NOTE TO INSTRUCTORS Contact your Elsevier Sales Representative for teaching resources, including slides and image banks, for Guyton and Hall Textbook of Medical Physiology, 14e, or request these supporting materials at: http://evolve.elsevier.com/Hall/physiology/ 1 4 T H E D I T I O N Guyton and Hall Textbook of Medical Physiology John E. Hall, PhD Arthur C. Guyton Professor and Chair Department of Physiology and Biophysics Director, Mississippi Center for Obesity Research University of Mississippi Medical Center Jackson, Mississippi Michael E. Hall, MD, MS Associate Professor Department of Medicine, Division of Cardiovascular Diseases Associate Vice Chair for Research Department of Physiology and Biophysics University of Mississippi Medical Center Jackson, Mississippi Elsevier 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103- 2899 GUYTON AND HALL TEXTBOOK OF MEDICAL PHYSIOLOGY, FOURTEENTH EDITION ISBN: 978- 0- 323- 59712- 8 INTERNATIONAL EDITION ISBN: 978- 0- 323- 67280- 1 Copyright © 2021 by Elsevier, Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notice Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted 2016, 2011, 2006, 2000, 1996, 1991, 1986, 1981, 1976, 1971, 1966, 1961, and 1956. Library of Congress Control Number: 2020936245 Publisher: Elyse O’Grady Senior Content Development Specialist: Jennifer Shreiner Publishing Services Manager: Julie Eddy Project Manager: Grace Onderlinde Design Direction: Margaret Reid Printed in Canada Last digit is the print number: 9 8 7 6 5 4 3 2 1 To Our Families For their abundant support, for their patience and understanding, and for their love To Arthur C. Guyton For his imaginative and innovative research For his dedication to education For showing us the excitement and joy of physiology And for serving as an inspirational role model Preface The first edition of the Textbook of Medical Physiology was review the basic principles needed for understanding the written by Arthur C. Guyton almost 65 years ago. Unlike pathophysiology of human disease. We have attempted to most major medical textbooks, which often have 20 or maintain the same unified organization of the text that more authors, the first eight editions of the Textbook of has been useful to students in the past and to ensure that Medical Physiology were written entirely by Dr. Guyton. the book is comprehensive enough that students will con- He had a gift for communicating complex ideas in a clear tinue to use it during their professional careers. and interesting manner that made studying physiology Our hope is that the Textbook of Medical Physiology fun. He wrote the book to help students learn physiology, conveys the majesty of the human body and its many not to impress his professional colleagues. functions and that it stimulates students to study physiol- Dr. John Hall worked closely with Dr. Guyton for ogy throughout their careers. Physiology links the basic almost 30 years and had the privilege of writing parts of sciences and medicine. The great beauty of physiology is the 9th and 10th editions and of assuming sole responsi- that it integrates the individual functions of all the body’s bility for completing the subsequent editions. different cells, tissues, and organs into a functional whole, Dr. Michael Hall has joined in the preparation of the the human body. Indeed, the human body is much more 14th edition of the Textbook of Medical Physiology. He is than the sum of its parts, and life relies upon this total a physician trained in internal medicine, cardiology, and function, not just on the function of individual body parts physiology and has brought new insights that have helped in isolation from the others. greatly to achieve the same goal as for previous editions— This brings us to an important question: How are the to explain, in language easily understood by students, how separate organs and systems coordinated to maintain the different cells, tissues, and organs of the human body proper function of the entire body? Fortunately, our bod- work together to maintain life. ies are endowed with a vast network of feedback controls This task has been challenging and fun because that achieve the necessary balances without which we researchers continue to unravel new mysteries of body would be unable to live. Physiologists call this high level functions. Advances in molecular and cellular physiology of internal bodily control homeostasis. In disease states, have made it possible to explain some physiology princi- functional balances are often seriously disturbed, and ples in the terminology of molecular and physical sciences homeostasis is impaired. When even a single disturbance rather than in merely a series of separate and unexplained reaches a limit, the whole body can no longer live. One of biological phenomena. However, the molecular events the goals of this text is to emphasize the effectiveness and that underpin the functions of the body’s cells provide beauty of the body’s homeostasis mechanisms as well as only a partial explanation of human physiology. The total to present their abnormal functions in disease. function of the human body requires complex control Another objective is to be as accurate as possible. Sug- systems that communicate with each other and coordi- gestions and critiques from many students, physiologists, nate the molecular functions of the body’s cells, tissues, and clinicians throughout the world have checked factual and organs in health and disease. accuracy as well as balance in the text. Even so, because The Textbook of Medical Physiology is not a reference of the likelihood of error in sorting through many thou- book that attempts to provide a compendium of the most sands of bits of information, we issue a further request recent advances in physiology. It is a book that contin- for all readers to send notations of error or inaccuracy to ues the tradition of being written for students. It focuses us. Physiologists understand the importance of feedback on the basic principles of physiology needed to begin a for proper function of the human body; feedback is also career in the health care professions, such as medicine, important for progressive improvement of a textbook of dentistry, and nursing, as well as graduate studies in the physiology. To the many persons who have already helped, biological and health sciences. It should also be useful we express sincere thanks. Your feedback has helped to to physicians and health care professionals who wish to improve the text. vii Preface A brief explanation is needed about several features most students will learn in more detail in other courses; of the 14th edition. Although many of the chapters have (2) physiological information of special importance to been revised to include new principles of physiology and certain fields of clinical medicine; and (3) information new figures to illustrate these principles, the text length that will be of value to those students who wish to study has been closely monitored to limit the book’s size so specific physiological mechanisms more deeply. that it can be used effectively in physiology courses for The ebook version provides links to additional content medical students and health care professionals. New including video animations and self-a ssessment questions references have been chosen primarily for their pre- that can be accessed with computers, smart phones, and sentation of physiological principles, for the quality of electronic tablets. For additional self- assessment beyond their own references, and for their easy accessibility. these textbook supplements, the reader may consider The selected bibliography at the end of the chapters lists using a copy of Guyton and Hall Physiology Review, which mainly review papers from recently published scientific includes more than 1000 practice questions referenced to journals that can be freely accessed from the PubMed site the textbook. We hope that these ancillary materials will at https://www.ncbi.nlm.nih.gov/pubmed/. Use of these assist readers in testing their understanding of basic prin- references, as well as cross- references from them, pro- ciples of physiology. vides much more extensive coverage of the entire field of We express sincere thanks to many persons who have physiology. helped to prepare this book, including our colleagues in Our effort to be as concise as possible has, unfortu- the Department of Physiology and Biophysics at the Uni- nately, necessitated a more simplified and dogmatic versity of Mississippi Medical Center who provided valu- presentation of many physiological principles than we able suggestions. The members of our faculty and a brief normally would have desired. However, the bibliogra- description of the research and educational activities of the phy can be used to learn more about the controversies department can be found at http://physiology.umc.edu/. and unanswered questions that remain in understanding We are especially grateful to Stephanie Lucas for excellent the complex functions of the human body in health and assistance and to James Perkins for excellent illustrations. disease. We also thank Elyse O’Grady, Jennifer Shreiner, Grace Another feature of the book is that the print is set Onderlinde, Rebecca Gruliow, and the entire Elsevier in two sizes. The material in large print constitutes the team for continued editorial and production excellence. fundamental physiological information that students Finally, we thank the many readers who continue to will require in virtually all of their medical studies. The help us improve the Textbook of Medical Physiology. We material in small print and highlighted with a pale lav- hope that you enjoy the current edition and find it even ender background (or identified by beginning and ending more useful than previous editions. double gray arrowheads in the ebook version) is of several different kinds: (1) anatomic, chemical, and other infor- John E. Hall mation that is needed for immediate discussion but that Michael E. Hall viii CHAPTER 1 U Functional Organization of the Human Body N I T and Control of the “Internal Environment” I Physiology is the science that seeks to explain the physi- Each type of cell is specially adapted to perform one cal and chemical mechanisms that are responsible for the or a few particular functions. For example, the red blood origin, development, and progression of life. Each type cells, numbering about 25 trillion in each person, trans- of life, from the simplest virus to the largest tree or the port oxygen from the lungs to the tissues. Although the complicated human being, has its own functional char- red blood cells are the most abundant of any single type of acteristics. Therefore, the vast field of physiology can be cell in the body, there are also trillions of additional cells divided into viral physiology, bacterial physiology, cellular of other types that perform functions different from those physiology, plant physiology, invertebrate physiology, ver- of the red blood cell. The entire body, then, contains about tebrate physiology, mammalian physiology, human physi- 35 to 40 trillion human cells. ology, and many more subdivisions. The many cells of the body often differ markedly from one another but all have certain basic characteristics that Human Physiology. The science of human physiology are alike. For example, oxygen reacts with carbohydrate, attempts to explain the specific characteristics and mech- fat, and protein to release the energy required for all cells anisms of the human body that make it a living being. The to function. Furthermore, the general chemical mecha- fact that we remain alive is the result of complex control nisms for changing nutrients into energy are basically systems. Hunger makes us seek food, and fear makes us the same in all cells, and all cells deliver products of their seek refuge. Sensations of cold make us look for warmth. chemical reactions into the surrounding fluids. Other forces cause us to seek fellowship and to reproduce. Almost all cells also have the ability to reproduce addi- The fact that we are sensing, feeling, and knowledgeable tional cells of their own type. Fortunately, when cells of a beings is part of this automatic sequence of life; these spe- particular type are destroyed, the remaining cells of this type cial attributes allow us to exist under widely varying con- usually generate new cells until the supply is replenished. ditions that otherwise would make life impossible. Human physiology links the basic sciences with medicine Microorganisms Living in the Body Outnumber Hu- and integrates multiple functions of the cells, tissues, and man Cells. In addition to human cells, trillions of microbes organs into the functions of the living human being. This inte- inhabit the body, living on the skin and in the mouth, gut, gration requires communication and coordination by a vast and nose. The gastrointestinal tract, for example, normally array of control systems that operate at every level—from the contains a complex and dynamic population of 400 to 1000 genes that program synthesis of molecules to the complex species of microorganisms that outnumber our human nervous and hormonal systems that coordinate functions of cells. Communities of microorganisms that inhabit the cells, tissues, and organs throughout the body. Thus, the coor- body, often called microbiota, can cause diseases, but most dinated functions of the human body are much more than the of the time they live in harmony with their human hosts sum of its parts, and life in health, as well as in disease states, and provide vital functions that are essential for survival of relies on this total function. Although the main focus of this their hosts. Although the importance of gut microbiota in book is on normal human physiology, we will also discuss, the digestion of foodstuffs is widely recognized, additional to some extent, pathophysiology, which is the study of disor- roles for the body’s microbes in nutrition, immunity, and dered body function and the basis for clinical medicine.  other functions are just beginning to be appreciated and represent an intensive area of biomedical research.  CELLS ARE THE LIVING UNITS OF THE BODY EXTRACELLULAR FLUID—THE “INTERNAL ENVIRONMENT” The basic living unit of the body is the cell. Each tissue or organ is an aggregate of many different cells held together About 50% to 70% of the adult human body is fluid, mainly by intercellular supporting structures. a water solution of ions and other substances. Although 3 UNIT I Introduction to Physiology: The Cell and General Physiology most of this fluid is inside the cells and is called intracellu- regulated, normally varying only a few millimoles per liter, lar fluid, about one- third is in the spaces outside the cells even with large changes in sodium intake, but these varia- and is called extracellular fluid. This extracellular fluid is tions of sodium concentration are at least 1 million times in constant motion throughout the body. It is transported greater than for hydrogen ions. rapidly in the circulating blood and then mixed between Powerful control systems exist for maintaining concen- the blood and tissue fluids by diffusion through the capil- trations of sodium and hydrogen ions, as well as for most lary walls. of the other ions, nutrients, and substances in the body at In the extracellular fluid are the ions and nutrients levels that permit the cells, tissues, and organs to perform needed by the cells to maintain life. Thus, all cells live in their normal functions, despite wide environmental varia- essentially the same environment—the extracellular fluid. tions and challenges from injury and diseases. For this reason, the extracellular fluid is also called the Much of this text is concerned with how each organ or internal environment of the body, or the milieu intérieur, a tissue contributes to homeostasis. Normal body functions term introduced by the great 19th-c entury French physi- require integrated actions of cells, tissues, organs, and ologist Claude Bernard (1813–1878). multiple nervous, hormonal, and local control systems Cells are capable of living and performing their spe- that together contribute to homeostasis and good health. cial functions as long as the proper concentrations of oxygen, glucose, different ions, amino acids, fatty sub- Homeostatic Compensations in Diseases. Disease is stances, and other constituents are available in this inter- often considered to be a state of disrupted homeostasis. nal environment. However, even in the presence of disease, homeostatic mechanisms continue to operate and maintain vital func- Differences in Extracellular and Intracellular Fluids. tions through multiple compensations. In some cases, The extracellular fluid contains large amounts of sodium, these compensations may lead to major deviations of the chloride, and bicarbonate ions plus nutrients for the cells, body’s functions from the normal range, making it diffi- such as oxygen, glucose, fatty acids, and amino acids. It cult to distinguish the primary cause of the disease from also contains carbon dioxide that is being transported the compensatory responses. For example, diseases that from the cells to the lungs to be excreted, plus other cel- impair the kidneys’ ability to excrete salt and water may lular waste products that are being transported to the kid- lead to high blood pressure, which initially helps return neys for excretion. excretion to normal so that a balance between intake and The intracellular fluid contains large amounts of potas- renal excretion can be maintained. This balance is needed sium, magnesium, and phosphate ions instead of the to maintain life, but, over long periods of time, the high sodium and chloride ions found in the extracellular fluid. blood pressure can damage various organs, including the Special mechanisms for transporting ions through the cell kidneys, causing even greater increases in blood pressure membranes maintain the ion concentration differences and more renal damage. Thus, homeostatic compensa- between the extracellular and intracellular fluids. These tions that ensue after injury, disease, or major environ- transport processes are discussed in Chapter 4.  mental challenges to the body may represent trade-o ffs that are necessary to maintain vital body functions but, HOMEOSTASIS—MAINTENANCE OF in the long term, contribute to additional abnormalities A NEARLY CONSTANT INTERNAL of body function. The discipline of pathophysiology seeks ENVIRONMENT to explain how the various physiological processes are al- tered in diseases or injury. In 1929, the American physiologist Walter Cannon This chapter outlines the different functional systems (1871–1945) coined the term homeostasis to describe the of the body and their contributions to homeostasis. We maintenance of nearly constant conditions in the internal then briefly discuss the basic theory of the body’s control environment. Essentially, all organs and tissues of the body systems that allow the functional systems to operate in perform functions that help maintain these relatively con- support of one another.  stant conditions. For example, the lungs provide oxygen to the extracellular fluid to replenish the oxygen used by EXTRACELLULAR FLUID TRANSPORT the cells, the kidneys maintain constant ion concentra- AND MIXING SYSTEM—THE BLOOD tions, and the gastrointestinal system provides nutrients CIRCULATORY SYSTEM while eliminating waste from the body. The various ions, nutrients, waste products, and other Extracellular fluid is transported through the body in two constituents of the body are normally regulated within a stages. The first stage is movement of blood through the range of values, rather than at fixed values. For some of the body in the blood vessels. The second is movement of body’s constituents, this range is extremely small. Varia- fluid between the blood capillaries and the intercellular tions in the blood hydrogen ion concentration, for exam- spaces between the tissue cells. ple, are normally less than 5 nanomoles/L (0.000000005 Figure 1-1 shows the overall circulation of blood. All the moles/L). The blood sodium concentration is also tightly blood in the circulation traverses the entire circuit an average 4 Chapter 1 Functional Organization of the Human Body and Control of the “Internal Environment” Lungs Arteriole U CO O 2 2 N Right Left I heart heart T pump pump I Venule Gut Figure 1-2. Diffusion of fluid and dissolved constituents through the capillary walls and interstitial spaces. Nutrition That is, the fluid and dissolved molecules are continually and excretion moving and bouncing in all directions in the plasma and fluid in the intercellular spaces, as well as through capil- lary pores. Few cells are located more than 50 microm- eters from a capillary, which ensures diffusion of almost any substance from the capillary to the cell within a few Kidneys seconds. Thus, the extracellular fluid everywhere in the body—both that of the plasma and that of the interstitial fluid—is continually being mixed, thereby maintaining homogeneity of extracellular fluid throughout the body.  Regulation ORIGIN OF NUTRIENTS IN THE of Excretion EXTRACELLULAR FLUID electrolytes Respiratory System. Figure 1-1 shows that each time blood passes through the body, it also flows through the Venous end Arterial end lungs. The blood picks up oxygen in alveoli, thus acquiring the oxygen needed by cells. The membrane between the alveoli and the lumen of the pulmonary capillaries, the alveolar membrane, is only 0.4 to 2.0 micrometers thick, and oxygen rapidly diffuses by molecular motion through Capillaries this membrane into the blood.  Figure 1-1. General organization of the circulatory system. Gastrointestinal Tract. A large portion of the blood pumped by the heart also passes through the walls of the gastrointes- of once each minute when the body is at rest and as many tinal tract. Here different dissolved nutrients, including car- as six times each minute when a person is extremely active. bohydrates, fatty acids, and amino acids, are absorbed from As blood passes through blood capillaries, continual ingested food into the extracellular fluid of the blood.  exchange of extracellular fluid occurs between the plasma portion of the blood and the interstitial fluid that fills the Liver and Other Organs That Perform Primarily Meta- intercellular spaces. This process is shown in Figure 1-2. bolic Functions. Not all substances absorbed from the The capillary walls are permeable to most molecules in gastrointestinal tract can be used in their absorbed form the blood plasma, with the exception of plasma proteins, by the cells. The liver changes the chemical compositions which are too large to pass through capillaries readily. of many of these substances to more usable forms, and Therefore, large amounts of fluid and its dissolved con- other tissues of the body—fat cells, gastrointestinal mu- stituents diffuse back and forth between the blood and the cosa, kidneys, and endocrine glands—help modify the tissue spaces, as shown by the arrows in Figure 1-2. absorbed substances or store them until they are needed. This process of diffusion is caused by kinetic motion The liver also eliminates certain waste products produced of the molecules in the plasma and the interstitial fluid. in the body and toxic substances that are ingested.  5