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CLINICAL

PATHOPHYSIOLOGY
made
ridiculously
simple™

WITH INTERACTIVE DIFFERENTIAL DIAGNOSIS CD

Aaron Berkowitz, M.D., Ph.D.

Clinical Pathophysiology
Made Ridiculously Simple

Aaron Berkowitz

MedMaster Inc.
Miami, Florida

Copyright © 2007 by MedMaster Inc
All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in
a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopy­
ing, recording or otherwise, without written permission from the copyright owner.
ISBN1 0# 0-940780-80-1
ISBN13# 978-0-940780-80-4
Made in the United States of America
Published by MedMaster, Inc.
P.O. Box 640028
Miami FL 33164
Cover by Richard March

Contents

Chapter Outlines ..........................................
Preface

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Acknowledgments .........................................

Chapter

1. The Cardiovascular System

Chapter

2. The Pulmonary System

Chapter

3. The Renal System

Chapter

4. The Gastrointestinal System

Chapter

5. The Endocrine System

Chapter

6. The Hematologic System

Chapter

7. The Nervous System

Chapter

8.

Rheumatology

Chapter

9.

Male and Female Reproductive Systems

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Chapter 1 0. Cases

Index

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............... Hypertension ...................... .... .. 37 Diseases of the Electrical System: Arrhythmias ....... 19 Restrictive Lung Disease ......... . 29 Diseases of the Heart Muscle ................................... .. 12 Alveolar Sac/Airway ......... 36 Review of Valves II: Review by Murmur . 40 Ventricular Tachyarrhythmias ..... 41 Sinusitis ... ............ 12 Tricuspid Regurgitation ........... 14 Obstructive Lung Disease . 3 8 Treatment of Bradycardia ......... .... ........................ Afterload............ 33 Tricuspid Valve ........................ 33 Noncyanotic Congenital Heart Disease ... .. ............... .. .. 16 Chronic Bronchitis .... ............... .................................... 2 Rheumatic Fever and Rheumatic Heart Disease ........ ......... 8 Aortic Valve ..... ...... .................... ...................... . ..... 12 Review of Congenital Heart Disease .......... 31 Aortic Regurgitation ............ 37 Bradyarrhythmia ( Bradycardia) ................... 16 Emphysema .. ........................................... 13 Blood Vessels .................... ...................... .. 23 Bronchiolitis ... ..... .................. .............. 37 Slow SA Node ...................... .. .............. .... 10 Congenital Aortic Stenosis ......... 40 Supraventricular Tachyarrhythmias ........ ............ 12 Components of the Pulmonary System . 20 Review of Obstructive and Restrictive Review of Arrhythmias ........... 32 Mitral Valve . ... 30 Other Causes of Cyanotic Heart Disease ........... 29 The Four Components of the Heart and Their Diseases . ................. ........... 10 Pulmonic Stenosis .. 6 Classification of Congenital Heart Diseases ........... Cardiac Infection.......... 42 22 Pharyngitis ..... 33 Mitral Stenosis .... 43 Aortic Aneurysm ...... .......... . ......... .. 44 Aortic Dissection....................... and Treatment of Heart Failure ................ 24 Heart Failure ....................... 44 v .............. 7 Transposition of the Great Arteries .... ...... 30 Cyanotic Heart Disease ..... ............................ 23 Pneumonitis .................... ......... ....... ........... 28 Pericarditis ........ .... 35 Pulmonary Valve .......... ...................... 23 Bronchitis .... 27 Left Heart Failure ... ... 22 Emboli Lung Disease Pulmonary Hypertension .... 27 Right Heart Failure ......... The Cardiovascular System . ..................... The Pulmonary System ..... ....................... ............. . .. .......... ............ ........... ..... 3 The Kidney in Heart Failure ..................... ..... 18 Asthma . ..... ....... .............. 42 Rhinitis .. 36 Pulmonic Regurgitation Review of Valves 1: Review by Pathology ................... 23 Epiglottitis ............ and Neoplasia ...................... ............ . 20 Diseases of the Heart's Vasculature: Angina and Myocardial Infarction ..... . .. 7 Tetralogy of Fallot .... 10 Patent Ductus Arteriosus (PDA) ....... 40 Treatment of Tachyarrhythmia ............... 28 Atrial Myxoma ........... ...... Tachyarrhythmias .... 28 Preload.......... 18 Bronchiectasis ........ . ......... 6 Fetal Circulation ........... ........... 43 ..................... ... .. 42 Peripheral Arteries and Aorta .... 28 Congenital Heart Disease ...... .. ........ 2 Endocarditis . .... ............ .... ...... .. 2 Myocarditis ....... ........Chapter Outlines Vasculitis ..... ........................... ............... 16 Pulmonary Function Testing ....... ..... ... 35 Pulmonic Stenosis ............... .. ................ .... ........ 11 Coarctation of the Aorta .... .......... 41 Respiratory Infections ..... ... 22 Laryngitis .......... 9 Aortic Stenosis ... ...... .................................. 31 The Valves and Their Diseases: Stenosis and Regurgitation .... . ... 4 Cardiac Neoplasia ..... 31 Atrial Septal Defect (ASD) and Mitral Regurgitation ......... Anatomical Overview....................... 12 Chapter 2 ........... ....... ................................... 6 Restrictive Cardiomyopathy .......................................................................... ............................. .... Inflammation.. 14 Obstructive and Restrictive Lung Disease ............. 37 Abnormal Conduction ( Heart Block) ....... ............... 24 Chapter 1........ 9 Ventricular Septal Defect (V SD) .... 36 ..... .......... Atherosclerosis of the Aorta ......................... ............ 21 Vascular Disease Outside the Heart: ...... ........... ................ 18 Cystic Fibrosis 38 ..................... .. ............. . ..................... 28 Symptoms and Signs of Heart Failure ........................... ... 30 Cardiac Hypertrophy .... 34 Tricuspid Stenosis ...... 30 Cardiac Dilatation ......................... 12 Membrane ... 44 Lipids and Lipid-Lowering Drugs .. ......... ............ ... 43 Peripheral Vascular Disease .... .......

........ 7 9 Small Bowel Tumors .... ............. 48 Laboratory Distinction Between Prerenal and Intrinsic Renal Failure 73 73 ..................... ................... ... 6 9 45 ............ ............ ............... ............... ................... ... 74 . ................. 55 ..... 56 .......... .... .... 80 Colon Cancer Colitis ..... 50 Causes of Intrinsic Renal Pathology: Diseases of Tubules and Glomeruli Nephrotic Syndrome Chronic Renal Failure .................... 7 9 Diseases o f the Large Intestine .................................. 72 .. .. 47 . .......... 47 ........ Drug Reactions (Pseudohyponatremia) .. 85 Acid-Base Pathophysiology Alpha-1 Antitrypsin Deficiency Hyperkalemia Respiratory Acidosis .. 46 Obstruction Muscle ... The Gastrointestinal System 71 Pleural Effusion ...... 45 Anatomical Overview Chylothorax.. .......... ...................... 66 Hepatic Neoplasm ................... 58 Viral Hepatitis Hyperosmolar Hyponatremia ............................... 84 Fatty Liver ( Hepatic Steatosis) Autoimmune Hepatitis ........ Failure to Contract and Relax: Achalasia Chapter 3...... ............... ..... 51 Urinary Tract lnfectinn (UTI) and Urinalysis .. 6 8 ........................................................ 80 Upper and Lower Gl Bleeding ..... 52 Hirschprung's disease ... 46 ....... 84 ..... 68 Ascites .................. 80 ............... 80 Inflammatory Bowel Disease (/BD): Crohn 's Disease and Ulcerative Colitis ........................... and Prothrombin T ime Hypovolemic Hyponatremia ...... ...... .. 74 Serum BU N/Creatinine Ratio .... 45 Chapter 4......................... 52 Tumors of the Urinary Tract ......... 71 72 ........ 47 Intrinsic Renal Failure ..................................... ... ........ 48 Other Causes of Gastritis ..................... and Alkaline Phosphatase ....................... .... .................... ...... 72 Failure to Contract Failure to Relax .................. 7 7 . 60 .............. 73 Other Causes of Esophagitis Esophageal Cancer .............................................. 46 Diseases of the Esophagus .... ............................................... ........ 85 ...... 63 Wilson's Disease ........................... 53 Basic Concepts ......... ... 85 ............. ....................... Pulmonary Physical Exam Percussion ..................................... ............. ........... ..... ............... 67 Portal Hypertension Metabolic Acidosis ...... Egophony........... 7 9 ............ ............. ......... 84 ....................... 73 .... ......... 85 .......... .. 82 Diseases of the Liver Hypervolemic Hypernatremia ... ........ and Whisper Pectoriloquy Clubbing 46 . 48 Peptic Ulcer Disease . ................. 7 9 ..... 66 Respiratory Alkalosis ................ 52 Diverticula . ........................................ 86 .. 4 4 Urine Anion Gap Tuberculosis Renal Tubular Acidosis (RTA) ............... 4 4 Lung Cancer ................................... 53 Fluids and Electrolytes ......... 83 Hypervolemic Hyponatremia ............. 48 Fractional Excretion of Sodium ( F E Na) Postrenal Failure 49 ........... ............. 82 Hypovolemic Hypernatremia ...... The Renal System Overview of Kidney Function Acute Renal Failure Prerenal Failure ... 7 7 Gastroparesis ........ ALT............................ ........................... 83 Hyponatremia .......... 59 Hyperkalemia and Hypokalemia ........ 52 Urethritis Cystitis ..... ..... 55 Overview of Liver Function ........... .. 73 Diseases of the Stomach ................. ............ ...... 6 4 .................. .. 73 Esophageal Varices ... 7 7 Urine sodium Loss of Intrinsic Factor .. 60 Hemochromatosis ...... 58 Bilirubin......................... 57 ..................... 55 Diarrhea .. 50 . . 83 ............... 7 9 Pyelonephritis ..................... 85 Diseases of the Liver Vasculature: Metabolic Alkalosis ... 55 Bilirubin and Jaundice Euvolemic Hypernatremia Liver Function Tests ......... .... .. ................. ....... 78 .................... ............. ............. ..... ............ 78 Diseases of the Small Intestine Malabsorption Obstruction .......... Albumin............................... 84 .. .. .......... 47 ........................Pneumonia ............ .................................. ....... ...... 7 7 .................. 50 ............................. 82 AST..................................................... and Pneumothorax ............... ........................................... ...... ............ 73 ........ 6 8 Overall Algorithm for Acid-Base Diagnosis ................... 85 Hypokalemia ......... 53 Hypernatremia and Hyponatremia Hypernatremia ..... 50 ....... ............... .... 46 Fremitus..................... 52 Urinalysis Obstruction Gastric Cancer Nephritic Syndrome ............................. ........................... 58 Diseases of the Liver Parenchyma Euvolemic Hyponatremia .................. Hemothorax.. 81 . 86 The Anion Gap vi Diverticula Reflux 72 ............................... .. .......... 68 Varices ................................................. 4 5 Diseases o f the Pleura and Pleural Space Pleuritis (Pleurisy) ... 78 .......

.... 116 Thyroid ... . .... . .. . . .... . .. .. ... .. ...... . . ... ........ ..... ... .. . . .. 122 Extracorpuscular Defects . . . 119 Diseases of the Anterior Pituitary . .. 126 .. .... 116 Weakened Bones: Osteoporosis and Osteomalacia .. . .. .. . . .. ... . 112 Symptoms and Signs of Hypercalcemia Treatment of Hypercalcemia Hypocalcemia .. ..... 1 06 with RBC Components .. .. .. .. 122 lntracorpuscular Defects: Problems Hemoglobin . ... ..and Hypoaldosteronism .. ... .. ... . .... 99 Hyper.. .... . .. . 104 Iron.... .. . 112 Tertiary Hyperparathyroidism .. .. ..... ... ....... ... . . .. . . . . 1 05 LH/FSH-Secreting Tumors .... ... . ... 126 ...... 90 History .... .... ...... . .. ... . . .. .. .... . . ... . .... 125 Elevated EPO . ... . .. .... .. .. 88 Biliary atresia Diseases of the Pancreas . .... 90 Physical Exam . 106 The Endocrine Pancreas and Glucose Regulation .... .. . . . . ... .. . ....... . . . . ... 119 Pheochromocytoma .. ... 116 Thickened and Weakened Bones: Chapter 5. . .. .. . .......... ... . .... . . . .... .. .. . .. .. . . ... .... .. .. 119 Bone Marrow Failure... .... ... .. .. ....... . . .. .. ...... .... .. . . . .. .. 118 .... .. 118 Thyroid Nodules and Thyroid Cancer Adrenal Glands ... ... . 1 22 Hypoglycemia .. . . ....... Pseudohypoparathyroidism Vitamin D Deficiency . ... . . . .. .. .. . 107 Membrane .. . 11 2 PT H-related Protein (PT HrP) . .... ..... . .. .. .......... 1 22 Growth Hormone Adenomas Bleeding and Acromegaly .. .. 125 .. . 99 Cushing's Syndrome ... ... .. 100 Too Few RBCs: Anemia .... . the Parathyroids... .. . ..... ... . .. .. . . . .. .... . . .. . . ..... .. .. . ..... 96 Hypothyroidism ...... ............ .... . . ... 88 Pancreatic Tumors . . ..... . .. 1 06 Prolactin-Secreting Adenomas Hypopituitarism . . .. vii ... .... 96 Tumors of Bone .... . 116 General Principles ... .. . . 124 Calcium.... .. ......... .. .... 88 .... . . . . . . ........ .. . . . . . ... .. .. . ... ...... . . ... 122 Diabetes Mellitus .. . . ... ... .... 104 Multiple Endocrine Neoplasia (M EN) ... . . 105 ACT H-Secreting Pituitary Adenomas ...... ... . .. . .... .... .... .. .. 116 Hyperthyroidism . .. ..... ... .. . . ..... ... . . ... . .... ... ... ..... . .. ... 88 Pancreatitis .... .. 115 Hypocalciuric Hypercalcemia and Hypercalciuric Hypocalcemia . .... ... 9 8 Red Blood Cells .. . ... ................. ..... . ... ..... .. 9 8 Components of the Hematologic System ..... ..... .... .. .... ...... . . . ... ... .. .. 11 2 ... .. . ..... .. ...... .. . ..... .. . .. ........ .. .... .... . . . .. ... . .... . 120 Increased Loss of RBCs: Bleeding T S H-Secreting Pituitary Adenomas . .. ... .. 111 Secondary Hyperparathyroidism ......... . . ... . . 122 .... ... .. ..... .. 115 Thickened Bones: Osteopetrosis ....... . . ....... .. .. ..... .. ... .. and Bone Hypercalcemia Elevated PT H Primary Hyperparathyroidism .. ... . ...... .. . . . .... ... ... .. .... . . . .. 122 Thalassemia . . .. . ...... ... .... .... .. . . ... . .. .. .... ...... . . ... .. .. . .. . . 118 Adrenal Insufficiency . .... 122 Sickle Cell Anemia . 110 Anemia of Chronic Disease . .. .. . . . . .. . .. .... . 118 Hemoglobin and Hematocrit ..... .. .. . .. ... ......... . .. ..... . ... . . . . . . ..... .. . . . .. . . .. . . ..... ... .. .. .... ... . . . ... .. .. .. ... ... 11 5 Treatment of Hypocalcemia ...... .... .... 120 Pituitary Adenomas and Hyperpituitarism ... . . .. .. ....... ... .. .. . .. .. 1 23 .. . . .... . . .... ... ........ .. . 9 4 Infection of Bone: Osteomyelitis ... ... . . .. ... . . . . .. .. . . 115 Diseases of Bone ... . .. .. ..... ... 102 Causes of Anemia . .. ...... .. 115 Symptoms and Signs of Hypocalcemia .. ..... .. ........ .. .......... ... 124 . B1 2 and Folate Deficiency . ...... ............. . .. . ... ... .. . .. 114 Binding of Calcium .. ....... .. .. ...... . .. . . ... . Renal Failure. .. .. . . . 119 Pituitary Gland ........ .. . .. . .. .. . ... . 114 Hungry Bone Syndrome . . .. . . .. ..... ........ .. ... ... 118 Thyroiditis .. .... 113 Treatment of Anemia .. . ... 113 .. ...... .. ... 111 Blood Smear . 125 Hyperproliferative States of the Bone Marrow: Polycythemia Vera . .. The Endocrine System ... .... . ... ... .... 89 Diagnosis of Abdominal Pain . .. ... ... .... 105 and Hemolysis ... ... 1 25 Review of Anemia ... .. 115 . . .... . . . . . . . ... . .. ...... ....... 104 Decreased Production of RBCs Congenital Adrenal Hyperplasia . . . .. .... . .. .. . ... . 11 0 Lab Findings in Hemolysis .. . .. . .. .. . . .... . ... . .86 Diseases of the Gall Bladder and Bile Ducts Gall Stones (Cholelithiasis) .. ... ... 1 25 Causes of Polycythemia . . .. .. . .. .. . ... . .. . . .. .. 88 Approach to Abdominal Pain . . .... ... .... . . .. ....... . . Hypoalbuminemia . 11 2 Bone Breakdown . ..... 105 Iron Deficiency Anemia . ...... . ......... .. ... 122 Hemolysis . .. 92 Imaging and Endoscopy .. ... ... ... . .. ..... ..... . ...... 105 Folate and B12 Deficiency .. .. ... .. .... . . 114 . .... ... ... . . . 1 08 Metabolic Pathways . . . . Aplastic Anemia . ... 125 Lab Findings in Polycythemia Treatment of Polycythemia . ... ... . . 1 23 . . 118 Symptoms and Signs of Anemia .. 112 Vitamin D-lnduced Hypercalcemia . . 87 Cancer of the Bile Ducts (Cholangiocarcinoma) 88 Inflammatory Diseases of the Biliary System ... . . ... 93 Decreased PT H: Hypoparathyroidism and ........ .... . . ... .. ... . 9 8 Chapter 6.... .... .. .. . . . ... . . . .. . .. ...... .. .. 9 4 Paget's Disease (Osteitis Deformans) ..... . .. ......... .. .. . . .. ... 92 Laboratory Tests . . . . . The Hematologic System . 1 06 ... .... . Too Many RBCs: Polycythemia ..... . .. . . . .. . ..... ......... 1 06 Diseases of the Posterior Pituitary ..... . 104 ... ... ... ....

. . . . . .. . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . .. 138 Cranial Nerve Ill (Oculomotor) . . .. . . . . . .. . . . . . . . . .. . . . . 165 Gout and Pseudogout . 165 Cranial Nerve VIII (Vestibulocochlear) . . . . . . . . . . .. . .. . . . . . . . . .. . . 161 . .. 127 Decreased Neutrophils . . . . .. . . . . . . . . . . .. . . . . . . . . . . 154 Encephalitis . . 128 Review of WBCs . 143 Cranial Nerve V (Trigeminal} . . . . . . . . . . . . . 1 51 . .. . . 167 . . . . . .. . . . . . . . 165 Spondyloarthropathies . . . . . . . . . .. . . . . 165 Cranial Nerve X (Vagus) .Lower Motor Neurons . .. . . . 163 . . . . . . . .. . 129 . . . . . . Neuromuscular Junction. . . . . . . 153 Epidural Hematomas Meningitis Decreased Platelet Number: . . . . . . . . . . . 138 Cranial Nerve I (Olfactory) Cranial Nerve II (Optic) . . . . 130 Thrombocytopenia . . . . . . . . . . . . . . . . . . .. . . . 147 Cranial Nerve XI (Spinal Accessory) Cranial Nerve XII ( Hypoglossal) viii . . . . .. 1 54 lntraparenchymal Hemorrhage Thrombotic Thrombocytopenic Coagulation (DIC) . . . . .. . . . . 129 Decreased Platelet Function or Number . . . . . .. .. .. 154 Subarachnoid Bleeding and Infection . . . . . . . . . . . . . . . The Nervous System . .. .. 155 . . . . . . . . . .. . .. . 128 Platelets and Coagulation Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 Epidural Abscesses . . . . . .. . . . .. . . . . . . .. . . . . . . . . .. . . . . 128 Basophils. . . . . . . . . . . . . 137 . ... .. . . 161 Lambert-Eaton Syndrome . . .. . . . . . . . . . 154 Bleeding and Infection in the Brain Brain Abscess . . . . . . . .. . . . .. .. . . . . . .. . . . . 154 . . . . . . . .. . . .. . . . . . . . . . . . . . 128 Decreased Lymphocytes . . . . . . . . . . . . .. .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 Diseases of Lower Motor Neurons. . . . 127 Increased Neutrophils . . . 145 Rheumatoid Arthritis (RA) Cranial Nerve IX (Glossopharyngeal) Osteoarthritis (OA) . . . . . . . 163 Immunosuppressive and Anti-Inflammatory Drugs Joint Disease: Arthritis . ... . . . . . . . . . . . . . . . . . . . . 154 . . . . . . . . . . . . . . . 133 . . 162 .. . .. . . . . . . . . .... . . .. . . . 163 Treatment of Autoimmune Diseases .. . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . 1 53 Lymphomas . Diseases of Anterior Horn Cells Diseases of Peripheral Nerves . . . . . . .. and Muscle Motor Pathway: Upper Motor Neurons . . . . .. . . . . . . . . .. . . . . . . . . . . . . . . Rheumatology . 144 Chapter 8. Mast Cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 Subdural Bleeding and Infection Subdural Hematomas Purpura (TIP/ HUS) . . . . .. . . . 161 . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . .. . . . . . . 137 . . .. . . . . . . . . . . . . . .. . . . . . . . . .. .. 148 Basal Ganglia . .. . . . . . . . 162 . .. . . . .. . . 126 Decreased Number of WBCs . . . . 163 Synovial Fluid Analysis . . . . . . . . . 128 Increased Lymphocytes . . . . 132 Hypercoagulable States: Tendency to Clot . . . . . . . . . 147 . . . . .. . 150 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 150 Diseases of the Brain . . . . . . 165 Infectious Arthritis . . . . . . . . . . . . . . . . . 129 Hypocoagulable States: Tendency to Bleed Decreased Coagulation Factors Platelet Dysfunction . . . .. .. . . . . . . . . . .. . . . . . . . . . . . . . . .. ... . 154 Cerebral Vasculature Brainstem .. .. . .. . . . .. . . . . . . . . 151 Antiepileptics . . . . . . . . . 152 Intracranial Infection and Bleeding . . . . . . . . . . . . . . . 128 Epidural Bleeding and Infection Multiple Myeloma .. . . . . . . . . 152 Pseudotumor Cerebri . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 133 Motor and Sensory Pathways . . . . . . . . . . . . . . . . . . . . . .. . . .. .. .. . . . . . . . 150 Mental Status Changes: Dementia and Delirium Seizures . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . .. . . . . . . . . . . . .. . . . . . . . . . . . . 132 Chapter 7. . . . . . . . . . . . . 143 Cranial Nerve VI (Abducens) . . . . . . . 132 Summary of Hypocoagulable States . . . . . . . 136 Brainstem and Cranial Nerves . . . . . ... . . . .. . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . 130 . . 148 . . . . . . . . . . . . .. . . .. ... . . . . 154 Subarachnoid Hemorrhage . . . . .. . . .. . . . . . .. . ... . . . . ... .. . . . . . . 128 Meningeal Signs . . .. . . . . . . . . . . . . . .. . .. . 159 . 148 .. . . 126 White Blood Cells and Immunology Hypersensitivity . . . . . . . . . . ... . . . . . . . .. . . . . . . . . . . . . .. . . . . . . . . 1 58 Diseases of the Spinal Cord Neuroanatomy and Localization Nerve Root Compression .. . . . . . . . . . . . . .. . .. . . . . . . . . . . . . . . . . 155 . 126 Immunodeficiency . .. . 138 . . .. . . . . . . . 141 Cranial Nerve IV (Trochlear) . . . . . .. . . . .. . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . 160 . . . . . . . . . . 154 Disseminated Intravascular Sensory Pathways . . . . . . . . .. . . . . . .. . . . . . . . ... . .. . . . . .. . . . . . . .. . . . . . 148 . . . . . . . . . . . . . .. . . . . . . . . . . . . . 156 . . . . . . . .. .. . . . Diseases of the Muscle . ... . . . . . . . . . . . . . 1 33 vs. 131 Subdural Abscesses . . . 155 Anatomical Overview . . . . . 128 Lymphocytes . . 152 Leukemias . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . .. . .. . . . . . . . . . . . . . . . and Eosinophils . . . . . . . . 148 Parkinson's Disease . . . . . . . . . . . . . . . . . .. . . . . . . .. .. . . . . . . . . . . . . 161 Diseases of the Neuromuscular Junction Myasthenia Gravis . . .. . . . . . . 126 Decreased Function of WBCs . . . . .. . . . . 1 27 Neutrophils . . . . . 135 Summary of Motor and Sensory Systems . . .. . . . . . . . . . . . . . . . . . . . . . . . . ... . 152 Elevated Intracranial Pressure Hydrocephalus . . .. . . . . . . . 128 The Hematologic Malignancies of WBC Lineage 128 Cerebellum and Basal Ganglia Cerebellum . . . 154 . 133 Cerebrospinal Fluid (CSF) Examination Central Nervous System Tumors Stroke Multiple Sclerosis . 133 Cranial Nerves . . 143 Cranial Nerve VII (Facial) . . . . 131 .. . . . . . . . . . . . . . . . . . . . .

........................ ... 16 9 Male Reproductive Organ Pathophysiology Prostate Prostatitis ..... 176 . 174 Pelvic Inflammatory Disease (PID) Neoplasia of the Female Genital Tract .............. 173 ..... 174 Testicular Cancer .......... ... 174 Polycystic Ovary Syndrome .......................... 16 9 . Oral Contraceptives................... 16 9 .................................. 16 9 Benign Prostatic Hypertrophy Prostate Cancer Testicles Orchitis Torsion .... 1 70 ix ............................ 174 Other Diseases of the Female Genital Tract .. 170 Inflammation of the Female Genital Tract Vaginitis Cervicitis ........... 170 Amenorrhea .................................. Cases ............................... 16 9 ..................... 16 9 ............. 173 .................... .... .................................. 170 Diseases of the Breasts Erectile Dysfunction ........16 9 . Male and Female The Menstrual Cycle Reproductive Systems ................................ 178 and Amenorrhea ....... Chapter 1 0................ 170 Infertility ................ 174 ........................16 9 ................................Chapter 9.................... 174 Endometriosis ........................................................ 170 The Menstrual Cycle. 170 ..................... 177 Female Reproductive Organ Pathophysiology .....

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and a much-welcomed change from the previously artificial sep­ aration of anatomy from physiology from pathology from biochemistry . and how. The chapters may be read in any order and are linked via cross-references. diagnostic algorithms. or lab finding and see all of the many diseases that could cause it. and treatment of these diseases are elaborated upon. "Everything you will learn here has essentially two goals: how to diagnose disease and how to treat it. I essentially wrote it as the book I wish I had during sec­ ond year to understand why I learned what I did in the first year. and psychosocial aspects of medicine can be found in many other sources. Aaron Berkowitz xi . and if an effort were made during all pre-clinical teaching to explain how mate­ rial is relevant to these goals. I wish someone had stood up on the first day of medical school and said. I try to present an aerial view of the "forest" of clinical pathophysiology. thus providing an overview of the functioning of a given organ system. and lab findings that they produce. but also to help you think pathophysiologically through the symptoms/signs and diagnos­ tic reasoning. sign." Although it seems like a simple statement." A section or even an entire chapter can be read in one or two sittings. and ultimately serve to enhance your ability to take care of your patients. The goal is to teach you how to develop a differential diagnosis. Following the estab­ lishment of this framework. but more importantly. The goal of the chapter of cases is not just to ask you"what's the most likely diagnosis?". allows the student to proceed in the opposite direction: one can select a symptom. etc. classified by pathophysiological mechanism. This book can help to serve as the "mental filing folders" for the deluge of information presented in the first two years of medical school. at present.Preface In retrospect. linking the study of pathophysiology with its relationship to normal physiology on the one hand. a strong framework for the learning. and application of medical knowledge would develop in each student from day one. In a complementary approach. which is then followed by what logically could cause malfunction of the organ system (pathology/pathophysiology). so none of these areas are treated in detail here. and with clinical reason­ ing in diagnosis and treatment on the other. where relevant. and treatment of diseases from this integrated perspective. all the while pointing out the "trees. Each chapter begins with a brief discussion of"how an organ system works" (anatomy/biochemistry/physiology). epidemiology. designed by Dr. Rather. the goal is not to"arrive at the answer" but rather to understand the possibilities and how to logically distinguish among them. if it were truly understood by students at the outset of medical school. . The book could also serve as a review for health professionals of any type at any level of training seeking a refresher on the basics. This book uses simple anatomical and physiological concepts to create a framework for the understanding of disease processes and the symptoms. diagnosis. as many USMLE­ type questions do. However. signs. In the most prevalent curricular model at present. and why what I was learning in second year would be relevant to what followed. Thus. . understanding. This is a book that will certainly help to prepare you for your course­ work and the USMLE. The move toward integration of the preclinical sci­ ences has been a large step toward this goal. The goal of this book is to fill that perceived void. how it can malfunction. specific disease mechanisms are discussed in this context. Information on histopathology. the accompanying CD-ROM. in principle. Stephen Goldberg. treatment protocols. how to evaluate a patient further to zero in on a diagnosis. this book would ideally serve as a guide to the second year of medical school as well as a review for the USMLE Step 1. it will provide you with a logical framework and reasoning strat­ egy with which to approach clinical medicine. there is no book that provides the student with a clear and concise overview of the mechanisms. and how to treat the disease diagnosed. signs. and the symptoms. diagnosis. the disease entities that can cause such mal­ function. one can diagnose and treat such entities.

This book is also humbly dedicated to the memory of David Atkins. enjoying many pearls of wisdom and many hearty laughs. suggestions. I was also incredibly fortunate to have many phenomenal expert reviewers. Steven Gittler. The book gained much from the input of all of these individuals. David Pearse. I am also very grate­ ful for the extraordinarily precise proofreading skills of Phyllis Goldenberg. I was privileged to study with him for the entirety of my undergraduate education. Derek Fine. I heartily thank Doctors Jay Adler. I alone am responsible for whatever imperfections remain. Dr. Marple Newtown High School. prose. to whom I express my deepest gratitude. Paxon Hollow Middle School. and has generously provided the illustrations and programmed the accompanying CD-ROM. and very helpful perspectives on pedagogical organization. and Joseph Shuman. and Johns Hopkins School of Medicine. Stephen Goldberg. support. David Newman-Toker. and making things ridiculously simple have been extraordinarily helpful in shaping this book at all stages of its conception and development. Russell Elementary School. This book is dedicated to all of the wonderful teachers who have been responsible for my education up to the present from Hillview Nursery School. and to my first teachers. whose suggestions were extremely helpful in making the flow of the text as clear as possible. Alison Moliterno. clinical and scientific insights. Paul Dworkin. Goldberg has helped me bring this book from its initial concep­ tion to its present quality. Todd Brown. John Flynn. one of my first mentors in the sciences­ and many other areas-at George Washington University. Each of the following physicians generously offered extremely valuable advice. xii . Though he was not known for making things 'ridiculously simple' by any means (his courses in neurobiology and comparative anatomy inspired both awe and fear among students). H. my parents and grandparents.ACknowledgments This book could not have been completed without the mentorship. George Washington University. and advice of Dr. Richard Preston. President of MedMaster Books. His insightful suggestions on pedagogy. Franklin Herlong.

Mnemonic for the atrioventricular (AV) valves : The tricuspid is on the right. Fig. the ventricles con­ tract. while this occurs.V.V. The right hearts pumps this blood to the lungs via the pul­ monary artery. Heart chambers and valves.V. During diastole . Deoxygenated blood from the right side of the body travels to the right heart by way of the venous system. THE CARDIOVASCULAR SYSTEM AN ATOMIC ALOVERVIEW Fig. we will examine the four T. 1 . The two atrioventricular valves (mitral and tricuspid) lie between the atria and the ventricles. Following this. There are four heart valves. BASIC CIRCULATORY CIRCUIT HEART F AILURE Figure 1-1 We will first discuss the manifestations and treat­ ment of heart failure as a means of reviewing cardiac physiology. the aortic and pulmonary valves prevent backflow of the blood that has just been ej ected during systole.V.CHAPTER 1.=Tricuspid Valve P.1 . The lungs oxygenate this blood and send it to the left heart by way of the pulmonary veins. During systole . the atrioventricular valves prevent backflow of this blood from the ventricles to the atria. =Pulmonic Valve M. THE CARDIOVASCULAR SYSTEM CHAPTER 1. while this occurs. Basic circulatory circuit. The mitral is on the left. This oxygenated blood is pumped by the left heart through the aorta to the body. and the aortic and pulmonic valves lie between the ventricles and their outflow vessels (aorta and pul­ monary artery). =Mitral Valve A. forcefully expelling blood into the outflow vessels. =Aortic Valve SVC = Sup Vena Cava IVC =lnf Vena Cava Pulmonary Artery Aorta IVC Figure 1-2 HEART CHAMBERS & VALVES 1 . the ventricles relax and fill with blood from the atria. 1 -2.

Left heart failure. the higher up in the lung fields these crack­ les will be heard (as the lungs fill with fluid from the bottom up). Right heart failure. Where else would the blood back up? Backup can reach the liver. Why? What changes Figure 1-3 2 . more specifically. The name congestive heart failure comes from the congestion in the lungs caused by backup of flow from a failing left heart. the venous return from the body via the superior and inferior venae cavae. Inferior Vena Cava B. This would decrease the flow from the left heart to the body. The right ventricle is not nearly as strong as the left ventricle. which is a straight shot to the right heart. and blood supply). by cardiac disease). now where does the blood back up? Where does the blood in the right heart come from? The simple answer is the body. Consider a patient who gets short of breath with activity. How could cardiac disease affect the lungs? Imagine that a patient's left ventricle cannot pump as well as it should (the causes of such pumping problems comprise the bulk of this chapter) . The worse the failure and the more fluid in the lungs. which causes short­ ness of breath (dyspnea ). PULMONARY HYPERTENSION Symptoms and Signs of Heart Failure We have been discussing how a failing heart causes blood to back up . - Fig. Orthop­ nea and paroxysmal nocturnal dyspnea are two addi­ tional symptoms that can appear in heart failure. De­ creased blood flow to the brain may cause drowsiness or changes in mental status. and the rest of the body via the in­ ferior vena cava. and shortness of breath . What would you expect to see on physical exam if the venous return backs up? An elevated jugular venous pressure (JVP). and the pathophysiological and clinical man­ ifestations of such diseases. This results in pulmonary edema. etc . LEFT HEART FAILURE Fig. The JVP thus serves as a sort of barometer of right heart pressure. The right ventricular walls are thus thinner than the walls of the more muscular left ventricle. 1-3B. how each can be affected by disease. Symptoms and signs of heart failure. THE CARDIOVASCULAR SYSTEM components of the heart (muscle. electrical system. valves. 1-3A. Right Heart Failure Fig. causing transudation of fluid into the lungs. Any dis­ ease process that increases resistance in the pulmonary vasculature (pulmonary hypertension) can cause the right heart's job to be increasingly difficult for this thin­ ner-walled ventricle. Left heart failure as a cause of right heart failure. The lungs may be affected directly (by pulmonary disease) or in­ directly (e. A. weakness. On physical exam. the abdomen. What symptoms might be caused by decreased forward flow? Decreased blood flow to the muscles and the rest of the body can result in fatigue. ) can be signs of right heart failure. you might hear crackles in the bases of the lungs as a result of this ex­ cess fluid. A failing heart also has trouble main­ taining forward flow this was the whole reason for this backup in the first place. 1-3C. and peripheral edema (fluid in the ankles. Because backup of flow in left heart failure can increase pressure in the pulmonary vasculature. If the right heart fails.g. . which in turn would cause blood to back up into the pulmonary vasculature (Fig. Orthopnea : The classic story is that a patient gets very short of breath upon lying down.CHAPTER 1. legs. hepatic congestion. 1-3A). Shortness of breath means that the lungs are somehow affected. The jugular veins in the neck are a straight shot to the superior vena cava. 1 -4. left heart failure can cause pulmonary hy­ pertension and subsequent right heart failure. Left Heart Failure Fig. whereas the left ventricle must squeeze into the higher-resistance systemic vascula­ ture. This backup increases pressure in the pulmonary veins. Thus. ascites (fluid in the abdomen). since it only squeezes into the low-pres­ sure pulmonary system.

the heart can handle it.g. Fig.g. and afterload is the resistance that the heart faces during systole. a patient with heart failure may tell the classic story that s/he cannot breathe as easily when lying flat. physiologically when one lies down? When one is standing. Treatment of he art failure. and Treatment of Heart Failure lol). More specifically. causing shortness of breath. preload is the blood pressure in the left ventricle at the end of dias­ tole. In heart fail­ ure . The heart's work is to pum p the preload . ''What would happen if you were to lie flat?''. gravity causes venous blood to pool in the feet. Normally. some people just like to sleep on a lot of pillows. When one lies down. right before the ventricles contract . • A related symptom is paroxysmal nocturnal dysp­ nea . there is decre ased forward flow and incre ased backup of flow. and the blood backs up into the lungs. Afterload. You can ask the patient. but if you ask. The pathophysiology is the same. all of this blood can find its way back to the heart more easily. the workload on the heart must be decre a s e d . 1-5. classically resolv­ ing when the patient gets up and goes to the window for air. metopro­ Preload.. or the resistance to flow in the arterial tree against which the heart must work (afterload is created by the arteries). Where does • 3 Decreasing backup by decreasing the heart's work. cardiac output must be increased. Preload is the pressure that fills the ventricles during diastole. "How many pillows do you sleep on?" Of course. suddenly increas­ ing the heart's work. The increase in filling time allows more blood to accumulate in the ventricles before con­ traction. though the end result is that the patient wakes up in the middle of the night coughing and short of breath. amrinone/milrinone) Decrease the rate of contraction to increase filling time (beta-blockers. To decrease backup. e. the preload comes to the heart from the venous system. Increasing forward flow by increasing car­ diac output can be accomplished by one of two ba­ sic mechanisms: .CHAPTER 1. . leading to a subsequent increase in car­ diac output. dopamine/dobuta­ mine.Increase the force of ventricular contraction (in­ otropes. Afterload is the sys­ temic vascular resistance. e. The goals of therapies are thus to increase forward flow and decrease backup of flow . To incre ase forward flow. digoxin/digitalis. but a weak and failing heart cannot. propranolol. THE CARDIOVASCULAR SYSTEM Decreased Increased Forward Backup of Flow Flow ·Fatigue • • Shortness of Breath ·Orthopnea ·Weakness ·Paroxysmal Nocturnal Dyspnea Shortness of Breath Increased Right Heart Work Backup of Flow Figure 1-4 • Increased JVP ·Edema ·Ascites SYMPTOMS AND SIGNS OF HEART FAILURE this come from? Originally.

reducing the intra­ vascular fluid volume. ACE inhibitors. 1 When the kidneys sense de1 4 Cirrhosis is scarring of the liver that can impede blood flow through the hepatic portal system. blood pools in the gut's venous system. which cause the patient to urinate more. . Also. How can preload be reduced? One can decrease venous return by dilating veins . E ffective volume depletion also occurs in cirrhosis.. Again. one can use diuretics . Success of diuretic ther­ apy can be monitored by observing the decrease in symptoms/signs related to excess fluid. the perfusion pressure in the kidneys decreases. The kidneys in heart failure. what could be done to preload and afterload to make the heart's j ob easier? Therapies should decrease pre­ load and decrease afterload. g. THE CARDIOVASCULAR SYSTEM TREATMENT OF HEART FAILURE INOTROPES BETA BLOCKERS tFORWARD FLOW ! BACKUP OF FLOW !HEART'S WORKLOAD Figure 1-5 against the afterload. 4-12). which slows the return of blood from the veins to the heart (nitrates have this action) . 1-6. Since cardiac output is weak in heart failure. The Kidneys in Heart Failure Fig. the effective blood vol­ ume that reaches the kidney decreases because a large volume of the body's blood supply stagnates in the mesenteric veins. Arterial dilators decrease afterload ( e . but the pressure at which this volume reaches the kidneys decreases. hydralazine) . such as shortness of breath and edema. In heart failure.CHAPTER 1. hence the term effec­ tive blood volume decrease. The blood volume itself is not changed. causing portal hypertension (see Fig. Due to this blockage in the venous retum.

Angiotensin II receptor blockers (ARBs) block the angiotensin II receptor. leading to a similar effect. THE CARDIOVASCULAR SYSTEM HEART FAILU R E (or cirrhosis or hypovolemia or renal artery stenosis) I Decreased blood flow to kidney I Kidney releases renin � i. Reducing angioten­ sin II production decreases both aldosterone release and angiotensin II-induced vasoconstriction.CHAPTER 1. Angiotensin II causes vasoconstriction. Angiotensin II also stimulates aldosterone re­ lease from the adrenal gland. which increases conversion of angiotensinogen to angiotensin I. An­ giotensin I is in turn converted to angiotensin II by an­ giotensin converting enzyme (ACE ) . which increases intravascular volume. 5 . which raises the blood pres­ sure. ADH increases water reabsorption in the kidneys. This increased intravascular volume further aggra­ vates the backup into the lungs and body as discussed above. ACE inhibitors (Fig. Additionally. This leads to increased sodium reabsorption by the kidneys.l-6) decrease the conversion of angiotensin I to angiotensin II. are the kidneys and ADH help­ ing by increasing plasma volume in heart failure? No. CJ k I I Angiotensinogen ACE Inhibitor ANGIOTENSIN II Cl Aldosterone release from adrenal Cl Aldosterone Antagonists Vasodilators Increased sodium reabsorption (along with water) Figure 1-6 creased perfusion pressure. Angiotensin I ACE O . thus in­ hibiting further increase in blood volume and blood pressure. How can the kid­ neys increase blood volume in response to decreased perfusion pressure? Through the renin-angiotensin­ aldosterone system. This system senses decreased re­ nal perfusion and releases renin. which causes wa­ ter to follow it. If the heart is already having trouble handling the existing blood volume. The increased vasoconstriction and increased blood volume raise the blood pressure. they try to increase this pressure by increasing blood volume. fur­ ther contributing to increased volume and increased blood pressure. the per­ ceived low volume status causes release of antidi- uretic hormone (ADH) from the posterior pituitary...

ele­ vated JVP). my­ ocardial infarction) and inflammation of the heart can also cause chest pain in addition to these symptoms. valves. chest pain can also arise from esophageal. weakness. electri­ cal system. Be it disease of the muscle. decreasing how much blood it can pulmonale . or coronary vasculature. . the left ventricle has to squeeze hard against the resistance posed by the stenotic aortic valve. note that blood goes from the left ventricle through the aortic valve to the aorta. anemia. musculoskeletal. if the heart is not functioning optimally. accept­ ing blood. If the musculature thickens (hypertrophy). they are certainly not exclusive to cardiac disease. the ventricle cannot relax as well. Need Increased bigger Resistance muscle A. Although the above symptoms are characteristic of cardiac disease of some sort. an electrical conduction system . 2-5). these are the sorts of symptoms that can occur. one cause of increased strain on the left heart is increased blood pressure in the arteries (hypertension). For example. Ischemic heart disease (e. or anxiety. any process that increases resistance in the pulmonary vasculature (pulmonary hypertension) can lead to right ventricu­ lar hypertrophy and eventual failure. Hypertrophy of cardiac muscle can be caused by genetic disease (hypertrophic cardiomyopa­ thy) or by certain pathophysiologic circumstances. Hypertrophy means in­ creased growth. CARDIAC DILATATION Figure 1-7 6 . Cardiac Hypertrophy. What causes right ventricular hypertrophy? Using the same logic. but why does the heart fail? The heart has four components that help it to pump blood: muscle. and the ventricle cham­ ber size is reduced. ej ecting this blood. pulmonic valve stenosis. This resistance is the afterload: what the heart works against. What circumstances make any group of muscles grow big and strong? Hard work. Fig.g. THEFOUR COMPONENT SOF THE HEART AND THEIR DISEASES Cardiac Hypertrophy We have just discussed the physiologic basis of the clini­ cal manifestations of heart failure. and pulmonary causes (Fig. paroxysmal nocturnal dyspnea. Aldosterone itself can be blocked at its receptor by al­ dosterone antagonists such as spironolactone. Over time. In aortic stenosis. or pulmonary disease. edema. angina. l-3B). this impedes the heart's ability to pump blood to the tissues. THE CARDIOVASCULAR SYSTEM receive (diastolic dysfunction ). If the musculature thins and weakens (dilatation). If any of these four elements is not working properly. and the heart's own blood supply. namely to the entire systemic vascular tree via the aorta. The left heart squeezes blood to the body. shortness of breath can also be due to pulmonary disease. they contract during systole. and it cannot contract as forcefully (systolic dysfunction). this can cause left ventricular hypertrophy. what site of increased resistance would cause the right heart to have to work harder? Since the right heart ejects into the lungs. What else might cause the left ventricle to have to work extra hard? Reviewing figure 1-2.CHAPTER 1 . What would cause the heart to have to work hard? Let's take it one side at a time. l-7A. Thus. Examples in­ clude left heart failure (Fig. orthopnea. the strength of the ventricular muscle decreases. values. shortness of breath) and increased "backup of flow" symptoms/signs (shortness of breath. which can lead to both "decreased forward flow'' symptoms/signs (fatigue. CARDIAC HYPERTROPHY Need more space in chamber B. Right heart failure secondary to a pulmonary cause is called cor Diseases of the Heart Muscle The ventricular muscles relax during diastole.

treats the underlying cause if possible. aiming to increase forward flow and decrease backup of flow (Fig. Although this growth may initially be compen­ satory. which can result in angina. the heart can di­ late over time to accommodate the extra blood leaking back into it across the aortic valve. and can eventually grow big and thick. Consequences of Cardiac Dilatation. When would the left ventricle end up with extra blood? In aortic regurgitation. the heart is too relaxed and does not give a good squeeze. such as amyloid (which can occur from amyloidosis or multiple myeloma) or iron in he­ mochromatosis. in what pathophysiological situation would the heart become bigger and floppier? Dilata­ tion occurs when the heart needs to handle more blood than usual. What if instead of all of the blood going forward during systole. alcohol . What is another reason that extra blood might leak back into the left ventricle? Hint: The aorta is one way out of the left ventricle. The dilated heart is big and baggy. Beta blockers and calcium channel blockers accomplish these goals. THE CARDIOVASCULAR SYSTEM viral myocarditis can cause dilated cardiomyopathy . pulmonic or tricuspid regurgitation can lead to right ventricular dilatation. As the cardiac muscle outgrows its blood supply. Restrictive Cardiomyopathy What could cause the right ventricle to be overloaded with extra volume? Similar to their analogues on the left. 1-7B. Consequences of Cardiac Hypertrophy. the treatment is the same as that for heart failure. it eventually reaches diminishing returns. Let's compare this situ­ ation to cardiac hypertrophy. In addition. the ventricle gets stiff and squeezes well but does not adequately relax." a dilated ventricle should have no problem relaxing. allowing for in­ creased filling and increased cardiac output. an atrial sep­ tal defect (ASD) or a ventricular septal defect (VSD) will lead to increased blood in the right heart. In contrast. Though sep­ tal defects are often birth defects. but its thick walls do not relax as well. and/or infarction. which can cause it to dilate. One The loss of a good squeeze leads to both diminished forward flow and backup of flow. Since it is "baggy. which results in decreased cardiac output. What normally assures that blood flows forward from the left ventricle through the aorta and not back into the atria? The mitral valve. and does not fill optimally. the heart will have to work harder to squeeze. can also lead to infiltration. aiming to increase forward flow and decrease backup of flow (Fig. Cardiac Dilatation. when the left ventricle contracts. Genetic diseases. so since the hypertrophied heart cannot relax as well. In hypertrophy. Cardiac Dilatation Fig. cardiac hypertrophy causes diastolic dysfunction. Pathophysiologic circumstances can also lead t o car­ diac dilatation. some of it squirted backward into the left atrium. This is called systolic dysfunction. forward flow de­ creases and backup of flow occurs. and Treatment of Cardiac Dilatation. the increased thickness of the hypertrophied ventricular wall also makes it more difficult to adequately per­ fuse. drugs. the muscle can get so thick that the chamber becomes quite small. 7 .l-5). instead of sending all of the blood out to the body. some of the ej ected blood leaks back through the aortic valve into the ventri­ cle.what's the only other way (as­ suming no holes)? The left atrium. If any process increases the resistance that the heart must pump against. Treatment is the same as for heart failure. thus.l-5). Otherwise. If the hyper­ trophied heart has a smaller chamber size. First. and right ventricular hypertro­ phy can lead to right heart failure symptoms and signs (Fig. not thick and strong like the hypertro­ phied heart. a dilated ventricle is weakened and thus gives a weaker squeeze during systole. Poor relaxation and small chamber size lead to decreased filling of the ventricles. it cannot fill optimally. If hard work makes the heart get big and thick. The pathophysiology in restrictive heart disease is essentially the same as in cardiac hypertrophy: the heart is stiff and does not re­ lax well (diastolic dysfunction). 1-4 ) . substances can accumulate in the heart muscle. Rarer diseases. Sec­ ond. However. in cardiac dilatation. causing a restrictive cardiomyopathy. If there is aortic regurgitation.CHAPTER 1 . Treatment of Restrictive Cardiomyopathy. Ventricular relaxation occurs during diastole . ischemia (decreased blood flow/oxygen supply) can oc­ cur. what does the hypertrophied heart do better than the normal heart. and what does it do worse? The hypertrophy allows the heart to squeeze better. Additionally. So a leaky mitral valve can lead to mitral regurgitation into the atrium. such as sarcoid and Pompe's disease. This will increase the amount of blood that the left ventricle re­ ceives. a VSD can also occur as a complication of a myocardial infarction. If the heart cannot relax opti­ mally. then flowed back into the ventricle during diastole? This would have the same effect on the left ventricle as aortic regurgita­ tion: the left ventricle would have to handle extra blood. In infiltrative diseases. Hypertrophy of the left ventricle can eventually lead to left heart failure symptoms and signs. Systolic dysfunction like that caused by cardiac dila­ tation can also occur from weakening of heart muscle secondary to ischemia (decreased blood flow/oxygen supply). Treatment of Cardiac Hypertrophy. the treatment( s) of choice should de­ crease heart rate and contractile force.

There are four valves and two possible pathologies for each (stenosis and regurgitation). THE CARDIOVASCULAR SYSTEM the open vs. The sound produced by the closure of the atrioventricular valves is 81. S2 heralds the beginning of diastole. and the aortic and pulmonic valves slam shut to prevent regurgitation back to the ventricles. 1-2. age of the patient. Definitive treatment for any valvular pathology is surgical repair or replacement. Also during this time. and S4 is more typical with a hypertro­ phied heart/diastolic dysfunction .CHAPTER 1 . 82 is the sound of the aortic and pulmonic valves slamming shut. When systole is complete. and we are back where we began. The filled ventricles then contract (systole) again. The Valves and Their Diseases: Stenosis and Regurgitation Review Fig. the mitral and tricuspid valves slam shut to prevent regurgitation into the atria. what could this sound represent? What happens during this phase of the cardiac cycle? Blood flows across the atrioventric­ ular valves into the ventricles. The heart valves allow blood to flow for­ ward and prevent blood from flowing backward.Genetic diseases • Hemochromatosis -Drugs • Radiation fibrosis -Alcohol ·Tumor infiltration . blood flows across the aortic valve to the aorta and through the pulmonic valve to the pul­ monary artery.g. 2006 8 . so there are eight basic valvular pathologies. During systole. If there is still blood left in the ventricles (e. and other clinical factors. If heard in the context of heart fail­ ure. Criteria for valve surgery can involve symptoms. it is a helpful way to remember that an 83 occurs in a Fig. What could go wrong with a valve? Valvular pathology can cause a valve to be bad at allowing blood to flow forward through it (stenotic) or bad at preventing back flow (re­ gurgitant). Summary of diseases of the heart muscle. the mitral and tricuspid valves must open to allow blood to pass from the atria to the ventricles for the next systole. a sound may be heard as blood flows in and splashes against the blood still left in the ventricle. 83 and 84 are extra heart sounds that can be heard in heart failure ( S3 can also occur normally in young patients) . As the ventricles contract. severity of valvular dysfunction. The active contrac­ tion that ejects blood from the ventricles is systole. S3 is associated with a dilated heartlsystolic dysfunction. . Fig 1 -8. depending on the type of valve lesion. because it could not squeeze it all out due to its poor systolic function).Muscular dystrophy I • � Restrictive Cardiomyopathy + Diastolic dysfunction • Associated with S4 Figure 1-8. Now. l-9A. • Systolic dysfunction • Associated with S3 Modified from Chizner: Clinical Cardiology Made Ridiculously Simple.Viral myocarditis • Scleroderma . MedMaster. Although this may not be exactly what produces the sound. The normal cardiac cycle. Since S3 occurs right after S2 (but well before S 1 ) . the relaxed phase of the cardiac cycle. closed status of the valves reverses. and/or find­ ings on echocardiography. blood fills the atria to prepare for the next cycle. During diastole. blood passes from the atria across the open mitral and tricuspid valves into the ventricles. • Dilated Cardiomyopathy: • Sarcoidosis I � Cardiac Dilatation + I. MORPHOLOGIC TYPES OF CARDIOMYOPATHY NORMAL CARDIAC RESTRICTIVE CARDIAC HYPERTROPHY CARDIOMYOPATHY DILATATION •Inherited (hypertophic cardiomyopathy) •Aortic stenosis • Hypertension I Cardiac Hypertrophy + • Diastolic dysfunction • Predisposition to ischemia •Amyloidosis • Coronary artery disease • Aortic regurgitation •Idiopathic • Mitral regurgitation Infiltrative Disease: myocardial fibrosis .

Since there is still blood left in the ventri­ cle because ofa weaker ventricular contraction than nor­ mal.. I DIASTOLE Aortic & pulmonic valves close (S2) Mitral & tricuspid valves open ___.I _ � S1 murmur of mitral/tricuspid regurgitation & VSD murmur of aortic/pulmonic regurgitation 9 . 84 The number 3 looks like a puffy dilated number. in a hyper­ trophied heart with diastolic dysfunction)._I & tricuspid valves close (S 1) & pulmonic valves open S1 S2 1&1 II " S1 S1 I murmur of aortic/pulmonic stenosis Figure 1-9 I �\. What could this sound represent? At the very end o f di­ astole.e. comes after 82 (and 83 if present). squeezing the last of their blood to the ventricles. Causes of aortic stenosis include . Mnemonic: cause of the increased resistance it presents to left ven­ tricular contraction. whereas the number 4 looks like a small chamber with rigid surroundings (hypertrophied ventricle). and just before 8 1 . the blood flowing in from the atria makes noise. \'-'-'--..____. c( :E a:: 0 z Mitral Aortic " SYSTOLE ti \'\ SYSTOLE ti \'\ S2 ..CHAPTER 1. THE CARDIOVASCULAR SYSTEM dilated heart. The S4 is a sound produced when Aortic Valve Aortic Stenosis can cause cardiac hypertrophy be­ the atria squeeze against a stiff ventricle (i. the atria contract.

the diastolic pressure is not maintained since instead of supporting the column of blood in the aorta. i. falling back. Still. The murmur of aortic stenosis is also referred to as a systolic ejection murmur. To deter­ mine the murmur of any type of valvular dysfunction. To review. and rheumatic heart disease. but still not all the way. so the murmur occurs after S2. diastolic pres­ sure.. dyspnea on exertion. but as the door opens more. There are two numbers. i. Other manifestations of aortic regurgitation. How would this widened pulse pressure manifest on physi­ cal exam? Imagine this gush of blood coming from the heart and then falling back . This can sometimes be so drastic that it can be visible. allowing only some "murmuring" blood through. . syncope. the pulses are called paruus et tardus . refers to the pressure being maintained when the heart is relaxed. . see Fig. The murmur must stop at S2 since that sound signifies that the aortic valve is closed (i. Aortic regurgitation affects blood pressure and pulses. leaving space through which backflow of blood can occur. because it gets louder as it proceeds and then diminishes before S2. Thus. the valve collapses. peo­ ple are always squeezing through.e. Thus. during diastole. and when the brain does not get enough blood. when the aortic valve allows regurgitation.g. In­ stead of blood slamming up against the carotids at high pressure. The top number. One final detail about the sound of aortic stenosis is that the quality of S2 changes . Fig. Why would this be? What does S2 signify? S2 signifies the closing of the aortic and pulmonic valves. . They can Due to decreased forward flow and increased backup of flow in aortic regurgitation. This is known as a systolic murmur. The murmur of aortic stenosis. during systole.g. some of the blood falls back down into the left ventricle. Which pressure (systolic or diastolic) will be affected and why? Assuming the squeeze is nor­ mal. Aortic Regurgitation can lead to a dilated left ven­ tricle. where the blood does not flow normally across the valve. Diseases that can lead to aortic root dilatation include Marfan's syndrome. Therefore. . The squeezed-out blood is normally prevented from falling too much in pressure because the aortic valve shuts behind it. systolic pressure and diastolic pressure (e. . it opens poorly and closes poorly (i. if there is aortic stenosis. . Gradually the valve opens more. S. the systolic pressure should be unchanged. If there is aortic regurgitation. the distance between the two numbers increases (widened pulse pressure). meaning weakened and delayed. First. You can actually feel this in the pulses (bounding pulses). . also feel weak and fatigued because flow t o the body is inadequate since the stenotic valve inhibits this flow. after a forceful squeeze. THE CARDIOVASCULAR SYSTEM aging (also called senile calcification). 120/80). . Other manifestations of aortic stenosis. Fig. the murmur of aortic regur­ gitation is a diastolic murmur. Finally. If the aortic valve is stiff. letting in a few screaming people. The murmur of aortic regurgitation. So how would the S2 change? S2 would be softer since it is the sound of only one valve (the pulmonic) slamming shut instead of two. This is a good im­ age for aortic stenosis : The murmur starts off quietly since the valve is only slightly opened.e. but it is still "murmuring" blood due to the narrowed opening. Another classic physical finding in aortic stenosis involves how the carotid artery pulse feels (carotid upstroke). 1-4). no more blood can flow through it). since the introduction of antibi10 . What symptoms would be caused by reduced flow in the carotids? The carotids feed the brain. This helps maintain pressure during diastole. heart failure symptoms can occur (e. 1 -9C. although the door does not open completely. it does not snap shut. Since the diastolic pressure falls and the sys­ tolic pressure stays the same. In aortic regurgitation. or with the patient's head actually bobbing with each pulse (De Musset's sign). ask yourself. This allows more blood to flow through. light­ headedness. the valve allows re­ gurgitation after closure. more screaming people can get through. At first it opens only slowly. Aortic regurgitation can occur because of weak­ ening of the valves or dilatation of the aortic root. the volume of the mur­ mur decreases. Dilatation of the root causes the valves to be farther apart from each other. as blood flow across the valve decreases. gushing out. systolic pres­ sure. patients with cardiac hypertrophy can have angina and/or myocardial infarction (because the thicker ven­ tricular wall cannot be adequately perfused). Mitral Valve Mitral Stenosis. when the heart is squeezing. Other mani­ festations of aortic stenosis are those that can occur as a result of the induced cardiac hypertrophy.e. and syphilis. between S1 and S2. a disease much less common in the U . Nearly all cases of mitral stenosis are caused by rheumatic fever. This is called a crescendo-decrescendo murmur. for example in the carotids (Corrigan's pulse). instead of brisk pulses. congenitally bicuspid aortic valve. etc. ''When does blood go across this valve?" Blood flows across the aortic valve when the left ven­ tricle contracts. What would the shape of this murmur be? Imagine a stiff door with lots of screaming people behind it trying to push it open. refers to the pressure during systole. it is sent up more slowly and with less force because it is "held up" by the aortic stenosis. How­ ever. Ehlers-Danlos syndrome.CHAPTER 1. and/or dizziness can occur. but weakly closes). When in the cardiac cycle could blood leak back through the aortic valve? S2 is the sound of the aortic valve clos­ ing.e. let's review what blood pressure actually measures. The bottom number. a mur­ mur will occur between S1 and S2. 1 -9B.

2 Mitral Regurgitation. this leads to higher left atrial pressure than if the stenosis were less severe. Because of the stretching of the electrical fibers induced by this di­ latation. and urgent surgical re­ placement of the valve is often necessary. which can lead to shortness of breath. blood flows backward across the mitral valve. Mitral stenosis causes the left atrium to dilate. the chronically elevated left atrial pres­ sure can cause pulmonary hypertension and even right heart failure. The acute problem is not well toler­ ated by the pulmonary system. The sound of the stiff mitral valve snapping open can sometimes be heard (opening snap). The timing of this snap re­ flects the severity of the stenosis.S. If the valve is stenotic.g. it is the first of these functions that is impaired. etc. also known as myxomatous degeneration). Thus. Why? S3 can be thought of as blood splashing against blood already in the ventricle. all of the blood that got inappropri­ ately ejected back into the atrium then returns to the ventricle during diastole: splash! Recall that if mitral regurgitation exists for a long time. and thus the upstream portion of the circuit is affected. which is also systolic? A subtle difference is that mitral re­ gurgitation lacks the crescendo-decrescendo pattern that is present in aortic stenosis.g. What are the roles of the mitral valve? First. Further up­ stream. Is the murmur of mitral regurgitation systolic or diastolic? In mitral regurgitation. What would this do to the opening of the valve? If the pressure is high. Fig. genetic.). but more common in developing countries. atrial fibrillation can develop. and the job of the mitral and tricuspid valves is to shut tightly so as to prevent backflow and maximize forward flow. often initiated by a systolic click. In mitral regurgitation. During systole. This contraction is quite forceful. aortic regurgita­ tion). otics.. l-9B. Since the regurgi­ tant mitral valve flops back with the onset of systole.. the valve will not open until later. Asso­ ciated findings can also help distinguish between aor­ tic stenosis and mitral regurgitation as causes of a systolic murmur. some patients who had rheumatic fever as children are still alive and can have resultant mitral stenosis. preventing it from closing optimally. In mi­ tral regurgitation. Forward flow is diminished since what was supposed to be part of the cardiac output is sent backward into the atria. Without the compensation of a dilated atrium. the heart will compensate by dilating to accommo­ date the increased blood volume (which can cause sys­ tolic dysfunction. so this is another systolic mur­ mur. an S3. the timing of the opening snap is inversely proportional to the severity of mitral stenosis: the more severe the mi­ tral stenosis. the mitral valve allows backflow into the left atrium during ventricular contraction. Other manifestations of mitral regurgitation. What is upstream? Immediately upstream from the mitral valve is the left atrium. If the mitral steno­ sis is severe. If the stenosis is less severe and the left atrial pressure is relatively less. Aside from ventricu­ lar dilatation. the pressure in the lungs acutely elevates due to the sudden onset of backward flow.. When does blood pass across the mitral valve? Between S2 and S1. the valve will snap open quite quickly. Where is the regurgitated blood going in mitral regurgitation? Back into the left atrium. this dilatation stretches the ring-like mitral valve. When would you expect this to occur? Shortly after S2. drugs. The murmur of mitral regurgitation. mitral regurgitation can be caused by de­ generation of the valve (mitral valve prolapse. Right Ventricle->Pulmonary Artery). . So chronic mitral regurgitation can lead to left atrial dilatation. Eventually. there is no time for compensatory dilatation of the left atrium to occur. Mitral regurgitation can be accom­ panied by an S3. since initially there is not enough pressure to snap it open. causes a mid-late systolic crescendo murmur. THE CARDIOVASCULAR SYSTEM tation can lead to left ventricular dilatation or it can be the result of ventricular dilatation. If cardiac dilatation exists for another reason (e. If mitral regurgitation develops over a long period of time. the pulmonary vasculature is also affected by this backup. to prevent back­ flow into the left atrium when the left ventricle con­ tracts during systole. rheumatic fever. dilatation of the atrium can allow it to adapt to accommodate the backflow. during diastole. if mitral regurgitation occurs acutely (e. Fig. this can cause shortness of breath. De­ spite decreased prevalence in the U. So this is a diastolic murmur. preventing signif­ icant elevations in pulmonary pressure. occurring between S1 and S2. or ischemic heart disease. endocarditis. This occurs during systole when the ventricles contract. 1 -9C. More rarely. the fatigue/forward flow symptoms are more prominent. Alternatively. the murmur is usually relatively constant from S1 to S2 (holosystolic or pansystolic murmur). papillary muscle rupture secondary to ischemia). the earlier the opening snap. a specific type of mitral regurgitation. Other manifestations of mitral stenosis. and second. Since pressure increases backward through the left atrium to the lungs. The murmur of mitral stenosis. How can you dis­ tinguish it from the murmur of aortic stenosis. the ventricles contract. to allow blood to pass from the left atrium to the left ventricle during diastole. Pulmonary conges­ tion is a prominent symptomatic feature in acute mitral regurgitation.CHAPTER 1 . whereas in more chronic mitral regurgitation. So mitral regurgi- 2 11 Mitral valve prolapse. mitral stenosis can occur congenitally or in endocarditis. ejecting blood into their respective outflow tracts (Left Ventricle->Aorta.

Pulmonary Valve Finally. pulmonic steno­ sis is almost always the result of a congenital anomaly of the valve. Tricuspid regurgitation also has a similar pathophysiology to its counterpart on the left.) Atrial dilatation from mitral regurgitation can lead to atrial fibrillation. How can one see a barometer of this right-sided pressure? The jugular vein is connected to the superior vena cava. Thus. as in mitral stenosis. the JVP can be elevated. which typ­ ically arises from calcification with age. and this can lead to a separation of the leaflets of the pulmonic valve. so changes in resist­ ance distal to this point (i. and thus increased pressure in the right heart can lead to elevated jugular venous pressure (JVP). Why would the aortic stenosis murmur remain unchanged? The main point of resistance responsible for the murmur in aortic stenosis is the valve itself. the normally low-pressure system in the lungs de­ velops high pressure. The systolic murmur of tricus­ pid regurgitation is best heard at the left lower ster­ nal border and increases with inspiration. Why would a change in systemic vascular resistance affect a mur­ mur? Given the choice of going through what is now a path with greater resistance (the body with clenched fists) and simply flowing back across the regurgitant mi­ tral valve. which is connected to the right atrium. what does this accomplish? This is one way to increase the systemic vascular resistance by clamp­ ing down on the arteries in the hand/arm. 2006 (Courtesy ofW. another way to distinguish between the sys­ tolic murmurs of aortic stenosis and mitral regurgita­ tion is through physical exam maneuvers. Due to the high pressure. In pulmonary hyperten­ sion. MedMaster. THE CARDIOVASCULAR SYSTEM of least resistance). the murmur is systolic (as in aortic stenosis). the blood chooses the mitral valve (the path 3 Pulmonic Stenosis. Unlike aortic stenosis..1 0. The mur­ mur is diastolic and best heard at the left lower sternal border. blood flow through this hole can also create a murmur. Tricuspid Regurgitation. Proctor Harvey. Right Sternal Border Tricuspid Valve Tricuspid Stenosis. 12 . this maneuver will increase the intensity of the mitral regurgitation murmur. and is The pulmonary artery comes from the right heart and the aorta comes from the left heart. the pulmonary artery may dilate. and this too would occur during systole. what other cardiac pathology could lead to a systolic murmur? Where else could the blood go during sys­ tole? If there is a ventricular septal defect. though it occurs over the pulmonic valve region (on the patient's left). Sites of cardiac auscultation.CHAPTER 1. mitral regurgitation. as in tricuspid stenosis. the aortic area is on the (patient's) right of the pa­ tient's sternum and the pulmonic area is on the (patient's) left of the patient's sternum. The murmur of pulmonic stenosis can be heard more prominently over the patient's left upper sternal border. while leaving the aortic stenosis murmur unchanged. From Chizner: Clinical Cardiology Made Ridiculously Simple. If you ask the patient to clench his/her fists. M. The pathophysiology in tricuspid stenosis is essentially the same as in mitral stenosis. clenched fists) will have lit­ tle or no effect on the murmur of aortic stenosis. but because of the way the anatomy is situated. and it radiates to the left axilla. The murmur occurs dur­ ing diastole. tricuspid stenosis results in right atrial dilatation/ increased pressure. Aortic stenosis is best heard over the aortic valve region in the right3 upper sternal border. Figure 1-10. Fig. Another dis­ tinguishing factor on physical exam is where the mur­ mur is heard best and where it radiates. Since blood passes across this valve during systole.e. as with aortic regurgitation. and it radiates straight up to the carotids. result­ ing in pulmonic regurgitation. Pulmonic Regurgitation. 1 . While a full discussion of the cardiac physical exam maneuvers is beyond the scope of this text. Because of increased regurgitation of blood into the right atrium and ele­ vated right atrial pressure. since the right heart ejects into the lungs. a quick review of one ma­ neuver will be helpful. One classically hears the murmur of mitral regurgitation over the cardiac apex. Pulmonic regurgitation lacks the changes in pulses and blood pressure seen with aortic regurgita­ tion. Just as mitral stenosis leads to left atrial dilata­ tion.D. ex­ cept that it occurs on the right side of the heart. SITES OF CARDIAC AUSCULTATION Aside from aortic stenosis and mitral regurgitation.

which can cause atrial fibrillation. aortic stenosis causes a systolic murmur. and congestive heart failure.1 1. (A stenotic valve can also be regur­ gitant. associated with S3 ·Hinders l Mitral regurgitation occurs when the mitral valve does not fully prevent backflow across the valve during systole. Summary of valvular pathology. increased left atrial pressure leads to increased pulmonary pressure. edema) would be predominant (if pathology is severe enough to cause signs/symptoms). they are rarer than left-sided valvular disease. thus decreasing systemic blood pressure during diastole. Review of Valves 1: Review by Pathology • Fig. diastole I Systolic murmur Diastolic murmur • Systolic dysfunction •S4 ·Syncope ·Angina • Infarction Figure 1-11 I' • L ventricular dilatation •S3 ·Widened pulse pressure • Heart failure symptoms r Systolic murmur mu ur Can cause: • L atrial dilatation ·Atrial fibrillation • Pulmonary congestion SUMMARY OF VALVULAR PATHOLOGY 13 I Diastolic • Can cause: • L ventricular hypertophy systole flow I Can cause: • Diastolic dysfunction during diastolic during stolic flow ·Occurs ·Hinders ·Occurs . Since blood passes across the mitral valve into the left ventricle during diastole. both mitral patholo­ gies can lead to left atrial dilatation. any of which can be regurgi­ tant or stenotic. resulting in a widened pulse pressure. Stenotic valves are hard to open and can also be hard to shut. thus not responsible for what is measured in the pe­ ripheral pulses. • Mitral stenosis increases the pressure in the left • In both mitral pathologies. Increased volume demand on the heart can lead to left ventricular dilatation (and thus systolic dysfunction. heart.) • Aortic stenosis greatly increases the work of the left Aortic regurgitation allows blood to flow back into the heart after systole. mitral stenosis causes a diastolic murmur. which can cause dyspnea.CHAPTER 1. Since blood normally passes forward across the aortic valve during systole. Since the blood is flowing back after systole. This leads to a systolic murmur. Also. causing it to enlarge. aortic regurgitation causes a diastolic murmur. There are four valves. THE CARDIOVASCULAR SYSTEM and heart failure symptoms). a stenotic valve can per­ mit some regurgitation. Murmurs can mimic the counterparts on the left. • • atrium. • Though tricuspid and pulmonic valve pathologies do occur. associated with S4) and can lead to syncope. Thus. which can cause hypertrophy (and thus dias­ tolic dysfunction. but right heart failure signs/symptoms (elevated JVP. 1 . angina/infarction.

Dur­ ing diastole.. and/or irregular. During systole.. allowing for regurgitation. leading to an immediate drop in forward flow. If this closure is incomplete. The cardiac conduction system.g. sudden death. in a patient with anemia or a fever). pulmonic stenosis. in pregnant women. aortic regurgitation. Thus. An arrhythmia is an abnormal heart rhythm: a rhythm that is too slow. Thus. Cells from different parts of the heart depolarize at different rates. tricuspid stenosis. mitral regurgita­ tion. too fast. the slowest spontaneous firing rate occurs in ventricular cells). and a ventricular septal defect. blood flows across the aortic and pulmonic valves. 1-13. then muscular contraction will be uncoordinated. and pul­ monic regurgitation. If they are incompe­ tent. in some cases. The only other direction blood could go during systole would be through a ventricular sep­ tal defect. The cardiac myocytes that depolarize fastest are those that make up the sinoatrial (SA) node. blood flows across the mitral and tricus­ pid valves.CHAPTER 1 . Fig. 1 . causes of a diastolic murmur include mitral stenosis. or. Diastolic Murmurs occur between S2 and S l. Fig. S UMMARY OF MURMURS Modified from Goldberg: Clinical Physiology Made Ridiculously Simple. aortic stenosis. blood will leak back during diastole. Each cardiac muscle cell (myocyte) spontaneously depolarizes at some intrinsic rate. The cardiac myocytes are connected. If the electrical activity of the heart is uncoordinated.1 2 . Summary of murmurs. so stenosis of either of these valves can lead to a systolic murmur. this would lead to a diastolic murmur. Sinoatrial node impulses travel to the myocytes of the atria. This can cause hy­ potension. rhythmic way. whereas regurgitant valves produce murmurs when blood is flowing backward/the wrong way across them. syncope. this too will create a systolic murmur. The fastest cells are in the atria. or in cases of pathologically increased flow (e. MedMaster. As one moves down the heart. Note that a systolic aortic flow murmur can also occur in normal individuals. 2004 14 . so the heart beats at the rate of whichever cells are depolarizing the fastest. The closed mitral (on the left) and tricuspid (on the right) valves prevent backflow dur­ ing systole (their closure is S l). The closure of the aortic and pulmonic valves (S2) ends systole and begins di­ astole. Systolic Murmurs occur between S l and S2. there is a decreasing rate of spontaneous depolarization (i. causes of a systolic murmur include Diseases of the Electrical System: Arrhythmias The electrical system of the heart conducts impulses to the cardiac muscle. THE CARDIOVASCULAR SYSTEM Review of Valves II: Review by Murmur Notice that stenotic valves produce murmurs when blood is flowing in the forward I normal direction across them. A ventricular arrhythmia can thus lead to inefficient ventricular contraction. SYSTOLE time DIASTOLE M itral /fricuspi d Insuffi ciency Mi tral Prol apse Mi tral/Tri cusp i d Stenosis Aorti c/Pul moni c Insuffi ci ency Aorti c/Pul moni c Steno si s Figure 1-12. tricuspid regurgitation.e. so if either of these is stenotic. causing it to contract in an or­ ganized. so aortic and pulmonic regur­ gitation can also lead to diastolic murmurs.

.. .. .. ·<�. . .. . . . . .1-. . . . .-. . . r ! .. . . .. . . . . . .. . .. . i .. l. . . . The flat interval until the next spike represents the time where the impulse is held up in the AV (atrioventricular) node before passing to the ventricles (this is called the PR interval). . � t. .. . ... . . +-J··+ -:7Njt· . .. .. . : 1 t r .. .fl 1 � l I 1 1 1 � 1 1 ! t �· � ... 1 . [ .. . . ...I . .. .j . j.. .. . . ... . .. . 1-14..· · · . . - -N- . . . j ..t..+.. .... . . . .. . {.. . : j : . j .. .. . ..· -. . . . . . r . -··+· l�-.. .-·. ! ... . · · · · ·· ·t . . . . :�-..· · · · r · · · · · · . . ... .. i� .. . . . .. . . . .. I I ... . .. !... . . . . . • L. .. : I . . .. .... . . . . . .l t 1 : . .. I .. ... .. j ... .. I . . ! j .. . When seen. .. . . . . ....· . . CARDIA C CONDUCTION SYS TEM AV NODE Fig. . . .. .! . ..u--/-! . . . . . . . . . . 1 .. .. I i . ········· . . .. r . The QRS complex represents ventricular depolarization and the T wave represents ventricular repolarization. . ! se:�e t ·f . ... . : . ! . . . I i . . .. . . fI .. :�--.. . . .-· · . . . . I ! - . .. . . . l. j ..J. .. :f .+. .. .. ... . 2. ! . . I. . . . . �� -.. .. . .. ... .··· i .. . . . . . l i l . .t! .. . but it is not always visi­ ble. . .. · . .. . . I . .· i . t I . . .. . . 1 .. . . . . . .. J . .. . .· · ·· .. .. .-J. . . .. . · ···· · · · ·· · ·· ..· -- . . .. ... . .J1 . Interval ··· · ·· · . . . ! . . J .. . � . . . . . .J . The U wave can become more promi­ nent in bradycardia (slow heart rates) or electrolyte abnormalities (e. .. . --··--- .. _ ... . P . .. o� seco d 1. ! .1 1' . .. .. . . . . I .r · . . .· -· ·.· -· ·· . . . +.. ...1. � I · ········ ······· ·· · ·· · · - · · · . . .. . . . . 1. . .. t.�. l .. T1'.. 1 ..� i1· . . .1 . I ... . . ! I 1 . 1".-1·t n H +t! � . .. . . .1 .. . + . .1 ...... ! 1 -nuratiot! .. ! l . 1.t. . ! j . the U wave may represent further depolarization in the ventricle or repolarization of the Purkinje system. . I . l .. ..�� 1 + . ! . .. . . . . � n . . .. .J .- . ....- ··-- -. .. .. l. 1-. . .1 .. ·-··· · · -·-- ·· ·······! · · · · · · · - I ' ··· · ·· · · .. f . t 1 n T T T T T T T . . . . . · ··. 1 .. ... . .. .+-. .. ... . .. . .. This causes the ventricles to contract as a unit. .. . ... · · · · · . 1. . ... �-. · ------- . I .. . .. -. .. . .. . +... . . where it is held up by a built-in delay before proceeding to the bundle of His and bundle branches..- .. .. -- - - ... .+. . . .. . . . ..· · · ······ · · · · · · . Normal QR S Figure 1-13 .. . i · + · ...+· + . .. ! . .-.. ! . . . .j . . . .r ·· · · · · · · ..· ··· II bi . l . the electrical signal spreads across the ventricles by way of the Purkinje fibers.. .. 1 . .. j -j--i I jI 1 j . f-... . . . "' " ' " j" " ' " ' l ' " ""f""' " ' f'r � . ..+ + · t·-.. . ... · : · ······· . . . . I . r j r r r � r r : ��� : 1 � r r 1 ! :.. . . ... . . . . ... . . I ..· . ! : . ��:�(.. i.+....·· ! I . . . l . .. .... t. . .. r . .·· · · .--�g. . . .-.. ! · · . . 1. . ... . . . .. ..j-. . . . : T : . . j . .-1. r .. -+. . . .. ..· ··· · . l . .t . . . .. .j . . ... . . · · · · · · · -- I 1 - . . .. . . : ! . . .. !.. . . ..: 1f . . . i - ! .. . . . . .. .. .. The P wave repre­ sents the electrical depolarization that occurs just prior to atrial contraction. ... . l ·····-·· ..5s::nd � . 1'.. .... .. l · ..- - . ..... .. . . . . · · .. . . . o T T I . ... . . . lJ . .... . . . .. .· . . . ... - i · . . . r . . . . H . .g. · . .. . . . I .. .. ..J .i ... ... .. .-. 1. m 1mY. : . . .... . .. I .. · . . ! Q · · . j .. . . .. .. ..-. . J.. .. .. ... . .. .· .....- . f-I .L... .. ...... . .· ' I . .· . .. THE CARDIOVASCULAR SYSTEM resulting in their synchronized depolarization and con­ traction.. �.-� .. "f" lI I i · ·. . . · · · · · ··-- . - ...j-..... 01 - • . . . . ········ -·-··-·· .-1. ... .... . ' . . ·· · · · . . . 1 .. . .. 1"". . . . . .. . 1. .. ..-· · · · . . .. +----i . . ... . J . .. . . . . r : �T : : : : . . . � .· ...J .-l +. . .. ...j . .. . . .... · · · · · ..1. . . . . . ... .... . .. . . .· · · ·.. : :L . . . . I .· · .· · . r- . j... .. j .. : . .. .1 j. hypokalemia). . ! ..·. : . .. •.·· ·· · ..f.. . .! .. . (�-. .... t :. . . . I · ·· · ........ . . ..!. .. JlJ.CHAPTER 1 . .... . I ! . . .. L� . . . . ... . . . I . . .. ...i. . .. . . l . · ... .· .. . ! . . Components of the EKG . R ! . I j .. . . .. · . . .. The electrical impulse then travels to the atri­ oventricular (AV) node. " .·· · · · .... . .. ! : I : . . . . . i . . . . 5 . ... .. ...· · . . . .. I ········· · · · . .. : . . . . ! . .. .. . . . ! I ! ! ! I . ... . The U wave can sometimes be seen in normal pa­ tients following the T wave.... . . . . . . . . ...-�� . . ..-!--..l�---------1 ...-j.l 1 '! i 1 T � T .. .. .. . . .. -�-..J. . . . .. . 0. .. . . .....··. · · · · ···· ···-· · ·· l ···· · · · · .1 . ·--·--- ..· . . . i I : .. . .. . . ...... . . .. Finally.. . . i -.. . l I · · ...... : · · --. Figure 1-14 15 · .. · ·· · · · · · · ! . I I . ..-·--·J. . . .. l : l. . .J. ..· --· . . .. .. . -:j .· .. . . ..o.. ....

or increased vagal tone. How would bradycardia secondary to a slow SA node look on EKG? The P wave should appear normal and the PR interval (which indicates the conduction of the im­ pulse) should also appear normal. Why would the SA node fire more slowly than usual? A decrease in SA node firing rate can be a normal physiological response (e.A. ventricles).e. tachy­ arrhythmia (tachycardia).. The next level of classification is where the aberration is coming from in the conduction pathway (atria vs. c. or in the bundle branches (Fig.. A heart rate can be regular (i. B. regularly irregular (i.e.g. 1 . Second-degree Mobitz type II. Bradyarrhythmia (bradycardia) is usually defined as a heart rate less Decreased SA node firing rate or Fig. trained athletes). and Third-degree (also known as complete heart block) .. while the sym­ pathetic nervous system increases heart rate ("fight or flight"). In heart block. 1 . than 60 beats per minute.1 5B. For a slow heart rate t o oc­ cur. Bradyarrhythmia (Bradycardia) Fig. but they will appear normal in configuration . or irregularly irregular (i. Increased vagal tone refers to increased activity of the vagus nerve (cranial nerve X)..13 ) . but the conduction is blocked somewhere along the route to the ventricles. a normal rhythm). there must either be a problem with the SA node (such that the impulses it is generating are at a slower rate) or there must be a block somewhere in the con­ duction system. which provides the parasympathetic input to the heart. because some of the arrhythmias are in fact perfectly rhythmic. certain drugs. Slow SA Node. an abnormal rhythm which is repeated over and over). a totally random pattern). Sinus bradycardia rhythm strip. in the bundle of His. The term arrhythmia can be confusing to musi­ cians. Bradyarrhythmia (bradycardia) vs. Cond uction block Abnormal Conduction (Heart Block).e. There are four types of heart block : First-degree.. Slower heart rates can also occur in normal people (e. 1 . 1-15. The parasympathetic nervous system slows heart rate ("rest and digest"). the sinus node pulses away at its normal rate. Causes of bradycardia. just faster or slower than normal.g.1 00 S inus bradycardia (heart rate < 60 S inus tachycardia (heart rate > 1 00 beats/mi n ) beats/mi n ) beats/mi n ) Figure 1-15 Fig. Second-degree Mobitz type I (also known as Wenckebach). Arrhythmias are first classi­ fied as either too slow (bradyarrhythmia or bradycardia) or too fast (tachyarrhythmia or tachycardia). CAUSES O F B RADYCAR DIA Figure 1-16 16 . The difference in si­ nus bradycardia would be that the rate would be slowed: the number of P and QRS complexes per unit time will be decreased. The block can occur in the AV node. during sleep) or the result of ischemia. Normal sinus rhythm (hea rt rate 60.1 6 .

CHAPTER 1 . and then the cycle repeats. On E KG. MedMaster.1 7 . In Mobitz type I (also called Wencke­ bach). This causes ventricu­ lar beats to be intermittently dropped entirely. If some isolated ventricular cells produce an escape beat. followed by a normally conducted beat. resulting in a widened QRS. the depolarization will spread in a less organized fashion. the PR interval is lengthened (criteria for diagnosis is > 0 . the PR interval progressively increases until fi­ nally an atrial impulse is not conducted at all. the ventricular cells can generate es­ cape beats. Ventricular escape beats. second-. MedMaster. Modified from Chizner: Clinical Cardi­ ology Made Ridiculously Simple. Rhythm strips of first-. those cells can escape the pacemaker's rhythm and generate j unc­ tional escape beats . 1 . This TYPES OF HEART BL OCK Fi rst-Degree AVB Mobitz I S econd-Degree AVB PR I NTE RVAL � 0 . VENTRICULAR ESCAPE BEATS Fig. If there is heart block at the AV node or below. 20 sec p p ( 3 : 2 "Wenckebach") Mobitz I I S econd-Deg ree AVB (3 :2) T h i rd-Degree AVB Figure 1-18. and depolarization of the muscle then proceeds uniformly. 2 seconds). how would the QRS of a ventricular escape beat look? Normally the QRS is narrow since the electrical im­ pulse is conducted rapidly to both ventricles via the Purkinje fibers. If the pace generated by the SA node slows below the intrinsic rate of cells in the AV node. In Mobitz type II. p p p p p PR I NTE RVAL I N C REAS I N G LY PROLO N G E D QRS DROPPED I N A REPEAT I N G PATTE R N p p p p p p p PR I NTE RVAL IS C O NSTANT FIXED RATIO O F C O N D U CT I O N ( P : Q R S ) ++-�� NO RE LATI O N S H I P BETW E E N P A N D Q R S Modified from Chizner: Clinical Cardiology Made Ridiculously Simple. Second-degree heart block is further divided into two types of blocks. 1-18. 2006 leads to a pause. the AV node does not conduct some proportion of incoming atrial impulses to the ventricles. Figure 1-17. Escape beat (widened Q R S ) Fig. THE CARDIOVASCULAR SYSTEM Each cell of the heart has its own intrinsic rate. In fi rst-degree heart block. and third­ degree heart block. How would AV block manifest on EKG? The PR interval represents the time that the impulse travels through the AV node. 2006 17 .

THE CARDIOVASCULAR SYSTEM In third-degree heart block. 2006 18 . above the ventricle) tachyarrhythmias. the cells around the AV node start firing at their own intrinsic rate. node's signal does not reach the ventricles. Arrhythmias origi­ nating in the atria or AV node are called supraventricular (i.15C). bradycardia can be caused by a slow SA node or decreased conduction. retrograde up AV node) Figure 1-19. Implantation of a pacemaker is usually necessary for second-degree Mobitz type II or third-degree heart block. MedMaster. which decrease parasympathetic stimu- Fig. this is a form of AV dissociation .e.CHAPTER 1. Tachyarrhythmias Tachyarrhythmias are classified by whether they origi­ nate above or within the ventricles. Modified from Chizner: Clinical Cardiology Made Ridiculously Simple. Supraventricular Tachyarrhythmias. 1.. In summary. 1 . Supraventricular Tachyarrhythmias Treatment ofBradycardia. retrog rade u p accessory pathway) S HORT PR "A ntidromic" AV Reentry Tac hycardia (anteg rade conduction down accessory pathway. treatment can either increase rate directly (beta ago­ nists such as isoproterenol or implantation of a pace­ maker) or decrease inhibition (anticholinergics such as atropine. This can happen as the sympathetic nervous system's response SUPRAVEN TRICULAR TA CHYARRHYTHMIAS SAWTOOTH APPEARANCE NO VISIBLE P WAVES AV Nodal Reentry Tachycardia Atrial F l utter MULTIPLE WAVELETS FIIIRILLATOI'IY WAVES (FINE TO COARSE) 3 OR MORE P WAVE MORPHOLOGIES Multifocal Atrial Ta chycardia Atrial Fibri llation WOLFF-PARKINSON-WHITE (WPW) SYNDROME SUPRAVENTRICULAR TACHYCARD IA IN WPW SYNDROME ACCESSORY PATHWAY � I I I I '!. there is no conduction at all from the atria to the ventricles. which is around 30-50 beats per minute. " Orth odrom ic" AV Reentry Tachycard ia (anteg rade conduction down AV nod e ..1 9 . Since the atria and ventricles then function totally inde­ pendently of each other in third-degree heart block. Since the SA lation of the heart). Sinus tachycardia is simply an increase in the SA node firing rate above 100 (See Fig. To increase heart rate.

Reentrant circuits can also involve the AV node itself (AVNRT) and/or an accessory pathway (AV RT. pulmonary em­ bolism. there is an accessory pathway that allows impulses to flow to the ventricles directly from the atria and vice versa. hyperthyroidism. this depolarization 19 . the ventricular rhythm cannot reach this speed. cardiomyopathy. What would the EKG look like? If multiple sites in the atria fire. pulmonary embolus). and then return to the atria retrogradely via the AV node. this rapid rate can be conducted to the ventricles via the accessory pathway. mesenteric ischemia (if it lodges in the GI vascular bed). This can lead to extremely rapid ventricular rates. AV node. Summary of the supraventricular tachyarrhyth­ mias . Since the beats that do make it through are essentially random. there will be multiple P wave morphologies : the P waves will have several different appearances and can occur at irregular intervals. fight/flight) or a pathophysiologic condition (e. etc. This could lead to stroke (if it goes up the carotids).g. one of which is slower than the other. Thus. as opposed to the normal sharp upstroke that oc­ curs with normally conducted electrical activity. ventricle. If a patient with an accessory pathway were to develop atrial fibrillation. Patients with atrial fibrillation are thus often given anticoagulants to pre­ vent clot formation in the atria. or multiple reentrant loops in the atria can lead to atrial fibrillation. Either the sinus node itself can take on a faster rate (sinus tachycardia). since part of the ventricle is activated early through the accessory pathway. This leads to an increased risk of clot formation in the atria. and hypertension. Atrial fib­ rillation can also occur idiopathically. the impulse travels first normally down the AV node to the ventricles. heart failure). there would be a shortened PR interval because the impulse bypasses the built-in delay of the AV node. The EKG appears as a wavy. coronary disease.. the fast rate originates in the ventri­ The next two tachyarrhythmias also have reentrant circuits. a reentrant loop occurs (from atria to AV node to ventricles back to the atria via the accessory pathway). In atrial flutter. which can be deadly. the atrial rate is typically between 200-400 beats per minute. If a clot forms in the left atrium. which has none of the built-in delays of the normal system. the QRS can appear abnormal. If you imagine this current looping around the atrium. The upstroke of the QRS reflects this in what is known as a delta wave . multiple sites in the atria can take on the role of firing (multifocal atrial tachycardia). If the ventricles depolarize in any way other than by the normal conduction system. What would the antidromic EKG look like? First. If the accessory pathway functions in the anterograde direc­ tion (antidromic). the ventricu­ lar rhythm is irregularly irregular.CHAPTER 1. there are many reentrant cir­ cuits spinning around in the atria. In multifocal atrial tachycardia (MAT) . the EKG can manifest a P wave after the QRS complex. AVNRT develops when the refractory period be­ comes altered in pathways through the AV node. AV nodal reentrant tachycardia (AVNRT) has a reentrant circuit involving the AV node itself.g. In AV NRT. a reentrant circuit in the atrium al­ lows electrical impulses to spin around the loop at very high speed instead of following the normal conduction pattern. and create an endless loop. In orthodromic Wolff-Parkinson­ White. If the accessory pathway functions in the retro­ grade direction (orthodromic). In atrial fibrillation . Usually the ventricle gets no faster than 100150 beats per minute unless there is an accessory pathway (discussed below). This can occur in patients with pulmonary disease. Wolff-Parkinson-White). disorganized baseline without rec­ ognizable P waves. reactivate the starting point. THE CARDIOVASCULAR SYSTEM reentrant circuit that involves the atrium. . the atrial impulses bypass the AV node. Rates in the atria can be over 400 beats per minutes.g. a large atrial reentrant loop can form in the atria. Causes of atrial fibrillation include a variety of heart diseases (e.. There are normally two pathways through the AV node. renal ischemia (if it lodges in the renal artery). Because fibrillating atria quiver instead of contract­ ing. This cycling of the impulse causes the tachycardia. In atrial flutter. Atrial flutter and atrial fibrillation are common ar­ rhythmias that have similar underlying pathophysiol­ ogy. In AVRT (e. Wolff-Parkinson-White syndrome). and an accessory pathway. you can also imagine the EKG: a saw-tooth ap­ pearance to the P waves. go directly to the ventricles. exercise. A delta wave is a more gradual beginning to the QRS. multiple sites in the atria take on very fast rhythms.. but due to the refractory period of the AV node. blood flow within them is quite turbulent. chaotic. and this P wave may be inverted since the impulse comes backward up through the atria. Atri­ oventricular reciprocating tachycardia (AV RT) has a cle. so the QRS will be normal. fever. both involving reentrant circuits . pulmonary disease. In ventricular tachyarrhythmias. a change in the refractory period of the slower pathway allows the electrical impulse to inappropriately come back up to the atrium after its normal path down the AV node. valvular disease. Ventricular Tachyarrhythmias. Second. lead­ ing to atrial flutter. to either a physiologic state (e. Reentrant circuits are circular pathways in which electrical im­ pulses can travel around the circle.g. it can pass to the left ventricle and then out the aorta.

prolonging repolarization. Ventricular arrhythmias. either the SA node (the pacemaker) is firing too slowly (sinus bradycardia ). Thus. The electrical (and thus muscular) activity in ven­ tricular fibrillation is even more uncoordinated than that of ventricular tachycardia because of the multiple circuits. quinidine. e.g. If the rate is too slow. just like atrial fibrilla­ tion results from multiple reentrant circuits in the atria. In marked contrast. which can result in extremely high ventricular rates. MedMaster.g. in­ creasing threshold. VENTRICULAR ARRHYTHMIAS Modified from Chizner: Clinical Cardiology Made Ridiculously Simple. Torsades can lead to syncope and/or ventricular fibrillation. Causes include anything that can prolong the QT interval. e. hypocalcemia and other electrolyte abnormalities (see endocrine chapter). Review of Arrhythmias In summary. Tachyarryhthmias are treated with drugs that decrease cardiac my­ ocytes' rate of firing. For example. Drugs that alter the cardiac action potential include: Class I antiarrhythmics (sodium channel blockers. the overall ability of the heart to do its job should not be greatly impaired by atrial arrhythmias (assum­ ing otherwise normal ventricular function). Additionally. resulting in a widened QRS. decreasing upstroke. e.g. similar to the mechanism described above for ventricular tachycardia. and congenital long QT syndrome. Fig. which can suddenly decrease forward flow ... sustained ventricular arrhythmias are often emergencies in need of defibrillation.g. regions of tissue re­ sponsible for generating the arrhythmia can be ab­ lated surgically or via catheter techniques.g. THE CARDIOVASCULAR SYSTEM will spread in a disorganized fashion. and cardiac output can thus be even more se­ verely impaired.. cardiac ischemia. Ventricular tachy­ cardia can result from a reentrant circuit in the ventri­ cle or from a group of ventricular cells firing at an increased rate . Treatment o{Tachyarrhythmia. Without immediate intervention. The name refers to the E KG appearance of this ventricular arrhythmia. Ventricular fibrillation may result from ischemia or infarcted areas of ventric­ ular tissue. since it appears to turn around the horizontal. Aside from loss of the atrial kick at the end of dias­ tole. too fast. This can be accomplished either by decreasing sympathetic stimulation of the heart or by acting at ion channels to alter portions of the car­ diac action potential. arrhythmias are abnormal heart rhythms that can be too slow. a myocardial infarction can lead to an area of dead tissue. tachycardia. this can even lead to sudden death. This area can have abnormal electrical conduction properties. sustained ventricular arrhythmias lead to uncoordinated muscular activity in the ventricle. Class III antiarrhythmics (which act at various ion channels and as beta block­ ers. 1 -20. and Class IV antiar­ rhythmics (calcium channel blockers. such as certain anti-ar­ rhythmics (e. or in an emergency. called Class II antiarrhythmics. thus creat­ ing a reentrant circuit. Ventricular fibrillation results from multiple reen­ trant circuits in the ventricles. sotalol). quinidine. and describes a specific type of ventricular Ventricular tachycardia (monomorphic) Ventricular fibrillation Torsades de poi ntes (polymorphic VT) Figure 1-20. Ventricular fibrillation may also result from ventricular tachycardia. verapamil). 2006 20 . If an arrhythmia does not respond to pharmacologic therapy. amiodarone. sotalol) and other drugs. electrical defibrillation may be necessary. e.. and/or irregu­ lar. Drugs that decrease sympathetic stimulation of the heart in­ clude beta-blockers. lidocaine).. Torsades de Pointes is French for twisting of the points.CHAPTER 1.

With increasing occlusion of the coronary vessel(s). Variant. but they also cannot adequately vasodilate. Infarction of the ventricular wall itself can result in its During exertion. . Now imagine a heart with bad atherosclerotic dis­ ease of the coronary vessels. this could lead to left heart failure with pulmonary congestion (back­ up) and decreased forward flow. Complications of Myocardial Infarction Angina and Myocardial Infarction Depending on which vessel occludes. and are generally divided into those which originate in the atria and/or AV node (i.g. AV NRT. hardens the blood vessel. . . then I would have to catch my breath . . Myocardial infarction can also be entirely asymptomatic or cause minor symptoms that the pa­ tient disregards (silent myocardial infarction). The vessel lumens are narrowed and thus blood supply to the heart is dimin­ ished. The situation is one of economics in that cardiac function is determined by how the supply (in this case of oxygenated blood) meets the demand (the cardiac muscular demand for oxygen). and many other factors can lead to blood vessel injury and inflammation. JVD). this is unstable angina. The heart is stable at rest . now I have to rest three or four times . . supply of blood through the narrowed vessels cannot keep up with de­ mand. but there is a block of the signal somewhere along the conduction pathway (heart block ). coronary thrombosis can en­ sue. In milder cases. a patient might say "I was previously able to walk four blocks. which can lead to thrombus formation and embolization (e. oxygen sup­ ply to the heart can be insufficient . ventricular fib­ rillation . but with exertion. now I can only walk two . smoking. causing a variety of con­ sequences. the vessels cannot supply sufficient 21 . If the right coronary artery is the site of occlusion. Ventricular tachyarrhythmias are dangerous because ventricu­ lar function can be so severely compromised as to cause an immediate decrease in forward flow. occlusion of the left anterior descending artery). . sweating. In economic terms. and this can manifest as chest pain/tightness and/or shortness of breath. " or "I used to have to rest once halfway up the steps in my house. If a large enough area of muscle infarcts and becomes nonfunctional. as opposed to vascular occlu­ sion. and can predispose to clot formation in the vessel. it means that one or more coronary vessels is nearly totally occluded. If the ischemic area is in the left ventricle (e. which can result in athero­ sclerotic plaque formation in blood vessels. For ex­ ample. the tissue supplied be­ comes ischemic. even the demands of the resting heart may be too great for what the diseased vessel(s) can supply. a portion of the mus­ cle can die. If this blood supply is compromised . Infarction of the papillary muscle can cause it to rupture. supraventricular: sinus tachycardia. In is­ chemic cardiomyopathy. Unstable angina is a precipitous state. It can thus occur at any time and is not related to the person's activity. Diabetes. . Ischemia of the conduction system can cause arrhythmias. When the pa­ tient experiences angina even without exertion. This can result in sudden death in some cases if immedi­ ate intervention does not occur. Diseases of the Heart's Vasculature: Angina and Myocardial Infarction The coronary arteries provide the heart's blood sup­ ply. Vasodilation of the coronary vasculature increases blood flow to the cardiac muscle to meet its increased demand for oxy­ gen. different regions of the heart can be affected.. atrial flutter. leading to acute mitral regurgitation. this can cause angina and/or myocardial infarction (heart attack). In the coronary vasculature. to the cerebral vasculature leading to stroke) and 2) they can transmit to the ventricle via the AV node (with some holdup) or via accessory pathways (directly). the heart beats both harder and faster to supply oxygen to the muscles. causing the occlusion to proceed to 100%. If collateral flow is inadequate. or Prinzmetal's angina occurs secondary to intermittent vasospasm .g. " or the SA node is working fine. .CHAPTER 1. decreasing cardiac function. AV R T. If an ather­ osclerotic plaque ruptures. dyspnea.g. leading to right heart failure signs (e. increasing exertion can get the heart into trouble because diseased vessels are not only nar­ row. THE CARDIOVASCULAR SYSTEM oxygen for the heart's demand. high choles­ terol. heart failure symptoms can occur (ischemic cardiomyopathy) . torsades de pointes). causing very fast ventricular rates. Wolff­ Parkinson-White) and those that originate in the ventricles (ventricular tachycardia. This nar­ rows the vessel lumen. Tachyarrhythmias are heart rates that are too fast . and this is known as myocardial infarction (or heart attack). there is less effective pump­ ing because part of the muscular wall has a damaged area that does not move as well as the rest.e. This situation is known as stable angina. this can affect the right ventricle. atrial fibrillation. However. high blood pressure. The classic story is that a patient has progres­ sively increased limitations on how much they can exert themselves before they have problems. . the heart may still be fine at rest. Atrial tachycardias can be dangerous for two reasons: 1) they can lead to turbulent flow in the atria . fever and/or other signs of dis­ tress. or when the level of exertion necessary to cause anginal symptoms decreases. Without oxygen. MAT. Myocardial infarction can present as chest pain unrelieved by rest (sometimes radiating down the left arm or into the jaw or neck). nau­ sea/vomiting.

aspirin). Consider the case of a young patient who has a stroke but is not in atrial fibrillation and has no atheroscle­ rotic disease. If the ventricle ruptures and the heart bleeds into this sac.g. amniotic fluid. Calcium channel blockers also increase coronary vasodilatation and de­ crease coronary vasospasm. anal­ ogous to unstable angina in the heart. For the latter reason. One cause of paradoxi­ cal embolus is a patent foramen ovale. A sep­ tal rupture will lead to a ventricular septal defect and a new systolic murmur. VASC ULA R DISEASEOUT SIDE THE HEART: P ERIPHERAL ARTERIESAND AORTA Emboli An embolus can be a clot (thrombus). ACE in­ hibitors and anticoagulants (e. Two treatment angles for remedying this mismatch are possible: decrease the heart's demand for oxygen and increase the vasodilation of the coronary vessels . De­ creasing the heart's demand for oxygen can be accom­ plished by beta-blockers and calcium channel blockers (both of which decrease both heart rate and contrac­ tile force). This is known as tamponade and can be quickly fatal. artery grafts (usually from the radial artery). either at the septum or in the free wall. or an air bubble that travels from somewhere to somewhere else. etc. the vas­ cular supply of the gut (causing mesenteric ischemia). cholesterol-lowering drugs may also be initiated (Fig. Further occlusion of the arter­ ies can lead to symptoms even at rest (rest pain). Atherosclerotic lesions of peripheral vasculature can cause claudication. retinal ischemia. These are examples of arterial emboli. which dilate the coronary vasculature. fat. calcium channel blockers. Thrombus from the DV T can travel to the right heart and then to the pulmonary artery. One cause of pulmonary embolus can be deep venous thrombosis (DV T) in the leg. a clot from the venous side can cross through this defect from right atrium to left atrium and lead to a stroke (paradoxical embolus).. the blood can quickly surround the heart. In angina. Treatment of Angina and Myocardial Infarction Treatment of Angina. stenting. by­ passing areas of occlusion. heparin) are compo­ nents of treatment for myocardial infarction as well as prevention of a subsequent myocardial infarction. For example. Increased vasodilation is accomplished with nitrates. or the renal vasculature (causing renal ischemia). In patients with ele­ vated cholesterol. If coronary occlusion is very ad­ vanced. 1-2 1). decreasing the heart's work by decreasing preload. The symptoms and signs of peripheral vascular disease are often re- 22 . which can cause symptoms and signs related to the ischemia of the affected organ. nitrates. Aspirin or other platelet in­ hibitors can be used to inhibit thrombosis formation. cholesterol plaque. quitting smoking. renal ischemia. ''Wait! The patient has venous thrombosis and is ending up with strokes?! How can that be if the venous return is to the right heart? Shouldn't the patient have pul­ monary emboli instead of strokes?" What could account for this? If the patient has an atrial or ventricular sep­ tal defect. In addition to the treatments discussed above for angina (lifestyle mod­ ifications. What if the patient is found to have recurrent DV Ts and strokes? Hopefully you are saying. such as mesenteric ischemia. One possible cause would be a hypercoag­ ulable state. angioplasty. weight loss). a congenital de­ fect leaving a hole that connects the atria. remember that the heart sits in the pericar­ dia! sac. reduction in fat intake. The former two procedures seek to open ex­ isting vessels. and can thus also be used as quick relief for anginal symptoms. the goal is to reperfuse the heart. Dietary and lifestyle modifi­ cations are necessary to prevent further progression of atherosclerotic diseases (e. which is relieved by rest. a clot (thrombus) that forms in a fibrillating atrium and travels through the arterial system (as an embolus) can affect the cerebral vasculature (causing stroke). they are also used in the treatment of variant (Prinz­ metal's) angina. tumor fragment. or bypass surgery can be performed. If an area of the heart is ischemic due to vascular occlusion. . THE CARDIOVASCULAR SYSTEM rupture. cholesterol-lowering agents. This most commonly occurs in deep leg veins. Venous thrombosis can occur in any hypercoagulable state (see hematology Chapter 6). Peripheral Vascular Disease Atherosclerosis can occur in any artery. A common site for venous clot formation is in a deep vein. beta blockers. The same risk factors and pathophysiological circumstances that lead to coronary arterial atherosclerosis can also cause atherosclerosis of peripheral arteries with sim­ ilar consequences. known as deep venous thrombosis (DV T). stroke. myocardial demand for oxygen exceeds the ability of the coronary vasculature to supply it.CHAPTER 1. Treatment of Myocardial Infarction. while the latter uses vein grafts (usu­ ally the saphenous vein from the leg). preventing it from adequately filling. Nitrates also dilate veins. As for ventricular free wall rupture. which is analogous to angina in the heart: exertion involving the muscles supplied by the compromised vessels leads to pain and weakness. or connection of the blocked coronary artery to the internal mammary ar­ tery to create an alternate pathway for blood flow. Thrombolytic drugs such as streptokinase and tissue plasminogen activator (t­ PA) or procedures such as angioplasty with coronary stenting can accomplish this goal.g.

which absorbs fats from the digestive tract into the circulation." because LDL largely transports cholesterol to the periphery (where it may be incorporated into atherosclerotic lesions). it also raises HDL by mechanisms less well understood). Chest X-ray may demonstrate a widened mediastinum. Fibrates and nicotinic acid also lower triglycerides . loss of pulses and differ­ ent blood pressures between the two arms may be present. . nail. ) as well as angio­ plasty and/or surgical bypass. cholesterol reduction. Treatments affecting the endogenous pathway: • HDL can be increased by nicotinic acid or fibrates (e. cholestyramine). hypertension. statins) . . • Bile acids can be sequestered in the GI tract.LDL can be decreased (nicotinic acid decreases hepatic production of VLDL. and poikilothermia (cold temperature). e. etc. which transports fats synthe­ sized in the liver between the liver and the peripheral tissues. paraly­ sis. infections (e. and beta­ blockers can be used to reduce blood pressure while awaiting surgery. Depending on size and rate of expansion. maintaining low serum lipids is one goal of prevention of atherosclerotic disease. Emer­ gency surgical repair is often necessary.CHAPTER 1 . LDL (low density lipoprotein) is often re­ ferred to as "bad cholesterol" and HDL (high density lipoprotein) as "good cholesterol.Inhibiting the enzyme HMG Co-A reductase. and connective tissue diseases such as Marfan Syndrome and Ehler's­ Danlos Syndrome can predispose to aortic dissection. especially in the case of thoracic aortic aneurysms (e. syph­ ilis).g.g. Aortic dissection is a tear in the intima of the aorta into which blood can flow. and/or tamponade (leading to hypotension. Fig. and vasculitis. Atherosclerosis of the Aorta Aortic Aneurysm Aside from dietary modification to decrease lipid intake. The ABI compares the blood pressure at the ankle with that in the arm. Lipid processing pathways and lipid-low­ ering drugs. pro­ moting their loss and hence increasing conversion of hepatic cholesterol to bile acids for secretion (bile acid sequestrants. and/or ankle-brachial index of blood pressure (ABI). the arms (supplied by the subclavian arteries) may be af­ fected. angiography. Other causes of aortic aneurysm in either the thoracic or abdominal portions include connective tissue diseases (such as Marfan Syndrome and Ehler's-Danlos Syndrome). ezetimibe). 23 . Other consequences of dissection can include Hepatic cholesterol production can be decreased by the following mechanisms : . Commonly affected sites include the buttocks/thighs (caused by disease of the distal aorta and/or iliac arteries. . THE CARDIOVASCULAR SYSTEM stroke (leading to neurological deficits) . Diagnosis can be confirmed by Doppler ultrasound. surgical repair is often necessary to prevent rupture. Normally. Aortic aneurysms may be asymp­ tomatic or may cause symptoms related to pressure on nearby structures. and skin can also occur in the affected re­ gion(s). . muffled heart sounds. and the endogenous pathway . Less commonly. On physical exam.g. syphilis. . pulselessness. An abdominal aortic aneurysm may be palpable as a pulsating mass on abdominal exam. compression of esophagus or trachea leading to dysphagia or cough). A lesser ra­ tio demonstrates decreased blood pressure at the an­ kle as compared to the upper extremity and indicates peripheral vascular disease of the lower extremity. ischemia here can also cause impo­ tence in men) and the calves (caused by disease of the popliteal and femoral arteries). 1 -2 1 .g. aortic regurgitation (leading to a diastolic murmur) . furthering the tear. . Lipids are processed in the body via two pathways: the exogenous pathway . Aortic Dissection • Aortic aneurysm/rupture is distinct from aortic dissec­ tion . Like treatment of atherosclerotic heart disease. Lipids and Lipid-Lowering Drugs Since elevated lipids are a risk factor for developing atherosclerosis. and HDL mostly transports cholesterol back to the liver from the periphery. what sites of pharmacologic intervention are possible? Atherosclerosis is one cause of aortic aneurysm (dila­ tation of the aorta). Dissection presents as "tearing/ripping'' chest and/or back pain. gemfibrozil). Trauma. yielding a ratio of 1.g. smoking cessation. a rate-limiting step in cholesterol synthesis (e. and elevated JVP). also known as resins. Changes in hair. pain. ferred to as "the 6 Ps": pallor. myocardial in­ farction. these should be equivalent. Atherosclerosis-induced aortic aneurysm occurs more commonly in the abdominal portion of the aorta. treatment of peripheral vascular disease involves di­ etary and lifestyle modifications (exercise. Treatments affecting the exogenous pathway: • Lipid absorption can be inhibited (e. pares­ thesias (uncomfortable sensory disturbances).g.

See Fig. 2004 Vasculitis Hypertension Vasculitis is an inflammation of blood vessels that can be caused by infection (Hepatitis B or C. fatigue. Modified from Goldberg: Clinical Biochemistry Made Ridiculously Simple. Secondary hypertension can be caused by any process that in­ creases arterial resistance. most commonly steroids. Renal disease can cause failure to adequately excrete sodium and water. drugs. blood volume. potential culprits are the kidneys .CHAPTER 1. 24 . causing increased renin secretion. causes of second­ ary hypertension must be ruled out. large). autoimmune disease (systemic lupus erythematosis. drugs (penicillin. changes in the blood vessels themselves. or inde­ pendent vasculitic syndromes . Lab features used in diagnosis are included in the table. THE CARDIOVASCULAR SYSTEM "GOOD" (m i n u s HD� c h olest erol ) !) Enterohepatic Circu lation Figure 1-2 1. sulfon­ amides. Renal artery stenosis can be caused by atherosclerosis or fibromuscular dysplasia of one or both renal arteries. Symptoms/signs of any vasculitis can include consti­ tutional symptoms (weight loss. This stenosis decreases blood flow to the kidney(s). Infectious causes. or drugs. fever) as well as consequences of ischemia including skin rashes/ ulcers. Additionally. hormonal changes . Vasculitis syndromes. leading to increased blood volume (secondary to aldosterone increase) and increased ar­ terial resistance (secondary to angiotensin increase). The vasculitic syn­ dromes are classified by the size of vessels that they affect (small vs. cytomegalovirus). and treatment involves immuno­ suppressive drugs. medium vs. Other features are specific to specific vas­ culitis syndromes. Arterial biopsy and/or angiogram is necessary for definitive diagnosis. Before making the di­ agnosis of essential hypertension. quinolones). increasing intravascular volume. and/or bowel infarction. neuropathy. renal dysfunction. 1-6. rheumatoid arthritis). Epstein Barr virus. Thus. Fig. and/or car­ diac output. MedMaster. This activates the renin-angiotensin­ aldosterone axis. 1 -22. Most cases of hypertension have no identifiable cause (essential hypertension) . stenosis of one or both renal arteries can lead to hypertension. and underlying systemic diseases must be ruled out before diagnosis of a vasculitic syndrome can be made.

myocard itis/heart fai l u re . Steroids Th rombangiitis obl iterans (Buerger disease) (small arte ries) Associated w/smoki n g . patients < 40. or Gl infection lgA i n lesions on biopsy Self. rash) Aortic arch and branches. ANCA may be i nvolved i n the pathogenesis of some vascu l itis. more common i n young men (20s-40s) . malaise. P-ANCA* Steroids Microscopic polyang i itis (small arteries) Skin findings. CRP. renal i nvolvement. n e u rologic. temple tende rness (pain when brus h i n g hair) . renal No specific test. visual loss. Coronary a n e u rysms can be visual ized with echo Aspi r i n . de rmatologic findings. a rthritis. p u l monary. renal i nvolvement. arthralgias/myalgias. skin findings. Polymyalgia rheumatica: Typically > age 50. Raynaud's in feet. abdom inal angina. G l . conj u nctivitis. a l l e rgic rh i n itis most common but any system can be affected Eosinoph i l i a . retinal changes Polyarte ritis nodosa ( PA N ) (med i u m -sized a rteries) Mononeu ritis m u ltiplex. and arms Rule out scleroderma Smoking cessation g reatly i m p roves p rognosis HenochSchon l e i n p u rpura (small arteries) Most common i n c h i l d re n . claudicatio n . changes i n pulses. C-ANCA is more commonly associated with Wegener's. legs. more common i n Asians. P-ANCA with C h u rg-Strauss and m ic roscopic polyangiitis. glomeru loneph ritis C-ANCA* Cyclophosphamide. THE CARDIOVASCULAR SYSTEM Figure 1 -22 Vasculitis Syndromes DISEASE Large Vessel Giant cell (Temporal) a rteritis AFFECTED VESSELS C LASSIC S Y MPTOMS/ SIGNS ( i n addition to fever.l i m ited . bruits. especially tem poral a rteries and extracran i a l vertebral arte ries Typically > age 50.CHAPTER 1 . hands. WBC may be e levated in all) ESR. Steroids C h u rg-Strauss vascul itis (small arteries) Asthma. claud ication in extremities. p u l monary. jaw claudication (pain w h e n chewing) DI AGNOSIS (ESR. steroids may help during symptoms Takayasu's arteritis Medium Vessel Small Vessel test Possi b l e association with H epatitis 8 *ANCA = anti neutrop h i l cytoplas m i c antibod ies. Commonly p receded by upper Resp. pain/stiffness in neck. shoulders Angiography Ste roids +1oth e r i m m u nos u p p ressives No specific Steroids +1cytotoxic agents Aorta and branches More common i n Asians. absent tem poral pu lses. rash . coronary a n e u rysms. I V lg Wegener's granulomatosis (small arte ries) Nasal/s i n u s . renal and pulmonary dysfunction (any organ system can be affected) ANCA (more commonly P-ANCA*) Cyclophosphamide. abdo m i n a l pai n . testicular i nfarction Kawasaki's disease (med i u m -sized arteries) Disease of young c h i l d re n . Fever. biopsy of temporal artery TREATMENT O THER Steroids Can co-occ u r with polymyalgia rheumatica (though either can occ u r separately). h i g h e r incidence i n Ashkenazi Jews and Asians. weight loss. p u l monary. CRP. pelvis. Headache. P u r p u ric ras h . cardiac. any system: C N S . C (cytoplasmic) and P (peri nuclear) refer to patte rns of h i stolog ic sta i n i n g of these antibodies in different d i seases. 25 . upper ai rway problems. hypertension.

A R B = Angiotensin Receptor Blocke r. 2006 26 .CHAPTER 1. J G = Juxtaglomerula r cells . AT 1 = Angiotensin I I type 1 receptor. THE CARDIOVASCULAR SYSTEM PHA RMA COL OGIC TREA TMENT OF HYPERTENSION C O N G ESTIVE H EART FAI LU RE (decreased myocardial contractility) f Sympathetic �� � � � / ! Cardiac Output ! Renal ( beta-adrene rg ic) a ctivity) BETA BLOCKERS (-) f Renin Angiotensinogen (live r) contractility) Pe rfusion Secretion (JG cells in kidney) y � f Angiotensin I � AC E t ' ' (lung ) T Angiotensin I I Resistance I N C REAS E D BLOOD PRESS U RE Note : ACE = Angiotensin Converting Enzyme . MedMaster. Figure 1-23. Modified from Chizner: Clinical Cardiology Made Ridiculously Simple.

. On which valve would you expect an IV drug abuser to have endocarditis? Drugs inj ected into the venous sys­ tem can cause infectious material to travel to the right heart. THE CARDIOVASCULAR SYSTEM Hormonal changes that can cause hypertension in­ clude : • • • • E ndoca rd i u m Hyperaldosteronism (increased aldosterone ----? in­ creased sodium reabsorption ----? increased blood volume) (Endocarditis) Increased cortisol. nitrates) or inhibition of vasoconstriction. and/or periph­ eral vasculitic lesions (if the embolus comes from the left side).CHAPTER 1. ) Changes in the arteries themselves that can lead to hypertension include aortic coarctation and vasculitis. . and symptoms generally include fever and a new heart murmur. e. surgical re­ placement of the valve may be necessary. Fig. weight loss. AND NEOPLA SIA IV drug abuse is a common cause of endocarditis. spironolactone). The course of infective endocarditis can be acute or subacute. Infectious emboli can form and lead to a pulmonary embolus (if the embolus comes from the right heart). cortisol can stimulate aldos­ terone receptors) Hyperthyroidism (excess thyroid hormone increases cardiac output) Viscera l -�. If the damage to the valve is enough to induce heart failure. blocking calcium-activated smooth muscle contraction (calcium channel blockers).. INFLAMMA TION. renal dysfunction. stroke. Decreasing arterial resistance can be accomplished by direct vasodilation (e. Nonin­ fectious causes of endocarditis include hypercoagula- 27 .g. Lupus-induced endocarditis is called Lib man-Sacks endocarditis . second­ ary to pheochromocytoma ( epinephrine/norepineph­ rine increase heart rate and arterial resistance. CARDIA C INFE C T ION. infecting the tricuspid (and/or more rarely the pulmonary) valve. Figure 1-24 Treatment of Hypertension Lifestyle modifications such as exercise. . Pericard i u m (Pericarditis) Increased epinephrine/norepinephrine. Fig. and dietary changes (such as sodium reduction) are an important component of managing hypertension.g. Pharmacologic treatment of hypertension. and/or blocking the renin-angiotensin system (ACE-inhibitors. Common bacterial causes of endocarditis include Streptococcus viridans and Staphylococcus au­ reus. demonstrating bacteremia and vegetations on the valve.g. e. Endocarditis. aortic aneurysm. pericardium . Pharmacologic treatment of hypertension aims to ei­ ther decrease blood volume (diuretics ) or decrease ar­ terial resistance . 1 -23. and aortic dissection. or stroke. Blood cultures and echocardiography are used to confirm the diagnosis. Sites of cardiac inflammation. Infection and inflammation of the heart can affect any of its three layers : endocardium.. retinopathy. . intracranial hemorrhage. Staphylococcus aureus is the most common cause of IV drug-related endocarditis. l -24. Any valvular disease can predispose to infectious endocarditis. Inhibition of vasoconstriction can be accomplished by blocking the sympathetic system (alpha blockers). myocardium. ble states (which can lead to thrombus formation on valves) and inflammatory conditions such as systemic lupus erythematosis. hydralazine. Endocarditis Treatment of infective endocarditis involves ex­ tended IV antibiotic therapy. also known as Cushing's syn­ drome (when in excess.. respectively. Infection can occur on a native valve or a prosthetic valve. inflammation of the endocardium. can result from noninfectious or infectious causes. Hyper­ tension can also cause kidney damage (nephropathy). angioten­ sin receptor blockers (ARBs)). Perica rd i a ! S pace Consequences of Hypertension ---oar- SITES OF CARDIAC INFLAMMATION Hypertension was discussed above as a cause of car­ diac hypertrophy and myocardial infarction. blocking aldosterone (aldosterone antagonists.

dermato­ myositis). subcutaneous nodules. they can "bob" around. The visceral pericardium lines the outer surface of the heart and connects to the parietal pericardium. lupus. Myocarditis Any cause of pericarditis can also result in a pericardia[ effusion. rheuma­ toid arthritis). Streptococcus . it can cause tamponade.g. position-dependent symptoms (e. retinal artery 28 . bacteria. inflammatory disease (e. mesenteric ischemia. an accumulation of fluid in the pericardia! sac. Because these tumors tend to be shaped like a ball on the end of a stalk. and distant heart sounds (since the fluid in the pericardium muffles the sounds' transmission to the stethoscope). Staphylococcus. and j oints. Often the pericardium must be surgically removed for definitive treatment of constrictive pericarditis. . This leads to backup of flow and impaired forward flow. this happens rapidly (i. it will back up into the venous system. syncope.CHAPTER 1 . lupus. Acute rheumatic fever is a complication of Group A streptococcus infection of the upper respiratory tract.g. . Treatment is directed toward the underlying cause and alleviating heart failure symptoms/signs if present. though various other viruses. causing intermittent. producing Kussmaul's sign. During inspi­ ration. drugs. dental work. severe restric­ tion of cardiac motion. Constrictive pericarditis can be a consequence of any of the above etiologies of pericarditis. an­ tibiotic prophylaxis is given prior to any procedure that could induce transient bacteremia (e. while bacterial pericarditis requires antibi­ otics and. meaning that it gets worse with deep inspi­ ration. fluid is removed from the pericardia! space by needle as­ piration (pericardiocentesis ). and/or other motor disturbances occurring a few weeks after a sore throat. Acute rheumatic fever manifests as fever. The pericardium can become inflamed (pericarditis) secondary to infectious or noninfectious causes. If constrictive pericarditis inhibits the right heart's ability to accept that blood. prosthetic valve).g. The long-term effects of the inflammation in the heart can include mitral stenosis and/or regurgi­ tation as well as aortic stenosis and/or regurgitation If pericardia! effusion occurs over a more prolonged time course. central nervous sys­ tem. Infec­ tion can be caused by viruses (echovirus and Cox­ sackie B are the most common). . trauma to the heart. renal failure. the pa­ tient can be observed without intervention. A classic sign of constrictive pericarditis is Kussmaul's sign : a rise in the JVP during inspiration. Noninfectious causes of pericarditis in­ clude connective tissue diseases (e. gram negatives). . gradual stretching of the pericardium can accommodate the effusion. which is often fatal. the pericardium becomes rigid and impairs filling of the chambers of the heart. radiation. Signs include hypotension (from decreased forward flow). Pericarditis The heart is contained within the pericardia! sac.g.g. malignancy. Patients with pericarditis Cardiac Neoplasia The most common neoplasias of the heart are metas­ tases. . and myocardial infarc­ tion (Dressler's syndrome is the name given to post­ myocardial infarction pericarditis). Pericarditis can also occur idiopathically. surgery).g. Treatment may also include anti-in­ flammatories such as aspirin. j oint pain. Atrial Myxoma Atrial myxoma is the most common primary cardiac tumor. the decrease in intrathoracic pressure brings blood into the heart. but drainage of the fluid by pericardiocentesis or surgery (pericardia[ window) is necessary if hemodynamic compromise arises. rheumatic heart disease. It is most commonly benign and found in the left atrium.e. any symptom/sign of congestive heart failure may be present. drainage of infection from the pericardia! space. chorea (un­ controllable purposeless movements). Rheumatic Fever and Rheumatic Heart Disease (rheumatic heart disease) .g. and parasites can cause my­ ocarditis). radiation). dyspnea). Due to what is thought to be an autoimmune response triggered by the bacterium. Emboli from the tumor can cause vascular occlusion (which could lead to stroke. On auscultation. often. In constrictive pericarditis. an inflammatory response occurs that can affect the heart. congenital lesion. . drugs. renal ischemia. Chest pain in pericarditis is pleuritic. The pain is often affected by position. one may hear a peri­ cardia[ rub . or bacteria (e. resulting in signs and symptoms similar to those in left and right heart failure. tuberculosis. are often febrile. which forms the pericardia! sac. increased JVP (from increased backup). cardiac injury leading to bleed­ ing into the sac). . To treat tamponade. Depending on the severity. skin. THE CARDIOVASCULAR SYSTEM If a patient is known to have valvular pathology that could predispose to endocarditis (e. or toxins (e. If Myocarditis can be caused by infection (Coxsackie B virus is the most common viral cause. Treatment depends upon the etiology: viral pericarditis is generally self­ limited. the sound of the inflamed pericardial lay­ ers rubbing against each other. Metastases can affect the heart itself or the pericardium. . it gets better when the patient leans forward and worse when the patient lies down. If asymptomatic.

The fetal lungs are nonfunctional and mostly collapsed. which eventually returns blood to the fetal right atrium via the inferior vena cava ( IVC ) . it will be mixed with deoxygenated blood that is on its way back to the heart. Modified from Goldberg: Clinical Anatomy Made Ridiculously Simple. a passageway in the intra-atrial septum that allows communication between the atria. 1 -25. and many errors can occur along the way: 8/1000 births have some type of congenital heart defect. fa­ tigue. So how does the fetus get 4 What are the only other veins that carry oxygenated blood? The pulmonary veins (from the lungs to the left atrium). Constitutional symptoms (e. weight loss) may also occur. THE CARDIOVASCULAR SYSTEM oxygenated blood? From the mother via the umbilical vein. . CONG ENITAL HEART DISEASE Notice that both the relatively more oxygenated blood from the IVC and the less oxygenated blood from the SVC both mix in the right heart. If the myxoma blocks the mitral valve. so an atrial tumor can cause a diastolic murmur. the fetus is bathed in fluid. The mo­ tion of the tumor on its pedicle can cause a "tumor plop" sound during diastole. so it would not do much good to have the lungs breathe. the more oxygenated blood The embryological development of the heart is com­ plex. However. It is called the umbilical vein because it is com­ ing towards the baby's heart (remember artery away from heart). but do not be fooled: the umbilical vein is carrying oxygenated blood to the baby. the IVC enters at an angle such that the blood is di­ rected towards the foramen ovale . After all. occlusion) . The fetal circulation. Atrial myxomas are treated by surgical removal . what type of mur­ mur would you expect it to cause? Atrial contraction occurs at the end of diastole. However. The murmur caused by atrial myxoma can be position-dependent. If this blood enters the fetal venous system. this inferior vena cava blood + oxy­ genated blood from the umbilical vein is still more oxygenated than blood coming from the superior vena cava ( SVC ) .g.CHAPTER 1. fever. a diastolic rumble may be heard. Thus. MedMaster 2004 29 . 4 The umbilical vein connects to the fetal venous system. = If the myxoma is in the atrium. THE FETAL CIRCULATION Figure 1-25. Fetal Circulation Fig.

This mixes the venous and oxygenated blood supplying the systemic circulation. If a baby feeds or exerts her/himself. Transposition of the great arteries. how do you think a patient could try to relieve these symptoms? If there were a way to increase systemic resistance. which connects the pulmonary artery to the aorta. thus decreasing the resistance in the systemic circulation. atrial septal defect (ASD). This blood then flows from the left ven­ tricle into the aorta. 5 The changes in pressure also result in closure of the foramen ovale. this would raise left-sided pressure. deoxy­ genated blood must somehow bypass the lungs and make it into the systemic circulation.e . which encourages blood to go from right to left (by making the path of least resist­ ance even less resistant). The arteries in these areas will dilate. which causes cyanosis. Treatment is surgical: patching shut the VSD and widening the pulmonary outflow tract. 5 Transposition of the Great Arteries Fig. What would allow deoxygenated blood to get from the venous system/right heart to the left side of the body? Though your first guess might be some kind of intrac­ ardiac shunt (e. 1. These shunt closures lead to the establishment of the adult circulation as described in Fig. In this condition. or by closing it with anti-inflammatories (e. Classification o f Congenital Heart Disease Congenital heart disease is divided into pathologies that cause cyanosis ("blue babies") and those that do not cause cyanosis.g. Tetra means four.g. as opposed to the ductus arteriosus. The stenotic pulmonary artery causes the deoxygenated blood from the right ventricle to flow through the V SD instead of the pul­ monary artery. This leads to increasing cyanosis. and thus decreases right­ to-left shunting. one which spans the middle portions ofboth ventricles). .. the lungs are almost en­ tirely bypassed either by direct passage from the IVC to the right atrium through the foramen ovale to the left atrium or from the right ventricle through the pulmonary artery through the ductus arteriosus to the aorta. the aorta and pulmonary artery connect to Prostaglandin levels are high during gestation. 1 -27. Thus. and these episodes are known as "Tet spells" ("tet" is short for tetralogy). and right ventricular hyper­ trophy (leading to a boot-shaped heart on a chest X-ray) secondary to pulmonic stenosis. Tetralogy of Fal­ lot is an example of this. One can take advantage of this fact in the treatment of some congenital heart disease by keeping the ductus open after birth by prostaglandin administration. the developing lungs use oxygen from the very little blood they do get for their own development). the right. Children do this by squatting. What about the re­ maining blood from the SVC and IVC that returns to the right atrium and passes to the right ventricle? It would not be of much use to have it travel through the lungs since they cannot yet oxygenate blood (in fact. The only situation in which a septal defect could lead to cyanosis would be if there is a V SD and right heart pressures are abnormally elevated so as to overcome left heart pressures. any com­ munication between the 2 circulations should not lead to cyanosis. 1 -26. the newly expanded lungs offer far less resistance than they did while they were collapsed. Most of the blood from the right heart ej ected through the pulmonary artery passes through a shunt called the ductus arteriosus. realize that due to relatively higher pressure in the left heart vs. This favors flow from the right heart/pulmonary artery to the lungs. Normally. If the decrease in systemic resistance increases right-to-left flow. an overriding aorta (i. From Goldberg: Clinical Anatomy Made Ridiculously Simple. s/he will need increased blood flow to vari­ ous parts of the systemic circulation. or ven­ tricular septal defect (V SD)). For cyanosis to occur. which increases resist­ ance in the arterial system. When the baby takes its first breath after birth. ASDNSD should not normally lead to cya­ nosis. Tetralogy of Fallot. The decrease in flow through the ductus arteriosus along with a decrease in prostaglandin levels causes the ductus arteriosus to close. Cyanotic Heart Disease Tetralogy of Fallot Fig.CHAPTER 1. . however. which also helps keep the ductus open.1 . MedMaster 2004 30 . TETRALOG Y OF FALLOT Figure 1-26. THE CARDIOVASCULAR SYSTEM from the IVC makes it across to the left heart (which can then pump it to the body). and there are four components of the pathology here : a VSD. Increased left-sided pressure will shunt a little more blood back to the right so it can go through the pulmonary system and get oxygenated. indomethacin) if it remains open.

. The main point to keep in mind is that for a cardiac lesion to cause cyanosis. From Goldberg: Clinical Anatomy Made Ridiculously Simple. However. totally anomalous pulmonary ve­ nous return. and then the blood comes back to the left heart and then is returned to the lungs. 1 -28.g.. Thus. Non. THE CARDIOVASCULAR SYSTEM the wrong ventricles: the pulmonary artery to the left ventricle and the aorta to the right ventricle. hy­ poplastic left heart. there must either be a right-to-left shunt (e. MedMaster 2004 lot). when these close at birth.g. efforts are made to keep the ductus arteriosus open after birth (by administer­ ing prostaglandins) until surgery can be performed to attach the great vessels to their appropriate ventricles.A . tetralogy of Fal- ATRIAL VENT R IC U LA R S EPTAL D E FECT S EPTAL D E FECT i Oz T 0 2 Atri u m T o2 R i g ht T Oz Oz Oz T Oz O z Ventricle i O t o z 2 Figure 1-28 P u l monary Artery TRANSPOSITION OF THE GREAT ARTERIES Other Causes of Cyanotic Heart Disease R i g ht = Oz ) Oz Left R i g ht O z Atri u m Oz Oz Atri u m R i g ht Left Ventricle Oz Oz Oz Oz Oz T Oz T Oz . P. This results in an increased amount of blood handled by the right heart.CHAPTER 1 . sometimes catheterization is performed. . If diagnosed in utero. there is no way of getting oxygenated blood to the tissues. Although these defects can be detected by murmur on physical exam and then visualized by echocardi­ ography.. blood flows through ASDs and VSDs from left to right.g. which can be deadly. which then returns to the right heart. de­ oxygenated venous blood returns to the right heart and then is ejected into the aorta to the systemic circulation. Catheterization findings in ASD and VSD. Figure 1-27. Ventricle i O t o 2 z I o2 CA THETERIZA TION FINDINGS IN A SD AND VSD 31 Left O z Atr i u m Oz Left Ventricle . In utero. etc. The left heart receives blood from the lungs and then ejects into the lungs. and many others. The result is two parallel loops instead of a continuous progression. Catheterization will demonstrate increased oxygena­ tion of the blood in the right side of the heart compared to normal patients. the communications between the two circula­ tions via the foramen ovale and ductus arteriosus allow for enough mixing to maintain oxygenation of tissues. such as a single ventricle. transposition of the great arteries). If there is an ASD or VSD. tetral­ ogy of Fallot) or the blood must somehow be bypassing the lungs (e. Fig. blood in the right heart will be a mixture of venous return from Noncyanotic Congenital Heart Disease Atrial Septal Defect (ASD) and Ventricular Septal Defect (VSD) Since left heart pressure normally exceeds right heart pressure (with a few exceptions e. . etc. There are other less common cardiac anomalies that can lead to cyanosis.cardiac causes of cyanosis in the newborn are dis­ cussed in case #3 in Chapter 10.

In such cases. if there is a hole. At birth. a holosys­ tolic murmur. the right side starts to win. the blood in the right atrium should still be purely venous deoxy­ genated blood. the left ventricle is stronger than the right ventricle. This causes the pressure to be so high in the lungs that the right-sided system eventually starts to be under higher pressure than the left. This is Eisenmenger syndrome (Fig. Atrial Septal Defect (ASD) . and so when it passes to the left side. due to the volume overload of the right heart. THE CARDIOVASCULAR SYSTEM the right side of the body (deoxygenated) and oxy­ genated blood that has traversed the defect from the left heart. but a large ASD can lead to significant overload of the right ventricle. respectively. which can result in its enlargement. This is Eisenmenger syndrome : a left-to­ right shunt causing pulmonary and right heart pres­ sures to increase so that the shunt reverses. bypassing the lungs since they would not be oxygenating this blood anyway. this allows blood ej ected by the right heart (which contains oxygenated blood from the mother) to pass from the pulmonary artery to the aorta. This is in contrast to ASD where both the right atrium and the right ventricle have in­ creased 02 (since oxygenated blood passes from the left atrium to the right atrium via the ASD and then from the right atrium to the right ventricle). leading to cyanosis.CHAPTER 1 . ejecting to the entire systemic vasculature instead of the low-pressure pulmonary system. What would happen if the ductus arteriosus did not close at birth? As with all other shunts we have described. Right-Sided Pressure Increasing RIGHT PRESS U RE > LEFT LEFT PRESS U RE > RIGHT Figure 1-29 E I S E N M E N G E R SYN DROME 32 . Additionally since the amount of blood ej ected by the right heart becomes greater than that ej ected by the left. the stronger left ventricle wins and pushes blood over to the right side. So when the heart squeezes.e. A small ASD can be asymptomatic. Diagnosis is made by echocardiography or MRI . Since there is not really a sub­ stantial amount of pressure across the ASD. causing cyanosis. which can eventually cause such severe pulmonary hy­ pertension that the pressure in the right heart over­ comes the pressure in the left heart. surgical repair of the ASD is necessary. This causes a fixed split of S2. pulmonic valve closure occurs later than aortic valve closure. resulting in blood flow from right to left through the defect. Patent Ductus Arteriosus (PDA) The ductus arteriosus serves as an in utero connec­ tion between the pulmonary artery and the aorta. Now the flow through the lungs is increased since the right heart is pumping extra blood (i. . . 1 -29. The blood in the right heart has not yet been oxygenated by the lungs. the left-sided pressure is Ventricular Septal Defect (VSD) . Eisenmenger syndrome. The murmur of VSD occurs when the ventricle contracts. A VSD causes increased flow to the lungs. increased flow across both tricuspid and pul­ monic valves can produce murmurs during diastole and systole. Fig. it is pumping both the venous return from the body and the oxygenated blood from the left ventricle that passes through the defect). At that point. pushing blood through the VSD to the left side.e. i. Thus. the body gets some blood without oxygen. Since the leak is from the left ventricle to the right ventricle. In the fetal circulation. reversing the shunt. The left ventricle normally has a harder j ob than the right ventricle. the blood flow across the ASD itself does not create a murmur. If there is only a VSD. the ductus arteriosus closes. 1-29). However. only the right ventri­ cle will have this elevated 02.

What would be the consequence of this? Blood pressure would be much higher in the upper extremities than the lower extrem­ ities. While the ductus is open in utero. so flow across the PDA will be from aorta to pulmonary artery . and then goes for another trip to the lungs and back to the left heart and round and round again. blood flows through it constantly throughout the cardiac cycle. What happens when the ductus closes at birth? The head and upper extremities receive normal blood flow since they occur proximal to the obstruction. This elevated pulmonary arterial pressure can subsequently result in right heart fail­ ure and/or sufficiently elevated pulmonary artery pressure so as to reverse flow through the PDA (anal­ ogous to Eisenmenger syndrome) . Left 33 . Aortic coarctation. which can lead to elevated pulmonary ar­ terial pressure. what happens in utero? The three ves­ sels of the arch are proximal to the obstruction. and left subclavian arteries. . This would allow deoxygenated blood from the pulmonary artery to pass to the aorta. the op ­ posite of in utero.CHAPTER 1 .e . and the left subclavian artery. A severe coarctation increases the resistance facing the left ven­ tricle. The result is that oxygenated blood from the aorta passes to the pulmonary artery. and all is well. The lower half of the body. Similar to the effect of aortic stenosis on the left ventricle. If the narrowing occurs proximal to the ductus (preductal coarctation). ventricular hypertrophy is also one potential conse­ quence of aortic coarctation. This extra work can lead to heart failure. there will be higher blood pressure in the right arm than in the left. Coarctation of the aorta can also result in higher blood pressure in the upper extremities than in the lower extremities. Pulmonic stenosis can occur as part of tetralogy of Fallot or independently. syncope. as with other left-to-right shunts. What kind of murmur occurs in aor­ tic stenosis? Systolic ejection murmur. If there is a patent ductus arteriosus. Also. How does the heart respond to increased re­ sistance in adult aortic stenosis? Hypertrophy. Why? If the coarctation occurs dis­ tal to the brachiocephalic. What if the ductus failed to close in preductal coarctation? Again. Hypertrophy can result in fatigue. If the coarct occurs distal to the bra­ chiocephalic take-off but proximal to the left subcla­ vian take-off. If this treatment fails. re­ sulting in a continuous machine-like murmur. blood from the pulmonary artery flows through the ductus arteriosus to the aorta distal to the obstruction to supply the lower body. the body will take advantage of collateral vessels along the undersurface of the ribs to supply the lower portion of the body. This in­ creases the work of the left heart since it is now re­ sponsible for the normal pulmonary venous return and the extra blood that comes through the shunt. Fig. Pulmonic Stenosis Pulmonic stenosis can occur in adults. THE CARDIOVASCULAR SYSTEM higher than right-sided pressure . dyspnea. surgical liga­ tion can be performed. and so blood from the left ventricle easily goes through these to the head and upper extremities. common carotid. depend­ ing on the severity. Most commonly it occurs near the ductus arteriosus. anti-in­ flammatories (i. the upper body will be normally supplied by the left ventricle. This results in the delivery of a mixture of deoxygenated and oxygenated blood to the Coarctation of the Aorta Coarctation of the aorta is a congenital narrowing of the aorta that can occur anywhere along its length. Since prostaglandins keep the ductus open. pulmonary blood flow increases. however. but it occurs more commonly as a congenital lesion. due to the narrowing of the aorta and the loss of the "detour" via the ductus arteriosus. but still distal to the three vessels men­ tioned above. and thus aortic coarctation produces a systolic ejection murmur. The ductus arteriosus is distal to the brachiocephalic ar­ tery (which gives rise to the right common carotid ar­ tery and right subclavian artery). causing cyanosis. What type of murmur would coarctation of the aorta cause? When is blood passing through the murmur­ producing area? Blood flows through the aorta during systolic ej ection. while the circulation distal to the coarct will get diminished flow. The murmur is systolic. Congenital Aortic Stenosis Congenital aortic stenosis is similar in pathophysiology to adult aortic stenosis : a congenitally stenotic valve in­ creases the workload on the left ventricle. and these notches can be seen on chest X-ray. leading to hy­ pertrophy. the left common carotid artery. pulmonic stenosis causes the right ventricle to hypertrophy. and can thus lead to congestive heart failure. Depending on whether the coarctation occurs proximal or distal to the ductus arteriosus. indomethacin) can be used to close the ductus. 1 -30. and eventual congestive heart failure. these vessels will all get normal flow. but the lower body will be supplied by the pulmonary artery through the ductus arteriosus to the aorta. Clinical manifestations of coarctation of the aorta. different manifestations can occur. One manifestation of this is the radiologic finding of rib notching: the enlarged collateral vessels under the ribs actually wear away at the rib surface over time due to their increased blood flow. has reduced blood flow. this can cause right heart failure. in a neo­ nate. Additionally. If severe.

As mentioned above. This can occur either via trans- 34 . blood must have some way of bypassing the lungs. Review of Congenital Heart Disease Congenital heart disease can be divided into diseases that cause cyanosis and those that do not. . In heart dis­ eases that cause cyanosis. e. "Things not fully opened" can lead to increased work of the chamber ejecting through the stenosed valve and sub­ sequent heart failure. From Goldberg: Clinical Anatomy Made Ridiculously Simple. VSD. The other pathologies are either "things left open" (ASD. in which the upper half of the body appears normal while the lower part of the body is cyanotic. MedMaster 2004 position of the great arteries. This can lead to differential cyanosis. the clinical consequences depend on the severity. lower half of the body.CHAPTER 1. or a shunt (but only if the right ventricle pressures are higher than the left ven­ tricle pressures through the shunt.g. THE CARDIOVASCULAR SYSTEM L common carotid artery Patent ductus arteriosus * = Preductal sites where coarctation can occur A ORTIC COARCTATION Figure 1-30. which can result in pul­ monary hypertension and right heart failure. In post-ductal coarctation. Aortic coarctation can cause differential cyanosis if it is preductal and the ductus fails to close. a very se­ vere coarctation can lead to heart failure. "Things left open" can lead to increased left-to-right flow. or "things not fully opened" (aortic and pulmonic stenosis) . PDA) . tetralogy of Fallot).

. Stiff chest wall 3..e. (e. c. emphysema. Respiratory muscle weakness Obstructive lung disease (resistance to expiration.J (/) (/) lJ. The lungs oxygenate the blood and eliminate carbon dioxide from it.g.J > 0 0 0 _J Alveolar membrane BRONCHIOLE NORMAL co Alveoli fill with fluid (edema. the airways (tracheal bronchi/ bronchioles). Then the alveolus contracts back down like a deflating balloon to let carbon dioxide out and begin the cycle anew. The lungs contain two basic compo­ nents: the tracheo-broncho-al veolar system (i. pus) Restrictive lung disease (resistance to inspiration): 1. Fig.g. What could cause this system to fail? A problem with the sac (alveolus). lJ. cystic fibrosis Problem with pulmonary blood supply: hypertension) SCHEMATIC OF LUNG COMPONENTS AND PATHOLOGY Figure 2-1 35 . THE PULMONARY SYSTEM CHAPTER 2. B. inflammatory. the airways and air sacs) and blood vessels.g. asthma. decreased alveolar elastic recoil): e. _J A. pulmonary chronic bronchitis. Stiff lungs with thick alveolar walls (e. THE PULMONARY SYSTEM COMPONENTS OF THE PULMONARY SYSTEM The alveolus is basically a sac that fills with air when one breathes in and allows that air to pass across a membrane into a blood vessel (an alveolar capillary). connective tissue disorders) 2. The alveoli are the final branches of the airways (trachea � bronchi � bronchioles � alveoli). or the blood vessels. Schematic of lung components. 2-lA. blood. pulmonary arterial embolus. The func­ tional unit of the lungs is the alveolus and its capillary. their membranes. D. E.CHAPTER 2.

In emphysema. the lung and the heart are both potential pathophysiological culprits. but can become inadequate for the needs of the body with activity. Each of these disease processes will be discussed in greater detail below under obstructive lung disease. What else can lead to exertional dyspnea? Angina from decreased heart perfusion due to atherosclerosis in the coronary arteries. etc. connec­ tive tissue disease. 2-lB). decreasing the force of expiration. A non-cardia­ genic cause of pulmonary edema is acute respiratory distress syndrome (ARDS). it was some­ how unable to do so. �l the sac has to do is fill up with oxygen. these patients actually stop breathing. In both types of Blood Vessels Fig. Additionally. 2-lD). for example.). exposure diseases such as silicosis. 2-lD. trauma. This can lead to exertional dyspnea. One cause of filled alveoli is cardia­ genic pulmonary edema: when the heart fails and blood backs up into the lungs. THE PULMONARY SYSTEM Alveolar Sac/Airway sleep apnea. 2-lB. How could the airway become obstructed? A foreign body (like an aspirated peanut in a child). and passes the oxygen across the membrane to the blood without problem. the result is daytime drowsiness because of frequent awakening at night caused by apnea. What could fill the sac? Pus (pneumo­ nia) or fluid (edema or blood). Any process that clogs the alveoli diminishes their ability to hold oxygen (and thus decreases their ability to oxygenate the blood in their capillaries). which can occur in septic shock. resulting in pul­ monary edema. there is thought to be diminished sensitivity of central receptors in the brain for this hypoxia/hypercarbia as well as a diminished response to these stimuli. The alveoli are the final branching of a tree that begins with the trachea. Fig 2-lC. 2-lC). Re­ strictive lung disease is discussed later in this chapter. blood can fill an alveolus if there is pulmonary hemorrhage. • The sac does not open adequately (Fig.g. Sup­ pose the sac opens. How could this happen? Either obstruction of the air way or inadequate elastic recoil of the al veoli. • The sac is unable to expire adequately due to either obstruction of the airways or decreased elastic re­ coil of the sac itself (Fig. Any disease that causes destruction or thickening of this membrane can reduce t�e diffusion of oxygen across it. airway ob­ struction can occur if the airways are hyper-reactive (causing them to constrict in response to cold and/or exercise and/or allergens as in asthma) or if damage to Fig. This can occur in Goodpasture's syndrome or second­ ary to lung cancer. Thickening of the alveolar membrane occurs in diseases that cause fibrosis of the lungs (e. and all the _ serve as a conduit for inspired/ rurways have to do IS expired gases. The trachea bifurcates into the bronchi. inflammation causes the pulmonary capillaries to be leaky. where the upper airway col­ lapses due to structural abnormalities. lung parenchyma causes increased collapsibility of the air ways (emphysema). which branch into alveoli. Restrictive lung disease can be due to stiff lungs. But then. So when you think about exertional dyspnea. In ARDS. In central sleep apnea. Any of these causes of restriction cre­ ate a situation where the airway cannot open all the way and is difficult to keep open. Unless there is extremely severe thickening of the membrane. a stiff chest wall.CHAPTER 2. oxygen diffusion is usually adequate for the body's needs at rest. or chronic mucus plugging (chronic bronchitis or cystic fibrosis) could all produce a mechanical obstruction. a tumor. The cen­ ters in the brainstem that "tell the lungs to breathe" stop working on occasion such that while asleep. These dis­ eases also cause restrictive pulmonary disease. This is different from obstructive sleep apnea. Fig. The goal of the pulmonary vasculature is to bring blood to the lungs to pick up oxygen and re- 36 . hypersensitivity. because fibrotic thickening restricts proper expansion of the lung. What problems could affect the alveolar sac and/or airways? • The sac is already filled with something other than air (Fig. eventually you would either gasp for air or pass out. which branch into bronchioles. suppose that when it was going to blow off the waste and breathe in again. asbestosis. So one reason that the sac would not open is if the brain is not doing its job. If you were to blow out all the air in your lungs and then hold your breath for a really long time. the damaged lung architecture also causes a decrease in the elastic recoil of al veoli. beryliosis. etc. The sac is unable to expire adequately. Destruction of por­ tions of the membrane can occur in emphysema. or respiratory muscle weakness. An obstruction anywhere would prevent the alveolus from returning to its deflated state and thus lead to retention of carbon dioxide and inability to initiate a new cycle. lead­ ing to a decrease in surface area available for gas exchange. pre­ venting adequate filling with oxygen. The sac does not open adequately. 2-lE. the elevated pressure causes transudation of fluid into the alveolar sacs. The sac is already filled with something other than air.. This is because the brain detects decreased oxygen (hypoxia) and in­ creased carbon dioxide (hypercarbia) and demands a breath. The sac can­ not open adequately if it faces some restriction to doing so (restrictive lung disease) or if the brain does not tell it to do so (central sleep apnea). Aside from pus and edema fluid. so it collapses quickly. takes in its oxygen. Membrane The alveolar membrane allows 02 across to the blood and C02 out from the blood.

destruction of alveolar membranes decreases the surface area available for gas exchange. When you breathe in. and they stretch. by smoking or alpha. So a small hole with air rushing through it gives high.CHAPTER 2. obesity) 3. There are two consequences of this floppiness: the al ve­ oli ha ve decreased elastic recoil. abdominal muscles) to help exhale. 1. and the bronchioles are more likely to collapse. hold it. OBSTRUCTIVE AND RESTRICTIVE LUNG DISEASE An important concept in pulmonary pathophysiology is the distinction between obstructive and restrictive lung disease. Increased resistance in the air ways (e. To whistle.1 an­ titrypsin deficiency). it does not matter how good the lungs are at oxygenating the blood since the blood cannot ade­ quately receive the oxygen. and then try to keep breathing in but with your chest still expanded.. Breathing at high lung volumes can also cause hyper-expansion on chest X-ray: the lungs ap­ pear too big (mostly in the superior-inferior axis) and flatten the diaphragm. This can cause shortness of breath and tachycardia. restriction makes it hard to get the air in. but also hematologic ones. THE PULMONARY SYSTEM flexible. flabby alveoli do not exhale well. Stiff lungs (e. So causes of shortness of breath include not only cardiac and pulmonary prob­ lems.. one type of chronic obstructive pulmonary disease (COPD). lease carbon dioxide. A stiff chest wall (e. Thus. combined with the increased collapse of bronchioles. that would give you the sense of what it is like to have a COPD or asthma flare. if the oxygen-carrying capacity of the blood decreases. Causes of obstruction include: Symptoms and Signs of Emphysema.g.. it sounds like rushing air.. allowing air in. how will the body compensate? It will try to obtain more oxygen by breathing more deeply and faster and by circulating the existing blood volume faster to get the most mileage out of it. those membranes are 37 . The resulting baggy. and then they relax. causing ob­ struction of the airways. Because of the decreased elastic recoil in these floppy alveoli.g. from a pulmonary embolus) could prevent transport of blood to the lungs for gas exchange. which can be fatiguing to the point that respiratory failure can ensue. anemia can decrease the body's ability to provide oxygen to the tissues. the alveolar walls are progressively destroyed (e.pitched noise. interstitial lung disease) 2. Increased tendency for air way closure (a component of asthma and emphysema) Restrictive lung disease makes it difficult to get the air If you were to take a very big deep breath. FVC is the amount of air that can be forcefully expired after a maximal inspiration. you must make a very small hole with your lips for the air to come out of. patients breathe at high lung volumes. If the lungs have trouble expir­ ing. foreign body. FEVl Under the microscope. What will you hear as the air tries to leave through ob­ structed airways? If you just blow through your wide­ open mouth. they are weaker in ex­ pelling air than normal "tighter" ones (imagine an old used balloon as opposed to a brand-new stiff difficult-to­ blow-up one). This decreased elastic recoil. Restrictive lung disease can be caused by: 1. tumor. chronic mucus plugging in chronic bronchitis) 2. intercostals. elevated pressure in the pulmonary vascular system.g.e. If the oxygen-carrying capacity of the blood decreases. the lungs look like honey­ combs: empty air spaces surrounded by alveolar mem­ branes. Their lungs may get so bad at exhaling that they recruit accessory muscles (e. An obstructed blood vessel (i. leading to dilatation of distal air spaces. Respiratory muscle weakness (neurological or neu­ romuscular disease) Mnemonic: obstruction makes it hard to get the air out. During a flare.g. An emphysema patient may also have a barrel-shaped chest. Mechanical obstruction of the air ways (e. Patients with emphysema may take a deep breath in and then have a prolonged expiratory phase because of the obstruc­ tion to expiration. kyphoscoliosis. What if there were a change in the blood itself? For example. this leads to hyperinflation and air trapping. pushing air back out. and the bronchioles collapse too easily.. Similarly. Another dis­ ease of the pulmonary blood vessels is pulmonary hypertension. in. In emphysema. floppier alveoli and bronchioles (as op­ posed to a lot of little tight ones in the normal lungs). This is em­ physema.. Obstructive Lung Diseases Pulmonary Function Testing Emphysema The pulmonary function test (PFT) used to distinguish obstructive from restrictive disease is the FEVl I FVC ratio (forced expiratory volume in one second divided by forced vital capacity).g. airway thickening from inflammation in chronic bronchitis) 3. leads to dif­ ficulty getting air out.. ob­ structed airways lead to wheezing on exam. If we take this honeycomb-like lung architecture and start tearing out some of the alveolar membrane.g. ankylosing spondylitis. If there is obstruction anywhere in the airways this will make it difficult for air to get out. In addition. we are left with bigge r.

2-2. the FEV 1/FVC ratio will de­ In chronic bronchitis. The Smoking is the most common cause of emphysema.. one just cannot get it all out no matter how hard one tries. Imagine blowing through a toilet paper tube: easy. The destruction of alveolar walls in emphysema leads to reduced surface area for oxygen uptake. FEVl/FVC ratio in obstructive lung disease. Here is a logical way of remembering the different pathologic findings between alpha1-antitrypsin emphysema and smok­ ing-induced emphysema: if a gene is missing in e very cell in the lungs as is the case in alpha-1 antitrypsin OBSTRUCTIVE LUNG DISEASE difference bet ween asthma and COPD is that asthma is reversible bronchoconstriction: the patient and PFTs improve after the exacerbation ends (usually � . This is due to an increase in obstruc­ tion. THE PULMONARY SYSTEM is how much air one gets out in the first second during this task. This is what is going on in the lungs in chronic bronchitis. Smoking is the main cause of chronic bronchitis. which is seen in alpha. another type of obstructive lung disease. do you expect the lungs to be destroyed focally or all over? All over. which results in increased breathing difficulty. respiratory infection can lead to a COPD flare in which the patient gets acutely worse. So if the top number goes down and the bottom one es­ sentially stays the same. the airways clog with mucus. the intrathoracic pressure exceeds the pres­ sure in the airways. Only the de­ creased FEV1/FVC ratio is present in all obstructive lung diseases. Asthma In asthma. the FEV 1 will be decreased and so the FEV 1/ FVC ratio will go do wn. leading to a decrease in FEVl I FVC ratio. A rarer genetic cause. causing resistance to airflow. and this is re­ flected in their similar PFT findings. So FEV 1 goes down. Since the main pathophysiologic process here is obstruction. asthma). Airways are filled with mucus plugs that obstruct expiration. This is known as pan­ lobular (panacinar) emphysema. these patients can have hyper-expan­ sion. With floppy emphysematous lungs. In emphysema the FEVl is decreased and the FVC is the same or decreased (though less so than FEVJ). cold air. adjacent to the air­ ways that bring the smoke in). FEV1 ll FVC- FEV 1 I FVC ratio THE F EV1/FVC RATIO IN OBSTRUCTIVE LUNG DISEASE Figure 2-2 38 ! . Emphysema and chronic bronchitis are both called COPD: their un­ derlying pathophysiology is obstructive. ___. However.g. assessing overall diffusion capacity of the lungs.. crease. prolonged expiratory phase. acces­ sory muscle recruitment. A test called the diffusion capacity of the lungs for carbon monoxide (DLCO) measures diffusion of carbon monoxide across the alveolar membrane. Emphysema from smoking mostly destroys the lungs nearer where the smoke enters (i. These patients usually have some degree of shortness of breath on exertion. DLCO will not decrease. Liver disease (cirrhosis) can also develop in alpha-1 antitrypsin deficiency.CHAPTER 2. wheezing. Some patients have features of both chronic bronchitis and emphysema. thus centrilobular emphysema is the characteristic pathologic finding of smoking-related emphysema. alpha-1 antitrypsin deficiency.e. since pulmonary function is impaired. Pulmonary Function Tests in Emphysema Chronic Bronchitis Fig. one cannot exhale as much in the first second as a normal healthy per­ son can. If a normal person tries to force all of the air out of the lungs. Hyper-reactivity refers to the fact that the airways are more likely to constrict in re­ sponse to these stimuli. a little remains. and exercise. and reduced FEVl. known as the residual volume. Although there is in­ creased residual volume in obstructive disease because of difficulty getting rid of air. and the airways collapse.. This airway collapse normally causes some residual volume to be left in the lungs. Just as with other causes of obstruction. Note that in other obstructive lung diseases where there is no alveolar destruction (e. Now imagine filling it with wads of wet paper towels until the lumen is practically obliterated: difficult. should be considered in a non-smoker who develops emphysema. DLCO de­ creases in emphysema.. just like in emphysema. This is because at a certain point in ex­ piration. just very sloooowwwwllllly. Possible triggers of this hyper-reactive response include allergens. most of the air can eventually be expired. A decreased FEV 1/ FVC ratio is the hallmark PFT find­ ing in obstructive lung disease. deficiency.1 antitrypsin deficiency-induced emphysema. the airways are hyper-reacti ve.

If you were about to fight (or flee from) a BRONCHODILATION Figure 2-3 39 . pulsus paradoxus may be noted. which worsens fur­ ther in acute exacerbations. So when feeling the pulse of a patient having an asthma attack. and urination." This increased venous return can be dra­ matic enough to distend the right ventricle to the point of compressing the left ventricle. no pit stops while you're running away). With the other obstructive diseases (i. During the flare. the parasympathetic nervous system is for rest and digest.. you would want your heart to beat fast to pump blood to your muscles for the strength to fight (or run away).. Bronchodilation. sometimes requiring intubation and mechanical ventilation. in­ creased lung volumes lead to very high negative pres­ sures in the chest. constricts the airways. When examining a patient having an asthma flare. Pulsus paradoxus can also occur in cardiac tamponade. Treatment of Asthma and COPD Flare. and your bowels and bladder to pause for a moment (i. Left ventricular outflow is the source of the peripheral circulation (and hence the pulse). How would you help a patient with COPD (or asthma) dur­ ing a flare? There are two processes that you can cor­ rect: closed air ways and inflammation. THE PULMONARY SYSTEM tiger. The parasympathetic nervous system does the op­ posite: slows the heart. and the patient can breathe nor­ mally again. So in an asthma or COPD flare where we want to open the airways. your airways to be wide open so you could get enough oxygen.. causing more venous return to get "sucked in. e. and the sympathetic system mediates ejaculation. and stimulates digestion. thus affecting left ventricular outflow. and can thus fatigue the respiratory muscles to the point of respiratory failure. Giving a beta-agonist to a patient who needs beta-blockers is obviously quite a bad idea.e. The parasympathetic system in the lungs works through acetylcholine. so you would want to inhibit this with anticholinergics. Sympathetic stimulation in the lungs works through beta-2 recep­ tors. Back to the airways: The sympathetic system opens the airways and the para­ sympathetic system constricts them. there is a chronic decrease in lung function. Though it does not exactly fit into this logical framework. one can feel decreased peripheral pulses during inspiration (pulsus paradoxus). bowel movements. When would you not want to use a beta agonist to open the airways? Recall that beta blockers are used in certain arrhythmias and also to slow the heart so as to decrease its energy needs when a patient has angina. with treatment). con­ stricts the pupils. so you would want agonists of these receptors.CHAPTER 2. 2-3. pa­ tients having an asthma exacerbation breathe at high lung volumes due to the obstruction. your eyes to open wide (pupillary di­ lation) to see the tiger. chronic bronchitis and emphysema). you must affect the pulmonary sympathetic and/or parasympathetic nervous systems. albuterol. such as ipratropium. Fig.e. we need to stimulate the sympathetic system and/or inhibit the parasympathetic system.g. As in emphysema. because The sympathetic nervous system is for fight or flight. the parasympathetic system mediates penile erection. To open the airways.

and dyspnea. Antibiotics are used to treat infections. sili­ con. an epithelial cell chloride trans­ porter found in exocrine glands. it is hard to take a good deep breath (or even a good normal breath). So lungs with restrictive disease are "too good" at getting rid of their air because they are stiff. FEVl/FVC ratio in restrictive lung disease. pneumoconiosis.1 At first this may not seem so bad. multiple scle­ rosis. In con­ trast to increased residual volume seen in COPD pa­ tients.CHAPTER 2. and residual volume increases. abnormal dilatation of a bronchus. to asbestos. rheu­ matoid arthritis. Since infection is thought to contribute to flares in COPD patients. What would this do to airflow? ( 1) The stiff alveoli contract more quickly and more forcefully. muscular dystrophies. . and snap back to their original shape instead of relaxing back to it. 2-4. expiratory muscles can be af­ fected. patients with restrictive disease generally have decreased residual volume. replacement of pancreatic en­ zymes.. Pa­ tients with bronchiectasis may be asymptomatic. The causes of restrictive lung disease include: As for treating the inflammation. Diagnosis is confirmed by a chloride sweat test. regular percussion of the back and chest to help clear secretions. in some instances of restrictive lung disease. obesity 3. the FEVl/FVC ratio remains normal. Restrictive Lung Disease Restrictive lung disease can occur if the lungs are stiff (fibrotic disease). The dilated airways are easily collapsible. THE PULMONARY SYSTEM these beta agonists can increase heart rate. but if the lungs get too stiff. the alveolar walls become thick and inflexible (in contrast to becoming weak and flimsy as occurs in emphy­ sema). Cystic fibrosis is caused by a mutation in the CFTR (cystic fibrosis transmembrane conductance regulator) protein. bronchiolitis obliterans organizing pneumonia (BOOP). called dornase or Pul­ mozyme). etc. radiation other: idiopathic pulmonary fibrosis. foul­ smelling sputum. steroids such as prednisone can decrease this component of the flare." chemical exposure) connective tissue disorder: scleroderma. so both FEVl and FVC are reduced in restric­ tive lung disease. and/or hemoptysis (coughing up blood). • • • • 2. which predisposes to pulmonary infection. Pulmonary Function Tests in Restrictive Lung Disease Fig." "bird breeder's lung. in some cases. ankylosing spon­ dylitis. myositis drug toxicity: amiodarone. Any of these can prevent adequate lung expansion. and thus bronchiectasis can be con­ sidered a chronic obstructive pulmonary disease. myasthenia gravis. In restrictive lung disease due to stiff lungs. which will show an elevated level of chloride in the sweat. Treatment involves drugs that break down the thick mucus (DNAse enzyme. and surgical resection of the affected lung lobe may be nec­ essary in certain cases if antibiotic treatment fails or if there is excessive hemoptysis. floating foul-smelling stools (from the malabsorption of fats). lung transplant may be necessary. These viscous secretions in the lungs can cause ob­ struction. 1. interstitial lung disease secondary to: • Cystic fibrosis is another cause of obstructive lung dis­ ease. if the chest wall is stiff. bronchodilators. Restriction of the lungs decreases total lung capacity (TLC).g. The prob­ lem with chloride transport leads to water flow abnor­ malities. and (2) stiff airways are less likely to collapse.e. However. lupus. If expiratory muscles are weak. beryllium. Cystic Fibrosis Stiff lungs. Viscous mucus in cystic fibrosis can also cause pancreatic insufficiency (resulting in malab­ sorption and. and dietary supplements to remedy malab­ sorption. The recurrent infections of cystic fibrosis are a com­ mon cause of bronchiectasis. amyotrophic lateral sclerosis (ALS). antibiotics are sometimes used in the treatment of an acute COPD flare. including cough. Bronchiectasis Bronchiectasis. recurrent pulmonary infections. Respiratory muscle weakness: Guillain-Barre. production of purulent. hypersensitivity pneumonitis ("farmer's lung. If both FEVl and FVC decrease pro­ portionally. FEVl can decrease less than FVC because the in1 40 There is an exception to this: in restrictive disease caused by respiratory muscle weakness. spinal cord injury Symptoms/signs can include: delayed passage of meco­ nium (the first stool in infancy). causing secretions to become more viscous. eosinophilic granuloma Stiff chest wall: kyphoscoliosis. and intestinal obstruction. biliary obstruc­ tion. cough. Repeated infection and consequent inflammation lead to COPD. thus wors­ ening angina. The defective gene is inherited in an autosomal recessive pattern. If the lungs are severely damaged. i. full exhalation cannot take place. failure to thrive. metho­ trexate. antibiotic treatment of infection. sarcoid.. e. diabetes). can occur congenitally or secondary to any infection that leads to inflammation and destruction of the airway. or if the res­ piratory muscles are weak. or may have intermittent symptoms related to infec­ tions. bleomycin.

we can de­ velop a framework for thinking about pathologies of the lung by considering how these different compo­ nents are affected. leading to similar symptoms. but the patient can have severe drops in blood oxygenation with exercise or even with mild activity.g. Pulmonary obstruction also occurs in asthma. In asthma. as opposed to centrilobular in smoking-in­ duced emphysema). Restrictive lung disease leads to a decrease in total lung capacity. Review of Obstructive and Restrictive Lung Disease Starting from the simple anatomical understanding that the lungs contain airways that end in alveoli. prolonged expiratory phase. or respiratory muscle weakness. PULMONARY HYPERTENSION Pulmonary hypertension is an increase of pressure in the pulmonary vasculature. The causes include intrinsic lung disease. and hyper-expansion on chest X-ray. the changes in pulmonary function are re versible. creased elastic recoil of stiff lungs or a stiff chest wall can preserve some of the force of the FEVL If the FEV 1 decreases less than the FVC. Accessory muscles may be re­ cruited to help inhale (e. Chronic bronchitis and emphysema are known as COPD and can occur ei­ ther separately or together. the alveoli cannot contract as well. depend­ ing on the extent of disease. This leads to a de­ creased FEVl I FVC ratio in obstructive lung disease. a diffusion defect can also occur. resulting in a diffusion defect. but with normal or decreased FVC. sternocleidomastoid) during inspiration. signs. At rest this might not be a problem. (The pathology in alpha. cystic fibrosis). The role of the alveoli is to fill with 02 (which passes across the alveolar membrane) and release C02. The opening of stiff air sacs sounds like crackles on auscultation.think of those floppy alveoli slowly con­ tracting against high resistance/collapsed airways). or de­ struction of the alveolar membrane leading to floppy collapsible airways (emphysema). often in smokers. these functions decrease. however. 41 . and can demonstrate wheezing. Thus. In fibrosis secondary to inflammatory lung disease. If the cause is pulmonary fibrosis. Treatment of restrictive lung disease is directed to­ ward the underlying etiology.or l FEV1/FVC RATIO IN RESTRICTIVE LUNG DISEASE Figure 2-4 If the airways are obstructed. In COPD. and blood vessels. the FEV 1/FVC ratio can be greater than normal. This leaves the lung hyper-expanded with retained C02.. What might you hear on ausculta­ tion of a patient with restrictive lung disease? Crack­ les are the sounds of the stiff alveoli popping open. the FEVl/FVC ratio in restrictive disease either increases or remains normal. steroids are generally used to reduce inflammation. blood. due to thickening of the alveolar membrane. THE PULMONARY SYSTEM FEV1 ! RESTRICTIVE LUNG DISEASE FVC (Total lung capacity decreases) !(!) FEV1 I FVC ratio . this leads to a thick alveo­ lar membrane. making it hard to get air out. asthma (in which case the obstruction is reversible).1 antitrypsin deficiency is panlobular. resulting in an increased or normal FEVl I FVC ratio. Emphy­ sema can also occur in alpha. They sound like velcro under the stethoscope. Symptoms and Signs of Restrictive Lung Disease Patients with restrictive disease can become very short of breath because of the increased work neces­ sary to open the lungs. A decreased DLCO is a hallmark of pulmonary fibrotic disease. These patients breathe at high lung volumes. If restrictive disease occurs secondary to pulmonary fibrosis (see causes above). the PFTs show a de­ creased FEVl (the amount of air that can be blown out in 1 second. and PFTs. alveolar membranes. Treatment of Restrictive Lung Disease In restrictive lung disease. If the alveoli clog with pus. or fluid. any cause of a stiff chest wall. Obstruction can occur from a foreign body. This manifests as a decrease in DLCO and can cause insufficient blood oxygenation with exercise or even mild activity. and/or accessory muscle use on physical exam. it is hard to get air in. Pulmonary fibrosis leads to a marked de­ crease in diffusion. chronic mu­ cus plugging (chronic bronchitis.CHAPTER 2. but FEV 1 can decrease less than FVC. depending on the severity of disease.1 antitrypsin deficiency. can end up retaining C02.

. you can see how this mecha­ nism would be helpful. arrhythmia. animals) or infectious ("the common cold" usually adenovirus. rhinorrhea ("runny nose"). Pulmonary Pulmonary hypertension creates extra resistance for the right heart.g. then all of the blood vessels of the pul­ monary vasculature perceive hypoxia. Allergic rhinitis is also treated symptomati­ cally. When there is one area of isolated hypoxia. can be al­ lergic ("hay fever. and can result in pulmonary hypertension. Fig.g. cough. and smoking cessation contributes to speedier recovery from these infections.. interstitial lung diseases) can also lead to pulmonary hypertension. If mucus outflow from the sinuses becomes impaired. causing a backup into the pulmonary system. and they will all constrict. Sites of respiratory infections. leading to sinusitis. cardiomyopathy.e. vasculitis. and So the origin of pulmonary hypertension is either pulmonary (i. right heart.g. e. Rhinitis Rhinitis. 2-5. one filled with pus from pneumonia). Additionally.g. COPD. valvular dysfunction. or the pulmonary vasculature itsel£ The left heart could ha ve decreased for ward flo w. pseudoephedrine.CHAPTER 2. nasal steroids). heart failure. But if the whole lung suffers from hypoxia (e... pulmonale). 2-6. Most commonly. this can lead to right-sided hypertrophy and failure (cor hypertension can arise from problems in the left heart. ventricular septal defect (see Chapter 1) or any other significant left-to-right shunt. the blood vessels constrict so blood will go elsewhere. Hy­ poxic vasoconstriction accomplishes this: In areas of the lung where oxygen tension is low. Problems with the pulmonary vasculature itself (e.. Fig. Causes of pulmonary hypertension. For the right heart to be responsible for increased pul­ monary pressure.g. The symptoms/signs include stuffed nose. antihistamines.g. mucus outflow becomes impaired by inflammation. disease in the vessels themselves or pulmonary disease that secondarily affect the vessels) or cardiac. rhinovirus). If there is an area of the lung that is not receiving much oxygen (e.g... e.. hypoventila­ tion from restrictive diseases of the lungs/chest wall/muscles). sneezing. VSD) Figure 2-5 42 Resistance in lung . treatment is generally geared towards relieving symp­ toms (e. dust. etc. there would have to be an increase in flo w from the right heart. THE PULMONARY SYSTEM Causes of Pulmonary Hypertension are backup from the left heart or increased flo w from the right heart. since the right heart pumps into the pulmonary vascular system. it is in the lung's best in­ terest to shunt blood a way from this area to a region of lung where it is more likely to be oxygenated. Sinusitis Sinusitis is inflammation of the sinuses. RESPIRATORY INFECTIONS Smoking causes inflammation and decreased mu­ cociliary function in the respiratory tract. primary pulmonary hypertension) or problems that affect the lung architecture such that ves­ sels are secondarily compressed (e.. along with reduction of exposure to allergen. hypoxic vasoconstriction can cause pulmonary hypertension. If uncorrected. the mucus trapped in the sinuses can create an environment that facilitates bacterial growth. high altitude. It predis­ poses to any of the infections listed below. Cardiac causes of pulmonary hypertension CAUSES OF PULMONARY HYPERTENSION LUNGS Backup from left heart LUNGS pulmonary veins Increased flow into right heart (e. In severe cases of allergic rhinitis. inflammation of the nasal mucosa. sore throat. Since infectious rhinitis is self-limited. desensitization via im­ munotherapy ("allergy shots") may be considered.g. This is obviously maladaptive." in response to pollen.

nasogastric/nasotracheal tubes. rhinovirus.. a muffled voice. Prolonged hoarseness by itself requires a search for an underlying cause such as a neurologi­ cal/neuromuscular disorder or neoplasia compressing the recurrent laryngeal nerve (e. Viral cases are self-limited. enlarged tonsils with or without exudates. and GERD-induced pharyngitis requires treat­ ment of GERD. and many others) or bacteria (Group A beta-hemolytic streptococci.. anatomical abnormality such as a deviated septum). Symptoms include rhinitis symptoms (which may have gone away and re­ turned).N gonorrhoeae. The causative organism is determined by throat culture. nasal polyps. diphthe­ riae. and many more). H. if present..S. influ­ enza. Although tonsillar exudates (white patches on the throat) are popularly thought to Epiglottitis Epiglottitis is inflammation of the epiglottis. parain­ fluenza virus. predisposition to sinusitis can occur with any cause of sinus inflammation (e. inflammation of the larynx. treating the infection with antibiotics. allergic rhinitis) and/or obstruction (e. vocal strain requires vocal rest.. and other signs of infection (malaise. head/neck cancer or vocal cord polyp). However. Pharyngitis Pharyngitis. GERD (gastroesophageal reflux dis­ ease). etc. C. Hemophilus influenzae. adenovirus.g. and headache.)�t"f" EPIGLOTTITIS . Symptoms include hoarseness and any upper respiratory infection (URI) symptoms. inflammation of the pharynx.CHAPTER 2.. which increases pressure on the sinuses). or viral infection (rhinovirus. THE PULMONARY SYSTEM SITES OF RESPIRATORY INFECTIONS ll'l'" llll-rrli!+PHARYNGITIS :.. epiglot­ titis is rarely seen in the U.!lll PNEUMONIA/PNEUMONITIS Figure 2-6 distinguish viral from bacterial pharyngitis.! BRONCHITIS ----ilr--. Symptoms include sore throat. chills. Laryngitis Laryngitis. Untreated group A beta hemolytic streptococcus pharyngitis can lead to rheumatic fever (see Chapter 1). It is most commonly seen in young children. today because of vacci­ nation against this organism. stridor (a high-pitched inspiratory sound).g. foul-smelling mucus. and pharyngeal erythema. oxymetazoline or phenylephrine).g. can be caused by viruses (adenovirus. pain/pressure around the eyes and cheeks (especially when leaning forward. they can be present with either etiology. and a classic posture: sitting 43 . influenzae.:o. Most commonly caused by Hemophilus influenza B. Treat­ ment is aimed at relieving obstruction with nasal spray decongestants (e. can be caused by vocal strain. Moraxella catarrhalis). In chronic sinusitis (greater than 3 months). and appropriate antibi­ otic treatment for this organism is initiated. fever. swelling resulting from an upper respiratory infection.. An inflamed epiglottis can lead to drooling (failure to clear secretions).g. respira­ tory distress. and Bran­ hamella (Moraxella) catarrhalis. Signs may include cervical adenopathy. and treating allergies.). surgical relief of obstruction may be neces­ sary if other treatments are unsuccessful.. The most common causes of sinusitis are Strep­ tococcus pneumoniae.

with about a 5% chance per year of progressing to reactivation or secondary TB (the risk in immunocompromised patients is about 10%/year).CHAPTER 2. parainfluenza. causing pneumonia. etc. Miliary TB refers to widespread TB infection.. This typically occurs in infants and is most commonly caused by respiratory syncytial virus (RSV). and/or night sweats. Klebsiella pneumoniae. Antibiotics are used to treat the infection. causing restrictive lung disease. Exposure to TB is generally through inhalation. THE PULMONARY SYSTEM forward with neck extended to ease breathing ("tripoding"). Such inflammation can be due to radiation.g.g. latent asymptomatic TB infec­ tion may be identified by PPD (purified protein deriv­ ative) testing. Pharyngeal exam should be avoided in patients with suspected epiglottitis because it can pre­ cipitate spasm. chemical inhalation (e. Aspiration can also lead to the subacute formation of a pulmonary abscess (area of necrosis in lung) or empyema (pus in the pleural space). Although viral bronchitis typically re­ solves spontaneously. Bacterial pneumonias tend to affect one lobe of the lung. Chronic bron­ chitis. and immunocompromised patients (e. dullness to percussion. adrenal tuberculosis. pesticides. and decreased breath sounds. dyspnea. tuberculous osteomyelitis. seizure. and pyrazinamide. Pathogens can reach the lungs from inhalation/aspiration or from hematoge­ nous spread from other sites of infection in the body. Tuberculosis (TB) Mycobacterium tuberculosis can affect any organ sys­ tem. tracheal intubation may be necessary if respiratory failure appears imminent. Fungal pneumonia (e. fluids. More often. and parainfluenza virus. for example.. cough (usually productive of sputum). Treatment is supportive and depends on severity (oxy­ gen.g. These may be seen on X-ray. It can also be caused by adenovirus. though many other bacteria (including 44 . Pneumonitis Pneumonitis refers to inflammation of the lungs rather than infection. stroke. if there is an area of consolidation (which most commonly occurs in bacterial pneumo­ nia). Mycoplasma pneumoniae. any of the organ systems mentioned above may be affected. Streptococcus pneumoniae is the most common cause of pneumonia. egophony. and/or fever 4-6 hours after exposure. As­ piration pneumonia occurs when vomit or food particles are inhaled. etc. and/or mechanical ventilation if necessary). Treatment includes isoniazid. Hemophilus influenzae. "farmer's lung" from moldy hay. Robitussin) and/or bronchodilators. Chest X-ray findings in pneumonia. caus­ ing an area of induration at the site of injection. a type of COPD. A Ghon complex is the presence of a Ghon focus plus calcified granulomas(s) in perihilar lymph nodes. Once exposed. tuberculosis bacteria are contained in granulomas in the lung (tubercles). tachycardia. or fungal.. and. for example during alcohol/drug intoxica­ tion.). Cryptococcus neoformans. hemoptysis. meningitis. Acute bronchi­ tis is typically viral (rhinovirus. influenza virus. respiratory syncytial virus.). an immune response will occur. which can calcify (Ghon focus)." etc. bacterial. and/or renal tuberculosis. If an individual has been exposed to TB. chest and/or abdomi­ nal pain. influenza virus. Symptoms of reactivation TB can include cough. and constitutional symptoms such as fever. or from chlorine. Aspergillus fumiga­ tus) can occur in immunocompromised patients (e. while viral and fungal pneumonias tend to produce more diffuse interstitial patterns. Pneumocystis carinii. Additionally. Symptoms/signs of pneumonia include fever.. and can be viral. initial infection remains asymptomatic. Treatment of pneumonia involves antibiotics for the offending organism and respiratory support if necessary. patients undergoing chemotherapy). pericarditis. trauma. weight loss. Acute hypersen­ sitivity pneumonitis can present as cough. Bronchitis is inflammation of the bronchi. Pneumonia Pneumonia is an infection of the lung parenchyma. in children. HIV/AIDS). Coxiella burnetii) and viruses (including RSV.g.g. adenovirus. Staphylococcus aureus. ethambutol. Treatment with the antiviral ribavirin is controversial. A PPD is the injection of protein antigens from killed TB. Chla­ mydia pneumoniae.. the cough itself can be palliated by anti-tussives (e. Chronic and/or recurrent exposure to toxins can lead to pul­ monary fibrosis. nasal flaring. Bronchiolitis Bronchiolitis is inflammation of the bronchioles. Inhaled droplets can cause a primary in­ fection presenting as pneumonia. or other loss of conscious­ ness. Legionella pneumophila. Patients must be monitored closely. patients may remain asymptomatic for long periods. and influenza) can also cause pneumonia. resulting in sudden airway closure. Cough and other upper respiratory symptoms are typi­ cally present. Symptoms can range from typical upper respira­ tory symptoms to symptoms of respiratory distress (wheezing. tachypnea. or hypersensitivity to an environmental antigen (e. in factories. parainfluenza virus).g. "bird breeder's lung..). Moraxella catarrhalis. is discussed above. Aside from the radiologic signs. elderly. Bronchitis patients with HIV. malaise. appear­ ing as a region of consolidation on X-ray. rifampin.

though ra­ diation and other environmental exposures (e. is diagnostic of pleuritis. Paraneoplastic syndromes most commonly associated with small cell lung cancer include syndrome of inappropriate anti-diuretic hormone secre­ tion (SIADH) (discussed in Chapter 3). hemoptysis). Squamous cell carcinomas of the lung can release parathyroid hor­ mone-related protein (PI'HrP). with a space between them called the pleural cavity. or pleural fluid LDH level > 2/3 upper limit for serum LDH. Chest radiograph will reveal an opac­ ity that may hide the angle of the diaphragm (blunt­ Pleuritis (Pleurisy) ing of the costophrenic angle). a myasthenia gravis-like syndrome (discussed in Chapter 7). and symptoms related to parane­ oplastic syndromes. yet also more amenable to chemotherapy. asbestosis) as well as uremia or pancreatitis. Lung cancer is commonly caused by smoking. causing hypercalcemia. The fluid can be analyzed for infectious organisms. the pleura can be­ come inflamed (pleuritis I pleurisy) and an effusion can occur in the pleural cavity (pleural effusion). while exudates are caused by inflammatory conditions that increase vascular permeability. dyspnea. Pleural friction rub is a grating sound that persists through the entire respiratory cycle. Thoracentesis to remove the fluid is necessary for diagnosis and as a therapeutic measure. Light's criteria state that the fluid is exudative if any of the following are met: pleural fluid protein/serum protein ratio> . and adenocarcinoma). mio­ sis. pleuritic chest pain. or it can be caused by penetrat­ ing chest trauma or esophageal rupture.g. superior vena cava (superior vena cava syndrome: faciaJ/arm swelling. inflammatory disease. neoplastic cells. ectopic adrenocor­ ticotrophic hormone (ACTH) production (discussed in Chapter 5). chemo­ therapy. su­ perior cervical ganglion (Horner's syndrome: ptosis. infection. Pleural Effusion Pleural effusions are classified as either transudates or exudates. night sweats). the pleura. pleural fluid LDH/serum LDH > . nephrotic syn­ drome. The first cri­ terion demonstrates the inflammatory nature of ex­ udates. Exudates can be caused by any of the causes of pleuritis (e. Pleuritis can be caused by pulmonary infec­ tion. lymph node involvement. which has two layers: one lines the lungs. Pathologically. pneumonia. hematogenous spread of infection to the pleura. treatment of the underlying cause is necessary. pus in the pleural space. Pleuritis (also called pleurisy) is inflammation of the pleura. malignant cells. it can also be caused by other pulmonary pathology such as pulmonary embolus. Although aspirin can relieve the pain of pleuritis. A pleural effusion can cause dyspnea. Other squamous cell carcinomas of the head and neck can also release PI'HrP. exudates tend to have a higher content of protein. Lung cancer can cause pulmonary symptoms (cough.jugu­ lar venous distension).6. squamous cell carcinoma. as­ bestos) can also increase risk of developing lung cancer. Inflammation of the pleura usually leads to a pleu­ ral effusion. the other lines the chest wall.. A transudate can be caused by congestive heart failure. Treatment of lung cancer involves surgery. PI'HrP is discussed in Chapter 5. lung cancer is divided into small cell lung cancer and non-small cell lung cancer (large cell carci­ noma. though only rarely heard on auscultation. THE PULMONARY SYSTEM LUNG CANCER Pleuritic pain is a sharp. Transudates (hydrothorax) are accumu­ lations of fluid arising from fluid excess alone with no change in vascular permeability. Although it is characteristic of pleural in­ flammation. cirrhosis.5. inflammatory cells. recurrent laryngeal nerve (hoarseness). and/or a pleural friction rub. and depends upon the stage of the disease as determined by tumor size. or hypoalbuminemia. 45 . local extent.. since the increased vascular permeability leads to a higher concentration of protein in the pleu­ ral fluid than would be caused by a transudate. Thus. and other clues to an underlying etiology. as­ bestos. fatigue. penetrating chest trauma. DISEASES OF THE PLEURA AND PLEURAL SPACE Empyema. fluid in the pleural space. The lungs are covered by a thin membrane. and is thus more highly elevated in exudates. stabbing chest pain that is made worse by breathing in or coughing. and radiation. It is caused by the inflamed portions of the pleura rubbing against each other. and it is also associated with certain paraneoplastic syndromes. Small cell lung cancer is its own category because it is generally more aggressive. cells. and distant metastasis. headache orthopnea. or lung cancer. can be a compli­ cation of pneumonia. and Lambert-Eaton Syndrome. or inflammatory disease. weight loss. LDH is an indicator of inflammation.CHAPTER 2. constitutional symptoms (fever. The accumu­ lation of fluid between the lung and the chest wall leads to dullness on percussion and decreased/absent breath sounds. Pathologically. neo­ plasia.g. A pleural friction rub. and/or solid materi­ als than transudates. symptoms related to compression of nearby structures such as the esophagus (dysphagia). A paraneoplastic syndrome occurs when a tumor causes signs/symptoms unrelated to direct effects of the tumor itself or metastases. anhidrosis). esophageal rupture.

Iatrogenic pneumothorax refers to introduction of air into the pleural space during mechanical ventilation. A tension pneumothorax can collapse the lung on the affected side and cause com­ pression of mediastinal structures." If there is edema fluid or consolidation (e.CHAPTER 2.g. inflammatory bowel disease and genetic primary club­ bing disorders (e. Smaller pneu­ mothoraces may resolve spontaneously. for example from a pen­ etrating chest wound. Traumatic pneumothorax can occur from a pen­ etrating chest wound or rib fracture puncturing the lung. and Pneumothorax tap a lung filled with air (as it should be). THE PULMONARY SYSTEM Chylothorax. whispering and speaking should be faintly audible and faintly vibratory to the touch. Blood in the pleural space (hemothorax) can oc­ cur from trauma or ruptured aortic aneurysm. and say­ ing "e" should sound like "e. and whisper pectoriloquy take advantage of this phenomenon. and can also include absent breath sounds on the affected side. pneumothorax appears as a line or pocket of radiolucency (darkness) between the lung and the chest wall. If you tap a lung filled with fluid or pus. Tactile fremitus is when one feels the vibrations on a patient's back as the patient speaks. Pneumothorax can cause chest pain and/or dysp­ nea. 1f you 46 . Spontaneous pneumothorax occurs from rupture of an alveolus. that area of the lung will be more solid than air-filled lung. pus in pneumonia). it will be dull to percussion. Egophony. This can occur secondary to any underlying pulmonary dis­ ease or idiopathically. respectively. Lymph in the pleural space (chylothorax) can be caused by trauma to or obstruction of the thoracic duct. What do these have in common? All of them test how well the lungs and thorax conduct sound. you hear a nice hollow. Whisper pectoriloquy is when one asks the patient to whisper a phrase and lis­ tens to the patient's back through a stethoscope. It is not known exactly why this occurs. whereas larger ones may require removal of the air by syringe aspira­ tion or chest tube placement. or lung biopsy. Pneumothorax is air in the pleural space. one asks the patient to say "e" (as in eat) and listens through the stethoscope to hear whether it sounds like "a" (as in say or bay). hypotension. Fremitus. PULMONARY PHYSICAL EXAM Percussion Tap a drum and you get a nice hollow. Other causes can include cyanotic heart disease. ha ve increased audibility of whisper pectoriloquy. ha ve in­ creased vibration felt on tactile fremitus.g. which can be fatal. Quick removal of air with a large bore needle is usually curative. and jugular venous distension.. pachydermoperiostosis. iatrogenic. and ha ve con version of "e " to "a " (egophony). Since a normal lung is filled with air. If the lung is filled with something A tension pneumothorax occurs when air enters the pleural space but cannot exit. Hemothorax. On chest X-ray. and since air does not conduct sound so well. What would make the lung sound hyper-resonant (more resonant than usual) to percussion? Hyper-resonance to per­ cussion must mean that there is more air than usual. or from procedures such as thoracentesis. familial clubbing). you hear a dull thud. Clubbing can be caused by many pulmonary dis­ eases. central line placement. or traumatic. Idiopathic spontaneous pneu­ mothorax occurs more commonly in tall young people. egophony. Physical exam may reveal decreased breath sounds and increased res­ onance to percussion. other than air. This can occur in asthma or COPD from hyper-expan­ sion/air trapping. By analogy.. resonant sound. and can be spontaneous. resonant s? und. malignancy. or it can be asymptomatic. Clubbing Clubbing is the swelling of the fingertips. Symptoms and signs are similar to those discussed above for pneumothorax. Hyper-resonance can also occur with a pneumothorax. and so it will conduct sound better. Fremi­ tus. since the thorax is filled with air surrounding the lung. if small. where the lung may be punc­ tured. To assess egophony. Tap a brick and you get a dull thud. leading to reduction in the angle between the nail and the nail bed. and Pectoriloquy Solids and liquids conduct sound better than air.

causing portal hyperten­ sion.g. the hydroxy in the 25 position comes from the liver and the hydroxy in the 1 position from the kid­ neys) • Production of erythropoietin COLLECTING SYSTEM (POSTRENAL) (ureter. blood pools in the gut's venous system. CLASSIFICATION OF ACUTE RENAL FAILURE ACUTE RENAL FAILURE Fig. and/or decreased erythropoietin (which can lead to anemia). . Cirrhosis is scar­ ring of the liver that can impede blood flow through the hepatic portal system. and ex­ crete wastes as urine. timely fashion. If the cause of renal failure i s a problem within the kidneys . Urine travels through the col­ lecting system into the ureters then to the bladder. .g. How would the kidneys (or an individual kidney) Another cause of prerenal failure is effective volume depletion . hem­ orrhage.25-dihydroxy-vitamin D3. Prerenal Failure So prerenal failure can occur from an actual decrease in the amount of blood reaching the kidneys (hypo­ volemia) or effective volume depletion (e. the heart does not pump adequately.to remove wastes . The kid­ neys get blood from the renal arteries. Two examples of effective volume depletion are congestive heart failure and cirrhosis. Classification of acute renal failure. there can be an increase of wastes in the circulation. in principle. urethra) If the kidneys fail. disequilibrium of fluids and elec­ trolytes. This decreased renal perfusion can result in prerenal failure (hepato-renal If the cause of renal failure is a decrease in blood supply to the kidneys (renal perfusion). e. Atherosclerotic disease of the renal arteries can also decrease flow to one or both kidneys.g.to maintain acid I base balance • Regulation of blood volume and blood pressure • Activation of vitamin D (to 1. and thus cannot adequately filter the blood. this is intrinsic renal failure . obstruction by stones or tumor. this is called prerenal failure . the kidneys do not get an adequate blood supply. Due to this blockage in the venous return. decreased activation of vitamin D (which can result in decreased calcium absorption and subse­ quent hypocalcemia). healthy. An important point about prerenal failure is that the kidneys themselves are.to maintain appropriate concentrations of electrolytes . Any circumstance that can cause decreased blood volume (hypovolemia) can lead to deceased renal flow (e. The only problem is that the kidneys do not receive the usual amount of blood to filter. syndrome) . This is when the kidneys are not adequately perfused despite the fact that the blood volume is not 47 . congestive heart failure or cirrhosis). reabsorb some substances back into the blood. the effective blood volume that reaches the kidneys decreases. they will work again. THE RENAL SYSTEM NEPHRON AND INTERSTITIUM (INTRINSIC RENAL) OVERVIEW OF KIDNEY FUNCTION Roles of the kidneys: • Filtration of the blood . THE RENAL SYSTEM CHAPTER 3. . In conges­ tive heart failure. where it is stored until it passes through the urethra to the outside world. bladder. dehydration). Postrenal failure i s due t o a problem i n the collect­ ing system (ureters/bladder/urethra). 3-1. Again. so they cannot do an adequate job filter­ ing. Figure 3-1 actually depleted (in fact it is increased in some in­ stances). filter the blood. leading to decreased renal perfusion . if the blood supply is restored in a In prerenal failure. be­ cause a large volume of the body's blood supply stag­ nates in the mesenteric veins.CHAPTER 3.

dehydration). the kidney does not re­ spond by reabsorbing. which will become important in a moment. Thus. creatinine con­ centration is easily measurable in the serum. it can serve as a measure of how well the renal filtering mechanism is working. Thus. In other words. parts include proximal tubule. distal convo­ luted tubule). Since this increases the concentration gradient of urea from nephron to blood. an elevated serum creati­ nine signifies renal failure of some sort. What would this do to the urine? If sodium and water are being reabsorbed from the tubular fluid. in effec­ tive volume depletion. . This point will become important when we discuss the lab findings that are used to dis­ tinguish prerenal failure from intrinsic renal failure.e. in a kidney failing due to intemal pathology. the creatinine rises. so it will not cause a disproportionate rise in BUN. where de­ creased renal perfusion causes the kidney(s) to increase reabsorption. post-. In effective volume depletion. but since there is no hypovolemia.g. namely BUN/creatinine ratio and fractional excretion of sodium (FENa). In intrinsic renal failure. and so the kidneys reabsorb sodium and water in an attempt to increase intravascular volume to correct the perceived hypovolemia. increased sodium and water reabsorption by the kidneys can be detrimental (see Fig. Sodium reabsorption is also part of the spree. Urine Sodium. intrinsic renal failure: BUN I Cr < 20:1. both discussed in more detail be­ low. Because prerenal failure increases wa­ ter reabsorption in the nephron. In contrast to prerenal failure. some of the glomerulopathies). one or both the kidneys "knows" that it is not getting enough fluid. and that renal function is impaired. In prerenal failure one or both kidneys are not adequately perfused. Another way to remember this is that if the kidney is failing due to intemal pathology. . the kidneys go on a reabsorbing spree in an attempt to restore intravascular volume. Since creatinine is freely filtered and only small amounts are secreted. some of the glomerulopathies. Laboratory Distinction Between Prerenal and Intrinsic Renal Failure One of the functions of the kidneys is to filter. Additionally. In prerenal fail­ ure. In prerenal renal failure. neys fail due to either volume depletion or effective vol­ ume depletion. but have a low con­ centration of sodium (typically less than 20 meq/L). Some causes of intrinsic renal failure have a more chronic time course (e. Thus.CHAPTER 3. Also. Thus. laboratory tests may be helpful. or intrinsic renal failure). Each nephron contains a glomerulus (tuft of capillaries and fil­ tration surface for filtering the blood). so the kidney is not trying to hold onto anything. loop of Henle. the ability to filter creatinine diminishes and the plasma creatinine rises. there is no hypovolemia. increased sodium and water reab­ sorption is crucial for attempting to maintain blood pressure. 1-6). the urine will be very concentrated. In both hypovolemia (prerenal) and drug/toxin-induced renal failure (intrinsic renal). This leads to a dilute urine but an increased excretion of sodium in intrinsic renal failure (typically greater than 40 meq/L). its ability to reabsorb is dimin­ ished. in any type of renal failure. and a collecting duct (further reabsorption/ secretion and delivery of urine to the ureters for delivery to the bladder). prerenal failure: BUN I The causes of intrinsic renal failure include diseases of the glomeruli (glomerulopathies) and tubules (tubu­ lointerstitial diseases). In actual hypovolemia the kidneys observe that the volume status is low. This is important to keep in mind when using laboratory findings to diagnose the etiology of acute renal failure. a tubule (for reab­ sorption and secretion of various ions and molecules. BUN is one of those other things that is also reabsorbed as part ofthis process1 and the ratio of BUN to creatinine will be> 20:1. this increases the concentra­ tion of urea left behind in the nephron. and so it wastes both water and sodium. One laboratory finding that distinguishes acute prerenal from acute intrinsic re­ nal failure is the blood urea nitrogen (BUN) to creatinine ratio in the blood. In contrast. one or both kidneys have been damaged and do not work properly. With real hypovolemia (e. while some are more acute phenomena (e. it cannot change what it reabsorbs anyway because it is not work­ ing properly. 48 . This is in contrast to prerenal failure. not in the urine). and serum BUN rises. this indicates that the glomerular filtration rate of this compound is inade­ quate. hemor­ rhage. since the kid­ Intrinsic Renal Failure The functional unit of the kidneys is the nephron. The end result is the same: the kidneys try to increase intravascular volume by reabsorbing sodium and water. when clin­ ical assessment cannot distinguish between acute pre­ renal and acute intrinsic renal failure. the onset of renal failure can be acute. 1 This is not exactly what happens but it is a useful way of remem­ bering the lab findings. If the serum creatinine level rises. This spree is reflected in a rise in BUN out of proportion to the rise in creatinine. THE RENAL SYSTEM react to low blood volume? The kidney(s) will try to re­ Serum BUN/Creatinine Ratio. . The one million or so nephrons of each kid­ ney are surrounded by an interstitium containing blood vessels and connective tissue. the BUN I creatinine ratio will be < 20:1 . and the rate at which the kidneys do so is known as the glomerular filtration rate (GFR) . One can imagine that absorb sodium and water in an attempt to replenish in­ travascular volume. Cr > 20:1. This results in a disproportionate rise in BUN in prerenal failure. the kidneys "think" that volume status is low. in intrinsic renal failure. creatinine rises. As one or both kidneys fail (whether it is pre-. urea dif­ fuses down this concentration gradient. (i. ischemia or drug/toxin-induced dam­ age to one or both kidneys causing acute tubular necro­ sis).g.g. .

there is no volume depletion and the damaged kidney is less able to reabsorb sodium.:40 meg/L Fractional Excretion of Sodium (FENa) <1% >2% LAB TESTS TO DISTINGUISH PRERENAL FROM INTRINSIC RENAL FAILURE Figure 3-2 49 . Fig. 20:1 10-15:1 + Urine[Na ] <20 meq/L :. If intravascular volume decreases (or in effective volume depletion). FENa = amount of sodium excreted amount of sodium filtered [ = (UNa xPCr) I (PNa x UCr) x x 100 100)] (U =urine. which results in a higher FENa (typically higher than 2%) in intrinsic renal failure. This makes the urine sodium concentration less reliable in determin­ ing whether the failure is prerenal or intrinsic renal because both urine sodium and water concentrations are changing. in any type of renal fail­ ure the creatinine will be elevated. This leads to relatively more sodium being excreted than in prerenal failure. the kidneys begin to actively pull water out of the tubular fluid. P =plasma.e. prerenal failure. when aldosterone is the main hormone counteracting perceived volume depletion in prerenal failure. this should make the urine quite concentrated. the kidney tries to increase volume by PRERENAL INTRINSIC RENAL Serum BUN: Creatinine ratio . Lab tests to distinguish prerenal from intrin­ sic renal failure. As the ADH system kicks in. of the sodium filtered. In summary. Thus. "If the kidneys in prerenal failure hold onto sodium and water. You might ask. and so FENa in prerenal failure is quite low (typically less than 1%). and thus actively reabsorb sodium to try to increase intravascular volume. Wouldn't this cause the urine concentra­ tion of sodium to actually end up being high (due to the extremely concentrated urine) in prerenal failure? And then in intrinsic renal failure. 3-2. THE RENAL SYSTEM Fractional Excretion of Sodium (FENa). A more accurate clinical measurement is the FENa (fractional excretion of sodium). shouldn't urine sodium concentration actually be low because the urine is so dilute?" Initially. the kidneys perceive a low volume state (real or effective). In intrinsic renal failure. i. This meas­ ures the percent of filtered sodium that gets excreted. and ADH increases water reabsorption. sodium is mainly what is reabsorbed. due to the very dilute na­ ture of the urine.. resulting in the pattern of urine sodium concentrations discussed in the previ­ ous paragraph. Cr =Creatinine) In prerenal failure.CHAPTER 3. relatively little sodium is ex­ creted.. Na =sodium. Dehydration will also cause ADH (an­ tidiuretic hormone) to be secreted from the posterior pituitary.

Ef­ facement in minimal change disease refers to the fact that the podocytes lose their foot processes. . Mnemonic to remem­ ber this: make one word. MRI or intravenous pyelogram can demonstrate obstruction. . Water flows out of a hypotonic solution. This blockage can cause renal failure. endogenous toxins (e. Nephrotic Syndrome Signs of nephrotic syndrome include edema . Nephritic has -iti(s) in it. leading to a concentrated urine (because the body is conserving water) but a low urine sodium concentration . autoimmune diseases or trans­ plant reaction). protein causes the intravascular fluid to be hypotonic to its surroundings (i.g. antibiotics. bladder. and urethra. the portion of the tube proximal to the obstruction will dilate. . .g. In the glomerulopathies that cause nephrotic syndrome." and keep repeating it to yourself (membranousssSpikes membranousssSpikes membranousssSpikes). . namely effacement of the foot processes of podocytes.g. ovary). Nephritic Syndrome The signs of nephritic syndrome include hypertension. So water will flow out of the hy­ potonic serum creating edema. .e. causing hyperlipidemia. Inflammation in the glomerulus leads to bleeding into the urine (hematuria ) as well as renal vascular changes that produce hypertension. meaning inflammation. Imagine the normal kidneys as a very selective sieve. vasculitis. light chains in multiple myeloma). acute tubular necrosis). and/or infection (pyelonephritis). This causes the filtration spaces between the podocytes to disappear. ultra­ sound can demonstrate dilation of the ureter proximal to the site of obstruction (hydroureter) with dilatation of the renal pelvis (hydronephrosis). bladder. Mnemonics for the pathological findings in some of the more common causes of nephrotic syndrome: • Minimal change disease has no change on light mi­ • Focal segmental glomerular sclerosis (FSGS) has focal segments of glomerular pathology on light mi­ croscopy. 3 Do not confuse membranous nephropathy with membranopro­ liferative glomerulonephritis (discussed in the next section).g. These spaces form part of the filtration system of the glomerulus. This protein wasting decreases serum protein (hypoproteinemia. protein­ uria (which causes foamy urine). This inflammation is either due to systemic inflammatory/immune complex dis­ ease (e. imagine that the sieve's holes are damaged so that they are not as selective as before. bowel. and in so doing it also increases production of lipids. its concentration of water is greater than that of its surroundings). there are pathological changes seen with electron microscopy. imagine that the kidney holds onto BUN disproportion­ ately more than creatinine's accumulation. e. hematuria.CHAPTER 3. 2 In minimal change disease. • Post-infectious glomerulonephritis (usually post strep: subepithelial humps) • Ig A nephropathy (A for mesangial deposits) • Membranoproliferative glomerulonephritis : suben­ dothelial deposits and mesangial deposits with a "tram track" appearance. Compare with membra- The glomerulopathies can be divided into those causing nephrotic syndrome and those causing nephritic syndrome. or a tumor in the genitourinary sys­ tem (e. . Podocytes are glomerular cells that nor­ mally have foot processes with spaces between them. One could imagine that BUN is also spilling through the broken sieve as a way of re­ membering the lower BUN/Cr ratio in intrinsic renal failure. pathologically forming a continuous layer.g. prostate) or adjacent systems (e. there is damage to the filtering mechanism of the glomerulus. and hyperlipidemia . Water and sodium pour through and urine sodium concentration is high but the urine is dilute . 2 croscopy. CT.g. and proteinuria . The decreased serum 50 . In acute renal failure it is prudent to rule out obstruction. THE RENAL SYSTEM holding onto salt and water. . hypoproteinemia. Causes of Intrinsic Renal Pathology: Diseases of Tubules and Glomeruli Mnemonics for the pathological findings of some of the more common causes of nephritic syndrome: Tubulointerstitial disease can be caused by drugs (e. im­ mune processes (e. usually man­ ifesting as hypoalbuminemia). keeping certain substances and excreting oth­ ers. As part of its reabsorption spree. This is because part of the body's attempt to restore intravascular volume is to hold onto sodium (which water follows). leading to protein wast­ ing in the urine (proteinuria). and thus the urine sodium is low. Ultrasound. in ureteral obstruction. "membranousssSpikes. The liver tries to in­ crease the production of serum proteins (since they are being lost in the urine). chemotherapy agents). • The hallmark pathologic finding in diabetic neph­ ropathy is Kimmelsteil Wilson nodules. Blockage here can occur from passage of renal stones into the ureters. • Membranous nephropathy has thickening of capillary walls and subepithelial spikes. which has different pathological findings. Any time there is obstruc­ tion of a tube. lupus) or infection. ischemia. Remember membra­ noussssspikes.g. If the kidneys fail due to an internal problem (in­ trinsic renal failure. 3 Postrenal Failure Postrenal refers to the ureters.

renal osteodystrophy can result in skeletal deformities or growth retardation. calcium cannot be absorbed from the diet. v The kidneys produce erythropoietin. and a predisposition to fractures and tendon ruptures. the kidneys activate vitamin D (by adding the 1-0H to make 1. In growing children with renal failure. hypertension. 3-3. Na+ Various systemic diseases can also affect the kid­ neys. . and the amount of calcium in the serum de­ creases. Serum Ca2+ . Although this bone resorption can be asymptomatic. Ca2+ EPO Vit D PO 42- Fig. and calcium concentration decreases. This is just a quick way to remember the salient histopathological features of each disease.CHAPTER 3.g. With­ out vitamin D.. vitamin D activation decreases. hydrogen ion.. Parathyroid hormone (PTH) in chronic renal failure. the parathyroid glands secrete parathyroid hormone in an attempt to increase blood calcium level. magnesium. SLE. Membranoprolif­ erative: subendothelial deposits. Sodium and . Thus. hypertension. urea excretion to remove nitrogenous wastes from protein catabolism). These toxins can lead to anything from fatigue. 3-4. Thus. since the parathyroids are hyperactive secondary to renal failure (see hyperparathyroidism in Chapter 5). bone pain. Figure 3-3 Why doesn't calcium accumulate like all of the other ions? Normally. calcium concentration decreases in chronic renal failure.25-dihydroxy-vitamin D). In renal failure. Wegener's granulomatosis. sodium.. it can also cause weakness. � PTH '- PARATHYROID HORMONE IN CHRONIC RENAL FAILURE Figure 3-4 51 !! . . So add parathyroid hormone to the list of things that go up in renal failure. Vitamin D . leading to renal osteodystrophy. Urea is one of the uremic toxins frequently examined by laboratory tests. potassium. and phosphate concentrations in the blood all increase. but it is only one of the many toxins that build up.. and multiple myeloma. diabetes. which can cause hypertension. If the kidneys fail. including systemic lupus erythematosus (SLE) amyloid. scleroderma. A more complete discussion of the pathology of these entities can be found in any pathology text. Fig. they cannot adequately excrete wastes (e. . . the glomerulopathies. ammonia. J K+ ClH+ Mg2+ CHRONIC RENAL FAILURE � NH 4+ Causes of chronic renal failure include diseases that affect either the kidneys or their blood supply.i PTH CHANGES IN SERUM CHEMICALS IN CHRONIC RENAL FAILURE water retention elevate intravascular volume. bone is constantly being broken down. Because of decreased calcium concentration in chronic renal failure. In advanced chronic renal failure..g. Changes in serum chemicals in chronic renal failure. Increased parathyroid hormone in renal failure is called secondary hyperparathyroidism. e. which can result in decreased red blood cell (RBC) count (ane­ mia). erythropoietin production decreases. he­ molytic uremic syndrome (HUS). THE RENAL SYSTEM nous: Membranousssssspikes vs. One way that parathyroid hormone increases blood calcium is to release it from bone. i. In renal fail­ ure.

ur­ gency (sudden necessity to urinate). which can occur congenitally or due to neurologic dysfunction in the bladder (e.e. pregnancy. If there are actual red blood cells or white blood cells in the urine with normal morphology. Red cells from the kidneys can occur in glomerulonephritis. . the bladder (cystitis). leading to in­ flammation of the urethra (urethritis). or renal disease if their morphol­ ogy is abnormal. presumably because of a shorter urethra and/or urethral irritation during sexual intercourse. toms/signs include pain during urination (dysuria ) and/or purulent urethral discharge. cystitis and urethritis. White cells from the kidneys can occur in acute interstitial nephritis. Symp- An important distinction must be made between cells and casts in urinalysis. or any cause of obstruction (stones. malaise. So cells in the urine may signify lower urinary tract disease is their morphology is relatively normal. Had the cells entered in the kidneys. which can demonstrate the presence of white cells (indicating inflammation) and infectious agents. enlarged prostate). red cells from the lower urinary tract can occur with urinary tract infection. Enterobacter) and less commonly by Staphylococcus (aureus and saprophyticus). tumor. hemorrhagic cystitis. e. Figure 3-5 52 . More specifically. Klebsiella. Pyelonephritis Pyelonephritis is caused by the same organisms that cause cystitis.CHAPTER 3. 3-5.g. Urinalysis Diagnosis of all of these disorders is confirmed by uri­ nalysis/urine culture.g.g. E. Ascent past the bladder to the kidneys is more likely if there is reflux of urine from the bladder back into the ureters(s) (vesicoureteral reflux). Symp­ toms can include increased urinary frequency. . dysuria. (Pyelonephritis) KIDNEY (Cystitis) -+--BLADDER Casts are conglomerates of protein and cells and al­ ways signify glomerular or tubular disease. and suprapubic pain. in the ureters. and/or the kidneys (pyelonephritis). Women are more prone to UTI than men. . . congenital anomalies of the genitourinary system. red cell casts occur in glomerular disease (remember the glomerulus is a tuft of blood vessels). URINARY TRACT INFECTION (UTI) AND URINALYSIS Cystitis Fig. Though infectious agents can spread hematogenously to the urinary tract. nephro­ lithiasis (stones). most infections enter at the urethra and ascend. Symptoms include flank pain. while white and epithelial casts occur in acute tubular necrosis and pyelonephritis. either of which can indicate UTI. bladder. Other predisposing factors to UTI include catheterization. (Urethritis) 1+---URETHRA URINARY TRACT INFECTION Leukocyte esterase (LE) and nitrate tests on the urine can be performed rapidly to screen for the white cells (LE) and bacteria (nitrate) in the urine. Cystitis is typically caused by gram negative organ­ isms (e. Proteus. they would have been squashed and damaged in the glomeruli and/or tubules. fever. secondary to spinal cord injury or di­ abetic neuropathy). UTI can occur anywhere in the genitourinary tract. and will appear deformed on micro­ scopic urinalysis. Urethritis Urethritis is commonly caused by sexual transmission of N gonorrhoeae or Chlamydia trachomatis. white cells from the lower uri­ nary tract can occur from infection. coli. or urethra). and any of the urinary symptoms listed un­ der cystitis. THE RENAL SYSTEM nausea. they must have entered it after the kidneys (i. or bladder can­ cer. Urinary tract infection (UTI). and mental status change to severe neurolog­ ical dysfunction and coma. It is more common in women.

Wilms' tumor is a pediatric kidney tumor that often presents as an abdominal mass. Most substances cannot pass freely across cell membranes. but can also cause symptoms of urgency and frequency.4 but water can . Bladder cancer often presents as hematuria. amount of sodium per unit fluid volume). Other symptoms/signs can include abdominal pain. Renal cell carcinoma can secrete erythropoietin (leading to poly­ cythemia). in this system. etc. . Mnemonic: Water flows out of a hypotonic solution. A 8 WATER HYPOTONIC HYPERTONIC EQUILIBRIUM HYPERTONICITY. The lipid bi­ layer of the cellular membrane allows free diffusion of water. hematuria. parathyroid hormone-related protein (PTHrP. However.g. hypertension. gases. Renal cell carcinoma also causes hematuria but may also present with flank pain and/or a palpable mass. . You might first guess that because there is more solute in B. solution B is hypertonic to solution A A 4 8 Ions and solutes can pass across membranes via transporters and channels. the membrane that separates the solutions only allows passage of water. THE RENAL SYSTEM TUMORS OF THE URINARY TRACT since is it has more sodium per solvent than solu­ tion A. Calcium metabolism and its disorders are discussed in Chapter 5. and nonpolar substances (e. Consider two solutions separated by a semipermeable membrane such that only water can diffuse between them. steroid hormones). acid/base). hypotonicity. Smoking and occupational exposure to toxic chemicals can predispose to malignancy of the bladder and kid­ neys. so water will flow from A to B. and/or renin (causing hypertension). . and water will thus flow down its concentration gradient to the B side. Osmotic pres­ sure is the name of the force that p ulls water from A to B.CHAPTER 3.g. glucose. FLUIDS AND ELECTROLYTES This section discusses the physiology and pathophys­ iology of water.e. but this is regulated and not free. The body's goal is to maintain a constant concentration of sodium (i. The simple system in Figure 3-6 is analogous to the separation of the extracellular space (i. this solute will flow to A to achieve equilibrium.(i. Renal cell carcinoma can also cause a variety of paraneoplas­ tic syndromes. must pass by way of protein channels. It does this in part by altering the amount of water present. . amino acids. resulting in hypercalcemia). transporters.e. 3-6. AND CONCENTRATION GRADIENTS Figure 3-6 53 . potassium.. HYPOTONICITY. sodium. and concentra­ tion gradients. etc. Ions. then A has more water than B. inter­ stitial and intravascular spaces) from the intracellu­ lar space by cellular membranes. or by shifts of water from the cells to the Basic Concepts Fig. Which way will water flow then? The goal is equilibrium.e. and/or fever. either by excreting or retaining water via the kidneys. In Figure 3-6 on the left. Hypertonicity. A paraneoplastic syndrome occurs when a tumor causes signs/symptoms unrelated to di­ rect effects of the tumor itself or metastases. Some hereditary syndromes (e. giving both solutions equal concentrations. Substances flow from areas of higher concentration to areas of lower concentration in order to achieve equilibrium (diffusion ). Sodium is the main extracellular cation. von Hippel­ Landau) can predispose to renal cell carcinoma. Solution A is hypotonic to B since it has less sodium per solvent than solution B. and H+fHCOa. so we can make predictions about the effects of various disturbances in electrolytes on intravascular volume. Another way to think about it is that if B has more solute than A.

In fact. only water can do so. it cannot pass freely through the cell membrane from the area of higher concentration to that of (No fluid shift) Q v Figure 3-7 SERUM TONICITY AND IV SOLUTIONS 54 . intravascular volume will increase in order to dilute the increased sodium load and prevent hypernatremia. it is the concentration of sodium in which we are interested. interstitial and intravascular spaces) and vice versa. This concentration depends upon the volume of water in which it is dissolved (i. lower concentration. Thus. Hypotonic saline. not the absolute amount. but more water than salt. If someone gains lots of water and salt but more water than salt. which makes it hypotonic com­ pared to the intracellular concentrations. sodium concentration increases (hypernatremia) de­ spite a decreased total amount of sodium. Isotonic saline. Concentration will be referred to with brackets : as [Na+] or [sodium].g. not the absolute amount of sodium. 3. no fluid shifts should occur. Since isotonic saline is at the same concentration as what is in the cells. Since sodium is a charged ion. 3-7. we are talking about the sodium concentration .e. one can determine what type of IV saline to use when replacing the in­ travascular volume of a hypovolemic patient (e. it will flow from cells to the intravascular space to dilute the in­ creased sodium concentration. so this will cause water to flow from the intravascular space into the cells. . causing some swelling of the cells (and prevent­ ing hyponatremia in the blood). In pathological states such as hypernatremia. 2.e. The intravascular volume will simply increase. concentration of sodium decreases (hyponatremia) de­ spite an increased amount of sodium. Water flows out of a hypotonic solution. 1. Fig. . Hypertonic saline. if someone loses lots of water and salt. THE RENAL SYSTEM extracellular space (i. . Thus. tration in the blood. This increases sodium concen­ Based on the above physiology. This leads to a dilution of the in­ travascular fluid. Serum tonicity and intravenous (IV) solutions. plasma volume). What will this increase in sodium concentration in the blood cause? Since water can diffuse.CHAPTER 3.

CHAPTER 3. If a patient needs re­ suscitation or s/he cannot drink and needs mainte­ nance fluids. if the cause of hypovolemic hyperna­ Tenting is when the patient's skin relaxes slowly when tugged upon. and are not truly euvolemic by a purist definition. which is why hyperaldos­ teronism can cause hypervolemia. diarrhea. as opposed to falling right back into place. Fig. To become hypovolemic. resulting in hypernatremia. 55 . possible causes of increased serum sodium concentration (hypernatremia) include : Electrolyte Ifluid imbalances must be corrected slowly. it should not be so hypertonic so as to induce hypernatremia). 3-8. there must be water loss. tremia is renal . one generally uses isotonic saline. thus decreasing sodium concentration in the urine . Such losses of water and/or sodium can be classified as renal losses or extrarenal losses . ) . aberration in volume status is not as extreme as in the other scenarios. shock). urine electrolytes can.and hy­ ponatremia do involve some fluid loss or gain. etc. stool . Extrarenal losses of water and/or sodium can occur through sweat. Sodium reabsorption causes wa­ ter to passively follow it. • Sodium is the main extracellular cation (higher concentration in the serum than in cells) and potas­ sium is the main intracellular cation (higher con­ centration in cells than in the serum). If the amount of sodium lost is greater than the amount of water lost. or remain relatively unchanged (euvolemia).g. this will result in hyponatremia. • ADH (antidiuretic hormone) causes water reabsorption. Sodium concentration can increase (hypernatremia) or decrease (hyponatremia) and in either case. If the water/sodium losses occur ex­ trarenally (i. So the distinctions hyper-. In hyperaldosteronism. Renal losses refer to renal diseases or diuretics that waste water and/or sodium. edema in hypervolemia. but sodium increases more than water/volume • Decrease in serum water/volume (which increases sodium concentration ) • Decreases in serum water/volume and sodium. The "-volemias" refer to what is perceived on clinical exam (i. a hypertonic solution can be used.e. fluid volume can be increased (hypervolemia). after ma­ j or burns. This can cause central pon­ tine myelinolysis (also known as osmotic demyelination syndrome) due to the dramatic fluid shifts that take place between the cells in the brain and the surround­ ing fluid. the kidneys will attempt to hold on to (normal volume status) states in both hyper. increased al­ dosterone increases sodium reabsorption. surgery. there will be a higher concentration of . Euvolemic If the clinical history and physical exam cannot dis­ tinguish between renal and extrarenal losses. Primary hyperaldosteronism can also cause hypervolemic hypernatremia. the brain does not have time to re-equilibrate. In extreme cases of hypov­ olemia (e. hypo-. If electrolyte/fluid imbalances are corrected too rapidly with IV fluids. Most commonly this is iatrogenic from the administration of sodium bicarbonate solutions or dialysis solutions. in states of electrolyte imbalance. Hypervolemic Hypernatremia. THE RENAL SYSTEM from blood loss. and to end up hypernatremic there must be more water loss than sodium loss if one is losing both. and eu. Hypovolemic Hypernatremia. decreased (hypovolemia). • Increase in serum sodium Neurons depend upon appropriate electrolyte concen­ trations for electrophysiological function. sweating. The pa­ tients simply appear euvolemic on exam since the 5 sodium. e. This is also called decreased skin turgor. the brain will respond by trans­ porting substances into the interstitium to compensate for this imbalance. Thus. Hypernatremia and hyponatremia. Since it is isotonic to cellular fluid. Thus. and thus does not cause symp­ toms/signs of hypervolemia or hypovolemia. or fluid shifts from the intravas­ cular space to the extravascular space. . Three additional key points to keep in mind: • AldosteRoNe causes Reabsorption of Na+ (sodium) and secretion ofpotassium . . an isotonic IV solution will increase intravascular volume without causing a shift of water into cells. . If the amount of water lost is greater than the amount of sodium lost. the result will be hypernatremia. dry mucous mem­ branes and/or tenting5 in hypovolemia). . etc. ) . There must be an increase in volume and sodium to cause both hyper­ volemia and hypernatremia. • Increases in serum sodium and water/volume. diarrhea.e. A hypertonic solution will stay in the intravascular space and pull more fluid into the intravascular space to try to dilute its hypertonicity (of course.g. sodium in the urine than if the losses are extrarenal.volemia refer to vol­ ume status as assessed on clinical exam. but water/volume decreases more than sodium Hypernatremia Most generally. Hypernatremia and Hyponatremia Sodium (Na+ ) is the main extracellular cation: its con­ centration is much higher in the serum than inside cells. etc . fluid shifts from burns.

etc. Increased ADH increases water 6 There are two broad categories of diabetes insip­ idus. Central diabetes insipidus is usually secondary to some intracranial process (tumor. reabsorption. Another cause of euvolemic hyperna­ tremia is diabetes insipidus . the kidneys' sensitivity to ADH decreases. secreted by the posterior pituitary.6 Diabetes insipidus is a loss of either antidiuretic hormone (ADH) secretion or a loss of ADH's action. head trauma. Euvolemic Hypernatremia. Diabetes mellitus is the disor­ der involving insulin. leaving behind a more concen­ trated (hypernatremic) serum. causes increased water reabsorption from the collecting ducts. One cause of euvolemic hypernatremia is hypodipsia . THE RENAL SYSTEM Add both H 0 and Na+ but add 2 S rn � � ffi more Na+ than H 0 2 Lose both H o and Na+ but lose 2 more H o than Na+ 2 � :X: Add Na+.CHAPTER 3. Although patients with euvolemic hypernatremia appear clinically euvolemic on physical exam. resulting in an increased and di­ lute urine output. minimal change in H o 2 HYPERNATREMIA AND HYPONATREMIA Figure 3-8 Typically these scenarios manifest as either urine [sodium] > 20 meq/L if the sodium losses are renal or urine [sodium]< 20 meq/L if the losses are extra-renal. glucose. and a more concentrated serum. ADH. the clin­ ical picture is usually one of euvolemia. Due to loss of ADH or its action in diabetes insipidus. resulting in a more concentrated urine and a more dilute serum. they are in fact losing some water. Decreased ADH decreases water reabsorption. Nephrogenic diabetes insipidus originates in the kidneys. urine output increases. In nephrogenic diabetes insipidus. In central diabetes insipidus. post-neurosurgery. discussed in Chapter 5. posterior pituitary secretion of ADH decreases. either from a congenital defect in the receptor (X-linked Note: Diabetes insipidus differs from diabetes mellitus (which is also simply called "diabetes"). minimal change in H 0 2 Add both H 0 and Na+ but add 2 more H 0 than Na+ 2 Lose both H 0 and Na+ but lose 2 more Na+ than H o 2 Lose Na+. 56 . usually caused by a hypo­ thalamic lesion. or decreased water intake. Though there is some water loss (in the urine) in diabetes insipidus.. meningitis/encephalitis).

urine concentration in response to IV ADH can help evaluate whether diabetes insipidus is nephrogenic or central . but water/volume increases more than sodium DIABETES INSIPIDUS GIVE ADH I tUrine concentration No change in urine concentration Problem not corrected Problem corrected =Central = Nephrogenic Diabetes Insipidus Figure 3-9 Diabetes Insipidus LABORATORY DIFFERENTIATION OF CENTRAL VS. the posterior pituitary will increase ADH secretion in an attempt to stimulate the non­ responding kidneys. If the kidneys are not responding to ADH (nephrogenic dia­ betes insipidus) . Thus. How would you know if the IV ADH works? The urine will become more concentrated since ADH increases water reabsorption from the collecting system. . from lithium. Laboratory differentiation of central vs. possible causes of decreased serum sodium concentration (hyponatremia) include : Fig. If you give IV ADH (also called ddAVP) to a patient and it works. Diagnosis of diabetes insipidus. 3-9. NEPHROGENIC DIABETES INSIPIDUS 57 . so serum ADH will be high. If • Decrease in serum sodium • Decreases in serum sodium and water/volume. you would know that the kidneys are able to respond to ADH. so serum ADH will be low. hereditary nephrogenic diabetes insipidus) or from di­ rect toxicity (e. that the diabetes insipidus is cen­ tral. 3-10. If the IV ADH does not work. and thus. Fig. Causes of hypernatremia. and thus the kidneys must be the problem (nephrogenic).CHAPTER 3. nephrogenic diabetes insipidus. THE RENAL SYSTEM ADH does not work. If diabetes in­ sipidus is central. which is used in the treatment of bipolar disorder).g. but sodium decreases more than water/volume • Increase in serum water/volume (which decreases sodium concentration) • Increases in serum water/volume and sodium. the kidneys will continue to waste water and the urine will remain dilute . Hyponatremia Most generally. the kidneys must not be capable of responding to ADH . the posterior pituitary secretion of ADH will decrease.

and psychogenic polydipsia can occur in psychiatric pa­ tients who drink excessively. In polydipsia.g. . fluid shifts [e. Small cell lung cancer is a common culprit. These are the basic ways that the body can lose fluid. it is clearly being inappropriately over-secreted. we can examine the urine electrolytes for diagnosis : if the urine sodium concen­ tration is greater than 20 meq/L . 1-6). renal disease) • Extrarenal losses (e.g. In hypovolemic hyponatremia. In diabetes insipidus. the diuresis leads to decreased intravascular volume (and thus increased serum sodium concentration). resulting in subsequent reabsorption in an effort to increase what is perceived as a low intravascular volume. To be hypovolemic and hyponatremic. there must be both water and sodium loss. In contrast. diarrhea. diuretics.g. In heart fail­ ure. diarrhea. and syndrome of inappropriate antidiuretic diuretic hormone secretion (SIADH). sweating. 7 8 decreases 58 Paraneoplastic SIADH occurs when a tumor secretes ADH. result­ ing in the hypervolemic hyponatremia. how would you distinguish between diabetes in­ sipidus and primary polydipsia? In diabetes insipidus. high se rum sodium concentration in diabetes insipidus. burns]) Euvolemic Hyponatremia can be caused by adrenal insufficiency. SIADH can result from intracranial pathology. either because of mental confusion or drug side effects. If ADH secretion occurs to the point of creating hyponatremia.. To be hyponatremic with an increased intravascular volume. or edema. Additionally. though other tu­ mors can secrete ADH as well. Euvolemic hypernatremia • Diabetes insipidus • Hypodipsia Excess water consumption (primary polydipsia ) can be seen in patients with hypothalamic lesions. Thus. 3-12. thus increasing intra­ vascular volume and diluting serum sodium. a para­ neoplastic syndrome. or from drug toxicity. hypothyroidism.CHAPTER 3. thus usually maintaining clinical euvolemia.. Two situations where the body inappropriately increases the intravascular volume are heart failure and cirrhosis. lots of water is being added to the plasma volume. If urine sodium concentration is less than 20 meq/L. or edema. Therefore. urine sodium concentration 7 in these situations. Syndrome of inappropriate antidiuretic hormone secretion (SIADH). The renal and extrarenal causes of volume loss were discussed in hypovolemic hypernatremia. perceived low volume activates ADH se­ cretion further increasing water retention. primary polydypsia. This also decreases the amount of blood seen by the kid­ neys. THE RENAL SYSTEM depending upon the concentration of sodium in the lost fluid. the kidneys are appropri­ ately holding onto sodium in an attempt to rectify the situation. as with hy­ povolemic hypernatremia. Hence the name for the syndrome: SIADH (Syndrome of Inappropriate Antidiuretic Diuretic Hormone). . ADH is either not present or does not work. Figure 3-10 Hypervolemic Hyponatremia. Given that they both cause large urine output.8 pulmonary disease such as pneumonia or tuberculosis.. the increase in plasma volume leads to hyponatremia . the sodium must be getting lost in some other way such as sweat. but relatively more sodium loss than water loss. so lots of water is being lost in the urine. The amount of wa­ ter retention exceeds that of sodium retention. such that the amount of sodium in the serum is diluted. Distinguishing primary polydypsia from dia­ betes insipidus. because the kidneys are attempting to retain sodium along with water. the kidneys sense decreased perfusion and try to in­ crease what it perceives as diminished intravascular volume (decreased effective circulating volume) via the renin-angiotensin-aldosterone system (Fig. these patients will also urinate large amounts (polyuria ). 3-11. In the scenarios of fluid loss secondary to excess sweat­ ing. the kidneys must be losing the sodium . in polydip­ sia.g. serum sodium concentration is a good way to distin­ guish between these two causes of polyuria: low serum sodium concentration in polydipsia. Cirrhosis of the liver can lead to effective volume depletion sec­ ondary to pooling ofblood in the mesenteric veins. cyclophosphamide (used a s a chemotherapy agent and __ Hypovolemic Hyponatremia. due to decreased forward flow by the failing heart. and it is the relative concentration of sodium in that fluid that will determine whether the result is hy­ ponatremia or hypernatremia. Fig.or hyponatremia. If the kidneys are work­ ing normally. So any cause of vol­ ume loss can lead to hyper. Fig. water is ei­ ther being added or retained. ADH secretion normally increases water reabsorption. stool. CAUSES OF HYPERNATREMIA Hypervolemic hypernatremia • Iatrogenic (hypertonic saline) • Hyperaldosteronism Hypovolemic hypernatremia • Renal losses (e. e.

l SIADH (t ADH) ·- Again. which are used to treat depression). the urine will be quite concentrated.. Causes of hyponatremia.CHAPTER 3. proteins. I:! 1 :' �� t H20 reabsorption I Concentrated urine Fig. since ADH causes water to be pulled out of the filtrate in the collecting duct. but this change in volume is usually not substantial enough to produce clinical signs of hypervolemia. Serum osmolality 2 x [Na+] + [glucose)/18 + [urea)/2. 3-13. ADH or + response to ADH) t H20 loss in urine t DISTINGUISHING PRIMARY POLYDIPSIA FROM DIABETES INSIPIDUS Figure 3-1 1 in some autoimmune diseases ) and SSRis (selective serotonin reuptake inhibitors. SIADH generally causes euvolemic hyponatremia. there is some increase in volume. Thus. Hyperosmolar Hyponatremia (Pseudohypona­ tremia). Osmolality refers to the amount of solute dissolved per kilogram solvent. An increase in glucose. 3-14. Fig. remember that the designation of euvolemic refers to what is seen on clinical exam most commonly. pulling water into the intravascular space to re-equilibrate things. not necessarily the actual pathophysiology: in SIADH. Although the absolute amount of SIADH Figure 3-1 2 59 l:i . lipids. Hyperosmolar hyponatremia (pseudohy­ ponatremia). Thus.8 = The normal value is around 290 mosmlkg. This would lead to an increased water to sodium ratio and thus hyponatremia. or urea could raise serum osmolality. urine sodium concentration is typically elevated in SIADH. THE RENAL SYSTEM DIABETES INSIPIDUS ( POLYDIPSIA . What would you expect to find on urinal­ ysis in SIADH? If ADH is over-secreted.

fluid shifts). CHF. Renal causes can be distinguished from extra-renal causes by urine [sodium]. hyperaldosteronism · Extrarenal loss .ADH secretion) or nephrogenic ( -1. polydipsia · t g l u cose • The hypervolemic states are secondary to fluid overload: t lipids • · t prote i n s · t u rea Figure 3-1 3 The hypovolemic states are secondary to fluid losses. the glucose concentration can raise the serum glucose levels to the point where lots of water is drawn into the intravascular space in an at­ tempt to maintain fluid balance. nephritic syndrome) Euvo l e m i c hyponatrem i a • SIADH • Polyd i ps i a • Adre na l i n s uffic i e n cy • The euvolemic states in both hyper. Summary. 3-15. remember the basics: in hyperna­ tremia there is either net gain of salt or net loss of wa­ ter. . When in doubt. Hyperkalemia Serum potassium concentration can increase second­ ary to three basic mechanisms: PSEU DOHVPO NATREMIA Figure 3-1 4 • Increased intake • Decreased urinary excretion • Increased movement of K+ from the cells into the bloodstream Fig. . Hyperkalemia and Hypokalemia Potassium (K+) is the main intracellular cation: its concentration is significantly higher inside cells than in the serum. 3-16. CAU S E S OF HYPONAT R E M I A Hypervo l e m i c hyponatremia · Ci rrh osi s · Hea rt fai l u re Fig. either renal (e. Urine [sodium] is typi­ cally greater than 20 meq/L in renal losses and less than 20 meq/L in extra-renal losses. In uncon­ trolled diabetes mellitus. · Neph rot i c synd rome • Hypovolemic hypo natre m i a · Re n a l l oss . cirrhosis. C auses of hyperkalemia 60 .and hypona­ tremia include aberrancies in ADH or changes in water consumption: . In hyponatremia.Hyponatremia: increased ADH secretion (SIADH). This can result in hy­ ponatremia and even hyperosmolar coma.An IV solution-generated hypernatremic one .Hypernatremia: diabetes insipidus. there is either net loss of salt or net gain of water.g.g. THE RENAL SYSTEM sodium is actually unchanged.renal response to ADH).An internally-generated hyponatremic one (e. the concentration of sodium is decreased by the water influx. diuretics ) or extra-renal (diarrhea. blood loss.CHAPTER 3. sweating. central ( -1. hypodipsia · Hypothyroidism Pseud ohyponatrem ia .

. I .V..J ""::.:..CHAPTER 3...." • · N eph rotic synd rome • • H ypothyroidism ll I' li • Renal vs.) CA USES OF HYPERKALEMIA Figure 3-1 6 61 li Polydipsia Ad renal insufficien cy • S IA D H (ADH t ) Figure 3-1 5 Renal failure i I' · Cirrhosis H ea rt fail ure • • HYPO VOLEMIA H YPONA TREMIA HYPERNA TREMIA i Acidosis It . THE RENAL SYSTEM HYPERVOLEMIA l EUVOLEMIA � I · Iatrogenic • Primary hyperaldosteronism • • Diabetes I nsipidus (ADH ! ) Hypodipsia Renal vs..:.· �. extrarenal losses ."··_. extrarena l li losses -·: �-____: Hyporeninemic hypoaldosteronism ACE inhibitors · Adrenal insufficiency · Spironolactone (or other aldosterone antagonist) • • ! Aldosterone or its effect Pseudo­ hyperkalemia Trauma Inc K + intake (oral...::..::'''!".· w_.

When unsure whether the hyperkalemia is real or an arti­ fact. In acidosis. Acidosis. Al­ ternatively. This situation is called pseudohyperkalemia since the serum potas­ sium is not really elevated.. i. This elevated potassium from cell breakdown can also explain a very common cause of elevated potassium on laboratory blood work: the blood cells in the blood draw lyse.. acidosis. rhabdomyolysis. one draws another sample of blood to re­ check the [K+]. there is too much H+ in the blood. So renal failure can lead to hyperkalemia. there is not enough H+ in the 62 . . releasing their potassium.. a decrease in aldosterone can cause hyperka­ lemia. This in turn can lead to hyperkalemia. Hypoaldosteronism can result from a decrease in aldosterone or a decrease in the re­ sponse to aldosterone (for more on hypoaldos­ teronism see Chapter 5) . . beta-blockers. insulin deficiency or resist­ ance.A decrease in flow rate in the distal nephron can lead to a perceived high concentration of potas­ sium in the nephron. . which moves from the cells to the blood to maintain electroneutrality. and hypoaldosteronism. A more likely cause of hyperkalemia due to increased in­ take would be an iatrogenic infusion of potassium at an inappropriately high dose. = = Fig.e. since these broken cells release their potassium when they lyse.. Acidosis (too much acid. I I I I t ' Hyperkalemia Figure 3-1 7 • • SHIFTS OF I('" and fl'" IN Hypokalemia A CIDOSIS A ND ALKALOSIS Increased intake. .e. thus inhibiting further se­ cretion of potassium into the nephron. cirrhosis) can result in a low distal flow rate. Since aldosterone is the hormone responsible for potassium secretion. . .Any process that leads to breakdown of cells can cause hyperkalemia. Fig. The body is willing to tol­ erate shifts in potassium in an attempt to re­ store acid/base homeostasis. i... Decreased excretion: renal failure. Aldosterone secretion from the zona glomerulosa of the adrenal cortex is stimulated by angiotensin (which is stimulated by renin se­ cretion by the juxtaglomerular apparatus of the kidneys).In renal failure. Hypovolemia or effective volume depletion (congestive heart fail­ ure. One of these is potassium. H+ moves from the blood into the cells in exchange for K+. and tumor lysis after chemotherapy. 3-3). One way to compen­ sate for an aberrancy in acid/base status is by exchanging K+ for H+. volume deple­ tion.AC I DO S I S li ( tt H+) 1: H+ K+ H+ . Com­ mon causes include crush inj uries or other maj or trauma. Shifts of K+ and H+ in acidosis and alkalo­ sis. resulting in increases in all serum electrolytes (except calcium. low [H+] high pH) are dis­ cussed in the next section. it would be quite difficult to induce hyperkalemia by ingest­ ing too much potassium unless there was a problem with the kidneys' excretion of potassium. 3-17. Because of the body's mechan­ isms for regulating K+ (discussed below). K+ -.Hypoaldosteronism. the kidneys have difficulty fil­ tering/excreting. high [H+] low pH) and alkalosis (too much base/not enough acid. This can lead to hyperkalemia. the elevated [K+] is just an artifact of the blood draw. in alkalosis. • Intracellular to extracellular shifts: pseudohy­ perkalemia.

CHAPTER 3. THE RENAL SYSTEM

R

- Like insulin, catecholamines also cause K+ entry
into cells. Therefore, blocking catecholamines
with beta-blockers (used in the treatment of hy­
pertension and heart disease) can decrease the
ability to move K+ into cells, resulting in hyper­
kalemia.

Fig. 3-18. Peaked T waves in hyperkalemia. Why does
hyperkalemia matter? The body expends a large pro­
portion of its energy running the Na+fK+ pump, which
pumps Na+ out of cells and K+ in. This pump maintains
the electrical system that allows for cardiac, neural, and
muscular function. If the extracellular potassium be­
gins to rise, the electrical potential across these mem­
branes is altered, and this can affect their function. A
worrisome outcome of hyperkalemia is cardiac dysfunc­
tion. On EKG, hyperkalemia first manifests as peaked
T waves, and can lead to ventricular fibrillation, which
can be fatal. Cardiac complications can be prevented
with the administration of calcium (usually adminis­
tered as calcium gluconate), which stabilizes the car­
diac membrane. Mnemonic: imagine a peaked T wave
as being peaked because it is a mountain of K+.

T

Q

s

PEAKED T WAVES IN HYPERKAL EMIA
Figure 3-1 8
blood, so the cells release H+ into the blood in ex­
change for K+ , which enters the cells from the blood.
This can lead to hypokalemia.

Hypokalemia
Fig. 3-19. Causes of hypokalemia.

- Insulin deficiency or resistance (e.g. , diabetes
mellitus) can also lead to hyperkalemia. Insulin
causes K+ entry into cells . A way to remember

Hypokalemia is logically caused by all of the opposites
of what caused hyperkalemia. Serum potassium con­
centration can decrease secondary to three basic
mechanisms :

that insulin causes K+ to move into cells is sim­
ply to remember its action on glucose. Insulin
causes glucose entry into cells. So just think of
insulin as something that moves things into
cells. Therefore, insulin deficiency or resistance
can decrease the ability to move K+ into cells, re­
sulting in hyperkalemia.

Renal loss
(e.g. d i u retics,
hyperaldosteronism)

Decreased intake

Increased loss (renal or GI)

Movement ofK+ from the blood into cells

G l loss
(vom iting,
d iarrhea)

i l nsulin

e-agonists

Dec K+ i ntake

CA USES OF HYPOKALEMIA
Figure 3-1 9

63

Alkalosis

CHAPTER 3. THE RENAL SYSTEM

Decreased intake. Since the body has many mech­
anisms of K+ regulation (aldosterone, insulin, cate­
cholamines), a potassium-deficient diet alone very
rarely causes hypokalemia, although it could be a
contributing factor.

ciency or resistance can cause hyperkalemia, and
insulin excess can cause hypokalemia.

Increased loss: renal vs. GI.

tal flow rate. A very increased rate washes away
potassium, making the lumen of the nephron ap­
pear to be lacking in potassium, which in turn
causes increased potassium secretion. This re­
sults in hypokalemia in the blood. Renal losses of
K+ due to this increased flow rate are commonly
seen in diuretic therapy. Renal loss of K+ can also
be induced by hyperaldosteronism . Causes of hy­
peraldosteronism include adrenal adenomas or
carcinomas that secrete aldosterone.

hyperaldosteronism

can

cause

Distal flow rate in the nephron is another determi­
nant of K+ metabolism. A low distal flow rate can
cause hyperkalemia, and a high distal flow rate can
cause hypokalemia.

Acid I base status affects potassium concentration.

Acidosis can cause hyperkalemia, and alkalosis can
cause hypokalemia.

Note from figure 3-20 : Decreases in pH, aldosterone,
catecholamines, insulin, and distal flow rate can cause
hyperkalemia. Increases in pH, aldosterone, cate­
cholamines, insulin, and distal flow rate can cause hy­
pokalemia.

- GI losses such as vomiting and diarrhea can
lead to potassium loss. Some of this loss is
direct, i . e . , potassium is lost in the vomit and
diarrhea. Vomiting can also result in indirect
urinary loss of K+ . Let's go through the indirect
K+ loss step by step. What happens when one
vomits? One loses lots of acid from the stomach.
If vomiting causes acid loss, an alkalosis will
remain behind in the serum. This is because
H+ loss leaves behind an excess of the base
HCOa -. This excess HCOa- eventually makes it
to the kidneys, and thus the tubule lumen has
more negatively charged ions than usual. One
way of compensating for that is secreting the
positive ion K+ into the lumen. So vomiting can
lead to increased loss of K+ in the urine, result­
ing in hypokalemia.

Acid/Base Pathophysiology
The blood pH is the negative of the logarithm of the
hydrogen ion concentration in the blood:
pH = - log [H+]
Normal blood pH is around 7 .4. An increase in blood pH
is called alkalemia, and a decrease is acidemia. Acido­
sis and alkalosis occur when the aberration of pH is
large enough to be pathologic. Since pH is the negative
log of the H+ concentration in solution, the pH goes
down as the [H+] rises (i.e. , more acid). On the other
hand if the [H+] falls (i.e. , more basic), the negative log
of [H+] becomes more positive, and the pH increases.

Extracellular to intracellular shifts. Insulin

Acid-base status in the serum is maintained by the
following equilibrium :

excess , beta agonist treatment (e. g. , albuterol for
asthma), and alkalosis can all lead to hypo­
kalemia (see Fig. 3-19). Contrast this with insulin
deficiency/resistance, beta-blockers, and acidosis
leading to hyperkalemia ( see Fig. 3-16). Insulin
excess can occur secondary to insulin therapy or
an insulin-secreting tumor (insulinoma ). When
treating diabetic ketoacidosis, a complication of
diabetes, one uses insulin to reduce blood sugar
and restore euglycemia. Because this will also
cause a shift of K+ into cells, risking hypokalemia,
the patient is simultaneously given IV potassium
chloride.

HCOa-

+

H+

H2COa

C02

+

H20

In acute acid-base disturbances, shifts in this equilib­
rium can partially buffer changes in pH away from
7.4. Over time, other more substantial compensation
is necessary through the organs that regulate HCOa-,
C02, and H+. What organs regulate these molecules?
The lungs are responsible for blowing off C02 (which
is a by-product of various metabolic reactions). The
kidneys regulate bicarbonate (HCOa-). Most bicarbon­
ate is reabsorbed in the proximal tubules, and a little
is reabsorbed in the distal tubules.

Fig. 3-20. Summary of factors affecting serum potas­
sium concentration.

AldosteRoNe causes Reabsorption ofNa+ and secre­
tion of K+. Hypoaldosteronism can cause hyper­
kalemia, and
hypokalemia.

Renal loss ofK+ can occur due to an increased dis­

Insulin also causes K+ entry into cells . Insulin defi­

The kidneys and lungs are the main generators of
(and compensators for) acid/base disturbances, but the
GI tract also handles acids and bases. Vomiting and di­
arrhea can thus also lead to acid/base abnormalities.
Acid (H+) concentration is higher in the stomach since
the stomach secretes acid to digest proteins. Base

Catecholamines (sympathetic nervous system) pro­
mote K+ entry into cells via beta receptors. Beta­
blockers can cause hyperkalemia, and beta agonists
can cause hypokalemia.

64

CHAPTER 3. THE RENAL SYSTEM


ell )

/� pH
w
/ 1
� [W] (Acidosis ) � Aldostero ne
K+

DISTAL FLOW RATE

� [W] (Alkalo sis ) � Aldosterone
w
K+


��

p

� Catecholamine s

H

S UMMARY OF FA CTORS A FFECTING
SERUM PO TA SSIUM CONCENTRATION
Figure 3-20

(HC03·) concentration is higher in the duodenum and
distally because it is secreted from the pancreas into
the duodenum to neutralize the stomach acid. So vom­
iting leads to acid loss (leaving a basic environment
behind, which can cause alkalosis) , and diarrhea leads
to base loss (leaving an acidic environment behind,
which can lead to acidosis).
The basic principles of acid/base pathophysiology
are as follows :

If the cause of an acidosis or alkalosis is respiratory,

the kidneys will compensate.

If the cause of an acidosis or alkalosis is renal, the

The kidneys cause disturbances via HC03-. HC03elevation via increased retention (or decreased ex­
cretion) can result in alkalosis ; HC03- decrease via
increased excretion can cause acidosis.

The lungs compensate for a metabolic disturbance
by doing to C02 whatever the kidneys did to HC03-.
For example, in a metabolic alkalosis, HC03- rises,
so the lungs retain C02 to compensate.

The kidneys compensate for a respiratory distur­
bance by doing to HC03- whatever the lungs did to
C02. For example, in a respiratory alkalosis, C02
decreases, so the kidneys decrease HC03- (i.e. , in­
creases secretion of HC03 -) to compensate.

Fig. 3-21. Henderson-Hasselbach equation. The last
two points above can be understood in terms of the
Henderson-Hasselbach equation. First, remember that
log 1
0. So if the ratio of [HC03-] to [C02] is 1, the
log of the ratio will be zero, and the pH will equal pK

lungs will compensate.

The lungs cause disturbances via C02. C02 in­
creases in respiratory acidosis ; C02 decreases in res­
piratory alkalosis.

=

65

CHAPTER 3. THE RENAL SYSTEM

pH = pK + log

[HCO�-]
[C02]

To maintain stable pH l og
,

[HC03·]
[C02]

should = 0

s h o u l d = 1 . If o n e is d i st u rbed , the other compensates by g o i n g in the s a m e d i rectio n .

TH E H EN D ERSO N-HASSELBACH EQUATIO N
Figure 3-21

What causes respiratory acidosis? That is, how could
one end up with too much C0 2? There must be either
over-production of C0 2, increased inspiration of C02 , or
decreased expiration of C02. How could these occur?
Overproduction occurs in hypercatabolic states (e.g. ,
malignant hyperthermia). Increased inspiration could
occur if there is increased concentration of C02 in the
inspired gas mixture. Decreased expiration of C02 is
the most common cause of respiratory acidosis. Why
would the lungs have trouble expiring? Obstruction
(foreign object, tumor, or obstructive lung disease),
damage to the lungs or chest wall (e.g. , pneumothorax),
or a problem with the muscles of respiration or their
neural input. Damage to the neural input can occur in
the central nervous system (e.g. , brainstem infarct, opi­
ate suppression of respiratory drive), the peripheral
nervous system (Guillain-Barre), or the respiratory
muscles (e.g. , myasthenia gravis).

(equilibrium pH). If either [HC03-] or [C02] is signifi­
cantly increased or decreased, the ratio of the two will
change from 1. Since this ratio is added to the pK to
give pH, a change in the ratio will change the pH. The
goal of compensation is always to maintain this ratio
at 1 so as to keep pH unchanged. So if the concentra­
tion of either C02 or HC03- goes up, the compensation
is that the other goes up. If the concentration of either
C02 or HC03- goes down, the compensation is that the
other goes down. For example, in metabolic alkalosis,
the cause is elevated HC03-, so to compensate (i.e. , re­
turn the ratio to close to 1) the lungs must raise C02.
In respiratory alkalosis, the cause is decreased C02, so
to compensate (i. e. , return the ratio to close to 1) the
kidneys must decrease HC03- (i. e. , excrete more
HC03 -). So the compensating organ always compen­

sates by making the substance it controls (i.e., HC03for the kidneys, C02 for the lungs) go in the same direc­
tion as the abnormality-causing substance.

Respiratory Alkalosis

If you understand the basic mechanism by which
respiratory acidosis occurs both physiologically and
biochemically, you can easily figure out the rest of the
acid/base disturbances. This goes for any individual
disturbance : learn one well and you can deduce the
other three.

Fig. 3-22B. Respiratory alkalosis. While respiratory
acidosis occurs from elevated C02, respiratory alkalosis
is caused by increased expiration of C02. This decrease
in C02 drives the reaction in fig. 3-22 in a way that at­
tempts to create more C02 to maintain equilibrium.
This is accomplished by the combination of HC03- and
H+, thus decreasing H+ (which raises pH). If the lungs
cause the pH to be high, the kidneys can compensate by
getting rid of HC03-, the body's own base, thus making
things less basic. So C02 decreases � equilibrium
shifts � decreased H + � alkalosis � the kidneys try to
get rid of base CHC03- decreases). So in respiratory al­
kalosis, pH is high, C02 is low, and HC03- is low.

Respiratory Acidosis
Fig. 3-22A. Respiratory acidosis. This is an acidosis
caused by elevated C02. Looking at the chemical reac­
tion at the bottom of fig. 3-22 , if the C02 is high, the
system moves towards equilibrium by running the re­
action toward the right, thus generating H+. This in­
crease in H+ leads to acidosis.

How could one end up with decreased C 02? The
only way is by breathing it off too rapidly, i.e. , hyper­
ventilating. Hyperventilation can be induced by a
physiological drive for more oxygen if there is hypox­
emia. Examples include high altitude and anemia.
Hyperventilation can also be drug-induced (e.g. , sali­
cylates)9, pain/anxiety-induced, stroke-induced, or in-

If the lungs cause an aberration, the kidneys will
compensate (and vice versa). If the H+ is high, how
could the kidneys buffer that? By retaining HC03-,
the kidneys give the blood a buffer that can "soak up"
the H+ generated by the lungs and thus restore a
normal pH. So C02 rises � equilibrium shifts � H +
rises � acidosis � kidneys try to buffer by increasing
HC03-. So in a respiratory acidosis, pH is low, C02 is
high, HC03- is high.

9

66

Salicylate toxicity can cause respiratory alkalosis and meta­
bolic acidosis.

H+ Decrease: • Shift ofH+ into cells . p H ) � Lung removes C02 to buffer Figure 3-22 duced by pulmonary pathology (e.CHAPTER 3.g. g. as discussed above. This can happen from over-diuresis. Pulling H+ out of the serum leaves behind a more basic envi­ ronment. Asthma can cause respiratory acidosis or respira­ tory alkalosis. which can result in respiratory alkalosis. (AldosteRoNe causes Reabsorption of Na+.. 67 Volume depletion (contraction alkalosis) : if fluid with a low bicarbonate concentration is lost. Initially. • exchanged across cell membranes to restore acid-base balance at the expense of disturbing K+ balance. Hypokalemia can be caused by diuretics. The reverse situation can also occur: hypo­ kalemia causes some K+ to leave cells in an attempt to correct the hypokalemia and it does this in ex­ change for H+. e./ � H �H + + + (. Aldosterone causes acid secretion. Metabolic Alkalosis Fig. For a metabolic alkalosis to occur [H+j must be decreased (which would leave behind excess base) or [HC03-1 must be m ­ • Vomiting (loss of H+ in vomited stomach acid) HCoa· Increase: creased. . etc. hyperaldosteronism. . this leads to an increase in bicarbonate concentration. hyperaldosteronism • Renal loss of H +. re­ sulting in respiratory acidosis. for example. . which enters the cells. Metabolic alkalosis means that there is an alkalosis not caused by the lungs. THE RENAL SYSTEM � H C0 3 "-' H Kid ney reabsorbs HC03. So hyperaldosteronism can lead to increased acid secretion. leaving behind a basic environment and thus alkalosis. As the obstruction becomes severe and the respiratory muscles fatigue. and se­ cretion of K+ and H+).j.to buffer "-' H C0 3 . an asthma attack causes hyperventilation. 3-22C.g.to buffer Kidney excretes ' ' + � (�pH) � Lung retains C02 to b uffer Hco3. . . C02 retention occurs. iatrogenic bicarbonate infusion) • Loss of acid (leaving behind a relative surplus of HCOs -).. which can cause alkalosis. pulmonary embo­ lus can lead to hyperventilation). Recall that H+ and K+ can be • Increased intake (e.

Aside from a history or lab chemistries that point toward an increased level of any of these substances.] or Na+ . the lungs must try to bring things back to normal by going "in the acid direction" by retaining C02. In a normal anion gap metabolic acidosis. and Cr. pH is low. Normally..HC03-.cr will be closer to zero or even positive. This would give an anion gap of 8. and one of those is the secretion ofH+ bound to NH3. e . pH is high. and C02 is low. The kid­ neys can secrete excess acid in the form of NH4 + (NH3 2 carrying an acidic H+) and H2P04. So i n metabolic acidosis.de­ crease or acid increase . bicarbonate loss.(HP04 . par­ aldehyde. (A very negative value means a high [NH4+] because of the negative sign on the NH4+ in the equation . b y blowing o ff more C 0 2 ) . one can rearrange the equation to: pensate for metabolic acidosis by decreasing C02 (i. The main causes of acid gain are usually grouped under the mnemonic MUD­ PILES (methanol. So in metabolic alkalosis. and thus the source of the acidosis is not renal. ) One must determine whether a metabolic acidosis is due to bicarbonate loss or acid gain.is decreased.e.12. namely Na+ + K+ + NH4+.carrying an acidic H+). . If there is an anion mean that the sum of cr and HC03. and C02 is high. Another way to think about this is in Urine anion gap. it will try to secrete that excess acid in the form of NH4+ . diabetic ketoacidosis. . isoniazid or iron. The urine should have an equal balance of positive and negative ions. wouldn't this also in­ crease the anion gap since one of the things being subtracted (HC03-) is now much lower?" Actually. i f the kidneys are responsible for the acidosis. Here HC03.Cl. Metabolic acidosis is caused by HC03. should equal Cr concentration: terms of the Henderson-Hasselbach equation: the com­ pensating molecule must do the same thing that the aberrant molecule did. Na+ is about 140. to compensate for an alkalosis elsewhere. If an acidosis is created by diarrhea. If the anion gap is higher than 10 . that must mean they are not working properly.is low. the urine anion gap calculation is meaningless. it is just a result of the algebraic solution to the first equation. This calculation is essentially the main extracellular cation minus the main extracellular anions .CHAPTER 3.is decreased gap in the serum. This results in acidosis. Thus. Thus. if there is diarrhea or a renal problem causing HC03. so C02 must rise to compensate. THE RENAL SYSTEM How would the lungs compensate for a metabolic al­ ion gap in situations where HC 03. 68 . One way is to remember that when C02 is high in the lungs.wasting. one looks at the urine anion gap .loss.is too high. If the urine anion gap is close to zero or pos­ itive. lactic acid. the Na+ + K+ .Cl-) very negative. Metabolic Acidosis Fig. salicylates). one must distinguish be­ tween a renal problem and diarrhea (the latter may be obvious clinically: i. when there is HC03. there tends to be an increase in serum chloride. HC03. The anion gap. due to various exchange transporters. Cr is about 108. If there is metabolic acidosis and the anion gap is normal.is about 24. This will make the equation (Na+ + K+ . there is also a calculation based on a few ion concentrations that can distinguish between acid gain vs.loss. and thus the kidneys are the source of the acidosis (renal tubular acidosis). In this scenario. This calcula­ tion uses serum ion concentrations. The lungs com­ Since it is easiest to measure Na+ . So kalosis? If HC03. HC03. we know the kidneys are working prop­ erly and secreting acid (in the form of NH4+) . this causes an acidosis. this must The urine anion gap is only useful in the setting of a non-anion gap metabolic acidosis. HC03. 3-22D . what would the lungs an elevated anion gap means that some other acid is present in serum that increases the gap (MUD­ PILE S ) . want to do to C02? There are two ways to think about this. and another acid is present. A normal anion gap metabolic acidosis means that bicarbonate loss is occurring secondary to either diarrhea or a renal problem. which is NH4+. The latter is often caused by addition of another acid to the serum.is elevated. ethylene glycol. the kidneys' defenses against acidosis are reabsorbing base (HC03-) or excreting acid in the urine. The negative sign before NH4+ does not refer to the charge. K+. the patient is having diarrhea). the kidneys are not appropriately responding to the acidosis by secreting NH4+. and thus not appropriately secreting NH4+. uremia. if the urine anion gap is very negative. and the kidneys are functioning normally. and is known as the anion gap : Na+ .is high. Normally. A logical question is: "But if one loses bicarbonate without addition of some other acid. but most likely diarrhea. This leads to maintenance of a normal an- Renal tubular acidosis (RTA) can be caused by a variety of conditions that lead to decreased hydrogen ion excretion. The kidneys have various ways of se­ creting acid in an attempt to maintain normal pH. and HC 03. shouldn't that cause an increased anion gap too? That is. Bicarbonate loss can be caused by diarrhea or some renal problem leading to HC03.[Cl- + O n the other hand.

amy­ loidosis).g. 11 Note: This is different from Fanconi's anemia . bicar­ bonate would be wasted in the urine. Na+ + K+ . extra acid (i. • If there is alkalosis and C02 is decreased. Fig. chemotherapy agents. What stimulates aldosterone? The renin-angiotensin-aldosterone axis. If the col­ lecting ducts do not adequately secrete acid. and (because now the diminished renal reabsorptive ca­ pacity is being overwhelmed). in association with autoimmune diseases. . So hyperkalemia and hyponatremia can be present in hy­ poaldosteronism. what do you think the urine pH will be? Basic. What other electrolyte abnor­ malities would you expect? If aldosterone is low. In Type 2 RTA. 3-23. in the end one does not end up with that much bicarbon­ ate in the urine. which is an autosomal recessive disease of the bone marrow leading to pancytopenia. drugs (e. Type 2 occurs in the proximal nephron (mnemonic: pro2imal) . one gives some bicarbonate to neutralize the acid. this must be a respiratory alkalosis: the HCOs. a serum bicarbonate less than expected • If there is acidosis and C02 is elevated. this must be metabolic acidosis (if HC03. which can result in an accumulation of H+ in the blood (acidosis). Then look at either acidosis. . elevated pH C02 or HCOs -. To treat an acidosis. aminogly­ cosides). What causes hypoaldosteronism? Al­ dosterone comes from the adrenal cortex.CHAPTER 3. If there is a metabolic acidosis. = - 69 . The low level of bicarbonate that is left from the initial wasting is small enough that it can be reabsorbed. caused by an ACE inhibitor) can lead to decreases in aldosterone levels. impaired H+ se­ cretion in the distal nephron occurs secondary to a ge­ netic defect of ion transporters. Some sources say that what was once referred to as type 3 is now thought to be a vari­ ant of type 1. it does not exceed the kidneys' (reduced) reab­ sorptive capacity. Fanconi's syndrome 1 1 is proximal tubule dysfunction.[Cl.12). the kidneys are appro­ priately secreting NH4+ in response to acidosis. while others say type 3 referred to a combination of types 1 and 2 . Therefore. which can be hereditary.is elevated. So a low level of aldosterone will lead to decreased H+ secretion. To distinguish between these two. this must be a respiratory alkalosis (if C02 is elevated.level be­ comes so low that when it arrives at the proximal tubule. Types 1 and 2 RTA are classified by where along the tubule the defect occurs : Type 1 occurs in the distal nephron (mnemonic : D l stal). HC03. this = = = bicarbonate therapy will lead to alkalanization of the urine . most often diabetic nephropathy) or decreased angio­ tensin (e. This basicity of the urine can lead to formation of kidney stones. to bonate (also because of the overwhelmed reabsorptive capacity of the kidneys).g. Determining the cause of metabolic acido­ sis.4 alkalosis. type 2. or from drug toxicity. hyporeninemic hypoaldosteron­ ism. this must be metabolic acidosis : the decreased C02 is the respiratory compensation). One might expect that the urine in Type 2 RTA should be basic like Type 1 RTA since one is wasting bicarbonate in the urine.is increased this must be a metabolic alkalosis (if HC03.e. Decreased pH First. Why would this cause metabolic acidosis? Remember that aldosterone is responsible for stimulating H+ secretion (aldosteRoNe causes Reabsorption ofNa+ and secretion of K+ and H+). but the story is a bit more complicated.is decreased. MUDPILES) must be present. Overall Algorithm for Acid/Base Disturbance Diagnosis normal . heavy metals). 7. • If there is acidosis and HC03.decrease is the renal compensation) . Decreased renin secretion (e.g.+ HC03 -] ). This low level of bicarbonate thus cycles through the system. Type 1 RTA (Distal). this must be respiratory acidosis (if C02 is decreased. In Type 1 RTA. or as apart of Fanconi's syn­ drome.(bicarbonate) in the urine will be elevated. In fact. This can occur from drug toxic­ ity. maintaining the same level . So because of the low level of bicar­ bonate in the circulation due to the initial defect. .is de­ creased. this must be respiratory acidosis : the elevated HCOs is the renal compensation). use the urine anion gap. and type 4. If it is very negative. look at the pH. or secondary to renal damage from proteins (multiple myeloma. . As bicarbonate is wasted. What would happen if the patient with Type 2 RTA was given an IV bicarbonate inj ection? Now the reabsorptive capacity would be overwhelmed. If the anion gap is normal. this must be a metabolic alkalosis: the elevated C02 is the respiratory compensation). Type 4 RTA is hypoaldosteronism. the plasma level ofbicarbonate decreases. so adrenal insufficiency is one cause. and a high urine bicar1 0 The term "type 3" is no longer in use. there is either diarrhea or renal tubular acidosis (RTA) . or toxins (e.g. calculate an anion gap using serum concentrations (N a+ . as a genetic defect. So re­ Distal. Na+ reabsorption and K+ secretion will both decrease. which can come from any cause of renal failure. • If there is alkalosis and HC03. and the urine would become alkaline with a high bicarbonate con­ centration. Type 4 is hy­ poaldosteronism (mnemonic: hypoaldoste4onism). . St for stones) member D l Stal : Type 1 = Type 2 RTA (Proximal) is a defect in bicarbonate re­ absorption. THE RENAL SYSTEM The three types of RTA are type 1 .cr (NH4+). If the anion gap is elevated (greater than or equal to 10. HC03 .

HCo3- � Serum gap s 1 0.( [Cr] + [HCo3-]) I Serum gap > 1 0. If the urine is not basic but becomes so with bicarbonate therapy.cr . the kid­ neys are not appropriately secreting NH4+ .CHAPTER 3.1 2 = Na+ . type 4 is more likely. this is most likely 70 . RTA. THE RENAL SYSTEM DETERMINING THE CA USE OF METABOLIC A CIDOSIS Calculate serum anion gap [Na+J . and thus the problem is intrinsic to the kidneys. If it is positive or zero. the cause must be diarrhea (hopefully you got that on the history). e .[Cr] = - [NH4+] Gap 2: 0 Figure 3-23 Type I ( distal) or Type 4 (hypoaldosteronism ) . this is more likely type 2 RTA (proximal) . If it is RTA with a basic urine. If the RTA is accompanied by hyperkalemia. i .1 2 (normal) Calcu late urine anion gap Urine [N a+] Uremia Diabetic ketoacidosis Paraldehyde I soniazid/Iron Lactic acid Ethylene glycol (antifreeze) Salicylates Gap <O + [K+] . .

esophageal varices.CHAPTER 4. . Problems with the muscle or its innervation FUNCTION ORGAN GENERAL PATHOLOGY ·Connects mouth • Obstruction ·Reflux • to stomach Prevents reflux • Esophagitis ·Varices ·Tumors • STOMACH ·Ulcer Acid secretion ·Churning • • Outlet obstruction ·Gastritis Releases food to duodenum • ·Tumors Secretes intrinsic factor ·Digestion SMALL INTESTINE • Absorption Gastroparesis • • • Pernicious anemia Malabsorption • Obstruction • Mesenteric ischemia ·Tumors LARGE INTESTINE • • H20 reabsorption Passage of stool *Can Occur Anywhere: • • Crohn's disease Obstruction ·Diarrhea Constipation • • Obstruction • Mesenteric ischemia ·Colitis ·Tumors ·Tumors OVERVIEW OF Gl FUNCTION AND PATHOLOGY Figure 4-1 71 . amongst numerous other functions. • Deficient digestion and/or absorption. THE GASTROINTESTINAL SYSTEM CHAPTER 4. small intestine. which can be due to : . tumors) The GI tract is a muscular tube from the mouth to the anus with different regions specialized for different diges­ tive functions.g. inflammatory bowel disease or bacte­ rial overgrowth) Since the GI tract is a muscular tube specialized for digestion and/or absorption .A problem with an absorptive surface of the GI tract (e.g. Overview of GI function and pathology. and large intestine. These regions are the esophagus. stomach.A problem with an enzyme or its secretion . GI bleeding) Fig. THE GASTROINTESTINAL SYSTEM ANATOMICAL OVERVIEW • Obstruction of the tube (e. mesenteric ischemia. the potential types of pathology are : • • Problems with the blood vessels/blood supply (e. .g. foreign objects. 4-1. The liver and pan­ creas are accessory organs that produce substances that aid digestion. .

Pathology of the large intestine can result in diar­ rhea or constipation. the esophagus will have decreased peri­ stalsis and be unable to relax the lower esophageal sphincter to allow passage of food to the stomach. dyspha­ gia for liquids can occur. 72 . So lung cancer or enlarged lymph nodes (e. abnormalities of the blood supply. So what could interfere with this transport or the coordinated muscular function it requires? Esophageal dilatation can occur in scleroderma and other connective tissue diseases. Thus. The sympathetic system is for fight/flight. re­ gurgitation of undigested food.g. From the outside.Small bowel tumors Colon cancer The following pathologies: • Patients with esophageal obstruction typically have trouble swallowing (dysphagia). pain in the chest (some­ times presenting like angina). and the parasympathetic system is for rest/digest. paral­ ysis (gastroparesis) and outlet obstruction are the corresponding pathologies of these two functions. (The food is undigested since it has not yet made it to the stomach). rings and/or webs can all cause obstruction. This can feel like trouble getting the food down. as well as in Chagas disease (infection with Trypanasoma cruzi). A problem with preventing motion back from the stomach can lead to reflux. inflammation. loss of intrinsic factor results in decreased B12 ab­ sorption (pernicious anemia).g. as the tumor grows and further encroaches on the lumen. If the stenosis is from a tumor. just behind the trachea..Gastric cancer . think about the anatomical location of the esophagus : the posterior mediastinum. Deficiency of transport can be sec­ ondary to obstruction . GI-tube-related • • Obstruction Obstruction Tumors : E sophageal cancer . and passes this undigested food to the outside world as stool. secondary to thrombosis or atherosclerosis (mesenteric ischemia) Inflammation Esophagitis Gastritis Colitis Crohn's disease are region-specific The esophagus is a tube that transports food from the mouth to the stomach and prevents motion in the opposite direction. which binds vitamin B12. a foreign object. secondary to metastasis or tuberculosis) can obstruct the esophagus from the outside. These dis­ eases cause damage to the collagenous architecture of the esophageal wall. • • • Blood supply abnormalities . DISEASES OF THE ESOPHAGUS Failure to Contract No digestion or absorption occurs in the esophagus. • The stomach produces acid (to break down food) and intrinsic factor.Ischemia due to loss of blood supply. or in some instances. Obstruction can also occur in the large intestine. The small intestine continues digestion and begins absorption of substances from the gut to the blood­ stream. If parasympathetic input is compromised. . The stomach also churns food and sends it to the small intestine. for example.Upper or lower GI bleeding . • • Dysfunction of the m uscle or its innervation • Outpouchings (diverticula) that prevent the food from going where it is supposed to go • Inability to prevent stomach contents from re-en­ tering the esophagus (gastroesophageal reflux dis­ ease: GERD) What can cause a blockage? From the inside of the esophagus. it is simply a muscular tube that transports food from the pharynx to the stomach by coordinated muscular contraction. Muscle Any muscle could fail in one of two ways: it could fail to contract or fail to relax . The large intestine reabsorbs water from the lumi­ nal contents. first this dys­ phagia would be for solid foods and then. the parasympathetic system tells the GI tract to do things related to digestion: squeeze to pass food down and open the lower esophageal sphincter to allow food to pass to the stomach. e. stores undigested food. an esophageal tumor. THE GASTROINTESTINAL SYSTEM In any region of the GI tract. Excess acid secretion can be associated with ulcer disease. Let's review the sympathetic and parasympathetic nervous systems with regard to the gastrointestinal system.CHAPTER 4. Failure of muscle to contract or relax could be due to a muscle itself or secondary to a problem with the nervous system that controls it. and tumors can occur. Malabsorption and obstruction can occur in the small intestine.

it must be coming from below the gastro-esophageal junction. Why would this hap­ pen? The sphincter could be incompetent or distorted (for example. they can rupture. a poorly understood process destroys postganglionic parasym­ pathetic neurons of the esophagus. and since these varices are under high pressure. As food trav­ els down the esophagus and gets stuck before the stomach. and this weakens its walls over time. the esophageal walls get stretched. Both can present as dysphagia secondary to obstruction from the tumor. If there is distal obstruction. Crohn's disease. and the patient vomits blood. Other Causes of Esophagitis In addition to being caused by GERD. This can present as chest pain that mimics angina. chest pain) and it is typically worse when bending over or when lying down after eating. the stomach could be creating excessive back-pressure. what should this bloody vomit look like? In an acute bleed. Failure to Contract and Relax: Achalasia In achalasia. Esophageal diverticula can also be caused by traction. still red) since it has not had time to make it to the stomach. A Zenker's diverticulum lies just behind the upper esophageal sphincter. 4-12). and can also cause respi­ ratory symptoms if the trachea is compressed or in­ vaded by the tumor. patients with a Zenker's diverticulum may regurgitate undigested food. bending over or ly­ ing down will allow stomach contents to spill back through to the esophagus.g. and infection. In im­ munocompromised patients. smoking and alcohol predispose to squamous cell car­ cinoma. and thus cannot be the result of a Zenker's diverticulum. Treatment involves surgery. It is an out-pouching of the lumen that causes food and drink to get stuck there instead of continuing down. Infectious esophagitis occurs only very rarely in otherwise healthy individuals. . Since dilated vein walls are more frag­ ile. causing esophageal bleeding. but is much more common in immunocomprised patients (e. esophagitis (in­ flammation of the esophagus) can be caused by medica­ tions (e.CHAPTER 4. Over time. the lower esophageal sphincter remains constricted and is unable to relax. . acid reflux can damage the esophagus. Do you expect that achalasia is caused by a problem of the sympathetic or the parasympathetic nervous system? Peristalsis and relaxation of the lower esophageal sphincter are both processes necessary for digestion.g. GERD can be painful (e. leading to Barrett's esophagus. appropriately named diffuse esophageal spasm . a premalignant condition (of metaplasia from squa­ mous epithelium to columnar) that predisposes to esophageal adenocarcinoma . usually caused by liver disease/portal hypertension (see Fig. Esophageal Varices Esophageal varices are dilations of esophageal veins. sour taste in the mouth. Some patients get an occasional spasm while others may have spasms every time they swallow. GERD-induced Barrett's esophagus predisposes to adenocarcinoma. This could cause pulsion diverticula proximal to the obstruction.g. which literally burns the esophageal mucosa (esophagitis). The constricted sphincter and proximal dilation classically resemble a "bird's beak" on barium swallow imaging. the proximal portion of the esoph­ agus tries to out-squeeze the obstruction. Because the food remains stuck there. later in the disease there is also failure to constrict: the lower two thirds of the esophagus lose the ability to peristalse. Esophageal Cancer There are two types of esophageal cancer. Failure to Relax Spasm can occur diffusely throughout the entire esophagus. and mycobacteria can cause esophagitis. and/or radiation. If the regur­ gitated food appears digested. e. chemotherapy.e. Alternatively. which could overcome the lower esophageal sphincter barrier. Reflux refers to the backwash of stomach acid up through the 73 . secondary to obstruction or gastroparesis (poor gastric motility). which is usually due to adj acent lymph nodes (most commonly from tuberculosis) that pull on the esophagus. . Why would there be increased stomach pres­ sure? Impaired emptying of the stomach is one possi­ bility. leading to dilatation of the esophagus proximal to the unre­ laxable lower esophageal sphincter. (Diverticula can also occur in the large intestine by a similar mech­ anism). Although achalasia means failure to relax. radiation. The parasympathetic nervous system is responsible for stimulating these processes. chemotherapy). the blood should be undigested (i. . pa­ tients with HIV or hematologic malignancy).g. Diverticula Diverticula are outpouchings of the esophagus. Candida. If a varix bleeds. THE GASTROINTESTINAL SYSTEM lower esophageal sphincter. The lower esoph­ ageal sphincter normally prevents food from coming back into the esophagus from the stomach. This is in Reflux Gastroesophageal reflux disease (GERD) is the most common disorder of the esophagus. This is because if the lower esophageal sphincter is incompe­ tent or if there is a hiatal hernia. If regurgitated food is undigested it has obviously not made it to the stomach. herpes simplex virus (HSV). in a hiatal hernia . the lower esophageal sphincter slides above the diaphragm). In achalasia. . Diverticula can also occur congenitally. heartburn. adenocarci­ noma and squamous cell carcinoma.

secretin.). THE GASTROINTESTINAL SYSTEM contrast to the digested blood that is vomited from more slowly bleeding gastric or duodenal ulcers in the stomach and duodenum. 4-2. · · • H istamine Gastrin Acetylcholine DISEASES OF THE STOMACH The stomach churns food. and produces intrinsic factor. Decreased Mucosal Protection Increased Acid Secretion Prostaglandins increase mucus secretion in the stomach. the protection offered by the gastric mucosal lining is essential. This leaves mucosal protection in the gut rel­ atively intact. leading to decreased B12 ab­ sorption (pernicious anemia). Thus. The mucous cells secrete a mucosal protec­ tive layer. celecoxib. prosta­ glandins. Under such stress. etc. pylori leads to ulcer formation by both of these mechanisms: the bacterium damages the mucosal lining and creates an inflamma­ tory process that leads to increased acid secretion.) also mediate inflamma­ tion and pain. the decrease in stomach per­ fusion can lead to decreased mucosal protection. etc. rofecoxib) selectively block the pain pathway and interact less with COX-1 (which is involved in stomach mucus se­ cretion). Causes of ulcer formation. during shock (due to sepsis. and this secretion is mediated in part by prostaglandins. since the massive bleeding does not have time to be digested (see Fig. basic pathophysiological causes of ulcer formation: de­ creased mucosal protection and increased acid produc­ tion . lets this digested food out (through the pyloric sphincter) to the duodenum for further digestion/ absorption. prolonged NSAID use can cause ul­ cers. . which aids in the absorption of B12. . burns.CHAPTER 4. predisposing to ulcer formation. hemorrhage. Non-steroidal anti-inflammatory drugs (NSAIDs) block these pain/inflammation pathways. Stomach patholo­ gies include: • Disruption to mucosal protection and/or excess acid production (associated with ulcer) Somatostatin Prostaglandins ·Secretin VI P • • • Loss of intrinsic factor. which is much darker (ap­ pearing like coffee grounds). This mechanism is stimulated by gastrin. many hospi­ talized patients are prophylactically placed on anti-ul­ cer medications since they may be subj ected to various physiologic stresses during hospitalization. Because of the acid secretion necessary for digestion. Molecules within the prostaglandin family Recall that the hormone gastrin. Regulation of gastric acid secretion. Therefore. Stress ulcers occur during severe physiologic stress . and VIP (vasoactive intestinal peptide). Fig. • Outlet obstruction preventing release of digested food to the duodenum • Loss of churning action (and/or loss of propulsion through the pylorus) (gastroparesis) • Gastritis (inflammation of the stomach) • Gastric cancer · REGULATION OF GASTRIC ACID SECRETION Figure 4-2 Peptic IDcer Disease (arachidonic acid. which can result in ulcer formation. There are two 74 . 4-3. and inhibited by somatostatin . and acetylcholine. histamine. The COX-2 inhibitors (e. e. but in so doing. Peptic ulcers can occur in the stomach (gastric ulcers) or in the duodenum (duodenal ulcers). Infection with Helicobacter pylori is one of the most common causes of ulcer. The parietal cells of the stomach secrete acid by pumping H+ into the stomach lumen in exchange for K+. 4-9). In Fig. H. secreted by the G cells of the stomach. Massive bleeding from gastric or duodenal ulcers can also cause bright red blood in the vomit. Tobacco and alcohol can also decrease mucosal protection. also decrease mucus secretion in the stomach. COX. produces acid to break food down. so COX-2 inhibitors have fewer GI side effects.g. stimulates acid secretion.g.

and changes in appetite. THE SECRETIN TEST Figure 4-4 75 . Perforated ulcers can present as acute abdominal pain with air under the diaphragm visible on X-ray. Secretin stimulates the pancreas to secrete bicarbon­ ate. vomiting (with red blood or digested blood. Nor­ mally secretin inhibits gastrin secretion . How does this secretin test work? Secretin is a hormone normally produced by the small intestine when food arrives from the stomach.e. 4-4. which neutralizes the duodenal contents. elevation of serum gastrin in response to se­ cretin) is diagnostic for Zollinger-Ellison Syndrome. Severe ulcer disease can lead to perforation of the duodenal or gastric wall. The increase in gastrin secretion by the gastrinoma leads to increased acid production. THE GASTROINTESTINAL SYSTEM NSAIDS tGastrin Stress ULCER CAUSES OF ULCER FORMATION Figure 4-3 Zollinger-Ellison syndrome . secretin injection will para­ doxically increase serum gastrin. Secretin Test. Consider the diagnosis of Zollinger-Ellison syndrome in patients with multiple ulcers at different sites. . A positive secretin test (i. tarry stools (melena). Emergency sur­ gery is necessary for repair of a perforated ulcer.CHAPTER 4. a pancreatic tumor called a gastrinoma secretes gastrin. causing ulcers. digested blood can look like "coffee grounds"). Fig. HC03H2 0 i [Gastrin] (No/Minimal Change in [Gastrin]) Symptoms and Signs of Peptic Ulcer Disease Ulcers can cause pain (see Fig. This diagnosis can be proved by marked elevation in serum gastrin and by elevation of serum gastrin in response to secretin. If there is a pancreatic gastrinoma. 4-5). nausea.

milk of magnesia. Although these are "classic" presentation patterns. How could you increase mu­ cus production? Remember that prostaglandins are partially responsible for increased mucosal secretion. Ulcer Treatment Fig. the acidic gastric contents could irritate a duodenal ulcer. Since acid se­ cretion in the stomach will exacerbate the pain of any denuded area of mucosa (i. it should make sense that eating causes pain in gastric ulcers. To directly affect acid secretion one must block the H+fK+ pump in the parietal cells . Another type of treatment approach increases the mucosal defense of the lining. 76 . . increase m ucosal pro­ tection . Turns tablets). One can also surgically sever the branches of the vagus nerve (cranial nerve X) that provide the parasympathetic input that stimulates acid-secreting cells (vagotomy). acid is secreted and the food is churned around before anything else happens. one can either directly decrease production by the parietal cell itself or de­ crease/block the chemicals that stimulate the parietal cell. we simply use base. Since increased acid secre­ tion and/or decreased mucosal protection can cause ul­ cers. THE GASTROINTESTINAL SYSTEM Gastric ulcer Duodenal ulcer TIMING OF ULCER SYMPTOMS Figure 4-5 Timing of Ulcer Symptoms prevent acid from being secreted. or eradicate H. Ulcers can form in the To neutralize acid. Antibiotics are used to treat H. To decrease stimulation of the parietal cells. 4-6. an ulcer). the H2 blockers (e.e. the proton pump in­ hibitors such as omeprazole or pantoprazole work in this way.e. raniti­ dine) block the H2 receptors on parietal cells. Pylori . Fig. duodenum and/or in the stomach. Gastric ulcers should always be biopsied to rule out gastric cancer. 4-5. ulcer pain can have a variety of relationships to eating patterns across patients. To decrease acid production . Many exceptions to the above patterns can occur. It is not until later after a meal that the food is passed into the duodenum. either by providing a mu­ cus-like substance or by increasing mucus production. Timing of ulcer pain. In which site would ulcer pain get worse immediately after eating and in which site would this pain occur somewhat later? What happens when food arrives in the stom­ ach? First. . since gastric cancer may ulcerate and thus appear similar to a peptic ulcer on endoscopy. pylori . if one is present. Examples in­ clude antacids such as magnesium or calcium salts (i. So duodenal ulcer pain typically occurs much later after a meal. one can block histamine. Ulcer treatment. The H2 receptors are the receptors to which histamine binds to stimulate acid release. and thus endoscopy is often necessary to make a defini­ tive diagnosis.g. . Misoprostol is a synthetic prostaglandin that increases mucosal secretion and protects against ulcer formation.CHAPTER 4. treatments include drugs that neutralize acid. Sucralfate forms a viscous gel in the stomach and helps to form a protective barrier. At that time.

leading to loss of intrinsic factor. . This condition. Crohn's disease. Nerve dysfunction here can be due to damage to the nerve itself or a block­ age of neural transmission to the stomach. and severe physio­ logic stress. and its diagnosis are discussed in the anemia section of the hematology chapter (Chapter 6). other infectious agents. Parasym­ pathetic input to the stomach comes from the vagus nerve (cranial nerve X).. from-the-outside obstruction can be caused by a pancreatic tumor.. Pernicious anemia (autoimmune gastritis ) is a condition in which antibodies form against the pari­ etal cells. ranitidine) Provides iProstaglan dins & mucosal \ Proton pump inhibitors secreti (e. where else can the gastric contents go . . Loss of Intrinsic Factor The parietal cells of the stomach produce intrinsic fac­ tor. or gastric cancer. Surgical opening of the sphinc­ ter is usually necessary in babies with congenital pyloric stenosis.g. Gastroparesis Gastroparesis is paralysis of the stomach. radiation. any drug that decreases gastric motility (e. Additionally. but backward? Thus. How could the pyloric sphincter become obstructed? As with the esophagus (in fact. A problem with the parasympathetic nerves to the stomach can lead to decreased stomach muscle activity and gastroparesis. NSAIDs. Without in­ trinsic factor. which can lead to anemia. The stomach is under the control of the enteric nervous system. with the whole GI tract). Obstruction To pass food to the duodenum. For the pyloric sphincter. Additionally. and reflux of bile and/or pancreatic secretions. Congenital py­ loric stenosis can present as a palpable olive-like mass on exam (the hypertrophied sphincter) and visible waves of peristalsis as the stomach tries in vain to overpower the stenosis. omeprazole) coating I j MUCOSAL PROTECTION t ACID SECRETION Figure 4-6 disease or by ingestion of a caustic substance. THE GASTROINTESTINAL SYSTEM ACh Vagotomy Sucralfate PARIETAL H2-blockers CELL (e. Since all parasympathetic nerves release acetylclwline at their synapses. Nerve damage can be secondary to diabetic neuropathy or other neuro­ logical diseases. In congenital pyloric stenosis. What would the symptoms be if the stomach is squeezing against a closed pylorus? Well. narcotic analgesics) can result in gastroparesis. the pyloric sphincter must be patent and the stomach must squeeze the food through it. Intrinsic factor binds B12 . the baby is born with a hy­ pertrophied pylorus. drugs that block acetyl­ choline can cause gastroparesis. the following may also cause gastric in­ flammation (gastritis): alcohol. E arly satiety and ab­ dominal distension can occur as well. its pathophysiology. it can occur from the inside or from the outside. a gastric polyp. B12 cannot be absorbed. . Other Causes of Gastritis In addition to H.CHAPTER 4.g. facilitating its absorp­ tion. whenever there is obstruc­ tion. from-the-inside obstruc­ tion can occur from a foreign body.g. pylori . the py­ lorus can become scarred shut by acid in peptic ulcer 77 . vomiting is a chief complaint.

!. so progno­ sis is often relatively poor by the time the tumor is discovered. Let's review the main steps and their potential correspon­ ding pathologies. Many of the causes of gastritis also predispose to development of gastric cancer (e. obstruction. The digested products are then absorbed across the intestinal membrane. H.Surface area . further metabolized by cells of the gut wall. which fur­ ther digest the food. Food is churned and broken down in the stomach and arrives in the small intestine. Any defect in di­ gestion/absorption can lead to malabsorption.g. radiation).Acid secretion . nausea/vomiting. Enzyme secretion (Primary duodenal.l.!. . pernicious anemia. THE GASTROINTESTINAL SYSTEM Gastric Cancer the small intestine is absorption. pancreatic. The main function of Deficit in Digestion . This stimulates release of cholecystokinin (CCK) and secretin by the duodenum. . Symptoms and signs (e. though MALT (mu­ cosa-associated lymphoid tissue).Churning J.g. and passed to the bloodstream. and bleeding are possible in the small intestine. Most commonly. Surgery may be supplemented with radia­ tion and/or chemotherapy for treatment. . Any problem along this path can lead to malabsorption. DISEASES OF THE SMALL INTESTINE As with any portion of the GI tract. Causes of malabsorption. and the correspon­ ding pathology is malabsorption . or biliary disease) . early satiety.g. gastric cancer is adenocarcinoma. Pylori infec­ tion. Transport Deficit in Absorption Lymphatic obstruction CAUSES OF MALABSORPTION Figure 4-7 78 .l. . tumors. GI stromal tumor (GIST).CHAPTER 4. 4-7. Crohn's disease). g. inflammation (e. and leiomyosarcoma (smooth muscle tumor) can also occur in the stomach. GI bleed) gener­ ally occur late in the course of the disease. Gastric cancer is more common in people of Asian de­ scent. which cause the gall blad­ der to release bile and the pancreas to release HC03 and digestive enzymes (e. Causes of malabsorption can be attrib­ uted to either problems with digestion or problems with absorption . chymotrypsin). Malabsorption Fig.

using nasogastric tube de­ compression. the presentation can be later in childhood if the disease is less severe. Celiac sprue (a. Over time this excessive squeezing can weaken the walls of the large intestine. colon cancer). Tropical sprue is endemic to tropical areas. Pathologically. and bleeding can occur in the large intestine. gallstones. drugs. Diverticula can lead to lower GI bleeding and/or pain. or malignant adenocarcinomas.Pancreatic insufficiency or failure causes a de­ crease in secretion of digestive enzymes. In severe diverticulosis.g. . Complete small bowel obstruction is a surgical emergency. Crohn's disease). vomiting. Al­ though Hirschprung's disease often presents as failure to pass meconium in infancy. Failure of the first can lead to constipation. and inflammatory changes (e. nearby tumors in other organs (e. Most typically this occurs in the de­ scending colon (which lies on the left side of the body). ulcerative colitis. There are two types of sprue: celiac sprue and tropical sprue. Hirsch­ prong's should thus be ruled out as a cause of chronic constipation in children. The reaction leads to inflammation of the small intestine mucosa and subsequent malabsorption. abdominal pain. . par­ tial small bowel obstruction can usually be managed by prohibiting oral intake. and/or fatigue. small bowel tumors (these are extremely rare). . classically in the left lower quadrant (di­ verticulosis). The bowel dilates massively proximal to this denervated stretch of colon (hence the other name for this disease : aganglionic megacolon). obstruction (most commonly due to colon cancer). tumors (e. . inflammation (e.g.a. weight loss. even creating a communi­ cation between the two. The functions of the large intestine are delivery of stool to the outside and some water and sodium reab­ sorption. GI stromal tumors (GIST). leading to diverticula. . or otherwise). by tumor) Hirschprung's Disease Hirschprung's disease is a cause of constipation in children. lactase defi­ ciency leading to lactose intolerance) DISEASES OF THE LARGE INTESTINE As with any region of the GI tract.Liver disease or gall bladder obstruction leads to decreased bile acids. Irrita­ ble bowel syndrome (abdominal pain. . and administering IV fluids.CHAPTER 4. Problems with Digestion A defect in digestion can occur secondary to : • Failure of stomach acid secretion or ch urning (See Gastroparesis) • Failure of enzyme secretion into the gut lumen . Crohn's disease). neural crest cells fail to migrate to the distal portion of the colon during development. Small Bowel Tumors Small bowel tumors are extremely rare. car­ cinoids.k. or sarcomas. Constipation can occur for either of two reasons: the muscles are not squeezing appropriately. and leiomy­ omas. non-tropical sprue. parasitic infection. the infectious agent that causes it is unknown. abetalipoproteinemia) • Obstruction of the lymphatics I lacteals (e.g. In Hirschprung's disease. 1 What sits next to the descending colon? The bladder.Duodenal resection leads to loss of cholecys­ tokinin secretion and thus secondarily to reduc­ tion in pancreatic and gall bladder secretion of digestive agents. Obstruction As with the rest of the GI tract. . Diverticula If a person's diet is low in fiber. Diverticula can also become inflamed (diverticulitis). spruel) • Biochemical aberrations in transport I intracellular metabolism (e. Causes of small bowel obstruction can include: adhesions from a prior surgery. while problems with the second can lead to diarrhea .g. these may be benign adenomas..Damage to the absorbing mucosa (Crohn's dis­ ease. the small intestine can become obstructed. • Failure or decrease of an enzyme (e. . THE GASTROINTESTINAL SYS TEM potentially resulting in nausea. the diverticula can rupture and adhere to the bladder. the pathophysiology has not yet been fully elucidated. 79 . or there is some sort of obstruction (tumor. hernias. lipomas. The condition improves when gluten is no longer consumed. and/or constipation with unknown etiology) may be due to problems with regulation of gastrointestinal muscu­ lar activity. pancreas). Problems with Absorption A defect in absorption can occur secondary to: • Reduced surface area Resection of bowel . lymphomas.g. the formation of hard stools can create extra squeezing work for the large intestine. Treatment is surgical. This colovesical fistula can cause pneumaturia (air in the urine) and fecaluria (fe­ ces in the urine). Small bowel tumors can cause bleeding and/or obstruction. gluten-sensitive en­ teropathy) is caused by a reaction to gluten. diarrhea.g. a component of wheat.g. radiation.

VIPoma) intolerance) VIPoma) Figure 4-8 80 . and/or colonoscopy is recom­ mended. remains in the large intestine. INFLAMMATORY BOWEL DISEASE (IBD): CROHN'S DISEASE AND ULCERATIVE COLITIS A rare cause of diarrhea is pancreatic cholera. flexible sigmoidoscopy. Bacillus) and some viruses (e. Fig. lactose (e. abdominal pain. This excess Na+. and achlorhydria). Causes of diarrhea. decreased absorption. ischemia.and K+ secretion (into the lumen from the cells) and inhibition of one of the luminal electrolyte transporters that is responsi­ ble for Na+ absorption (from the lumen into the cells). hypokalemia. changes in bowel habits (timing. radia­ tion injury. Because colon cancer is so common. barium contrast X-ray. which results in an osmotic gradient that draws in water.g. Genetic predisposition to colon cancer oc­ curs in people with a strong family history or genetic syndromes such as hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP). Norwalk virus) cause di­ arrhea by direct damage to the intestinal wall. Other bacteria (e. drugs (e. For example. Thus. . shape of stools).. Shigella.g. relaxes gut musculature. and Cl. This condi­ tion is also known as V!Poma. Treatment involves surgery. Campylobacter. or inflammatory bowel disease ( see below). infection. infection. VIP secretion in­ hibits gastric secretion. and increases pancreatic bicarbonate secretion. where a tumor (usually in the pancreas) secretes vasoactive intestinal peptide (VIP). lower GI bleeding (often occult). resulting in over-secretion and/or decreased absorption. This damage also affects these transporters. leading to diarrhea.g. From the name ulcerative coli­ tis.. and/or lower GI bleeding. coli can also produce toxins that affect the various trans­ porters. In fact. (e. and/or intestinal obstruction.. K+. Excess VIP increases adenylate cyclase activity in the large intestine. E. What could cause too much fluid to end up at the end of the large intestine? Excess secretion.g. Colon Cancer Colon cancer (adenocarcinoma) is one of the most com­ mon cancers. which should have been broken down and absorbed in the small intestine. rotavirus. lactose.in the lumen increases lu­ minal osmolarity. or WDHA (watery diarrhea. it should be clear that the primary feature of this disease is ulceration in the colon.g. which results in increased secretion and The underlying etiology of these disorders has not yet been fully elucidated. Werner-Morrison syn­ drome. regular screening after age 50 us­ ing fecal occult blood testing. Colon cancer can present with symptoms includ­ ing abdominal pain. Colitis Inflammation of the colon (colitis) can occur secondary to infection. chemotherapy. amount. Symptoms/signs can include changes in bowel pat­ terns. Normally. water is naturally drawn into the lumen. . a patient with lactose intoler­ ance lacks adequate lactase enzyme. Since this increases the solute concentration of the in­ traluminal fluid compared with the cellular fluid around it. . or presence of some substance that increases osmolarity of the colonic contents. THE GASTROINTESTINAL SYSTEM Diarrhea decreased absorption as described above.CHAPTER 4.g. aside from the occasional occurrence of backwash ileitis. and/or radiation. ulcera- CAUSES OF DIARRHEA t Secretion t Lumen Osmolarity l Absorption (e. What else could cause excess secretion or decreased absorption? The bacterium Vibrio cholera has a toxin that activates adenylate cyclase. 4-8. This leads to activa­ tion of transporters that increase Cl. antibiotics). Salmonella. leading to decreased absorption of Na+ and/or increased secretion of K+ and CI-.

sclerosing cholangitis (in­ flammation of the bile ducts). on the other hand. blood in the stool is a common presenting symp­ tom. bleeding (e.. Mnemonic : Crohn's crosses boundaries. skin findings (pyoderma gangrenosum. When a patient vom­ its blood or has blood in the stool . scleritis). the most likely loca­ tion of the bleeding can be deduced from the history. gastric ulcer) esophageal varices) or massive bleed below GEJ BLACK/TARRY (melena) =Distal Gl bleed =Upper Gl bleed (e.g.g.g. bright red blood (hematochezia) also means that the blood has come RED DARK (coffee grounds) =Above GEJ =Below GEJ (e.g. 4-9. can occur anywhere along the GI tract. Crohn's disease . Let's begin with bloody vomit. if the bleed is so large and/or rapid that the blood does not have time to be digested. erythema nodosum). including aphthous ulcers (canker sores in the mouth). UPPER AND LOWER GI BLEEDING Fig. bleeding hemorrhoid) (e. and causes transmural inflammation (crossing histologic bound­ aries) and fissures (boundary-crossing tears). A number of associated findings can occur in inflam­ matory bowel disease. and this makes it much darker.g.CHAPTER 4. IBD can also increase colon cancer risk. and/or eye findings (iritis. As for bleeding from the rectum.. Because of the ulcer­ ation.. . If the bleeding is above the gastroesophageal j unction (GEJ). gastric ulcer) or massive upper Gl bleed or right colonic bleed LOCALIZING Gl BLEEDING Figure 4-9 81 . bleeding esophageal varices). Crohn's disease can occur from mouth to anus. Crohn's disease's effects on the small intestine can lead to mal­ absorption and B12 deficiency anemia (because dam­ age to the terminal ileum decreases B12 absorption).. the blood will have been di­ gested. If the bleeding is coming from the stomach or lower. from mouth to anus. THE GASTROINTESTINAL SYS TEM tive colitis is limited to the colon. this blood is not digested and should appear bright red in vomit (e. Localizing GI Bleeding. A massive rapid­ onset bleed from an ulcer can also cause bright red blood in the vomit. This results in the classic "coffee grounds" vomit typically found with a bleeding gastric or duodenal ulcer.

thus producing conju­ gated (direct) bilirubin. bleeding colon cancer. bleeding diverticula.g. and produces bile. What would happen if the liver failed? • Decrease in detoxification reactions . where the sclerae and skin turn yellow. For example. Summary: Red blood from mouth or anus indicates a source close to the site of bleeding whereas dark. One component of bile is bilirubin. occurs due to an increase in either con­ jugated or unconjugated bilirubin in the circulation. detoxifies vari­ ous substances. DISEASES OF THE LIVER Overview of Liver Function The hepatic portal vein drains the gut's venous sys­ tem.. facilitating their absorp­ tion.g.. digested blood indicates a more remote source.. THE GASTROINTESTINAL SYSTEM from a source relatively near to the site of exit. bleeding from the right colon).CHAPTER 4. Also. stools will typically be described as black and tarry (melena) since the blood has come from higher up in the GI tract and has thus been digested. � c w 1-w <o C!J­ ::::10 -. . e. a bleeding ulcer). 4-10. carrying absorbed nutrients to the liver.g. increasing the risk of bleeding • Failure of the liver to secrete conjugated bilirubin or failure to conjugate it. Bile emulsifies fats in the GI tract. Jaundice . the blood will not have had time to be digested and can appear as bright red blood in the vomit or stool. resulting in ac­ cumulation of toxic substances in the blood. When red blood cells break down. as well as various proteins and lipids.1-----ABC breakdown . which can lead to hepatic encephalopathy • Decrease in gluconeogenesis. which can decrease clotting factor production. Bile is produced in the liver and then drains through the intrahepatic biliary system into the extra­ hepatic biliary tree. The liver conjugates this bilirubin. which can cause j aundice Bilirubin and Jaundice Fig. The conjugated bilirubin is secreted into the bile. the liver provides much of the glucose during fasting (via gluconeogenesis and glycogenolysis). Bile metabolism and causes of jaundice.z Z::::l O< ()"":I z ::I Secretion to bile l Passage of bile BILE METABOLISM AND CAUSES OF JAUNDICE Figure 4-10 82 . since it has not been digested. . a product of the breakdown of old (or damaged) red blood cells. These are broad generalizations: If there is a sudden onset of massive bleeding below the gastroesophageal junction. stores glycogen. If there is an upper GI bleed (e.. lower GI bleeding can appear as melena. if the blood remains in the GI tract long enough before being excreted (e. . The liver performs many metabolic functions. unconju­ gated (indirect) bilirubin forms in the circulation. . bleeding hemorrhoids. which can cause fast­ ing hypoglycemia • Decrease in protein production .

Similarly. primary biliary cirrhosis) or extrahepatic (e. while a decrease in albumin is gen­ erally associated with chronic liver disease. Any disease that can damage the liver can decrease the liver's ability to secrete bilirubin (e. stones. Mnemonic: In Crigler-Najjar syn­ drome patients cannot conjugate bilirubin. Pro­ thrombin time can also be elevated with anticoagulant therapy (e. Obstruction can be due to various pathologies of the biliary tract (e. or the biliary tree is obstructed. 4-10). Decreased serum albumin can also occur in inflammatory diseases.e. measuring the integrity of the extrinsic pathway by prothrombin time is a good marker of the liver's synthetic capacity. prothrombin time assesses the extrinsic pathway of the clotting cascade. Jaundice is not the only color change when there is elevated bilirubin in the circulation due to obstruction. AST (aspartate aminotransferase) and ALT (alanine aminotransferase) are two liver enzymes involved in metabolic reactions. malnutrition. . Liver Function Tests AST. Albumin and prothrombin time assess the liver's synthetic function. In long-standing obstruction.g. In Crigler-Naijar this enzyme is extremely reduced or absent. Since secretion of bilirubin is the rate-limiting step in this process.CHAPTER 4. Elevated alkaline phosphatase can also come from bone break­ down. alkaline phos­ phatase can be mildly elevated in liver disease. So although any elevation of bilirubin (conjugated or unconjugated) can lead to jaundice. alcoholic. conjugated (di­ rect) bilirubin is often elevated in liver disease. an enzyme that participates in conjugation. the cells of the bile ducts release alkaline phosphatase ("alk phos"). 4 Mnemonic: alk phos obstruction. 4 83 Dark urine from jaundice only occurs when the bilirubin is con­ jugated. 2 When the biliary tree is obstructed. What would cause a backup of conjugated bilirubin in the blood? Either the liver does not accomplish the final step of secreting the bilirubin into the bile ducts. or autoimmune hepatitis). = Bilirubin. albumin. and may even be asymptomatic.g. Any obstruction in the biliary tree can cause a backup of conjugated bilirubin. Dubin-Johnson and Rotor syndromes are genetic defects that impair secretion of bilirubin into the bile. whereas in Gilbert's it is only mildly reduced. deficient clotting (and hence elevated prothrombin time) can result from liver disease. granu­ loma. so albumin level measures the liver's capacity for protein synthesis. albumin level can decrease in liver disease. Since factor VII is rapidly degraded. and Prothrombin Time Bilirubin. Albumin. or decreased con­ jugation of bilirubin by the liver. there must be either increased production of bilirubin. and Alkaline Phosphatase Elevated prothrombin time is more associated with acute liver disease. Thus. cancer. and prothrombin time are meas­ ures of liver function . se­ vere trauma. Although AST. Specifically. leading to an elevation of uncon­ jugated bilirubin. Since bilirubin comes from the breakdown of old or damaged red cells. they are mark­ ers of injury to hepatocytes CAST and ALT) or the bile ducts (alkaline phosphatase). resulting in unconjugated jaundice. inflammatory disease. Alkaline phosphatase is mainly present in the cells of the bile ducts.g. the liver cells release AST and ALT into the circulation. namely factor VII. ALT. 6-10).g. The site of obstruction can be intrahepatic (e. THE GASTROINTESTINAL SYSTEM For unconjugated (indirect) bilirubin to increase. Prothrombin time measures function in part of the clotting cascade (see Fig. from a failure to secrete bilirubin or biliary obstruc­ tion) that the urine can become dark. patients can't get the bilirubin into the liver (decreased uptake) and cannot conjugate it. the AST and ALT may begin to rise as well. Gilbert's is a much milder disease." they do not measure liver function . toxin-induced hepatic failure or infectious. and alkaline phosphatase are commonly referred to as "liver function tests. Congestive heart failure reduces blood flow to the liver. this means that the bilirubin has made it into the liver and conju­ gation has occurred. . . nephritic syndrome). coumadin) and vitamin K deficiency. Since the liver synthe­ sizes most of the coagulation factors. cancer). stricture. In Gilbert's syndrome. . This increase can exceed the liver's capacity to conjugate. which can decrease delivery of bilirubin for conjugation. 2 3 Both Crigler-Naijar and Gilbert's syndromes are associated with mutations in uridinediphospho-glucuronate glucuronosyl­ transferase (UGT). cancer). Bile salt deposits in the skin lead to severe itching (pruritis). Albumin is a serum protein syn­ thesized by the liver. and diseases causing pro­ teinuria (e.g. Decreased uptake and conjugation can also occur secondary to two genetic syndromes: Crigler-Naj­ jar and Gilbert's. de­ creased uptake ofbilirubin by the liver. Excess pigment that arrives in the urine leads to dark (tea-colored) urine. 3 Lack of bile pigment making it to the GI tract (secondary to the obstruction) leads to lack of this pigment in the stool (clay-colored stools). ALT. In liver disease.. stones. . it is only when the elevation is predominantly conju­ gated (i. . What about increases in conjugated bilirubin? If the elevation of bilirubin is largely conjugated. though typically the rise is far less dramatic than that of the alkaline phosphatase. but the AST and ALT are generally elevated to a much greater extent. any cause of hemolytic anemia would lead to increased pro­ duction of bilirubin. This is because unconjugated bilirubin is not water­ soluble and thus does not end up in the urine.g. . Rather. Bilirubin is discussed above as a measure of the liver's ability to perform enzymatic and metabolic function(s) such as conjugation of un­ conjugated bilirubin and secretion of conjugated bilirubin (see Fig. Thus.

toxin­ induced liver disease (e. • • Scree n i n g : anti . and cause an acute h epatitis. cAg = core antige n . Any liver disease can lead to jaundice and elevation ofliver enzymes. There is some association with obesity and diabetes. alpha-1 antitrypsin deficiency. Diseases of the Liver Parenchyma Fatty Liver (hepatic steatosis) can occur secondary to alcohol abuse (alcoholic liver disease) or in patients with no history of alcohol use (non-alcoholic fatty liver disease). de­ creased serum albumin.H BV antibodies h e l p c u re i nfection. Increased conjugated bilirubin.H BeAg = Low i nfectivity (sAg = s u rface anti g e n . Non-alcoholic fatty liver (also known as nonalcoholic steatohepatitis NASH) is a condition in which liver disease develops with the same histological pattern as in alcoholic liver disease despite lack ofsignificant alcohol consumption. - Figure 4.Never becomes c h ronic Acute vi ral hepatitis F u l m i nant hepatitis: severe acute hepatitis with rapid destruction of the liver C h ronic hepatitis (1 0%) .1 % develop f u l m i nant hepatitis . which is scarring of the liver parenchyma. Complications: • • Hepatitis E • Fecal-oral • F u l m i nant hepatitis Ci rrhosis Hepatitis ( l i ke hepatitis A) Modified from G l adwin and Trattler: Clinical Microbiology Made Ridiculously Simple. 4-11.50% will get chronic hepatitis .g.Asymptomatic carrier . elevated AST and ALT indicate liver injury and elevated alkaline phosphatase can suggest biliary obstruction .C h ronic persistent hepatitis . Viral hepatitis. autoimmune liver disease.Hepatitis Delta Virus (H DV) • Hepatitis C • • • • Hepatitis D • • • • Blood transfusion Needle sticks Sexual Across the placenta Blood transfusion Needle sticks • • Sexual Across the placenta • • • • • • • Anti . . Cirrhosis can cause an elevated pres­ sure/resistance to blood flow and thus portal hyperten­ sion . drugs. alcohol). Viral Hep atitis.I ncreased risk of developing primary hepatoce l lu la r carcinoma Coi nfection: H BV and H DV are acq u i red at the same time. no active d isease p rotective against repeated i nfection H BsAg = D i sease (Acute or C h ronic) Anti. e . GGT (gamma. Wilson's disease.H AV l g M = Active d isease Anti -HAV lgG = Old.glutamyltransferase) is typi­ cally elevated in alcoholics.H CV antibodies Serology is not very helpful since detectable titers of lgM and lgG anti-H DV are p resent only fleeti ngly. Any of these diseases can also eventually lead to cirrhosis. jaundice. hepatic steatosis. THE GASTROINTESTINAL SYSTEM In summary. and a painful enlarged l iver .C h ronic active hepatitis Coi nfection or superi nfection with . Anti .20% will develop ci rrhosis . MedMaste r 84 2004 . and/or increased prothrombin time can all indicate decreased liver function . Cirrhosis (or any of its causes) can also increase the risk of hepatic cancer (hepatocellular carcinoma).1 1 Viral Hepatitis TYPE TRANSMISSION Hepatitis A • Hepatitis B • • • • Fecal-oral Blood transfusion Needle sticks Sexual Across the placenta CLIN ICAL • • • • • SEROLOGY Acute viral hepatitis: fever. Superi nfection: H DV i nfects a patient with c h ronic hepatitis B who cannot man ufacture Anti-H bsAg antibodies. Causes of liver disease include: viral hepatitis. Drug Reactions can be acute (adverse reaction to a drug or overdose) or chronic (i. Addi­ tionally. Fig. classically in a 2 :1 ratio. and he­ patic neoplasia. eAg = envelope antigen) Complications: • • • Primary hepatocellular carci noma Ci rrhosis Acute viral hepatitis . from sustained use). .CHAPTER 4. hemochromatosis.H BsAg = i m m u n ity: p rovides p rotection against repeat infection l g M anti-H BcAg = New i nfection l g G anti-H BcAg = Old i nfection H BeAg = H i g h i nfectivity Anti . Alcoholic liver disease typically produces mild elevations of AST:ALT.

hemochromatosis. should warrant a work-up for hemochromatosis. In Wilson 's disease.g. Rupture of a tumor can lead to acute ab­ dominal pain. rash. Benign hepatic adenoma is more common in women and often secondary to oral contraceptive use. The skin can become bronze. leading to deposition of copper in the liver (which can lead to cirrhosis). autoimmune hepatitis tends to affect women predominantly and can be associated with other autoimmune conditions (e. Autoimmune Hep atitis. even in a healthy patient. Metas­ tases to the liver are more common than primary hepa­ tocellular carcinoma in the United States. Iron accumulation in the pancreas can cause diabetes. which will both be elevated in hemochromatosis. THE GASTROINTESTINAL SYSTEM Liver biopsy demonstrating excess copper can confirm the diagnosis. Deficiency of this enzyme in the lungs can lead to (panlobular) emphy­ sema. A low alpha-1 antitrypsin level in the serum and genetic testing (phenotyping) are neces­ sary for diagnosis. Disease of the Liver Vasculature: Portal Hypertension Fig. Hepatic portal system and sites of origin of portal hypertension. aflatoxin) as well as anything that causes cirrhosis (e. constrictive pericard itis) INTRAHEPA TIC (e. some clinicians would ar­ gue that a mild elevation of liver enzymes (AST /ALT). The work-up assesses transfer­ rin saturation and ferritin. and radiation. chemotherapy. weight loss). alcohol.CHAPTER 4.g. Ma­ lignant tumors may be primary or metastatic. restrictive card iomyopathy.g. . Anti-smooth muscle antibodies are associated with autoimmune hepatitis. Iron deposition in the liver can result in cirrhosis. g . thyroid disease). This can lead to iron deposition in the heart. g . Hemochromatosis is an autosomal recessive disease that results in an abnormally high amount of iron in the blood. Deposition in the pituitary can also occur. and these H E PATIC VEIN POSTHEPA TIC (e. brain (which can cause movement disor­ ders). causing restrictive cardiomyopathy. . while deficiency of this enzyme in the liver can lead to cirrhosis. another autosomal recessive dis­ ease. since iron can be deposited there as well (hence the nickname ''bronze diabetes" for hemochromatosis). there is decreased copper excretion. malaise. Budd-Chiari synd rome. The portal venous sys­ tem branches extensively within the liver. An enlarged liver or palpable mass may be present on physical exam. Risk for hepatocellular carcinoma is increased by vari­ ous carcinogens (e. Genetic testing and liver biopsy to measure iron can confirm the diagnosis. Alp ha-1 antitryp sin deficiency.. hepati­ tis B and C infection). and/or the eyes (which can result in a Kayser­ Fleischer ring).g. 4-12. Elevated alpha-fetoprotein (AFP) is often seen with hepatocellular carcinoma. Treatment involves surgery. The hepatic portal vein brings blood to the liver from the gut. . Like many other autoim­ mune diseases. . ci rrhosi s) P R E H E PATIC (e. Therefore. Hep atic Neop lasm may be benign or malignant. Low serum ceruloplasmin (the serum protein that carries copper) and increased urinary cop­ per are the classic lab findings in Wilson's disease. right heart fa i l u re. It is thought that hemochromatosis is far more common than previ­ ously imagined. thrombosis) PORTA L VEIN HEPATIC PORTAL SYSTEM AND SITES OF ORIGIN OF PORTAL HYPERTENSION Figure 4-1 2 85 . Any of these may cause right upper quadrant pain and con­ stitutional symptoms (fever. arthralgia.

the hepatic venous system can be divided into 3 regions: prehepatic (the portal vein). Bleeding varices require immediate in­ tervention using vasoconstrictive drugs to reduce flow to the varices (e.CHAPTER 4. many of the more chronic causes of cirrhosis result in a slower emergence of portal hypertension. The serum-ascites albumin gradient (SAAG) can help de­ termine if the etiology is portal hypertension or not. . umbilical vein. The umbilical veins can sometimes be seen on physical exam as a caput medusa (varicose veins around the navel). so resistance to flow in this system can also increase portal pressure (e.g. Another way to reduce pressure in varices is by sur­ gical shunting. 5 DISEASES OF THE GALL BLADDER AND BILE DUCTS Fig. SAAG > 1. A large number white blood cells in the fluid in­ dicates inflammation or infection. an increase in pressure in the hepatic vascular system. reducing the risk of variceal rupture.1 g/dl. . Thus. toxic chemicals can affect the brain. in an attempt to prevent their rupture. If the patient survives. and in other causes of ascites. secondary to right heart failure. though ascites can also re­ sult from infection. Shunts give the blood a path of lesser re­ sistance so as to reduce pressure on varices. These veins are not accustomed to handling such large blood volume and they dilate (varices). What are the consequences of hepatic venous system obstruction? An acute event (like thrombosis of the portal or hepatic vein) can lead to acute liver failure. restrictive cardiomyopathy. re­ sulting in delirium (hepatic encephalopathy). . intrahepatic (the portal venous system within the liver itself) . Thus. and thus has a lower albumin con­ centration than ascites fluid in infection or malig­ nancy. or endo­ scopic ligation (putting rubber bands around the varices). 6 Although shunts reduce flow to varices. endo­ scopic sclerotherapy (burning the varices). The classic scenario in which to sus­ pect bleeding varices is an alcoholic patient who comes to the emergency room vomiting blood. or con­ strictive pericarditis). As discussed above. The enlarged spleen starts overdoing its job (hypersplenism) . the SAAG tends to be higher in portal hypertension than in other causes of ascites (since a smaller number is being subtracted from the serum albumin concentration). Biliary tree anatomy. or a trans­ jugular intrahepatic portosystemic shunt (TIPS) can be placed linking the hepatic portal vein to the hepatic vein directly. The common hepatic duct j oins the cystic 6 There are many possible causes of thrombosis. causing a massive ( and often lethal) bleed. including any cause of a hypercoagulable state (see Chapter 6). beta-blockers can be used to reduce portal pressure. which joins with the inferior vena cava. Cytology can be performed to look for malignant cells. much of the blood that normally passes through the liver now gets back to the heart without undergoing the myriad of chemical reactions that normally occur in the liver. Fluid in portal hypertension tends to be relatively dilute. The backup into the spleen causes it to enlarge. 86 The "jugular" part of the name is because the shunt is placed through catheters inserted into the jugular vein. Portal hypertension. cultures can be performed to search for specific organisms. or if a shunt allows circumven­ tion of the liver. and post-hepatic (the hepatic vein). If this system is blocked for any reason. If liver failure decreases detoxification reactions. A shunt can be placed from the hepatic portal vein to the inferior vena cava. can result from pathol­ ogy at any of these sites: • A large amount of blood flows through the portal system to the liver. The enlarged hemorrhoidal veins around the anus can present as hemorrhoids.g. Prehepatic : The portal vein can be thrombosed. • Posthepatic : The hepatic vein can be thrombosed (Budd­ Chiari syndrome). which can lead to ascites (fluid in the abdomen) and varices (venous dilatation). A sample of ascites fluid can be extracted (paracentesis) and studied to diagnosis the cause of as­ cites. the liver is a major metabolic and detoxification center.1 g/dl. SAAG < 1. which fuse to form the common he­ patic duct. Ascites Cirrhosis-induced portal hypertension is the most common causes of ascites. However. and esophageal/gastric veins. Generally. SAAG is measured by subtracting the albumin con­ centration in the ascites fluid from the albumin level in the serum. and so it re­ verses flow back down the portal system into other veins to do so. THE GASTROINTESTINAL SYSTEM Varices branches rej oin to form the hepatic vein. and nephrotic syn­ drome. The esophageal and gastric venous dilatations (varices) can rupture. 5 • Intrahepatic : Any liver disease that causes cirrho­ sis can cause changes in the vascular system lead­ ing to portal hypertension. The intrahepatic bil­ iary system in the liver gives rise to the right and left hepatic ducts. These veins include the splenic vein. the blood needs to find a way back to the heart. hemorrhoidal veins. in portal hyperten­ sion. which causes an increased removal of blood elements and can lead to anemia. malignancy. 4-13. vasopressin or octreotide). or from the splenic vein to the renal vein. The hepatic vein connects to the inferior vena cava.

. Upon arrival of partially digested food in the duodenum from the stomach . Excess choles­ terol occurs in the classic "female. Obstruction also leads to backup of bile/bilirubin._-.). What could go wrong with bile ducts? Since we're deal­ ing with tubes. as long as concentrations of all components nee- 87 . duct (which leads to the gall bladder) to form the common bile duct. This stimulates contraction of the gall bladder and release of bile. Excess pigment can occur secondary to hemolysis (e. MedMaster 2004 essary for bile synthesis are in the appropriate equi­ librium. stones should not form in the biliary sys­ tem. Ultrasound of the biliary system can look for stones or dilation of the ducts (which would suggest distal obstruction). in sickle cell disease).. THE GASTROINTESTINAL SYSTEM R. and biliary atresia are the most common causes of biliary obstruction. Predisposition to gallstones forma­ tion also occurs when there is excessive stasis in the gall bladder. Another type of pigment stone. this is choledocholithiasis and can lead to cholecystitis (inflammation of the gall blad­ der). which is then stored in the gall bladder. causing black stones or cholesterol stones. Obstruc­ tion prevents bile from making it to the duodenum. classically in the right up­ per quadrant.__. alk phos is typically elevated. This leads to intermittent crampy pain. Gallstones (Cholelithiasis) Normally. Remember that in obstruction. HEPATIC DUCTS A M PULLA OF VATER MAIN PANC REATIC . Large gallstones that stay in the gall bladder are not as bad as they sound. which emulsifies fats for absorption. How could the biliary system become obstructed? Obstruction by a gallstone or tumor. fat. If the stones are small enough to pass into the cystic duct. The two main components are (1) pigment from bilirubin breakdown and (2) cholesterol.. leading to j aundice and potentially to liver damage.CHAPTER 4.J DUCT BILIARY TREE ANATOMY Figure 4-1 3... The liver constantly produces bile._. but get stuck before the common bile duct. inflamma­ tion I scarring of the biliary tree. cholecystikinin (CCK) is released. bowel obstruction. Modified from Goldberg: Clinical Anatomy Made Ridiculously Simple. forty. & L. brown stones.. respectively. which usually unites with the pan­ creatic duct at its entry into the duodenum. they simply stay there since they are too big to pass into the cystic duct or common bile duct. The obstruction of a tube is painful because the proximal tube ( and in this case the gall bladder) squeezes to try to push the obstruction away (a simi­ lar phenomenon occurs with kidney stones passing into the ureters. fertile" sce­ nario. etc.g.. obstruction is one possibility. Ex­ cesses of either of these components can lead to stone formation. and this can lead to decreased fat breakdown. causing fat malabsorption. can form from the products of bacterial metabolism in biliary infection.

leading to inability to se­ crete its digestive enzymes. and many other autoimmune diseases. (Remember the rhyme/chant "sclerosing cholanGI­ tis. sclerosing cholanGitis. the Kasai procedure removes the obliterated ducts and reconnects the duodenum to the liver to normalize the flow of bile. When a gallstone lodges in the distal bile duct at its entrance to the duodenum. The treatment of cholangiocarcinoma involves surgery. excess glu­ cagon secretion leads to hyperglycemia. So pancreatic cancer should be part of the differential diagnosis ofj aundice. usually ulcerative co­ litis. Inflammatory Diseases of the Biliary System Primary Biliary Cirrhosis is an autoimmune dis­ ease in which the autoimmunity is directed at the in­ trahepatic biliary ducts. This can obstruct the pancreatic duct and is one of the most common causes of pancreatitis. The two most common causes of pancreatitis are alcohol and gallstones. primary sclerosing cholangitis. Remember that obstruction leads to elevated alk phos. where it j oins the pancreatic duct. and the bile ducts' release of alkaline phosphatase when damaged. hypercalcemia. In glucagonoma. for example. Other p ancreatic tumors include gastrinoma (see Zollinger-Ellison Syndrome). This not only affects gall bladder out­ flow but liver bile outflow as well. Pancreatic cancer.g. Glucagon normally increases blood sugar. leading to gallstone ileus. lipase. Antimitochondrial antibod­ ies are associated with primary biliary cirrhosis. It presents as jaundice and can lead to cirrhosis severe enough to require liver transplantation if not detected early. Due to the anatomical location of the pancreas (adj acent to the bile ducts). ulcerative coLitis. leading to j aundice. The stone can pass all the way to the entrance of the duct at the duodenum. The post-opera- 7 88 Amylase can also be elevated if there is a salivary gland tumor (salivary amylase). For more on cystic fibrosis. 7 Other causes of pancreatitis. The result is scarring and obstruction of these ducts. and somatostatinoma . Cancer of the Bile Ducts (Cholangiocarcinoma) Cholangiocarcinoma can obstruct the bile ducts. . endocrine and exocrine. see Chapter 2. primary biliary cirrhosis. the anatomy is such that this can also obstruct the distal pancreatic duct. The resulting malabsorp­ tion can give rise to floating. and toxins. foul-smelling stools. This can lead to jaundice. scorpion bite. Analogous to the liver's re­ lease of AST and ALT when injured. . The pancreas has two main functions. include drugs. primary sclerosing cholangitis predominantly affects men. Cholangiocarcinoma is associ­ ated with parasitic infection (e. As with any organ. amylase) and bi­ carbonate into the duodenum (first portion of the small intestine). VIPoma (see diarrhea). chymotrypsin. THE GASTROINTESTINAL SYSTEM The stone can also pass into the common bile duct and obstruct it. a cancerous growth within it can obstruct the bile duct. . Pri­ mary biliary cirrhosis predominantly affects women. thickened secretions clog the pancreas. radiation. the pancreas releases amylase and lipase when affected. DISEASES OF THE PANCREAS The stone can pass into the duodenum and obstruct it. A rash called necrolytic migrating erythema is commonly found in patients with glucagonoma. but is often asympto­ matic and discovered incidentally upon removal of the gall bladder for cholelithiasis. Clonorchis sinen­ sis) of the liver. Gallstones also predispose to development of gall bladder cancer.CHAPTER 4. malabsorp­ tion can occur. ulcerative coLitis . aside from alcohol and gall­ stones. Pancreatic Tumors Primary Sclerosing Cholangitis is a disease of the larger bile ducts."). If there is a problem with the pancreas' abil­ ity to make or secrete its digestive enzymes. . and hereditary pancreatitis syndromes. the pancreas can become in­ flamed (pancreatitis) or develop cancer. The exocrine function is the production and release of digestive en­ zymes (trypsin. Excess somatostatin secretion in somatostatinoma Biliary Atresia Biliary atresia is inflammation and obliteration of the extrahepatic biliary system in the neonate. Pancreatitis Pancreatitis is an inflammation of the pancreas. The endocrine portion regulates blood glucose via glucagon and insulin (see Chapter 5). tive proximity of the gut environment to the liver can result in infection (ascending cholangitis). Gall bladder cancer can pres­ ent just as does cholecystitis. Bile duct cancer (cholangiocarcinoma) risk is elevated in primary sclerosing cholangitis. Pancreatitis generally presents as mid-epigastric pain radiating to the back. so these levels can be elevated in pancreatitis. Treatment is surgical . gluca­ gonoma . In cystic fibrosis. Primary sclerosing cholangitis is associated with inflammatory bowel disease. Somatostatin normally inhibits production of GI hormones and secretions. . leading to jaundice. insulinoma (see hypogly­ cemia in Chapter 5). and chemotherapy. In contrast to autoimmune hepatitis.

bile duct. ureters. or a hyper­ coagulable state can cause mesenteric ischemia (is­ chemia and potential infarction of a region of gut). ureters). in sickle cell) • Ovaries: cysts. or alco­ holic hepatitis) • Pancreas: pancreatitis (many potential causes in­ cluding. . viral. de­ creased insulin secretion (causing diabetes mellitus). Other causes of obstruction include tu­ mors (of the GI tract or adj acent organs). vasculitis. physical exam. tumors. What can make tubes hurt? One cause is obstruc­ tion. and the testicle/spermatic cord can all twist around them­ selves. ovaries. the reproductive system (females : ovaries. . THE GASTROINTESTINAL SYSTEM causes inhibition of pancreatic enzymes (leading to malabsorption. gynecologic procedures). What is in the abdomen? The GI system (stomach. Abdominal pain is a common complaint in the emer­ gency room and office. a gastric or duodenal ulcer can perforate. bladder). liver. . pan­ creas). Causes of inflammation in abdominal organs include: The next question is: How can each of these be painful? We can divide the abdominal contents into tubes (gut. and blood vessels .g. What can obstruct these tubes? Kidney stones can obstruct ureters . Pregnancy itself can cause abdominal pain. but if it turns out that either of these is present in the past medical history. leading to intense pain. when the pregnancy inappropriately im­ plants in the fallopian tube or elsewhere in the ab­ domen.g. 89 . kidneys). We have already mentioned that ischemia/infarction can occur due to obstruction (e. hernia (if a loop of bowel gets stuck in the hernia opening and ob­ structs itself). pancreas. What could get stuck in the fallopian tubes? Any female patient of reproductive age with abdominal pain needs a pregnancy test. or ectopic pregnancy How could the blood supply cause pain? Is­ chemia/infarction is quite painful. If a patient complains of abdominal pain. small intestine.g. let's answer the fol­ lowing questions: What structures are in the ab­ domen. For ex­ ample. but so can a tubal (ectopic) pregnancy. . and how can these things cause pain? With any type of pain. An embolus in an abdominal vessel.g. diarrhea. herpes zoster (shingles). males: embryologically. Tubes can also cause pain if they perforate.g. the spleen .CHAPTER 4. gastritis. An abdominal aortic aneurysm can also cause abdominal pain. What else might obstruct the fallopian tubes? Pelvic inflammatory disease (PID) is an infection of the female reproductive organs that often presents as lower abdominal pain (common culprits are gon­ orrhea and chlamydia). What can cause pain in the abdominal wall? Trauma. • Bowel: inflammatory bowel disease. gallstones can obstruct bile ducts. Additionally. this would certainly cause you to re-juggle your list of pos­ sible etiologies. torsion or herniation can lead to ischemia of the tube in question. autoimmune. and hence weight loss). fallopian tubes. Appen­ dicitis is usually due to obstruction from a fecalith or hypertrophy of lymph tissue in the appendix. secondary to torsion or hernia). So pus or abscess (tuba-ovar­ ian abscess) can also obstruct tubes. most commonly gallstone obstruction of the pancreatic duct and alcoholism) • Kidney: infection (e. and the abdominal wall. think about what is in/near the re­ gion of interest and what might cause any of these things to be painful. The GI tract can also become obstructed. Infection or inflammation of any tube can also cause pain. Before we deal with the ques­ tions. pyelonephritis) • Spleen : infarction (e. and volvulus (twisting of the intestine around itself). What is another way a tube can get obstructed be­ sides getting something stuck in it or against it? One way is torsion : the gut. the urinary system (kidneys. the blood supply to all of these organs from the abdom­ inal aorta and its branches. vasculitis or a hypercoagulable state might not be first on your list in a differential diagnosis. . What can make the solid organs hurt? Any organ with a tumor (benign or malignant) can cause pain due to stretching of the organ's capsule or pressure on adjacent structures (although not all tumors cause pain). solid or­ gans (liver. This squeezing of the tube against resistance leads to the phenomenon of cramping. and can refer pain to the abdomen). uterus. and decreased gall bladder activity (which can cause gallstones). Anything that could cause inflammation/swelling could be painful. the testes descend from the ab­ domen. APPROACH TO ABDOMINAL PAIN Why is obstruction painful? Any obstructed tube builds up pressure behind it. as can ischemic bowel or a diverticulum. hernia. the fallopian tube/ovary. spleen. torsion. prior surgery. large intestine. gall bladder. and lab tests that you would use to solve a case of abdominal pain. colitis • Liver: hepatitis (e. A com­ mon cause of bowel obstruction is adhesions/scarring from previous abdominal surgery (e.

CHAPTER 4. In all quadrants: bowel Bilateral posterior: kidneys/ureters Midline. The four quadrants. left ovary/fallopian tube RUQ : liver. and ischemia or infarction secondary to alteration in blood supply. perforated. abdominal organ dysfunction can produce other symptoms and signs. bleeding varices . Alteration in the blood supply (such as that due to an embolus) is typically sudden in onset. kidneys. the patient can have referred pain in the j aw or down the left arm. and 5 keep the diaphragm alive"). In addition to pain. An inferior myocardial infarction or lower lobe pneumo­ nia can thus present as abdominal pain . In the clas­ sic heart attack scenario. Pain afferents from the viscera often share spinal cord synapses with sensory afferents from other parts of the body. or tumor of solid organs. what is painful is not so much the blockage but the proximal squeezing of the tube trying to squeeze the obstruction away. we have the GI .g. Timing. which migrates to the right lower quadrant. bladder Bilateral : ovaries. 5. The later right lower quadrant pain signifies peri­ toneal irritation in that specific location. Blood or pus in the urine or in the stool or from the vagina could indicate renal. and blood vessels. Fig. inflammation. etc. solid organs can get inflamed. Diaphrag­ matic irritation thus refers pain to the sites of somatic innervation of C 3. THE GASTROINTESTINAL SYSTEM Diagnosis of Abdominal Pain or a focus of endometriosis on the abdominal wall can also cause abdominal pain. in the abdomen. Severity/quality.g. 4-9). Vomiting blood that is red vs. acute hepati­ tis) or any other inflammatory process. namely the shoulder blades. when the viscera scream in pain. 4. phenomena such as jaun­ dice. The diaphragm is innervated by the phrenic nerve ("C 3. 4. decreased albumin. Thus. elevated bilirubin. Associated symptoms . and the blood supply which branches off the aorta: tubes. Solid organ pain (e. It can be sharp or dull. Fever can be due to an infection (pelvic inflammatory disease. Appendicitis classically begins as peri-umbilical pain. the spleen. and right lower quadrant (RLQ). or infected. The testicles descend from the abdomen during development. . it is more likely to be above the gastroesoph­ ageal junction. testicular torsion. and/or coagulation dysfunction (due to decreased clotting factor production) with concomitant abdominal pain could help make a diagnosis of some hepatic problem. but there is typically no squeezing or cramping sensation. The most likely cause(s) of pain in any given region are those related to the organ(s) that are in that re­ gion. right upper quadrant (RUQ). their scream may sound to the brain like some other part of the body screaming. If the pain is unrelated to eating or bowel move­ ments. GI . left lower quadrant (LLQ).g. Upper midline (posterior): pancreas. gastroenteritis. the ab­ dominal wall may be the site of pathology. History To review. inflam­ mation) is generally more constant. anterior: uterus. 90 . We mentioned above that causes of pain in the abdomen are obstruction of tubes. from tumor. so asking the patient "Where does it hurt?" is a good place to start. see Ch. inflamed. gall bladder. gastroesophageal junction. 9). The structures in each of these regions are as follows. The abdomen is typi­ cally divided in the left upper quadrant (LUQ). Com­ monly. How would these types of pain differ? In ob­ struction. bile duct RLQ : appendix. Recall the various responsibilities of the liver: bilirubin conjugation. Thus. detoxi­ fication reactions. right ovary/fallopian tube The diaphragm lies just above the abdomen. e. solid or­ gans. vomiting blood that is digested (coffee grounds) can suggest the source of bleeding (if it is red blood. 4-14. and thus abdominal pain can be re­ ferred pain from the testicles (e. spleen LLQ : descending colon (common site of diverticula). The peri-umbilical pain is referred pain . and tends to occur with postural changes and/or tensing of the abdominal wall muscles. and the lungs and heart lie just above the diaphragm. Abdominal vis­ cera also refer pain. posterior: aorta Referred pain . respectively. whereas a tumor characteristically has a more insidi­ ous time course. or gynecologic cause of abdominal pain. How would this feel? Typically squeezing leads to cramping pain . or develop a neo­ plasm. ureters LUQ : stomach. patients with a ureteral stone writhe and can­ not get comfortable as a result of this cramping. and reproductive systems. . protein manufacturing. and blood vessels can have an aneurysm or lead to ischemia/infarction. . infection. Vomiting can result from obstruction or gastroenteritis (which might have accompanying fever and/or diarrhea). see Fig. aorta Lower midline. pyelonephritis. infection. So pain in the region of the right shoulder blade can sig­ nify gall bladder disease. The differential diagnosis for abdominal pain comes from realizing that tubes can get obstructed. urinary. infected.

?} AORTA _ LLQ RLQ APPENDIX BLADDER Figure 4-1 4 Examples: 91 .CHAPTER 4.�c:.· ASCEN DING --+----j• COLON SMALL I NTESTI N E �·�-\-.. THE GASTROINTESTINAL SYSTEM RUQ L UQ R KIDNEY L KIDNEY .#.DESCENDING COLON ___Jl--r.:.

g. 92 A high WBC count can indicate an infectious/ inflammatory process (e. bleeding ulcer) or undi­ gested (bright red and thus likely from above the gas­ troesophageal junction. Obviously. ruptured ovarian cyst. ovary. and imaging can help you to zero in on a diagnosis. or if there is congestion secondary to portal hypertension or right-sided heart failure. observation is important in assessing the severity of the situation: Do you need to stabilize this patient before taking a history? What's there? The liver and the gall bladder. . Physical Exam What's there? Pancreas. . Colitis can also . This is the classic presentation of a gallstone ("fat. this would increase the likelihood of pancreatitis or ulcer. ectopic pregnancy. fallopian tube. a chest X-ray would be necessary to evaluate the possibility of pneumonia. for example. and aortic aneurysm. . . deep palpation or light touch? Rebound pain (which oc­ curs when withdrawing one's hands from the abdomen) and guarding (spontaneous contraction of the abdomi­ nal musculature) indicate peritoneal inflammation (peritonitis). obstruction. bleeding varices)? Observation.g. and pelvic inflammatory disease are all possibilities. What's there? Appendix. what else is there? Left ovary/tube. inferior myocardial infarction. A 45-year-old woman has crampy RUQ pain after finishing dinner. Physical. A lot of air makes a hollow sound. lipase) would favor pancreatitis. radiating through to the back. looks like coffee grounds and thus comes from the stomach or lower. The renal artery or aorta can be occluded by atherosclerosis and can create bruits. THE GASTROINTESTINAL SYSTEM • • A 50-year-old man has "boring'' pain in the center of the upper abdomen. fever. e. fluids and solids make dull sounds. A 30-year-old woman has severe RLQ pain.g. you can percuss out its size. forty. fertile female"). Labs (e. Is the patient writhing in pain (e. High-pitched sounds and/or absence of bowel sounds can both be due to obstruction (imagine the obstructed bowel not making any noise or air squeaking by the obstruction). pel­ vic inflammatory disease). What could cause cramps? Obstruction of a tube. Because the liver is solid and dull. type of pain. This is the classic story for diverticulitis. so ovarian neoplasm would also be on the list. So a lot of air (e. in a dilated bowel proximal to an obstruction) would give a tympanitic sound.g. That differential will serve to guide your history. Palpation. liver disease)? Is the patient vom­ iting? Is the vomit bloody? Is the blood in the vomit di­ gested (i. and im­ aging can help to distinguish among them. Laboratory Tests • The point of presenting these brief vignettes is to demonstrate an important point: upon hearing the chief complaint. A 75. there are many other reasons for WBC count to be elevated (see Chapter 6). part of the small intestine. . ovarian torsion. . Fluid (e.g. . if there is tumor in the liver (primary or metastatic).CHAPTER 4. and thinking about the anatomy and physiology of the abdominal organs. physical exam.year-old man has LLQ pain. This can occur in pelvic inflammatory dis­ ease. ascites) would be dull. . peritonitis)? Is the abdomen distended (e. a high WBC with LLQ pain. Although this story is classic for gall bladder disease. and cough.g. the inferior border of the heart. el­ evated amylase.e. acute appendicitis. stomach. So appendicitis. ascites or obstruction of a tube causing proximal dilation)? Does the patient look diaphoretic. in the case of abdom­ inal pain. appendicitis. . So your initial differential should include pancreatitis. and diagnostic work-up to arrive at the diagnosis. If you now find out that the patient is an alcoholic. e.g. would be key to nar­ rowing down this differential. • Pelvic exam can help to determine if pelvic inflam­ matory disease or any of the gynecologic causes dis­ cussed above are producing the abdominal pain. • Auscultation. and a high WBC count with RLQ pain could be appendicitis. .g. Of course. Which quadrant is painful? Is the pain on A young boy has periumbilical pain for 3 hours and now complains of pain in the RLQ.g. ulcer. . . remember that right next to the upper quadrants are the lower lung fields. However. but if it were a woman.g. The time course.g. . and the aorta. • Percussion. a differential be­ gins to form in your mind. Is there a pulsating mass (abdominal aortic aneurysm)? A classic story for appendicitis. labs. etc. clammy (e. some kind o f obstruction o f some tube)? I s the patient lying absolutely still (e. pale. bleeding or myocardial infarction)? Does the patient have caput medusa or other evidence of dilated veins (e. or with ruptured bowel. could be diverticulitis . It may be enlarged in any cause of cirrhosis. though it would also typically present with sudden pain and swelling of the scrotum. So if the case were a 45-year-old woman with RUQ pain. but what else is there? Referred pain from a torsed testicle could also cause RLQ pain.

cancer). sources of bleeding. tumors. Alkaline phosphatase. THE GASTROINTESTINAL SYSTEM Imaging and Endoscopy present with abdominal pain and an elevated WBC count. .g.). or the appendix (for appendicitis). or varices. . Conjugated bilirubin can be elevated in any liver disease. secondary to primary biliary cirrhosis. • Abdominal MRI and CT scanning can be used to look for malignancy. hepatitis) as opposed to biliary tract obstruction. congestive heart failure. and/or nephrotic syndrome). or causes of obstruction. 93 • Abdominal X-rays can identify dilated loops of bowel in obstruction and some types of kidney stones and gallstones. barium) can allow for a more detailed view of possible obstructions or peristaltic dysfunction. • Percutaneous transhepatic cholangiography ( PTC) and endoscopic retrograde cholangiopancreatogra­ phy (ERCP) can be used to assess intrahepatic duc­ tal dilatation (e. tumors. Dubin-Johnson syndrome. Unconjugated bilirubin can be elevated in hemolytic anemia.CHAPTER 4.g. biliary obstruction (which can be second­ ary to a tumor. Remember that AST and ALT are usually dispropor­ tionately higher than alkaline phosphatase if due to liver disease (e. Alk phos is elevated in ob­ struction of the biliary tree (e. . and Gilbert's syndrome. but alkaline phosphatase will be elevated to a much greater degree. inflammatory changes. severe trauma. • Prothrombin time increases in liver disease. or Rotor syndrome. or inflammatory disease of the biliary system). etc. Bilirubin. stones.g. Biopsies can be ob­ tained during endoscopy and varices can be ligated or sclerosed. Crigler-Najj ar syndrome. the ovaries and fallopian tubes (for cysts. • Serum albumin decreases in liver disease (and also in inflammatory disease. Re­ member that alkaline phosphatase can also come from bone. • Amylase and lipase are classically elevated in pan­ creatitis. . • Ultrasound can be used to examine the gall bladder and biliary tree (for dilatation and stones). ectopic preg­ nancies. . Administration of contrast (e.g. AST and ALT can be elevated in obstruction if the obstruction is bad enough to start damaging the liver. and to obtain biop­ sies to examine neoplastic growths and/or sites of inflammation/infection. • Upper endoscopy can be used to examine the esoph­ agus and stomach for causes of ulcer. etc. liver tumor. • • • AST IALT can be elevated in any disease of the liver. • Lower endoscopy can be used to examine the colon for sources of bleeding. a gallstone. Amylase can also be high with certain salivary gland tumors.).

... THE ENDOCRINE SYSTEM gonads) t o secrete their hormones. which stimulate s the thyrotroph cells of the anterior pituitary to secrete thyroid-stimulating hormone (TSH). the hypothalamus secretes thyroid hormone releasing hormone (THRH). the adrenal. which stimulate the pituitary to release stimulating hormones. F o r example. � (. * = Releasing hormones HYPOTHALAMUS POSTERIOR PITUITARY BAR �: (i) J E '. GENERAL PRINCIPLES Fig... The hypothalamus produces releasing hor­ mones. � BREAST (Milk release) CORPUS LUTEUM TESTES (Leydig cells) THE HYPOTHALAMIC-PITUITARY-TARGET ORGAN AXIS Figure 5-1. g. The stimulating hormones stimulate target organ s ( e .. THE ENDOCRINE SYSTEM CHAPTER 5. ./ s + (tH20 absorpti on) UTERUS (Contraction) .. 5-l. Modified from Goldberg: Clinical Physiology Made Ridiculously Simple.��. . MedMaster 2004 94 . thyroid ...CHAPTER 5. TSH stimu­ lates the thyroid gland to rele ase thyroid hormone (T4 and T3). The hypothalamic-pituitary-target gland axis .

THE ENDOCRINE SYSTEM Endocrine diseases are generally divided into hy­ per. Of course. The pituitary/hypothalamus over-stimulates the target gland ( a secondary disorder). At each level of the hypo­ cause: thalamic-pituitary-target organ axis there is negative feedback from each step on the previous ones. Negative Feedback 3 . The prolactin system is an exception to the above in that it is an inhibitory system: hypothalamic dopamine inhibits prolactin release from the anterior pituitary.e. this time the target organ will not respond to ex­ ogenous hormone stimulation.states (states of decreased hormone secretion). some genetic mutation). If the house is cold. This pre­ vents over-secretion of any hormone. the thermostat senses that the right point has been reached and the heat goes off again.CHAPTER 5. This is negative feedback. 3. squamous cell carcinoma of the lung can secrete parathyroid hormone-related protein ( PTHrP).. decreasing their secretion of TRH and TSH. there will be high stimulating hormone lev­ els because the organ producing the hormone is trying to get the target organ to respond. So at a cer­ tain equilibrium temperature. there will be decreases in both tar­ get gland hormone and stimulating hormone levels. 5-2.states (states of increased hormone secretion) and hypo. because of loss of negative feedback from the hypo-active target gland. there will be low target hormone level and high stimulating hormone level. thyroid hormone (T4 and T3) secreted by the thyroid exerts negative feedback on the hypothal­ amus and pituitary. In a primary hypo­ disorder. etc. but the function that is supposed to be initiated by the hormone will not occur. 1 .. There is some ectopic site of hormone production. There is a congenital or acquired problem of the tar­ get gland.g. The concept of negative feed­ back is extremely important in understanding both the physiology of endocrine disorders and the lab tests used in their diagnosis. For example. if the heat stayed on indefinitely. Increased hormone secretion or action could occur be­ Fig.disorder. both target gland hormone and stimulating hormone levels will be high. In a primary hyper. THYROID 5 . struma ovarii ( an ovarian tumor) can secrete thyroid hormone. small cell lung cancer can secrete adrenocorticotropic hormone (ACTH). An example is nephrogenic diabetes insipidus. 4. In a secondary hyper. The receptors of the target organ do not respond. Negative feedback. The target hormone receptors could be hyperactive (i. P ITU ITA RY 2 . This should be correctable by exogenous injection of the hormone. The pituitary does not secrete enough stimulating hormone (a secondary disorder). T4 and T3 NEGATIVE FEEDBACK Figure 5-2 95 .disorder. the thermostat senses this drop in temperature and turns on the heat. In a secondary hypo. The hypothalamus does not secrete enough releas­ ing hormone (a tertiary disorder). 4. thyroid) over-secretes due to pathology directly affecting it (a primary disorder). 2 . respectively. This would cause high hormone levels. The target gland (e. However. the concentration of the hormone secreted by the target gland will be high. It is called "negative" because the feedback turns the system off. A commonly used analogy is that of a thermostat. which is discussed in Chapter 3 . (a primary disorder). The hormone is defective. Again. Decreased hormone secretion or action could occur be­ cause: 1 . For example. the house would get too hot. but the stimulating hormone concentration (from the pituitary) will be low due to increased negative feedback from the hyperactive target gland.disorder.

heat intol- One needs only one laboratory value to distinguish be­ tween primary and secondary hyperthyroidism. Graves' disease is an autoimmune disorder that causes hyperthyroidism. primary hyperthyroidism.CHAPTER 5.g. ism. amiodarone toxicity. Fig. hypothyroidism (decreased thy­ roid hormone secretion). Graves' disease can have some additional clin­ ical features that distinguish it from other causes of hyperthyroidism: Graves' ophthalmopathy (inflam­ mation of extraocular muscles and periorbital tissue leading to bulging of the eyes. as­ sociated autoimmune disorders (e. . Causes of Hyperthyroidism Causes of hyperthyroidism include toxic nodules. pretibial myxedema3 (non-pitting edema on the anterior knee). 3 ____ 1 2 Most of the thyroid hormone secreted is T4.g. the TSH will be high . Although a small amount of T3 is made in the thyroid. and thyroid nodules and neoplasia. 2. e.g. is different. and that iod should make you think of the thyroid. in some cases.. THYROID A toxic nodule is a thyroid nodule that becomes in­ dependent of the pituitary and secretes excess thyroid hormone. The pituitary over-stimulates the thyroid to secrete thyroid hormone (secondary hyperthyroidism).g.e. Graves' disease. secondary hyper­ thyroidism. 4 Amiodarone is an anti-arrhythmic drug that can cause hyper­ thyroidism or hypothyroidism. The pathophysiology. The thyroid secretes thyroid hormone (T4 and T3). Primary and secondary hyperthyroid­ ovarian tumor that secretes thyroid hormone. e. a pituitary tumor. decrease 96 . elevated thyroid hormone will increase negative feedback on the pituitary and hence decrease TSH. 5-2). dyspnea." this would increase negative feedback on the pituitary. The end result in situations 1-3 above would be the same : hyperthyroidism (elevated thyroid hor­ mone). What would you expect to happen to TSH in struma ovarii? No matter what the source. tachycardia ( some­ times even atrial fibrillation). amiodarone toxicity. however. THE ENDOCRINE SYSTEM roidism. . the TSH will be low. notice the iod in its name? Amiodaranoe contains iodine in its structure. Graves' disease. Which one? Thyroid hormone increases in both cases so that is not helpful (unless the diagnosis of hyper­ thyroidism itself is in question).To remember that this drug af­ fects the thyroid. TSH secretion is stimulated by THRH from the hypothalamus (Fig. stimulating the thyroid to release thyroid hor­ mone. called proptosis or ex­ ophthalmos ).g. e. the autoantibodies bind to the TSH receptors in the thyroid and act just like TSH. high metabolism (weight loss). toxic nodule.g.. most T3 comes from peripheral conversion ofT4 toT3. Hyperthyroidism There are three general mechanisms by which hyper­ thyroidism can occur: 1 . the body produces antibodies against some part of it­ self. ... Graves' disease is the most common cause of hyperthyroidism. the gland secretes excessively because the Symptoms and Signs of Hyperthyroidism Any disease of the thyroid can cause it to enlarge (goiter). which would 2 TSH secretion. caused by the over-secretion of TSH by the pituitary. Pretibial myxedema is actually a type of edema found in Graves' disease. So TSH will be low in struma ovarii. which causes hyper­ thyroidism.4 and struma ovarii. thyroid hormone "stimulates. Some exogenous source of thyroid hormone exists. The following are discussed here : hyperthyroidism (increased thyroid hormone secretion). In autoimmune disorders. secondary hyperthy­ roidism). Other causes of hyperthyroidism include a pituitary tumor that secretes TSH (i. "myxedema coma" is a coma induced by severe hypothyroidism). ask yourself: What hor­ mone does this organ secrete? What stimulates it to do so? (Another hormone? A certain metabolic state?) What would happen if this organ were over-secreting? Under-secreting? How would these states affect the various hormone levels in the negative feedback loop? How will this affect laboratory diagnosis? is secondary. 5-3A-B. Thy­ roid hormone secretion is stimulated by TSH secretion from the pituitary. struma ovarii (an ovarian tumor)." and so a hyperthyroid person has many hyper active signs/symptoms. In the first instance. thyroiditis (thyroid inflamma­ tion). The thyroid over-secretes thyroid hormone (primary hyperthyroidism ) e. If the hyperthyroidism With each endocrine organ. In Graves' disease.e. In the second situation. the thy­ roid over-secretes due to some problem involving the gland itself. . vitiligo. 1 which regulates various aspects of metabolism. Think about negative feedback: If the thyroid itself were to secrete lots of hormone "without being told to. and. i. an 3. and struma ovarii. pituitary tumor. So TSH is the key to distinguishing between primary and secondary hyperthyroidism. perni­ cious anemia). pituitary causes it to do so . So in primary hyperthy- Note:The term myxedema by itself often refers to the condition of hypothyroidism (e. What does thyroid hormone do? Most generally.

secondary hyperthyroidism is TSH. anxiety. etc. _ C. hyperthyroidism speeds up many phys­ iologic functions. . metoprolol..g. SECONDARY HYPOTHYROIDISM (origin outside thyroid.. anti-TSH re­ ceptor antibodies can be found in the serum in many (but not all) cases. PRIMARY HYPOTHYROIDISM (origin outside thyroid. SECONDARY HYPERTHYROIDISM (origin in thyroid) --. propranolol. pretibial myxedema. . e.AND HYPOTHYROIDISM Figure 5-3 erance. TSH will be low in primary hyperthyroidism (e.--- !Negative Feedback lT4& T3 tT4 & T3 A. THE ENDOCRINE SYSTEM t Negative --"-­ Feedback ---. Graves' disease.g.g.CHAPTER 5. e.. PRIMARY HYPERTHYROIDISM B..g. increased appetite. or atenolol) can be used for symptomatic relief of tachycardia. and/or thyroid bruit (rushing sound over thyroid on auscultation) will point toward a diagnosis of Graves' disease. Diagnosis of Hyperthyroidism Treatment of Hyperthyroidism Clinically. 97 . though Graves' disease can be pres­ ent with none of these signs. dif­ fuse goiter. ---- HYPOTHYROIDISM HYPERTHYROIDISM T4& T3 t TSH Secondary Hyperthyroidism i t Primary Hypothyroidism l t Secondary Hypothyroidism l l Primary Hyperthyroidism l HYPER. Beta-blockers (e. Beta-blockers are typically used in cases where the hyperthyroidism will resolve spontaneously (e.. nerv­ ousness. in addition to low TSH. thyroiditis). tremor.. in pituitary) (origin in thyroid) _ 4 . The laboratory test to as­ sess primary vs..g. ophthalmopathy. hot skin. Graves') but high i n secondary hyperthyroidism.. ---- lT4& T3 D. in pituitary) .. etc. In As mentioned.

Malignant neoplasms are treated surgically. Hashimoto's thyroiditis is an autoimmune disease. Nodules may be asymptomatic. hemorrhage. we restore what is missing: thyroid hormone. A defini­ tive diagnosis is made by fine needle aspiration biopsy.g. this decreases negative feed­ back on the pituitary. In addition to Hash­ imoto's thyroiditis.CHAPTER 5. cold intolerance. and/or anemia. fatigue. but is more common in other parts of the world (Himalayas. where it is referred to as endemic goiter. Symptoms and Signs of Hypothyroidism Hyperthyroidism speeds everything up. amiod arone). 5-3C-D. the treatment goal is t o reduce the amount of circulating thyroid hormone. Primary and secondary hypothyroidism. inflammation. Decreased thyroid hormone synthesis decreases negative feedback.S. or radio­ therapy with Jl31. post-surgical damage I removal. can cause hyperthyroidism or hypothyroidism as well as thyroid enlargement and/or pain. follicular. so the TSH will be low. This elevation of TSH stimulates the thyroid gland to hy­ pertrophy. prematurely gray hair). So in primary hypothyroidism. but can also be a non­ neoplastic entity such as cyst. and/or agents to treat hyper. increasing TSH production. and delivery of a baby (postpartum thy­ roiditis). autoimmunity (subacute lymphocytic thyroiditis) . bradycardia. medullary. drugs that are toxic to the thyroid gland (e. or tumor (either a non-functioning 98 . Tertiary hypothyroidism can be caused by hypothal­ amic under-activity or tumor. Causes of Hypothyroidism Thyroiditis Causes of primary hypothyroidism include congenital thyroid problems . In either case. Remember that TSH is the key: TSH is elevated in pri­ mary hypothyroidism and decreased in secondary hypothyroidism. . Secondary hypothyroidism can result from pituitary pathology such as infection . In cases of thyroid hormone hypersecretion (e. hyperplasia. Thyroid Nodules and Thyroid Cancer A thyroid nodule can be a neoplasm such as an adenoma (benign) or carcinoma (papillary. amiodarone. discovered for the first time on physical exam .or hypothyroidism may be used in treatment of thyroiditis. the pituitary is the problem: the pituitary is not secreting an adequate amount of TSH.. the thy­ roid hormone level is low . more definitive treatment is preferable to long-term treat­ ment with anti-thyroid drugs : the thyroid can be re­ moved surgically or destroyed by radioactive iodine (!131). by definition. In secondary hypothy­ roidism. nodules can cause symptoms of hyper­ thyroidism and/or symptoms related to compression of nearby structures such as the trachea (causing cough) or esophagus (causing dysphagia). infiltra­ tion . . arthralgias. Goi­ ter can be present. Andes. or anaplastic). or a focal region of thyroiditis.g. hypothyroidism can also be due to either primary thyroid dysfunction or second­ ary to pituitary dysfunction. Graves' disease).g. Hypothyroid­ ism slows everything down : symptoms of hypothy­ roidism can include weight gain. myalgias. Either of these treatments can lead to hy­ pothyroidism. Both methi­ mazole and p ropylthiouricil decrease thyroid hor­ mone synthesis. Iodine deficiency causes hypothyroidism because iodine is necessary for thyroid hormone synthesis. Thyroiditis. If the thyroid itself is the root of the problem and is not producing any thyroid hormone. The antibodies are directed against thyroid peroxidase (TPO) and thyroglobulin (TG). radiation. THE ENDOCRINE SYSTEM tumor within the pituitary or a brain tumor impinging upon it). In most cases. leading to the goiter associated with iodine deficiency. which causes it to cease functioning partially or entirely. Hypothyroidism Fig. con­ stipation. resulting in a lympho­ cyte infiltration of the thyroid gland. Alps). while benign nodules are often observed if they are asymptomatic. Iodine deficiency is uncommon in the U. inflammation of the thyroid gland. hypoventilation. Laboratory Diagnosis of Hypothyroidism Like hyperthyroidism. NSAIDs. vitiligo. the TSH level will be elevated. steroids. iodine deficiency . Treatment of Hypothyroidism To treat a hypothyroid patient. diabetes Type 1. and propylthiouricil also reduces peripheral T4 to T3 conversion. weakness. The above-mentioned serum auto­ antibodies (anti-TPO and anti-TG) can be present in Hashimoto's thyroiditis. Hashimoto's thyroiditis sometimes occurs with other autoimmune diseases (e. due to iodinization of salt. Alter­ natively. other causes of thyroiditis include viral infection (de Quervain's thyroiditis). Hashimoto's thyroiditis . Thyroxine is the synthetic form of T4 that is generally used.

Hypoaldos­ teronism can result from a decrease in aldosterone or a decrease in the response to aldosterone . Hyperaldosteronism is an increase in aldosterone.and hypoaldosteronism . and the renin and aldosterone levels will be elevated . a potassium-sparing diuretic that acts by inhibiting aldosterone. ADRENAL GLANDS The adrenal glands secrete a number of hormones : al­ dosterone. and epinephrine. ACE inhibitors prevent angiotensin-stimulated aldosterone release. or any of the conditions opposite to those just listed: i. In addition to actual hy­ potension. other chronic kidney diseases. In contrast. decreases in renin/angiotensin. e . Adrenal insufficiency can decrease cor­ tisol. cortisol) have wide-ranging functions. Pseudohypoaldosteronism : The renal aldosterone There are two general causes of hyperaldosteronism : receptors are not responsive to aldosterone. cirrho­ sis. Th us. Causes include adrenal adenoma and adrenal carcinoma. hyponatremia. Cortisol secretion is stimulated by secretion of ACTH ( adrenocorticotropic hormone) from the pituitary. THE ENDOCRINE SYSTEM 1 . The adrenal glands are over-stimulated to secrete (secondary hyperaldosteronism ). The adrenal cortex is not secreting aldosterone (adrenal insufficiency). • The sex hormones are discussed in chapter 9.. hypokalemia. In hyporeninemic hypoaldostero­ Over-secretion of epinephrine occurs in pheochro­ nism. and hypotension stimulate aldosterone release and can lead to second­ ary hyperaldosteronism. nephrotic syndrome) can cause secondary hy­ peraldosteronism. hypernatremia. and de­ crease the immune response. are the zona glomerulosa (which secretes aldosterone). The adre­ nal medulla secretes epinephrine. AldosteRoNe causes Reabsorption of sodium (Na+) and secretion of potassium (K+) and hydrogen ion (H+) in the kidneys. hypertension. or hypotension.g. 99 . Cushing's syn­ drome. 2. hyperkalemia. spi­ Hyperaldosteronism ronolactone. The three zones of the cortex of the adrenal gland.e.CHAPTER 5.g. mocytoma. and congenital adrenal hyperplasia are discussed below. primary failure of the adrenal glands or reduced ACTH levels can cause adrenal insufficiency. ACTH secretion from the pituitary is stimulated by CRH (corticotropin-releas­ ing hormone) from the hypothalamus. hyponatremia. it is not the pituitary gland that tells the adrenal cortex to secrete aldosterone. Renin may ele­ vate in response to congestive heart failure. One or both adrenal glands are hyperactive (pri­ mary hyperaldosteronism ). or drugs. Decreased aldosterone secretion occurs in adrenal failure. Glucocorticoids (e. Hyperaldosteronism can cause hypernatremia. hypoaldosteronism is a decrease in aldosterone. adrenal insufficiency . norepineph­ rine.g. cir­ rhosis. hy­ pokalemia. Increased aldosterone secretion occurs if the adrenal glands themselves hyper-secrete. hypoaldosteronism can lead to hyponatremia and hyperkalemia. from exterior to interior. . The clinical manifestations of cortisol elevation are called Cush­ ing's syndrome . What causes aldosterone secretion? The renin-angiotensin-aldosterone system is one way of stimulating aldosterone. or if the adrenal glands are stimulated by renin/angiotensin. then this is secondary hyperaldosteronism. primary hyperaldosteronism). Hypoaldosteronism Since aldosterone is responsible for sodium reabsorp­ tion and potassium excretion. or volume depletion. e. Unlike the thyroid and the cortisol system of the adrenal glands. Hyper. congestive heart failure. glucocorticoids. Recall that aldosterone causes sodium reabsorption (which raises blood pressure) and potassium excretion. pheochromocytoma . If one or both adrenal glands over-secretes ( i . They are stress response hormones that in­ crease blood pressure and gluconeogenesis. Possible causes of aldosterone deficiency : The renin-angiotensin stimulus for aldosterone is deficient. Hyperkalemia can also stimulate aldosterone so as to promote K+ secretion in an effort to decrease serum K+. and hypertension.. if the kidneys' secretion of renin is stimulating aldosterone secretion. renin will be low since its secretion by the kidneys will be suppressed by negative feedback from the increased aldosterone secretion. Causes include hyperkalemia. renin secretion is diminished by kidney damage due to diabetes. hyponatremia. . and zona reticularis (which secretes sex hormones). and hypotension..and Hypoaldosteronism • Possible causes of decreased response to aldosterone : Drugs can cause aldosterone resistance . fluid redistribution leading to effective volume depletion (e. Hyper. sex hormones. zona fasciculata (which secretes glucocorticoids). hyperkalemia.

easy bruising. edema. a buffalo hump on the back. Causes of Cushing's Syndrome Symptoms and Signs of Cushing's Syndrome Fig. hypertension. Causes of Cushing's Syndrome. diabetes.CHAPTER 5. Diagnosis of Cushing's Syndrome If the diagnosis of Cushing's syndrome is suspected. Over-stimulation of the adrenal glands by an ec­ topic ACTH producing tumor. one must first confirm that there is indeed elevated cortisol secretion. hirsutism. acne.e. and/or cognitive effects (anything from mood/ affect changes to psychosis). 3. The most common site of ectopic production is a small cell lung cancer. checking the level of cortisol in the saliva in the late evening. This can be do ne by either check­ ing a 24-hour urinary collection for free cortisol. virilization. Over-stimulation of the adrenal glands by an ACTH-secreting tumor in the pituitary. THE ENDOCRINE SYSTEM Note : Cushing's syndrome is any state listed above which creates pathologic hypercortisolism. Primary over-secretion by one or both adrenal glands (adrenal adenoma or carcinoma). 1. Cushing's disease is the specific case of hypercortisolism result­ ing from an ACTH-secreting pituitary adenoma. purple striae. a moon face. Iatrogenic (i. osteoporosis and/or osteonecrosis. 2. immunosuppres­ sion. This sce­ nario is known as Cushing's disease . from long-term treatment with steroids).. weakness. Hormone-secreting Pituitary Tumor (Cushing's disease) Cushing's Syndrome CAUSES OF CUSHING'S SYNDROME Figure 5-4 100 . In Cushing's syndrome any or all of the following can be present: truncal obesity. Cushing's Syndrome Cushing's syndrome refers to a pathological elevation of cortisol. 5-4. though other cancers can produce ACTH as well. or determining if cortisol level suppresses 4.

Localizing Cushing's Syndrome: Pituitary vs. The ectopic site is. the pituitary should respond to this negative feedback. ease (i. 5-5). this should remove negative feedback. Nor­ mally. this hyper-secretion will increase nega­ tive feedback on the pituitary and thus ACTH should be low. giving the steroid dexamethasone should mimic cortisol and exert negative feedback on the pi­ tuitary. in comparison. What would you expect metyrapone to do to ACTH in a normal per­ son? If cortisol synthesis decreases. this indicates that Cushing's syn­ drome exists. If the pituitary is over-secreting ACTH (Cushing's disease) and you give high dose steroids. decreasing ACTH output from the pituitary. Metyrapone inhibits cortisol synthesis and can also be used to localize Cushing's syndrome. e. so failure to suppress the ACTH level with high dose dexametha­ sone indicates an ectopic source of elevated ACTH. this suggests Cushing's syndrome. The dex­ amethasone suppression test relies on the principle of negative feedback to localize the source of ACTH. so ACTH will not change in a metyrapone test if the cause of Cushing's syndrome is ectopic ACTH production. but does not localize the site responsible for the over­ production. ACTH level will be suppressed by the high dose dexametha­ sone suppression test. going totally nuts. If one or both adrenal glands are autonomously hy­ per-secreting. when localizing the ACTH source in Cushing's syndrome the pituitary does respond to neg­ ative feedback and ectopic sites do not.. THE ENDOCRINE SYSTEM If a low dose dexamethasone suppression test does not suppress ACTH. This may be the pituitary (Cushing's dis­ ease) or an ectopic site of ACTH production. Typically ectopic sites secrete more ACTH.CHAPTER 5. the combination of high ACTH and hypercortisolism means that something is over-se­ creting ACTH. On the other hand. ectopic sites of ACTH production are generally non-responsive to negative feedback. one must distin­ guish between pituitary ACTH secretion and ectopic ACTH secretion. the pituitary still responds to negative feedback. It sort of makes intuitive sense that a crazy tu­ mor that is not even part of the endocrine system would secrete far higher levels of ACTH than a mere hyper-functioning endocrine tumor that is simply overdoing it. but needs a higher level than normal. A pi­ tuitary source of elevated ACTH (Cushing's disease) will respond by increasing ACTH secretion when metyrapone is given . An ectopic site ofACTH produc­ tion does not respond to negative feedback. In summary. That is. As mentioned above. Fig. pituitary hyper-secretion of ACTH). So in Cushing's dis­ normally when exogenous glucocorticoids are given (dexamethasone suppression test. The response HI-DOSE DEXAMETHASONE I Negative feedback on pituitary \ No negative feedback on ectopic source of ACTH No change in ACTH lACTH HIGH-DOSE DEXAMETHASONE SUPPRESSION TEST Figure 5-5 101 . but does not indicate the source of ACTH over-production. and ACTH level should decrease. causing an increase in ACTH. 5-5. If any of these is present. Ectopic Fig. Dexamethasone Suppression Test. If ACTH and cortisol are both high.

hypoglycemia. but the rest of the adrenal still Fig. Lack of CRH (corticotrophic releasing hormone) from the hypothalamus (tertiary adrenal insuffi­ ciency). Without aldosterone. Thus. and hyperpigmentation can help to distinguish primary adrenal insufficiency from secondary insufficiency. POMC (pro-opio-melanocortin). catheters are threaded up into the pet­ rosal venous sinuses that drain the pituitary. This re­ sults in hyperpigmentation. Hy­ pothalamic lesions or tumors can cause tertiary adrenal insufficiency due to decreased CRH stimulation of ACTH release from the pituitary. if it does not decrease. Hypotension. CRH is then administered through the catheter. cortisol is low. and/or anemia. Because ACTH and MSH share a common precursor. hyponatremia. and from the "cort. the level of ACTH in the catheter near the pitu­ itary should have a higher level of ACTH than observed in the periphery ( 3 : 1 or greater is diagnostic). hair loss. and imaging studies are unrevealing (since pituitary tumors can be extremely small). both cortisol and aldosterone secretion will be affected. Symptoms of adrenal insufficiency can include weak­ ness. • Adrenal hemorrhage (known as Waterhouse­ Friedrichsen syndrome if it is secondary to N. For additional confirmation. signs/symptoms will reflect both aldosterone and cortisol loss. 2 . and ACTH level is measured both in the sinus and simultaneously from a peripheral vein. In inferior petrosal sinus sampling.Polyglandular autoimmune syndrome Type 2 : (Adrenal insufficiency with either autoimmune thyroid disease or insulin-dependent diabetes mellitus with possible vitiligo. Inferior Petrosal Sinus Sampling. Another characteristic that can be seen in primary adrenal insufficiency that is not seen in secondary ad­ renal insufficiency is hyperpigmentation ." realize that ACTH predominantly stimulates cortisol secretion from the adrenal glands. this increased ACTH produc­ tion will also cause excess MSH to be produced. Adrenal Insufficiency Causes of primary adrenal insufficiency include : Adrenal insufficiency can be caused by: • 1 . lightheadedness. Treatment of Cushing's Syndrome Cushing's syndrome is treated by the surgical removal (or in some cases radiation) of the offending tumor. and/or pernicious anemia) disease). ACTH production is increased due to loss of negative feedback. Lack of ACTH stimulation from the pituitary (sec­ ondary adrenal insufficiency). dehydration. also known as Addison's Autoimmune disease Polyglandular autoimmune syndrome Type 1 (HAM: hypoparathyroidism. Sodium wasting can lead to hypotension. 5-6. since ectopic sites generally do not respond to CRH. to negative feedback is assessed via ACTH level: If it decreases. meningitidis. mucocutaneous candidiasis) . weight loss. cortisol secretion decreases. In any cause of adrenal insufficiency.g. Aldosterone is regulated largely by concentrations of sodium and potassium as well as the renin­ angiotensin-aldosterone axis. meningitidis) • Tumor metastases to the adrenal gland Secondary and Tertiary Adrenal Insufficiency Pituitary lesions or tumors can lead to secondary adre­ nal insufficiency due to decreased ACTH secretion. Decreased ACTH se­ cretion in either scenario decreases cortisol secretion from the adrenal gland. adrenal insuffi­ ciency. hyperkalemia. tuberculosis. Remember that aldosteRoNe causes Reabsorption of Na+ and secretion of K+ in the kidneys. hemorrhage can also be caused by an­ ticoagulant treatment) • Infection (e. Primary Adrenal Insufficiency Since both cortisol and aldosterone secretion are affected in primary adrenal insufficiency. If the adrenal gland itselffails (primary adrenal insufficiency). If the pituitary is over-secreting (Cushing's dis­ ease) . 3 . ACTH levels are then measured in the pituitary catheters and from a peripheral vein. premature ovar­ ian failure. and potassium will accumulate. Primary and secondary adrenal insuffi­ ciency. Pathology of one or both adrenal glands (primary adrenal insufficiency . ACTH (or CRH) deficiency will lead to decreased cortisol with normal aldosterone. In adre­ nal insufficiency. ACTH and MSH (melanocyte stimulating hormone) have a com­ mon precursor. fatigue. but the renin-angiotensin-aldosterone axis still w orks.CHAPTER 5. Sometimes the source of ACTH cannot be determined from these tests. salt craving. sodium will be wasted. or tapering of the glucocorticoid therapy if the Cushing's is iatrogenic. THE ENDOCRINE SYSTEM renal glands). so hyponatremia and hyperkalemia are commonly seen in primary adrenal insufficiency. that means the secretor was n ot responsive (ectopic). In secondary (or tertiary) adrenal insufficiency (decreased ACTH stimulation of the ad- 102 . N. ACTH stands for adrenocorticotropic hormone. that means the secretor was responsive to negative feedback (pituitary). vomiting. . A pituitary to periphery ACTH ratio of 2 : 1 or greater indicates a pituitary adenoma.

This is also why patients on steroid treatment 5 Diagnosis of Adrenal Insufficiency It is possible that a patient can have primary adrenal insufficiency without manifesting hyperpigmentation or other distinguishing characteristics. 103 . not Hyponatremia may still occur in secondary adrenal insuffi­ ciency because cortisol deficiency can increase ADH secretion. Adrenal insufficiency can also occur when a patient goes through withdrawal after abrupt termination of steroid treatment. which can cause hyponatremia. Thus. Pa­ tients on steroids who go for surgery with out this increased stress dose of steroids lack the ability to in­ crease steroid secretion in response to stress on their own. Increased ADH increases fluid retention. THE ENDOCRINE SYSTEM Adrenal cortex Aldosterone NORMAL Renin/ Angiotensin Renin/ Angiotensin SECONDARY ADRENAL PRIMARY ADRENAL INSUFFICIENCY INSUFFICIENCY PRIMARY AND SECONDARY ADRENAL INSUFFICIENCY Figure 5-6 functions nonnally. How can one confinn the diagnosis and localize whether the adrenal insufficiency is primary or secondary using laboratory tests? First. Steroid treatment provides exoge­ nous negative feedback to the pituitary. but rather tapers them. the pituitary takes time to recover its function. If steroids are abruptly stopped. This is why one never stops steroids abruptly after prolonged treatment. adrenal insuffi­ ciency can occur. diluting serum sodium concentration. 5 who need surgery are often given a stress dose of ex­ tra steroids to accommodate the increased stress.CHAPTER 5. there is no hyperkalemia in secondary and tertiary adrenal insufficiency. if both cortisol and aldosterone are low. this suggests primary adrenal insufficiency as dis­ cussed above (because the whole adrenal is failing. and during that time. which may result in adrenal failure.

. THE ENDOCRINE SYSTEM cytomas stimulate b oth alpha and beta receptors (alpha=vasoconstriction. the problem must be the adrenal's inability to respond. and pancreas tumors. primary adrenal insufficiency). The drug of choice is phenoxybenzamine. MEN comes in 3 types: MEN 1. The ACTH Stimulation ("Cort Stim'') Test. Congenital Adrenal Hyperplasia Fig. and tremor. why is there hyperplasia?" Any of the enzyme defects that can cause congenital adrenal hyperplasia leads to de­ creased cortisol synthesis . unilateral adrenal tumors. MEN 2a. primary adrenal insufficiency . ACTH level in­ the problem was m ost likely that the gland was previ­ ously being under-stimulated. Pancreas MTC --7 MTC MEN1 Parathyroid --7 PITUITARY GLAND 6The most common place a pheochromytoma can occur outside of the adrenal is the organ ofZuckerkandl (a para-aortic com­ ponent of the sympathetic plexus). 5-7. or there is long­ standing secondary adrenal insufficiency.e. keep parathyroid tumors and add MTC (medullary thyroid carcinoma) and pheochromocy­ toma. Congenital adrenal hyperplasia is a group of disorders caused by enzymatic defects in adrenal steroid biosynthesis. this sug­ gests primary adrenal insufficiency (because of loss of negative feedback from the adrenal on the pituitary). secondary or terti­ ary adrenal insufficiency .e. either the adrenal gland is the problem and cannot respond. Pheochromocytomas are said to follow the "rule of lOs": 10 % are bilateral. the vasodilation of the beta system will be inhibited while the alpha-receptors remain stimulated (by the pheochromocytoma's epi­ nephrine secretion). then one must replace both cortisol and aldosterone.. Then to make 2b. Classically. The diagnosis can be confirmed by elevated urine levels of catecholamines and their metabolic by-products. the symptoms are paroxysmal (i. It is a catecholamine-se­ creting tumor that most commonly occurs in the adrenal medulla. In females this can lead to menstrual irregularities and hirsutism. If the cort stim fails to cause a rise in blood cortisol levels. norepinephrine/epinephrine) cause vaso­ constriction and thus hypertension. i. .e. Aldosterone level is not rou­ tinely used clinically.. most pheochromocytomas are benign.g. Treatment o f Adrenal Insufficiency Treatment of adrenal insufficiency depends upon its etiology. which must mean that the insuffi­ ciency is secondary or tertiary). With decreased negative feedback.6 and 10% are malignant.e. The catecholamines secreted by pheochromo- MEN2a MEN2b Parathyroid Marfanoid body habitus Pituitary Pheo. To distinguish between these two. If the failure also affects aldosterone (i. This drug is given to control blood pressure until surgical removal of the tumor. keep two (Pheo and MTC) and add marfanoid body habitus. If we give some ACTH by inj ection and it does not work (i. To make 2a. Additionally. but what measurable laboratory findings will low aldosterone cause? Low sodium and high p otassium. parathyroid. If al­ dosterone production is affected by the biochemical abnormality. A pheochromocytoma is a rare but extremely danger­ ous cause of hypertension. "If biosyn­ thesis in the adrenal gland is decreased.. a longer dose of ACTH is given (usually 6-8 hours) and in these cases.. The pituitary lies between the hypothalamus and the target glands in the chain of command of endocrine 104 . If a beta-blocker is given alone for the tachycardia. sweating. surgery. ifACTH is high.e. primary adrenal insuffi­ ciency still will not respond. The catecholamines secreted by the tumor (i. cortisol level does not rise). they come on once in awhile and then resolve) and include headache. etc). the three Ps : pituitary. what could occur? A loss of aldosterone can lead to hyperkalemia and salt wasting. At first you may ask. 10% are not in the adrenal gland. whereas secondary adre­ nal insufficiency finally will (though usually only partially). then one replaces cor­ tisol with glucocorticoids. merely cortisol secretion). i. This can lead to extreme hyper­ tension. MEN 2b. called metaneph­ rines. So if a cort stim test increases cortisol level. palpi­ tations.. aldosterone is fine. which results in in­ creased androgenic precursors. Aldosterone replacement can be accom­ plished with fludrocortisone. Mnemonic ( see chart): MEN 1. which can lead to severe hypotension. bronchodilation). MULTIPLE ENDOCRINE NEOPLASIA (MEN) Pheochromocytoma Patients with MEN develop tumors in multiple en­ docrine organs.e. Decreased cortisol results in decreased negative feedback on the secretion of ACTH .CHAPTERS. So beta blockade sh ould never be given alone to a patient with a pheochromocytoma. Mnemonic: phenoxy and pheo are similar words. e. hydrocortisone with an increased dose for stress (illness. creases. such that the adrenal is slow to respond. tachycar­ dia. --7 Pheo. If cortisol is the only deficient hormone (i. an alpha-receptor blocker. In other words. The most common form is a deficiency of 2 1-hydroxylase. beta=vasodilation.. This elevation of ACTH in the developmental period causes the hyperplasia.e.

radiation or surgical removal of pituitary adenomas is first-line treatment. follicle stimulating hor­ mone (FSH). arthritis. ears. so so­ matostatin (commercially available as octreotide) can be used to shrink these tumors. leutinizing hormone (LH). and rings not fit­ ting anymore can be clues to the diagnosis. 7-7). by compressing the pi­ tuitary so as to cause hypopituitarism. That is. Negative feedback on pituitary CONGENITAL ADRENAL HYPERPLASIA Figure 5-7 Growth Hormone Adenomas and Acromegaly. What would the labs show? Elevated thyroid hormone and elevated (or inappro­ priately normal) TSH. Growth hormone level itself is not a very reliable di­ agnostic test because of its pulsatile release. The anterior pituitary secretes thy­ roid-stimulating hormone (TSH). and you give some sugar. function (Fig. Anatomically. adrenocorti­ cotrophic hormone (ACTH). ) 105 . A tumor that secretes growth hormone will make things big. The hands. Subtle signs like gloves. 5-1). which causes elevated thyroid hor­ mone with decreased TSH. this enlargement occurs over a long time and may be so insidious as to not be noticed by the patient. TSH-Secreting Pituitary Adenomas can cause sec­ ondary hyperthyroidism . if quite large. can all en­ large. the pituitary sits beneath the optic chiasm. Diseases of the Anterior Pituitary Pituitary Adenomas and Hyperpituitarism Pituitary adenomas are usually benign tumors. etc. Because of enlargement in the face and hands. and prolactin. This is the specific case of Cushing's syndrome known as Cushing's disease. pituitary tumors may present with bitemporal hemianopsia (loss of the lateral visual field in each eye) because of pressure on the chiasm (see Fig. With the exception of prolactinomas (which often respond to dopamine agonists). Now what would you expect to happen in a patient with a growth hormone secreting-tumor? Well what has happened with all of the other over-secreting tu­ mors when we tried to give them negative feedback? ACTH-Secreting Pituitary Adenomas lead to in­ creased cortisol secretion. shoes. If you give a glucose load to a normal patient. what would you expect this to do to growth hormone secretion? If growth hormone raises blood sugar. snoring. growth hormone raises blood sugar (just like glucagon. THE ENDOCRINE SYSTEM ADRENAL l Cortiso ! HYPERPLASIA ynthesis i ACTH secretion from pituitary . Surgery is usually nec­ essary for complete cure. sleep ap­ nea. Growth hormone stimulates release of insulin-like growth fac­ tor (IGF). which is where fibers from both optic nerves (CN II) cross. However. feet. If a growth hormone-secreting tumor is suspected.CHAPTER 5. another diagnostic test that can be used is a glucose challenge test. lips. Somatostatin inhibits growth hormone. cortisol. The posterior pituitary se­ cretes oxytocin and ADH (vasopressin). this should de­ crease growth hormone secretion in a normal person. (Compare this to primary hyperthyroidism. Thus. and ep­ inephrine).1. Growth hormone is one of the hormones that coun­ teracts insulin's actions.1 can be seen on laboratory testing with a growth hormone-secreting tumor. and/or carpal tunnel syndrome can occur. tongue. so an elevated level ofiGF. growth hormone (GH). They can cause pituitary dysfunction by either oversecret­ ing a hormone or.

infer­ tility. infiltrative processes (e. e. decreased li­ bido. elevated prolactin can cause impotence. 7-7). In women. • • Decreased clearance ofprolactin.. impotence. infections (e. • Hypothalamic lesions . Aside from dopamine antagonists .. in renal failure Hypopituitarism A pituitary tumor may be metabolically silent. Mnemonic: A com­ mercial: "Is your glucose gone? Get GLUCAGON! Glu­ cagon will RAISE your glucose in a flash!" Insulin and which could decrease dopamine secretion. e. a craniopharyngioma. emotional instability. If the tumor is so big that it compresses the pituitary. The endocrine cells of the pan­ creas secrete insulin and glucagon. Insulin drives glucose into cells. amy­ lase) and bicarbonate into the duodenum (first portion of the small intestine). Prolactin-Secreting Adenomas. Pituitary ap oplexy is pituitary hemorrhage. most likely a growth hormone-secreting tumor. i.. it may not secrete anything. 106 .e. So if growth hormone does not decrease in response to a glucose tolerance test. Glucagon is for when glucose is gone. metastases). shingles from herpes zoster. these patients can present with hypogonadism. these patients may have bitemporal hemianopsia (Fig. radiation. and sometimes gynecomastia in men. In children. which is lactation despite lack of pregnancy (of course one should still be certain by checking a pregnancy test). chymotrypsin. which can result from rupture of an adenoma..g. infertility. and/or hemorrhage can damage the pituitary. this indicates a source of growth hormone that is resistant to negative feed­ back. • Loss of GH in a child can result in growth failure. dopamine agonists are the first-line treatment for inhibiting the growth of prolactino­ mas. e. prolactinoma can thus cause galactorrhea. tuberculo­ sis). • Loss of LH/FSH causes central hypogonadism . Hypothalamic-releasing hormones stimulate secre­ tion of most anterior pituitary hormones. surgical re­ moval is often necessary. which is thought to activate the same neural path­ way that suckling would Loss of ACTH leads to secondary adrenal insuffi­ ciency. this can result in pubertal delay.CHAPTER 5. hemochromatosis. Loss of TSH causes secondary hypothyroidism. this could lead to dysfunction of the gland (hyp opituitarism). autoimmune dis­ eases (e. Though these situations can cause failure of all pituitary function (panhyp opitu­ itarism ). THE ENDOCRINE SYSTEM Usually they do n ot respond at a normal level. If dopamine agonist treatment fails. histiocytosis X). Postpartum refers to the time period after delivery of a baby. thus re­ leasing prolactin secretion from its inhibition • • Diabetes insipidus (ADH deficiency) and SIADH (ADH excess) are discussed in the renal chapter (Chapter 3). Prolactin inhibits gonadotropic-releasing hormone (GnRH) secretion from the hypothalamus. In addition to non-functioning pituitary tumors. The exocrine cells of the pancreas secrete di­ gestive enzymes (trypsin. the following are the effects of lack of each individual hormone : LH/FSH-Secreting Tumors. various tumors ( craniopharyngioma. which regulate blood glucose level. dopamine released from the hypothalamus inhibits prolactin release from the anterior pituitary. Since the pituitary 7 Peripartum refers to the time period surrounding the birth of a baby. Diseases of the Posterior Pituitary What effects would dopamine antagonists (e. other causes of hyperprolactinemia include : Chest wall injury. These tumors can cause symptoms because of their growth.. THE ENDOCRINE PANCREAS AND GLUCOSE REGULATION The pancreas has exocrine functions and endocrine functions. con­ trary to what one might have expected.g. Prolactin is the hormone responsible for milk production.g. Since the LH and FSH that these tumors secrete are usually non -functional..g.or postpartum 7 hemorrhage in the mother results in hypovolemia and subsequent pitu­ itary damage. whereas deficiency in adults can lead to fatigue. Elevated prolactin can thus cause dimin­ ished libido and irregular menses in women. When else are dopamine agonists used? To treat dopamine deficiency in Parkinson's disease.g.g. Decreased GnRH leads to reduced FSH and LH secretion by the pituitary. and decreased libido can occur. sarcoidosis). primary CNS tumors. menstrual irregularities. Prolactin is an exception: its secretion is under inhibitory control of dopamine secreted by the hypothalamus. and/or changes in weight. leading to decreased function. for treatment of schizophrenia) have on prolactin? A dopamine antagonist will release prolactin from its in­ hibition and thus lead to increased prolactin secretion... it causes release of glucose into the blood for the tissues that need it.g. Because dopamine normally inhibits prolactin-se­ creting cells. in adults. That is. lipase. Sheehan's syndrome occurs when peri. lies beneath the optic chiasm.

Insulin and glucagon. Glycolysis (glucose breakdown for energy) is also stim­ ulated. can be sent to the brain and heart and used for energy production in those organs. there is either decreased insulin secretion or insensitivity to insulin. after a big meal for example. a nor­ mal blood glucose concentration. THE ENDOCRINE SYSTEM teet the brain and heart.This keeps the mother's blood sugar high enough to make sure that some glucose gets to the fetus. obesity. 8 Type 2 diabetics increase insulin secre­ tion to compensate for peripheral tissue resistance but ­ Glucagon is secreted during a fast when blood sugar is low.CHAPTER 5. and protein. . Without insulin's effects. Diabetes Mellitus In diabetes mellitus.1. if we really need glucose to make energy. You may ask. The risk of devel­ oping type 2 diabetes is correlated with age. Cortisol. Fig. BLOOD SUGAR t t I Storage as: · Glycogen (glycogenesis) · Fat · Protein Glycolysis + stream ATP BLOOD SUGAR . leading to a loss of insulin produc­ tion. insulin is released (from the beta cells of the pancreas). the energy­ producing process!?" In starvation the goal is to pro- 8 Diabetes can also occur in pregnancy (gestati onal diabetes). Exaggeration of this insulin resistance can lead to gestational diabetes. When there is lots of glucose around. glucose cannot be moved into cells. the underlying pathophysiology is insulin resistance. 5-8. and nor/epinephrine also raise blood sugar levels. and hyper­ glycemia (increased blood sugar) can occur. and family history. why would we be inhibiting glycolysis. "Wait. and since there is a surplus. The goal of glucagon is to m o­ bilize glucose stores from the liver so that this glucose glucagon work in concert to maintain euglycemia. growth hor­ mone. / t Glucagon secretion d� ucose release from cells Gluconeogenesis Glycogenolysis CELLS INSULIN AND GL UCAGON Figure 5-8 10 7 . In Type 2 (adult-onset) diabetes. so insulin promotes both glu­ cose storage and its breakdown. Type 1 (juvenile-onset) diabetes is believed to result from an autoimmune process that destroys the beta­ cells of the pancreas. fat. the goal of insulin is to re duce blood sugar levels. It is normal in pregnancy for there to be some increased insulin resistance. Glucagon decreases glycolysis and increases glu­ coneogenesis (glucose formation) and glycogenolysis (breakdown of glycogen to release glucose). all cells are wel­ come to have glucose.1. Note that glycogenesis and glycolysis are both stimulated by insulin . it can be broken down to make energy (ATP) or stored (as glycogen). Since this is a time of plenty. In­ sulin stimulates glucose uptake into cells and its stor­ age as glycogen (glycogenesis).

since increased sugar provides a medium for bacterial growth. Hypoglycemia The main counter-regulatory hormone to insulin is glucagon. 108 . o r counter insulin resistance . diaphoresis. treatments function ei­ ther to decrease blood sugar. Elevated blood glucose can predispose to dental caries (cavities) and increased infections such as vaginitis. Like glucagon. What's ketosis? When starv­ ing. Diagnosis of Diabetes Mellitus Symptoms and Signs of Diabetes Mellitus Loss of insulin (type 1 diabetes) or insulin resistance (type 2 diabetes) both result in hyperglycemia. Thus. The complications listed above are acute. This can result in a massive osmotic diuresis (renal water loss) and subsequent hypotension. thus decreasing glucose available for absorption. despite plenty of glucose (hyper­ glycemia). postural hypotension. the body breaks down fat to satisfy its metabolic needs. or 2 hours post-glucose tolerance test plasma glucose � 200 mg/dL. See also hyperosmolar hyponatremia (pseudo­ hyponatremia) in Chapter 3 (Fig. in severe insulin deficiency. since there is still enough insulin to prevent ketosis from occurring. since the body is starving (albeit in the midst of plenty). and thiazolinediones decrease insulin resistance. one must replace the patient's insulin . Any area with small blood vessels can be affected over time. ketoacids can form in excess (ketosis). and/or bowel and bladder problems. Thus. polyneur opathy . sweaty feeling you get when you skip meals and run around all day. im­ potence. Elevated blood glucose makes the blood hypertonic. coronary artery disease. which can lead to blindness). Diabetes Treatment. What side effects would you expect from such a drug? If you increase the osmolarity of the bowel lumen's con­ tents. the serum hyper­ osmolarity causes p olydypsia (increased thirst) and polyuria (increased urine volume because the hyper­ osmolarity pulls water into the intravascular space). (This is the "D" in MUD PILES. nephropathy (which can result in renal failure). creating an osmotic pressure that sucks water into the vascular space. Consequences of autonomic neuropathy in diabetes can include diabetic gas­ troparesis (poor stomach motility). and tachycardia. Inefficient use of glu­ cose can lead to weight loss and excessive appetite (polyphagia ). If the patient has type 1 (or advanced type 2) diabetes. How would one decrease blood sugar? Well. In the short term. For more on metabolic acidosis. 5-9. and growth h ormone also increase blood sugar. Dia­ betes is a risk factor for peripheral vascular disease. Instead. thus needing in­ sulin replacement just like type 1 diabetics. and/or polyphagia. then water will be pulled into the gut. glycemic control substantially reduces the risk of de­ veloping these complications. If dietary intervention and exer­ cise are ineffective. and this leads to ketoacid (ketone body) forma­ tion. where does blood sugar come from? Either from oral intake or from gluconeogenesis. sulfonylureas increase in­ sulin secretion. so dietary modification is essential in managing diabetes. THE ENDOCRINE SYSTEM eventually this mechanism fails. and stroke. Hyper­ glycemia has both short-term and long-term compli­ cations. glucocorti­ coids (steroid treatment can lead to hyperglycemia/ diabetes). The official diagnostic criteria are fasting plasma glu­ cose � 126 mg/dL. how else can we decrease blood sugar? Metformin is a commonly used diabetic treat­ ment that decreases hepatic gluconeogenesis. increase insulin secretion . and/or neuropathy. and/or auton omic neuropathy . n orepinephrine I epinephrine (get some sugar for that fight or flight! ). Chronic hyperglycemia is detrimental to both the microvasculature and larger vessels. we want to reduce the patient's sugar intake. resulting directly from hyperglycemia and inefficient glucose metabolism. When blood glucose is low enough to cause epi­ nephrine secretion. the whole "fight or flight" response comes out: anxiousness. 9 Good 9 As for affecting insulin. But consider a patient with early type 2 with some insulin resistance but who maintains some insulin secretion. Treatment of Diabetes Mellitus Fig. This is known as a hyperos­ molar nonketotic state and can lead to coma. Neuropathy from diabetes can be peripheral mononeuropathy. 3.14). ketosis can occur. The main laboratory abnormality is high blood sugar. polydypsia. which takes place mostly in the liver. Type 2 diabetics can bum out the pancreas. This is why acarbose is not used as com­ monly as metformin. this glucose cannot be m oved into cells and utilized. Diabetic ketoacidosis is a metabolic acidosis. Diabetes is referred to as "starvation in the midst of plenty" since. see Chapter 3). and insulin resistance. A non­ ketotic state is more likely to occur in a type 2 diabetic. This causes that shaky. Clinical features can include polyuria. In some cases. Extreme hyperglycemia can cause massive fluid shifts. leading to retinopathy (microvascular changes in the retina. this glucose stays in the blood and gets excreted by the kidneys. A less commonly used drug is acarbose . If there is no insulin at all (type 1 dia­ betes).CHAPTER 5. leading to diarrhea. inadequate insulin secretion. Treatments are targeted to combat high blood sugar. random plasma glucose � 200 mg/dL with polyuria and polydipsia. First. an alpha glucosi­ dase inhibitor that inhibits gut enzymes that nor­ mally break down starches to release glucose.

and response to carbohydrates . In a normal individual. Decreased Counter-Regulatory Hormones Decreased glucagon.. adrenergic (e. With any endocrine problem. hypoglycemia can occur despite normal hormone secretion. Thus. In these situations.. a high insulin level without a correspondingly elevated C-peptide suggests exoge­ nous insulin administration. adrenal insufficiency). What is meant by excessive diabetes treatment is fairly obvious. could be secondary to liver failure or glycogen storage disease. If exogenous insulin is inj ected. For example.. hypogly­ cemia should not normally occur during a short fast (e. If there is an insulinoma.g. a non-diabetic taking insulin. norepinephrine/epinephrine. THE ENDOCRINE SYSTEM PANC R EAS Glucose absorption G UT stre am DIABETES TREATMENT Figure 5-9 Hypoglycemia is defined by Whipple's triad : low plasma glucose . gluconeogensis. 109 . but there could be Excess Insulin a problem with the actions they are supposed to induce. C-peptide will be elevated with insulinoma..g.. diaphoresis. decreased cortisol (e. In this case. C-peptide is also se­ creted when proinsulin is cleaved to form insulin. insulin should be low if blood sugar is low.e. anxiety) and/or neuroglucopenic (e.e. e. ) Since the insulin is endogenous.g. the hormones could be normal. counter-regulatory hormones have actions that lead to maintenance of blood sugar level. weakness. slurred speech. head­ ache. while glucagon. An insulinoma is an insulin-secreting tumor usu­ ally found in the pancreas. or decreased growth hormone (e.g. the body's counter­ regulatory mechanisms (i. cortisol. seizure).g. during an overnight fast. So how could inap­ propriately low blood sugar occur? Either there must be excess insulin. Given the body's regulatory mechanisms. (Normally. A problem with gluconeogenesis Excess insulin can occur with ( excessive) diabetes treatment or insulinoma. hunger. symptoms of hypoglycemia. insulin will be normal or elevated despite hypogly­ cemia.. from hypopituitarism) can cause hypoglycemia.CHAPTERS. or decreased counter-regulatory hormones.. between meals). The symptoms can be How can you make this diagnosis? Normally when in­ sulin is secreted endogenously. glucagon-induced gluco­ neogensis) keep blood glucose levels normal despite lack of glucose intake. i. however "foul play'' can also occur. coma. . What could cause hypoglycemia? Remember that insulin decreases blood sugar. confu­ sion. and growth hormone increase blood sugar. the site of pathology may be either the hormone's secretion or its action. there is no cleavage and hence no C-peptide.g.

there must be increased intake and/or absorption of calcium (mediated by elevated PTH. Vitamin D increases absorption of cal­ cium and phosphate from the gut. PTH in­ creases blood calcium by: stimulating osteoclasts to break down bone • increasing reabsorption of calcium by the kidneys • increasing conversion ofinactive vitamin D to active vitamin D (which increases calcium reabsorption and PTH. B LOOD [CALCI U M] . excess of either hormone can cause hypercalcemia. By decreasing reabsorption of phosphate by the kidneys (and hence increasing excretion). Calcitonin decreases blood calcium by using the calcium to build bone. 5-1 1 . which only increases blood calcium. its role is more minor. elevated vitamin D). 5-10. Located in the neck. in medullary thyroid cancer) or deficiency do not tend to affect calcium level. calcitonin. Treatment of hypoglycemia is directed at the under­ lying cause.or hypocalcemia. So vitamin D increases blood cal­ cium and blood phosphate . THE PARATHYROIDS. and so its elevation (e. PTH and vitamin D raise blood calcium level. Specific causes of hypercalcemia include : Vitamin D. Causes of Hyper. increases bone re­ sorption (to release calcium and phosphate into the circulation). 3-4) can lead to hypocalcemia. since vitamin D is responsible for increased calcium absorp­ tion from the gut. or shifts of calcium from bone into the circulation. and decrease of either can cause hypocalcemia. This distinction becomes important when looking at laboratory tests to diagnose hypercalcemia. leading to its loss in the urine. and vitamin D. Since calcium is stored in bones and excreted by the kidneys. and also increases phosphate reabsorp­ tion in the kidneys. Three hormones regu­ late calcium concentration : parathyroid hormone (PTH). granulomatous disease. Why is this impor­ tant? PTH's action on bone causes release of both calcium and phosphate. Since PTH and Vitamin D increase blood calcium. diseases that affect the bones or the kidneys can cause hyper. whereas bone sequestration of calcium ("hungry bone syndrome") and renal failure ( see Fig. Bone breakdown and decreased renal excretion of calcium can lead to hypercalcemia. Hypercalcemia Fig. PTH secretion is not regulated by the pi­ tuitary. Fig. AND BONE • Calcitonin is the antagonist hormone to vitamin D from the GI tract) PTH also decreases reabsorption of phosphate by the kidneys. but by serum calcium concentration.g.CHAPTER 5. However. Al­ though calcitonin also affects calcium metabolism. the reversal of symptoms with glucose administration can help to es­ tablish the diagnosis. decreasing renal reabsorp­ tion of calcium. PTH causes elevated blood calcium and decreased blood phosphate. For cal­ cium to be elevated. and malabsorp­ tion can decrease calcium absorption from the gut. The largest calcium store in the body is the bones. CALCIUM. milk-alkali syndrome) CA L CIUM REGULATION t BLOOD [CALCIUM] Figure 5-10 110 J. calcitonin decreases blood calcium level. Compare this with PTH.and Hypocalcemia. THE ENDOCRINE SYSTEM If acute hypoglycemia is suspected. Thus. as­ suming normal renal function and normal hormone activity. PTH pre­ vents hyperphosphatemia. it would be difficult to cause an aberrant state of calcium merely by altering intake. Calcitonin is secreted by the C cells of the thyroid in response to high blood calcium levels. elevated levels of vitamin D can cause increased absorption of calcium. As with other ions. decreased excretion of cal­ cium. Calcium regulation. • Increased intake : excess ingestion from milk and calcium carbonate antacids such as Turns (milk-al­ kali syndrome) • Elevated PTH (hyperparathyroidism) • Elevated vitamin D (lymphoma.. the four parathyroid glands secrete parathyroid hormone in response to low blood calcium level. PTH.

So hyper­ parathyroidism results in a low serum phosphate and a high urine phosphate . However. Fig. lithium) • Miscellaneous . ) Because PTH induces release of calcium from bone. What about phosphate? Remember PTH's effect on the kidneys : decreased phosphate absorption/increased excretion.Hyp ocalciuric hypercalcemia (which causes both decreased excretion and increased bone resorp­ tion. urine calcium is actually high in primary hyperparathyroidism because the hypercal­ cemia in the blood overwhelms the absorptive capac­ ity of the kidneys for calcium. so decreased glucocorticoids can cause increased blood calcium. In fact. multiple adenomas in different glands. immobi­ lization. Mnemonic: PTH is stimulating lots of receptors in the kidneys. which can decrease in­ travascular volume. cAMP is part of many receptor­ stimulated second messenger cascades. excess calcium spills into the urine. Once this capacity is surpassed. (Alkaline phosphatase can also be elevated in biliary obstruction. Usually. thus increasing calcium concentration .Paraneoplastic syndrome (e. glucocorticoids de­ crease renal calcium reabsorption and increase calcium excretion. ) What about urine calcium? You might think it would be low since PTH increases renal calcium reab­ sorption. pheochromocy­ toma) .Adrenal insufficiency (Adrenal insufficiency can cause hypovolemia. Decreased renal excretion10 (thiazide diuretics. 5-14) .g. Elevated PTH Primary Hyperparathyroidism is excess secretion of PTH by the parathyroid gland(s).CHAPTERS. hyperthyroidism) blood calcium level. 111 . THE ENDOCRINE SYSTEM I nc Dec I nc CA LC I UM INTA KE/ A BSO R PTION RENA L CA LC I UM EXC RETION Dec Dec CAUSES OF HYPER. An elevated serum PTH is obviously also present. multiple myeloma. 3-4). Renal fail­ ure results in decreased vitamin D activation. In primary hyperparathyroidism. which leads to lots of second messenger cascades. Additionally. or parathyroid lO Another finding in hyperparathyroidism is in­ creased urinary cAMP. Lab Findings in Primary Hyperparathyroidism. alkaline phosphatase can be elevated. serum calcium will be high.. Note: renal failure does not cause hypercalcemia. Increased PTH will raise primary bone tumor. as in any cause of bone breakdown.AND HYPOCALCEMIA Figure 5-11 • • Bone breakdown (secondary to metastasis to bone. though hyperplasia (growth of all four glands). the un­ derlying pathology is a parathyroid adenoma in one gland. which causes hypocalcemia (See Fig. cancer are also possibilities. it is often simply an elevated calcium on routine blood screening that raises suspicion for pri­ mary hyperparathyroidism.

and cAMP are increased in the urine. Some hematologic malig­ nancies can produce osteoclast-activating factors (e. calcium will be released from bone. in PTHrP-mduced hypercalcemia. vitamin D-independent hypercalcemia will inhibit both of these hormones. be­ cause thyroid hormone stimulates osteoclasts. constipation/abdominal pain/pancreatitis. this PTH-independent. and malaise. So secondary hyperparathyroidism is not related to the pituitary as with other secondary en­ docrine diseases. . Symptoms and Signs of Hypercalcemia Mild hypercalcemia can be asymptomatic and inciden­ tally noticed on lab testing (this is often how primary hyperparathyroidism is diagnosed). In a diagnostic work-up for hypercal­ cemia. squamous cell lung cancer is the culprit. so urine cAMP will be low . Summary of hypercalcemia laboratory find­ ings. moans and psychiatric overtones. 112 . bone breakdown. PTH-Related Protein (PTHrP) . So in primary hyperparathyroidism: Calcium and PTH are elevated in the serum. 1 1 Therefore. phosphate. there is low PTH. Metastases to bone can cause local destruction by their growth. The other lab findings are the same as those in hyper­ parathyroidism since the PTHrP functions just like PTH. Effect of elevated vitamin D on PTH and vice versa. the elevated calcium will decrease PTH level via neg­ ative feedback. arthralgia.g. bones. not the PTHrP itself. see Fig. elevated urinary cAMP. Fig. leading to hypercalcemia . Treatment thus involves vitamin D therapy and/or management of renal disease. This can occur secondary to vitamin D deficiency or renal failure (which causes hypocalcemia secondary to decreased vitamin D acti­ vation. Parathyroidectomy is often neces­ sary to treat tertiary hyperparathyroidism. night sweats. Vitamin D-Induced Hypercalcemia Lymphocytes in lymphomas and granulomas (e. weakness. hence decreasing their levels in the serum. after the resolution of the renal failure or after renal transplantation . sarcoid. Hyperthyroidism can also cause hypercalcemia. Secondary Hyperparathyroidism. etc . consider other causes of bone breakdown such as Paget's disease. but the decreased vitamin D is thought to relate to the PTHrP-induced hypercalcemia. . rather. However. phate. Calcium. 5-12. the result­ ant high calcium level will inhibit PTH release by the parathyroids. re­ sulting in hypercalcemia. The parathy­ roid glands are not under control of the pituitary. However. Because PTHrP works just like PTH. causing bone breakdown. except that vitamin D is decreased in THrP­ related hypercalcemia . Tertiary Hyperparathyroidism occurs when sec­ ondary hyperparathyroidism persists inappropriately Patients with metastases to bone commonly have bone pain and X-ray and/or MRI findings. various cytokines). vitamin D is actually el­ evated in primary hyperparathyroidism.25-form . and elevated urme calcium. 3-4). tuberculosis. THE ENDOCRINE SYSTEM the effect of which is spilling some excess second messenger into the urine." meaning renal stones. PTH secretion is regulated entirely by calcium con­ centration. as well as fatigue. and phosphate is de­ creased. Note that the reverse is not true: Since PTH actually increases conversion of vitamin D from the 25-form to the 1. The decrease in these hormone levels means there is not much stimulation of their receptors in the kidneys. Note : Secondary hyperparathyroidism is discussed here because it is a cause of elevated PTH. PTHrP can be measured in the serum to confirm the diagnosis. fatigue. laboratory testing will show increased calcium and a low PTH . a disorder of excessive bone forma­ tion and breakdown. The real reason for cAMP secretion is far more complex and beyond the scope of this text. Most commonly. which can lead to hypercalcemia. There are some tumors that secrete a compound known as PTH­ related protein (PTHrP). The classic de­ scription of hypercalcemia is "stones. Parathyroidectomy is the treatment of primary hy­ perparathyroidism.g. but rather to blood calcium concen­ tration: A decrease in blood calcium causes an increase in PTH secretion. which can lead t o bone destruc­ tion.25-vitamin D (the more active form). and The exact reason is not known. Prolonged immobilization can also lead to bone breakdown and subsequent hyper­ calcemia. abdominal groans. but breast and kidney tumors can also produce PTHrP. Patients with hematologic malignancies may have various aber­ rancies in their blood cell counts. This elevation in active vitamin D increases calcium reabsorption. ) can increase conversion of 25-vitamin D to 1 . low serum ph os­ . 5-13.CHAPTER 5. it is a result of hypocalcemia. If vitamin D excess causes hypercalcemia. Thus. Remember that metastases to bone are not the only way to end up with bone destruction and subsequent hypercalcemia. As far as lab findings. secondary hyperparathyroidism it is not a cause of hypercalcemia. J! 11 Fig. Bone Breakdown PTHrP and lymphomas are not the only ways that ma­ lignancy can result in hypercalcemia.

1. increase cal­ cium excretion (loop diuretics . shifts to bone. · 113 . increased excretion of calcium.v i t D to 1. -n f f ! . inhibit bone resorption (calcitonin and bisphosphonates). THE ENDOCRINE SYSTEM J i Ca 2 + ( i PTH L i Vitam i n D (co nve rs io n of 2 5 .CHAPTERS. The first three of these are mediated by decreases in PTH and/or vitamin D. note : thiazide diuretics increase calcium reabsorption).1. surgery for hyperparathyroidism.g. Causes of Hyper.1. f f VITAM I N D 1: �--' SUMMARY OF HYPERCALCEMIA LABORATORY FINDINGS Figure 5-13 psychiatric disturbances. PTH rP f .1.. Fig. f f f BON E B R EAKDOWN f f . and/or treat the un- 5-1 1 . one can dilute blood calcium (hydration with IV solutions). A shortened QT interval on EKG can also occur. Hypocalcemia Treatment of Hypercalcemia To decrease blood calcium level. .1. or binding of calcium in the circulation.and Hypocalcemia. steroids for granulomatous disease). .1. f . derlying cause (e. Hypocalcemia can be caused by decreased intake I ab­ sorption of calcium.2 5 -vit D) l EFFEC T OF ELEVATED VITAMIN D ON PTH AND VICE VERSA Figure 5-12 Serum Ca 2 + Serum P0 2 " Urine cAM P PTH Vit D 4 PRIMARY HYPERPA RATHYR OIDISM f . Mnemonic: Lots of CALifornians are short QTs (cuties).1.

. malabsorp­ tion.Drugs (e. and the parathyroids are responding to that hypocalcemia by secreting PTH. PTH receptors may be resistant to PTH. Since vitamin D is made in the liver and is activated in the kidneys. or malabsorption of vitamin D. calcium) • Miscellaneous .Hypoalbuminemia . patients will manifest the features of Albright's hereditary osteodystrophy (and have a similar mutation) but maintain PTH-responsive receptors. sepsis) Decreased PTH: Hypoparathyroidism and Pseudohypoparathyroidism Hypoparathyroidism can be caused by: • Vitamin D Deficiency Congenital absence ofthe parathyroids (e. one of three scenarios is possible: 114 This is different from ost eop orosis. 5. gonadotropins. (A similar scenario occurs in nephrogenic diabetes insipidus.Hypercalciuric hypocalcemia (increased calcium excretion and decreased bone resorption see Fig. . thus lead­ ing to elevated. which in­ cludes features such as short stature. ectodermal dystrophy) • Familial (i. albeit ineffective PTH. genetic) hypoparathryoidism • Surgical damage I removal of the parathyroids.CHAPTER 5. renal disease.g. a hypoparathyroid state exists. . • Infiltrative disease of the parathyroids (e. but they are not actually hypoparathyroid.14) .g. 3. chemotherapy agents. mucocutaneous candidiasis) and APECED (autoimmune polyendocrinopathy can­ didiasis.g. Fanconi syndrome : proxi­ 2 . foscarnet.Pseudohypoparathyroidism (PTH resistance) • Vitamin D deficiency (decreased intake. DiGeorge Vitamin D deficiency can result from decreased expo­ sure to UV light. . In pseudohypoparathy­ roidism. and round face. the bones are suddenly free from the constant breakdown that was being caused by the over-secretion ofPTH. Occasionally. THE ENDOCRINE SYSTEM Specific causes of hypocalcemia include : • 1. hypo.Hyperphosphatemia (e. PTH level will be high . Decreased PTH .Pancreatitis (fats released from pancreas bind Pseudohypoparathyroidism. mal tubule dysfunction leading to loss of calcium and other electrolytes) • Shift to bone (hungry bone syndrome) • Binding of calcium . The condi­ tion of having receptors that are non-responsive to PTH is known as pseudohypoparathyroidism..) Pa­ tients with pseudohypoparathyroidism type la also have Albright's hereditary osteodystrophy. Alternatively. low vitamin D can lead to problems in growing bone and the growth plate (rickets). The sudden decrease in PTH causes the hungry bones to se­ quester calcium for re-growth. . rhabdomyolysis) . and glucagon. 1 2 syndrome is a problem with the third and fourth branchial pouches in which the thymus and parathy­ roids are absent) • Autoimmune destruction of the parathyroids in rare diseases such as HAM (hypoparathyroidism.g. adre­ nal insufficiency. phenytoin) . example from thyroid surgery • Magnesium (a 2+ ion like calcium).Severe I chronic illness (e. for Hungry Bone Syndrome After surgical correction of hyperparathyroidism. obesity. but to no avail. if calcium is low and PTH is high. Vitamin D deficiency is causing the hypocalcemia. since patients with this disorder have many of the same features seen in pseudohypoparathyroidism. liver or renal disease can lead to decreased vitamin D and subsequent hypocalcemia. which can lead to hypocalcemia. where renal ADH receptors are unresponsive to pituitary ADH. which affects the parathyroids' secretion of PTH .g. where the bones are porous and brittle due to a decrease in bone mass that occurs primarily in the elderly. Wil­ son's disease) • Metastases to the parathyroids 12 If calcium and PTH are both low. Vitamin D deficiency in adults results in osteomalacia (a decrease in bone density and min­ eral content causing bone softening). Additional manifestations of pseudohypoparathy­ roidism type la are resistance to TSH. inadequate dietary intake of vitamin D.e. resulting in hypocalcemia. This can also occur following thyroid sur­ gery for correction of hyperthyroidism as a response to increased bone breakdown during hyperthyroidism. In children.Hypoparathyroidism . This condition carries the wonderful name pseudopseudohypoparathyroidism. the PTH receptor resistance to PTH is due to mutations in a G protein involved in signal transduction from the PTH receptor. .g. PTH itself may be abnormal/non-functional .or hyper­ magnesemia can lead to hypocalcemia. liver disease) • Increased excretion (e. . See Osteoporosis in Bone section below.

so calcium deficiency. In the case of malabsorption. The result is decreased urine calcium (hypocalciuria) and increased blood calcium (hyper­ Hypoalbuminemia Since some calcium is bound by albumin. The result is increased urine calcium (hyper­ calciuria) and decreased blood calcium (hypocalcemia). and the parathyroids respond by in­ creasing PTH secretion. drugs/toxins. infections. If there is a high level of cal­ cium. thinks. weakened. " HYPERCALCIURIC H YPOCALCEMIA AND HYPOCALCIURIC HYPERCALCEMIA Figure 5-14 1 15 . I nephron there's not enough Ca2+ arou n d . or they can develop primary or metasta­ tic tumors. Symptoms and Signs of Hypocalcemia The classic signs of hypocalcemia are tetany. and the parathyroids respond by decreasing PTH secretion. If calcium is high. and hyper­ parathyroidism can weaken bones. " there's not enoug h Ca 2+ arou n d . and infected. the CaSR would transmit the message to try to hold on to calcium. seizures. the recep­ tors transmit that message to the parathyroids. Hypercalciuric Hypocalcemia and Hypocalciuric Hypercalcemia The calcium-sensing receptors (CaSR) on parathyroid cells sense the surrounding calcium level. calcemia). HYPOCALC/URIC HYPERCALCEMIA CaSR receptor i n parathyroid gland thinks. parenteral calcium is sometimes necessary. the receptors transmit that message to the parathyroids. which would render oral treatments ineffective. Diagnosis of rhabdomyolosis can be confirmed by myoglobin in the urine. the CaSR malfunc­ tions such that it "thinks" there is too much calcium around even when there is not. This is known as "factitious hypocalcemia" be­ cause ionized calcium is actually normal. This leads to decreased PTH secretion and decreased calcium retention in the nephron. I nephron there's lots of Ca2 + arou n d . aroun d . and treatment is largely supportive (managing fluids and elec­ trolytes and using diuretics to increase excretion of toxic muscle breakdown products). severe acute hypocalcemia can require IV repletion of cal­ cium. one cause of which is rhabdomyolysis . THE ENDOCRINE SYSTEM Fig. decreasing calcium excretion and increasing blood calcium. a decreased albumin level can lead to a decreased total calcium level. Trousseau's sign (inflating a blood pressure cuff around the arm causes a tetanic spasm of the wrist).g. " Hey. Chronic hypocalcemia can be remedied with cal­ cium and vitamin D supplements unless there is significant malabsorption. fractured. nephrotic syndrome. If calcium is low. Treatment of Hypocalcemia there's lots of Ca2 + In addition to treating the underlying cause. HYPERCALCIURIC HYPOCALCEMIA CaSR receptor i n parathyroid gland thinks. the CaSR malfunc­ tions such that it "thinks" there is not enough calcium around even when there is. Bones are composed of calcium phosphate. muscle diseases (e. So high calcium shortens the QT interval. myopathies). " The CaSR is also expressed in the nephron. polymy­ ositis. reducing blood calcium. and other maj or physiological stresses. Binding of Calcium Binding of calcium can occur in hyperphosphatemia . low calcium lengthens the QT interval. Chuos­ tek's sign (tapping over the facial nerve causes a twitch). cir­ rhosis. Diseases of Bone Bones can become thickened. burns. and a prolonged QT interval. " Hey. In hypocalciuric hypercalcemia. circumoral paresthesias. Rhabdomyoly­ sis is muscle breakdown and can occur secondary to massive trauma/injury. This leads to increased PTH secretion and increased calcium retention in the nephron. If calcium is low. 5-1 4. .CHAPTER 5. " Excretes Ca2+ Reabsorbs C a2 + CaSR receptor i n CaSR receptor i n thinks. " Hey. extreme exertion. Decreased albumin can occur in malnutrition. "Hey. Hypercalciuric hypocalcemia and hypocal­ ciuric hypercalcemia. the nephron responds by increasing calcium ex­ cretion. In hypercalciuric hypocalcemia. liver disease. vitamin D deficiency.

leading to disorganized. Extreme cases can thus lead to high output heart failure as the heart strug­ gles to supply the excess vasculature. there are sev­ eral primary bone tumors (e. In these disorders. an intermediate phase. Osteopetrosis is a genetic disease in which osteoclasts fail to break down bone. and calcitonin prevent further progression of osteoporosis. Paget's can be managed with bisphosphonates. PTH in­ jections can be used to stimulate bone growth. prolonged immobilization. X-ray will not demonstrate bony change for several weeks after infection. Osteoporosis is common in elderly women (from estrogen deficiency). Bone pain. in whom the condition tends to be far less severe. The uncontrolled bone for­ mation is disorderly. steroids or vitamin D may be used in treatment. bones may appear hyper-dense. vitamin D deficiency leads to a decrease in bone density and mineral content. Tumors of Bone Bone is a common site of tumor metastasis. This process may occur in any bone and/or multiple bones. which can lead to increased fracture risk. Impingement of new bone on the bone marrow can compromise hematopoiesis. What might in­ crease bone formation? Either increased activity of os­ teoblasts or decreased activity of osteoclasts. but can expe­ rience bone pain (including headache if the skull is involved). most com­ monly in the spine.. On X-ray. The disease can present in infants (called malignant osteopetrosis) or adults. or bone scan may also show changes. which inhibit osteoclast de­ struction of bone. causing bone softening. Although surgery may be necessary to relieve nerve compression. osteosarcoma. Estrogen replacement. and frontal bossing (enlargement of the forehead). These primary tumors are far less common than metastases to bone and tend Thickened and Weakened Bones: Paget's Disease (Osteitis Deformans) In Paget's disease of bone. IV antibiotics are used to treat the infection. In addition. IV drugs. A variety of genetic defects can cause osteoclast dysfunction. os­ teoarthritis. fracture. In children. cal­ cium supplements. throm­ bocytopenia. In the hot phase. ribs. and erythema (redness) over the affected bone. bisphosphonates. some trigger (hypotheses include infectious and genetic possibili­ ties) leads to overactivity of osteoclasts and massive bone resorption . deafness (from bone around cra­ nial nerve VIII and middle ear ossicles).. and in patients with elevated cortisol (Cushing's. Like osteo­ porosis. weaker bone. fever. and immun­ odeficiency/immunosuppression. Alkaline phosphatase may be elevated from bone break-down.CHAPTER 5. there is repeated bone re­ sorption and bone formation. Biopsy/aspiration of affected bone can be used for diagnosis and culture to identify the offend­ ing organism. while Salmo­ nella is more common in patients with sickle cell dis­ ease. and skull. In adults. exogenous steroid treat­ ment). and osteomyelitis can also occur in osteopet­ rosis. bone marrow transplant is the only curative therapy. This phase is followed by a compen­ satory osteoblast response mixed with continued osteolytic activity in which bone is re-formed in a dis­ organized fashion. which can predispose to fracture. Predisposing factors include vascular insufficiency. X-ray demonstrates decreased bone density. Cranial nerve compression can lead to facial palsy (nerve VII) or deafness (nerve VIII). THE ENDOCRINE SYSTEM Thickened Bones: Osteopetrosis Normally PTH and calcitonin mediate a dynamic equilibrium between bone formation (by osteoblasts) and bone resorption (by osteoclasts).g. and a sclerotic ("cold") phase. chills. bowed. resulting in anemia. and/or immunosuppression. this bone weakening leads to a predisposition to fracture. osteo­ blastoma. anorexia nervosa). In some cases.g. and peripheral nerve compression can cause carpal tunnel syndrome. Bone density scanning is often used to assess the degree of osteoporosis and fracture risk. surgical treatment is used to correct any nerve compression or arthritis. The affected bone is highly vascularized. and these fractures can be difficult to heal. Infectious agents can reach bone hematogenously from other sites of infection or from contiguous spread during trauma or surgery. rickets also causes growth plate abnormalities. Patients may be asymptomatic. Ewing's sarcoma). chronic diseases. aureus is one of the more common causes generally. Rickets/Osteomalacia. though soft tissue swelling may be visible early on. there is continued disorganized bone formation. Bony growths can entrap cranial nerves or peripheral nerves. CT. In the cold or sclerotic phase. Weakened Bones: Osteoporosis and Osteomalacia Infection of Bone: Osteomyelitis Osteoporosis is decreased bone mass. arthritis. Calcium/vitamin D intake and exercise can help to prevent osteoporosis. 116 . though possible anywhere in the skeleton. Paget's disease occurs in three phases: a lytic ("hot") phase. fractured. Paget's can pre­ dispose to osteosarcoma. but treatment of the underlying disease is generally not necessary. or poor diet (e. so it can feel warm to the touch. In infants. Staph. Symptoms include bone pain. the elderly in general (senile osteoporosis). spinal steno­ sis. MRI. and in some cases surgical debridement is also necessary. or otherwise abnor­ mal.

CHAPTER 5. THE ENDOCRINE SYSTEM
to occur in long bones (e.g. , femur). A primary or
metastatic tumor in bone can cause pain, predispose
to fracture, or be asymptomatic, being diagnosed inci­
dentally on X-ray or another radiologic imaging study.
Multiple myeloma is a proliferation of plasma cells
(terminally differentiated B cells) that occurs most
commonly in bone (see Chapter 6).

117

Note : Whether bone i s weakened (e.g., osteoporosis,
osteomalacia, or tumor growth) or whether a disease
increases bone formation (e.g. , osteopetrosis or Paget's
disease), the patient is predisposed to fractures . This is
because the diseases causing increased bone forma­
tion often produce abnormal architecture of this newly
formed bone.

CHAPTER 6. THE HEMATOLOGIC SYSTEM

CHAPTER 6. THE HEMATOLOGIC SYSTEM
COMPONENTS OF THE
HEMATOLOGIC SYSTEM

decreased number of RBCs or a decrease in RBC
function (e.g., a problem with hemoglobin, the mole­
cule that carries oxygen). This results in inade­
quate oxygen delivery to the tissues. How would
the body compensate for this? Hint: What other
organs can control oxygen and blood? The heart/
circulatory system, the lungs, and the kidneys. How
would the heart respond to anemia? In an effort
to increase perfusion of the tissues, the heart in­
creases its rate, so tachycardia can be one sign of
anemia (though tachycardia can occur in many
other circumstances as well). If there is not enough
oxygen to go around, the most important organs
(e.g., the brain) get first dibs, so blood is shunted
away from the skin, leading to pallor. When the body
needs more rapid oxygen delivery to tissues (e.g.,
during exercise or heavy exertion), there may be
dyspnea when the lungs and heart struggle to sup­
ply the tissues with adequate oxygen. What can
the kidneys do? The kidneys can secrete more
erythropoietin, to stimulate the bone marrow to pro­
duce RBCs.

The hematologic system includes the red blood cells,
white blood cells, platelets, coagulation factors, bone
marrow, lymph nodes, and spleen. Red blood cells
(RBCs) carry oxygen from the lungs to peripheral tis­
sues, white blood cells (WBCs) are part of the immune
system, and platelets and coagulation factors coordi­
nate the formation of clots to prevent bleeding. The
bone marrow is the site of formation of new blood
elements (hematopoiesis) in the adult. The spleen is
involved in hematopoiesis in the fetal period and; in
adults, the spleen filters out infectious organisms and
malformed, damaged, or old red blood cells. The lymph
nodes are localized sites of lymphatic tissue, including
white blood cells responsible for fighting infection.
Fig. 6-1. Pathology in the hematologic system. Pathol­
ogy in the hematologic system can be due to increased or
decreased number (or function) ofany ofits components.

RED BLOOD CELLS

Symptoms/signs of anemia thus include tachycar­
dia (heart trying to pump blood more vigorously to
make up for the less "effective" blood), pallor (blood
shunted away from skin to organs), and exertional
dyspnea.

Red blood cells contain hemoglobin, which carries oxy­
gen to the tissues. RBCs are produced in the bone mar­
row; erythropoietin (EPO) secretion from the kidneys
increases RBC production. Anemia is a decrease in
RBC number or function. Polycythemia is an increase
in RBC number.

Hemoglobin and Hematocrit. Normal hemoglobin

concentration is around 13.5-17.5 g/dl for men, 12-16
g/dl for women. Hematocrit is the percent of the blood
that is actually RBCs (i.e., not plasma, etc.). A normal
hematocrit for a man is about 41-53%, for a woman
about 36-46%.

Too Few RBCs: Anemia
Symptoms and Signs of Anemia

In anemia there is a decrease in the oxygen-carrying
capacity of the blood. This occurs secondary to a

INCREASE

DECREASE

Platelets/
Coagulation factors

RBCs

WBCs

Polycythemia

Infection
Inflammation
Malignancy

Hypercoagulable
state

F

Anemia

lmmunodeficiency

Hypocoagulable
state

1:

T

=-=

PATHOLOGY IN THE HEMATOLOGIC SYSTEM
Figure 6-1
1 18

CHAPTER 6. THE HEMATOLOGIC SYSTEM

Kidney

·

Renal failure ( J. EPO)

EPO

Bone


t;!>l!i�v

Blood
vessel

CAUSES OF ANEMIA
Figure 6-2
neys' ability to secrete EPO is diminished, which can
result in anemia. If renal failure is the cause of ane­
mia, one would also expect to see electrolyte abnor­
malities and elevated BUN and creatinine.

Causes of Anemia

6-2. Causes of anemia. Causes of a decrease in
RBC number or function include:

Fig.

Decreased production of RBCs
- Secondary to a problem with the bone marrow
- Secondary to a problem with erythropoietin
(EPO), e.g., renal failure
- Secondary to a lack of raw materials necessary
for RBC synthesis: B12, folate, iron

What could cause decreased bone marrow produc­
tion of RBCs? Infiltrative processes (e.g., myeloma,
leukemia, bone marrow metastases from other can­
cers), aplastic anemia, or decreased materials neces­
sary for RBC production (iron, B12, folate).

Loss of RBCs
- From bleeding, obvious (e.g., hemorrhage) or oc­
cult (e.g., GI bleed)
- From destruction (hemolysis)

Aplastic anemia is a loss of hematopoietic cells lead­
ing to pancytopenia (decrease in all blood cell types).
It can be caused by drugs, viruses, or autoimmune
processes. Both infiltrative processes and aplastic
anemia would cause low levels of WBCs and platelets,
in addition to just a decrease in RBCs. If a hematologic
malignancy exists in the bone marrow, the number of
the malignancy-causing hematologic cell population
will be extremely high. Patients with hematologic ma­
lignancy may also experience constitutional symp­
toms such as fever, night sweats, and fatigue.

Production of defective RBCs (i.e., a problem with
one of the components of the RBC. Though it may
not alter RBC number, this will alter RBC function,
thus leading to anemia).

Decreased Production of RBCs
Bone Marrow Failure, Renal Failure, Aplastic
Anemia. In adults, RBCs form in the bone marrow.

RBC production is stimulated by erythropoietin
(EPO), which is secreted by the kidneys. So anemia
secondary to decreased production of RBCs could re­
sult from either a problem with EPO secretion or a
problem in the bone marrow. In renal failure, the kid-

Iron, B12, and Folate Deficiency. Aside from intrin­

sic bone marrow disease or renal failure, the bone
marrow may simply not have the materials necessary
to make functional RBCs, namely iron, folic acid, and
B12. Deficiencies of any of these can cause anemia.

1 19

CHAPTER 6. THE HEMATOLOGIC SYSTEM
are still big. This leads to a macrocytic anemia. Fo­
late and/or B12 deficiency also alters DNA synthesis
in white blood cells, the result of which can be seen in
polymorphonuclear white cells (PMNs) on blood
smear. Although PMN nuclei are normally multi­
lobed (2-3 lobes), the folate or B12 deficiency leads to
hypersegmentation of PMN nuclei (i.e., 5-6 lobes).
How does one distinguish between folate and B12
deficiency if both lead to macrocytic anemia with
hypersegmented neutrophils? One can check B12
and folate levels. Additionally, B12 deficiency can
lead to neurological symptoms such as numbness and
tingling due to problems with the dorsal columns
of the spinal cord. Folate deficiency does not lead to
such symptoms.

Iron Deficiency Anemia. Iron is necessary for hemo­
globin production and function. Hemoglobin gives
RBCs their nice red color and full shape, so when there
is not much iron around, the result is pale
(hypochromic), small (microcytic) red blood cells. Thus,
iron deficiency is a hypochromic, microcytic anemia.
Other symptoms, signs, and lab abnormalities in
iron deficiency anemia: Patients can have pica (crav­
ing ice or other non-food objects). Mnemonic: Imagine
that the body "knows" it is craving iron and seeks
metal-flavored things to munch on. (It is not known
why this really happens.) As with any anemia,
symptoms/signs such as pallor, tachycardia, and exer­
tional dyspnea may be present. Serum iron will obvi­
ously be low.
Fig.

Why would someone be deficient in folate or B12?

6-3. Ferritin and transferrin (TIBC) in iron defi­

ciency anemia. Ferritin is a protein that stores iron.
Most ferritin is found in the liver, spleen, and bone
marrow, and some ferritin circulates in the blood. If
there is excess iron in the blood, ferritin concentration
in the blood increases to bind the extra iron. In iron de­
ficiency, ferritin has no need to come into the blood and
bind iron. Thus, ferritin is low in iron deficiency ane­
mia. Transferrin transports iron in the blood. Trans­
ferrin saturation is typically measured indirectly by
assessing the total iron binding capacity (TIBC). What
would happen to the binding capacity in iron defi­
ciency? It should increase since there is not much iron
to bind. Another way of saying that there is increased
binding capacity is that there is decreased transferrin
saturation. So in iron deficiency, ferritin is low and
TIBC is elevated (meaning that transferrin satura­
tion is decreased).

Inadequate intake (diet). Folate is found in leafy
vegetables and fresh fruits; deficiency can be seen
in alcoholics and in the elderly. B12 is found in liver,
muscle, eggs, dairy, seafood, so a strict vegan diet or
severe malnutrition can result in B12 deficiency.
Increased demand (e.g., pregnancy, malignancy)
Decreased absorption
- For either B12 or folate: Secondary to disease of
the terminal ileum, which is the final portion of
the small intestine (e.g., sprue, Crohn's disease)
- For B12: Secondary to decreased intrinsic factor
(e.g., pernicious anemia, gastritis)
Drugs (e.g., methotrexate is a folate antagonist)

In the stomach, parietal cells secrete a protein
called intrinsic factor, which binds B12 and allows it
to be absorbed in the terminal ileum. So a problem
with the production of intrinsic factor or with the ter­
minal ileum could lead to B12 deficiency.

Folate and B12 Deficiency. Folate and B12 are in­
volved in DNA metabolism. If there is inadequate
folate and/or B12, the red blood cells do not form prop­
erly, and they are released prematurely while they

In pernicious anemia, autoantibodies are produced
against parietal cells, causing a decrease in the produc­
tion of intrinsic factor. The loss of intrinsic factor re­
sults in a loss of B12 absorption. Other gastric diseases
that damage the parietal cells .can also lead to intrin­
sic factor deficiency (e.g., autoimmune gastritis).
"Extra space
to bind"

Two main types of pathology can affect the terminal
ileum: infection (with bacterial overgrowth) or inflam­
matory disease (e.g., Crohn's disease or sprue).
Surgery that removes a portion of the ileum will also
reduce its ability to absorb B12 (because the absorp­
tive surface area is decreased). How could you figure
out which one of these causes of B12 deficiency is pres­
ent? The Schilling test.

"No need
to store"

8

FERRITIN AND TRANSFERRIN (TIBC) IN
IRON DEFICIENCY ANEMIA

Fig. 6-4. Schilling test. The Schilling test localizes the
site of pathology in B12 deficiency. In this test, a pa­
tient gets an intramuscular injection of nonradioac­
tive B12. This saturates the patient's B12 receptors.

Figure 6-3
120

THE HEMATOLOGIC SYSTEM THE SCHILLING TEST ABNORMAL NORMAL ••• 812* A PHASE24�"" 6•6 812* +IF 6 Loading IM dose 812 PERNICIOUS ANEMIA Implies ! Intrinsic Factor was the cause of 812 Implies terminal ileum disease was the cause of 812 deficiency Figure 6-4 12 1 .CHAPTER 6.

and renal ischemia. What else does it have? Like all cells. the membrane. RBCs have membranes and metabolic enzymes. or sprue. For example. In thalassemia. in many cases these problems are related: a problem with a component of the RBC changes its shape. If a patient is overtly hemorrhaging.g. Increased Loss of RBCs: Bleeding and Hemolysis Bleeding. lack of intrinsic factor. every­ thing in phase 1 is repeated. Sickle Cell Anemia arises from a mutation in the beta chain of hemoglobin that causes it to malform. dissemi­ nated intravascular coagulation. asplenia (destruction of the spleen from chronic clogging and infarction). sickle cell) or cause inadequate amounts of alpha or beta chains (thalassemia) to be formed. Autoimmunity (e. If there is still no radioactive B12* in the urine on phase 2. THE HEMATOLOGIC SYSTEM Extracorpuscular defects The patient then ingests radioactive B12 (shown as B12* in the figure). hemoglobin. This can be due to bacterial over­ growth. "target cells" (erythrocytes with a dark spot in their pale centers causing them to look like targets) may be seen. idiopathic/primary or secondary to lupus or neoplasia). Anemia can also be caused by RBC de­ struction or because of a problem with one of the com­ ponents of the RBC (membrane. The Schilling test determines whether B12 deficiency is secondary to in­ trinsic factor loss (pernicious anemia) or terminal ileum disease (e. stroke.g. we would expect to see this radioac­ tive B12* in the urine. and ra­ dioactive B12* should appear in the urine. How would you distinguish be­ tween the two? In phase 2 of the Schilling test. The decreased amount of he­ moglobin in each cell results in anemia. a hyperactive spleen. strange-shaped red cells (schis­ tocytes) such as "helmet cells" may be seen on blood smear. infection (e. B12 deficiency can occur secondary to inadequate intake. The anemia is microcytic.g. In the case of intravascular trauma. hemolytic uremic syndrome) can all lead to hemolysis. the cause of the anemia should be relatively obvious. acute chest syndrome (ischemia in the lungs).. meta­ bolic enzymes). causing it to get destroyed or tar­ geted for removal by the spleen.g. but all of the receptors are saturated (due to that intramuscular injection of B12). and post-splenectomy. etc. In summary. Mnemonic to remember that thalassemia is a microcytic anemia: The red cells are small in tha­ lassemia because they don't have much hemoglobin in them. colon can­ cers can bleed slowly and the blood can blend with the stool.. it has no nucleus and no mitochondria. with RBC components Fig. the radioactive B12* should be bound by intrinsic factor (IF) and ab­ sorbed in the ileum. iron deficiency. The RBC is essentially a sac of hemoglobin. and metabolic enzymes. When red cells carrying this malformed protein deoxygenate. Crohn's disease. In fact. RBC components and pathologies.. so it never gets into the blood. sickle cell disease. and thus never appears in the urine. drugs (e. So the lack of radioactive B12* in the urine indi­ cates either pernicious anemia. How­ ever.. What would happen in a normal patient (or in a patient who is B12 deficient due to de­ creased dietary intake)? In such cases. sprue. or some other problem with absorption of B12. Genetic muta­ tions can cause hemoglobin protein to form incorrectly (e. malaria). Hemoglobin protein is a tetramer composed of 4 sub­ units: 2 alpha chains and 2 beta chains. cold weather. Crohn's disease. but now the patient is also given intrinsic factor. they adopt a sickled shape. So the three components of the RBC are hemoglobin. So in a normal patient.g. or in­ travascular trauma from a prosthetic heart valve or a microangiopathic hemolytic syndrome (e. Target cells can also be seen in liver disease. If there is no intrinsic factor. RBC destruction can be caused by external factors (extracorpuscular defects) or problems with the RBCs themselves (intracorpus­ cular defects). or decreased absorption in the terminal ileum. never makes it to the kidneys. the radioactive B12* never gets absorbed. which can both shorten their life span and occlude small blood vessels. Membrane. 6-5. a patient with a slowly evolving anemia may be having slow internal bleeding. we know that intrinsic factor could not fix the problem. Internal or external hemorrhage can lead to anemia.CHAPTER 6. quinidine). RBCs must squeeze through the tiniest capillaries and thus their ability to "squish" is essen­ tial. infections. thus covertly disguising blood loss over time. This sickling is more likely to occur under times of physio­ logic stress such as fever. penicillin. and renal failure. either of which can cause anemia.. bacterial overgrowth). The sickling clogs small blood vessels and can cause acute painful crises. the radioactive B12*.. will be ex­ creted in the urine where it can be measured. Thalassemia results from mutations that cause loss of one or both alpha chains or one or both beta chains of the hemoglobin tetramer. Hemolysis. Thus. now in excess. exogenous intrinsic factor should correct it.g. there must be some problem with absorption in the terminal ileum. Intracorpuscular defects: Problems In pernicious anemia there is no intrinsic factor. Properties of the RBC membrane facilitate this 122 . If the problem is pernicious ane­ mia. If the radioactive B12* is ab­ sorbed into the bloodstream. Long-term con­ sequences of sickle cell anemia can include gallstones (from the elevated level of bilirubin caused by hemoly­ sis).

either due to an overwhelming amount of indirect bilirubin that the liver 123 . When hemolysis causes red cell breakdown. and normally account for about 1-2% of the RBCs in circulation. squeezing. sickle cell..g.g.. and subsequent anemia.. The reticulocyte count. fava beans) causes the red cells to be oxidatively damaged beyond their ability to repair themselves. funny-shaped red cells (schistocytes) may be present.. LDH (lactic acid dehydrogenase) is elevated in hemolytic anemia. the number of precursors released prematurely into the circulation increases. Imagine that you are working in a cupcake factory. Sum­ mary of findings in hemolytic anemia: increased indi­ rect bilirubin. Now imagine there is an increased demand for cup­ cakes..g. Reticulocyte count is elevated in hemolytic anemia (Fig. In so do­ ing. defects of the RBC components that lead to hemolysis. if the underlying etiology involves microvascular disease leading to red cell trauma. 6-6). 4-10). free serum haptoglobin level is reduced since the haptoglobin is bound by he­ moglobin (and thus is no longer free). and destruction of red cells leads to its release into the circulation. If there is hemolysis. G6PD is involved in protecting the RBC against oxidative stress. resulting in destruction and anemia. Metabolic Pathways. pyruvate kinase deficiency) RBC COMPONENTS AND PATHOLOGIES Figure 6-5 cannot conjugate.g. thalassemia) (e. Haptoglobin is a protein in the blood that binds hemoglobin. Thus in hemolytic anemia.. putting the icing on cupcakes as they go by on a conveyor belt. Pyruvate kinase is neces­ sary for glycolysis.g. Though these problems with RBC components rep­ resent quite different pathophysiologic entities. certain drugs. Two enzyme deficiencies of RBCs are pyru­ vate kinase deficiency and G6PD (glucose-6-phosphate dehydrogenase) deficiency. Fig. from infection. Since RBCs lack mitochondria. The red cell is just a sac of he­ moglobin: no nucleus. In anemia. Reticulocytes are immature red cell precursors. LDH is a red cell enzyme. causing anemia.. spherocytosis) (e. If abnormalities cause RBC membranes to not be as deformable as they should be. ox­ idative stress (e. These pathologies are known col­ lectively as the intracorpuscular defects.. THE HEMATOLOGIC SYSTEM (e. and they will be released into the world without Lab Findings in Hemolysis RBC breakdown produces indirect bilirubin. inevitably you will miss a few. you are likely to miss a lot more cupcakes. destroyed RBCs release lots of hemoglobin into the circulation. the end results are the same: The abnormalities lead to decreased function and/or destruction of RBCs. or due to a problem with the liver or biliary system (see Fig.CHAPTER 6. increased LDH. Jaun­ dice occurs when bilirubin is elevated. This results in jaundice and elevated indirect bilirubin. so the conveyor belt goes by at a doubled rate . In patients with a deficiency of this enzyme. decreased free haptoglobin. If they go by relatively quickly. G6PD. The liver conjugates this bilirubin to form direct bilirubin. increased reticulocytes. and its absence can result in dam­ age and death to the RBCs. indirect bilirubin levels can rise beyond the capacity of the liver to conjugate it. and. Notice that they are all hereditary abnormalities. they rely on glycolysis for energy. no mitochondria. they get stuck in the spleen and destroyed (e. hereditary spherocytosis). 6-6. only hemoglo­ bin and some enzymes surrounded by a membrane. the body tries to increase RBC production.

g. If there is impaired re­ lease of iron. 124 . more immature cells than usual make it out into the circulation unfinished. or "funny shaped. (Note: This is the opposite of what is seen in iron deficiency. That is. where ferritin decreases and TIBC increases. there is very little capacity left to bind more. which will increase reticu­ locyte count. the appropriate response is to in­ crease RBC production. A high retic­ ulocyte count can only occur if the anemia is not a problem of production. So in anemia of chronic disease. So the combination of anemia and an elevated reticulocyte count suggests RBC loss is causing the anemia. the red cells are little and pale). or folate deficiency." Micro­ cytic anemia occurs in iron deficiency (mnemonic: without iron. ferritin increases and TIBC decreases. macrocytic (larger-than-normal cells). cancer.CHAPTER 6. The reticulocyte count is useful for evaluating ane­ mia. B12.. in anemia of chronic disease. whereas some are due to difficulties in synthesizing RBCs (iron. Ferritin and transferrin (TIBC) in anemia of chronic disease. iron is inappropriately stored instead of being released to tissues that need it. This can occur when there is B12 or folate de- Anemia of Chronic Disease 6-7. Tha­ lassemia also leads to microcytic anemia (mnemonic: thalassemia leads to decreased amounts of hemoglo­ bin and thus smaller cells). Similarly in anemia. The TIBC decreases in anemia of chronic disease: because the iron is already mostly (inappropriately) bound. loss of EPO. or bone marrow failure). Some of the anemias are caused by blood loss (hemorrhage. Chronic systemic diseases (autoim­ mune diseases. or folate deficiency). a bone marrow problem or iron. Macrocytosis oc­ curs when RBCs are released too early from the bone marrow. ferritin is elevated. the body seeks to churn out RBCs more quickly to respond to the increased de­ mand. If RBC count is low. hemolytic anemia). and in so doing.) icing. chronic infections) can cause anemia for various reasons. one of which is dysfunc- Fig. either from hemorrhage or hemolytic anemia. a normal or low reticulocyte count in the presence of anemia signifies that there is a problem with RBC production (e. B12. THE HEMATOLOGIC SYSTEM !Iron !Folate !812 ! EPO Bone marrow failure Hemorrhage/ Hemolysis tRBC production tReticulocyte count THE RETICULOCYTE COUNT Figure 6-6 tional iron utilization. Thus. Blood Smear We can broadly classify the anemias discussed above based on the appearance of RBCs on blood smear as microcytic (smaller-than-normal cells). what will happen to ferritin and TIBC? Since iron is stored in excess (inappropriately) and ferritin is used for storage. Thalassemia can also cause target-shaped RBCs to appear.

WBC nuclei are also affected. in hemoly­ sis or hemorrhage. iron. bone marrow problem.«:- FERRITIN AND TRANSFERRIN (TIBC) IN ANEMIA OF CHRONIC DISEASE Figure 6-7 ever. the anemia is due to a loss of RBCs. B12. In hemolysis or hemorrhage. THE HEMATOLOGIC SYSTEM IRON DEFICIENCY ANEMIA ANEMIA OF CHRONIC DISEASE ' t t ' FERRITIN TRANSFERRIN (TIBC) . blood loss vs. The cause is not fully understood. but the ones we referred to in this section are sickled cells. spherocytes. infection). or worse. and loss of EPO in renal failure. and is thus increased in an effort to counter the anemia... autoimmune disease). Causes of decreased production include iron. the bone marrow starts churning out immature RBCs (reticulocytes) before they are finished.CHAPTER 6. hemo­ globin. Elevated EPO could occur either as a normal response to needing more RBCs. by a tumor). there are many of them. Treatment of Anemia Too Many RBCs: Polycythemia Treatment of anemia depends on the underlying etiol­ ogy and severity. resulting in hypersegmented PMNs. What would you expect to hap­ pen to EPO levels in polycythemia vera? If the RBC count is inappropriately high.. folate. Hyperproliferative State of the Bone Marrow: Polycythemia Vera.. As for funny shaped RBCs. this should cause nega­ tive feedback on EPO. In B12 and folate deficiency. and thus EPO level is low in polycythemia vera.. and tar­ get cells. So a hyperprolif­ erative state of the bone marrow or excess EPO secre­ tion could lead to polycythemia.. because in an effort to replenish the RBC count. extracorpus­ cular (autoimmune. In any condition in which oxygen supply to the tissues is inadequate.. or folate deficiency... Anemia can also be classified by blood smear find­ ings: microcytic vs. and B12 supplementa­ tion can be used to remedy deficiencies of these nutrients. schistocytes. which can lead to headache. Alternatively. macrocytic vs. drug.g. production of defective RBCs. or metabolic enzyme problem) vs. the pri­ mary disease must be treated. Blood transfusion may be necessary in se­ vere cases. since maturation of the red cells is disturbed by lack of the materials fundamental for proper DNA synthesis. Polycythemia vera is a myelopro­ liferative disease that increases production of RBCs (and usually other hematologic lineages). the reticulocyte count will be in­ appropriately normal or even decreased since it is the production that is impaired. reticulocyte production is unimpaired. Iron. or folate deficiency). Polycythemia is an increase in the number of RBCs. or from an anomalous over-production (i. Causes of Polycythemia RBC production occurs in the bone marrow under the stimulation of erythropoietin (EPO). The reticulocyte count should increase in response to anemia. ficiency.e. He­ molysis can be further subcategorized as secondary to defects that are intracorpuscular (membrane. bone marrow problems.. '"'jk��. Review of Anemia Anemia is a decrease in red cell number or function. funny shaped (see Elevated EPO. Why would we need more RBCs? The job of the RBC is oxy­ gen transport.:. EPO will increase in an attempt to raise RBC count to increase oxygen previous section)... Anemia can be classified by mechanism: decreased production vs. An increase in the number of red cells makes the blood more viscous. How- 125 . thrombosis and/or stroke. If the anemia is a result of an underlying disease process (e. helmet cells. B12. Causes of blood loss can be internal or external hemorrhage or hemolysis. if anemia is due to a problem with RBC produc­ tion (EPO problem.

and this can cause ex­ cessive RBC production (polycythemia). and right-to-left cardiac shunts can all cause chronic hypoxia. antiphospholipid antibodies. one must remedy the cause of the hypoxia. EPO will be decreased in polycythemia vera. Examples include Pneumocystis carinii. Over­ activity of the immune system is at the root of hyper­ sensitivity. Lab Findings in Polycythemia Hematocrit and hemoglobin rise in polycythemia. complement. Over-activity of WBCs (hy­ persensitivity) can cause autoimmunity and allergy. infection ofWBCs). The complement proteins are another component of the immune system. and macrophages ingest and destroy foreign material. there can either be too few or too many WBCs. Chronic lung disease.. eosinophils. but increased if there is an ectopic source of EPO or if the poly­ cythemia is secondary to hypoxia. phlebotomy is used to remove some of the excess blood. monocytes. Graves' Disease 126 Response to tuberculosis test. M. pernicious anemia. WHITE BLOOD CELLS AND IMMUNOLOGY The white blood cells (WBCs) are responsible for im­ munity against infection. dust. Hypersensitivity. If the cause of poly­ cythemia is a myeloproliferative disorder. systemic lupus erythematosis. rheumatic fever. infections that do not usually occur in normal hosts. and cytomegalovirus (CMV). Any of these cell types (or complement) can be present in extremely low levels or in excess. Although initially this is an appropriate response. Cryptococcus. Immunodeficiency can lead to opportunistic infections. the EPO elevation will be chronic. autoimmune hemolytic anemia.CHAPTER 6. Too few WBCs or decreased activity of WBCs can lead to immunodeficiency. hemangio­ blastoma. 6-8. sleep apnea. Since WBCs form in the bone marrow. living at a high altitude. the result is immunodefi­ ciency: a predisposition to infections. causing this response to be destructive while trying to be protective. hepatocellular carcinoma. rejection of transplanted . In the meantime. since the kidneys produce EPO). Cryptosporidium. to reduce hema­ tocrit to a safer level and make the blood less viscous. or antibodies).g. The most common tumor sources of elevated EPO are renal cell carcinoma (which makes sense. Hypersensitivity Fig. for a variety of reasons. anything that adversely affects the bone marrow can lead to a de1 Opsonization is the attachment of antibody and complement to foreign material. Neutrophils. lgM antibodies Type Ill Immune Complex Antigen-Antibody complexes -t tissue damage Post-infectious glomerulonephritis. myasthenia gravis. WBCs are a diverse group specialized for various aspects of immunity. chronic carbon monoxide exposure. Sometimes the host re­ sponse to antigens is excessive. i. This hypoxia leads to an eleva­ tion of EPO in an attempt to raise the oxygen-carry­ ing capacity of the blood.. if the hypoxia is chronic. and autoimmune disease. insect bite) Incompatible blood transfusion. Causes of immunodeficiency are decreased num­ ber or decreased function of any element of this system (WBCs. THE HEMATOLOGIC SYSTEM delivery to the tissues. Goodpasture's Disease. some drug reactions. Histoplasmosis. Treatment of Polycythemia If the polycythemia is secondary to hypoxia. polyarteritis nodosa Type IV Cell mediated/delayed Previously sensitized T-lymphocytes release cytokines and/or attack targets organs -t mast cells basophils Allergy (food. An extremely high number of one specific WBC lineage can indicate hematologic malignancy. chemotherapy is usually necessary.l Basophils. and mast cells are important in the aller­ gic response. rheumatoid arthritis. Immunodeficiency If any type of WBC (or complement) decreases in quan­ tity or in its ability to function. anaphylaxis. Mycobac­ terium auium intracellulare (MAl). which underlies allergy. and uterine fibroids. tuberculosis. an elevated number of WBCs is ex­ pected to occur in infection. Decreased Number of WBCs Decreased WBCs can occur secondary to decreased production (bone marrow problem or congenital defi­ ciency) or loss (e. targeting this foreign material for phagocy­ tosis and destruction. Figure 6-8 Hypersensitivity EXAMPLES TYPE MECHANISM MEDIATED BY: Type I Anaphylaxis lgE Type II Cytotoxic lgG. Since WBCs fight infection. Increased WBC count also occurs in inflammatory conditions. As with red blood cells. Lymphocytes produce antibodies (which are for im­ mune memory as well as for opsonization).e. Toxoplasmosis. A tumor can also be a source of elevated EPO.

The neu­ trophils are part of the myelogenous lineage.g. (2) leukocyte adhesion deficiency causes adhesion prob­ lems. Opsonization of bacteria Pathology can occur at any of these levels. and de­ stroy it with toxins (namely oxidative radicals).. This opsonization chemically attracts WBCs (chemotaxis). THE HEMATOLOGIC SYSTEM crease in WBCs. Decreased Function of WBCs Fig.g. and (5) failure of toxin production occurs in chronic granulomatous dis­ ease and myeloperoxidase deficiency. 6-9. DiGeorge syndrome: T cell deficiency secondary to im­ paired thymus development) or an infection specific to that lineage (e. and malignancy can all lead to elevated levels of neutrophils.g. HIV for lymphocytes).. chemotherapeutic agents). drugs (e. WBCs ar­ rive at the foreign material and phagocytize it.g. A decrease in one specific lineage most likely indicates either a congen­ ital deficiency in the production of that lineage (e. infection (e.. A decrease in all WBC lineages (along with RBCs and platelets) most likely indicates a problem with the bone marrow. HIV. What follows are brief specifics related to each spe­ cific cell of the WBC family. First. Overview of the immune system and its pathology.CHAPTER 6.. and infiltration by primary or metastatic tumor. As num­ bered in the figure: (1) complement deficiency or anti­ body deficiency can lead to failure of opsonization. Examples include radiation.. Via adhesion to blood vessel walls and locomotion through tissue. Epstein-Barr virus). (3-4) Chediak-Higashi disease causes problems with locomotion and phagocytosis. Neutrophils Increased Neutrophils Infection. OVERVIEW OF THE IMMUNE SYSTEM AND ITS PATHOLOGY Figure 6-9 127 . foreign material is opsonized (by com­ plement and antibodies). inflammatory diseases. so acute myelogenous leukemia (AML) and chronic myelogenous CCC Complement (cccccc) - • granulomatous disease Myeloperoxidase deficiency F ��:.

Decreased Neutrophils (or Decreased Function of Neutrophils) A decrease in neutrophil number can occur from drug toxicity. some cell line escapes normal regu­ lation and reproduces itself in an out-of-control fashion. Symptoms/ signs of leukemia and lymphoma are quite non-specific and can include fever. Lym­ phocytes can thus be elevated in chronic inflammatory diseases.g. and night sweats. Mast Cells. Basophils. infections.. So leukemia can lead to a high number of cells in one white cell lineage and a decrease in oth­ ers.. Lymphocyte count is also preferentially ele­ vated in some viral and fungal infections. Problems with antibody production include genetic diseases such as X-linked agammaglobulinemia. as well as decreases in RBCs (causing anemia) and platelets (causing spontaneous mucosal bleeding. Remember that lymphomas are proliferations of white cells in lymphoid tissue (nodes. spleen. HIV). (Mnemonic: IgE is involved in allergE). fatigue. chemotherapy. whereas the others are all more common in adults. In severe combined immuno­ deficiency (SCID). etc. In any malignancy. and selective lgA deficiency. common variable immune deficiency. 6-9. e. and parasitic infections. and monocytes).).) Decreased Lymphocytes (or Decreased Function of Lymphocytes) Lymphomas A decrease in lymphocyte number can occur from drug toxicity. The Hematologic Malignancies of WBC Lineage Radiation and chemotherapy are used to treat hematologic malignancies.. mast cells. easy bruising).g. liferations of white cells in the bone marrow. and elevated urine protein (Bence Jones proteinuria). bone pain. Eosinophils can be elevated in neoplasia. (ALL can also be called acute lymphocytic leukemia. or in the setting of pancytopenia (e. whereas chronic leukemias result from proliferation of mature cells. and/or pathologi­ cal fractures. Lymphomas are divided into Hodgkin's and non­ Hodgkin's lymphomas. secondary to bone marrow failure). Acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) are the lympho­ cyte lineage's analogues of AML and CML. lymph nodes. this falls into two broad classes: leukemia and lymphoma. weight loss.g. Lymphocytic leukemias (ALL and CLL) involve the lymphocyte lineage (that gives rise to T and B lymphocytes). whereas leukemias are prolifera­ tions in the marrow.CHAPTER 6. resulting in immunodeficiency. or in pancytopenia (since all blood cell lineages decrease in pancytopenia.. A decrease in neutrophil function can occur at any of the points dis­ cussed in Fig.. spinal cord compression. whose classic appearance resem­ bles "owl eyes" under the microscope. infections (e. erythrocytes. and Eosinophils Basophils. A pathological hallmark of Hodgkin's disease is the Reed-Sternberg cell. asthma. lymph node enlargement. Multiple Myeloma Multiple myeloma is a proliferation of plasma cells (terminally differentiated B cells) that occurs most commonly in bone. a lack of adenosine deaminase. Leukemias are pro- Review of WBCs The WBCs are components of the immune system and fight infection. sec­ ondary to bone marrow failure). a genetic defect leads to premature death of B and T cells (e. malaise. congen­ ital deficiencies. spleen). elevated serum protein. Non-Hodgkin's lymphoma is a proliferation of B or T cells.g. whereas neutrophil count is generally elevated in bacterial in­ fections. Lymphocytes Increased Lymphocytes Neutrophils generally arrive first at the site of inflam­ mation. Acute leukemias in either lineage are due to a prolif­ eration of precursor cells.g. chemotherapy. Multiple myeloma can thus cause bony destruction. rare congenital de­ ficiencies. a decrease in WBCs (or their 128 . which leads to inability to catabolize toxins produced in purine metabolism). The malignant cells over-produce non­ functional antibodies. which can result in hypercalcemia. whereas the precursor that proliferates in Hodgkin's disease is unknown. Leukemias If one cell line in the bone marrow escapes normal regulation and begins hyperproliferating. In the hematologic system. THE HEMATOLOGIC SYSTEM leukemia (CML) are the two hematologic malignancies involving this lineage. Thus. eosinophils. One of the chief functions of lymphocytes is antibody production. and platelets. collagen vascular disease. allergy. production of other hematologic cell lineages decreases since their space and resources in the bone marrow become inadequate. basophils. whereas lymphomas are proliferations of white cells in lym­ phatic tissue (e. and IgE are involved in allergy. This elevated protein can lead to kidney damage. Myelogenous leukemias (AML and CML) arise from the lineage that gives rise to gran­ ulocytes (neutrophils. while lymphocytes typically arrive later. ALL is more common in children.

radiation). S. or as a result of hema­ tologic malignancy. and coumadin. Deficiencies in either platelets (or their function) or any of the coagu­ lation proteins can lead to excessive bleeding. and X) need vitamin K for their synthesis. Thus. If the cell number is decreased while another cell type is markedly increased. there may be bone marrow disease (e. Heparin. Decrease in vWF can thus result in a decrease in factor VIII. so the problem must be with factor VII. bleeding into the joints (hemarthrosis). If there is a decrease in sev­ eral WBC lineages. XI. VII. IX. heparin. This is why PT and PTT are tested together. Remember Extrinsic = VII = PT = Coumadin. VIII). Platelets and coagulation fac­ tors interact to plug sites of bleeding. Hypocoagulable states arise from either decreased coagulation factors. PT and PTT also assess the final common pathway. IX. antithrombin III) can lead to hypercoagulability.. Fig.. Prothrombin time (PT) and partial thromboplastin time (PTT) are laboratory measure­ ments used to examine how long clotting takes. the ability to effectively form a clot diminishes.e. thus assessing the integrity of the clotting cascade. Hemophilia A (Classic he­ mophilia) is a deficiency of factor VIII.e. An extremely high WBC count is more consistent with a malignant process. Intrinsic=PTT =XII. Pro­ thrombin time (P T) assesses the extrinsic pathway (VII). or de­ creased platelet number (thrombocytopenia). works by in­ creasing antithrombin III activity. PTT has an extra T "inside" it and it measures the intrinsic pathway. XI.. Hemophilia is an example of a genetic disease (X-linked) that leads to clotting factor deficiency. which exposes tissue factor to the circulation). think "What could be affecting this cell type?" The answer could be drugs. An increase can occur in response to infection or inflammation (in­ cluding autoimmune disease). PT. PT is used to monitor the effect of coumadin therapy. an abnormal (i. a normal PTT with an abnormal PT tells you that XII-XI-IX-VIII-X-V-II must be working (since PTT is normal). This can lead to ex­ cessive bleeding/bruising from minor trauma. a hypocoagulable state. IX.g. excessive bleeding during a menstrual period (menorrhagia). If there is immunodeficiency with normal cell counts. and some of which (II. X. PTT. Mnemonic: "Hint" Heparin = Intrinsic pathway. Partial thromboplastin time (P T T) assesses the intrinsic pathway (XII. an infection. Coumadin. Decreased Coagulation Factors The clotting factors are proteins. blood in the urine (hematuria). Typically. IX. an anticoagulant. XI. secondary to infection.. and II. V. If there is a decrease in a certain WBC type with all others remaining normal. or a rare genetic disease. neutrophil number increases in acute processes and lymphocyte number increases in chronic processes. Hemophilia B (Christmas disease) is a deficiency of factor IX. prolonged) PT could mean a problem with the extrinsic pathway or the final common pathway. Mnemonic: PTT is a longer name than PT and the intrinsic path­ way has more factors. A normal PT with an abnormal PTT tells you that VII-X-V-II is work­ ing.e.g. Hypocoagulable States: Tendency to Bleed If platelets or coagulation factors are low. from vitamin K deficiency.. VIII =Heparin. Of course. 6-10. pinpoint red dots on the skin. If there is a modest increase in one type of WBC. there is a normal number but the cells them­ selves are nonfunctional) or a deficit in some other im­ mune component (e. from a genetic mutation leading to a dysfunctional protein or inadequate amount of it. For example. i. von Willebrand's disease leads to a decrease in von Wille­ braud's factor (vWF). and/or bleeding be­ tween periods (metrorrhagia). Petechiae. are more common in platelet dysfunction or when the number of platelets is low. Abnormal PTT could mean a problem with the intrinsic pathway or the fi­ nal common pathway. When there is a problem with the clotting cascade.g. primary or metastatic ma­ lignancy. although some types of infections do not follow this pattern: viruses can have elevated lym­ phocytes in the acute phase. another anticoagulant. P T T is followed in heparin therapy. it takes longer for coagula­ tion to occur. whereas deep bleeding is more com­ mon when there is a disorder of coagulation factors. while parasites can have elevated eosinophils. many of which are synthesized in the liver. IX. Both feed into the common path­ way: factors X. THE HEMATOLOGIC SYSTEM function) will result in immunodeficiency. so the problem must be with XII. or VIII. this could be due to decreased function of a certain cell type (i. VII. Also. a protein that stabilizes factor VIII. this could be due to infection or in­ flammation. PLATELETS AND COAGULATION FACTORS The coagulation system has two components: platelets and coagulation factors. decreased platelet function. Deficiency in clotting factors can thus occur from liver failure. An excess of platelets or a defi­ ciency of anti-thrombotic proteins (e.. There are two clotting pathways: intrinsic and extrinsic. nose­ bleeds.CHAPTER 6. Mnemonic: Metro is be­ tween periods and a metro goes between two places. complement or antibody). 129 . interferes with coagula­ tion by affecting the vitamin K-dependent factors: II. protein C. or as with any protein. this should raise suspicion for a hematologic malignancy. The intrinsic pathway is initiated when there is damage on the inside of a blood vessel and the extrinsic path­ way is initiated when there is tissue injury (extrinsic to the blood vessel.

. von Willebrand's factor (vWF). THE HEMATOLOGIC SYSTEM EXTRINSIC PATHWAY (tested by PT) INTRINSIC PATHWAY (tested by PTT) Tissue Factor Coumadin interferes with vit K dependent factors: II._�1 \ Fibrin Figure 6-10 stick to vessel wall. so von Willebrand's disease detrimentally affects both the platelet clotting mechanism and the coagulation cascade. there is a defect in GP Ib-IX (the link to vWF). specifically to glycoprotein Ib-IX on the platelet membrane. The big picture: Platelets Pathology can occur at any of these steps. platelets need to adhere to the vessel wall. IX. call more platelets. Upon arrival. In vonWille­ brand's disease there is a decrease in. which results in a de­ crease in the ability of platelets to bind to the vessel wall.2 In Bernard-Soulier syndrome. thromboxane. serotonin. Ad­ hesion to the vessel wall requires von Willebrand's factor. VII.. In storage pool diseases. Decreased Platelet Function or Number Platelet dysfunction Fig..CHAPTER 6. .. which also leads to de­ creased ability of the platelet to bind to the blood ves­ sel wall. The platelet is then activated to secrete molecules that signal other platelets to come to the site (e. and then stick to each other. Platelet function and pathology. and then stick to each other to form an aggregate clot._ Removes excess thrombin __ .g. or absence of. X (monitored by PT) � cr Heparin enhances antithrombin Ill (monitored by PIT) Antithrombin Ill I Prothrombin activator II (Prothrombin) Activates (Fibrinogen) t t----. se­ crete substances to call more platelets to the site.. ADP). 6-11. there is a decrease in the storage pool of signaling molecules normally 2 130 vWF also stabilizes factor VIII of the coagulation cascade.. platelets are linked together by form­ ing fibrin bridges between GPIIb/GPIIIa receptors on the platelets' surfaces. which serves as a bridge from the vessel wall to the platelet.. To make a clot.

g. THE HEMATOLOGIC SYSTEM 1 .g. the inhibition of this enzyme (e. marrow failure due to: • Malignancy (some other cell proliferating and crowding bone marrow space) • Radiation • Drugs (e. p latelet serotonin. purpura.. classically presenting as fever. (fi brinoge n . HIV. Call for m ore to one a nothe r GP l i b/l i la Storage pool disease Glanzmann's throm basthenia ( ! s ig nal i ng molecules) • T h ro m bocyto pe n i a (d e fect in GP l i b / l i l a) • PLATELET FUNCTION A ND PATHOL OG Y Figure 6-11 lature (microangiopathy) and/or genetic predisposition3 can lead to platelet aggregation and thrombus forma­ tion. caused by E. schistocytes on smear. elevated LDH). infection (e. cancer. Shigella). pregnancy. In contrast to disseminated in­ travascular coagulation (see below). E. by an autoantibody) plays a role in the patho­ physiology of the disease. quinidine) • Autoimmunity (e. coli. The platelet aggregation causes thrombocytopenia. alcohol.. idiopathic thrombocytopenic purpura (ITP)) • Consumption/inappropriate platelet aggregation . heparin. increased reticulocytes.g.Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome ('ITP/HUS).Disseminated intravascular coagulation 3 In thrombotic thrombocytopenic purpura I hemolytic uremic syndrome (TI'P I HUS).I X) 2. neurological signs. coagulation factors are not affected. The microvascular occlusion results in widespread is­ chemia.g.. which occurs more commonly in children. ..e. and drugs. P l atelets stick platelets (thromboxane. TTP can be fatal if plasmapheresis (plasma exchange) is not Platelet loss I destruction due to: • Infection • Drugs (e.. either there is decreased production of platelets.S o u l i e r syn d ro m e (defect i n G P l b. or platelets are somehow getting destroyed: Decreased Production. G P l b-IX) • • 3. Laboratory signs include throm­ bocytopenia and hemolytic anemia (manifesting as de­ creased red cells. damage to microvascu- 131 Deficiency in a von Willebrand factor-cleaving metalloprotein­ ase (gene: ADAMT S 1 3 ) can lead to platelet aggregation and TTP. Platel ets adhere '-----. and PT and PTT are thus normal.. In Glanzmann's thrombasthe­ nia. a defect in the GP IIb!IIIa complex causes inabil­ ity to bind with other platelets via fibrinogen. Why would platelet count decrease? As with the other blood elements. and/or hemolytic anemia (secondary to damage to RBCs as they pass through thrombus-oc­ cluded microvasculature). released by the platelet. thrombocytopenia.CHAPTER 6. chemotherapy agents) • Infection HUS and TTP are thought to have the same underly­ ing pathophysiology. i. Decreased Platelet Number: Thrombocytopenia. coli).. ADP) von Willebrand's disease ( ! vWF) B e r n a r d . . In patients without this genetic defect.:o� to blood vessel wa l l �--I (vWF. but HUS is generally the name given to the syndrome when it occurs following a diarrheal ill­ ness (e. renal dysfunction.g.g. Causes of initial microvascu­ lar injury include autoimmune processes. altered mental status.

for example in a hospitable bed or on an airplane. clotting factor decrease or defects can lead to bleeding problems despite normally function­ ing platelets.) are often used in hospitalized patients who are not moving around very much. chronic infectious.. or chronic inflam­ matory disease Complications of child birth (amniotic fluid embo­ lus.. leading to hypercoagulability. malignancy. Rocky Moun­ tain spotted fever. Infections (e. vitamin K deficiency or liver dysfunction can lead to decreases in clotting factors and bleeding. infection. radiation. or lack of secretory compounds necessary to facilitate this process.g. oral contraceptives. Deficits or dysfunction of plate­ lets or coagulation factors can thus lead to decreased ability to form clots. 132 . which can cause bleeding prob­ lems. Chronic DIC can occur over a more subacute time course with more variability in lab findings. a mutation of factor V. and antithrombin III serve as checks and balances in the clotting system to prevent venous thrombosis. abruptio placentae) These conditions can activate the clotting cascade directly (by release of pro-coagulants or inhibition of anti-coagulant proteins) or indirectly due to endothe­ lial injury in the blood vessels. for example. platelets can be decreased. and the diffuse throm­ bosis can consume so many platelets and coagulation factors so as to lead to bleeding. or drugs). bruis­ ing.g. DIC can be caused by: • • • • Alternatively. S. respiratory. Without this control on the system. in ITP or TTP/HUS. Examples include pulmonary embolism if the clot goes to the pulmonary artery. and fibrin split products such as D dimer (evidence of clotting) can be elevated. THE HEMATOLOGIC SYSTEM initiated immediately and continued until symptoms and signs improve. bleeding. and stasis. causes factor V to be unable to be inactivated by protein C. The resultant diffuse clotting can lead to thrombosis. this can have various con­ sequences.g. retained dead fetus. and mesenteric is­ chemia if the clot lodges in the mesenteric vasculature.g. and not all of these fea­ tures are always present. to the lung (pulmonary embolus). with other platelets. Stasis occurs when people are immobile. Parts of the clot can break off and embolize. renal. Summary of Hypocoagulable States The clotting system consists of the platelets and the coagulation cascade.g. Other predisposing factors to hypercoagulability in­ clude anti-phospholipid antibodies (which can be asso­ ciated with lupus or occur independently). Protein C.g. Thrombocytopenia can also occur from loss of platelets in the periphery... Depend­ ing on where the clot lodges. and ischemia of any organ can occur along with features of the underlying disease. support stock­ ings. That is why prophylactic measures (e. heart failure. fresh frozen plasma and/or platelet transfusion). he­ parin) and pro-coagulation (i. subcutaneous heparin. Schistocytes (damaged RBCs) may be observed on smear because RBCs are damaged when passing through the sites of thrombus. Disseminated intravascular coagulation (DIC) can lead to both thrombosis and bleeding. malaria) Massive trauma or surgery Any neoplastic. and/or neurological dysfunction may be pres­ ent. hemophilia) can lead to decreased clotting ability and hence bleeding. Thus. Vitamin K is necessary for the synthesis of certain clotting factors. turbulent flow (e.e. stroke if the clot ends up in the cerebral vasculature. Platelet dysfunction can occur at various levels due to the platelets' inability to bind with the vessel wall. Plasmapheresis is thought to remove of­ fending toxins and also replace deficient serum factors. pregnancy. In addition to treating the underlying cause.. hepatic. In acute DIC.CHAPTER 6. Additionally. Mutation can lead to deficiency of one of these proteins. there can be a tendency toward hypercoagulability. and some coagulation fac­ tors are formed in the liver. gram negative sepsis. Thus. in atrial fibrillation). Why would platelets be low? Since they are pro­ duced in the bone marrow. PT and PTT can be elevated (be­ cause of consumption of clotting factors in clots).. management of the manifestations is complex because one must balance anticoagulation (e. etc. e. Stasis can lead to deep venous thrombosis (DVT): clot formation in a deep vein (most commonly a deep leg vein). Factor V Leiden. any problem with the bone marrow can lead to thrombocytopenia (hematologic malignancy or metastasis to bone marrow. Hypercoagulable States: Tendency to Clot Hypercoagulability can lead to clot formation. There is some variabil­ ity in possible lab findings. genetic defects leading to decreased or defective clotting proteins (e..

the tongue.. <( z a: (/) MUSCLE I Although this chapter is organized by region.g. stroke). planning. neurodegener­ ation). occipital lobes). Lower Motor Neurons Fig. THE NERVOUS SYSTEM CHAPTER 7. sub­ cortical structures (e. are called upper motor neurons (UMN).. one of its roles is communication between the brain and the thoracic and abdominal viscera.1 .CHAPTER 7. The nervous system may be divided most simply into the central nervous system (brain and spinal cord) and the peripheral nervous system (peripheral nerves).. The cell bodies in the motor cortex project their axons (through the internal capsule) in the corticospinal tract.--- Internal capsule <( .g. Multiple sclerosis (MS) can affect the entire central ner­ vous system (spinal cord and brain) and amyotrophic lateral sclerosis (ALS) affects the motor pathway in (anterior h orn cell) MOTOR (CORTICOSPINAL) PATHWAY Figure 7-1 133 . The vagus nerve (cranial nerve X) is an exception: although it is a cranial nerve. smell. Localizing the lesion within the nervous system 2. facial sensation) to the brain. 7. and coordinating movement... or both (e. The primary motor pathway is comprised of two main components: upper motor neurons (projecting from cortex to spinal cord) and lower motor neurons (projecting from spinal cord to muscle). while peripheral nerves in­ nervate the rest of the body. the myelin (e.... Determining a differential diagnosis for what could cause a lesion at this location Motor and Sensory Pathways Motor Pathway: Upper Motor Neurons vs.. and brainstem (midbrain.g. at the neu­ romuscularjunction. the peripheral nerve(s) (motor. ANATOMICAL OVERVIEW Clinical reasoning in neurology proceeds in two steps: NEUROANATOMY AND LOCALIZATION 1. cere­ bellum. The cranial nerves transmit sensory information from the head (e.g... one attempts to determine whether the lesion is in the brain. multiple sclerosis. parietal lobes.___.. The upper motor neurons synapse on anterior horn cells in the anterior spinal cord. basal ganglia). lan­ guage.. These corticospinal tract fibers. (Crossing to left in medulla) c a: 0 0 . the main motor pathway... not all diseases fit neatly into a regional category. Schwann cells provide the myelin in the periphery while oligodendrocytes myeli­ nate the central nervous system. ) to initiating. These anterior horn cells and their axonal projections in In addition to the anatomical regions at the macro level.. cross (decussate) in the lower medulla (in the medullary pyramids). THE NERVOUS SYSTEM both the central nervous system and in the peripheral nervous system. and then descend as the lateral corticospinal tracts in the spinal cord. Disease processes can affect the neurons themselves (e.. Motor (corticospinal) pathway.. sensory. Gray matter is clus­ ters of neuron cell bodies. or both?). . Guillain­ Barre).. pons. from the cortex through the spinal cord. to perceiving and interpreting sensory stim­ uli from the outside world and the viscera. hearing. while the peripheral nerves transmit sensory in­ formation from the rest of the body to the brain by way of the spinal cord. the spinal cord. temporal lobes..__. The motor output of the brain occurs via some of these same nerves: cranial nerves innervate various parts of the head (for moving the facial muscles. � c w ::!: The brain is a control center for everything from higher cognitive functions (reasoning. the nervous system is divided into gray and white matter on the micro level. or in the muscle itself The brain is further divided into the cerebral hemispheres (frontal lobes. the eyes. sight... and medulla). RIGHT MOTOR CORTEX . thalamus. ).g. etc. These fibers descend in the brainstem. and white matter is their myelinated axon pathways. etc.. and changes in these functions can be clues to the site of pathology.. attention. When localizing a lesion. taste. Each area performs specific functions.

. Imag­ ine a lower motor neuron lesion (i. One example is Babinski's sign.. The affected muscles become paralyzed. These lower motor neurons synapse on the muscles. primitive reflexes can resurface be­ cause of the loss of upper motor neuron inhibition. 1 In newborns. a state of tonic contraction. If you stroke the bottom of the foot. in the inter­ nal capsule. or spinal cord). especially if it is present symmetrically bilaterally. I !1 • • • UMN LESIONS I' WEAKNESS/PARALYSIS Spasticity Reflexes Babinski's sign t UPPER AND LOWER MOTOR NEURON LESIONS Figure 7-2 134 . without classic "upper motor neuron signs. Upper and lower motor neuron lesions. and left to its own devices it would twitch (fasciculate). In addition. reflexes eventually become exaggerated or hyperactive. With this loss of inhibition from above.CHAPTER 7. Reflexes would be diminished or lost. the lower motor neuron fires spontaneously. unilateral clonus flaccid paralysis. Babinski's sign is not found with lower motor neuron lesions. Although a bit of clonus (or other hyperreflexia) can be normal. THE NERVOUS SYSTEM peripheral nerves are called lower motor neurons (LMN). Babinski's sign is normal in newborns. anywhere from the motor cortex through the corti- I • • • • • LMN LESIONS I • WEAKNESS/PARALYSIS Flaccidity J. I Babinski's sign indicates an upper motor neu­ ron lesion anywhere from the motor cortex through the corticospinal tract's path in the brainstem and spinal cord. there will be different signs accompanying this weakness. The classic symptoms of a lower motor neuron lesion are Clonus is repetitive. because of the loss of higher control. What do you think would happen to the affected muscle(s)? You could try to tell the mus­ cle(s) to move. and the left mo­ tor cortex controls the right side of the body. rhythmic contraction of a muscle when it is stretched. Because of the crossing (decussation) of the corticospinal tract in the medulla. the result will be weakness of the affected muscle(s). The muscle would no longer be under any control. injury of anterior horn cells and/or the peripheral nerve(s) in which their axons travel). If the big toe goes up.e. the right motor cor­ tex controls the left side of the body. causing spasm in the affected muscles. The muscle(s) would be paralyzed and would be floppy (flaccid). the big toe will go up. diminished or absent reflexes. since myelination is not yet complete. 2 Acute upper motor neuron lesions (e. fascic­ ulations. However.. and is abnormal in adults. and. the toes should normally curl down.. depending on whether this lesion affects the upper or lower motor neurons. this is Babinski's sign. . Clonus is another example of disinhibition. 2 If there is a lesion anywhere in the motor pathway. commonly seen in the ankle. cospinal tract in which its axons run (i.e. spinal shock from an infarct) can present with flaccid paralysis and loss of reflexes. but the signal would never arrive. muscle atrophy. Also. Reflexes Fasciculations Muscle atrophy 1." Now consider a lesion of an upper motor neuron. Fig.g. 7-2. over time. brainstem.

Thus. If the lesion is below the decussa­ tion (e. forming the spinothalamic tracts. and position sense (proprioception).. in the spinal cord or a peripheral nerve).g. Both pathways also transmit some light touch sensation. the classic symptoms of an upper motor neuron lesion are spastic paralysis and increased reflexes. The spinothalamic tract carries pain and temperature sensation. continuing as the medial lemnisci (which project to the thalamus). etc. Babinski's sign) and clonus. Modified from Goldberg: Clinical Neuroanatomy Made Ridiculously Simple. muscle spindle. 7-3. Why body as the lesion. If the lesion is above the decussation of the corti­ cospinal tract in the medullary pyramids. THE NERVOUS SYSTEM known as the anterolateral tracts).-c: I I I I I I I I LEFT BODY LEFT BODY ·PROPRIOCEPTION ·PAIN ·DISCRIMINATION •TEMPERATURE (& some light touch) ·VIBRATION ( & some light touch) SENSORY PATHWAYS Figure 7-3.CHAPTER 7. is this significant? Imagine a lesion of the posterior col­ umn on the left side at about the level of the belly but­ ton. one would lose discriminative touchlvibra- Sensory Pathways Fig. vibration. .g. All of this sensory input comes from the periphery (skin. Important anatomy: The (or other hyperreflexia) should raise suspicion for an underlying upper motor neuron lesion. The posterior columns transmit discriminative touch. MedMaster 135 2005 .. and then cross in the medulla.. The two main sensory pathways are the posterior columns (also known as the dorsal columns) and the spinothalamic tracts (also RIGHT SENSORY CEREBRAL CORTEX RIGHT THALAMUS pinothalamic tract lemniscus Posterior --columns . Since the sensory information has come from that same side of the body (and stays on that side until the brainstem). including disinhibition of primitive reflexes (e. the motor deficit will be on the same (ipsilateral) side of the spinothalamic pathways cross immediately in the cord.) via peripheral nerves that enter the spinal cord posteriorly. the motor deficit will be on the opposite (contralateral) side of the body from the lesion. Sensory pathways. The posterior columns stay ipsilateral (same side) until the brain­ stem.

and exit as separate anterior (ventral) motor and posterior (dorsal) sensory roots. More precisely.) is all lost on only one side of the body (with the other side entirely normal). There are disease processes that affect specific fiber types and can thus lead to a purely sensory or purely motor peripheral neuropathy. the story with peripheral neuropathy is not quite so simple. pain. and peripheral nerve lesions. For example. since some light touch sensation is preserved in fibers that cross. Loss of everything on only one side must localize to somewhere outside of the spinal cord. Also. If one entire half of the spinal cord is dam­ aged. where they synapse onto neurons that cross there and ascend to the thalamus as the medial lemniscus. THE NERVOUS SYSTEM tion/position sense on the same side. etc. ipsilateral lesions of the spinal cord often do not result in much loss of light touch.. 7-5). first or­ der sensory neurons synapse immediately upon ar­ rival in the cord. The internal capsule contains the subcortical white matter from the motor system traveling toward the brainstem as well as sensory projections from the thalamus to the sensory cortex. distal to the lesion (i. The difference between symptomatic patterns resulting from lesions of roots. Brown-Sequard syndrome.. So paralysis and discrimination I vibration sense I proprioception loss will occur on the same side of the body below the level of the lesion. whereas loss of pain I temperature will occur on the contralateral side of the body below the level of the lesion. some fibers carrying light touch actually cross right away in the spinal cord. which will occur on the contralateral side of the body. most of the axons of the first order sensory neurons travel all the way to the medulla.g. leading to contralateral hemiparesis and sensory loss.e. could this possibly be due to spinal cord pathology? It could not. all the deficits will be on the ipsilateral side of the body except pain and temperature loss. but this would be in a region limited to the distribution of the nerve. The motor and sensory pathways run very close to each other but separately through the brainstem and spinal cord. is discussed in more detail later in this chapter.CHAPTER 7. Note that light touch can be relatively spared because it runs in both the spinothalamic tract and the posterior (dorsal) columns. a I LEFT BODY 3 As discussed later in this chapter. The fibers in these roots then join to form mixed motor/sensory peripheral nerves. only the spinothalamic tract (pain and temperature fibers) crosses in the spinal cord. What if a lesion destroyed the entire left half of the cord? Remember. middle cerebral artery). As a result. from there down). because a spinal cord lesion would typically have some contralateral effect because of the crossing of the spinothalamic tract. brainstem lesions. in the spinothalamic tract. In the posterior columns.. Summary of Motor and Sensory Systems The cortex is the starting point of the motor system and the end of the sensory systems (i. + + Posterior Proprioception Vibration Discrimination \ Mo RIGHT BODY Relatively large lesions commonly affect both motor and sensory pathways where these pathways run close to each other. Fig. in this case on the right side.e. tempera­ ture sensation.. some dis­ tal branches of peripheral nerves carry only sensory or only motor fibers. Examples include large cerebral strokes (e. What about a lesion of the spinothalamic tract on the left side? Since the fibers in that tract came from the right side. light touch. and the second-order neurons cross and ascend as the spinothalamic tract. Dermatomal sensory deficits only occur with focal spinal cord lesions or nerve root compression. 7-5. a lesion of the spinothalamic tract on the left would lead to loss of pain and temperature sensation below the lesion on the contralateral side. A periph­ eral nerve lesion could also lead to loss of motor and sensory function together on one side. Compression of sensory (posterior/dorsal) nerve roots as they enter the spinal cord leads to symptoms con­ fined to specific dermatomes. etc. where ascend­ ing sensory input from the body finally arrives). Fig. peripheral nerves. If everything (strength. However. 7-4. Dermatomes. a middle cerebral artery stroke can cause ischemia/infarction of both the motor cortex and the sensory cortex on one side. BROWN-SEQUARD SYNDROME Figure 7-4 136 . stripes in a zebra-like sensory map (Fig.

From top to bottom. nerves). respectively. Some disease processes selectively affect only motor or only sensory neurons/nerves. "Pure motor" strokes. and medulla.CHAPTER 7. 7-5). and the descending motor and ascending sensory pathways just discussed. can occur from small lacunar infarcts of the motor fibers of the internal capsule or the motor pathway in the brainstem. con­ nections with the cerebellum. A mnemonic to remember where the cranial nerves exit/enter is: 1-4 are in the midbrain. "Pure sensory" strokes can result from infarction of the thalamus or sensory path­ ways in the brainstem. This is not 137 . THE NERVOUS SYSTEM DERMA TOMES Figure 7-5. pons. In the PNS. 7-6. Modified from Goldberg: Clinical Neuroanatomy Made Ridiculously Simple. 5-8 are in the pons. MedMaster 2005 In the CNS. Prolapsed discs or tumors that compress only the anterior (ventral) or posterior (dorsal) roots can also lead to isolated motor or sensory findings. These small lesions can lead to stroke with only motor deficits or only sensory deficits. This is because the motor and sen­ sory fibers are relatively separate in the spinal cord and spinal roots (whereas they tend to be mixed in peripheral Fig. The Brainstem and Cranial Nerves Brains tern brainstem contains most of the cranial nerve nuclei. isolated motor or sensory deficits typi­ cally occur with small isolated lesions in very specific places. which is an oc­ clusion of a small penetrating vessel in the brain. and certain types of peripheral neuropathy selectively impair sensory fibers. amyotrophic lateral sclerosis affects only motor neurons. For example. the brainstem is divided into midbrain. and 9-12 are in the medulla. An example is a lacunar infarct. Cranial nerve nuclei of the brainstem. Recall that sensory (posterior/dorsal) root com­ pression leads to symptoms in a dermatomal distribution (Fig. causes ofisolated motor or sensory deficits include root lesions or diseases affecting the motor or sensory systems specifically. for instance.

may not be crossed. menin­ gioma. but the general scheme is a helpful one. So a brainstem lesion above this decussation in the medulla will impair motor and sensory function on the opposite side of the body but impair cranial nerve function on the same side (since the cranial nerves project ipsilaterally). Thus. 7 -7) does not connect to the brainstem like most other cranial nerve pathways.g. the most common cause is nasal obstruction (e. If a pa­ tient has lost his/her sense of smell.. fitting 3. which receives fa­ cial sensation information from cranial nerve V (trigeminal nerve). spans much of the brainstem and extends into the upper spinal cord. The primary excep­ tion is cranial nerve IV (the trochlear nerve). The cranial nerves generally exit the brainstem an­ teriorly and project ipsilaterally.e.. the olfactory nerve. if cranial nerve function is diminished on the left with paralysis and/or sensory loss on the right side of the body below the head. the optic nerve. There are four main exceptions: 1. It is not until the medullary pyramids (at the bot­ tom of the medulla) that motor fibers in the corti- 138 . Cranial nerve I is the only cranial nerve that does not connect at all to the brainstem.g. 2. If cranial nerve function and paralysis and/or sen­ sory loss below the head are on the same side. these lesions can produce pattems similar to cerebral lesions: all signs in the face and body occur­ ring on the same side. which exits the brainstem posteriorly and projects to the con­ tralateral superior oblique muscle. So a lesion of cranial nerve I leads to anosmia. may be involved in eye-head orienting reflexes). However. but the visual pathway carried in cranial nerve II does not project to the brainstem. loss of smell. a meningioma) impinging on the olfactory nerve. leading to hypogonadism). deficits locochlear nerve) straddle the ponto-medullary junction.. 5 The visual pathway (Fig. This is because some of the fibers from the cortex can incur lesions on their way down before arriving at their brainstem nuclei. The visual pathway fibers in cranial nerve II project to the lateral genic­ ulate nucleus of the thalamus.g. The spinal trigeminal nucleus. These crossed signs are charac­ teristic of brainstem lesions.. For example. Cranial Nerve II. CRANIAL NERVE NUCLEI OF THE BRAINSTEM Figure 7-6 perfectly true. Cranial nerve I (olfactory nerve) does not project to the brainstem at all but to olfactory cortex.CHAPTER 7. cerebral cortex. from a cold or sinusi­ tis). this gen­ erally implies a lesion above the brainstem (e. 5 Cranial nerve II also sends minor projections to the suprachias­ matic nucleus of the hypothalamus (involved in circadian rhythms) and the superior colliculus (function in humans poorly understood. conveys visual in­ formation from the eyes to the brain for visual process­ ing (Fig. 6 .. So a lesion of CN II or its pathway leads to a visual defect (i. thalamus). blindness in part or all of the visual field in one or both eyes). 7 .8* * Exceptions: See text Cranial Nerves Cranial Nerve I. That is. The vestibular nuclei of cranial nerve VIII (vestibu­ 4 In some cases of small midbrain or upper pons lesions. although crossed signs can only occur with brainstem lesions. Cranial nerve II (optic nerve) does contain fibers that project to the midbrain (pretectal nucleus) for the afferent limb for the pupillary light reflex. THE NERVOUS SYSTEM PONS cospinal tract cross to the other side. 7 -9). Do you think a tumor is more likely to cause unilateral or bilateral anosmia? A tumor (e. this would indicate a brainstem lesion on the left.g. crossed signs do not occur with all brainstem lesions. 7-7). or a tumor (e. frontal lobe mass) would probably lead to uni­ lateral loss of smell as it would generally impinge on CN I on only one side. CN I projects to the temporal lobe olfactory area. transmits smell information from the nose to the brain. Kall­ mann's syndrome (loss of olfactory neurons and GnRH-secreting cells. Other causes of anosmia include aging. 4.4 CN 5* . trauma (skull fracture impinging on the olfactory nerve). internal capsule. the afferent limb of pupillary light reflex that is carried in CN II travels to the midbrain. Sensory fibers (from the posterior columns) also cross nearby in the medulla (becoming the medial lemnisci as they as­ cend). CN II is also the affer­ ent (sensory) limb of the pupillary light reflex (Fig.

there are two projections (on each side). whereas a beam of light com­ ing from the extreme left will hit the right portions of both retinas. Modified from Goldberg: Clinical Neuroanatomy Made Ridiculously Simple. For example. which converts the light information into elec­ trical impulses. if you look straight ahead and imagine a beam of light com­ ing from the extreme right. which is the pos­ terior-most portion of the cerebral cortex.CHAPTER 7. whereas one from the bottom will hit the top. From there. that beam will hit the left portions of both retinas. Light hits the retina. into the 1-4 (midbrain). Similarly. THE NERVOUS SYSTEM The easiest way to remember where information from the visual fields travels in this system is to start with how light comes into the eye. after which they are known as the optic tracts. light coming from the top zaps into the bottom of the brain and light coming from the bottom zaps into the top of the brain. one going superiorly. 9-12 (medulla) schematic. light from the right zaps into the left brain. A beam from the top will hit the bottom of the retinas. 5-8 (pons). half of whose axons cross at the optic chi­ asm. and one going inferiorly (Meyer's loop). MedMaster 139 2005 . The lesions and associated visual deficits in this figure will be dis­ cussed below. These path­ ways synapse in the occipital cortex. Fig. 7-7. This pattern is maintained in the brain: the left brain contains information about the right visual field and the right brain contains information about the left visual field. Light coming from the left zaps into the right brain. These electrical impulses travel in the optic nerves. RIGHT VISUAL FIELD LEFT EYE VISUAL FIELD RIGHT EYE VISUAL FIELD 0 ()C) () () �� �(J () () Left Right retina retina LEFT EYE VISUAL FIELD � LEFT OCCIPITAL CORTEX RIGHT EYE VISUAL FIELD 0 ()f) �� �� ()() VISUAL PATHWAYS AND LESIONS Figure 7-7. Visual pathways and lesions. The optic tracts synapse in the lateral geniculate nuclei (LGN) of the thalamus.

Draw the eyes seen from above. What's lost is the information that crosses.CHAPTER 7. and these beams hit the left portions of both retinas. THE NERVOUS SYSTEM Fig. this eye is blind and the other eye is fine. Draw two lines coming straight off the outer por­ tions of them. 3. The following discussion refers to Fig. Schematic of visual pathway. draw a diagram that will help you remem­ ber how this system works. SCHEMATIC OF VISUAL PATHWAY Figure 7-8 140 . 4. while information from lateral retinas stays ipsilateral. 7-7 . Since no information is go­ ing from this eye to the brain. Lesion of the optic nerve. The pituitary lies right beneath the optic chiasm. . this should make sense. This is the right visual field. and the lower visual field ends up in the superior portion of the brain (parietal lobe and superior occipi­ tal cortex).oo 2. Following the steps below. What could cause this? Think anatomically. 7-8. This is bitemporal hemi­ anopsia. Just as information from the visual fields ends up on the contralateral side of the brain. If you follow logically how the light hits the retinas. the upper por­ tion of the visual field ends up in the inferior portion of the brain (temporal lobe and inferior occipital cor­ tex). 2. and from the left eye this is the right (nasal) visual field. Informa­ tion from the lateral parts of both retinas still makes it to the brain. Draw two parallel light beams coming from the right. 1. which comes from the me­ dial parts of the retinas: the left (temporal) visual field of the left eye and the right (temporal) visual field of the right eye. Draw two lines coming off the inner portions that cross to join the outer lines. 1. Information from the medial retinas crosses at the chiasm. Lesion of the optic chiasm at the midline. So the result is loss of the lateral (tempo­ ral) visual fields on both sides (because the outer visual fields hit the inner retinas). What information is this? From the right eye this is the left (nasal) visual field. and the medial (also called nasal) visual fields end up on the lateral surface of each retina. Another observation from this diagram is that the lateral (also called temporal) visual fields end up on the medial surface of each retina. 3. Notice that all infor­ mation from the right visual field ends up on the left side of the brain. and Note: The information from the right visual field is carried in the outermost line from the left eye and the innermost line from the right eye. 4.

Parasympathetic constriction is mediated by fibers traveling in CN III. radiations. the left-sided loops carry in­ formation about the right visual field. and the right­ sided loops carry information about the left visual field.CHAPTER 7. and medial rectus muscles. Lesion of the occipital cortex. the oculomotor nerve. the superior oblique and lateral rectus mus­ cles are unopposed and pull the eye down and out. which sends fibers to the muscles of pupillary constric- anopsia. cataract formation. because the efferent signal is sent via both oculomotor nerves to both pupils so as to cause a symmetrical pupillary response (7. Pupillary light reflex. innervated by cranial nerve VI). it is extensively represented. including retinal disease. tumor. far-sightedness (hyperopia). 7-9.so pupillary dilation is sympathetic and constriction is parasympathetic. A lesion of the entire oc­ cipital cortex on one side leads to complete loss of the contralateral visual field (homonymous hemianopsia). it innervates all extraocular muscles that are not innervated by cranial nerve IV (which inner­ vates superior oblique) and cranial nerve VI (which innervates lateral rectus). = Cranial Nerve III. 14 1 .. The Edinger-Westphal nuclei send parasympathetic fibers via the oculomotor nerve (III) to the ciliary ganglion. shining light into either eye causes constriction of both pupils. To assess the eye itself. Since the inferior oblique." wanting to fight or flee . This nucleus then sends bilateral projections to the ipsilateral and contralateral nuclei ofEdinger-Westphal in the mid­ brain (EW nuc in Fig. lower visual field information travels in the up­ per loop. Maintaining the "opposites" pat­ tern. A postchiasmatic lesion of one optic tract thus leads to loss of the entire contralateral visual field. So a complete lesion of cranial nerve III causes an ipsilateral eye that is "down and out" with a fixed. Fig. ophthalmo­ logic examination can be performed to look for retinal disease and cataracts. Thus. THE NERVOUS SYSTEM Refractive errors such as near-sightedness (myopia).lOA). or occipital cortex). tract. The optic tracts carry all of the information from the contralateral visual field (the lateral retinal fibers from the ipsilateral eye and the crossed medial retinal fibers from the contralateral eye). When you test the outer visual fields in a patient. inferior. . Such refractive errors can be cor­ rected with glasses or contact lenses: concave lenses for myopia. So a lesion of III weakens all eye muscles on that side except superior oblique (which in­ torts and depresses the eye. This reflex is accomplished by the optic nerve (afferent) and the oculomotor nerve (efferent). or a "pie in the sky'' lesion. The cross­ ing fibers in the chiasm carry the outer visual fields. Do you expect parasympathetic input to constrict or dilate the pupil? Well.a If this pathway is in­ tact bilaterally. or dam­ aged by vascular or inflammatory disease. innervated by cranial nerve IV) and lateral rectus (which abducts [laterally moves] the eye. In other words. . also called a right upper quadrantanopsia. 7-9). Of course. causing bitemporal hemianopsia. and upper visual field information travels in the lower loop.. optic nerve. Visual loss can also be caused by non-neurological diseases of the eye. Cranial nerve III can be compressed by aneurysm. innervates four extraocular muscles: the inferior oblique and the superior.e. Mnemonic: coyote chi-outy. when would the pupils dilate? When someone is "wide eyed with fear. So what kind of visual deficit would a left Meyer's loop lesion cause? A loss of the right upper visual field. quadrantanopsia) indicates a lesion of the vi­ sual pathway (i. Lesion of the visual pathway in the optic radiations (parietal and temporal lobe). lesions in­ volving only one of these vascular territories can lead to homonymous hemianopsia with macular sparing: loss of the entire (contralateral) visual field with a small half­ circle of vision preserved at the center. Since the center of the visual field (corresponding to the macula or the retina) is arguably the most important. Visual information from the lateral geniculate nucleus of the thalamus on each side travels toward the visual cortex in an upper loop in the parietal cortex and a lower loop in the temporal lobe (Meyer's loop). hemi­ 6 The CN II projections for the pupillary reflex exit CN II prior to the lateral geniculate nucleus of the thalamus (where visual informa­ tion is sent) and synapse instead in the pretectal nucleus of the mid­ brain. convex lenses for hyperopia and presbyopia. A strictly superior lesion leads to contralateral lower quadrant field loss. dilated ("blown") pupil and drooping eyelid. we are left with a dilated pupil and a drooping eyelid (ptosis). will improve if the patient reads through a pinhole or with appropriate corrective lenses. infectious or inflammatory processes. thus a midline pituitary tumor could press on the chi­ asm at the midline. When light shines into the eye. so a chiasmatic lesion causes loss of the outer (tempo­ ral) visual fields (bitemporal hemianopsia). Since the levator palpebrae muscles and pupillary constrictors are also lost. and medial rec­ tus muscles stop working in a complete cranial nerve III lesion. An upper loop lesion leads to a con­ tralateral lower quadrantanopsia. and a strictly inferior lesion leads to contralateral upper quadrant field loss. and receives dual blood supply from both middle and posterior cerebral arteries. How can one distinguish visual loss caused by a visual pathway lesion from visual loss caused by a problem with the eye itself? Any type of visual field deficit (e. Cranial nerve III also in­ nervates the levator palpebrae muscle (which raises the eyelid) and provides parasympathetic innervation to the pupil. you are assessing the integrity of the fibers that cross in the chiasm. superior. g. the pupil normally constricts in response. or age-related changes to the eye. inferior. Lesion of the optic tract. age-related accommoda­ tion/focusing difficulty (presbyopia).

Right CN3 LESION C. The situation in 7-lOC (CN II lesion) is called a relative afferent pupillary defect. NORMAL (both pupils constrict consensually) Light B. one notes dilation of the pupil on the side of the CN II (af- 142 . however. and constriction in the contralateral eye is called the consensual response. Right CN2 LESION PUPILLARY LIGHT REFLEX Figure 7-9 Pupillary constriction in response to light in the ipsi­ lateral eye (into which light is shined) is called the di­ rect response. and the af­ fected pupil can be called a Marcus Gunn pupil. light shined in the right eye can still be transmitted through this afferent pathway and cause constriction of the left pupil (7-lOB). Aright CN III lesion would prevent the right eye from constricting in re­ sponse to light in either eye.CHAPTER 7. when one moves a light back and forth between the two eyes. In this test. if CN II is still intact on the right. A rel­ ative afferent pupillary defect can be demonstrated by the swinging flashlight test. THE NERVOUS SYSTEM pretectal nuc A. both eyes would constrict if light is shined in the left eye since the afferent signal arrives in the brainstem and the efferent pathway (both CN Ills) is intact (7-lOC).Aright CN II lesion would lead to no pupillary constriction of either eye if light is shined in the right eye (since the right CN II does not transmit the afferent information). however.

Superior oblique intorts the eye. Whenever there is a loss of one of these rotatory functions (intortion/extortion). Because of the way this muscle attaches to the eye. So deficits are ipsilateral to a peripheral CN IV lesion. Cranial Nerve VI. Argyll-Robertson pupils. ferent) defect. Arlie's pupil can be caused by damage to the ciliary ganglion (which contains the parasympathetic input from CN III that constricts the pupil). often respond­ ing more normally during accommodation. The constricted pupil in Horner's syndrome still responds normally to light and near stimuli (ac­ commodation response) since parasympathetic (i. the left lateral rectus.Innervation of the chewing muscles . there may be a head tilt to compensate. 5-8 pons.e. and what nerves innervate these muscles? To look to the left. What muscles are responsible for these actions. which abducts the eye (turns it lat­ erally). classi­ cally caused by syphilis. Pupillary asymmetry is referred to as anisocoria. the abducens nerve. the trochlear nerve. Cranial Nerve V. but con­ tralateral to a lesion in the brainstem nucleus. The syndrome is most common in younger women (i. while the spinal nucleus of V spans much of the brainstem and extends into the up­ per spinal cord (Fig. sinuses. Thus. Many drugs..10. Inferior oblique elevates the eye. superior rectus ele­ vates it.e. 7 -6). the trigeminal nerve. 7. especially when the eye is adducted (turned medially). Holmes-Adie syndrome is the association of Arlie's pupil with absent deep tendon reflexes (usually in the leg and ankle) and orthostatic hypotension (and/or other autonomic dysfunction). CN VII (facial nerve) is the efferent (mo­ tor) limb. Remember that part of cranial nerve V follows 1-4= midbrain. constricting) input is still intact. sensory loss local­ ized to only one of these facial regions would imply a lesion between the face and the trigeminal ganglion from which the branches emerge. just sensation) and cornea Other sensation: part of the tympanic membrane and part of the meninges = • Motor . Mnemonic: Adie A dilated pupil. Although the light and near responses are usually lost together. 9-12 = medulla.Facial sensation: including skin. inferior oblique extorts it. a blink of the eyelid in response to stimulation of the cornea. To accomplish this. innervated by the left abducens nerve (VI). and mandibular. tongue (not taste. So this blink reflex can be absent in either a CN V or a CN VII lesion. spinal cord lesions. has one job: it innervates the superior oblique muscle. maxillary. The ptosis results from loss of sympathetic input to the tarsal muscles. Horner's syndrome is the triad of ptosis (drooping eyelid). Cranial Nerve IV.Innervation of the tensor veli palitini muscle (a muscle of the soft palate) There are three branches of CN V that bring sensory information to the brain from the face: ophthalmic. 143 . and motor (to chewing muscles) are found in the pons. constrict in accommodation but do not react to light. both eyes must move left in a synchro­ nized fashion. a lesion of cranial nerve VI leads to ipsi­ lateral inability to abduct the eye. but also as part of accommodation for focusing on near objects. leading to extortion and weakness of Fig. average onset in 30s). Lateral brainstem infarcts.. 7 So a lesion of cranial nerve IV would reduce the ability to intort and depress the eye. and it does not re­ spond to light shined directly on it. THE NERVOUS SYSTEM downward gaze. systemically ad­ ministered drugs will cause symmetrical effects in both eyes. can have a variety of effects on the pupils. proprioception. Thus. This is because that pupil is re-equili­ brating after constricting consensually from light shined in the contralateral eye. inferior rectus de· presses it. Most commonly. Sensory loss on one entire side of the face would imply a lesion between the brain and the trigeminal ganglion. innervates the lateral rectus. has several functions: • Adie's pupil is a dilated pupil that constricts only very gradually when exposed to light. miosis (constricted pupil) and anhidrosis (loss of sweating) due to lesion of the sympathetic pathway somewhere along its path from its origin in the hypo­ thalamus down to the cervical spinal cord to the supe­ rior cervical ganglion back up to the face and eyes. legal and illegal. The right medial rectus.CHAPTER 7. Conjugate gaze pathway. When you want to look to the left. the superior oblique intorts and depresses the eye. which retract the eyelids. = CN V is the afferent (sensory) limb of the corneal re­ flex. Sensory: . abducts the eye (turns it later­ ally). but administration of a drug into only one eye can cause a unilateral effect. Mnemonic: An Argyll-Robert­ son pupil Accommodates but does not React. and part does not: Facial light touch. This is because the superior oblique's depressor function is strongest when the eye is adducted. and apical pulmonary tumors can all cause Horner's syn­ drome. your left eye abducts (turns laterally) and your right eye adducts (turns me­ dially). The pupils not only constrict in response to light. Argyll­ Robertson pupils also tend to be small and unequal. innervated by the right oculomotor nerve (III) adducts the right eye (turns it 7 Note: Superior oblique depresses the eye. Cranial nerve IV is the only cranial nerve that projects contralaterally.

HIV).g. How can you prove that this is an INO and not some problem with the right medial rectus or the right cranial nerve A patient with an upper motor neuron lesion (e. The communication is con­ tralateral because the MLF coordinates abduction in one eye with adduction in the contralateral eye. CEREBRAL CORTEX a a CN Ill CNVI Cranial Nerve VII is the facial nerve. which is the same side as the MLF after it has crossed to the side of the affected CN III nucleus. 7-1 1). the left eye abducts (turns left) but the right eye cannot adduct (turn left). Lyme Disease. and tumor impinging on the seventh nerve (e. Herpes-Zoster. whose func­ tions include: • Innervation of the facial musculature and the stapedius muscle of the inner ear • Taste sensation from the anterior 2/3 of the tongue (CN IX does the rest of the tongue) MLF PONS • • Lacrimal gland stimulation • Sensation from parts of the inner and exterior ear Fig. while sparing the forehead. forehead included. the medial longitudinal fasciculus (MLF) in the brainstem allows for communication between the nu­ cleus of VI (in the pons) and the contralateral nucleus of III (in the midbrain). The most common causes of INO are brainstem strokes and multiple sclerosis. in addition to the contralat- 144 .. The motor cortex lower face area projects only to the con­ tralateral VII nuclei. since the facial nerve is still carrying input to the forehead from ipsilateral cortex (right-most panel of Fig. the right eye will still adduct on convergence. To accomplish these conjugate eye move­ ments.g. the facial nerve on each side receives contralat­ eral cortical input for the forehead and lower face in addition to ipsilateral cortical input for the forehead. MedMaster 2005 medially).g." it of course also projects to both right forehead and lower face. Though the left motor cortex says "to fore­ head. So when the pa­ tient looks to the left. The side of the lesion is named for the side of medial rectus dysfunction. For example.. A lesion of the facial nerve (CN VII) will cause weak­ ness of the muscles of the whole face. but normal forehead movements..1 1). the figure shows the input to the left CN VII. multiple sclerosis.CHAPTER 7. THE NERVOUS SYSTEM III? Since convergence uses a different pathway. a lesion of the right MLF means that the left abducens (VI) nucleus in the pons cannot communicate with the right oculo­ motor (III) nucleus in the midbrain. CONJUGATE GAZE PATHWAY Figure 7-10. Since innervation to the forehead comes to the facial nerve from both sides of the brain. Adduction on convergence proves that the right medial rectus and right CN III are intact and that the lesion must thus be in the right MLF._-GAZE CENTER Clinical Neu­ roanatomy Made Ridiculously Simple. sarcoidosis. in which the eye ipsilateral to the le­ sion cannot adduct (turn medially) during attempted conjugate gaze. trauma. unilateral cortical lesions can affect the muscles of the lower face. Bell's palsy is an idiopathic palsy of CN VII. Thus. on that same side (middle panel of Fig. a cortical stroke) will have loss of contralateral lower face movements. L Each motor cortex forehead area projects to both the contralateral VII nucleus and the ipsilateral one. It is possible to have bilateral INOs (from bilateral MLF le­ sions): on leftward gaze the right eye does not adduct (turn left) and on rightward gaze the left eye does not adduct (turn right). Upper and lower motor neurons of CN VII. The facial nerve (CN VII) carries all of this information from both sides of the cortex. Modified from Goldberg: Salivary gland stimulation (submaxillary and sub­ mandibular. 7-1 1 . Similarly. CN IX does the parotid) LATERAL �_. acoustic neuroma). 7. Note: For simplicity. Causes of facial nerve palsy include infectious dis­ eases (e. A lesion of the MLF results in internuclear ophthal­ moplegia (INO).

and you will notice that your eyes try to maintain straight-ahead position = 145 . anemia).. An example of a lesion that affects the eighth nerve is an acoustic neuroma. con­ veys sound and head movement/position information to the brainstem from the cochlea and semicircular canals.. rological causes of dizziness and balance problems in­ clude various systemic diseases (e. but most vestibular information arrives lower.CHAPTER 7. cardiovascular disease. straddling the pons and medulla. the vestibulocochlear nerve.g.g. Auditory information arrives in the brainstem in the pons as expected (given "5-8 pons"). benign paroxysmal positional vertigo. Cranial Nerve VIII. Turn your head back and forth as if say­ ing "no" while continuing to read. Non-neurological causes of hearing loss in- elude middle ear infection/congestion and damage to the tympanic membrane. The vestibula-ocular reflex keeps vision steady while the head moves by causing the eyes to move in the opposite direction from the head as the head turns (assuming the eyes are not trying to follow a moving object). These slow-growing tumors of CN VIII can lead to unilateral hearing and/or vestibu­ lar deficits. Meniere's disease). it projects to the ipsilateral forehead via the right facial nerve. Non-neu­ . THE NERVOUS SYSTEM To forehead & lower face To forehead To forehead & lower face & lower face To L forehead Facial nerve "Smile" "Smile" "Smile" "Wrinkle your brow" "Wrinkle your brow" "Wrinkle your brow" • • Paralysis of contralateral • Forehead normal Paralysis of entire ipsilateral face lower face UPPER AND LOWER MOTOR NEURONS OFCN VII Figure 7-11 eral projections of the right motor cortex. and inner ear diseases (e. Try it. ossicles. or cochlea. also called vestibular schwannoma.

the eyes move in the opposite direc­ tion. CN IV. The direction of nystagmus is named for the fast phase (i. conscious patients. and thus a brainstem lesion may be the cause of the coma. 7-12. slow deviation toward the cold water side will occur without the subsequent quick return.e. and/or CN VI). followed by a quick return in the opposite direction (i.CHAPTER 7. or certain drugs. brainstem. If the eyes move in the same direction as the head. If the eyes do not deviate in response to the cold water. A doll's eye maneuver should not be performed if cervical spine injury is suspected. toward the side without cold water). In comatose or unconscious patients with an intact brainstem. the direction of the flicking back).. Pathological causes include le­ sions of the peripheral vestibular system. this implies that the vestibulo-ocular reflex is not working. you test the integrity of this system. When you do a "doll's eye" test in a comatose patient. occur pathologically. this causes the eyes to move slowly toward the cold side. Cold calories. Nystagmus is oscillation of the eyes. Nystagmus can occur normally at the extremes of gaze. e. Lack of response to cold calories can also occur secondary to some types of drug intoxication. the brainstem gets in­ formation from CN VIII and transmits it to the rele­ vant eye movement nuclei (CN III.. Fig. or cerebellum.repetitively moving slowly to one side and then flicking back rapidly.e. In normal. Putting cold water into one ear (cold caloric testing) mimics a temporary lesion of the vestibular system on that side.. generating the appropriate eye movements. Before performing cold calories. the tympanic membrane should be examined to assure that it is intact. the brainstem is intact.g. what the eyes do when observing passing telephone poles out the window of a moving train . This is a complex reflex. there may be a lesion anywhere along this pathway (or there may be too much wax in the ear to perform the test adequately). Cold calories assess the integrity of the vestibularNIIIIVI/ MLF/III system. If when the head is turned in one direction. THE NERVOUS SYSTEM by turning in the opposite direction from that of your head. but can also Fast component Slow component �/ � NORMAL COLD WATER • COMA WITH COLD WATER • INTA CT BRAIN STEM BRAINSTEM COLD WATER DYSFUNCTION OR DRUG INTOXICAT ION COLD CALORICS Figure 7-12 146 • .

and genitals receive their parasympa­ thetic input from sacral spinal cord. lungs. rectum. ear. descending colon. and X) Fig. THE NERVOUS SYSTEM Cranial Nerve IX. VII. The vagus sup­ plies the parasympathetic input to the heart. If the uvula elevates symmetrically in the midline. If the uvula deviates to the left. and tympanic membrane (note sharing of function in these re­ Sensation from part of the external ear and tym­ panic membrane Note the complementary relationship between CN VII and CN IX with regard to taste (anterior 2/3 of tongue = CN VII. posterior 113 = CN IX) and salivation (submandibular and submaxillary glands= CN VII. where is CN IX is the afferent component of the gag reflex (CN X is the efferent component). " Say Ah h h " "Say Ahhh" R I GHT-SI D E D N ORMAL UVULA R CN X (vaga l ) LESION RETRA CTION ( Deviation to left) PALATE DEVIATION Figure 7-13 147 . parotid gland = CN IX).) The vagus nerve has a variety of other functions as well: glossopharyngeal nerve. When you ask a patient to "Open wide and say 'Ahhh. has several functions: • Sensation and taste from the posterior third of the tongue and sensory input from the palate • Motor input to the stylopharyngeus muscle of the pharynx • Stimulation of the parotid gland • Transmitting visceral sensory information from the carotid body (oxygen tension) and carotid sinus (vol­ ume) receptors to the nucleus solitarius of the medulla • • Carries sensory information to the brainstem from the viscera and the aortic arch (oxygen tension and blood volume information) • Provides motor input to one muscle of the tongue (palatoglossus) and all muscles of the larynx and pharynx except the stylopharyngeus muscle (CN IX) and tensor veli palatini muscle (CN V) • Sensation from the pharynx.1 3 . (The bladder.CHAPTER 7. think parasympathetic. both sides of the pharynx are tugging sym­ metrically. the Cranial Nerve X is the vagus nerve. Palate deviation. and most of the GI system. so CN IX lesion can lead to absent gag reflex. gions by CNs V.'" you are assessing the va­ gus nerve. 7. IX. When you think vagus.

If the lesion affects the upper motor neurons (i. CN XII. and/or vertigo. and the uvula deviates to the normal side.. Thus. Cerebellum and Basal Ganglia The cerebellum and basal ganglia are both involved in coordinating movements. Symptoms of vagus nerve damage include hoarse­ ness (from the loss of laryngeal muscle innervation). Recurrent laryngeal nerve le­ sions result in hoarseness. and absent gag reflex. Thus. The recur­ rent laryngeal nerve. When you ask a patient to shrug against resistance and to turn his/her head against your hand. a lesion of the right vagus nerve allows the left side to win the tug­ of-war. putamen. from cortex down to but not including the nucleus in the medulla).e.. 7-15. Cerebellar deficits occur ipsilateral to the side in which the lesion occurs. the weak side is contralateral to the lesion. and sends output to the cerebral cortex (by way of the thalamus) to adjust these movements. intention tremor (normal at rest. A lower motor neuron lesion on one side would lead to ip­ silateral shoulder drop and weakened shrugging. multiple sclerosis. THE NERVOUS SYSTEM the lesion? If the uvula is pulled more to the left. the hypoglossal nerve.CHAPTER 7. 7-14. inner­ vates the sternocleidomastoid and the trapezius mus­ cles. If one side is lesioned. Fig. the tongue will go straight out. Cere­ bellar dysfunction can be caused by toxins (e. Functionin g ri g ht muscles push ton g ue to left " Stick out your tong u e" " Stick out you r tong ue" NORMAL LEFT HYPOGLOSSAL (CN XII) INJURY OR RIGHT CEREBRAL STROKE TONGUE PROTRUSION Figure 7-14 148 . and sub­ stantia nigra) are part of a loop circuit that begins and ends in the cortex. cerebellar lesions can result in ataxia (uncoordinated movement. as well as weakness turning the head against resistance toward the opposite side (because the sternocleido­ mastoid muscle normally rotates the head to the con­ tralateral side). the spinal accessory nerve. Fig. this must mean that the right is weak. which is in­ nervated by CN X). testing strength and symmetry. trouble swallowing.g. globus pallidus. If the lesion af­ fects the lower motor neurons. to touch a target or to pick up a glass).g. Basal Ganglia The basal ganglia (caudate. dysdiadochokinesia (inability to perform rapid alternating movements). tumor. the weak side is ipsilat­ eral to the lesion. imbalance. stroke. innervates the muscu­ lature of the tongue (except palatoglossus.g. Cerebellum The cerebellum uses feedback from the spinocerebel­ lar tracts (which travel uncrossed from the spinal cord) to monitor movements while they are taking place. a branch of the vagus. nucleus accumbens. tremor when intending to move. If they both work perfectly together. and/or paraneoplastic syndromes. The tongue muscles on each side push the tongue to the opposite side. subthalamic nu­ cleus. can be compressed by tumor or damaged in neck surgery (e. as demonstrated in finger-to-nose and heel-to-shin tasks). Summary of cranial nerve functions.. you are assessing CN XI. Tongue protrusion. thyroid surgery). In contrast to cerebellar lesions.. the other side will push the tongue toward the weak side. Cranial Nerve XI. alcohol). nystagmus. The cere­ bellum is also involved in balance and posture. e.

meni nges. cornea. which spans brain stem and extends i nto upper spinal cord) Lateral rectus (Abducts eye) • CN VIII Facial sensation (including face itself. THE NERVOUS SYSTEM Figure 7.1 5 Summary o f cranial nerve functions Nerve Name Function Projects to/from: Lesion can lead to: CN I Olfactory Smells Olfactory cortex i n temporal lobe • CNII Optic Sees • • • • CN I l l Oculomotor CN IV Trochlear CN V Trigeminal Midbrain Superior oblique (depresses and i ntorts eye) Midbrain • • Abducens CN V I I Facial • Eye down and out • P u p i l d i lated Weakness of downward gaze. and part of tympanic membrane) Chewing m uscles Tensor veli paliti n i muscle • • Superior col liculus (eye-head reflexes) Moves eyes : all m uscles except lateral rectus (done by VI) and s u perior oblique (done by IV) • Constricts pupils • Accom modates lens • Elevates upper eyelids • • CN VI Lateral geniculate nucleus of thalamus (vision) Pre-tectal nucleus of m i d b ra i n (pupil lary light reflex) Hypothalamus (circad ian reflexes) Anosmia (loss of smell) Medulla I m p a i red gag reflex Parasympathetic i nput to and sensory from viscera Larynx Swallowing/Palatal elevation Medulla • Ste rnocleidomastoid (turns head to opposite side Trapezius (elevates shoulders) Medulla Taste (posterior t h i rd of tongue) Parotid gland Carotid body and carotid sinus • • I n n ervates tong u e musculat u re for tongue protrusion (to opposite side) • • Medulla 149 • Hoarseness ( recu rrent l a ryngeal n e rve) D ifficu lty swallowing I m paired palatal elevation Weakness turning head to opposite side Shoulder d rop/weakness Ton g u e deviation to weak (affected) side . Extortion (can cause head tilt) • • • I n nervates facial m u sculat u re Taste (anterior 2/3 of tongue) Submandibular and submaxil lary glands Lacrimal glands Sensory from parts of inner ear Pons • • Hearing • Balance Pons (some vestibular n uclei extend i nto the medul la) • • • • • • • • • CN X Vagus • • • CN X I Spinal accessory • • CN X I I Hypoglossal Sensory to palate Swallowing Facial weakness Decreased taste D ry eye • Hearing loss Tin n itus Balance difficu lties Vertigo • N ystag m u s • • • Glossopharyngeal Decreased facial sensation Absent corneal reflex Weakness of chewi ng I nability to abd uct eye • CN I X Visual defect I m pai red p u p i l lary response t o l i g ht Pons • Vestibulocochlear Pons (except spinal nucleus.CHAPTER 7. ton g u e .

metabolic disorders. and have difficulty starting. so some of these very same dopamine agonists used in the treatment of Parkinson's disease can also be used to shrink pro­ lactinomas (see Chapter 5). What would you expect side effects of dopamine ag­ onists to be? Well. frontotemporal dementia. allowing it to in­ hibit the cortex. focal neurologi­ cal deficits. drugs. Indirect strate­ gies include agonists of the dopamine receptors (bromocriptine. has been in­ hibited (i. Otherwise. hypothyroidism. either directly (L-dopa) or indirectly. and depression. Thus. personality. HIV. hunched-over gait. Dopamine input from the substantia nigra to the striatum excites the direct pathway and inhibits the indirect pathway. which tend to cause problems during intended move­ ment. Loss of dopamine from substantia nigra degeneration in Parkinson's leads to decreased activity of the direct pathway and increased activity of the indirect path­ way. it is important to rule dopaminergic input to the striatum is increased corti­ cal excitation. stroke. Since Parkinson's disease involves a shortage of dopamine. Re­ fractory cases can sometimes benefit from surgical le­ sion of the Gpl (part of the over-active inhibitory indirect pathway) or deep brain stimulation of the subthalamic nucleus. tumors (primary or metastatic). which sends projections to the cerebral cortex via a few inter­ mediate structures. vas­ cular disease. Mental Status Changes: Dementia and Delirium Dementia is a progressive change in cognitive func­ tion. the overall result of normal docrine diseases. Before considering a diagnosis of a dementia syndrome such as Alzheimer's disease. involuntary movements resulting from contralateral lesion of the subthalamic nucleus).. a direct pathway (internal segment of the globus pallidus (GPi) � ven­ trolateral nucleus of the thalamus (VL) � motor areas of the cerebral cortex) and an indirect pathway (exter­ nal segment of the globus pallidus (GPe) a subtha­ lamic nucleus (STN) � GPi � VL � motor areas of the cerebral cortex). abscess. resting tremor. cerebrovascular disease (e.16C). and the substantia nigra normally inhibits it.. . drugs. Lyme disease). Finally. treatment attempts to restore dopamine. seizures.g. etc.g. in Parkinson's disease there is decreased excitation of the cortex and increased inhibition of the cortex (7. hemorrhage). or psychological disorders. Huntington's disease (autosomal dominant-inherited degeneration of the caudate/putamen). Delirium is an acute change in mental status. patients may have a shuffling. con­ genital diseases. or Lewy body disease. Notice that the indirect pathway is always as­ sociated with inhibition: It inhibits the cortex. The corollary is that dopamine antagonists used to treat schizophrenia can lead to dyskinesias (abnormal movements). Any of these can result in headache. The substantia nigra projects to the striatum (caudate and putamen). endocrine disease. an area of the midbrain that sends dopamin­ ergic projections to the striatum (caudate and putamen). while the indirect path­ way. This causes an overall decrease in mo­ tor cortical activity.CHAPTER 7. Dementia differs from delirium in its time course. hemiballismus (violent. and making turns when walking. The loss of dopamine input to the striatum commonly results in the symptomatic triad of bradyki­ nesia (slow movement). Parkinson's Disease Parkinson's disease is a degeneration of the substan­ tia nigra. multi-in­ farct dementia). like dementia. This is because the direct pathway is out other causes of cognitive decline. Chorea can also occur secondary to Wilson's disease (see Chapter 5). Such causes include infections (e. and chorea (involuntary choreiform (dance-like) move­ ments). Thus. meningitis7). ropinirole. monoamine oxidase inhibitors such as selegiline). resulting in bradykinesia and rigidity. delirium can be caused by infections. mental status changes. Cognitive decline can include changes in memory. and speech as well as delusions and disin­ hibition. Parkinson's disease. inflammatory diseases. hydro­ cephalus. not the brain. 7-16. trauma. dystonia (painful muscular contraction leading to undesired and often unusual postures). Parkinson's dis­ ease disinhibits the indirect pathway. drugs. stimulated to excite cortex. and I or elevated intracranial pressure.e. pergolide. and cogwheel rigidity. THE NERVOUS SYSTEM .g. Examples include the resting tremor of Parkinson's (see below). medications. stop­ ping. vascular disease (e. prevented from inhibiting) (7-16B). lesions of the basal ganglia tend to cause un­ wanted movements at rest. Additionally. en­ Fig. coma. some of which are treatable.. DISEASES OF THE BRAIN As with any organ. the brain can be affected by infec­ tion (viral encephalitis.16A). pramipexole) and drugs that decrease dopamine breakdown (e. So dopamine therapy can lead to hallucinations.g. Dopaminergic projections to the striatum synapse on two pathways. what disease is caused by too much dopamine? Schizophrenia. and Sydenham's chorea (chorea in rheumatic fever). The direct pathway excites the cortex and the indirect pathway inhibits it (7. remem­ ber that dopamine inhibits prolactin... which normally inhibits the cortex. 7 150 Meningitis is actually an infection of the meninges. unilateral.

drug withdrawal. to name a few of countless causes. fever. The presence of an aura (visual. Recurrent seizures (e. stroke. Antiepileptics either inhibit excitation of neurons or increase inhibition of them. and some people convulse a bit after syncope. and structural abnonnalities of the brain (e. Substantia Nigra MOTOR R EGIONS OF CEREBRAL CORTEX EXCITED Dopamine NORMAL Direct Pathway I ndi rect Pathway MOTOR REGIONS OF CEREBRAL CORTEX INH I BITED PARKINSON'S DISEASE PARKINSON'S DISEASE Figure 7-16 and/or repetitive stereotyped motions can all be char­ acteristic of seizure. or auditory).. seizure disorders can also be due to congenital structural abnonnalities of the brain. Additionally. In adults.g.g. in epilepsy. an EEG (electroencephalogram) can pick up abnonnal firing patterns in the brain that could indicate underlying seizure foci.CHAPTER 7. loss of bowel/bladder control. while GABA Single isolated seizures usually do not require anti­ epileptic treatment. When in doubt. tumor). though aura can also occur in mi­ graine. tongue biting. head trauma. THE NERVOUS SYSTEM A. vascular malfonnation. Antiepileptics It is important to distinguish a seizure from syncope (fainting). infections. Glutamate is the main ex­ citatory neurotransmitter in the brain. medications.g. In children. tumor. a first seizure warrants a search for some struc­ tural lesion (e. though they do require a search for an underlying cause. stroke). or recurrent seizures. olfactory.. Di rect Pathway Indirect Pathway MOTOR REGIONS OF CEREBRAL CORTEX B. Seizures Isolated seizures arise from abnonnal electrical activity in the brain and can be caused by electrolyte or glu­ cose abnonnalities. Some of these disorders may be caused by ion channel malfunction (channel­ apathy). post-surgery) require ongoing treatment with antiepileptics.. disorders of decreased inhibition/increased excitation in the brain can cause epilepsy. 151 .

but there is some space between it and the posterior aspect of the vertebrae in the spine.g.). Although it can be seen as a reaction to medication. Cerebrospinal fluid (CSF). in subarachnoid hemorrhage. Dandy-Walker). Hydrocephalus The dura mater adheres tightly to the inner surface of the skull.. The last three (hypertension. One sign of increased ICP is papilledema (swelling of the optic nerve as seen on retinoscopy). fixed. Infection or bleeding can occur in any of these places or in the brain itself. double vision).. ventric­ ular dilatation) or any pathology that could raise in­ tracranial pressure. which can result in the rapid onset of neuro­ logical symptoms and signs (e.g. visual changes. Acetazolamide. The subarachnoid space contains the CSF. 7. infection). one can de­ crease synaptic degradation of GABA (vigabatrin) or block GABA reuptake in the presynaptic neuron (tiga­ bine). This is thought to decrease CSF production. dilated pupil. symptoms and signs of elevated ICP are present. Arnold-Chiari. Its production is in equilibrium with its reabsorption back into the venous system via the arachnoid granulations. Obstructive causes of hydrocephalus are also referred to as non-communicating hydrocephalus. The increased CSF causes the ventricles to enlarge. carbamezapine. a lumbar puncture can be dangerous since it can cre­ ate a negative pressure in the spinal canal that can precipitate herniation.. since there is no obstruction to pre­ vent CSF from communicating within the ventricular system or between the ventricles and the subarach­ noid space. blurred vision. So antiepileptic drugs either inhibit glutamate activity or increase GABA activity. and irregular respirations) are known as Cushing's triad or Cushing's response.g. one could inhibit sodium channels that stimulate the action potential in the presynaptic neuron (e.g. mental status changes. ethosuximide). Elevated Intracranial Pressure The intracranial space is limited. circulates through the ventricles and bathes the brain. Glutamate can be inhibited by decreasing its release from the presynaptic neuron or preventing the postsy­ naptic neuron from responding... Extreme ICP elevation can cause herniation of the brain through the foramen magnum. urinary in­ continence. headache. bradycardia.g.. reabsorption (from blockage of arachnoid villi. be­ havioral changes. during preg­ nancy. which directly adheres to the brain. IV mannitol can be administered to decrease ICP : mannitol increases the osmolarity of the blood so as to draw water from the edema into the blood. If a patient has elevated ICP. Intracranial Infection and Bleeding Fig.. etc. seizures. As for inhibiting re­ lease of glutamate. which blocks the AMPA glutamate receptor).e. The sub­ dural space lies between the dura mater and the arachnoid. thus increasing in­ hibition (hence decreasing firing) of these neurons. . and bleeding can elevate intracranial pressure. there is no ventricular enlargement as in hydrocephalus). but the brain appears normal when scanned (i. inflammatory disease. particularly obese women. hypertension. Sites of intracranial bleeding and infection. which can be seen on MRI or CT. one could inhibit calcium channels of the presynaptic neuron that allow the calcium influx that leads to synaptic vesicle fusion/release of neuro­ transmitter (e. Hydrocephalus can be caused by increased CSF pro­ duction (e. To increase GABA or its effectiveness. a carbonic anyhdrase inhibitor. vomiting. visual changes (e. bradycar­ dia. papilledema. Symptoms/signs include headache. post-stroke. e. Pseudotumor cerebri is most com­ mon in women. choroid plexus tumor). papilledema. is often used for treatment. decreased CSF 152 .g..g. Note that both of these drugs have "gab" in their names for GABA. since ventricular obstruction prevents communication within the ventricular system or between the ventri­ cles and the subarachnoid space. This is why many patients re­ ceive a CT scan before undergoing lumbar puncture: to look for signs of intracranial pressure (e. produced by the choroid plexus. phenytoin. Pseudotumor Cerebri In pseudotumor cerebri (also known as idiopathic I be­ nign intracranial hypertension). it can also occur id­ iopathically. Or.g. topira­ mate. and elevated ICP on lumbar puncture.. Non­ obstructive causes are examples of communicating hydrocephalus. Benzodiazepines and barbiturates act at the post-synaptic chloride channel where GABA acts. nausea. headache. Symptoms and signs of hydrocephalus include vi­ sual disturbances.g. The subarachnoid space is the space be­ tween the arachnoid and the pia mater.1 7 . blackouts. and during systemic illness. by tumor or congenital malfor­ mation. they enhance chloride influx. and neurological deficits. THE NERVOUS SYSTEM I is the main inhibitory one. A disturbance in this equi­ librium causes hydrocephalus and elevates ICP. hemiparesis) and/or coma or death. unsteady gait. edema (from infection. valproic acid) and/or postsynaptic neurons (e..g. and/or irregular respira­ tory patterns. e. Symptoms of increased intracranial pressure (ICP) in­ clude nausea. or ventricu­ lar obstruction (e. Treatment includes removing CSF via lumbar puncture (in communicating hydro­ cephalus) or placing a shunt from the ventricular sys­ tem that drains either into the abdomen or the atrium of the heart (in obstructive hydrocephalus). leading to a decrease in ICP. so tumors.CHAPTER 7.

CHAPTER 7. THE NERVOUS SYSTEM

I

E p i d u ra l s pace
(epi d u ra l hemorrhage/
a bscess)
D U RA MATER

B RA I N PA RENC HYMA
(cerebra l hemorrhage/
a bscess; encephalitis)

SITES OF INTRACRANIAL BLEEDING AND INFECTION
Figure 7-17

Infectious agents can arrive at the brain or meninges
via hematogenous spread from other sites (endocardi­
tis, pneumonia), spread from nearby infections (sinusi­
tis, orbital cellulitis, or otitis in the case of intracranial
infection; osteomyelitis, paraspinous abscess, or psoas
abscess in the case of spinal infections), or from infec­
tion during trauma or neurosurgery.

hip and knees (Brudzinski's sign). If one flexes the
thigh at the hip, and attempts to straighten the pa­
tient's leg at the knee, this will be met with resistance

(Kernig's sign).
Epidural Bleeding and Infection

Epidural Hematomas are caused by trauma to the
skull that ruptures the middle meningeal artery,
leading to bleeding between the dura mater and the
skull. Symptoms and signs include headache, nausea
and vomiting, seizure, and symptoms/signs of elevated
ICP. Sometimes patients with epidural hematoma
maintain (or regain) consciousness for a period after
the trauma, called a lucid interval. Blood is drained
surgically by drilling burr holes in the skull.

Any bleeding or infection in or around the brain can
cause headache, nausea/vomiting, seizure, mental sta­
tus changes, elevated ICP (and its associated signs/
symptoms), and/or papilledema. Fever is often present
in infection. Subarachnoid hemorrhage and meningitis
irritate the meninges, resulting in meningeal signs.
Meningeal Signs

Irritation of the meninges (e.g., in subarachnoid hem­
orrhage or meningitis) can lead to pain during any
maneuver that puts traction on them. This is why
meningeal irritation causes a stiff neck: to avoid such
traction, the neck stiffens (like guarding in peritoni­
tis). On physical exam, if one attempts to flex the pa­
tient's neck, this will cause involuntary flexing of the

Epidural Abscesses can be caused by hematoge­
nous spread of infectious agents or spread from
nearby infection. Such infections include osteomye­
litis, paraspinous abscess, or psoas abscess in the
spine; sinusitis, orbital cellulitis, or otitis in the skull;
or infection during a neurosurgical procedure. In the
skull, epidural abscess can cause the symptoms of

153

CHAPTER 7. THE NERVOUS SYSTEM
(N meningitidis) or ear infection (Hemophilus in­
fluenza), or post-surgery or trauma (Staph., gram neg­

elevated ICP (headache, nausea/vomiting), focal neu­
rological signs, and/or seizures. In the spinal cord,
epidural abscess can cause back pain, radicular pain
(pain radiating along a dermatomal distribution),
and/or bowel/bladder incontinence. Spinal epidural
abscesses are more likely to occur than intracranial
ones because there is more space· between the dura
mater and overlying bone in the spine than in the
cranium (where the dura is tightly adherent to the
skull). Staph. aureus and Streptococcus are common
pathogens. Treatment involves antibiotics and surgi­
cal drainage.

atives). Fever, headache, meningeal signs, stiff neck,
photophobia (increased sensitivity to seeing light),
seizures, and/or mental status changes may occur.
The most common offending organisms are:

In neonates: group B Streptococcus
In children: H. influenza, Strep. pneumoniae, N

meningitidis

In adults: Strep. pneumoniae and N meningitidis.

Tuberculosis and Listeria monocytogenes can also
cause meningitis.

Subdural Bleeding and Infection

Subdural Hematomas are caused by head trauma that
tears bridging veins between the brain and the dura. Clot­
ting disorders, thrombocytopenia, and alcoholism
(because of both head trauma and thrombocytopenia
from liver dysfunction) can increase the risk of subdural
hematoma. Symptoms are those of increased intracranial
pressure and/or focal neurological deficits. These symp­
toms can arise acutely following trauma or more insidi­
ously over weeks/months (chronic subdural hematoma).
Chronic subdural hematoma in the elderly can be caused
by brain atrophy, which stretches the bridging veins, pre­
disposing them to spontaneous rupture with even minor
trauma (e.g., a fall). If extensive, blood from subdural
hematoma must be drained surgically.

Viral meningitis (enterovirus, varicella zoster virus,
herpes simplex virus, HIV) and fungal meningitis
(e.g., cryptococcus, candida, histoplasmosis-more
common in immunocompromised patients) can cause
similar symptoms, but usually have a more subacute
presentation than bacterial meningitis.
Diagnosis is made by CSF examination (see below).
Treatment involves antibiotics targeted to the infec­
tious organism.
Bleeding and Infection in the Brain

Intraparenchymal Hemorrhage can be caused by
hypertension, trauma, aneurysm/arteriovenous mal­
formation (AVM) rupture, intracranial tumor bleed­
ing, and post-stroke hemorrhage. Symptoms/signs can
include headache, seizure, focal neurological deficits,
or mental status changes. Meningeal signs can also oc­
cur if the bleeding extends into the subarachnoid
space. Surgical treatment is often necessary unless
the amount of hemorrhage is small, in which case the
patient can be stabilized and observed.

Subdural Abscesses (empyema) can arise via spread
of infectious material from intracerebral abscess,
meningitis, sinusitis, trauma/surgery, intracerebral
infections, otitis, or hematogenous spread from a dis­
tant site. Symptoms and signs are those of increased
ICP. Staph. aureus, Streptococcus, and gram negative
bacteria are the most common pathogens. Abscesses
are treated by antibiotics and surgical drainage.
Subarachnoid Bleeding and Infection

Brain Abscess. A cerebral abscess can arise when

Subarachnoid Hemorrhage is most commonly sec­

infection spreads to the brain from nearby infections
(meningitis, sinusitis, otitis), distant infections (via
hematogenous spread), or during surgery. Symptoms/
signs may include fever, headache, nausea/vomiting,
seizure, focal neurological deficits, and mental status
changes. Staph. aureus, Streptococcus, anaerobes, H.
influenza, tuberculosis, fungi, and protozoans can all
cause cerebral abscesses. Treatment involves appro­
priate antibiotic therapy and surgical drainage.

ondary to rupture of an aneurysm or less commonly to
rupture of an arteriovenous malformation (AVM). The
sudden-onset headache of subarachnoid hemorrhage
is classically described by the patient as the "worst
headache of my life." Meningeal signs and signs of el­
evated ICP may also be present. Diagnosis is made by
seeing blood in the CSF on lumbar puncture and evi­
dence of bleeding on CT or MRI. Patients should be
stabilized and prepared for surgical clipping of the
aneurysm or intravascular coiling, an interventional
radiologic procedure that blocks off the aneurysm with
micro-coils.

Encephalitis is usually viral (e.g., herpes simplex
virus, enterovirus, mumps, rabies, mosquito borne
viruses such as West Nile Virus and St. Louis
Encephalitis), but it can also be caused by parasites
(e.g., toxoplasmosis) or some atypical bacteria (e.g.,
Listeria, Bartonella, Rickettsia, Mycoplasma). Fever,
headache, nausea/vomiting, seizures, focal neurologic

Meningitis is infection of the meninges and CSF from
hematogenous spread (e.g., Strep. pneumoniae from
pneumonia), entry via the upper respiratory tract

154

CHAPTER 7. THE NERVOUS SYSTEM
other cranial nerve deficits if the tumor impinges on
the brainstem.

deficits, and/or altered mental status may be present.
Diagnosis is made by identifying evidence of the infec­
tious agent in the CSF, or in some cases by brain
biopsy. Treatment is directed against the offending or­
ganism (e.g., acyclovir for herpes simplex virus) if
available. When treatment does not exist for a partic­
ular organism, patients' systemic manifestations are
treated as necessary for stabilization.

Gliomas include astrocytoma (including glioblas­
toma multiforme), oligodendroglioma, and ependy­
moma. Ependymomas arise from cells of ventricular
lining and can thus lead to obstruction/hydrocephalus.
CNS lymphoma can be primary (most common in im­
munocompromised patients, e.g., AIDS) or secondary
(metastasis from another site of lymphoma). All of
these tumors develop more commonly in the cerebral
hemispheres though they can occur elsewhere in the
brain. Medulloblastoma is a childhood tumor that, in
contrast, is most common in the cerebellum.

Cerebrospinal Fluid (CSF) Examination

Examining the CSF by lumbar puncture (spinal tap) is
key in the diagnosis of suspected meningitis/encephalitis.
In any infection, WBC count and protein will be ele­
vated. In bacterial meningitis, there will be a pre­
dominance of polymorphonuclear cells (PMNs), while
mononuclear cells typically predominate in fungal
and viral meningitis and encephalitis. Gram stain can
be used to identify bacterial pathogens and PCR can
be used to identify viral ones. Tuberculosis and bacte­
ria also cause a decrease in CSF glucose to less than
2/3 the amount of serum glucose.

Treatment of all CNS tumors is by some combina­
tion of surgery, radiation, and/or chemotherapy.

Stroke
Occlusion of cerebral vasculature from plaque forma­
tion, emboli, or thrombosis can lead to acute cerebral
ischemia (stroke). Ischemia can be caused by:

Blood in the CSF can indicate intracranial bleeding
(e.g., subarachnoid hemorrhage). How can this be dis­
tinguished from blood simply from the trauma of the
tap? In a lumbar puncture, multiple tubes of CSF are
taken. If the tap is traumatic, the amount of blood in
the CSF samples will decrease with each successive
tube. If there is intracranial bleeding, the amount of
blood in each tube will be relatively constant. Addi­
tionally, blood that has been in the CSF for more time
(6- 12 hours) will be broken down, giving the CSF a yel­
lowish color (xanthochromia). Blood arising from the
trauma of the tap will not have time to break down,
and thus will not produce xanthochromia.

Emboli that lodge in the cerebral vasculature (e.g.,
from a fibrillating atrium, vegetations on an in­
fected valve, or from a hypercoagulable state)

Atherosclerotic plaque, which can occlude the
carotid arteries, the vertebro-basilar system, or
their branches in the brain

Venous occlusion (e.g., secondary to thrombosis)

Arterial dissection in the carotid or vertebro­
basilar system following trauma or chiropractic
manipulation

Central Nervous System Tumors
Tumors of the brain or meninges can cause headache,
seizure, nausea/vomiting, focal neurological deficits,
mental status changes, and/or elevated ICP (and
its associated symptoms/signs). Spinal cord tumors
can cause symptoms of nerve compression, Brown­
Sequard syndrome (Fig. 7-4), or syrinx (discussed
below in the Spinal Cord section). Primary tumors or
metastases from other sites can cause any of these
signs/symptoms.

Severe hypotension, which can be caused by cardiac
dysfunction (e.g., arrhythmia, cardiac arrest, post­
surgery) and severe hypovolemia. This can lead to
infarction of cerebral areas at the boundaries of the
major vascular territories (watershed infarcts).

A transient ischemic attack (TIA) is a harbinger of
stroke to come. Critical narrowing of the carotid or
vertebrobasilar system or small pieces of plaque that
embolize can cause stroke-like symptoms that only
last for a few seconds, minutes, or hours. Amaurosis
fugax is one classic TIA symptom: transient ischemia
in the ophthalmic artery (a branch of the internal
carotid) causes temporary blindness. Patients often
describe this as appearing "like a curtain coming
down." (Patients may also describe retinal detachment
in a similar way.)

Meningiomas are typically benign tumors that can oc­
cur on any portion of the meninges, thus causing practi­
cally any neurological symptom or sign depending on the
brain region(s) or cranial nerve(s) that are impinged
upon by the tumor. Surgical removal is standard treat­
ment, though radiation is used if the tumor is inoperable.

Treatment of an acute event (e.g., with thromboly­
sis) and prevention (e.g., lowering blood pressure,
quitting smoking, decreasing cholesterol, taking as­
pirin to inhibit platelets) are similar to such measures
in myocardial ischemia/infarction.

Acoustic neuroma I vestibular schwannoma is a be­
nign tumor of cranial nerve VIII (vestibulocochlear)
that can cause unilateral hearing loss, vertigo, and/or

155

CHAPTER 7. THE NERVOUS SYSTEM

teries), which supply the lateral portions of the pons

Cerebral Vasculature

and the anterior cerebellum. The basilar artery also
gives rise to the superior cerebellar arteries (which
supply the brainstem and cerebellum) before splitting
into the posterior cerebral arteries (which supply the
occipital lobes). Posterior communicating arteries link
the anterior and posterior circulation, creating what is
known as the Circle of Willis.

Fig. 7 - 1 8 . Cerebral Circulation.

Anterior Circulation. The common carotid arteries
branch to form the external and internal carotid arter­
ies. The internal carotids give rise to the middle and
anterior cerebral arteries. The middle cerebral arteries
supply much of the lateral surfaces of the hemispheres
while the anterior cerebrals supply much of the me­
dial surfaces.

Based on the neurological symptoms/signs during
the stroke, one can determine the part of the brain and
vascular supply that are affected.

Posterior Circulation. The vertebral arteries arise
from the subclavian arteries. The vertebral arteries
feed the medial medulla and give off the posterior in­
ferior cerebellar arteries (PICAs), which supply the lat­
eral brainstem and inferior cerebellum. The vertebral
arteries then fuse over the medulla to form the basi­
lar artery. The basilar artery feeds the medial pons
and gives off the AICAs (anterior inferior cerebellar ar-

Fig. 7-19. Homunculus and vascular territories of ACA

and MCA. Imagine the homunculus as sunbathing on
the brain, legs dangling between the hemispheres,
leaning back over the external surface. Based on the
vascular anatomy, a stroke of the middle cerebral ar­
tery will affect the face, as well as the arm, and to a

Ant. Comm. a.
Middle
Cerebral a.

(
{

7

Posterior
Cerebral a.

Int. Carotid a.

.

. . l /.A Middle
�v
. Cerebral a.

\.OQ.
, , ....�

Post. Comm a.

Sup.
cerebellar a.
:.:.-.-,;:--..._
... _

Ant. inferior
cerebel lar a.
PICA

CIRCLE OF
WILLIS
CC
EC

=
=

Common carotid a.
External carotid a.

Aorta

CEREBRAL CIRCULATION
Figure 7-18.

Modified from Goldberg: Clinical Neuroanatomy Made Ridiculously Simple, MedMaster

156

2005

The left hemisphere houses the areas responsible for language production (Broca's area) and comprehension (Wernicke's area). all on the contralateral side). THE NERVOUS SYSTEM Broca1S area LOBES OF THE BRAIN Vertebral A. A more proximal occlusion of the mid­ dle cerebral artery can lead to combined aphasia: loss of both language production and comprehension.CHAPTER 7. Broca's area receives its blood sup­ ply from the anterior branch of the middle cerebral ar­ tery. a lack of motivation due to ischemia/infarction of part of the frontal lobe. 7 -7). Anterior cerebral artery strokes can also lead to abulia. the leg (all on the contralateral side since we are far above the decussation in the medulla). Modified from Goldberg: Clinical Neuroanatomy Made Ridiculously Simple. Lacunar infarcts involve the small penetrating branches that feed deeper brain structures. What visual defect would you expect from damage to one occipital lobe? Homonymous hemianopsia on the con­ tralateral side (Fig. leading to flowing yet senseless speech and inability to follow commands. namely the occipital lobe. but patients will still be able to understand spoken and written language. For example. Thus. Broca's aphasia is an expressive aphasia: there is diffi­ culty producing spoken and written language. Wernicke's aphasia is a receptive aphasia: difficulty understanding language (both spoken and written). a problem producing the mouth/tongue movements necessary for speech. MIDLINE VIEW LATERAL V I EW CROSS SECTIONAL V I EW THE HOMUNCULUS PCA CEREBRAL CIRCULATION THE HOMUNCUL US AND VASCULAR TERRITORIES OF A CA AND MCA Figure 7-19. whereas Wernicke's area receives its blood supply from the posterior branch of the middle cerebral artery. Note that certain lesions at any variety of locations may cause dysarthria. 2005 branch of the middle cerebral artery (which can cause Broca's aphasia) or the posterior branch (which can cause Wernicke's aphasia) by the patient's pattern of language deficits. These strokes can cause isolated motor or isolated sensory deficits. a middle cere­ bral stroke can be further localized to the anterior The posterior cerebral artery supplies the posterior part of the brain. a stroke of the anterior cerebral artery will cause sensory and motor dysfunction that is greater in the leg than in the arm (again. but pre­ served comprehension. MedMaster lesser extent. speech will be affected. and thus preserved ability to follow commands. Al­ ternatively. pure motor deficits can occur from lacunar infarct of the motor fibers of the internal capsule 157 . In such lesions.

which travel in peripheral nerves. the peripheral nervous system is unaffected. infection. Fig. spinal cord tract lesions can cause pain/temperature/vibration sense loss and/or motor dysfunction.4). Just as upper motor neuron lesions of skeletal muscles cause spasticity. The term "multiple" in the name refers to the characteristic multiple lesions in multiple sites in the CNS. The patho­ physiology is not yet fully elucidated but is postulated to involve autoimmunity. which evolves in a series of nor­ mal periods punctuated by flares. the "insulation" gets damaged in the central nervous system (brain and spinal cord). etc. dysdiadochokinesia. vertebral. but the most common is the relaps­ ing-remitting course. and the poste­ rior cerebral arteries. Thus. and though the afferent pathway for the pupillary reflex travels in CN II to the brainstem. Midbrain stroke (posterior cerebral artery ischemia) can cause: • Ipsilateral cranial nerve III palsy (the affected eye appears down and out. it is upper motor neurons that are affected in multiple sclerosis. Different patterns of clinical findings depend on which vascular territory is affected. In multiple scle­ rosis.3. the superior cerebellar arteries. cranial nerve I does not project to the brain­ stem. The bladder also has upper motor neurons (in the spinal cord) and lower motor neurons arising from sacral levels 2-4 (S 2. and/or a combination of these factors. The medulla is supplied by the vertebral arteries and the posterior inferior cerebellar arteries. and/or basilar ar­ • Deficit of CN XII (ipsilateral tongue weakness­ tongue deviates toward side of lesion) Multiple Sclerosis bellar artery ischemia) can cause any or all of the fol­ lowing: Ipsilateral CN V deficit (facial numbness) • effect on the cerebellum Pontine stroke (basilar and/or anterior inferior cere­ • Deficits of CN IX and CN X (dysarthria/dysphagia and/or deviation of uvula away from the lesioned side) sympathetic fibers. which can arise at multi­ ple points in time. with a fixed and dilated pupil) • Contralateral hemiplegia (body/limb weakness) from effect on the corticospinal tract (Remember. 158 . and medulla = cra­ nial nerve nuclei 9-12. Babinski's sign. cerebellar lesions can lead to ataxia. vomiting) Ipsilateral Horner's syndrome (loss of descending • Contralateral hemiplegia (body/limb weakness) from effect on the corticospinal tract • Contralateral sensory changes in the body/limbs from effect on the medial lemniscus and spinothal­ amic tract • Ipsilateral ataxia and dysdiadochokinesia from The loss of myelin in the CNS leads to a slowing of nerve conduction. • Any CNS deficit can occur in multiple sclerosis. Recall that brainstem lesions are the only le­ sions that can cause crossed signs: symptoms/signs in­ volving the face ipsilateral to the lesion and the body contralateral to it. THE NERVOUS SYSTEM or the corticospinal tract in the brainstem. 7-6). etc. What type of mo­ tor deficits would you expect.. anhidrosis) The midbrain is supplied by the top of the basilar artery. Keep in mind the main basic principle of brainstem anatomy: midbrain = cranial nerve nuclei 1-4.CHAPTER 7. the visual pathway of CN II does not. tery ischemia) can cause any or all of the following: Deficit of the lower portion of ipsilateral CN V (ip­ silateral loss of facial sensation) • If one thinks of nerve axons as electrical wire. pons = cranial nerve nuclei 5-8. A pure sen­ sory deficit can occur from infarct of the thalamus. Strokes of the brainstem are more complicated since there is a lot of anatomy/function packed into a tiny space. leading to ipsilateral ptosis. brainstem lesions can cause dysfunction of any cranial nerve.) • Ipsilateral CN VI deficit (loss of eye abduction) • Ipsilateral CN VII deficit (facial weakness) • Contralateral hemiplegia (body/limb weakness) from effect on the corticospinal tract • Deficit of the vestibular portion of CN VIII (vertigo. Multiple sclerosis has various types of clinical courses. Medullary stroke (PICA. despite the 1-4 mnemonic for the mid­ brain. which can present as urinary frequency and urgency. miosis. Symptoms vary depending on the site of the lesion: subcortical white matter lesions can result in cognitive dysfunction. increased reflexes. it is myelin that provides their insulation. The pons is supplied by the middle of the basilar ar­ tery and anterior inferior cerebellar arteries. upper motor neuron lesions of the bladder cause spasticity of the bladder. upper or lower motor neu­ ron-type lesions? Multiple sclerosis is limited to the central nervous system. (Also review the exceptions. genetics. which can cause spastic­ ity.

The spinal cord. there is bilateral loss of pain/temperature sensation in one ring around the body at that level with normal function above and below (suspended sensory level). In syringomyelia. The people falling towards the center are falling with their arms out in front of them. Where is the demyelinating lesion in this case? For INO. See Fig. 7-20. with feet toward the center. leg fibers me­ dial). the nerves to and from the head are not carried in the spinal cord. This makes its management complex. along a "zebra stripe" of a dermatomal diagram (radiculopathy). VHermitte's sign is when electrical sensations run down the spine when the patient bends his/her head forward. but in cranial nerves. The people relaxing on top Notice in Fig. 7 -3). falling perilously toward its center. the white matter runs on the outside and the gray matter is on the inside. The people falling perilously toward the center represent the corticospinal and spinothalamic tracts (arm fibers medial. determined by many factors in each individual case.CHAPTER 7. Glatiramer acetate is a mixture of small peptides related to proteins in myelin. Let's take the example of a syrinx to review the anatomical layout. Treatment for multiple sclerosis is immunomodula­ tory. the lesion must be in the MLF ipsi­ lateral to the eye that cannot adduct when the other eye abducts (though it should still adduct on convergence). since the bulging presses first against the more centrally located fibers of these tracts.. Some classic multiple sclerosis signs: Uthoffs phe­ nomenon is a worsening of symptoms in the heat (clas­ sically weakness or sensory changes after a hot bath or vigorous exercise). Expansion of the syrinx can affect the lateral corticospinal and spinothalamic tracts in a cervical to sacral progression. Multiple sclerosis is also a com­ mon underlying cause of internuclear ophthalmoplegia (INO) (Fig. i. leg fibers lateral). Note that al­ though this mnemonic puts heads on the figures. including interferon and/or glatiramer acetate (Copaxone). Mnemonic: Imagine two people lying comfortably on top of the cord. and treatments have various side effects. Also imagine people lying on either side of the cord. Within the tracts of the spinal cord. Multiple sclerosis can present in a wide variety of severities and courses. DISEASES OF THE SPINAL CORD Fig. 7-20 that the dorsal/posterior (sensory) fibers enter and ventral/anterior (motor) fibers exit via roots that join to form peripheral nerves. The people relaxing on the top represent the posterior columns (arm fibers lateral. Since only the crossing fibers are affected. Periphera l nerve Anterior root ( motor) THE SPINAL CORD Figure 7-20 159 . Discs that prolapse and impinge on either a sensory or motor root can thus cause isolated sensory or motor symp­ toms in a dermatomal distribution.e. The spinal cord's organiza­ NERVE ROOT COMPRESSION tion is "inside out" compared with the brain: in the spinal cord. the central canal expands. Glatiramer ac­ etate's mechanism of action is thought to occur by modifying the immune processes involved in the patho­ genesis of multiple sclerosis. An expanding syrinx causes sensory and motor deficits below it (since sensory and motor fibers entering and exiting above the syrinx will be unaffected). 7-5 for review of dermatomes. THE NERVOUS SYSTEM are oriented in the opposite way. the fibers from different regions of the body are aligned in a specific way (lamination). 7-1 1). The first fibers to be affected are the pain/temperature fibers crossing to become the spino­ thalamic tract (Fig.

g. CS/6 Biceps I B rachioradialis C7/8 Triceps Fig. or the involve­ ment of a large area that is not restricted to a single dermatome in cortical or brainstem lesions. those that affect the peripheral nerves. patellar uses L3-4 (quadriceps).) can also occur. motor findings are localizable to the spe­ cific spinal root. (By the way. and 4 control bowel.. NEUROMUSCULAR JUNCTION.g. Commonly tested reflexes. Weakness alone with no sensory changes implies a problem specifically affecting motor pathways (e. bladder. knees and say 3-4. THE NERVOUS SYSTEM Nerve roots can be compressed by prolapsed/herni­ ated disc(s). sensory findings tend to occur only in the dermatome of the affected root.CHAPTER 7. The sensory fibers bring back infor­ mation about light touch. what other signs/symptoms can help localize the site of the lesion? If the weakness involves damage to lower motor neurons (i. or peripheral nerve). stroke). 3.. joints. or with a spinal cord lesion affecting both mo­ tor and sensory pathways (e. etc. sympathetic fibers to the vari­ ous organs. so the L4 disc hits the L5 root.. palmar surface of arm and say 5-6. nerve root. decreased/absent reflexes. this indicates a spinal cord lesion (Fig. 7-2 1 . and erectile function. and triceps is innervated by C7-8. temperature. A prolapsed disc usually affects the root below it. These roots join with the posterior (or dorsal) roots (sensory fibers) to form the peripheral nerves. The ankle re­ flex uses S l-2 (gastrocnemius). etc. tumor(s). such as fasciculations. those that affect the NMJ.. and muscle atrophy. we would expect other lower motor neuron signs. If lesions affecting any component of the motor system will lead to weakness. g. a specifically affected area in mononeuropathy (e. there are visceral motor fibers to sweat glands.) Motor neuron axons traveling in peripheral nerves eventually synapse with muscle cells at the neuromuscular junction (NMJ). contralateral middle cerebral artery stroke). or spinal stenosis. a "stocking/glove" pattern of sensory deficits in peripheral polyneuropa­ thy.. but it is much less common. transverse myelitis in multiple sclerosis). the cerebral hemispheres (e. Thus. Lateral herniation (L4 disc to L4 root. Mnemonic: Touch your ankles and say 1-2. and those that affect the muscles themselves. the brainstem (e. If there is loss of motor function and light touch/proprioception on one side and pain/temperature sensation loss on the opposite side. etc. Peripheral neuropathy typically leads to distal muscle weakness. where do the parasym­ pathetic neurons come from? The vagus nerve and sacral spinal cord. the L5 disc hits the S l root.g. These are grouped together because their 160 .. numbness.g. while my­ opathy typically leads to proximal muscle weakness. The axons of anterior horn cells (lower motor neurons) exit the spinal cord anteriorly (ventrally) as the anterior (or ventral) roots. biceps/brachioradialis is innervated by C5-6. Only excitation is possible at the NMJ. the periph­ eral nerves generally carry both motor fibers traveling to the muscles and sensory fibers from the skin. palmar surface of the hand and the first two fin­ gers in median nerve compression). and muscles. L5 disc to L5 root. pain. so compression at this level can lead to incon­ tinence and impotence. Figure 7-21 DISEASES OF LOWER MOTOR NEURONS. What if there were weakness and also sensory changes (loss of feeling. pain/temperature sensation loss)? Weakness and sensory changes to­ gether can only occur with lesions of peripheral nerve(s). In nerve root compression.e. AND MUSCLE clinical presentations often share a common feature: weakness. anterior horn cell. Review figure 7-20. 7-4). and pro­ prioception. and the neurotrans­ mitter is acetylcholine. In nerve root compression. This is in con­ trast to distributions of symptoms such as the com­ plete loss of sensation that occurs below a certain point in spinal cord compression. pure motor There are diseases that affect the anterior horn cells. S1/2 Ankle reflex Plantar flexion COMMONLY TES TED REFLEXES S 2. Additionally. elbow (dorsal surface) and say 7-8 .

or ischemia/infarct. While many cases are idiopathic. Peripheral neuropathy (multiple distal portions of nerves af­ fected. Pe­ ripheral neuropathy can be caused by damage to either the axons themselves or the myelin (Guillain­ Barre is an example of a demyelinating peripheral neuropathy). This leads to a mixture of both upper and lower motor neuron findings: weakness. the other decreases the amplitude of nerve conduction. Which do you think is which? Myelin insu­ lates the axon so as to allow for faster nerve conduc­ tion. loss of pain/temperature sensation. paraneoplastic syndromes. an enzyme that cleaves acetylcholine into its component parts for reuptake by the presynap­ tic neuron.. or both. systemic dis­ eases (e. Mononeuropathy multi­ plex (multiple individual mononeuropathies) indicates a systemic underlying pathology such as diabetes. Diseases of Anterior Horn Cells The juvenile spinal muscular atrophy syndromes affect the anterior hom cells. So myelin loss decreases velocity of nerve conduction. So blocking acetylcholinesterase decreases acetylcholine breakdown. the median nerve in carpal tunnel).. lead. and its clinical hallmark is that mus­ cles are more likely to fatigue. but the symp­ toms are what you would expect from a disease process that exclusively affects the anterior horn cells: weak­ ness/flaccid paralysis.g. motor deficits.. sensory func­ tion will be normal. increasing the amount of acetylcholine in the synapse that can compete with Peripheral neuropathy can cause sensory deficits. The diagnosis of myasthenia gravis can be confirmed by detecting the acetylcholine receptor antibody in the blood or by EMG (electromyelography) study. and/or tingling. trouble swallowing (dysphagia). one would not expect sensory deficits (as can be present in pe­ ripheral neuropathy) or pain (as can be present in in­ flammatory muscle disease). This is accomplished by acetyl­ cholinesterase.. AIDS. the neuromus­ cular junction. Poliomyelitis can also se­ lectively affect the anterior horn cells. This EMG finding confirms what is seen clinically: sus­ tained firing that leads to fatigue. Since we do not want our muscles to stay contracted perma­ nently. some decreased. toxins (e.g. which demon­ strates fatigue during repetitive stimulation.g. autoantibodies are produced against the acetylcholine receptors on muscle cells at the neuromuscular junction. Axonal damage decreases the amplitude of nerve conduction. The sensory deficits in peripheral neuropathy can include loss of light touch. Myasthenia pro­ duces weakness. e. spastic paralysis.. fasciculations. or are there multiple sites of pathology? A mononeuropa­ thy (problem limited to one nerve) could indicate entrapment (e. chemotherapy agents. Diseases of the Neuromuscular Junction Amyotrophic lateral sclerosis (ALS) affects the ante­ rior hom cells and the corticospinal tract. which can manifest as ptosis (drooping eyelids) and quick fatigue of eyelids during prolonged upward gaze (ptosis time). autoimmune diseases (e. amyotrophic lateral sclerosis). leprosy). and/or trouble speaking (dysarthria). some increased reflexes. myasthenia can also occur secondary to a thymoma (a tumor of the thymus). 161 . de­ creased or absent reflexes.CHAPTER 7. infection.g. The details of classifica­ tion are beyond the scope of this text.g.. Myasthenia gravis must be distinguished from weakness caused by disease of peripheral nerve or dis­ ease of the muscle. lead). or the actual muscle(s). muscle atrophy. The motor deficits in peripheral neuropathy are of the lower mo­ tor neuron variety: flaccid paralysis/weakness. alcohol). genetic diseases (e. In myasthenia gravis. vasculitis.g. Guillain­ Barre). diabetes. decreased/absent reflexes. At the neuromuscular junction the motor neurons release the neurotransmitter acetycholine. polyarteritis nodosa). Myasthenia Gravis In myasthenia gravis.. Relatively rapid fatigue can also be demonstrated by the patient's inability to maintain arm abduction for more than a brief period. Is only one nerve involved. One type of disease process slows nerve conduction. stroke. loss of propriocep­ tion. These antibodies block the receptor so that acetylcholine cannot bind and stimulate muscular contraction. THE NERVOUS SYSTEM The extent of deficits is useful in classifying periph­ eral neuropathies.g. and/or symptoms such as neuropathic pain.g. The muscles of the face are often profoundly affected. which stim­ ulates post-synaptic receptors on the muscle cells. Nerve conduction studies can help dis­ tinguish between axonal and demyelinating causes of neuropathy. . hereditary motor and sensory neuropathies such as Charcot-Marie-Tooth syndrome). diabetes. there must be a mechanism for getting rid of that acetylcholine. drug toxicity). trauma. and metabolic deficiencies (B 1 2 deficiency).g. or toxicity (e. depending on whether the pathology is specific for a given fiber type. Diseases of Peripheral Nerves Many types of pathology can cause peripheral neu­ ropathies: infection (e. "stocking/glove" distribution) also typically results from systemic pathology (e. numbness. In disease processes that affect anterior horn cells without affecting the peripheral nerves.

g. facioscapulohumeral dystrophy). a compet­ itive inhibitor for binding sites on acetylcholinesterase. repeti­ tive stimulation (clinically or by EMG) actually pro­ duces transient improvement. Lambert-Eaton syn­ drome. though it can also arise with other cancers. The pathophysiology is slightly different from myasthenia gravis: autoantibodies form against the pre-synaptic calcium channels. Metabolic myopathies include mitochondrial myopathies and glycogen storage diseases. Muscle problems also tend to present with proximal weakness as opposed to the distal weakness typically noted in neuropathies.g. Lam­ bert-Eaton syndrome is most commonly seen with small cell lung cancer.. Thus immunosuppression is used if myasthenia gravis is severe. and the metabolic myopathies. This too would present as weakness but should not have sensory changes or changes in reflexes. This fact can be used for diagnosis (Tensilon test) and treatment (pyri­ dostigmine) of myasthenia gravis. any patient with muscle weakness might feel slightly better from increased stimulation of their muscles by acetylcholine. The dystrophies are genetic diseases with specific patterns of involvement (e. Tensilon acts quite quickly. fected to a lesser extent than in myasthenia. Diseases of the Muscle Weakness can also be due to a problem with the mus­ cles themselves. which blocks acetylcholinesterase. One treatment for myasthenia is pyridostigmine. inflammatory myopathies.CHAPTER 7. can occur as a paraneoplastic syndrome. In Lam­ bert-Eaton syndrome. removal of the thymus can lead to improvement of symptoms.or hy­ pothyroidism). it does not correct the underlying cause of the weakness: the immune system's production of autoantibodies. hyper. Inflammatory dis­ eases include dermatomyositis and polymyositis (see Fig. since there is usually some underlying systemic process affecting the muscles. leading to decreased synaptic activity at the NMJ. Although pyri­ dostigmine can improve symptoms of weakness. this is the exact opposite effect of what occurs in myasthenia gravis. dramatic improvement following the Tensilon test gen­ erally indicates myasthenia gravis. this re­ sults in weakness.. myotonic dystrophy. which thus increases the life of acetylcholine in the synapse. so a patient with myasthenia gravis will feel a fast (but temporary) im­ provement of weakness. independent of a perfectly function­ ing nervous system. Duchenne's muscular dystrophy. Inflammatory diseases of the muscles typically cause muscle pain and tenderness. Lambert-Eaton Syndrome A myasthenia-like syndrome. Tensilon is the trade name of edrophonium. THE NERVOUS SYSTEM antibodies for postsynaptic binding. 8-1). Additionally. As in myasthenia. This Tensilon test is not a sure­ fire proof of myasthenia gravis. as well as steroid-induced myopathy and myopathies from un­ derlying endocrine dysfunction (e. However. Diseases of the muscle can essentially be divided into the dystrophies. though muscles of the face are af- 162 . muscular problems (unless they are from injury) tend to be fairly symmet­ rical. because the problem is failure of calcium influx to trigger acetylcholine release. In some cases. Muscle pain and tenderness can help to distinguish myopathy from neuropathy or myasthenia as causes of weakness.

CHAPTERB. RHEUMATOLOGY

CHAPTERS. RHEUMATOLOGY
Rheumatology deals with diseases involving joints,
autoimmunity, or both. In autoimmune diseases, the
normal self-tolerance of the immune system breaks
down, and the immune system attacks the body. Infec­
tious triggers and genetics may play a role in suscep­
tibility to autoimmunity, but the pathophysiology of
these diseases has not yet been fully elucidated.

Autoimmune diseases are a diverse group. Some au­
toimmune diseases affect only individual organs (e.g.,
diabetes type I affects the pancreas; primary biliary
cirrhosis affects the bile ducts; Hashimoto's thyroidi­
tis affects the thyroid), and some can affect nearly all
organ systems. Many autoimmune diseases have
serum auto-antibodies associated with them, though
such autoantibodies are neither 100% specific nor
100% sensitive for the diseases. In some autoimmune
diseases, it is uncertain whether these autoantibodies
are part of the cause of the disease or a result of the
underlying disease process.

Inhibiting cytokine synthesis (e.g., NSAIDs, COX-2
inhibitors)
Blocking cytokines, preventing them from acting
(e.g., anti-TNF antibodies, soluble TNF receptors)

In joint disease, first-line anti-inflammatory ther­
apy often involves NSAIDs (non-steroidal anti-inflam­
matory drugs), which block cytokine synthesis
(specifically prostaglandins). Older NSAIDs (e . g.,
ibuprofen, naproxen) inhibit both COX (cyclooxyge­
nase)-1 and COX-2 enzymes. Though blocking COX-2
leads to the desired anti-inflammatory effect, one side
effect of COX-1 inhibition is decreased prostaglandin
synthesis in the gut, which can predispose to ulcer.
COX-2 inhibitors (drugs whose names end in "-cox­
cib") selectively block the COX-2 enzyme, thus inhibit­
ing inflammation with fewer gastrointestinal side
effects. Soluble TNF (tumor necrosis factor) receptors
and anti-TNF antibodies block TNF, an inflammatory
cytokine.

Fig. 8-1. Features of selected rheumatologic diseases.
The primary features of several diseases and their as­
sociated autoantibodies are listed in this table. In ad­
dition to the features characteristic of any given
autoimmune disease, constitutional symptoms (fever,
malaise) are often present as a result of the inflamma­
tory process. Also, inflammatory markers such as ESR
(erythrocyte sedimentation rate) and CRP (C-reactive
protein) may be elevated in the serum in any of these
diseases.

JOINT DISEASE: ARTHRITIS

TREATMENT OF
AUTOIMMUNE DISEASES

Arthritis is inflammation of a joint or several joints,
and can be caused by infection, autoimmune disease,
or joint trauma. Symptoms can include joint pain,
stiffness, warmth, and/or swelling.

Since the underlying cause of the loss of self-tolerance
and/or over-activity of the immune system is not fully
understood, treatment is directed against the inflam­
matory response itself, which can be blocked at vari­
ous levels. Of course, due to the inhibition of the
immune system that some of these drugs produce,
bone marrow suppression and subsequent immuno­
suppression can result, predisposing to infection.

Causes of arthritis are classified as inflammatory
(e.g., rheumatoid arthritis, spondyloarthritis, infec­
tion, crystal-induced) or non-inflammatory (e.g., osteo­
arthritis, trauma, hemarthrosis). Any type of arthritis
can cause pain, limitation of motion, swelling, and/or
tenderness of the joint. Inflammatory causes will also
tend to have systemic features (constitutional sys­
tems or effects on other organ systems), aggravation
with rest (e.g., prolonged morning stiffness), relief
with use, and warmth and redness of joints. Non­
inflammatory arthritis tends to be aggravated by mo­
tion and relieved by rest. Arthritis can affect a single
joint (monoarticular), several (2-4) joints (oligo­
articular) or many joints (polyarticular). Any cause of
polyarticular arthritis can also present first in a
single joint.

Immunosuppressive and
Anti-Inflammatory Drugs
Drugs inhibit the immune system at various levels by:

Preventing the secretion of inflammatory cytokines.
Cyclosporine specifically inhibits T-lymphocytes,
preventing them from secreting interleukins. Cor­
ticosteroids, among the most commonly used im­
munosuppressive agents, alter gene expression,
leading to a decrease in the inflammatory response.
Corticosteroid treatment can cause Cushing's syn­
drome (See Fig. 5-4).

Causing death of inflammatory cells (cytotoxic
agents). Methotrexate, cyclophosphamide, azathio­
prine, leflunomide, and mycophenolic acid alter
DNA synthesis, causing death of rapidly dividing
cells, among them lymphocytes involved in the in­
flammatory response.

163

CHAPTERS. RHEUMATOLOGY

Figure 8-1 Features of Selected Rheumatologic Diseases
SEROLOGICAL
MARKERS

TREATMENT

Gl ulceration, CNS lesions,
glomerulonephropathy,
peripheral neuropathy,
arthritis, vasculitis, skin
lesions

(none)

Steroids

Proximal muscle weakness,
often painless, though myalgia
sometimes occurs.
Dermatologic manifestations:
heliotrope rash (around eyes),
"mechanic's hands"
(hyperkeratosis of hands),
Gottron's papules over joints

Interstitial fibrosis of lungs,
cardiomyopathy, arthritis,
dysphagia, increased risk
of malignancy

Anti-Jo-1, anti-Mi-2,
elevated creatine
kinase (from muscle
breakdown);
diagnosis confirmed
by muscle biopsy

Steroids ± other
immunosuppressives

Polymyositis

Proximal muscle weakness,
often painless, though myalgia
sometimes occurs

Interstitial fibrosis of lungs,
cardiomyopathy, arthritis,
dysphagia

ANA, Anti-SAP, antiJo-1, elevated
creatine kinase (from
muscle breakdown);
diagnosis confirmed
by muscle biopsy

Steroids ± other
immunosuppressives

Sarcoid

Pulmonary (cough, dyspnea),
arthritis, lymphadenopathy

Any organ system can be
affected: e.g., CNS,
cardiac, renal

Elevated serum
ACE; granulomas on
biopsy

Steroids

Scleroderma

Thickened skin, Raynaud's
phenomenon (cold or stressinduced closure of peripheral
arteries leading to pallor and
cyanosis, e.g., in fingertips)

Pulmonary fibrosis,
esophageal dilatation and
GERD, myocardial fibrosis,
pericardia! effusion, renal
involvement; CREST
variant: calcinosis,
Raynaud's, esophageal
dysmotility, sclerodactyly,
telangectasia

Anti-Scl-70;
Anti-centromere
in CREST

Anti-inflammatories for
arthritis, ACE-I for renal
involvement/hypertension,
calcium channel blockers
for Raynaud's;
Penicillamine (mechanism
uncertain) in some cases

Sjogren's Syndrome

Dry eyes, dry mouth

Pulmonary fibrosis,
peripheral neuropathy,
increased risk of other
autoimmune diseases
(e.g., rheumatoid arthritis)
and B cell lymphoma,
parotid gland enlargement

Anti SS-A (Ro) and
Anti SS-B (La)

Symptomatic: eyedrops

Can affect ANY organ
system: arthritis, pleuritis,
pericarditis, seizures,
psychosis,
immunodeficiency,
thrombocytopenia,
nephrotic or nephritic
syndrome ...

ANA, anti-DNA, antiSM, anti-Ro, anti-La;
anti-histone in drug
induced lupus

Steroids, azathioprine,
cyclophosphamide,
methotrexate,
cyclosporine

DISEASE

CLASSIC FEATURES

ADDITIONAL FEATURES

Behc;:et's Disease

Oral and genital aphthous
ulcers, uveitis

Dermatomyositis

Malar rash (butterfly rash on
Systemic Lupus
Erythematosus (SLE) cheeks), photosensitivity, fever

ANA stands for anti-nuclear antibodies. Autoimmune diseases not on this table but discussed elsewhere in this book: rheumatoid arthritis
(Fig. 8-2); autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis (Chapter 4); and Hashimoto's thyroiditis and
Graves' disease (Chapter 5).

164

CHAPTERB. RHEUMATOLOGY
tends to occur with activity of the joint. Although
morning stiffness may occur, it is typically brief as op­
posed to the prolonged stiffness in rheumatoid arthri­
tis. Knee, hip, spine, and hand joints are the most
commonly affected in OA. PIP and DIP joints can both
be affected (vs. RA, which usually does not affect the
DIP, see Fig. 8-3). The MCP joints are typically unaf­
fected in osteoarthritis (vs. RA, which usually does af­
fect the MCP, see Fig. 8-3). Osteophytes (bone spurs)
can form, which can lead to spinal stenosis, nerve com­
pression, esophageal compression (if the osteophyte is
on the anterior spine and compresses the esophagus),
Heberden's nodes (DIP spurs), and/or Bouchard's
nodes (PIP spurs).

Synovial Fluid Analysis
In monoarticular arthritis, since the disease process is
specifically localized, synovial fluid analysis from the
involved joint is used for diagnosis. Synovial fluid
analysis can detect infectious agents, crystals, blood,
and WBCs. Crystals may indicate gout or pseudogout;
blood (hemarthrosis) could result from trauma, hemo­
philia, or anticoagulant treatment. Synovial fluid is
classified as noninflammatory, inflammatory, or septic
(infectious) based on the number of white blood cells
(WBCs). Non-inflammatory < 2000 WBCs; inflamma­
tory > 2000 WBCs; septic > 100, 000 WBCs.

Fig. 8-2. Arthritis. The features of the different types
of arthritis are summarized in this table.

Spondyloarthritis

Rheumatoid Arthritis (RA)

Spondyloarthritis is characterized by spinal arthritis
(which can cause back pain/stiffness), enthesopathy
(inflammation of insertions of tendons and ligaments
to bone, which can lead to dactylitis, also called
"sausage digits"), peripheral arthritis, extra-articular
features (including eye, skin, and GI pathology), no
rheumatoid factor (RF) in the serum, and a genetic as­
sociation with HLA-B27. The spondyloarthropathies
include anklyosing spondylitis, reactive (Reiter's)
arthritis, inflammatory bowel disease-associated
arthritis, and psoriatic arthritis. The features of these
diseases are listed in Fig. 8-2.

Rheumatoid arthritis is an autoimmune disease,
though the cause(s) of this disorder have not yet been
fully elucidated. In rheumatoid arthritis, inflamma­
tion of the synovium (the inner lining of the joint cap­
sule) and the resultant cascade of inflammatory
molecules lead to joint damage. Like many autoim­
mune diseases, RA is more common in women. Any
joint(s) can be affected, but symmetrical involvement
of the hands and/or feet is a common presentation.

Fig. 8-3. Joints of the hand. In the fingers, the MCP
(metacarpal phalangeal) and PIP (proximal interpha­
langeal)joints are often affected in rheumatoid arthri­
tis. The DIP (distal interphalangeal) joint is the only
joint in the hand not usually affected in RA (though it
is commonly affected in osteoarthritis).

Infectious Arthritis
Infectious arthritis can arise from hematogenous
spread from another site of infection, contiguous
spread (e.g., from osteomyelitis), trauma, or surgery.
Predisposing factors include diseased joints, prosthetic
joints, IV drug use, immune deficiency, and trauma.
Infection most commonly affects one single joint
(commonly the knee), and concurrent fever is usually
present in addition to the signs/symptoms of joint
inflammation. Diagnosis is made by synovial fluid
analysis (> 100, 000 WBCs). Because infectious arthri­
tis typically presents acutely, gout must be ruled
out due to its similar acute presentation. Common
pathogens include Gonorrhea, Staph. aureus and gram
negatives. Salmonella arthritis can occur in sickle cell
disease. More rarely, mycobacteria, a variety of viruses
(parvovirus B19, HIV, rubella, hepatitis), and fungi
(blastomycosis, candida, coccioidomycosis, cryptococco­
sis, histoplasmosis, sporotrichosis) can also cause
arthritis.

Although a short period of stiffness in the morning
and/or after any period of inactivity can occur in any
joint disease, prolonged morning stiffness (e.g., greater
than 30 minutes) is more typical of RA and other types
of inflammatory arthritis (i.e., not in osteoarthritis). As
with any autoimmune disease, constitutional symp­
toms can be present in rheumatoid arthritis (malaise,
weakness, fatigue). Any organ system can be affected
by the underlying inflammatory disease process in
RA, leading to any or all of the following: vasculitis,
anemia, lymphadenopathy, splenomegaly, pulmonary
nodules, pleural effusions, pericarditis, and/or scleritis.
Serum rheumatoid factor (RF) is present in the major­
ity of cases. Over the long term, joint inflammation/
destruction can lead to nodule formation and deformi­
ties in the joints.

Lyme disease is another infection that can cause
arthritis. The infectious organism, Borrelia burgdor­
feri, is typically transmitted by tick bite. The tick bite
often (but not always) causes a target- shaped rash
(erythema migrans). Symptoms can include fever,
malaise, lymphadenopathy, and arthritis. If untreated,
Lyme disease can progress to chronic arthritis,

Osteoarthritis (OA)
Osteoarthritis is the most common cause of arthritis
in adults. Aging, excess weight, joint trauma, and/or
genetic predisposition can lead to damage of articular
cartilage. Gradual onset of pain in one or severaljoints
is the primary feature of osteoarthritis. This pain

165

TREATMENT

Figure 8-2 Arthritis
DISEASE

EPIDEMIOLOGY

JOINTS INVOLVED

FEATURES OF
ARTHRmS

OTHER FEATURES

SERUM

SYNOVIAL
FLUID

Rheumatoid arthritis

More common in
women

Symmetrical; any joint, but
hands and feet common
(especially MCP and PIP
of hand)

Prolonged morning
stiffness; long term:
deformation of joints and
nodule formation

Constitutional symptoms;
vasculitis, anemia,
pulmonary nodules,
pericarditis, scleritis

RF

lnflam.

NSAIDS,
sulfasalazine, antimalarials, steroids,
methotrexate, TNF
alpha antagonists

Osteoarthritis

Most common in
older adults

Knee, hip, spine, hand
(DIP and PIP)

Gradual onset, pain with
activity, much shorter
period of morning
stiffness than RA

Osteophyte formation can
cause spinal stenosis,
esophageal compression

NON- inflam.

Weight loss,
physical therapy,
NSAIDS, COX 2
inhibitors, steroid
injections, surgery

Ankylosing
spondylitis

More common in
men, often emerges
in young adulthood

Spine, sacroiliac joint,
peripheral joints

Gradual onset of back
pain, stiffness

Peripheral enthesopathy,
dactylitis, conjunctivitis,
uveitis; spinal changes can
cause restrictive lung
disease; cardiac
involvement*

HLA-827

lnflam.

NSAIDS, TNF
alpha antagonists

Can be acute onset
(mimicking gout) or
more RA-Iike
presentation; arthritis
mutilans (bone
resorption) can occur

Psoriasis is a silver scale
that appears most
commonly on the elbows,
knees, and scalp; ocular
involvement; cardiac
involvement*

HLA-827

Psoriatic arthritis

Any age, men and
women equally
affected

Hands, wrists, ankles,
feet, DIP

......

g;

lnflam.

NSAIDS, steroids,
TNF alpha
antagonists



�!:J:j

!:J:j

Reactive arthritis
(Reiter's syndrome)

Several weeks after
GU or Gl infection

Feet/legs, hands/arms
most common

Inflamed joint(s) 2-4
weeks after infection

Skin/eye

HLA-827

lnflam.

NSAIDS, steroids,
antibiotics

I SO-associated
arthritis

Associated
w/Crohn's or
ulcerative colitis
(UC)

Spine, sacroiliac,
peripheral joints

Gradual onset of pain
and stiffness

UC, Crohn's and
associated features

HLA-827

lnflam.

Steroids,
sulfasalazine

Infectious arthritis

Predisposition: IV
drug use, trauma,
prosthetic joints,
immunocompromise

Commonly single joint
(knee), but multiple joints
possible

Acute onset of joint pain,
swelling, redness

Gout

More common in
men

Most common: big toe, but
other joints possible

Acute onset of joint pain,
swelling, redness

Pseudogout

More common in
men

Can have monoarticular
presentation (knee
common) or polyarticular
presentation

Acute (mimicking gout)
or indolent (mimicking
RA)

Hyperuricemia
may be present

Tophi in chronic gout

*Cardiac involvement (in psoriatic arthritis and ankylosing spondylitis) can include valvular disease, arrhythmia, and/or myocarditis.

Infectious,
organisms

Antibiotics

lnflam.,
monosodium
urate crystals

Acute: Antiinflammatories
(NSAIDS,
colchicine)
• Chronic:

lnflam.,
calcium
pyrophosphate crystals

NSAIDS,
colchicine


��

0
a

Obesity .g.etabolism) or from di�t (e. Gout and Pseudogout In these two diseases.g. e. and spasticity A classic acute gout attack is pain/warm.g. and heart block.Overconsumption of purines in meats and alco­ holic beverages (note: alcohol can also increase urate product�on) . Diagnosis is made by iden­ tification of antibodies to B.g.g. RHEUMATOLOGY l Affected inOA Affected in RA DIP = Distal interphalangeal joint PIP = Proxima.Increased cellular turnover. of first presentation are pos­ sible.. nucleic acid m. they are calcium pyrophosphate crystals. see Fig. 7 -11). Uric acid excess can occur if there is: 167 .ation caused by uric acid crys­ tals. diuretics) Overproduction of uric acid . meats). Both diseases are more com­ :ruon in men.. or drugs (e. self-mutilation. Tophi are clumps of uric acid crys­ tals in soft tissues that can be palpated on exam.g. Lesch-Nyan syn­ drome: an X-linked syndro:rue with severe :{IGPRT deficiency. Uric acid crystals only form in the setting of hy­ peruricemia (uric acid excess)..thlswelling in a single joint. men­ tal retarda. joint inflammation is caused by crystals that form in the synovial fluid. Uric acid is a norm. • • In all cases of infectious arthritis.HGPRT (hypoxanthine-guanine phosphoribosyltransferase) deficiency. antibiotic treat­ ment is directed against the offending organism. Gout is joint inflamm. most commonly the big toe (called podagra)..rgdorferi in the serum. e. kidney stones..! interphalangeal joint MCP = RA Rheumatoid arthritis = Metacarpal phalangeal joint OA = Osteoarthritis JOINTS OF THE HAND Figure 8-3 neurological disease (CN: VII lesion is common.CHAPTERS. Chronic hyperuricemia can lead to renal insufficiency. but other sites. renal failure. which may come from the body itself (e. Gout Decreased excretion of uric acid (e. alco­ hol. hematologic malignancy .. In gout. causing hyperuricemia. and the formation of tophi. these are uric acid crystals. diuretks). A gout attack can be provoked by trauma.tion.al breakdown product of purines. bu. in pseudogout.

colchicine. and steroids. Weight loss and decreased consumption of alcohol and purine-rich foods (meat. In addition. urate-lowering agents can be used. Synovial fluid will be inflam­ matory in gout (i. treatment involves anti-inflammatories such as NSAIDs and colchicine. hypothryoidism. allopuri­ nol. Treatment of an acute attack of gout is aimed at de­ creasing the inflammatory response.. Anti-in­ flammatories commonly used for acute gout attacks are NSAIDs.CHAPTERB. which inhibits xanthine oxidase. it will have > 2000 WBCs). RHEUMATOLOGY Diagnosis of gout is confirmed by seeing needle­ shaped monosodium urate (MSU) crystals in synovial fluid. pseudogout is not caused by elevated plasma level of a crystal-forming substance. Pseudogout can present acutely in onejoint like gout (though more commonly in the �ee.e. These agents func­ tion by decreasing uric acid production (e. Diagnosis: Synovial fluid demon­ strates inflammation (>2000 WBCs) and rhomboid­ shaped crystals that are weakly positively birefringent. 168 .g.. mearnng that on polarized light. but by increased accumulation of such sub­ stances in the synovial fluid. and/or hemochrom­ atosis. Pseudogout Pseudogout isjoint inflammation caused by calcium py­ rophosophate crystals. meaning that they are yellow when parallel to polarized light and blue when perpendicular to this light (the opposite is true of calcium pyrophosphate crystals in pseudogout). an enzyme at a late step in purine metabolism) or decreasing renal uric acid reabsorption (e. as opposed to the big toe in gout).g. alcohol) are important components of long-term prevention of gout attacks. Unlike gout. Uric acid crystals are strongly negatively bire­ fringent. but these are debated. probenecid). mimicking rheumatoid arthritis. while the goal of chronic therapy is to lower serum uric acid. As with gout. they are blue when parallel and yellow when perpendicular (note all oppo­ sites of MSU crystals). The cause of this accumu­ lation is unknown but is thought to be secondary to production of calcium pyrophosphate in the joint by chondrocytes.. There may be an association with hyper­ parathyroidism. . or it can sometimes have a more indolent onset.

CHAPTER 9. and/or pain in the low back. and thus the patient may be asymptomatic. chills. or during urologic procedures. Some suspect difficult-to-culture organisms as causes. Hormonal therapy seeks to remove hormonal stimulation (mainly testosterone stimulation) of the prostate. Testicles During development.. malaise). Enlargement can compress the urethra. Chlamydia. and nocturia (increased urination at night). urgency. hesitancy. Their function is to produce sperm and seminal fluid. leading to retention of urine. anti-androgen therapy (blocking testosterone)..prazosin. with a high incidence in older men. Antibiotics are used for treatment. These bacteria can enter the prostate via the urethra. urgency (sudden need to urinate). Alpha blockade (e.g. Screening via digital rectal exam (DRE) and serum prostate-specific antigen (PSA) are therefore extremely important in men over 50. In immunocom­ promised patients. and Chla­ mydia trachomatis. orchitis can be caused by fungi and mycobacteria. easing urinary flow through the urethra. and/or on ejaculation. including WBCs on uri­ nalysis.or fungi. Prostate The prostate gland surrounds the urethra and se­ cretes some of the seminal fluid. MALE AND FEMALE REPRODUCTIVE SYSTEMS MALE REPRODUCTIVE ORGAN PATHOPHYSIOLOGY terone formation. and constitutional symptoms (e. e. decreasing testosterone stimulation of prostate growth. The in­ flamed prostate is tender and soft ("boggy") on exam. radiation.. "tangled" (torsion). chemotherapy. frequency (frequent need to urinate). and back pain resulting from spine metastases can be a presenting symptom. urinary frequency. and they can develop testicular cancer. pelvis. Treatment can include sur­ gery. NSAIDs and sitz baths (sitting in warm water) can be used to relieve pain.). other urinary symptoms (frequency. Infection (prostatitis) or enlargement (benign prostatic hyper­ trophy) of the prostate can cause any or all of these symptoms Prostate Cancer Prostate cancer is one of the most common cancers in men.g. MALE AND FEMALE REPRODUCTNE SYSTEMS CHAPTER 9. Bone metastases are common. leading to a variety of urinary symptoms.Mycobacteria. Gonorrhea and Chlamydia can also cause epididymitis (inflammation of the epididymis). poor urinary stream strength. Because of its loca­ tion. hesitancy (starting and stopping of urinary stream). but oral antibiotics are used for bacterial Benign Prostatic Hypertrophy With age. Treat­ ment is either pharmacologic or surgical. the prostate can be removed by transurethral resec­ tion of the prostate (TURP ) or open surgery if it is too large to be removed by TURP. such as incomplete bladder emptying. but no organism can be cultured from urinalysis. so the urethra often remains unaffected. The causative organism can be cul­ tured from urinalysis. coli and other gram negative rods. Prostate can­ cer arises most often in the peripheral part of the prostate. Urinalysis demonstrates WBCs and can be used to culture causative organisms. Chronic prostatitis can lead to recurrent UTis. which predisposes to urinary tract infection. causing a decrease in LH secretion and a subsequent decrease in testosterone secretion. LHRH ago­ nists initially increase LH secretion (and testosterone secretion) but the over-stimulation of LHRH receptors eventually leads to their down-regulation. Diagnosis is made by transrectal ultra­ sound-guided biopsy. urgency. Symptoms can include fever. and/or nocturia. hematogenously. though Gonorrhea and Chlamydia are also potential culprits. The testicles can become inflamed (orchitis).g. dysuria (pain during urination). If pharmacologic therapy fails. Symptoms and signs of orchitis include testicular pain. or LHRH (LH releasing hormone) agonists. pathology of the prostate can cause symptoms of urethral obstruction: incomplete emptying of the blad­ der. Orchitis Orchitis is testicular inflammation. the prostate enlarges. Inhibition of 5-alpha reductase (e.g. N gonorrhoeae.. Viral orchitis resolves sponta­ neously. and/or hormonal ther­ apy. Prostatitis Prostatitis (inflammation of the prostate) can be acute or chronic. So-called "non-bacterial" prostatitis can cause any/all of the above symptoms and signs. Bacterial causes include E. This can be accomplished by orchiectomy (re­ moving the testicles removes the main source of testos­ terone).Mycoplasma. Mumps is the most common cause of orchitis. fluoroquino­ lones and trimethoprim-sulfamethoxazole (TMP­ SMZ) have the best prostate penetration. swelling. fever. finasteride) decreases testos- 169 . the testicles descend from the abdomen to their place outside the body in the scro­ tum. poor urinary stream strength.ter­ azosin) relaxes smooth muscle. etc. Obstruction can weaken the bladder over time.

Approximately every 28 days from puberty until menopause. MALE AND FEMALE REPRODUCTIVE SYSTEMS FEMALE REPRODUCTIVE ORGAN PATHOPHYSIOLOGY causes.tes the follicle to secrete estrogen.CHAPTER 9. FSH stimu­ la.. If the ovum is not fertilized. Tes­ ticular torsion is most common in men under 30. a woman releases an ovum and prepares the uterine wall for implanta­ tion. causes the ovum to be released (ovulation) and the follicle to be­ come the corpus luteum. Note that estrogen can function both to increase LHIFSH secretion (leading to. The Menstrual Cycle Fig. estrogen secretion from the folli­ cle stimulates an increase in LH and FSH secretion from the pituitary. Prompt surgical repair is necessary to prevent loss of the testicle secondary to infarction. which causes the proliferation of the endometrial lining. Treatment involves surgical removal of the affected testicle combined with radia­ tion and/or chemotherapy. These processes are mediated by LH (leuteinizing hormone).a common treatment for impotence. preparing it for implantation in the event of pregnancy (ovum: fol­ licular phase. 9-1. as can any psychological issues in the man or between the man and his _partner. preventing ovulation. antidepressants. beta-hCG (human chorionic gonadotropin). If the ovum is not fertilized. diabetes. diagnosis is made by ultrasound. or it can present as a testicular mass. This feedback loop leads to an LH surge. stroke) can lead to erectile dysfunction. pain. the continued estrogen and progesterone secretion will inhibit FSH and LH. Viagra (sildenafil). leading to their decreased secretion. The estrogen and progesterone stimu­ late development of secretory glands in the en­ dometrium (ovum: luteal phase. and/or a sensation of testicular "fullness. the testes descend from the abdomen during development and thus can refer pain there. FSH (follicle stimulating hormone). resulting in a decrease in estrogen and prog­ esterone secretion. AFP (alpha fetoprotein). atherosclerosis. diabetes) or the nervous system (depression. Thus. around Day 14 in the cycle.. which. Erectile Dysfunction Achievement of erection is as dependent on neurologic and vascular function as it is on psychological factors. cGMP is broken down by PDE-5.g. Oral Contraceptives. Amenorrhea The distinction between primary amenorrhea and sec­ ondary amenorrhea does not refer to the localization of the problem as in other endocrine disorders. Testicular pain can be treated with ice. This can be caused by trauma. trauma/surgery. The now low estrogen and progesterone al­ low forFSH and LH secretion to rise again. causing compromised flow through the testicular artery and ischemia. The most common sites of metastasis are the retroperitoneal lymph nodes and the mediastinum. and LDH (lactate dehydrogenase) may be elevated in the serum as tumor markers. and Amenorrhea Torsion Torsion is the twisting of the spermatic cord. or diseases that affect the vasculature (e. swelling and erythema of the scrotum. This decreases breakdown of cGMP. The Menstrual Cycle.g. causing sloughing of the endo­ metrium (menstruation). endometrial lining: secretory phase). any medications (e. In what is a rare physiologic instance of a pos­ itive feedback loop. works by inhibiting PDE-5. or from predisposition secondary to undescended testes or a congenital "bell clapper" deformity (which allows for extra ease of rotation of the spermatic cord). causing entry of blood into the penis. infertility. exercise. which pro­ longs erection. The fall in LH and FSH leads to the degeneration of the corpus luteum. Day 1 of the menstrual cycle corresponds to menstru­ ation. and/or nausea/vomiting. endometrial lining: proliferative phase). Erection occurs via vasodilation. Failure of testicular descent at birth (cryp­ torchidism) is a risk factor for development of testicu­ lar cancer. abdominal pain. which stimu­ lates production of cGMP. and analgesic therapy.which secretes estrogen and progesterone. returning the cycle to the beginning. Birth control pills (oral contraceptives or OCPs) are combi­ nation estrogen/progesterone pills that serve to sup­ press LHIFSH. estrogen. and progesterone. hypertension. Symptoms and signs include severe scrotal pain. This is accom­ plished when paraysmpathetic nerves innervating the penile vasculature release nitric oxide. The menstrual cycle. Testicular Cancer Testicular cancer can be completely asymptomatic. at which time a new ovum-containing follicle begins to grow under the influence of FSH (follicle stimulating hormone) from the pituitary. The abdominal pain is referred pain. beginning the cycle anew. which causes vasodilation. Primary amenorrhea refers to the situation in which a woman 170 . antihy­ pertensives). bed rest." It is more common in relatively young men (usually younger than 40). ovulation) and to inhibit it (at the end of the luteal phase). the prepared en­ dometrium is sloughed during menstruation.

ICI.OFU>va eUTI!\. From Goldberg: Clinical Physiology Made Ridiculously Simple. VM PRtriA'-'< FO&.L.H FSH C. MedMaster 2004 171 . MALE AND FEMALE REPRODUCTIVE SYSTEMS L.CHAPTER 9.t:'" 0 ' I - ' THE MENSTRUAL CYCLE Figure 9-1.

Causes of amenorrhea. The latter two con­ ditions cause XY individuals to appear female exter­ nally despite lacking functional female internal genitalia. 9-2. Starting from the bottom.CHAPTER 9. vaginal agenesis. In any case of amenorrhea. nization or androgen insensitivity.. Sheehan's syndrome) or if there is a tumor within the pituitary or nearby. the ovaries can be nonfunc­ tional in Turner's syndrome. Examples include imperforate hymen. Working our way up.g. Secondary amenorrhea refers to the situation in which a woman has ceased menstru­ ating. cancer chemotherapy) or as a result of meno­ pause. The hypothalamus can fail to secrete GnRH because of a tumor. a pregnancy test (hCG) needs to be ordered to rule pregnancy in or out. anatomical anomalies can occur that block the pas­ sage of menses. or disorders such as testicular femi- I GnRH • � • • Hypothyroidism Hyperprolactinemia FSH/LH l uP1 l � Estrogen Anatomical abnormalities CAUSES OF AMENORRHEA Figure 9-2 172 .g... or fail secondary to drugs (e. The pituitary can fail in its FSH/LH secretion secondary to hemorrhage (e. congenital deficiency (e. Kallmann's syn- Fig. Pathology can occur anywhere along this axis. MALE AND FEMALE REPRODUCTIVE SYSTEMS has never menstruated. primary and secondary amenorrhea have overlapping but slightly different differential diagnoses.g. Assuming the woman is not pregnant.

This causes the pituitary to in­ creaseFSH release to try to increase estrogen secretion from the failing ovaries. ectopic pregnancy) FEMALE REPRODUCTIVE PATHOLOGY Figure 9-3 beta-hCG level to rule in/out pregnancy. SerumFSH can be measured to localize the site of pathology. hypothalamus) can present as primary or secondary amenorrhea. Altematively. imaging and karyotyp­ ing. "frothy" Protozoans (no reaction) Metronidazole (oral) Candida White. can lead to itch­ ing/buming and an increase or change in vaginal dis­ charge and/or odor. Infectious causes of vaginitis. Common infec­ tious culprits include Trichomonas vaginalis (a proto­ zoan). and if warranted. and/or severe stress. History and physical should also assess the possibility of anorexia. atrophy of the vaginal wall in post-menopausal women. the level of estrogen they secrete decreases. or because of stresses such as excessive weight loss or exercise. drome: loss of GnRH secreting-cells and olfactory neu­ rons). MALE AND FEMALE REPRODUCTIVE SYSTEMS OVARIES (Polycystic ovaries. vulvar or vaginal cancer in rare cases. 9-4.CHAPTER 9. thick. Inflammation of the Female Genital Tract Anything from the ovaries and up (pituitary. this suggests ovarian failure. inflammation of the vagina. Other important lab tests in amenorrhea are prolactin (to rule in/out hyperpro­ lactinemia). Vaginitis Vaginitis. Gardnerella vaginalis (bacterial vaginosis). hygiene products. thin "Clue cells" (cells with many small bacteria attached to the surface) Gives fishy odor (positive "whiff test") Metronidazole (oral or vaginal cream) 173 . Fig. 9-3. IfFSH is high. "curds" Branching yeast (no reaction) Topical antifungals Gardnerella (Bacterial vaginosis) Gray. So in primary amenorrhea it is im­ portant to rule out anatomical abnormalities by careful physical exam. Candida albicans (yeast infection). TSH (to rule in/out hypothyroidism). thyroid. excessive exercise. and infection. Why? If the ovaries fail. Female reproductive pathology. Hypothyroidism and hyperprolactine­ mia can also lead to amenorrhea. Inflammation/irritation can be caused by intercourse (and/or its associated products: lubricants. and a Fig. latex).since the anatomy must be intact if periods have occurred in the past. ovarian cancer) FALLOPIAN TUBES (salpingitis. structural abnormalities of the uterus and vagina can only present as primary amen­ orrhea. reducing the negative feedback onFSH secre­ tion from the pituitary. Figure 9-4 Vaginitis ORGANISM DISCHARGE WET MOUNT KOH/WHIFF TEST TREATMENT Trichomonas Yellow.

positive pregnancy test. Diagnosis is confirmed by extreme elevation of beta-hCG and a "snowstorm" appearance on ultrasound. Gestational Trophoblastic Disease (GTD) Gestational trophoblastic disease (GTD) occurs when a sperm fertilizes an "empty" ovum. Although occasionally a mass may be pal­ pable on bimanual example. so-called "blighted ovum" can be fertilized by one sperm. GnRH ag­ onists do indeed stimulate the receptors of LH. e. i. Less commonly. on the ovaries. This can be accomplished with oral contracep­ tives. metaplasia of other tissues into endometrial tissue. and Ovarian Neoplasia Fig. Immediate surgical removal is necessary. laparoscopic exam with biopsy is necessary to confirm the diagnosis. and ectopic pregnancy.e. Early bleeding may occur. danazol (inhibitor of LHIFSH). HPV infection in men usually leads to an asympto­ matic carrier state. Symptoms of endometriosis can include pain during menstruation (dysmenorrhea) and intercourse (dyspareunia). Neoplasia of the Female Genital Tract. Thus. Since sites of endometriosis contain functional endometrial tissue. Vaginal lesions. Chlamydia and gonorrhea infections of the lower genital tract tend to be asymptomatic. Cervicitis Inflammation of the cervix can be caused by trauma. This empty. resulting in decrease in FSHI LH secretion. This cervical discharge can be cultured for Chlamydia and gonorrhea. These men do not develop symp­ toms but can transmit the virus to sexual partners. Cervical. Vaginal exam often demonstrates purulent cervical discharge and cervical motion tenderness (pain on movement of the cervix). The latter two are results of scarring of the uterus/tubes from the in­ fection. Vaginal. sometimes with nausea/vomiting. Polycystic Ovary Syndrome (P COS) Polcystic ovary syndrome (PCOS) is characterized by in­ creased androgens. HSV and HPV cervicitis generally co-exist with vaginitis. Patients may notice vesicle-like material in vaginal bleeding. or infection.and FSH-secreting cells of the anterior pituitary. and the uterus may be too large or too small for the presumed stage of pregnancy. and beta-hCG is moni­ tored to observe expected decrease after removal. leading to amenorrhea. The GnRH agonist might at first sound illogical. hirsutism 174 . they are stimulated by estrogen just as the uter­ ine lining is. Such an egg can result from maternal nondisjunction. A classic symptom of cervical disease (in­ cluding malignancy) is post-coital bleeding (bleeding immediately following intercourse). Men can also get any of the infections in Fig. Treatment involves antibi­ otic therapy. since GnRH stimulates LH andFSH release. guarding). MALE AND FEMALE REPRODUCTIVE SYSTEMS Fig. causing pelvic inflammatory dis­ ease (PID). tuba-ovarian ab­ scess. Ab­ dominal exam reveals tenderness and can also show signs of peritonitis (rebound. and vascular/lymphatic dissemination of endometrial tissue. gonorrhea. and/or infertility. Theories of endometriosis include retrograde menstruation. or elsewhere in the pelvis or abdominal cavity. 9-5. If medical therapy is unsuccessful. endometriosis tissue can be removed surgically. infertility.herpes simplex virus (HSV). creating a complete mole. A mole can present as pregnancy: enlarged uterus. 9-6. Choriocarcinoma can invade blood vessels and metastasize to any organ. and even out into the abdominal cavity. Neoplasia of the Female Genital Tract Vulvar. on the outer surface of the uterus or rectum. choriocarcinoma is very responsive to chemotherapy (usually involving methotrexate). e. and human pa­ pilloma virus (HPV). blocking this estrogen stimulation reduces symptoms caused by the ectopic endometrial tissue. Fortunately. but contin­ uous stimulation leads to a down-regulation of these re­ ceptors. 9-5. with the lungs being a common site. and GnRH ago­ nists. mole and abnormal triploid fetal tissue. abdominal and/or pelvic pain. an ovum with no maternal chromosomes in it. malignancy. Chlamydia.g.. an ovum with one set of maternal chromosomes can be fertil­ ized by two sperm causing the formation of a partial Other Diseases of the Female Genital Tract Endometriosis Endometriosis is the presence of endometrial tissue outside of the endometrium (inner uterine wall). radiation.. 9-5.. which then duplicates. Pelvic Inflammatory Disease (PID) Pelvic inflammatory disease (P ID) presents as acute abdominal pain. Uterine.Fail­ ure of beta-hCG to decrease indicates either incomplete removal of mole or possible malignant transformation (choriocarcinoma). Sites of endometriosis may be small or can be larger tumor-like endometriomas (also known as "chocolate cysts" because of the appearance of the thick dark liq­ uid they contain). nausea/vomit­ ing. leaving one ovum with twice as much genetic material as normal and the other with none. but these agents can spread past the cervix to the endometrium (myometritis/endometritis) and fallopian tubes (salpingitis). Complications of PID can include Fitz-Hugh-Curtis syndrome (inflammation/fibrosis surrounding the liver from intra-abdominal spread). It is not known for sure how the en­ dometriosis arises (or arrives) at these sites.CHAPTER 9. causing the symptoms discussed in Fig.g.

melanoma Itching. cardiac effects Painful chancre Figure 9-6 Neoplasia of the Female Genital Tract HISTOLOGY SYMPTOMS/SIGNS DIAGNOSIS OTHER TREATMENT Vulvar cancer Squamous (most common). biopsy Surgery. When present: Vague abdominal/pelvic pain/bloating. dysgerminoma) (same as cysts) Ultrasound/ laparoscopy/biopsy Surgical removal Ovarian cancer Epithelial. pain. Ducreyi (Chancroid) Chancre: painless ulcer Primary: Lesion Secondary: Systemic symptoms (constitutional+ rash) Tertiary: Abscesses (gummas). increased risk for cervical Papules Biopsy (HPV) (genital warts.CHAPTER 9. can be accompanied by constitutional symptoms Vesicles (that can coalesce) Viral culture (Tzanck Prep: multinucleated giant cells) Acyclovir Human papilloma virus Painless. pelvic mass Tumor markers CA-125. Ultrasound. Female fetuses exposed to DES in utero are at higher risk for clear cell carcinoma of the vagina. Sex cord/Stromal (Sertoli-Leydig cell. Granulosa-theca cell) Germ cell (teratoma. FTAABS (treponema! antibody screen) Penicillin Ulcerated papule Gram stain (gram negative anaerobic) Erythromycin or ceftriaxone Treponema pallidum (Syphilis) • • • • H. urinary symptoms. cryotherapy Ulcerated papule VORL. MALE AND FEMALE REPRODUCTIVE SYSTEMS Figure 9-5 Vaginal Lesions ORGANISM SYMPTOMS SIGNS DIAGNOSIS TREATMENT Herpes simplex virus (HSV) Painful. condyloma acuminata) cancer Topical creams. Torsion possible ? acute pain. infertility. aFP. palpable mass (can be asymptomatic) Scan. clear cell Vaginal bleeding Biopsy Rare. CT scan Surgery/chemo/ radiation biopsy * DES= Diethylstilbestrol. DES is a synthetic estrogen that was once used during pregnancy in women who were at high risk for miscarriage. LDH. embolization Endometrial cancer Adenocarcinoma most common (also leiomyosarcoma. mass may be palpable Ultrasound/ laparoscopy Observationmost resolve spontaneously Benign ovarian neoplasia Epithelial (serous. stromal sarcoma) Post-menopausal bleeding Endometrial sampling/ Surgery/radiation/ chemo Ovarian cysts Follicular or corpus luteum Asymptomatic or abdominal/pelvic bloating/pain. CNS effects. germ cell. b-hCG can be elevated in the serum with certain tumors. noticeable lesion Biopsy Rare Surgery/radiation/ chemo Vaginal cancer Squamous (most common). clear cell associated w/ in utero DES* exposure Surgery/radiation/ chemo Post-coital bleeding Pap smear screens for cervical metaplasia Associated w/H PV Surgery/radiation/ chemo PATHOLOGY Cervical cancer Squamous Uterine fibroids Benign leiomyomas Bleeding. or stromal cell (metastasis to ovary also possible) Often asymptomatic leading to diagnosis at advanced stage and poor prognosis. APR (false positives possible). 175 . dysuria. mucinous adenomas).

as breast pain or inflammatory changes of the overlying skin.g. movable Biopsy None needed Intraductal papilloma Women ages 35-55 Bloody discharge from nipple Biopsy Removal Breast cancer Risk increases with age Lump noticed by woman or physician. and a warm and erythematous region of the breast. Staph. thus. family his­ tory. and chemotherapy. chemotherapy (abnormally increased body hair). 9-7. nulliparity (no pregnancy). Mastitis presents as acute breast pain. Diseases of the Breasts Diseases of the breasts can be classified as inflamma­ tory or neoplastic. 5-9). and/or in the genital region). infertility.e. Although breast cancer can present as a breast mass or. Treat­ ment involves antibiotics. and fat necrosis all cause pain. pain is acute and usually unilateral (and generally accompanied by fever and erythema). OCPs also decrease LH. This can result in a firm mass that may mimic breast cancer. Inflammatory and neoplastic diseases of the breasts. screening is essen­ tial. lumpiness of breasts on exam Biopsy None needed Fibroadenoma Very common in younger women (20s-40) Mass: firm. Oral contraceptives can restore a regular menstrual cycle. aureus is the most common causative agent. Breast Cancer Risk factors for breast cancer include prolonged estrogen exposure (i. The underlying cause of the increased an­ drogens is unknown. most commonly Staph. will also have polycystic ovaries on ultrasound examination. Treatment of breast cancer involves a combination of surgery. Glucose tolerance may be impaired. tender mass Biopsy None/excision NEOPLASTIC DISEASES Fibrocystic changes Very common in women of all ages Cyclic diffuse pain (usually right before period). and. ty pe II diabetes mellitus and acantho­ sis nigricans (velvety darkened areas of skin. Inflammatory diseases include mastitis and fat necrosis. Biopsy can be accom­ plished by fine needle aspiration or surgical excision. it is treated with weight loss/exercise and metformin (SeeFig. If diabetes is present. fever. from early menarche or late menopause). Fig. while neoplastic diseases in­ clude a variety of benign lesions and breast cancer. acne.. depending on the extent of disease. testosterone. more rarely. pain or skin changes Biopsy Surgery. and increasing age. this must be treated with surgical drainage. Most cases. Diagnosis is confirmed by increased serum androgens (e. 176 . and to have annual breast exams by a phy sician and mammograms after age 40. MALE AND FEMALE REPRODUCTIVE SYSTEMS Figure 9-7 Inflammatory and Neoplastic Diseases of the Breast PATHOLOGY EPIDEMIOLOGY PRESENTATION DIAGNOSIS TREATMENT INFLAMMATORY DISEASES Mastitis Nursing women. In mastitis. Fat necrosis presents as tender­ ness when the area is touched. Fat necrosis can occur secondary to trauma or sur­ gery. but they should al­ ways be biopsied to rule out breast cancer. on the back of the neck. well-circumscribed. fever. radiation. most com­ monly in the axillae. obesity. If an abscess forms. Note: Fibrocystic changes. but not all. in some cases. Most breast masses are benign. thus decreasing androgen production and reducing hirsutism and acne. A palpable mass or suggestive mammography find­ ings are indications for biopsy. radiation. analgesics Fat necrosis Secondary to trauma or surgery Firm. and a warm and erythematous region of the breast Clinical Antibiotics. . it is most often asymptomatic. Women should be advised to do self breast exams monthly. aureus Acute breast pain. but the pain in fibrocystic changes is cyclic and usually bilateral. mastitis.CHAPTER 9. androstenedione) and increased LH with normalFSH. Mastitis is an infection of the breast that most com­ monly occurs in women who are nursing a newborn. rarely. The syndrome most commonly emerges in late adolescence. painless.

g. and adoption are possible alternatives for couples seeking a child. Problems in the female can be divided into those af­ fecting ovulation and those affecting the anatomy. Diagnosis is made by semen analysis. 177 . and/or laparoscopy). 9-2) or ac­ quired (e. the sperm must be able to exit the male upon ejaculation. hormonal abnormalities (e. or failure of implantation of the fertilized ovum. Problems with any of these steps can lead to infertility. amenorrhea workup (if applicable) and examination of the female anatomy (by hysterosalpingogram. While anatomical abnormalities are generally treated with surgery.. and the sperm must be able to make it to and fertilize the ova.. Infertility In order for a successful pregnancy to occur. endometriosis. uterine fibroids. testicular disease (cancer. orchi­ tis). LHIFSH deficiency). If no therapy is possi­ ble. Anatomical prob­ lems can lead either to failure of sperm to arrive at the ovum and fertilize it. MALE AND FEMALE REPRODUCTIVE SYSTEMS Problems affecting ovulation are any that can cause menstrual cycle disturbances (see Fig.g. the male must produce an adequate number of viable sperm. ovulatory problems may be treated with hormonal therapy. The female must produce viable ova. or blockage of the vas deferens or seminiferous tubules (which can occur congenitally or secondary to cystic fibrosis or prior surgery). in vitro fertilization. ultrasound. 9-2).CHAPTER 9. Anatomi­ cal problems can be congenital (see Fig. and the ova must be able to successfully implant in the uterus. use of a sperm donor. scarring from pelvic inflammatory disease). Problems in males leading to a low sperm count or malformed/malfunctioning sperm include chromoso­ mal abnormalities.

a sign of anemia. whereas mitral regurgitation would be holosystolic. So what could cause a murmur during systole? Stenosis of either the aortic or pulmonic valves could cause a murmur.CHAPTER 10. fatigue. the esophagus.e. and how can these entities cause pain? In the chest: the lungs.. and maneuvers. clenching the fists) will increase the intensity of mitral regurgitation and have no effect on aortic stenosis. Location of the murmur. Recall that stenotic valves take a little time to open and then the blood flows through and creates a murmur. both of which are manifestations of ischemia. edema).35-7. the two systolic murmurs can be distin­ guished by maneuvers. What happens "downstream" when there is aortic stenosis? Because of the stenotic valve. Is it over the aortic area or the pulmonic area? The tricuspid or the mitral? Recall that the aortic area is to the patient's right of the ster­ num and the pulmonic area is to the left. in the left ventricle) in aortic stenosis? The increased re­ sistance faced by the left ventricle can lead to left ven· tricular hypertrophy. Finally... the blood to the carotids arrives more weakly and late (parvus et tardus). esophageal cancer.0 mEq/L HC03..g. Myocarditis. and the shut mitral and tricuspid valves pre­ vent back-flow into the atria.2 mg/dl CASE! On routine exam of an otherwise healthy 78-year-old man. to the carotids. How can you distinguish among these causes? Asso­ ciated symptoms. the heart. A dilated left ventricle can also laterally displace the PMI and could cause an S3. What can make the esophagus hurt? Acid reflux (GERD). shortness of breath) and/or ischemic symptoms (e. angina). Possible causes of pain of these organs: injury. associated signs. Cl· 95-105 mEq/L pH 7. What can make the heart hurt? Chest pain can be a sign of angina or myocardial infarction. A VSD could also cause a systolic mur­ mur. CASES Normal Serum Values: Na+136-145 mEq/L Radiation. This can help to determine whether surgery is necessary. neoplasia. inflammation. Regurgitant mitral or tricuspid valves could also cause systolic murmurs since the backflow through these regurgitant valves would occur during systole as well. radiation. CASE2 Associated symptoms may or may not be present de­ pending on the severity of the valvular pathology. infec­ tion. K+ 3. Mitral regurgitation can also cause atrial fibrillation. Mitral regurgitation ra­ diates to the left axilla. Both ventricular hypertrophy and ventric­ ular dilatation can be seen as ventricular enlargement on chest X-ray. What are the possi­ ble etiologies of this murmur? What can help you deter­ mine the cause? What happens normally during systole? The ventri­ cles pump blood out through the aortic and pulmonic valves.22-28 mEq/L Associated signs.5-5. regurgitant valves just flop right open with the slight­ est push. and esophagitis.45 pC02 33-45 mm Hg BUN 7-18 mg/dl Creatinine 0. Se­ vere aortic stenosis can lead to syncope and "decreased forward flow" symptoms (weakness. a systolic "flow murmur" can be either normal. Left ventricular hypertrophy can cause a laterally displaced PMI (point of maximal im­ pulse) and possibly an S4. hyper­ tension. quality of the murmur. and hypercholesterolemia presents to the ER with chest pain. Mitral mur­ murs are best heard near the cardiac apex (Fig. 178 . endo­ carditis. Echocardiography can confirm the diagnosis. an enlarged left atrium can be seen on chest X·ray if mitral regurgita­ tion is present. and ribs/muscles. obstruction (of the esophagus). So aortic stenosis would be a systolic ejec­ tion murmur with a crescendo-decrescendo pattern. muscle strain. Maneuvers that increase pe­ ripheral resistance (e. Mitral regurgitation can cause "backup of flow" symp­ toms (shortness of breath. which can be seen on EKG. and costochondritis. 1-10). It can also measure the severity of the valvular lesion. which can result in left ventricular dilatation. The murmur of aortic stenosis radiates straight up . ischemia. and pericarditis are examples of cardiac in­ fection/inflammation. aorta.g. Quality of the murmur. A 65-year-old woman with a history of diabetes. Finally. Mitral regurgitation causes increased volume demand on the left ventricle. On the other hand. esophageal rupture. location of the murmur. because the blood would pass through narrowed openings during systole. typically only pericarditis causes chest pain. you note a systolic murmur. Since mitral regurgitation also increases the volume demands on the left atrium. What is the differential diagnosis? Starting simply..6-1. what is in the chest. CASES CHAPTER 10. What happens "upstream" (i. or it can occur with fever. though out of these.

GERD will be relieved by antacids and can be exacerbated by lying horizontally or bending over. A pulmonary embolus can also present acutely as chest pain and/or shortness of breath. when it is infarcted) some of the cardiac enzymes.CHAPTER 10. D-dimer level in the serum is a diagnostic marker that can also help to rule in or out the diagnosis of pulmonary em­ bolism. What can make the lungs hurt? Infection (pneumo­ nia). ripping pain" radiating 179 . Methemoglobinemia is one cause of Region I Radiation. What are the possible etiologies? We have seen various cardiac causes of cyanosis in Chapter 1 (e. pulmonary embolus. and/or arm. and high levels of these enzymes can be indicative of car­ diac injury (e. Can you think of any other organ systems whose dysfunction could lead to cyanosis? The lungs may bring the oxygen to the blood and the heart may bring the blood to the lungs. When suspecting pulmonary embolism. palliation. spiral CT scanning or ventila­ tion perfusion scanning is often necessary.e. jaw. tracheoesophageal fistula. An EKG can show signs of right heart strain and a chest X-ray can reveal signs of infarction. The pain of myocardial infarction can radiate to the chest. "tearing" in dissec­ tion. quality. creatine kinase (CK) and troponin. So hemoglobinopathy is one possible cause of neona­ tal cyanosis. For example.. congenital di­ aphragmatic hernia. Quality. stabbing upon breathing in if the pain is pleuritic. deoxygenated blood is somehow making it into the circulation. the chest X-ray is often completely normal in patients with pulmonary embolism. How would you distinguish between the pain of GERD and the pain of a heart attack and/or angina? Remember the pathophysiology: GERD occurs secondary to reflux of acid from the stomach to esopha­ gus. Palliation. an EKG can assess the possibility of a cardiac-related cause of chest pain. When in doubt. is­ chemia or rupture of an organ are acute events." this could be angina or GERD.g. inflammation of the lungs (or pleura). i. ''burning" in GERD. since it can be fatal if not immediately repaired. CASE3 A newborn baby looks blue. are released into the bloodstream.. your clinical history should elicit characteristics of the pain (e. Alternatively. Pericarditis pain can also get worse when a patient lies down. and there may be a widened mediastinum on chest X-ray. blood pressures in the arms may differ. muscle strain. This would cause shortness of breath. since these positions increase reflux. In aortic dissection. Pericarditis can cause a pericardia[ rub to be heard on auscultation. If the "same chest pain has happened before.. Timing. tetralogy of Fallot.e.g.. the heart could be fine. What part of the blood is necessary for oxygen uptake? Hemoglobin. timing. It is useful to distinguish between acute on­ set and more protracted onset of pain. Examples include meconium aspiration. etc.g. myocardial infarction). The patient may report "tearing. In what situa­ tions would you expect the patient to have pain from ei­ ther of these pathophysiological bases? Cardiac pain would most likely occur when the difference between the supply and demand of oxygen is exacerbated. However. but it is characteristically re­ lieved when the patient leans forward. More specific examples of such acute events include myocar­ dial infarction.. Aortic dissection is an acute cause of chest pain that should always be considered. Associated findings I diagnostic tests: What can make the aorta hurt? Dissection.g. CASES through to the back. esophageal rup­ ture. a symptom we would not expect to find in GERD. trans­ position of the great arteries). and aortic dissection. but these are not present in all cases.. Any time you deal with pain. and pul­ monary embolus. A detailed discussion of the predictive value and timing of the presence of various cardiac enzymes is beyond the scope of this text. in a time of increased demand such as increased physical activity/exercise. the pain of GERD or pneumonia can come about less suddenly. Exercise should have no effect on GERD's symptoms. The quality of the pain may also give clues to its origin: "pressure" in ischemia. Infections such as endocarditis or pneumonia will often cause fever and an increased WBC count. e. Let it suffice to say that when cardiac tissue dies (i. cardiac ischemia occurs from a mismatch of oxygen demand and supply in the myocardium. but the blood itself may be incapable of receiving the oxygen. What is the differential diagnosis? If the baby is blue. What can make the ribs/muscles hurt? Costochon­ dritis. and the lungs may not be doing their job of oxygenating the blood. region) that can help to refine your differential diagnosis: What does the pain feel like? Where does it hurt? Did it begin suddenly or gradu­ ally? How long has the pain been there? Has anything like this ever happened before? What makes it better or worse? Endocarditis can present with a new cardiac murmur.

Rather than a new murmur. interstitial dis­ ease. just because there is bradycardia does not nec­ essarily mean that there is pathology. CNS dysfunction can lead to respiratory depression. would be a new systolic murmur. The diagnosis can be confirmed with an echocardiogram or by pericardiocentesis.g. First. ventricular wall rupture leading to tamponade. what does that tell you? It must mean that forward flow is decreased (hypotension). a 67year-old woman suddenly complains of chest pain.e. or the SA node is firing normally. What are the possible pathophysiologic mechanisms underlying this slow heart rate? CASE6 A 45-year-old woman complains of shortness of breath when she climbs stairs or runs... Ane­ mia can be ruled in or out by looking at hemoglobin. Tamponade can be caused by ven­ tricular rupture after a myocardial infarction as in this case.g.. angina. With any symptom or sign. decreased blood pressure. previous myocardial infarction (i. infarc­ tion of the conduction system).. This triad of symptoms (increased JVP. pulmonary (e. or an S3 or S4. progressive interstitial lung disease.g. wheezing) or anemia (e. hematocrit.g. but there is no new murmur here. conduc­ tion block. Cardiac function can be assessed with EKG. If the blood pressure is down but the JVP is up. anemia). heart failure). hyperexpansion. calcium channel blockers. Pathology in the blood. What is your differen­ tial diagnosis? A heart rate below 60 is defined as bradycardia. there 180 . hypothyroidism. A chest X-ray could indi­ cate whether there is cardiac enlargement. Finally. pale. How could that be? There must be something be­ tween the heart and the stethoscope that was not there before.. paroxys­ mal nocturnal dyspnea) or pulmonary disease (e. or hematological (i. etc. Causes include ischemia of the SA node (e. and urgent surgical repair is essential. and distant heart sounds. but the sig­ nal is getting blocked somewhere (heart block). pneumothorax)? Is there tachycardia and pallor (which could indicate anemia)? Is there fever and spu­ tum production (e. heart. the cause can be cardiac (e. Pulmonary function can be assessed with pulmonary function tests (PFTs). Let's say that on examination this patient has in­ creased JVP hypotension. and neuromuscu­ lar disorders can lead to impairment of respiratory muscle function.g. orthopnea.g.. How could you distinguish among these by history and physical exam? What are the potential pathological causes of brady­ cardia? Either the pacemaker (the SA node) is firing slowly. What are the possible etiologies of these symptoms? On physical exam: is there a displaced point of maximal impulse/impact (PMI)... tumor.g.. and blood smear. Methemoglob­ inemia can be induced by toxin ingestion or an inborn error of metabolism. papillary muscle rupture leading to acute mitral regurgitation.g. Unfortunately. and/or neuromuscular system can lead to cyanosis....g. lungs. or has the course been more chronic and in­ dolent (e.g. and weak. She is confused.g. em­ physema. in this case there are distant heart sounds. allergens. think of all of the possi­ ble physiologic mechanisms that could lead to its ap­ pearance. and flow is backing up (elevated JVP). drugs (e.. conditioned athletes. ventricular fibrillation. On history: does the patient have a history of car­ diac or pulmonary disease or of predisposing factors to either (e. Now what do you think? . beta blockers. or exercise (e. many of these patients do not survive. When a patient presents with shortness of breath on exertion. and children can have asymptomatic bradycardia. athero­ sclerosis). hyperexpansion. and ventricular septal rupture. CASES hemoglobinopathy in the newborn. when pulmonary func­ tion is impaired). and distant heart sounds) is known as Beck's triad and is associated with car­ diac tamponade. that would indicate cardiac disease? Does lung percussion yield dullness (e. anti-arrhythmics). pulmonary congestion. CASE4 A 60-year-old man is found to have a pulse of 40 beats per minute on physical exam.g..g. or infiltrative diseases.. exer­ cise stress testing and/or coronary angiography.g. which could indicate a hypertrophied or dilated heart)? Is there a murmur.CHAPTER 10.e.. hypertension for cardiac disease or smok­ ing for pulmonary disease)? Are there additional symptoms of cardiac disease (e. If there were acute mitral regurgitation. or any other arrhythmia). pneumonia or COPD flare)? There are a variety of post-myocardial infarction complications that could cause these symptoms: a sec­ ond myocardial infarction. or cardiac disease)? CASE5 Ten days after an acute myocardial infarction. arrhythmia (e. Arrhythmia or acute mitral regur­ gitation are possible. seeking strange foods such as ice in iron deficiency or peripheral numbness/tin­ gling in B12 deficiency)? Are there episodic exacerba­ tions in response to cold. Some elderly patients. asthma). short of breath. consolidation or edema) or increased resonance (e.

The CPAP keeps the airway open. elevated JVP and ascites indicate right heart failure. This backup is manifested in edema. When you go back for a closer look at this patient. tension pneumothorax. ipratropium (to block acetylCholine receptors. hyper­ expansion in pulmonary obstructive disease. CASES A 7-year-old boy complains of "getting tired" in gym class. The diagnosis is exercise­ induced asthma. or steroids and/or drugs like cromolyn (which block the inflammatory response).g.g. elevated JVP. Restrictive lung disease can still have a normal FEVl/FVC ratio. What is the most likely diagnosis? This patient may have sleep apnea.. and oxygen saturation are examined for signs of apneic events.g. which increases the vascular resistance. and/or consolidation in pneumonia. and fever. and some minor tightening of the skin of the hands and forehead. further history reveals that the child only has trouble breath­ ing during heavy exercise. EKG could assess the possibility of arrhythmia. etc. This increased workload eventually causes failure of the thin-walled right heart (cor pul­ monale). hyperexpansion on chest X-ray) point to obstructive lung disease. PFTs revealed a normal FEVl/FVC ratio with decreased DLCO. e. arrhythmia). What is the most likely pathophysiology underlying these symptoms? The edema.CHAPTER 10. With this child.. CASE7 A 65-year-old man with a long history of smoking pres­ ents with acute onset of shortness of breath. you notice some dilated capillaries in the nail beds. CASE9 An obese 55-year-old man complains of dozing off at work and even once while driving. cardiac causes must be ruled out. Chest X-ray could indicate anatomical abnormalities. and blood backs up into its input. perhaps sec­ ondary to infection. CASES he tries to catch his breath. In this patient. and ascites. with exertional dyspnea. A normal FEVl!FVC ra­ tio tells us that this is probably not obstructive lung disease.. but does not rule out lung disease. pulmonary em­ bolus. CASE10 A 75-year-old man with long-standing pulmonary fibrosis from extensive asbestos exposure now pre­ sents with edema. wheezing. thus preventing apnea second­ ary to upper airway collapse. life­ threatening causes must be ruled out. The combination of normal FEVl/FVC ratio and decreased DLCO is most consistent with restrictive lung disease secondary to pulmonary fibrosis. One can give the child an inhaler of albuterol (to activate beta receptors and open the air­ ways). . and beta-agonists to activate the sympathetic nervous system to open the airways (e. which is the venous system. When the right heart fails. preventing optimal diffusion. Treatment would involve antibi­ otics to fight the infection. elevated JVP and ascites. Patients diagnosed with sleep apnea benefit from weight loss and/or a nasal continuous positive airway pressure (CPAP) mask at night. albuterol. its forward pump­ ing ability is reduced. prednisone). His wife reports that he snores quite loudly. The decreased DLCO tells us that the membrane is somehow thickened. sleep stages. Congenital defects must be consid­ ered in children and could be suggested by murmurs on physical exam and confirmed by echocardiography. confirming your diagnosis. thus blocking the parasympathetic system's closure of the airways). Pul­ monary fibrosis leads to distortion of the architecture of the pulmonary vasculature. This pulmonary hypertension leads to increased work for the side of the heart that is pumping into it: the right heart. In this patient. What is the most likely diagnosis and how would you treat the patient? With acute onset of shortness of breath. The snoring in­ dicates some narrowing of the airway at night. during which the pa­ tient's sleep is observed overnight in a sleep lab. as long as the patient does not have cardiac disease). Dur­ ing the study. CASE11 A mother brings in her 4-year-old daughter because she says the child's urine looks dark. This may be accompanied by episodes of complete upper airway obstruction during sleep that result in repeti­ tive hypoxemic events and arousals from sleep. The frequent interruptions in normal sleep can result in extreme fatigue during the day. causing pulmonary hypertension. A test for anti-cen­ tromere antibodies comes back positive. The diagnosis could be confirmed by doing a sleep study. some telangectasia. She says this is the 181 . You suspect that this patient has sclero­ derma with pulmonary fibrosis. cardiac (myocardial infarction. The history of long-standing pulmonary fibrosis should lead you to expect that pulmonary hy­ pertension has given rise to these symptoms. breathing patterns. Further history reveals that the tiredness seems to be a difficulty with breathing. the smoking history and signs of obstruction (wheezing. and his mother notices that he seems to be making a funny whistling sound when . The accompanying fever and acute onset seem most consistent with a COPD flare. anti-inflammatories to combat the inflammation (e. What is the differen­ tial diagnosis? Again. A chest x-ray shows hyperexpansion of the lungs.

genitals) source.and the urine volume is increased.g.. glomerular) source of bleeding from a lower GU tract (i. To distinguish the two by history. this occurs in nephrogenic diabetes insipidus (Fig. a low HC03with acidosis suggests metabolic acidosis.2." If the blood is coming from the genitals or urethra it is more likely to be visible as red. HC03..9 C02 22.. why would a child have glomeru­ lonephritis? What is one question you should defi­ nitely ask? Ask the mother "did the child just recently get over a sore throat?" Post-infectious (often strepto­ coccal) glomerulonephritis can cause hematuria in a child. give a differential diagnosis. What about the urinalysis could help you distin­ guish whether the bleeding is up at the level of the glomeruli or coming from lower in the genitourinary tract? Red cells that come from bleeding in the glomeruli would appear squished and damaged in uri­ nalysis. If the urine is cola-colored and there is no history or evidence of trauma. ask whether there is frank blood or if the urine is rather "cola-colored. Here. alkaptonuria).and C02 are both de­ creased.e. Here." It is important to rule out genital or urethral trauma (e. 3-9).e.e. Why is it important that this was the first time the urine was dark? If the child were younger (or the urine has always been dark) you would want to consider inborn errors of metabolism (e.g. sickle cell) can cause hemo­ globinuria.. If there is no response to ddAVP. which could mean fluid loss . central is most likely. CASE13 A patient is brought to the emergency room uncon­ scious. Any association of sodium/volume abnormalities and neurosurgical procedures should make you think of some problem with ADH.2. Diabetes insipidus can be central or nephrogenic.e. but what out­ side the genitourinary system could lead to dark urine? • Hypovolemic hypernatremia (i. Damaged glomeruli in glomerulonephritis can also lead to elevated protein leaking through into the urine (proteinuria). and increased dilute urine output. So this must be metabolic acidosis with respiratory com- Three days after resection of a pituitary tumor. the opposite of dilution). So if we have an increased urine output and increased serum sodium. UTI) can also cause hematuria and would present with the complaint of pain on urination and WBCs in the urinalysis. How will this help make the diagnosis? If the kidneys respond to the ddAVP by retaining water.. Choose from one of the following.. • Hypervolemic hypernatremia (i. so a decreased C02 could not cause an acidosis. = = = = = = � R espiratory acidosis � Respiratory alkalosis � Metabolic acidosis � Metabolic alkalosis CASE12 With a pH of 7. pH 7. This is diabetes insipidus. massive hyper­ tonic intake leading to hypernatremia and increased urine output in an attempt to get rid of the excess volume. but can children have stones? They can if they have ge­ netic disorders of metabolism or medications that cause hypercalciuria or hyperuricosuria. Red cell casts always signify glomerular dis­ ease. the urine will become more concentrated. CASES first time it has ever looked dark. What is the differential diagnosis? An elevated serum sodium with an increased urine output means one of three possibilities: 182 . we are dealing with acidosis. Serum sodium is measured at 160.g. abuse) as a cause of hematuria. HC03. is ADH increased or decreased? In hematuria. leading to an increased dilute urine output and hypernatremia in the serum secondary to this water loss. given the history of pituitary surgery. massive loss of urine fluid leaves behind a hypernatremic serum) Euvolemic hypernatremia (i. Urinalysis shows cal­ cium oxalate crystals. How can you check? You can give an injection of ddAVP (synthetic ADH). The labs show Na+ 145.CHAPTER 10. you know that respiratory acidosis comes from increased C02.. Second. So it looks like there is a failure of ADH..e. thus indicating cen­ tral diabetes insipidus. The increased serum sodium here suggests concen­ tration of the serum (i. This could occur from an IV solution). a pa­ tient develops confusion. lethargy. Cl114.e. K+ 5. urethra. What is the differen­ tial diagnosis? • Dark urine could signifY hematuria. Is ADH elevated or de­ creased in this case? ADH causes an increase in water absorption from the collecting duct. and suggest the most likely diagnosis. Dark urine can be a sign of jaundice from conjugated bilirubin. Fluid is not being appropriately retained but rather lost. The next question then is whether it is respiratory or meta­ bolic acidosis.e. Infection (i. What does this suggest? First.. whereas blood from a glomerulopathy tends to turn the urine "cola-colored. Crystals in urinalysis can be present in such instances. the urine will remain dilute. This will only occur if the kidneys can respond. You know hematuria in adults should raise suspicion for stones (especially when accompanied by flank pain). less drastic urine fluid loss leaves behind a hypernatremic serum) Any hemolytic anemia (e.. bladder. it is necessary to distinguish an up­ per genitourinary tract (i...

Now what's causing it? In metabolic acido­ you put hypotonic solution in the veins. tachycardia. How do you explain the labs? What would you expect to see on physical exam? How would you treat the abnormality? CASE15 On wotk-up of a hyperte»Jsive patient.Cr. so the question is whether this is prerenal.5. this has something to do with dehydration. or problems with any of the steps just listed can lead to jaundice. But what does dehydration have to do with the abnormal BUN and creatinine? An ele­ vated creatinine signifies renal failure. In an ef­ fort to counteract this. How can we distinguish between prerenal and intrinsic renal fail­ ure? BUN/Cr ratio holds a clue. and secreted into the bile. lactic acid. What is your first thought? When sodium and potassium are aberrant in op­ posite directions. water would flow out of the vasculature into cells. so it would be effective in causing a net increase in intravascular volume without losing much fluid to the ceils.. Genetic diseases can also cause jaundice: Gilbert's (problem getting bilirubin into the liver and conjugat­ ing it).. 3-7). Crigler-Najjar (C-N patients cannot conju­ gate). As always. think of aldosterone. diarrhea. Alternatively.e. The labs show BUN= 75. CASE16 = A 59-year-old patient notices that his eyes and skin seem to be turning yellow. In this case 145 . we would expect the urine to be very concentrated (since the water was pulled out by ADH) and also for FENa to be decreased (because aldos­ terone stimulates sodium reabsorption). eth­ ylene glycol. 3-2). Postrenal failure occurs from obstruction and if this is an acute event (i. CASES pensation. liypertonic saline is generally used only in extreme cases of hypovolemia. e. Conjugated bilirubin is water-solu­ ble. How do you expand intravascular volume? That is.. CASE14 After a long day outside at a family picnic in mid-July. when potassium is up and sodium is down. sis. 4-10). isotonic saline would be appro­ priate for volume expansion (Fig. liver pathology of any sort and biliary tract obstruction can both lead to a backup in the process and hence jaundice. So in­ creased RBC breakdown (hemolysis). or isotonic saline? If 183 . shock.g. isoniazid/iron. so we do have an anion gap. and its absence from the stool (e. this will expand volume and be at equilibrium with cellular fluid. uric acid. salicylates). Cr= 2. What would the labs show? Remem­ ber the physiology underlying prerenal failure: the kidneys are not being adequately perfused. tenting of the skin.9. The presence of calcium oxalate crystals in the urine is most consistent with = ethylene glycol ingestion. etc. you notice that sodium is 155 and potassium 2.g. do you want hypertonic. think of decreased aldosterone (e.. The treatment: volume expansion with IV fluids. or postrenal failure. Hy­ peraldosteronism can be primary or secondary (see Chapter 5). and Dubin-Johnson (cannot secrete) (Fig. Aldosterone causes reabsorption of Na+ (sodium) and secretion of potassium. Thus. From the history of disorientation following heat ex­ posure.and the possibilities are the MUDPILES (Methanol.g. nephrolithiasis) one would expect complaints of flank pain. and vomiting. which is the definition of prerenal failure.. Remember that a BUN/Cr ratio greater than 20:1 generally indicates prerenal failure (Fig. renal. think of el­ evated aldosterone.. Hyperaldosteronism is one cause of hypertension. paraldehyde. So elevated sodium and decreased potas­ sium could indicate that aldosterone is elevated. Unconjugated bilirubin is insoluble in water." They say she had just been getting over a bad bout of food poisoning from which she had diarrhea and vomiting.HC03-. secondary to obstruction) can make the stool light. if you give hypertonic saline. Why does that happen? Bilirubin comes from breakdown of red blood cells (RBCs) and is then taken up into the liver. but we want to increase the intravascular volume.(9+114) 22. What does an anion gap tell us? It tells us that there is some extra acid in the serum accounting for the gap . re­ member that volume expansion needs to be done gradually to prevent central pontine myelinolysis (also known as osmotic demyelination syndrome). the first step is to determine whether there is an anion gap or not. diabetic ke­ toacidosis. so elevated conjugated bilirubin can end up turn­ ing the urine dark. Is prerenal failure a logical diagnosis for this patient? Yes. this would expand the volume and pull in more volume due to its higher tonicity. adrenal insufficiency).5 30. hypotonic.CHAPTER 10. hematuria. What other questions can you ask? Does the person What would you expect to find on exam as signs of dehydration? Dry mucous membranes. Finally. an 85-year-old woman is brought to the ER after her family found her acting "weird. This leads to reabsorption of sodium and water respectively from the filtrate in the collect­ ing tubule. If you give isotonic saline. conjugated. In this case. How do you calculate an anion gap? Na+. The point here is just to remind you that when sodium is up and potassium is down. Here the BUN/Cr ratio is 75/2. dehydration leads to decreased perfusion of the kidneys. What is the differential diagnosis? What causes jaundice? Elevated bilirubin. the kidneys go on a reabsorb­ ing spree via the renin-angiotensin-aldosterone and ADH systems.

g. CASE17 A 56-year-old male patient tells you that he has been having abdominal pain about 3 hours after he eats.. risky sexual behavior)? Pain (which could indicate some kind of inflammation)? Recent drug or toxic in­ gestion of some sort? ity of gastrinoma (Zollinger. s/he must be emergently stabilized. hemochromatosis.Ellison syndrome). stones. or ulcerative colitis. anal fissure. The presence of black tarry stools (melena) generally means the blood has traveled in the GI tract for a sig­ nificant distance (e. A very rapid-onset bleed from below the gastroesophageal junction can also cause red blood to appear in the vomit.g. Are there any signs of portal hyper­ tension (caput medusa. Your next task is to find out the source of the GI bleed. and like her heart is beating very fast. colon cancer. liver tumor. i.e. but he does not bring any in for you to see. because the blood would be fresh. same task: Where is the blood com­ ing from? Again. or tumor-pancreatic. so gastric ulcers tend to cause pain with eating since the acid irritates the ulcer. Alternatively. biliary. and decreased serum albumin can indicate liver disease. Is the liver tender? This could indicate inflammation or bil­ iary obstruction. What is the differential diagnosis? As in Case 18. Ultrasound: Are stones visible? Dilated bile ducts that indicate obstruction (e. 4-10)? Imaging.. e. AST/ALT elevation. remember the principle that close to the source of bleeding generally= red.. right-sided colon cancer can also cause melena. is the liver enlarged? This could indicate congestion (right heart failure or portal hypertension). Is alk phos (o for obstruction) also elevated? Is bilirubin elevation predominantly conjugated or un­ conjugated (Fig.. tattoos. So in the stools. CASE18 A 46-year-old patient tells you he's been vomiting On physical exam. Wilson's.g.. Labs. Sup­ pose you find a high serum gastrin. autoimmune liver disease)? Risk factors for viral hepatitis (e. "How does acid end up getting secreted in the first place?'' One hormone that causes acid secretion is . What is the differential diagnosis? This could be simple heartburn/indigestion. Let's say the patient is stable.CHAPTER 10. How can you con­ firm the diagnosis of Zollinger-Ellison syndrome? The secretin test (Fig. Now what do you think? This patient must have lots of acid. a tachyarrhythmia. 4-9. Next. An EKG and blood sugar during symp­ toms could help give clues as to whether either of these etiologies is present. Duodenal or gastric? When one eats. as in this case (Fig. elevated prothrombin time. cirrhosis. This could be from the esophagus (e. What is your differential di­ agnosis. Multiple duodenal ulcers require checking serum gastrin level to explore the possibil- you for what she calls ''panic attacks. however.g. and he is found to have multiple scattered duodenal ulcers. tumor. and small bowel tumors are all potentially close by)? Percutaneous transhepatic cholangiography (PTC) and endoscopic retrograde chol­ angiopancreatography (ERCP) can be used to assess in­ trahepatic ductal dilatation (e..g.1 If this hormone is really high. a bleeding gastric or duodenal ulcer. What else could cause these symptoms? A pheochromocytoma can produce ___ 1 Gastrin 184 . duodenal ulcers typically hurt later when the acid passes from the stomach to the duodenum. if the patient seems to have wan­ ing consciousness or is hypotensive.. bleeding gastric or duodenal ulcer). ascites)? blood. etc. the stomach starts releasing acid right away. infection.. Red blood in the vomit usually means a source above the gastroesophageal junction. not digested. hypo­ glycemia." She says she feels suddenly extremely anxious. CASES have a history of alcohol abuse (which could cause cir­ rhosis)? How about a family history of liver disease (e. and how will you proceed? A psychological disorder is certainly a possible cause of panic attacks. but ruling out physiological causes is essential. Dark coffee grounds vomit generally means a source below the gastroesophageal junction. one must first determine whether the patient is stable. 4-5). it could be coming from some tumor that is producing it.).g. but an ul­ cer should also be considered. See Fig. So you ask yourself. red blood (hematochezia) could be from a hemorrhoid. secondary to primary biliary cirrhosis. etc. What is the differential diagnosis? With bleeding. 4-9. primary biliary cirrhosis. See Fig. CASE20 A 45-year-old woman schedules an appointment with You order an endoscopy on this patient. 4-4).g. varicose veins. bleeding varices).. He gets some relief with over-the-counter antacids. hot. hemorrhoids. CASE19 A 67-year-old patient says he saw blood in his stools. from primary sclerosing cholangitis. etc. first establish whether the patient has bled a lot and needs immediate IV fluids and sta­ bilization. It feels like burning and is mostly in the upper abdomen. e.g.

and the reticulocyte count tells you whether this is a problem with blood loss (hemolysis or bleeding in which case the reticulocyte would be high) or a problem with production (in which case the reticulocyte count would be low). a few things should jump out at you: Na+and K+being aberrant in opposite directions.. If this patient is otherwise healthy with otherwise normal labs (i. increased bone breakdown (e.g. primary hyper­ parathyroidism or secondary hyperparathyroidism in renal failure). this is most likely a case of hyperparathyroidism. pituitary TSH-secreting tumor).e. so you would want to examine the thyroid and order a TSH. parathyroid can­ cer. it is "too low'' given the scenario. On exam you notice darkened areas of skin on his elbows. and calci­ tonin.. or bone metas­ tases). etc. If PTH is decreased. If it is normal or high.g. 5-6. de­ creased renin (hyporeninemic hypoaldosteronism). His blood pressure is 90 I 65. lympho­ mas. Urine cAMP increases in PTH-related disorders.e. tory distinction of primary from secondary adrenal insufficiency in Fig. So increased PTH (e. your history should include an assessment of cancer risk (family history. e.. CASES paroxysmal symptoms when the blood pressure and heart rate rise. you note that his hema­ tocrit is lower than normal. Paget's disease. How will you work him up? Why is this patient anemic? From the routine blood work you should also have an MCV (mean cell volume) and a reticulocyte count. What is the most likely diagnosis? In any case of weakness/fatigue/weight loss. What will that tell you? If the TSH is abnormally low. Since there is anemia. the reticulocyte count should be elevated. What would make you suspect the adrenal gland in this case? The above features plus the hyperpigmentation.2. fatigue. Review the labora- 2 CASE23 A 37-year-old man comes for a physical for work. you do not ex­ pect lymphoma or renal disease). The urine cAMP offers a window into whether the hypercalcemia is PTH-in­ duced or not. i. and hypoten­ sion. granulomas).g. this could be a case of vitamin D excess (Fig. The elevated MCV tells you that this is a macrocytic anemia.g. night sweats. hyperpigmentation. vitamin D.). that would indicate increased negative feedback. If PTH is elevated.. The Na+and K+abnormalities tell you that this has something to do with aldosterone. In this case. and his labs show a sodium of 130 and a potassium of 5.g. that would be most consistent with second­ ary hyperthyroidism (e. so if it is normal. See Fig. so that when ACTH levels are increased. 2 Why would aldosterone be de­ terone is creased? Aldosterone is secreted from the adrenal cortex (specifically. while it should not increase in vitamin D-in­ duced hypercalcemia or bone breakdown. He is otherwise healthy and all other labs are normal.. His history and physical are completely normal. primary bone tumor. If TSH and thyroid hormone are both high. CASE22 A 60-year-old male patient's routine blood work comes back showing elevated calcium... or parathyroid hyperplasia. Urine metanephrines (catecholamine breakdown products) can be measured to look for evidence of pheochromocytoma. When his routine blood work comes back. What is the dif­ ferential diagnosis? Calcium is regulated by PTH. 5-12). Is the normal reticulocyte count normal? No. shortness of breath. If this is primary hyperparathyroidism. Macrocytic Decreased 185 . You also want to consider depression. POMC. In this case the MCV was slightly elevated and the reticulocyte count was normal. One can also check PTH level. Calcium is stored in the bones and excreted by the kidneys. blood in the stools. ACTH secretion from the pituitary increases in an effort to stimulate the failing gland. Increased potassium and decreased sodium suggest that aldos­ . Remember that aldosterone secretion is under the influence of potassium concentration and renin (which is secreted in response to decreased sodium concentration). Additionally. the ori­ gin can be a parathyroid adenoma. 5-13. leading to hyperpigmentation. Why are these important? The MCV tells you whether this is a macrocytic or mi­ crocytic anemia. or decreased renal excretion of calcium can all lead to hypercalcemia. you should also check a PTH and a urine cAMP. So we are dealing with a macrocytic ane­ mia due to a problem with RBC production. or PTHrP-related hypercalcemia. increased vitamin D (increased con­ sumption or increased ectopic conversion. from the zona glomerulosa of the adrenal gland). ACTH and MSH share a common precursor. primary hyperthyroidism (e. and weight loss. MSH also becomes in­ creased. Remember that if the adrenal gland fails in primary adrenal insuffi­ ciency. So decreased aldosterone can occur from hypokalemia (not the case here). Imaging can help distinguish among these. bone breakdown. CASE21 A 50-year-old man complains of weakness. This is a case of primary adrenal insufficiency. it would be helpful to check thy­ roid hormone level. Grave's disease). and you should do a com­ plete workup for malignancy (looking for evidence of hematologic malignancy on blood work and evidence for other tumors on imaging studies). hyper­ thyroidism can cause such symptoms. or a problem with the adrenal cortex.CHAPTER 10.

Coagulation defects can be assessed by checking the PT and PTT.e. In Wernicke's aphasia. Regarding the pattern of deficits in the face." PT is normal. What about CASE25 A parent brings her 2-year-old son to your office be­ cause she says he seems to "bleed a lot and bruise eas­ ily even from the smallest injuries. IX. 6-4) and find that in phase 1 there is no radioactivity in the urine. Com­ prehension is also impaired in Wernicke's aphasia. there is some­ thing wrong with the clotting cascade. so you want to assess the pa­ tient's oxygen saturation and probably get a chest X­ ray stat. leading to pul­ monary embolism.. Here PT is nor­ mal and PTT is elevated. The difficulty comprehending commands.g. it must be a problem with either platelets or coagulation factors. That is. is the most likely diagnosis (Hemophilia A is the diag­ nosis if an assay tells you that factor VIII is decreased. This is a receptive aphasia. von Wille­ brand's disease. the B12 level was found to be low. a vegan diet) can lead to B12 deficiency. This in­ dicates that B12 was not absorbed. the problem is with one of the following: XII.. What is the differential diagnosis? If both PT and PTT are normal. This stasis can lead to deep venous thrombosis. The diagnosis in this patient turned out to be Crohn's disease. yet a bleeding dis­ order clearly exists. Thus. or decreased dietary intake (e. the lesion is in the brainstem or cerebral hemispheres. CASE26 A parent brings her 4-year-old daughter to your office because she says she seems to "bleed a lot and bruise easily even from the smallest injuries. depending on the severity of the disease. suggests a true problem with language as op­ posed to just articulation of speech. In this patient. This tells you that the intrinsic pathway is affected." PT and PTT are both normal. and what antibodies underlie its pathophysiology?3 What diagnostic test can make the distinction be­ tween decreased intrinsic factor and terminal ileum disease?4 You run this test (Fig." Where is the lesion? Acute onset shortness of breath should make you think of a number of potentially lethal etiologies such as pulmonary embolus. Loss of both motor and sensory function over a large region on the same side suggests that this lesion is higher than the spinal cord. the fact that he has had orthopedic surgery on his leg means he is probably not moving around very much. which can embolize via the right heart to the pulmonary artery. 7-11). etc. What is the differential diagnosis? If the patient has a bleeding disorder. What is the name of the disease in which there is loss of intrinsic factor. His left side is completely normal. VIII. the problem must be with the platelets. anti-parietal cell antibodies The Schilling test = 186 . since the alteration of factor VIII level may be minimal. remember that lesions of the cranial nerve VII pathway that allow forehead sparing result from upper motor neuron le­ sions of nerve VII (Fig. CASES anemias caused by problems with RBC production in­ clude B12 deficiency and folate deficiency. There is de­ creased sensation on the right side. He is unable to follow simple commands such as "Raise your left hand. His wife says that he is not making any sense when he talks and does not seem to understand what she says to him. storage pool diseases). XI. which is made in the parietal cells of the stomach.CHAPTER 10. See Fig. B12 is absorbed in the terminal ileum by being bound to in­ trinsic factor. Glanzmann thrombasthenia. but sentences do not make any sense. This can be further assessed by looking at platelet number and function. loss of intrin­ sic factor. pneumothorax. in the cerebral hemispheres or internal capsule. Hemophilia 3 4 Pernicious anemia. You must run phase 2: Give the pa­ tient radioactive B12 and intrinsic factor to see if that corrects the problem. In this case. a 47-year-old man develops acute onset shortness of breath and chest pain with deep inspiration. If one of them is abnormal. so can you make a diagnosis? Not yet. Hemophilia B if factor IX is decreased). but PTT is elevated. words themselves are clearly artic­ ulated. This lesion thus localizes to somewhere above the brainstem. What is the differential diagnosis? CASE27 A 75-year-old man awakens to find that he is unable to move his right arm and barely able to move his right leg. however. CASE24 Ten days after removal of a benign osteoma from his tibia. How can we distin­ guish between the two? The fact that he is having trou­ ble with speech could indicate Broca's or Wernicke's aphasia (left cerebral hemisphere) but could also be a problem with CN XII leading to difficulty with tongue movements. Which side? Right­ sided findings left-sided cerebral lesion. i.. myocardial infarction. This means there is terminal ileum disease.g. Bernard-Soulier syndrome. This can either be decreased number (throm­ bocytopenia) or decreased function (e. Realize that a normal PTT does not exclude von Willebrand's disease. You notice at first glance that his face seems to be drooping on the right side but that he raises his eyebrows symmetri­ cally. This suggests a lesion in Wernicke's area.. Factor VIII can also be decreased in von Willebrand's disease. Either terminal ileum disease. 6-11. In this case it does not.

Recall that mul­ tiple sclerosis only affects the central nervous system (i. which localizes to the right medial longitudinal fasciculus. He also notices increasing clumsiness and weakness of his left hand. The right hand is entirely normal in function and sen­ sation. Also. and Babinski's sign indicate an upper motor neuron lesion.g. The difficulty with coordinat­ ing movements localizes to the cerebellum. Where are her multiple sclerosis lesions? After attempting to lift a heavy bookcase. not the peripheral nervous system). L5 disc affecting L5 root or S1 disc affecting the S1 root) is also possi­ ble.(C)7-8 ankle-knee-biceps-triceps. has acne. 7-18. points to a problem with 187 . The upper motor neuron lesion here could be anywhere from the motor cortex to the brain­ stem to the spinal cord. There are motor and sensory (including pain per­ ception) deficits in the same place. you check her visual fields and notice a deficit in peripheral vision on both sides. This is classic carpal tunnel syndrome. her left eye abducts but her right eye does not adduct. but it is less common.e. A spinal cord lesion would give loss of motor/proprioception/discrimina­ tion ipsilateral to the lesion and loss of pain and tem­ perature contralateral to the lesion. Concerned about the car accident. but which nerve root and which disc? First we must determine the nerve root. She tells you she got into a car acci­ dent last week because she tried to change lanes and didn't see that there was a car next to her. On exam you notice that on leftward gaze. this is most likely a prolapse of the L5 disc impinging upon the S1 root. an L4 prolapse (hitting the L5 root) would not affect any re­ flexes. Thus. On physical exam you note an absence of the ankle reflex on the left. What is the differential diagnosis? This sounds like Cushing's syndrome: an elevation of blood cortisol either due to adrenal hyperactivity. or ectopic ACTH (e. This pa­ tient is having a left MCA stroke. the prolapsed disc is usually at the spinal level directly above this nerve root." the arm weakness greater than the leg weakness? This indicates a lesion affecting the lateral surface of the left hemisphere more so than the medial surface. and thus can only affect the brain and spinal cord (and thus only up­ per motor neurons). Cushing's syndrome plus symptoms of a chiasm lesion point to Cushing's disease. pinprick. Lateral disc herniation (e. 7-19.. increased reflexes. We have a little help here: the absent ankle reflex. The ocular movement problem is internuclear oph­ thalmoplegia (Fig. = CASE29 A 45-year-old lab technician complains of pain and "electrical shock" sensations in his left hand at night. Where is this lesion? This is a bitemporal hemi­ anopsia. which means a midline chiasmatic lesion. though her right eye adducts on convergence. (L)3-4. The patient is otherwise healthy. the special case of Cushing's syndrome that occurs secondary to a pituitary adenoma. the median nerve.. Her left leg is indeed stiff with hyperactive reflexes and a positive Babinski's sign. leading to sensory and motor dysfunction in the distribution of this nerve. You notice she has gained lots of weight. Swelling of the tendons in the carpal tunnel are thought to put pressure on the median nerve. in this case. but this would have different sensory signs (namely on the lateral thigh and anterior/lateral calf). Remember (S)l-2. Tapping the palmar surface of the left wrist sends "electrical shocks" through the first two fingers. Where is the lesion? This is classic disc herniation. since L5 is not part of any reflexes. and has purple striae on her abdomen. What is the diagnosis? CASE31 A 45-year-old female patient whom you have not seen in awhile comes in for a physical. The loss of motor and sensory function in the territory of one nerve. on the palmar surfaces of the thumb and first two fingers on the left hand. The reproduction of symptoms by tapping on the wrist is known as "Tinel's sign. and temperature. On physical exam you note decreased sensation to light touch. You also notice difficulty with finger-to-nose and heel-shin testing in both limbs.. (C)5-6. a 55-year-old man notices tingling pain down the back of his left leg all the way down to the foot. CASES the nerve. 7-10). in­ creased ACTH from the pituitary (i. CASE28 CASE30 A patient with known multiple sclerosis complains of double vision when looking to the left and some stiff­ ness in her left leg. so we know this le­ sion is not in the spinal cord (since the pain fibers in the spinothalamic tract cross). specifically involving its posterior branch. Cushing's dis­ ease). The thumb is weak and its muscle is atrophied.. See Figs.e.g. Loss of the ankle reflex along with these sensory findings indi­ cates an S1 nerve root lesion. Note that L4 disc prolapse hitting the L5 nerve root is also common. small cell lung cancer).CHAPTER 10. Would you classify the left leg problems as upper or lower motor neuron defi­ cits? Spasticity.

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9 Brudzinski's sign 153 congenital heart disease 29 aphasia 157. 49. 85 alveolar sac 36 syndrome 161 Chediak-Higashi disease 127 cholelithiasis 87 130. 139. 42 Corrigan's pulse 10 arrhythmias. 99. 130 ascites 2. 20. 26. 58. cardiac 14-21 calcitonin 110 corticospinal tract 133 arthritis 163-168 Candida vaginitis 173 coumadin 129. 23. 175 Churg-Strauss vasculitis 25 amyotrophic lateral sclerosis 161 biliary atresia 88 Chvostek's sign 115 anemia 118-125. 120 chancroid 175 Adie's pupil 143 Babinski sign 134 Charcot-Marie-Tooth adrenal insufficiency 102 basal ganglia 148 afterload 3. 185 bilirubin 82 chylothorax 46 anemia of chronic disease 124 blood smear 124 cirrhosis 4. 55. 86 caput medusa 86 cranial nerves 138 asthma 38 cardiac arrhythmias 14-21 Crigler-Najjar syndrome 83 atherosclerosis 23 cardiac auscultation 12 Crohn's disease 80. 31 carotid upstroke 10 acid-base pathophysiology 64-70 atrioventricular node 15 cerebellum 148 acoustic neuroma 145. 149 atrial flutter 19 cardiac hypertrophy 6 ACE inhibitors 5. 24.99 atrial myxoma 28 cardiac neoplasia 28 achalasia 73 atrial septal defect 30. 26. 174. 155 autoimmune diseases 163 cerebral vasculature 156 acromegaly 105 AV (atrioventricular) node 15 cerebrospinal fluid 155 ACTH stimulation test 104 AVNRT 19 cervical cancer 175 acute renal failure 4 7 cervicitis 174 Addison's disease 102 B12 deficiency 119. 26. 186 Budd-Chiari syndrome 85 conjugate gaze pathway 143 aplastic anemia 119 Buerger disease 25 constrictive pericarditis 28 ARBs (angiotensin II receptor BUN/creatinine ratio 48.INDEX abdominal pain 89-93. 186 colon cancer 80 aortic aneurysm 23 bronchiectasis 40 complement deficiency 127 aortic coarctation 33-34 bronchiolitis 44 condyloma acuminata 175 aortic dissection 23 bronchitis 38 (chronic). 85 angina 21 bone tumors 116 claudication 22 angiotensin II receptor blockers bounding pulses 10 clonus 134 amenorrhea 170. 183 COPD 37-40 blockers) 5 bundle of His 15 Argyll-Robertson pupils 143 cor pulmonale 6. 140 Bell's palsy 145 cholangiocarcinoma 88 benign ovarian neoplasia 175 cholecystitis 87 Bernard-Soulier syndrome choledocholithiasis 87 osteodystrophy 114 aldosterone 5. 33 (acute) 104 Brown-Sequard syndrome 136 congenital aortic stenosis 33 aortic valve 1. 27. 6 basophils 128 Albright's hereditary Beh�et's disease 164 chiasm. 184 atrial fibrillation 19 cardiac dilatation 7 abducens nerve 143. 13. 97 disease 3 7-40 beta cells of pancreas 107 chronic renal failure 51 amiodarone toxicity 96 beta-hCG 173. 172 bradyarrhythmia 16 clubbing of fingers 46 anion gap 68 bradycardia 16 coagulation factors 129 anisocoria 143 brain abscess 154 coarctation of aorta 33-34 ankylosing spondylitis 166 brainstem 137 cold calories 146 antiepileptics 151 breast cancer 176 colitis 80 antithrombin III 132 Broca's area 157. chronic obstructive pulmonary 39. 106. 131 beta agonists 39 cholesterol 23 beta blockers 3. 13 aortic stenosis 9. 22. 47. 102 aldosterone antagonists 26 alpha-1 antitrypsin deficiency 38. 7. 44 congenital adrenal hyperplasia (ARBs) 5 aortic regurgitation 10. optic 105. 186 189 .

187 epidural abscess 153 giant cell arteritis 25 thrombasthenia 131 epidural hematoma 153 gliomas 155 Cushing's triad 152 epiglottitis 43 glomerular filtration rate 48 cyanotic heart disease 30. 88 cystitis 52 119. 142 emboli 22 HPV 175 human papilloma virus 175 disease 174 emphysema 37 GFR 38 hungry bone syndrome 114 encephalitis 154 Ghon complex 44 hydrocephalus 152 endocarditis 2 Ghon focus 44 hyperaldosteronism 99 190 . 166. 93 Henoch-Schonlein purpura 25 ductus arteriosus 30 Gardnerella vaginitis 173 heparin 129. 132 gastric cancer 78 hepatitis 84 dysarthria 157 gastrinoma 75. 149 heart chambers 1 dexamethasone suppression factor V Leiden 132 heart failure 1-6 test 101 fat necrosis of breast 176 heart murmurs 14 diabetes insipidus 56. 132 esophagus. 73 gastrointestinal bleeding 81-2. 88 hereditary spherocytosis 123 dysdiadochokinesia 148 gastroesophageal reflux herpes simplex virus 175 dyspnea 2 disease 72. diseases of 72 delirium 150 ethylene glycol 68 dementia 150 extracorpuscular defects 122 dermatomes 136 Hashimoto's thyroiditis 98 HDL 23-24 heart block 16 dermatomyositis 164 facial nerve 144. Edinger-Westphal nucleus HGPRT deficiency 167 Hirschprung's disease 79 Hodgkin's disease 128 184 gastroparesis 77 homonymous hemianopsia 141 egophony 46 genital warts 175 homunculus 156 Eisenmenger syndrome 32 GERD 72 Horner's syndrome 143 EKG 15 gestational trophoblastic 141. 124 helmet cells 122 diastolic murmurs 14 fetal circulation 29 hemarthrosis 129 differential cyanosis 34 FEVliFVC ratio 38. 8 diabetes mellitus 107-108 FENa 49 Helicobacter pylori 74 diarrhea 80 ferritin 120.INDEX CSF 155 endometrial cancer 175 Cushing's disease 100 endometriosis 174 Gilbert's syndrome 83 Cushing's response 152 eosinophils 128 Glanzmann's Cushing's syndrome 99. 167 fluids and electrolytes 53-64 hematuria 129 disseminated intravascular focal segmental coagulation 132 glomerulonephritis 50 hemochromatosis 85 hemoglobin 118 diverticula of esophagus 72. 118. 73 folate deficiency 119. 41 hematochezia 81 digitalis 26 fibroadenoma of breast 176 hematocrit 118 dilated cardiomyopathy 7 fibrocystic breast changes 176 hematopoeisis 118 DIP joint 165. 182 fatty liver 84 heart valves 1.149 179-180 cystic fibrosis 40. erectile dysfunction 170 glomerulonephritis 50 erythropoietin (EPO) 51. 92. 125 glucagon 106 esophageal cancer 73 glucagonoma 88 esophageal diverticula 73 gout 166. 167 De Musset's sign 10 esophageal varices 73 Graves' disease 96 deep venous thrombosis (DVT) esophagitis 73 Guillain-Barre syndrome 161 22. gall bladder disease 86 Henderson-Hasselbach 135. 130 DVT 22. 120 hemolysis 122 diverticula of large intestine 79 foramen ovale 29 hemolytic uremic diverticulitis 79 fremitus 46 syndrome 131 hemophilia 129 diverticulosis 79 DLCO 38 G6PD deficiency 123 hemothorax 46 dorsal (posterior) columns 120. 40. 159 gallstone ileus 88 equation 65 Dubin-Johnson syndrome 83 gallstones 87. 100-2. glossopharyngeal nerve 147.

187 intracorpuscular defects 122 menorrhagia 129 intracranial pressure. elevated menstrual cycle 170 P wave 15 metabolic acidosis 68 Paget's disease of bone 116 152 intraductal papilloma of breast metabolic alkalosis 67 pancreatic cancer.INDEX hypercalcemia 110 Kallman's syndrome 138. 110 jaundice 82 mitral opening snap 11 Parkinson's disease 150 jugular venous pressure 2 mitral regurgitation 11. 70. 120-122 metyrapone 102 pancytopenia 119 iodine deficiency 98 Meyer's loop 141 panhypopituitarism 106 iron deficiency 119 microscopic polyangiitis 25 paradoxical embolus 22 irritable bowel syndrome 79 miliary tuberculosis 44 paraneoplastic syndromes 45. 57-60 Lyme disease 165 hypoparathyroidism 114 lymphocytes 128 oculomotor nerve 141. 183 multifocal atrial tachycardia 19 hypernatremia 55-57 hyperparathyroidism 111 lacunar infarcts 157 multiple endocrine neoplasia 104 hyperpituitarism 105 Lambert-Eaton syndrome 162 multiple myeloma 128 hypersensitivity 126 large intestine. 106. 139. 154 ovarian cysts 175 144. 140 lED-associated arthritis 166 Marcus Gunn pupil 142 optic nerve 138. 77. 149 liver function tests 83 hypoglycemia 108 lung cancer 45 115 disease 31 nystagmus 146 hypokalemia 63-64 lupus 51. 99 leukocyte esterase 52 hypocalcemia 113 L'Hermitte's sign 159 hypocalciuric hypercalcemia Libman-Sachs endocarditis 27 nephritic syndrome 50 erythema 88 lipid-lowering drugs 23. 88 metrorrhagia 129 pancreatitis 88 intrinsic factor 72. 149 hypopituitarism 106 lymphomas 128 olfactory nerve 138. diseases of 79 multiple sclerosis 158 hypersplenism 86 laryngitis 43 muscular dystrophy 162 hypertension 24 LDL 23-24 myasthenia gravis 161 hypertension treatment 26 Lesch-Nyan Syndrome 167 myocardial infarction 21 hyperthyroidism 96 leukemias 128 myocarditis 28 hypertrophic cardiomyopathy 6 leukocyte adhesion myxedema 96 hypoalbuminemia 115 deficiency 127 necrolytic migrating hypoaldosteronism 64. 13 partial thromboplastin time 129 mitral valve 1. 149 orchitis 169 Ig A nephropathy 50 mast cells 128 Immunodeficiency 118. 162 parathyroid hormone 51. 164 hyponatremia 55. 126 mastitis 176 orthopnea 2 inferior petrosal sinus sampling mebranoproliferative osteitis deformans 116 102 infertility 177 inotropes 3 glomerulonephritis 50 medial longitudinal fasciculus 144 osteoarthritis 165 osteomalacia 116 osteomyelitis 116 insulin 106 melena 82 osteopetrosis 116 insulinoma 109 membranous nephropathy 50 osteoporosis 115 internuclear ophthalmoplegia meningioma 155 ovarian cancer 175 meningitis 153. 10 patent ductus arteriosus 32 atrophy 161 191 . 53. 149 hypothyroidism 98 obstructive lung disease 37 opsonization 127 malabsorption 78 optic chiasm 105. 176 IV solutions 54 milk-alkali syndrome 110 minimal change disease 50 58. 24 neuroanatomy 133 hypocoagulable states 129 liver diseases 84 noncyanotic congenital heart hypoglossal nerve 148. 172 mitral valve prolapse 11 hypercalciuric Kawasaki's disease 25 Mobitz I heart block 17 Kayser-Fleischer ring 85 Mobitz II heart block 17 hypocalcemia 115 hyperkalemia 60-63 Kernig's sign 153 MUDPILES 68. 13 paroxysmal nocturnal dyspnea 3 juvenile spinal muscular mitral stenosis 10.

33 spinal accessory nerve 148. 159 post-infectious glomerulonephritis 50 postrenal failure 47. 114 supraventricular polycythemia 118. 41 Sjogren's syndrome 164 pituitary apoplexy 106 pulmonary valve 12 small intestine. 149 pleural effusion 45 pulsus paradoxus 39 spinal cord 159 pleurisy 45 pulsus parvus et tardus 10 spinothalamic tract 135. 172 peripheral vascular disease 22 PTH-related protein (PTHrP) pernicious anemia 120 45.112 SIADH 58-60 sickle cell anemia 122 pharyngitis 43 PTT 129. 106 rhythm strip 17 testicular cancer 170 prolactin-secreting rickets 116 testicular torsion 170 Rotor syndrome 83 tetralogy of Fallot 30 Rousseau's sign 115 thalassemia 122 prostatic hypertrophy 169 S1 sound 8 thrombangiitis obliterans 25 prostatitis 169 S2 sound 8 thrombocytopenia 129. 168 sarcoid 164 pelvic inflammatory disease 89. diseases of 78 platelet dysfunction 130 pulmonic regurgitation 12 somatostatinoma 88 platelets 129 pulmonic stenosis 12. 181 roidism 114 secondary pericardia! rub 28 pseudotumor cerebri 152 pericardiocentesis 28 psoriatic arthritis 166 hyperparathyroidism 51 secretin test 75. 129 SA node 14 pectoriloquy 46 pseudogout 166. 130 seizures 151 peripheral neuropathies 161 PT H 51.INDEX patent foramen ovale 22 prothrombin time 83. 131 protein C 132 S3 sound 8 thrombotic thrombocytopenic protein S 132 S4 sound 8 adenomas 106 prostate 169 third-degree heart block 17 prostate cancer 169 purpura 131 192 . 167. 104 pulmonary edema 2 sinus tachycardia 18 sinusitis 42 PIP joint 165. 125 referred pain 90 syndrome of inappropriate subdural abscess 165 podagra 167 tachyarrhythmias 18 polycystic ovary syndrome 174 antidiuretic hormone polycythemia vera 125 reflux 72 polymyositis 164 Reiter's syndrome 166 portal hypertension 85 renal failure 47-52 synovial fluid analysis 165 posterior (dorsal) columns 120. 50 respiratory alkalosis 66 restrictive cardiomyopathy 7 secretion 58 51. 110 Sheehan's syndrome 106. 130 sinoatrial node 14 pheochromocytoma 27. 60 Schilling test 120-121 pseudohypoparathyroidism 114 schistocytes 122 pseudopseudohypoparathy- scleroderma 164. 174 peptic ulcer disease 74 pericardia! effusion 28 pseudohyponatremia 59. 166. 159 pleuritis 45 pupillary light reflex 141-143 spondyloarthritis 165 pneumonia 44 Purkinje system 15 stroke 155-158 pneumonitis 44 pyelonephritis 52 struma ovarii 96 pneumothorax 46 pyruvate kinase deficiency 123 subarachnoid hemorrhage 154 poliomyelitis 161 QRS complex 15 subdural hematoma 154 polyarteritis nodosa 25 QT interval 20. 183 pericarditis 28 PT 129. renal osteodystrophy 51 syphilis 175 renal tubular acidosis 68-69 syringomyelia 159 respiratory acidosis 66 systemic lupus erythematosis 135. 167 pulmonary function testing 37 pituitary adenoma 105 pulmonary hypertension 6. 99. 113. 115 prerenal failure 47-50 rheumatic fever 28 Takayasu's arteritis 25 primary biliary cirrhosis 88 rheumatic heart disease 28 temporal arteritis 25 tachyarrhythmias 18 primary sclerosing cholangitis 88 rheumatoid arthritis 165 Tensilon test 162 Prinzmetal's angina 21 rhinitis 42 testicles 169 prolactin 95. 164 systolic murmurs 14 PR interval 15 restrictive lung disease 40 preload 3 rhabdomyolysis 114.

150 trochlear nerve 143. (TIA) 155 transposition of the great syndrome 53 von Willebrand's disease 130 tophi in gout 167 vulvar cancer 175 Waterhouse-Friedrichsen syndrome 102 149 varices 86 Wegener's granulomatosis 25 vasculitis 24. 149 ventricular septal defect 30. 88. 184 . 31 Wilson's disease 85. 25 Wernicke's area 157 Trichomonas vaginitis 173 ventricular arrhythmias 19-20 Whipple's triad 109 tricuspid regurgitation 12 ventricular escape beats 17 widened pulse pressure 10 tricuspid valve 12 ventricular fibrillation 20 Wilms' tumor 53 trigeminal nerve 143. 147. 155 urethritis 52 vestibulocochlear nerve 145. 149 ventricular Wolff-Parkinson-White arteries 30 tuberculosis 44 tachyarrhythmias 19 syndrome 19 ventricular tachycardia 20 U wave 15 vesicoureteral reflux 52 ulcerative colitis 80 vestibular schwannoma 145.INDEX thrombus 22 urinary tract infection 52 VIPoma 88 thyroid cancer 98 urinary tract tumors 53 vitamin D 110. 133. 112 thyroid nodules 98 urine anion gap 68 vitamin D deficiency 114 thyroiditis 98 urine sodium 48 vitamin K deficiency 129 TIA 155 uterine fibroids 175 von Hippel-Landau TIBC 120 Uthoff's phenomenon 159 Torsades de Pointes 20 vaginal cancer 175 transferrin 120 vaginitis 173 transient ischemic attack vagus nerve 16. 149 urinalysis 52 vestibulo-ocular reflex 145 193 xanthochromia 155 Zollinger-Ellison syndrome 75. 76.

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