Physiology Second Edition, Apuntes de Biología

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Case Files

Physiology

Second Edition EUGENE C.TOY, MD

The John S. Dunn Senior Academic Chief and Program Director Obstetrics and Gynecology Residency The Methodist Hospital, Houston Clerkship Director and Clinical Associate Professor Department of Obstetrics and Gynecology University of Texas Medical School at Houston Houston,Texas

NORMAN WEISBRODT, PhD

Professor and Interim Chairman Department of Integrative Biology and Pharmacology University of Texas Medical School at Houston Houston,Texas

WILLIAM P. DUBINSKY, JR., PhD

Professor of Integrative Biology and Pharmacology University of Texas Medical School at Houston Houston,Texas

ROGER G. O’NEIL, PhD

Professor of Integrative Biology and Pharmacology University of Texas Medical School at Houston Houston,Texas

EDGAR T. WALTERS, PhD

Professor of Integrative Biology and Pharmacology University of Texas Medical School at Houston Houston,Texas

KONRAD P. HARMS, MD

Associate Program Director Obstetrics and Gynecology Residency The Methodist Hospital, Houston Assistant Clinical Professor Weill Cornell College of Medicine Houston,Texas

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To my outstanding obstetrics and gynecology residents who exemplify excellence and make coming to work each day a joy: Erica, Amber, Brad, Tara, Barrett, Kelli, Jennifer, Tametra, Stephen, Kristin, Tina, Lauren, Jessica, Vian, Kathryn, and Stan.

—ECT

To our many medical students over the past 25 years who have taught us so much.

—NW, WPD , RGO, ETW

To my wife, Heidi, and sons, Koen and Kort, for their many sacrifices on my behalf and their unwavering love and support. To my parents, Paul and Lois, for their guidance and love throughout my life. To my brother, Kent, for being a great role model and my best friend.

—KPH

❖ DEDICATION

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❖ CONTENTS

CONTRIBUTORS vii

ACKNOWLEDGMENTS ix

INTRODUCTION xi

SECTION I

Applying the Basic Sciences to Clinical Medicine 1

Part 1. Approach to Learning Physiology 3

Part 2. Approach to Disease 3

Part 3. Approach to Reading 3

SECTION II

Clinical Cases 9

Fifty-One Case Scenarios 11

SECTION III

Listing of Cases 417

Listing by Case Number 419

Listing by Disorder (Alphabetical) 420

INDEX 423

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❖ ACKNOWLEDGMENTS

The inspiration for this basic science series occurred at an educational retreat led by Dr. L. Maximilian Buja, who at the time was the Dean of the University of Texas Medical School at Houston and is currently Executive Vice President for Academic Affairs. It has been such a joy to work together with Drs. Weisbrodt, Dubinsky, O’Neil, and Walters, who are accomplished scientists and teachers. It has been rewarding to collaborate with Dr. Konrad Harms, a friend, a scholar, and an excellent teacher. Dr. Harms found collaborating with his father, Dr. Paul Harms, a neuroendocrinologist and reproductive physiolo- gist at Texas A&M University, to be a true privilege, joy, and honor. I appreci- ate the many hours and talent of Alaina Johnson, who reviewed the entire manuscript and served as a major consultant. I would like to thank McGraw- Hill for believing in the concept of teaching by clinical cases. I owe a great debt to Catherine Johnson, who has been a fantastically encouraging and enthusiastic editor. At the University of Texas Medical School at Houston, I would like to recognize the bright and enthusiastic medical students who have inspired us to find better ways to teach. At Methodist Hospital, I appreciate Drs. Mark Boom, Alan L. Kaplan, Karin Pollock-Larsen, H. Dirk Sostman, and Judy Paukert, and Mr. Reggie Abraham. At St. Joseph Medical Center, I would like to recognize our outstanding administrators: Phil Robinson, Pat Mathews, Laura Fortin, Dori Upton, and Drs. John Bertini and Thomas V. Taylor. I appreciate Marla Buffington’s advice and assistance. Without the help from my colleagues, Drs. Simmons, Schachel, and McBride, this book could not have been written. Most important, I am humbled by the love, affection, and encouragement from my lovely wife, Terri, and our four children, Andy, Michael, Allison, and Christina.

Eugene C. Toy

ix

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❖ INTRODUCTION

Often, the medical student will cringe at the “drudgery” of the basic science courses and see little connection between a field such as physiology and clin- ical situations. Clinicians, however, often wish they knew more about the basic sciences, because it is through the science that we can begin to understand the complexities of the human body and thus have rational methods of diagnosis and treatment. Mastering the knowledge in a discipline such as physiology is a formidable task. It is even more difficult to retain this information and to recall it when the clinical setting is encountered. To accomplish this synthesis, physiology is opti- mally taught in the context of medical situations, and this is reinforced later during the clinical rotations. The gulf between the basic sciences and the patient arena is wide. Perhaps one way to bridge this gulf is with carefully constructed clinical cases that ask basic science-oriented questions. In an attempt to achieve this goal, we have designed a collection of patient cases to teach physiology- related points. More important, the explanations for these cases emphasize the underlying mechanisms and relate the clinical setting to the basic science data. We explore the principles rather than emphasize rote memorization. This book is organized for versatility: to allow the student “in a rush” to go quickly through the scenarios and check the corresponding answers and to provide more detailed information for the student who wants thought-provoking explanations. The answers are arranged from simple to complex: a summary of the pertinent points, the bare answers, a clinical correlation, an approach to the physiology topic, a comprehension test at the end for reinforcement or emphasis, and a list of references for further reading. The clinical cases are arranged by system to better reflect the organization within the basic science. Finally, to encourage thinking about mechanisms and relationships, we inten- tionally used open-ended questions in the cases. Nevertheless, several multi- ple-choice questions are included at the end of each scenario to reinforce concepts or introduce related topics. We appreciate the good feedback from the various medical students from across the country. We have adopted many of these suggestions. In this second edition, there have been 30 cases that were substantially rewritten and 16 new figures to improve the readability and explanations. We think this second edi- tion is an even better product.

HOW TO GET THE MOST OUT OF THIS BOOK

Each case is designed to introduce a clinically related issue and includes open- ended questions usually asking a basic science question, but at times, to break up the monotony, there will be a clinical question. The answers are organized into four different parts:

xi

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PART I

1. Summary
2. A straightforward answer is given for each open-ended question.
3. Clinical Correlation —A discussion of the relevant points relating the basic science to the clinical manifestations, and perhaps introducing the student to issues such as diagnosis and treatment.

PART II

An approach to the basic science concept consisting of two parts

1. Objectives —A listing of the two to four main principles that are criti- cal for understanding the underlying physiology to answer the question and relate to the clinical situation.
2. Discussion of the physiologic principles.

PART III

Comprehension Questions —Each case includes several multiple-choice questions that reinforce the material or introduce new and related concepts. Questions about the material not found in the text are explained in the answers.

PART IV

Physiology Pearls —A listing of several important points, many clinically rel- evant, reiterated as a summation of the text and to allow for easy review, such as before an examination.

xii INTRODUCTION

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APPLYING THE BASIC SCIENCES TO CLINICAL MEDICINE 3

PART 1. APPROACH TO LEARNING PHYSIOLOGY

Physiology is best learned through a systematic approach, by understanding the cellular and macroscopic processes of the body. Rather than memorizing the individual relationships, the student should strive to learn the underlying rationale, such as: “The cell membrane allows passage of some molecules and not others based on lipid solubility, size of the molecule, concentration gradi- ent, and electrical charge. Because the cell membrane is formed by a lipid bilayer, molecules that are lipid-soluble pass through more easily. Smaller molecules and those without an electrical charge also transfer more easily. Finally, the concentration gradient ‘drives’ the molecular transport, with the larger gradient providing a greater ‘force’.”

PART 2. APPROACH TO DISEASE

Physicians usually tackle clinical situations by taking a history (asking ques- tions), performing a physical examination, obtaining selective laboratory and imaging tests, and then formulating a diagnosis. The synthesis of the history, physical examination, and imaging/laboratory tests is called the clinical data- base. After a diagnosis has been reached, a treatment plan usually is initiated, and the patient is followed for a clinical response. Rational understanding of disease and plans for treatment are best acquired by learning about the normal human processes on a basic science level; similarly, being aware of how dis- ease alters the normal physiologic processes is best understood on a scientific level. Physiology also requires the ability to appreciate the normal workings of the human body, whereas pathophysiology focuses on how disease or dis- ruption of the normal state affects the same mechanisms. The student should strive to learn the reason a disease manifests as certain symptoms or signs.

PART 3. APPROACH TO READING

There are six key questions that help stimulate the application of basic science information to the clinical setting:

**1. What is the likely mechanism for the clinical finding(s)?

2. What is the likely cellular response to a certain change in** **environment?
3. With the biochemical findings noted, what clinical processes are** **expected?
4. Given physiologic readings (hemodynamic, pulmonary, etc.), what** **is the likely disease process?
5. What is the likely cellular mechanism for the medication effect?
6. What graphic data best depict the physiologic principle?**

APPLYING THE BASIC SCIENCES TO CLINICAL MEDICINE 5

is phosphorylated by a specific protein kinase. That kinase is inacti- vated in the presence of insulin, reducing the phosphorylation of glyco- gen synthase. The reaction is reinforced by an insulin-dependent activation of protein phosphatase-1 that dephosphorylates and activates glycogen synthase. Protein phosphatase-1 has multiple substrate pro- teins within the cell, one of which is phosphorylase. Phosphorylase catalyzes the breakdown of glycogen and is activated by phosphoryla- tion with PKA and inactivated by dephosphorylation. Thus, after the ingestion of a carbohydrate-containing meal, the rise in plasma insulin levels will cause an activation of glycogen synthase and an inhibition of phosphorylase. A fall in the plasma glucose reduces secretion of pancreatic insulin and stimulates secretion of glucagon. The hepatocyte responds to these changes with a decrease in protein phosphatase activity (as a result of decreased insulin levels) and an increase in PKA activity (as a result of elevated glucagon lev- els). The overall effect is an increase in glycogenolysis with the pro- duction of glucose.

3. With the biochemical findings noted, what clinical processes are expected? This is the converse of explaining clinical findings by reference to cellular or biochemical mechanisms. An understanding of the underly- ing molecular biology allows an extrapolation to the clinical findings. The student is encouraged to explore relationships between micro- scopic function and clinical symptoms or signs. The patient is aware only of overt manifestations such as pain, fatigue, and bleeding. Usually, substantial subclinical changes are present. The student’s understanding of these relationships, as depicted below, provides opportunities to detect disease before it is clinically evident or to dis- rupt the disease process before it becomes advanced. Biochemical → Cellular → Subclinical changes → Clinical symptoms

One example is the understanding of the development of cervical can- cer. It is known that human papillomavirus (HPV) is the primary onco- genic stimulus in the majority of cases of cervical intraepithelial neoplasia (CIN) and cervical cancer. HPV, particularly in the virulent subtypes, such as 16 and 18, incorporates its DNA into the host cervical epithelium cells, leading some women to develop CIN. Over years, the CIN progresses to cervical cancer; when this becomes advanced, it becomes evident by the patient’s development of abnormal vaginal bleeding, lower abdominal pain, or back pain if metastasis has occurred. Awareness of this sequence of events allows for the possible develop- ment of an HPV vaccine, assays for HPV subtypes to assess the risk of CIN or cancer, and cytologic analysis of CIN when it is still asympto- matic (Pap smear), with appropriate treatment before cancer arises. The

6 CASE FILES: PHYSIOLOGY

result is a 90% decrease in mortality from cervical cancer compared with the situation before the advent of the Pap smear.

4. Given physiologic readings (hemodynamic, pulmonary, etc.), what is the likely disease process? The clinician’s ability to interpret data relative to the physiologic and pathophysiologic processes is fundamental to rational therapy. For instance, a pulmonary artery catheter may be used to approximate the measure of a patient’s left atrial pressure. In an instance of severe hypoxemia and diffuse pulmonary infiltrates on a chest radiograph, a common diagnostic dilemma is whether the patient has fluid overload and is in congestive heart failure or whether this represents acute res- piratory distress syndrome (ARDS). In volume overload, the increased hydrostatic pressure drives fluid from the pulmonary capil- laries into the pulmonary interstitium, leading to inefficient gas exchange between the alveoli and the capillary. The treatment for this condition would be diuresis, such as with furosemide, to remove fluid. In contrast, with ARDS, the pathophysiology is leaky capillaries, and the pulmonary capillary pressure is normal to slightly low. The ther- apy in this case is supportive and entails waiting for repair; diuresis may lead to hypovolemia and hypotension. In essence, the question is whether the patient is “wet” or “leaky,” and the wrong therapy may be harmful. The pulmonary artery wedge pressure catheter is helpful in this case, because high pressures would suggest volume overload whereas normal-to-low pressures would suggest ARDS with leaky capillaries. 5. What is the likely cellular mechanism for the medication effect? The student is best served by understanding the cellular mechanisms for not only physiologic responses but also responses to medications. For instance, an awareness of the behavior of digoxin allows one to understand its effect on the heart. Digoxin is a cardiac glycoside that acts indirectly to increase intracellular calcium. Digitalis binds to a specific site on the outside of Na+-K+-ATPase, reducing the activity of that enzyme. All cells express Na+-K+-ATPase, but they express differ- ent isoforms of the enzyme; the isoforms expressed by cardiac myocytes and vagal neurons are the most susceptible to digitalis. Inhibition of the enzyme by digitalis causes an increase in intracellular Na+^ and decreases the Na+^ concentration gradient across the plasma membrane. This Na+^ concentration provides the driving force for the Na+-Ca^2 +^ antiporter. The rate of transport of Ca 2 +^ out of the cell is reduced, and this leads to an increase in intracellular Ca 2 +^ and greater activation of contractile elements and an increase in the force and velocity of contraction of the heart. The electric characteristics of myocardial cells also are altered by the cardiac glycosides. The most important effect is a shortening of the action potential that produces a shortening of both atrial and ventricular refractoriness. There is also an