endothelial cell selectin that normally binds to selectin or CD11a/ neutrophils. CD18 deficiency (4) Clinical findings (a) First manifestation in either type is delayed separation of the umbilical cord (usually separates and sloughs by the end of the second postnatal week). Neutrophil enzymes are important in cord separation; therefore in a histologic section of the surgically removed umbilical cord, no neutrophils would be seen adhering to venular endothelium or be seen in the interstitial tissue. Transmigration (b) Additional clinical findings include severe gingivitis, poor wound healing, and (diapedesis): movement peripheral blood neutrophilic leukocytosis (loss of the marginating pool). of neutrophils from 5. Transmigration (diapedesis) of neutrophils venules into interstitial a. Neutrophils moving along the venular endothelium dissolve the venular basement space membrane (release type IV collagenase) exposed by previous histamine-mediated endothelial cell contraction and enter the interstitial tissue. Exudate: protein- and cell-rich fluid (pus) b. Plasma-derived fluid rich in proteins and cells (i.e., exudate, pus) accumulates in the interstitial tissue. Exudate: dilutes c. Functions of exudate bacterial toxins; (1) Dilutes bacterial toxins, if they are present provides opsonins (2) Provides opsonins (IgG, C3b) to assist in phagocytosis (see later) 6. Chemotaxis of neutrophils Chemotaxis: directed migration of neutrophils a. Neutrophils follow chemical gradients that lead to the infection site. b. Chemotactic mediators bind to neutrophil receptors. Chemotaxis mediators: Mediators include C5a, LTB4, bacterial products, and interleukin (IL)-8. C5a, LTB4, bacterial c. Binding causes the release of calcium, which increases neutrophil motility. products, IL-8  40   Rapid Review Pathology Bacteria IgG (opsonin) Bacteria O2 Respiratory Fc receptor NADPH burst C3b (opsonin) NADPH oxidase Neutrophil complex C3b cell membrane NADP+ – O2 (superoxide) receptor Deficient in CGD SOD H2O2 H O H2O + Fe 2+ Fenton reaction 2 2 – GSH peroxidase Hydrolases Cl OH GSH GSSG ria MPO a cte B HOCl (bleach) NADP+ NADPH Phagolysosome Cofactor for MPO NADPH Hydrolases G6-P 6PG oxidase MPO Glucose-6-phosphate Bacteria dehydrogenase 3-6: O2-dependent myeloperoxidase system. A series of biochemical reactions occurs in the phagolysosome, resulting in the production of hypochlorous free radicals (bleach; HOCl ) that destroy bacteria. Conversion of H2O2 to OH using reduced Fe2+ as a source of electrons is called the Fenton reaction. NADPH produced by the pentose phosphate shunt is a cofactor for NADPH oxidase, which is deficient in CGD. A decrease in the cofactor NADPH (i.e., glucose-6-phosphate dehydrogenase deficiency) also interferes with the normal functioning of the O2-dependent MPO system. IgG and C3b are opsonins that facilitate the actions of phagocytic leukocytes (neutrophils, monocytes). CGD, Chronic granulomatous disease; Fe2+, reduced iron; GSH, reduced glutathione; G6-P, glucose 6-phosphate; GSSG, oxidized glutathione; H2O2, peroxide; MPO, myeloperoxidase; NADP, oxidized form of nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate; OH , hydroxyl free radical; 6PG, 6-phosphogluconate; SOD, superoxide dismutase. 7. Neutrophil phagocytosis (Fig. 3-6) a. Neutrophil phagocytosis is a multistep process, consisting of opsonization, ingestion, and killing. Opsonins: IgG and C3b; b. Neutrophil opsonization enhance neutrophil ability to ingest bacteria (1) Opsonins attach to bacteria (or foreign bodies). (a) Opsonins include IgG, the C3b fragment of complement, and other proteins Opsonins: IgG and C3b; (e.g., C-reactive protein). enhance neutrophil (b) Neutrophils have membrane receptors for IgG and C3b. recognition and (2) Opsonization enhances neutrophil recognition and attachment to bacteria (and attachment of bacteria foreign bodies). Bruton (3) Bruton agammaglobulinemia is an opsonization defect (refer to Chapter 4). agammaglobulinemia: In Bruton agammaglobulinemia, pre–B cells cannot mature to B cells; therefore opsonization defect plasma cells, which are derived from B cells, cannot synthesize immunoglobulins (lack of IgG) (i.e., IgG). c. Neutrophil ingestion Neutrophil ingestion: (1) Neutrophils engulf (phagocytose) and then trap bacteria in phagocytic vacuoles phagosome → phagolysosome (phagosomes). (2) Primary lysosomes empty hydrolytic enzymes into phagocytic vacuoles producing Chédiak-Higashi phagolysosomes. syndrome: cannot form In Chédiak-Higashi syndrome (refer to Chapter 2), there is a defect in microtubule phagolysosomes function, which prevents lysosomes from fusing with phagosomes to produce a phagolysosome. MPO: neutrophil/ monocyte lysosomal d. Neutrophil killing of bacteria/fungi by the O2-dependent myeloperoxidase (MPO) system enzyme (see Fig. 3-6) (1) O2-dependent MPO system only present in neutrophils and monocytes (not O2-dependent MPO macrophages) system: most potent MPO is a neutrophil/monocyte lysosomal enzyme. microbicidal system (2) MPO system most potent microbicidal system available to neutrophils and NADPH oxidase enzyme monocytes complex: converts (3) Production of superoxide free radicals (FRs) molecular O2 to NADPH oxidase enzyme complex converts molecular O2 to superoxide FRs, which superoxide FRs releases energy called the respiratory, or oxidative, burst.  Inflammation and Repair   41 (4) Production of peroxide (H2O2) SOD converts (a) Superoxide dismutase (SOD) converts O2 – to H2O2. superoxide free radicals (b) Some peroxide is converted to hydroxyl FRs by iron via the Fenton reaction to H2O2 (refer to Chapter 2). End-product O2- (5) Production of bleach (HOCl ) dependent MPO system: MPO in the phagolysosome combines H2O2 with chloride (Cl–) to form bleach hypochlorous FRs (HOCl ), which kill bacteria and some fungi. (6) Chronic granulomatous disease (CGD) and MPO deficiency are examples of diseases that have a defect in the O2-dependent MPO system. Chronic granulomatous disease (CGD) is an X-linked recessive disorder (65% of cases) or autosomal recessive disorder (30% of cases). The X-linked type is characterized by a mutation in the CYBB gene that encodes for a component in the NADPH oxidase enzyme complex (PHOX system) rendering the complex dysfunctional. The reduced production of O2 – results in an absent respiratory (oxidative) burst. Catalase-positive organisms that produce H2O2 (e.g., Staphylococcus aureus, Nocardia asteroides, Serratia marcescens, Aspergillus species, and Candida species) are ingested but not killed, because the catalase degrades the H2O2 produced by these pathogens. Myeloperoxidase is present, but HOCl is not synthesized because of the absence of H2O2. However, catalase-negative organisms (e.g., Streptococcus species) that produce H2O2 are ingested and can be killed when myeloperoxidase combines H2O2 (derived from the bacteria) with Cl– to form HOCl. Granulomatous inflammation occurs in tissue, because the neutrophils, which can phagocytose bacteria but not kill most of them, are eventually replaced by cells associated with chronic inflammation, mainly lymphocytes and macrophages. Macrophages fuse to form multinucleated giant cells, which is a characteristic feature of granulomatous inflammation. Patients with CGD have severe infections involving the lungs (pneumonia is the most common presentation), skin, visceral organs, and bones. The classic screening test for CGD is the nitroblue tetrazolium (NBT) dye test. In this test, leukocytes in a test tube are incubated with the NBT dye, which turns blue if superoxide FRs are present, indicating that the respiratory (oxidative) burst is intact (considered to be a positive test). The NBT dye test is negative in the X-linked type of CGD (NBT dye is not converted to a blue dye), because the NADPH oxidase enzyme complex is dysfunctional. Because of its lack of sensitivity, the NBT dye test has essentially been replaced by a more sensitive test involving oxidation of dihydrorhodamine to fluorescent rhodamine, which is abnormal in both variants of CGD. Treatment of CGD involves prophylaxis and treatment of infections and bone marrow transplantation. Myeloperoxidase (MPO) deficiency differs from CGD in that both O2 – and H2O2 are produced (normal respiratory burst). However, the absence of MPO prevents synthesis of HOCl. (7) Deficiency of NADPH (e.g., glucose-6-phosphate dehydrogenase [G6PD] deficiency) produces a microbicidal defect. (a) NADPH is a cofactor for the NADPH oxidase complex; therefore absence of G6PD deficiency: lack of NADPH in G6PD deficiency, a hemolytic anemia (refer to Chapter 12), renders NADPH interferes with the enzyme nonfunctional. normal function of the (b) Patients with G6PD deficiency are very susceptible to bacterial and certain O2-dependent MPO fungal infections because the O2-dependent MPO system is dysfunctional. system (8) Table 3-1 compares CGD and MPO deficiency. e. Neutrophil killing of bacteria by O2-independent microbial systems O2-independent systems: (1) Oxygen-independent systems for killing bacteria refer to the release of lethal lactoferrin (neutrophils), substances that are located in leukocyte granules. MBP (eosinophils) (2) Examples include: (a) Lactoferrin (present in neutrophil granules), which binds iron that is necessary for normal bacterial growth and reproduction (b) Major basic protein (MBP), an eosinophil product that is cytotoxic to Histamine: most helminths important chemical mediator of AI F. Chemical mediators in AI (Table 3-2) 1. Chemical mediators derive from plasma, leukocytes, local tissue, and bacterial products. Example—arachidonic acid mediators are released from membrane phospholipids in macrophages, endothelial cells, and platelets (Fig. 3-7) 2. Short half-lives (e.g., seconds to minutes) 3. May have local and systemic effects Example—histamine may produce local signs of itching or systemic signs of anaphylaxis 42   Rapid Review Pathology TABLE 3-1 Comparison of Chronic Granulomatous Disease and Myeloperoxidase Deficiency CHRONIC GRANULOMATOUS MYELOPEROXIDASE DISEASE DEFICIENCY Inheritance pattern X-linked recessive Autosomal recessive NADPH oxidase Absent Present Myeloperoxidase Present Absent Respiratory burst Absent Present Peroxide (H2O2) Absent Present Bleach (HOCl) Absent Absent TABLE 3-2 Sources and Functions of Chemical Mediators MEDIATOR SOURCE(S) FUNCTION(S) Arachidonic Acid Metabolites Prostaglandins Macrophages, endothelial cells, PGE2: vasodilation, pain, fever platelets PGH2: major precursor of PGs and PGI2: vasodilation; inhibition of platelet thromboxanes aggregation Thromboxane A2 Platelets Vasoconstriction, platelet aggregation Converted from PGH2 by thromboxane synthase Leukotrienes (LTs) Leukocytes LTB4: chemotaxis and activation of neutrophil adhesion molecules Converted from arachidonic acid LTC4, LTD4, LTE4: vasoconstriction, by lipoxygenase-mediated increased venular permeability, hydroxylation bronchoconstriction Zileuton inhibits 5-lipoxygenase: ↓synthesis LTB4, LTC4, LTD4, LTE4 Montelukast is a leukotriene receptor antagonist: ↓activity of LTC4, LTD4, LTE4 Bradykinin Product of kinin system activation Vasodilation, increased venular by activated factor XII permeability, pain Chemokines Leukocytes, endothelial cells Activate neutrophils and stimulate their migration through the endothelium to the site of infection (chemotaxis; see Fig. 3-5) Complement Synthesized in liver (acute phase C3a, C5a (anaphylatoxins): stimulate mast reactant) cell release of histamine C3b: opsonization C5a: activation of neutrophil adhesion molecules, chemotaxis C5–C9 (membrane attack complex): cell lysis Cytokines IL-1, TNF Macrophages (main source), Initiate PGE2 synthesis in the anterior monocytes, dendritic cells, hypothalamus, leading to production of endothelial cells fever Activate endothelial cell adhesion molecules TNF is a promoter of apoptosis (refer to Chapter 2) IL-6 Primary cytokine responsible for increased liver synthesis of acute phase reactants (APRs), such as ferritin, coagulation factors (e.g., fibrinogen), and C-reactive protein IL-8 Chemotaxis Histamine Mast cells (primary cell), platelets, Vasodilation, increased venular enterochromaffin cells permeability Nitric Oxide (NO) Macrophages, endothelial cells Vasodilation, bactericidal Free radical gas released during conversion of arginine to citrulline by NO synthase IL, Interleukin; PG, prostaglandin; TNF, tumor necrosis factor.  Inflammation and Repair   43 Cell membrane phospholipids Phospholipase A2 Inhibited by corticosteroids Linoleic acid ω6 Arachidonic acid 5-Lipoxygenase Cyclooxygenase Inhibited by Zileuton Inhibited by aspirin/NSAIDs LTB4, LTC4, LTD4, LTE4 PGG2 Receptors inhibited by Montelukast Thromboxane synthase Prostacyclin synthase TXA2 PGH2 PGI2 Platelet Endothelial cell PGE2 PGF2α 3-7: Simplified arachidonic acid metabolism. Arachidonic acid is released from membrane phospholipids by phospholipase A2. It is converted into prostaglandins (PGs) and thromboxane A2 (TXA2) in platelets from PGH2, the precursor prostaglandin, and into leukotrienes (LTs) by 5-lipoxygenase. Linoleic acid is an ω-6 essential fatty acid that is used to synthesize arachidonic acid. Phospholipase A2 is inhibited by corticosteroids; 5-lipoxygenase, by zileuton; receptors for LTC4, LTD4, LTE4, by montelukast; and cyclooxygenase (COX), by aspirin and NSAIDs. The COX-1 isoform (not depicted) is constitutively expressed in various tissues, whereas the COX-2 isoform (not depicted) is induced by various growth factors and proinflammatory cytokines. See text and Table 3-2 for further discussion. NSAIDs, nonsteroidal antiinflammatory drugs; PGI2, prostacyclin. 4. Mediators have diverse functions including: a. Vasodilation Examples—histamine, nitric oxide, PGI2 b. Vasoconstriction Example—thromboxane A2 (TXA2) c. Increasing venular permeability Examples—histamine, bradykinin, LTC4, LTD4, LTE4, C3a, and C5a (anaphylatoxins) d. Producing pain Examples—PGE2, bradykinin e. Producing fever Examples—PGE2, IL-1, TNF f. Chemotaxis Examples—C5a, LTB4, IL-8 g. Liver synthesis of acute phase reactants (APRs; e.g., fibrinogen, ferritin, complement, hepcidin, C-reactive protein) IL-6 stimulates APR synthesis. G. Types of AI 1. Location, cause, and duration of inflammation determine the morphology of an inflammatory reaction. 2. Purulent (suppurative) inflammation a. Definition—localized proliferation of pus-forming organisms, such as S. aureus (e.g., skin abscess; Fig. 3-8A). b. S. aureus contains coagulase, which cleaves fibrinogen into fibrin and traps bacteria and S. aureus: most common neutrophils, and therefore keeps the lesion localized. cause of a skin abscess 3. Fibrinous inflammation Fibrinous inflammation: a. Definition—inflammation due to increased vessel permeability, with deposition of a exudate covering fibrin-rich exudate on the surface of the tissue (see Fig. 3-8B). serosal surfaces (heart, b. Commonly occurs on the serosal lining of the pericardium, peritoneum, or pleura. lungs, peritoneum) (1) Friction rub may be heard over the precordium in fibrinous pericarditis associated with a myocardial infarction or rheumatic fever (refer to Chapter 11). (2) Friction rub may be heard over the precordium or lungs in fibrinous pleuritis secondary to a pulmonary infarction or pneumonia (refer to Chapter 17). (3) Small bowel obstruction from serosal adhesions between other loops of bowel may occur from peritoneal irritation related to previous abdominal surgery (refer to Chapter 18). 4. Serous inflammation a. Definition—inflammation with a thin, watery exudate that has an insufficient amount of Serous inflammation: fibrinogen to produce fibrin. thin watery exudate; b. Examples—blister in second degree burns, viral pleuritis blister, viral pleuritis  44   Rapid Review Pathology A B C 3-8: A, Purulent (suppurative) inflammation. The photograph shows a skin abscess (furuncle) due to Staphylococcus aureus. Abscesses are pus-filled nodules located in the dermis. Note the multiple draining sinus tracts filled with pus. B, Fibrinous inflammation. The surface of the heart is covered by a shaggy, fibrinous exudate. C, Pseudomembranous inflammation. There is necrosis and a yellow-colored exudate covering the mucosal surface of the colon due to a toxin produced by Clostridium difficile. (A from Bouloux P: Self-Assessment Picture Tests Medicine, Vol. 1, London, Mosby-Wolfe, 1997, p 33, Fig. 66; B from Damjanov I, Linder J: Pathology: A Color Atlas, St. Louis, Mosby, 2000, p 25, Fig. 1-59; C from Grieg J: Color Atlas of Surgical Diagnosis, London, Mosby-Wolfe, 1996, p 202, Fig. 26-10.) Pseudomembranous 5. Pseudomembranous inflammation inflammation: a. Definition—bacterial toxin–induced damage of the mucosal lining, producing a shaggy diphtheria, Clostridium membrane composed of necrotic tissue. difficile b. Examples include pseudomembranes associated with: (1) Clostridium difficile, in pseudomembranous colitis (see Fig. 3-8C). (2) Corynebacterium diphtheriae, which produces a toxin causing pseudomembrane formation in the pharynx and trachea (see Fig. 17-5D). H. Role of fever in AI 1. The O2-binding curve (OBC; refer to Chapter 2) is right-shifted. Fever is beneficial: OBC More O2 is available for the O2-dependent MPO system. right-shifted, ↓bacterial/ 2. It provides a hostile environment for bacterial and viral reproduction. viral reproduction 3. In hospitalized patients, fever is most commonly due to bacterial infections targeting the respiratory tract, urinary tract, or skin and soft tissue. I. Termination of AI Chemical mediators 1. AI mediators have a short half-life. have a short half-life. 2. Production of lipoxins (antiinflammatory mediators) Lipoxins: inhibit a. Derive from arachidonic acid metabolites (e.g., LXA4, LXB4) transmigration/ b. Inhibit transmigration and chemotaxis of neutrophils chemotaxis; enhance c. Signal macrophages to phagocytose apoptotic bodies apoptosis 3. Production of resolvins a. Synthesized from ω-3 fatty acids Resolvins: inhibit b. Inhibit production and recruitment of inflammatory cells to the site of AI recruitment inflammatory cells 4. Increased clearance of neutrophils by apoptosis J. Consequences of AI Neutrophils cleared 1. Complete resolution of AI from the inflammatory a. Occurs with mild injury to cells that have the capacity to enter the cell cycle (e.g., labile site by apoptosis and stable cells). b. Examples—first-degree burn, bee sting 2. Tissue destruction and scar formation a. Destruction of tissue and scar tissue occurs with extensive injury or damage to permanent cells. Consequences: b. Examples—third-degree burns, acute myocardial infarction resolution, scar tissue, 3. Formation of abscesses (localized collection of neutrophils with liquefactive necrosis) abscess, progression to Example—lung abscess may develop after aspiration of oropharyngeal material chronic inflammation 4. Progression of AI to chronic inflammation II. Chronic Inflammation (CI) A. Definition of CI Prolonged inflammation (weeks to years) that most often results from persistence of an injury-causing agent Infection: most common B. Causes of CI cause of chronic 1. Infection is the most common cause of CI. inflammation Examples—tuberculosis (TB), leprosy, hepatitis C  Inflammation and Repair   45 3-9: Chronic inflammation. This tissue shows an infil- 3-10: Granulation tissue. Note the mixture of acute trate of predominantly lymphocytes and occasional (neutrophils) and chronic inflammatory cells (lympho- plasma cells (cells with eccentric nuclei and perinuclear cytes, plasma cells, macrophages) intermixed with clearing, white arrow). (From Damjanov I, Linder J: dilated, small vessels. Numerous, plump fibroblasts Anderson’s Pathology, 10th ed, St. Louis, Mosby, 1996, (arrows) laying down type III collagen are also present. p 390, Fig. 18-7B.) (From Damjanov I, Linder J: Anderson’s Pathology, 10th ed, St. Louis, Mosby, 1996, p 436, Fig. 19-2B.) 2. Autoimmune disease Examples—rheumatoid arthritis, systemic lupus erythematosus 3. Inflammatory reaction to sterile agents Examples—silica, uric acid, silicone in breast implants C. Morphology of CI Monocytes and/or 1. Cell types that define CI macrophages: primary a. Monocytes and macrophages (key cells); lymphocytes, plasma cells, and eosinophils leukocytes in chronic (Fig. 3-9). inflammation b. Transforming growth factor (TGF)-β is chemotactic for macrophages, lymphocytes, and fibroblasts. 2. Destruction of parenchyma With loss of parenchyma, there is loss of functional tissue, with repair by fibrosis. 3. Formation of granulation tissue a. Definition—highly vascular tissue composed of blood vessels and activated fibroblasts (Fig. 3-10). (1) Blood vessels derive from preexisting blood vessels and de novo from endothelial cell precursors recruited from the bone marrow (i.e., angiogenesis). Granulation tissue: blood vessels, Important growth factors in angiogenesis—vascular endothelial cell growth factor, fibroblasts fibroblast growth factor, epidermal growth factor, platelet derived growth factor, TGF-β Granulation tissue: (2) Vascularization is essential for normal wound healing. precursor of scar tissue (3) Granulation tissue is precursor of scar tissue. b. Fibronectin is required for granulation tissue formation. Fibronectin: key (1) Cell adhesion glycoprotein located in the extracellular matrix (ECM) adhesion glycoprotein in ECM; chemotactic factor It binds to collagen, fibrin, and cell surface receptors (e.g., integrins). for fibroblasts and (2) Chemotactic factor that attracts fibroblasts (synthesize collagen) and endothelial cells endothelial cells (form new blood vessels, angiogenesis) 4. Comparison table of AI and CI (Table 3-3) Granulomatous 5. Granulomatous inflammation inflammation: a. Definition—specialized type of chronic inflammation specialized type of chronic inflammation b. Causes (1) Infections Granulomatous (a) Examples—TB and systemic fungal infection (e.g., histoplasmosis) infections: TB, systemic (b) Infections caused by TB and systemic fungi are usually associated with caseous fungi (e.g., necrosis (i.e., soft granulomas; refer to Chapter 2). histoplasmosis) Caseation is due to lipid released from the cell wall of dead pathogens. Noninfectious (2) Noninfectious causes granulomatous (a) Examples—sarcoidosis and Crohn disease inflammation: (b) Sarcoidosis and Crohn disease have noncaseating granulomas (i.e., hard sarcoidosis, Crohn granulomas). disease  46   Rapid Review Pathology TABLE 3-3 Comparison of Acute and Chronic Inflammation ACUTE INFLAMMATION CHRONIC INFLAMMATION Pathogenesis Microbial pathogens, trauma, Persistent AI, foreign bodies (e.g., burns silicone, glass), autoimmune disease, certain types of infection (e.g., TB, leprosy) Primary cells involved Neutrophils Monocytes/macrophages (key cells), B and T lymphocytes, plasma cells, fibroblasts Primary mediators Histamine (key mediator), Cytokines (e.g., IL-1), growth prostaglandins, leukotrienes factors Necrosis Present Less prominent Scar tissue Absent Present Onset Immediate Delayed Duration Few days Weeks, months, years Outcome Complete resolution, progression Scar tissue formation, disability, to chronic inflammation, amyloidosis (refer to Chapter 4) abscess formation Main immunoglobulin IgM IgG SPE effect Mild hypoalbuminemia Polyclonal gammopathy; greater degree of hypoalbuminemia Peripheral blood leukocyte response Neutrophilic leukocytosis Monocytosis AI, Acute inflammation; SPE, serum protein electrophoresis; TB, tuberculosis. Cell types in tuberculous c. Morphology of a granuloma granuloma: (1) Definition—pale, white nodule with or without central caseation macrophages and CD4 (2) Usually well-circumscribed in tissue (see Fig. 2-15G) helper T cells (3) Cell types in an infectious granuloma (e.g., tuberculosis) Epithelioid cells: (a) Epithelioid cells (activated macrophages) and mononuclear cells consisting of macrophages activated CD4 helper T cells, specifically, TH cells of the TH1 type (memory T cells) by interferon-γ from (b) Multinucleated giant cells formed by fusion of epithelioid cells CD4 TH1 cells Multinucleated giant cell nuclei are usually located at the periphery of the granuloma. Multinucleated giant cells: formed by fusion (4) TNF-α is important in the formation and maintenance of TB and systemic fungal of epithelioid cells granulomas. (a) TNF-α and interferon-γ recruit cells for granuloma formation. (b) TNF-α inhibitors cause the breakdown of granulomas, which may result in dissemination of disease (e.g., disseminated TB). (5) Specifics concerning the sequence of events in the formation of a granuloma are fully discussed in Chapter 4 under type IV hypersensitivity reactions. Tissue repair: III. Tissue Repair parenchymal cell A. Factors involved in tissue repair regeneration, repair by 1. Parenchymal cell regeneration connective tissue 2. Repair by connective tissue (fibrosis) Cell regeneration: only B. Parenchymal cell regeneration labile and stable cell 1. Cell regeneration depends on the ability of cells to replicate (refer to Chapter 2). can regenerate a. Labile cells (e.g., stem cells in epidermis) and stable cells (e.g., fibroblasts) can replicate. b. Permanent cells cannot replicate. Cell regeneration: Cardiac and striated muscle are replaced by scar tissue (fibrosis). permanent cells cannot regenerate 2. Cell regeneration depends on factors that stimulate parenchymal cell division and migration. Stimulatory factors include loss of tissue and production of growth factors (Table 3-4). 3. Cell cycle (Fig. 3-11) a. Phases G0 phase: resting phase (1) G0 phase of stable cells Resting phase of stable parenchymal cells (2) G1 phase G1 phase: most variable phase in cell cycle (a) Synthesis of RNA, protein, organelles, and cyclin D (b) Most variable phase in the cell cycle G1 phase: synthesis of (3) S (synthesis) phase DNA, RNA, protein Synthesis of DNA, RNA, and protein.  Inflammation and Repair   47 TABLE 3-4 Factors Involved in Tissue Repair FACTOR FUNCTIONS Growth Factors Vascular endothelial cell growth factor Stimulates angiogenesis (embryonic angiogenesis, particularly in the (VEGF) heart), repair of tissue, cancer angiogenesis (stimulates from preexisting vessels) Stimulation factors: TNF released by macrophages, hypoxia via hypoxia-inducible factor released by cells Fibroblast growth factor (FGF) Chemotactic for fibroblasts; stimulates keratinocyte migration, angiogenesis, wound contraction Epidermal growth factor (EGF) Stimulates keratinocyte migration, granulation tissue formation Platelet-derived growth factor (PDGF) Chemotactic for neutrophils, macrophages, fibroblasts, endothelial cells (angiogenesis), smooth muscle cells (angiogenesis) Transforming growth factor-β (TGF-β) Chemotactic for macrophages, lymphocytes, fibroblasts, smooth muscle cells (angiogenesis) Interleukins (IL), Cytokines IL-1 Stimulates synthesis of metalloproteinases (i.e., enzymes containing trace metals) Stimulates synthesis and release of acute phase reactants from the liver Tumor necrosis factor (TNF) Activates macrophages; stimulates release of acute phase reactants