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INTRODUCTION TO CLINICAL NUTRITION

SECOND EDITION, REVISED AND EXPANDED

VISHWANATH M. SARDESAI Wayne State University

Detroit, Michigan, U.S.A.

M A R C E L

MARCEL DEKKER, INC. D E K K E R

NEW YORK BASEL

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Preface to the Second Edition

Since the publication of the rst edition of this book, the continued dramaticprogress in nutrition knowledge required a critical review and evaluation of theentire text. The goal of this revised edition is to facilitate the study and under-standing of this dynamic and challenging discipline. All chapters in this edition havebeen revised and updated to reect our changing knowledge in this eld. Excessivedetail and redundancy have been minimized as far as possible without detractingfrom clarity and accuracy.

The book is divided into four parts as before. Three new chapters have beenadded and some chapters have been expanded. Chapter 1, Introduction: Funda-mentals of Nutrition, now contains a new section on genenutrient interaction.This section along with the chapters glossary will help clarify the terms usedthroughout the text.

Chapter 6, Inorganic Elements (Minerals), has a new section on diet andhypertension. Some minerals, such as sodium, potassium, and calcium, are known toaect blood pressure. Thus in context, the role of nutrition as it relates to hypertensionis considered.

A new chapter (Chapter 21, Nutritional and Metabolic Eects of Alcohol)has been added because alcohol is interrelated with nutrition. Alcohol providescalories (an estimated 56% of the calories that are consumed in the American diet)and aects the metabolism of nutrients. Thereforealthough alcohol is not anutrientit has an important, if indirect, role in the eld of nutrition.

Chapter 22, Nutritional Epidemiology, is also new. Numerous initial nd-ings in nutrition research continue to come from epidemiological studies as was trueduring the discoveries of several vitamins during the early part of last century.Epidemiology is being used more extensively to determine the relationship betweendiet and disease. In several chapters, statements are made based on epidemiologicalstudies, cohort, or case-control research designs. Therefore, the reader isprovided with a chapter to help clarify the methods used and their applications inthe eld of clinical nutrition.

While the rst edition was being written, the eld of nutraceuticals was in itsinfancy; it has grown rapidly since 1998. Chapter 28, Nutraceuticals, has been

iii

expanded to include several more functional foods, including biotechnology advancesin the development of new foods, such as h-carotene-rich yellow rice.

Alternative MedicineNutritional Supplements (Chapter 29) is new. In therst edition, some supplements were briey discussed in Vegetarianism and OtherPopular Nutritional Practices. However, this content is now explored more fully ina new chapter. Interest in supplements has grown rapidly over the past few years.People want to have control of their health. They also use common and traditionalherbs from many cultures and belief systems. Physicians should know about this eldin general, the supplement law passed by Congress in 1994, the role of the U.S. Foodand Drug Administration, and the benets and consequences of some commonlyused supplements including herbs. Are some supplements potions or poisons? Thetopic is discussed via an evidenced-based approach, as well as through a criticalanalysis of some products.

Selected clinical cases are presented in most chapters. All the patient cases(except one) are real, published in medical literature. Cases are essential because theyallow the reader to apply the discussed principles. Analyzing cases helps studentscomprehend why nutrition principles are important in the health sciences and hownutrition principles are involved in day-to-day professional practices.

As was the rst edition, this book is designed to be a textbook and referencesource in clinical nutrition for medical students and practitioners in the elds ofmedicine, dentistry, dietetics, nursing, pharmacy, and public health. The ultimatefocus of this edition is the clinical nutrition practices of these professionals andstudentsand, more importantly, the nutritional needs of their current andfuture patients.

Vishwanath M. Sardesai

Preface to the Second Editioniv

Preface to the First Edition

It is impossible to overestimate the tremendously important role that nutrition playsin the maintenance of human health, longevity, and community well-being. Dietaryfactors have been implicated in the etiology of at least four of the ten leading causesof death in the United States: heart disease, cancer, diabetes, and stroke. Nutrition isalso crucial in many of the currently common problems such as obesity, hyper-tension, hypercholesterolemia, and osteoporosis. Since the advent of parenteralnutrition in clinical medicine, there has been renewed interest in nutrient require-ments, especially the changes associated with bypassing the gastrointestinal tract.

Interest in nutritional information is not conned to the medical profession.Public interest in the subject is more evident today than ever before. Most in-dividuals regard their physicians as the primary source of such information, yet ina recent extensive study of oce-based primary care physicians, 68% stated thatthey had received inadequate nutritional training in medical school, and 86%indicated that more nutritional information should be taught as part of the basicmedical curriculum.

Because doctors are admittedly not being trained to give adequate advice inthis critical eld, their patients have turned to unqualied, unregulated, self-claimedexperts in nutrition. This has caused a tremendous increase in food faddism andoutright fraud. A report by the Surgeon General stated that nutrition fraud is theleading example of health fraud at the present time.

In 1985 the Committee of the Food and Nutrition Board of the NationalAcademy of Sciences was commissioned to evaluate the status of nutrition trainingand education of the nations physicians. Its report stated that Nutrition educationprograms in U.S. medical schools are largely inadequate to meet the present andfuture demand of the medical profession. The Committee recommended thatnutrition be a required course in every medical school in the United States and thata minimum of 25 classroom hours be devoted during preclinical years to the teachingof basic nutritional material. The National Nutrition Monitoring and RelatedResearch Act of October 22, 1990, mandated that Students enrolled in U.S.medical schools, as well as physicians practicing in the United States, have accessto adequate training in the eld of nutrition and its relationship to human health.

v

Many medical schools have started to increase the number of hours fornutrition education, but a common concern among medical educators is how toteach all the materials currently known in the already overcrowded, information-dense curriculum. Another problem is the lack of a suitable nutrition textbook thatcovers, in sucient detail, all topics of importance to medicine, and that focuses onthe interaction of nutrition and disease. For example, to understand the signicanceof topics such as essential fatty acids, eicosanoids, and detoxication, both pertinentbiochemistry and nutritional aspects have to be in one place.

This resource is written to serve as the collective textbook for medical studentsduring the preclinical years by addressing the multidisciplinary requirements. It isbased on a course that has proven extremely eective in teaching nutrition to medicalstudents. Selected nutritional aspects as they relate to human health and disease andthose which are generally covered during the rst two years are included.

The science of nutrition deals with the processes by which components of foodare made available to the body for meeting energy requirements, for building andmaintaining tissues, and, in more general terms, for the maintenance of optimumfunctional health. Thus, nutrition is concerned with issues traditionally considered tobe biochemical (e.g., digestion, absorption, transport, metabolism, biochemicalnature, and the function performed by individual substances). The basic coursematerial in this text is likely to be better received and understood after the studentshave been introduced to biochemistry, especially the metabolic aspects.

The book is divided into four major parts. The rst chapter, Introduction:Fundamentals of Nutrition, denes the terminology as used in the science ofnutrition and briey discusses the bodys need for nutrients and its ability to adaptwithin limits to conditions of nutrient deciency or excess. Since water is coveredextensively in biochemistry and physiology courses, only its role as a nutrient isincluded in this chapter, instead of having a separate chapter for this topic.

Part I starts with an overview of digestion and absorption of macronutrients,and is followed by a chapter that deals with the need for energy and energy-yieldingsubstrates (carbohydrate, fat, and protein), the importance of protein in the diet(primarily to supply amino acids), and the eect of deciency and excess of eachof these macronutrients. Separate chapters cover the pertinent biochemistry andnutritional roles of essential fatty acids and the biochemistry of eicosanoids, theirrelation to various diseases, and strategies for dietary manipulation of eicosanoidformation. The chapter on eicosanoids (although actually not nutrients) followsessential fatty acids which serve as precursors of these biologically active com-pounds. Individual inorganic elements and vitamins, including vitamin-like sub-stances, are presented in detail in terms of chemistry, food sources, biochemical role,their physiology and metabolic interrelation, and the eects of deciency and excessof each of the micronutrients.

Part II covers the special nutritional needs during pregnancy, lactation, and thelife cycle in relation to physiological changes.

Part III deals with the assessment of nutritional status, and focuses on theinteraction of nutrition and some selected diseases (e.g., obesity, hyperlipidemia,osteoporosis, diabetes, and genetic diseases).

Part IV covers topics of special interest. These include dietary ber, antiox-idants, vegetarianism, and other popular nutritional practices, toxicants occurring infood, additives, and how the body metabolizes many of the toxic substances present

Preface to the First Editionvi

in the diet. The role of nutrients in biotransformation (detoxication mechanism) isalso discussed. The chapter Nutraceuticals is included because of the recentincreased interest in the health eects of some foods, and their possible roles inthe prevention of some chronic diseases. The health-promoting properties of manyof these foods are attributed to their content of specic non-nutrient substances,most of which act favorably on the bodys detoxication mechanisms. Therefore, thistopic follows the chapter entitled Nutritional Aspects of Biotransformation.

The science of nutrition, important as it is to human welfare, has had a very longhistory. Centuries ago, the relationship between nutrition and medicine began withthe recognition by Hippocrates that food was the source of energy and body heat.Early physicians recognized the relation between certain foods and such classicaldeciency diseases as scurvy and pellagra. Today, our knowledge of the fascinatingrole of nutrition is growing at a geometrical rate. To help all those involved in humanhealth to keep pace with its growth is the purpose of this book.

This text should be useful not only for students in the eld of traditionalmedical practice, but also for those in osteopathic medicine, dentistry, and otherhealth professions. It should be of particular interest to students who are directingtheir careers toward community medicine and family practice. Nutrition is a vitallyimportant component not only of individual health, but equally vital to communitywell-being.

Vishwanath M. Sardesai

Preface to the First Edition vii

Acknowledgments

I would like to thank the many people who have contributed to the development ofthe second edition. Students, classroom instructors, and reviewers provided con-structive comments and suggestions that were most helpful during the revision. I alsoreceived several letters from readers of the rst edition. Their encouraging commentsare appreciated.

I am grateful to my colleagues, Drs. Leonard Malkin and Vasily Studitsky,Department of Biochemistry and Molecular Biology, Wayne State University, andMs. Anne Greb, Center for Molecular Medicine/Genetics, Wayne State University,for reviewing the section on genenutrition interaction in Chapter 1; to Dr. WilliamCrossland, Department of Anatomy, Wayne State University, for reviewing Chapter12 on nutrition during pregnancy; and to Dr. Alan Buchman, Department of Inter-nal Medicine, Northwestern University School of Medicine, for helpful discussionon government regulations of nutritional supplements. I am also grateful to Dr.Benjamin Caballero, Center for Human Nutrition, Johns Hopkins University, andDr. Dharam Agarwal, Institute of Human Genetics, University of Hamburg,Germany, for allowing us to reproduce their previously published gures; Ms. KarenLienhart, Michigan State University, for editorial assistance; Ms. Amie Dozier fromthe Medical Education Support Group at Wayne State University for preparing newgures; Ms. Cherrie Mudlo and Ms. Nancy Sternisha, Detroit Receiving Hospitallibrary and Ms. Pamela Gannon, Librarian of our Schiman Medical Library, forassisting me in numerous literature searches; and Ms. Theresa Stockton, ProductionEditor, Ms. Susan Lee, Acquisitions Editor, and the sta of Marcel Dekker, Inc., fortheir guidance and patience during the completion of this project.

I wish to acknowledge the outstanding secretarial support of Ms. MelodyAndrews. She typed the manuscript with remarkable speed and accuracy, and withtremendous dedication and skill. She deserves special commendation.

As always my wife, Sudha, and children, Amey and Gauri, have been patient,supportive, and in good spirits throughout the always-arduous process of reading,writing, and editing involved in the completion of this project.

ix

Contents

Preface to the Second Edition iiiPreface to the First Edition v

PART I: BIOLOGY AND BIOCHEMISTRY

1 Introduction: Fundamentals of Nutrition 1I. Terminology 1II. The Need for a Variety of Foods 3III. Respiratory Quotient 3IV. The Need for Energy 4V. The Need for Digestion, Absorption, and Utilization of Nutrients 4VI. Enteral and Parenteral Nutrition 5VII. Adaptation 7VIII. Water as a Nutrient 8IX. Food Allergy 9X. GeneNutrient Interaction 10

Denitions 14References 14

2 Digestion of Carbohydrates, Lipids, and Proteins 17I. Introduction 17II. Carbohydrates 20III. Lipids 22IV. Proteins 25V. Malabsorption Syndromes 27

References 31

3 Requirements for Energy, Carbohydrates, Fat, and Proteins 33I. Energy 33II. Carbohydrates 37III. Fat 39IV. Proteins 40

xi

V. Use of Body Energy Sources During Hypometabolism andHypermetabolism 49References 51

4 Role of Essential Fatty Acids 53I. Fatty Acids 53II. Neutral Fat 54III. Properties of Fat 54IV. Dietary Sources and Health Eects of Trans Fatty Acids

and Phytosterols 56V. Saturated Fatty Acids 57VI. Monounsaturated Fatty Acids 57VII. Essential Fatty Acids 58

References 68

5 Eicosanoids 71I. Prostaglandins 71II. Thromboxanes 75III. Prostacyclins 75IV. Leukotrienes 75V. Lipoxins 76VI. Cytochrome P450-Derived Products 77VII. Inhibitors of Eicosanoid Biosynthesis 78VIII. Eects of Diet on Eicosanoids 81

References 84

6 Inorganic Elements (Minerals) 85I. Essential Macrominerals 86II. Essential Trace Elements 102III. Ultratrace Minerals 128

References 132

7 VitaminsAn Overview 139I. Historical Perspective 139II. Denition 139III. Names 140IV. Classication 140V. Functions 141VI. Deciency 141VII. Need for Supplements 142VIII. Hypervitaminosis 143IX. Antivitamins 143X. Enrichment of Foods 144

References 146

8 Fat-Soluble Vitamins 147I. Vitamin A 147II. Vitamin D 157III. Vitamin E 166

Contentsxii

IV. Vitamin K 171References 176

9 Water-Soluble Vitamins I 181I. ThiaminB1 181II. Riboavin 187III. Niacin 192IV. Pantothenic Acid 198V. Biotin 201

References 207

10 Water-Soluble Vitamins II 211I. Folic Acid 211II. Vitamin B12 216III. Pyridoxine 224IV. Vitamin CAscorbic Acid 230

References 238

11 Vitamin-Like Substances 241I. Choline 241II. Carnitine 243III. Bioavonoids 245IV. Lipoic Acid 246V. Coenzyme Q 247VI. Inositol 248VII. p-Aminobenzoic Acid 250

References 252

PART II: SPECIAL NUTRITIONAL NEEDS

12 Nutritional Aspects of Pregnancy and Lactation 255I. Nutrition Prior to Pregnancy 255II. Nutrition During Pregnancy 256III. Nutrition During Lactation 269

References 271

13 Nutrition and Development 273I. Fetal Development 273II. Extrauterine Development 277III. Nutrition and Development During Infancy 278IV. Nutrition and Development During Childhood 288V. Nutrition and Development During Adolescence 290

References 292

14 Nutrition and Aging 295I. Aging 295II. Eect of Nutrition on Longevity 296III. Role of Antioxidants 298IV. Factors Aecting Nutrition Status 298

Contents xiii

V. Nutrient Requirements 301VI. Lifestyle 303

References 303

PART III: NUTRITION AND SPECIFIC DISORDERS

15 Nutritional Assessment 305I. Anthropometric Measurements 306II. Clinical Evaluation 307III. Laboratory Assessment 310IV. Dietary Assessment 315

References 315

16 Obesity and Eating Disorders 317I. Classication 318II. Pattern of Fat Deposition 319III. Prevalence 320IV. Causes of Obesity 321V. Assessment of Obesity 324VI. Medical Complications 326VII. Diet for Weight Reduction 327VIII. Fad Diets 328IX. Pharmacotherapy 328X. Eating Disorders 330

References 335

17 Cholesterol and Hyperlipidemia 339I. Cholesterol 339II. Lipoproteins and Lipid Transport 342III. Plasma Cholesterol and Risk of Heart Disease 347IV. Plasma Triglycerides and Risk of Heart Disease 348V. Dietary Management 349VI. Drug Therapy 350VII. Hypocholesterolemia 351VIII. Eects of Low Blood Cholesterol 352IX. Inborn Errors of Cholesterol Biosynthesis 352

References 353

18 Osteoporosis 355I. Factors Contributing to Bone Mass 356

References 365

19 Nutritional Aspects of Diabetes 367I. Classication and Epidemiology 367II. Diagnosis of Diabetes 370III. Mechanism of Insulin Action 370IV. Complications of Diabetes 371V. Dietary Management 374VI. Dietary Factors 374

Contentsxiv

VII. Physical Activity 377VIII. Lifestyle Modication to Reduce Risk of Type II Diabetes 378

References 380

20 Nutritional Aspects of Genetic Disease 381I. Carbohydrate Metabolism 381II. Amino Acid Metabolism 385III. Disorders of Lipid Metabolism 391IV. Miscellaneous 395V. Summary 396

References 399

21 Nutritional and Metabolic Eects of Alcohol 401I. Absorption 402II. Distribution 402III. Nutritional Signicance of Alcohol 403IV. Metabolism 404V. Rate of Alcohol Metabolism 406VI. Metabolic Eects of Alcohol 408VII. Eect of Alcohol on the Body 409VIII. Nutritional Implications 412

References 416

22 Nutritional Epidemiology 417I. Historical Perspective 417II. Techniques/Approaches 419III. Epidemiologic Measures 423IV. Signicance of Epidemiological Studies 425V. Few Examples of Nutritional Studies 425

References 427

PART IV: SPECIAL TOPICS

23 Dietary Fiber 429I. Fiber 429II. Fiber and Disease 432III. Recommendations for Fiber Intake 436IV. Overconsumption of Fiber 437V. Sucrase Deciency and Protection Against Colonic

DiseaseA Report 437References 438

24 Antioxidants and Health 441I. Free Radicals 441II. Formation of Free Radicals 441III. Free Radicals in Biological Systems 443IV. Protection from Free Radicals 443V. Benets of Free Radicals 445VI. Free Radicals and Diseases 446

Contents xv

VII. Large Doses of Antioxidants 450References 450

25 Toxicants Occurring Naturally in Foods and Additives 453I. Toxicants in Food 453II. Additives 458

References 465

26 Vegetarianism and Other Popular Nutritional Practices 467I. Vegetarianism 467II. Kosher Diet 470III. Zen Macrobiotic Diet 470IV. One-Emphasis Diets 471V. Organically Grown Foods 471VI. Natural Foods 474VII. Health Foods 474VIII. Megadoses of Vitamins and Nonvitamins 475IX. Hair Analysis 476

References 479

27 Nutritional Aspects of Biotransformation 481I. Detoxication Process 483II. Factors Aecting Detoxication 489

References 494

28 Nutraceuticals 495I. Introduction 495II. Interest in Nutraceuticals 496III. Fruits and Vegetables with Health-Promoting Properties 498IV. Need for Additional Research 511V. Seafood 512VI. Use of Biotechnology in the Food Industry 513VII. Dietary Modulation of Colonic Microorganisms 514

References 516

29 Alternative Medicine: Dietary Supplements 519I. History of Supplement Regulation in the United States 520II. Safety and Ecacy of Supplements 521III. German Commission E Report 524IV. Benecial Eects 525V. Adverse Eects of Dietary Supplements 529VI. Alternative Medicine and Cancer 537VII. Supplements and the ElderlyIs There a Need? 537VIII. Why People Use Alternative Therapies 538IX. The Role of Physicians 539X. Conclusion 540

References 541

Index 543

Contentsxvi

1Introduction: Fundamentals of Nutrition

The science of nutrition deals with the processes by which components of food are made

available to an organism for meeting energy requirements, for building and maintaining

tissues, and, in a more general sense, for maintaining the organism in optimal functional

health. Thus, nutrition is concerned with many issues traditionally considered to be

biochemical (e.g., digestion, absorption, transport, metabolism, and biochemical func-

tions performed by individual chemical substances).

I. TERMINOLOGY

Nutrients are those chemical substances needed for the growth and maintenance of

normal cells, both in animals and plants. The present emphasis, however, is on human

cells and tissues. Clinical nutrition is a medical specialty dealing with the relationship

between disease and nutrition. Acute and chronic illnesses are caused by deficiencies of

dietary components, and others by their excesses.

Malnutrition is a condition characterized by inappropriate quality, quantity,

digestion, absorption, or utilization of ingested nutrients. It includes: undernutrition

low food intake (calorie deficiency) leading to growth suppression or other deficiency

signs and overnutritionconsumption of too much food and/or single nutrients leading

to specific toxicities.

Some 4550 chemical entities are now known to be required by humans, either

preformed in food or added as an appropriate chemical substitute. These can be divided

into six main categories: carbohydrates, fats, proteins, vitamins, inorganic elements, and

water. Dietary fiber, although not classified as nutritionally essential, is important in

maintaining good health. The term essential or dietary essential means that we must obtain

the nutrient from our diet either because we lack the biochemical machinery to

manufacture it or we cannot make enough of it.

Recommended Dietary Allowances (RDAs) are developed by the Food and Nutrition

Board of the National Academy of Sciences. They are defined as the levels of intake of

essential nutrients considered, in the judgement of the Committee of Dietary Allowances of

the Food and Nutrition Board, on the basis of available scientific knowledge to be adequate

to meet the known nutritional needs of practically all healthy persons. Nutrient allowances

1

are categorized into 17 classifications based on age and sex. The recommended intakes of

essential nutrients must, therefore, by definition, exceed the requirements of almost all

individuals in the group. The Food and Nutrition Board normally meets every 6 years to

consider currently available information and to update their recommendations. The RDAs

are meant to apply only to a healthy population and should be met from the consumption of

a wide variety of readily available foods. They should not be confused with nutrient

requirements of individuals because these are too variable. Rather, an RDA represents an

average level of daily intake of a nutrient, which over time approximates the RDA, and thus

the nutritional inadequacy will be rare in that population. RDAs do not provide the needs

that have been altered as a result of disease states, chronic usage of certain drugs, or other

factors that require specific individual attention.

The term minimal daily requirement (MDR) is the minimum amount of a nutrient

from exogenous sources required to sustain normality (i.e., the absence of any biochemical

hypofunction that is correctable by the addition of greater quantities of that nutrient).

Individuals consume food more for the satiation of energy needs than for individual

nutrients. Therefore, to express the quality of any food in relation to its content of specific

nutrient, the term nutrient density is used. It is defined as the concentration of a nutrient

per unit of energy (e.g., 1000 Cal) in a specific food. For any nutrient, the higher the

nutrient density the better the food source; for example, one whole green pepper contains

20 mg of vitamin C and provides 4 Cal, while one medium sweet potato also contains 20

mg of vitamin C but provides 100 Cal. Therefore, green pepper is a much better source of

vitamin C than sweet potato.

A. Metabolism

All cells have in common two major general functions: energy generation and energy

utilization for growth and/or maintenance. These may be termed metabolic reactions or

simply metabolism. Anabolism broadly refers to processes in which relatively large

molecules such as proteins are biosynthesized from small nutrient materials such as

amino acids. These reactions require energy, which is available in cells in the form of

stored chemical energy in high-energy phosphate compounds. Catabolism is the degra-

dation of relatively large molecules to smaller ones. Catabolic reactions serve to capture

chemical energy (in the form of adenosine triphosphate, ATP) from the degradation of

energy-rich molecules. Catabolism also allows nutrients (in the diet or stored in cells) to be

converted into the building blocks needed for the synthesis of complex molecules.

Intermediary metabolism refers to all changes that occur in a food substance beginning

with absorption and ending with excretion.

In the adult there is a delicate regulated balance between anabolic (synthetic) and

catabolic (degradative) processes. In the growing child, the input of nutrients and

anabolism exceed catabolism so that the growth of tissues may occur. In the aging

process or in wasting diseases, the catabolic processes exceed anabolic ones.

B. Homeostasis

The body tends to maintain a state of equilibrium within its internal environment; this is

often referred to as a dynamic equilibrium or homeostasis because it occurs despite

changes in the external environment. The maintenance of equilibrium is governed by an

adequate supply of nutrients, a balance between nutrients, a normal complement of

enzyme systems, the secretion of hormones that regulate metabolic rates, and controls by

Introduction to Clinical Nutrition2

the nervous system. Homeostasis plays a vital role in the body because tissues and organs

can function efficiently only within a narrow range of conditions.

II. THE NEED FOR A VARIETY OF FOODS

Recommended daily allowances should be met by a variety of foods for several reasons.

Most foods contain more than one nutrient but no single food item supplies all the essential

nutrients in the amounts that are needed. Certain dietary components (e.g., carotenes,

fiber, and possibly others) that are not considered required may nevertheless have a

beneficial effect on body functioning. The greater the variety of foods, the less likely one

can develop a deficiency or an excess of any single nutrient. Variety also reduces the

likelihood of being exposed to excessive amounts of toxic substances that occur naturally

in foods and to additives or contaminants that may be present in any single food item. A

simple approach to adequate nutrition is to consume a variety of foods. Foods can be

selected from each of the Four Basic Food Groups (Table 1). The foods from the milk

group are major sources of calcium, protein, and riboflavin; items in the meat (and meat

substitutes) group supply protein, fat, iron, and other minerals as well as several vitamins.

Fruits and vegetables are rich in vitamin C and are precursors of vitamin A, while the

bread and cereal group provides carbohydrate, several B vitamins, and iron.

In addition to the food from the basic food groups, other items (e.g., tea and certain

spices) can provide nutrients and antioxidants that have been claimed to be good for

health. Tea is a rich source of manganese and flavonoids, which have antioxidant

properties. Black pepper is a good source of chromium.

III. RESPIRATORY QUOTIENT

During the course of oxidation of body fuels, oxygen is consumed and carbon dioxide is

produced. The molar ratio of carbon dioxide produced to oxygen consumed is known as

the respiratory quotient (RQ) and is characteristic of a given substrate. The measurement

of RQ, therefore, provides a means of assessing the type of fuel component that is being

metabolized. For carbohydrate, the RQ is 1, and for fat it is approximately 0.7, as given

by the following reactions:

C6H12O6 glucose 6O2 ! 6CO2 6H2OC16H32O2 palmitate 23O2 ! 16CO2 16H2O

TABLE 1 Basic Four Food Groups

Group Food Major nutrients

Milk Milk and other dairy products Calcium, protein, riboflavinMeat Meat, poultry, fish, eggs Protein, fat, iron, other minerals

Beans, peas, nuts, seeds(meat substitutes)

Fruits andvegetables

All varieties of fruits and vegetables,green yellow vegetables

Vitamin C, vitamin A precursors

Bread andcereal

Bread, cooked cereal, dry cereal,rice, pasta

B vitamins, iron, carbohydrate

Fundamentals of Nutrition 3

The RQ of protein is difficult to measure because it is not oxidized completely in the body

(the nitrogen of protein is eliminated in the urine); however, it is usually taken to be 0.8. On

the basis of analytical data for the average protein, it is generally estimated that 1 g of

urinary nitrogen represents the metabolism of 6.25 g of protein, the utilization of 5.91 L of

oxygen, and the production of 4.76 L of carbon dioxide. Therefore, by measuring the

amount of urinary nitrogen produced, the quantity of protein oxidized can be estimated. The

rest of the metabolic energy must be from a combination of fat and carbohydrate, and

the percentage of each can be determined from the protein-corrected RQ. A normal adult

who consumes a mixed diet has an overall RQ of 0.85. This value is increased by in-

creasing the amount of carbohydrate in the diet, and it is reduced by increasing the amount

of fat in the diet. When glucose is used to synthesize fat, the RQ increases to above 1.

The major endogenous source of fuel is the body fat that, on average, is about 15 kg

in a 70-kg adult male. Stored glycogen in the liver and muscle amounts to about 200 g. On

a short-term basis such as an overnight fast or acute exercise, glycogen is utilized first

(RQ > 0.95). As the fast or exercise continues and glycogen is depleted, the oxidation of

fatty acids becomes the major energy source and the RQ decreases. This mechanism

allows the body to withstand long periods of low dietary energy.

Another way to determine the RQ is by measuring heat production (using a

respiratory calorimeter or respirometer). This can be done at the same time as the

measurement of oxygen consumption and carbon dioxide excretion. This technique is

useful to assess the energy expenditure and the type of fuel substrate oxidized under

controlled conditions, such as when the subject walks on a treadmill or rides a stationary

bicycle. It can also assess the RQ in stressed or hypermetabolic patients receiving

intravenous glucose. In some patients with compromised lung function, an increase in

carbon dioxide production (e.g., during glucose oxidation, RQ = 1) can precipitate

respiratory failure. Part of the glucose can be replaced by fat to lower carbon dioxide

production and the RQ; thus, the lung has less carbon dioxide to excrete. If the RQ is greater

than 1, it indicates the patient is making fat and it is a signal to reduce glucose intake.

IV. THE NEED FOR ENERGY

The human body needs a continuous regulated supply of nutrients. Energy is required for

all body processes, growth, and physical activity. Even at rest, the body requires energy

for muscle contraction, active transport of molecules and ions, and synthesis of macro-

molecules and other biomolecules from simple precursors. For example, the heart pumps

approximately 8000 L/day of blood in about 80,000 pulsations. The daily energy required

for this heart function alone is estimated to be equivalent to lifting a weight of 1000 kg to

a height of 10 m. In most processes, the energy is supplied by ATP. Energy is liberated

when ATP is hydrolyzed to adenosine diphosphate (ADP) and inorganic phosphate. A

resting human consumes about 40 kg of ATP in 24 hr. The amount of ATP in the body

tissues is limited but is generated continuously from the fuel stores to supply the required

energy. These fuel stores must be replenished via food intake.

V. THE NEED FOR DIGESTION, ABSORPTION, AND UTILIZATIONOF NUTRIENTS

The body cannot use the raw materials as they are found in ingested complex foods

and beverages. Dietary elements need to be digested in the alimentary tract to

Introduction to Clinical Nutrition4

substances that can cross the epithelial barrier. Absorption requires sufficient ab-

sorptive surface for contact, healthy mucosal cells for uptake, and an intact system

for intracellular and extracellular transport system. Most of these processes are

energy dependent.

After absorption the energy-yielding substrates and other nutrients are transported to

the cells. The conversion of the substrates into energy involves a series of biochemical

changes. Many of these changes require the assistance of enzymes; these are proteins

produced by the cells of the body to be used by same cells or other cells. Some enzymes

do not act by themselves but require the assistance of coenzymes (e.g., active forms of

some vitamins) or cofactors (e.g., minerals). Finally, the excess nutrients and their

degradation products are eliminated via excretory pathways so that they do not accumulate

and reach toxic levels. Therefore, the assimilation of dietary nutrients and their proper

functions require the participation of several organs, enzymes, and biochemical processes.

Defects in any of these steps can affect the availability of a nutrient and cause nutrient

deficiency, toxicity of a metabolite, or some other health problem despite the consumption

of an adequate diet.

Lactase-deficient individuals cannot hydrolyze lactose efficiently and are unable to

consume milk without experiencing diarrhea. The loss of small intestinal surface (as in

surgical ablation or pathological atrophy) can compromise absorption. Some nutrients after

absorption, if not metabolized properly, can be toxic. Given below are two examples of

inborn errors of metabolism, one involving an essential nutrient, phenylalanine, and the

other involving fructose.

Phenylketonuria (PKU) is an inherited autosomal recessive metabolic disorder that

results from a deficiency of the enzyme phenylalanine hydroxylase, which catalyzes the

transformation of phenylalanine to tyrosine. Phenylalanine, therefore, is metabolized by an

alternate pathway forming phenylpyruvic and phenyllactic acids and, as a result, there is a

buildup of phenylalanine and phenylpyruvic and phenyllactic acids in the blood. These

compounds act as toxins to the developing nervous system and cause mental retardation

unless the disease is treated early. Phenylalanine is essential in the diet, so the disease can

be treated nutritionally by restricting the amount of this amino acid to a level that is just

sufficient to meet the requirement for growth and small molecule synthesis. In addition,

adequate amounts of tyrosine (which becomes an essential amino acid for a patient with

PKU) must be supplied in the diet.

In hereditary fructose intolerance, the individual has a deficiency of the enzyme

fructose-1-phosphate aldolase. When fructose-containing foods are ingested, there is

accumulation of fructose-1-phosphate; this inhibits some important metabolic steps and

causes hypoglycemia and other problems. Fructose is not essential, so the disease can be

treated by eliminating fructose-containing foods from the diet.

VI. ENTERAL AND PARENTERAL NUTRITION

Many patients either cannot or should not use their gastrointestinal (GI) tract, or

cannot maintain an adequate oral intake because of anorexia and/or dysfunction of the

GI tract. This is especially true of patients with severe infections or burns and those

recovering from acute trauma and major surgical procedures who are also hyper-

metabolic and have increased energy and protein requirements. To meet their nutrient

requirements, specialized nutritional feeding must be instituted as either enteral or

parenteral feeding.

Fundamentals of Nutrition 5

A. Enteral Feeding

Enteral nutrition is the provision of liquid formula diets by tube or mouth into the GI tract.

It is essential for the maintenance of gastrointestinal mucosal growth and function. Enteral

feeding is indicated in patients with a normal GI tract who cannot or will not eat or in

whom oral consumption is inadequate. Nutrients are delivered in a suitable (liquid) form

through feeding tubes introduced at various points into the alimentary tract.

Several options exist for the route of tube feeding. The route is determined by the

anticipated duration of tube feeding, the disrupted step(s) in the normal process of

obtaining nutrients, and the risk of aspiration. The name of the feeding route usually

includes both the type of tube placement and the site of formula delivery. For example,

nasogastric indicates nasal placement with gastric delivery of formula, whereas gastros-

tomy indicates ostomy placement with gastric delivery of formula. Metabolic complica-

tions of tube feeding include hyperglycemia, electrolyte abnormalities, and fluid

imbalance. Regular biochemical determinations are needed to identify developing

abnormalities and to allow correction before severe problems occur.

B. Parenteral Feeding

This is the administration of nutrients by the intravascular route. Parenteral feeding is

initiated when the GI tract should not be used or when because of GI dysfunction adequate

enteral nutrition cannot be achieved. Total parenteral nutrition (TPN) is the administration

of an individuals entire nutrient requirement. Nutrients have to be in a form that normally

enters the circulation after digestion and absorption. When parenteral nutrition (PN) is

necessary, the type of venous access must be selected. PN nutrient formulations may be

administered via peripheral veins or central veins, depending on the anticipated duration

of PN therapy, degrees of malnutrition, nutrient requirement, and availability of venous

access. Peripheral administration is considered when PN is expected to be necessary for

less than 7 to 10 days and the patient has fairly low energy and protein needs because of

minimal stress. An isotonic solution of glucose, amino acids, vitamins, and minerals can

be administered via a peripheral vein for sufficient nitrogen balance; however, it cannot

provide more than 600 Cal/day, which is not even adequate for the energy requirement at

rest. Higher concentrations of caloric nutrients produce a hypertonic solution that can

damage tissues at the site of entry and increase the risk of thrombosis. PN through a

central vein is preferred for patients whose gastrointestinal tracts are either nonfunctional

or should not be used for more than 7 to 10 days, and for patients who have limited

peripheral venous access or have energy and protein needs that cannot be met with

peripheral nutrition formulations. If TPN is to be prolonged, sufficient calories must be

infused either as a lipid emulsion or a hypertonic glucose solution, which requires a central

venous catheter.

The bowel atrophies when nutrients are provided exclusively by vein. It has been

shown that the addition of glutamine in TPN prevents the deterioration of gut perme-

ability and preserves mucosal structure. There is also significant improvement in nitrogen

balance with glutamine-containing TPN formulation in comparison to glutamine-free

formulation during the first 3 days after abdominal surgery. Glutamine is added in the

TPN as a dipeptide such as glycyl-glutamine because glutamine itself is unstable under

the high temperature and pressure of sterilization conditions.

The PN nutrition therapy may be associated with multiple metabolic complications.

The most common abnormalities are hypokalemia, hypomagnesemia, hypophosphatemia,

Introduction to Clinical Nutrition6

and hyperglycemia. Routine monitoring of these serum parameters to identify compli-

cations early is necessary to manage or prevent complications.

VII. ADAPTATION

The human body has a powerful ability to take care of itself under various conditions. It

obtains what it needs from widely differing diets; within limits it protects itself from

some toxic substances present in foods; and it tries to survive by adapting its metabolism

when dietary nutrients are in short supply.

One of the main objectives of the living organisms existence with its environment is

the maintenance of a favorable nitrogen economy. The metabolic activity of proteins or

turnover (the process of breakdown and resynthesis) is a continuous process, constantly

undergoing modulation to respond to the adaptive stresses placed upon the organism from

the environment. Amino acids must be obtained to replace those lost by the inefficiencies

of the turnover process (particularly for the essential amino acids). Energy substrates must

be continuously available to fuel not only synthetic processes, but also to support the

activity of these proteins whether it be hormonal, enzymatic, organ function, or

locomotion. The body maintains all these vital functions at a relatively constant rate

when dietary replacement is often intermittent or erratic.

The body has an amazing ability to adapt. Biological clocks are set to inform the

individual that repletion of nutrients is required (e.g., hunger); however, if nutrients are not

forthcoming, adaptation to endogenous stores of fuels can be accomplished. Hormonal

activity is precisely integrated to maintain continuous supplies of nutrients. Nutrition is

indeed an endogenous event.

Under normal conditions, about 10% of dietary iron is absorbed, but when there is a

deficiency of this nutrient the absorption is more efficient. On the other hand, when there is

an excess of iron in the body, the amount absorbed is curtailed substantially. Almost all the

ascorbic acid (vitamin C) present in a normal diet is absorbed, but consumption of larger

doses reduces its absorption efficiency. Long-term ingestion of larger doses of vitamin C

causes induction of the enzyme involved in the catabolism of ascorbic acid. When the

plasma level of ascorbic acid is at or below the normal range, there is very little ascorbic

acid excreted in the urine because of its efficient reabsorption by renal tubules. The amount

excreted increases when plasma levels of the vitamin are higher than normal. The body

adapts to larger doses and thus the daily requirements for the vitamin increases. Vitamin

deficiency signs can appear when long-term ingestion of large doses of vitamin C is

discontinued. It may take several weeks for the body to readjust itself for the lower doses.

Whenever there is a shift in the quantity or the nature of the fuel supply, the

enzymatic constitution changes so as to make most efficient use of the material at hand.

This is especially true of the liver, which plays a major role in balancing the flow of

different metabolites. During starvation, the body has to adapt to substrate deprivation. It

has to rely on its own fuel stores, and it stops synthesizing the enzymes required for the

digestion of food and for handling the excesses of foodstuffs; instead, the amino acids are

used for more pressing purposes.

At the beginning of starvation, glycogen is broken down to glucose, which is

oxidized to provide energy. The glycogen stores are limited and are totally dissipated

within the first 3 days of fasting. Body fat then plays a major role as the source of energy.

Some tissues (e.g., the brain, red blood cells) use only glucose as a source of energy. The

brain cannot use fatty acids because these substrates do not readily cross the bloodbrain

Fundamentals of Nutrition 7

barrier. Because fatty acids cannot be converted to glucose, those tissues that use only

glucose for energy have to rely on body protein catabolism (amino acids) for the formation

of glucose. Although body protein represents a substantial source of calories, there is no

storage or depot protein, per se. Each protein molecule serves some important structural,

contractile, or enzymatic function. Survival is not possible if 2533% of the body protein

is lost.

After glycogen stores are depleted, skeletal muscle protein is used as a source of

glucose for some tissues. During the first 35 days of starvation approximately 75 g of

protein per day is used for energy. This is equivalent to about 300 g of muscle; at this

rate, body protein can diminish quickly. Therefore, during fatty acid catabolism (and in

the absence of carbohydrate catabolism) ketone bodies are synthesized and the brain

adapts to use these metabolites as energy sources. Amino acids are still used to provide

glucose to tissues that rely entirely on this substrate; however, the amount of protein

required is only about one-third of that needed without this adaptation. Thus, to lengthen

survival time, the body tries to conserve body protein and uses fat and fat-derived fuels as

the major energy sources.

VIII. WATER AS A NUTRIENT

Water, sometimes called the silent nutrient, is taken for granted in nutritional

consideration. A deficient intake, however, can produce death faster than that of any

other nutrient. Total body water in humans varies from 55% to 65% of the body weight

depending on body composition. Lean body tissues contain approximately 75% of water,

but adipose tissue has very little water. Therefore, the percentage of water is greater in

lean than in obese individuals.

Most of the body water is found within three major body compartments: intracellular

fluid (within the cells) has about 70%, interstitial fluid (e.g., lymph) has about 20%, and

blood plasma has about 7%. The latter two compartments together come under the

extracellular fluid category. The remaining 3% of body water is in the intestinal lumen,

cerebrospinal fluid, and other body compartments. The body controls the amount of water

in each compartment mainly by controlling the ion concentrations in each compartment.

Intracellular water volume depends primarily on intracellular potassium and phosphate

concentration. Extracellular water volume depends primarily on extracellular sodium and

chloride concentration.

The body has three sources of water: ingested water and beverages, the water

content of solid foods, and metabolic water, which is derived from the oxidation of

carbohydrate, fat, and protein. The latter amounts to some 300350 g per day in an

average adult male. According to composite estimates, 100 g of starch yields 55 g of water,

100 g of fat yields 107 g of water, and 100 g of protein gives 41 g of water. Water is

absorbed in the upper small intestine and is distributed by way of the lymph and blood into

and from the various tissues and cells of the body. Eventually, water is excreted via the

kidneys, sweat, expired air, feces, and so on.

Under ordinary conditions, the water balance between the cells and the fluids of the

body is maintained at a constant level. The loss of water equals the intake and

endogenous formation, and is in the range of 24 L. Water intake is regulated mainly

by thirst, and the output is controlled by antidiuretic hormone and the kidneys. If

excessive amounts of water are ingested, the kidneys excrete the excess. On the other

hand, if the fluid intake is low, the kidneys excrete a more concentrated urine so that less

Introduction to Clinical Nutrition8

water is lost from the body. Starvation or a carbohydrate-restricted regimen is associated

with an acute loss of body water (e.g., 11.5 L), which represents the water normally held

by glycogen storage in the tissues.

Water is vital to the body as a solvent and lubricant and as a medium for transporting

nutrients and waste. It also has a role in body temperature regulations. A decrease in body

water can result either from an inadequate intake or from excessive excretion (e.g.,

sweating, vomiting, or diarrhea). Loss of electrolytes along with water may also occur

under the latter conditions.

Normally the total osmotic effects of the plasma, interstitial fluid, and the intra-

cellular fluid are all the same. The osmotic effect is attributable mostly to inorganic ions

but also to nonelectrolytes such as glucose, urea, and proteins. Consequently, gains or

losses of electrolytes, especially sodium or potassium, or changes in their concentrations

are usually followed by shifts of fluid to restore osmotic equilibrium.

Abnormalities of extracellular fluid volume are generally caused by net gains or

losses of sodium and accompanying gain or loss of water. Volume depletion may result

from unreplaced losses such as with prolonged sweating, vomiting, diarrhea, or burn

injury. A fluid volume excess tends to result from diseases, such as kidney or heart failure,

which prevent the excretion of sodium and water. Early signs of water loss include

headache, fatigue, loss of appetite, flushed skin, heat intolerance, light-headedness, dry

mouth and eyes, and a burning sensation in the stomach. Signs of more advanced

dehydration include clumsiness, sunken eyes and dim vision, and delirium. The prevalence

of kidney stones is higher in populations with low urine volume, which is related to fluid

intake. Increased fluid intake to allow for urine volume of about 2 L/day can prevent or

reduce the incidence of stone formation.

Although a multitude of factors determine water requirements under ordinary

circumstances a reasonable allowance is 1.5 mL/Cal for infants or 1015% of body

weight/day. For adults the corresponding values are 1 mL/Cal or 24% of body weight /day.

IX. FOOD ALLERGY

An allergy may be defined as any unusual or exaggerated response to a particular

substance, called an allergen, in a person sensitive to that substance. Allergies are the

result of the reactions of the bodys immunological processes to foreign substances

(chemical substances in such items as foods, drugs, and insect venom) or to physical

conditions. The reaction is caused by an allergen, either alone or coupled with a hapten,*

which stimulates the production of antibodies. Subsequent exposure to previously

sensitized antibody-producing cells may precipitate an allergic reaction. The symptoms

range from sneezing to vomiting, from headaches to hives, from edema to diarrhea, and

many more, some minor and some quite serious. These effects are believed to be due to

the release of histamine by an immunological reaction.

Allergies are classified into two broad classes: (a) immediate and (b) delayed.

Immediate allergies, as implied by name, are those that occur within minutes to an hour

or so after the ingestion of the offending food. Delayed allergies occur hours (at least 4 hr)

or days after exposure to the allergen. Immediate allergies are mediated by a specific class

*A hapten is a small molecule that cannot by itself stimulate antibody synthesis but can combine with a protein

to stimulate antibody formation.

Fundamentals of Nutrition 9

of antibodies known as immunoglobulins E or IgE. With the exception of celiac disease,

which is an abnormal intestinal immune response to wheat, rye, and barley, the role of

delayed hypersensitivity in adverse reaction to foods remains poorly understood.

Certain allergies tend to be hereditary in that they are passed on from the parent to

child. The word atopy is used to describe a group of allergic diseases that occur in man

and that are the result of genetic abnormality.

Many individuals are particularly sensitive to certain foods, just as others are to

pollen or other particles in the air they breathe. Some foods are more likely to produce

allergic reactions than others, but practically all foods can produce an allergic reaction in

some people. Proteins are often considered the causative agents, and undoubtedly they are

in most cases, but there are some assertions in the literature that fats and even

carbohydrates can be responsible. Many different foods have been associated with

allergies. They all contain proteins, one or more of which enter the body across the

intestinal epithelium and elicit an immune response; however, any major alteration in the

protein such as heat denaturation usually results in the loss of its allergenic properties. For

example, raw or pasteurized milk may cause an allergic reaction, but if the same milk is

boileda process that denatures the proteinsthe sensitive individual may be able to

consume it without an allergic reaction.

The foods that cause allergic reactions most frequently are milk, eggs, wheat, corn,

legumes, nuts, and seafood. Also, some people are allergic to strawberries and other

berries, citrus fruits, tomatoes, and chocolate. Foods that rarely cause allergic reactions

include rice, lamb, gelatin, peaches, pears, carrots, lettuce, and apples.

The best treatment after the offending food or foods is identified is to plan an

adequate diet that does not contain the allergen.

Food intolerance is an adverse reaction to food that does not involve an immune

response. Several basic mechanisms produce clinical manifestations of food intolerance.

For example, the failure to digest lactose due to a deficiency of lactase leads not only to

inefficient utilization of dietary lactose but also to a disordered gastrointestinal physiology.

Metabolic or biochemical abnormalities can alter the intermediary metabolism of a

substance. Inborn errors such as phenylketonuria and galactosemia have this effect and

are described in Chapter 20.

X. GENENUTRIENT INTERACTION

The relation of genes to nutrition is obviously a two-way relationship. Thus, not only

genes profoundly affect nutrient metabolism but also, in turn, nutrients regulate gene

expression. Before discussing their interrelationship, a brief review of gene structure and

expression follows.

A. Genetic Structure

Genetic information is encoded in the sequence of a linear polymer of purine and

pyrimidine bases termed deoxyribonucleic acid (DNA). This genetic message codes for

the building and operation of the human body. The message is written in an alphabet

that uses only four letters: A, C, G, T. Each of the letters represents one of the four

bases that are chemical building blocks of DNA. A stands for adenine, C for cytosine, G

for guanine, and T for thymine. The nucleotides, which spell out the genetic message,

are arranged in a linear sequence in the double-stranded helical DNA molecule. The two

Introduction to Clinical Nutrition10

strands of DNA are complementary copies of each other to form two antiparallel

polynucleotide strands that are twisted into a double helix. The nucleotides on one

strand pair with the complementary nucleotides on the other strand; adenine is paired

with thymine and guanine is paired with cytosine. The genetic message is read not as a

single letter but rather it is grouped into a three-letter word. Each three-letter word is

called a codon, which specifies one of the 20 possible amino acids that are the building

blocks for all proteins.

Human DNA is estimated to consist of about 3 billion base pairs per haploid

genome. Because humans are diploid organisms two copies of DNA exist. Therefore, the

actual number of base pairs is 6 billion. DNA strands are covered with histone and

nonhistone proteins that allow them to be supercoiled and twisted into compact structures

termed chromosomes. There are 23 pairs of chromosomes per somatic nucleus: 22 pairs

of autosomes numbered by descending size and one pair of sex chromosomes (XX,

female; XY, male). These chromosomes are located in the nucleus of the cell.

During mitosis the chromosomes are unwound; the DNA helix is split apart and

copied. Each replicated strand creates a complementary copy of the original double helix,

allowing the transmission of a complete set of genetic information into each daughter

cell. In meiosis, a reduction division of genetic information occurs. Homologous

chromosomes are paired, duplicated, and separated. Only one member of each pair of

chromosomes is allowed to segregate into a gamete. Thus a diploid germ cell gives rise to

a haploid sperm or egg that contains an assortment of one of each of the 23 pairs of

homologous chromosomes in the parental cell. During fertilization, sperm and egg unite

to create a zygote with a complete set of 46 chromosomes.

In its simplest form, a gene is a segment of a DNA molecule containing the specific

code for the amino acid sequence of a polypeptide chain and the regulatory sequence

necessary for expression. A gene product is usually a protein, but can occasionally

consist of a ribonucleic acid (RNA) that is not translated. The human genome contains

enough base pairs to make a million average-size proteins, but there are only about

30,00060,000 genes. Genes are composed of coding spaces (exons) intercepted by

noncoding sequences (introns). Only about 10% of the entire human genome is composed

of exons.

Gene expression refers to the process whereby a gene gives rise to its product,

namely, its unique polypeptide. It consists of three phases: (a) transcription; (b)

translation; and (c) posttranslational modification. This is a highly controlled process.

Transcription is the process whereby messenger (m) RNA is synthesized in the

nucleus using a strand of the double helix DNA as a template. The mRNA and

other RNAs are then transported from the nucleus to the cytoplasm where the RNA

sequence is decoded or translated to determine the sequence of amino acids in the

protein being synthesized. The process of translation occurs in ribosomes. Translation

involves transfer (t) RNAs, which provide the molecular link between the coded base

sequence of the mRNA and the amino acid sequence of the protein. Many proteins

undergo extensive posttranslational modifications. The polypeptide chain that is the

primary translation product is folded and bonded into a specific three-dimensional

structure that is determined by the amino acid sequence itself. Two or more

polypeptide chains, products of the same gene or of different genes, may combine

to form a single, mature protein complex. Other modifications may involve cleavage

of the protein to remove specific amino-terminal sequences, addition of phosphate, or

various amino acid modifications.

Fundamentals of Nutrition 11

B. Effects of Nutrients on Gene Expression

The formation of purine and pyrimidine bases in the DNA and RNA require the

participation of folic acid, vitamin B12, and other nutrients. Mechanisms that regulate

gene expression play a critical role in the function of genes. The transcription of genes

is controlled by a group of DNA-binding proteins (transcription factors) that determine

which regions of the DNA are to be transcribed. Nutrients bind to these proteins to

form nutrientprotein complexes that target small (815 nucleotides) DNA regions.

Transcription control is exerted by that portion of the DNA, called the promoter

region, to which transcription factors bind. Several nutrients have a role in the

transcription process. In many instances, the specific DNA-binding protein contains

zinc. Zinc binds to histidine and cysteine residues in the linear portions of these

proteins. This binding results in the formation of a loop finger in the protein that

permits the folded region to bind DNA sequences in the promotion region. Thus,

without zinc the transcriptor factors cannot bind and stimulate transcription of the gene.

Nutrients such as vitamins A and D and some hormones have their effects on the

expression of specific genes because they bind to these zinc fingers that in turn bind to

specific DNA sequences.

The gene remains turned-on, directing the synthesis of more protein until some-

thing causes it to be switched off. A common mechanism of gene regulation is negative

feedback. The presence of a large amount of the protein product from the gene can

interfere with the binding of transcription factors (inducers) that originally turned the

gene on. When this happens, the gene is turned off. There are several nutrients that also

control the transcription or translation processes. For example, dietary cholesterol exerts

an inhibitory effect on the transcription of the gene for hydroxymethylglutaryl CoA

reductase, a key enzyme in cholesterol synthesis. Alterations in the diet have striking

effects on the expression of a number of genes. Polyunsaturated fatty acids regulate the

expression of many genes that are involved in lipid metabolism. Vitamin A, in the form

of retinoic acid, modulates the expression of a variety of genes that encode for many

types of proteins, including growth factors, transcription factors, and enzymes. Copper

appears to stimulate the transcription of superoxide dismutase gene.

Nutrients and hormones may affect the synthesis of specific proteins by regulating

several steps in the translation and posttranslational processing. For example, cellular

iron concentration directly affects the translation and stability of mRNA for ferritin and

transferrin receptor proteins. The synthesis of proteins in the translation process depends

on the availability of constituent amino acids and energy. The changes required in the

posttranslational process are dependent on the availability of vitamins K and C and

several other nutrients. Thus, nutrients serve as regulators of the gene expression.

C. Genetic Variation and Nutrition

Genetic predisposition is known to contribute to variations in the incidence and

prevalence of chronic nutritional diseases among individuals, families, and nations.

The lifetime risk of non-insulin-dependent diabetes mellitus is about 40% in children

with one diabetic parent. Studies in the United States have shown that 50% of the

variance in plasma cholesterol concentration is genetically determined. Also, 30% to

60% of the variations in blood pressure is genetically determined. Studies in coronary

artery disease suggest 15% variance in the U.K., whereas it is 51% in the Hawaiian

Introduction to Clinical Nutrition12

population, indicating significant differences between populations. The variance in bone

density is genetically determined. Osteoporosis is a metabolic bone disease with strong

genetic predisposition.

Mutations in the genes are known to cause several disorders. Some of the disorders

can be treated nutritionally. Well known are the single-gene disorders that are expressed

as phenylketonuria, lactose intolerance, and celiac disease. A diet restricted in phenyl-

alanine largely circumvents the neurological damage in classic PKU. Lactose intolerance

can be managed by dietary lactose exclusion, and celiac disease can be managed by

dietary exclusion of gluten-containing foods.

In several metabolic disorders there is altered binding of a cofactor (often a

vitamin) to the mutant enzyme. It may be possible to provide a large excess of the

cofactor and overcome the altered binding ability to the enzyme impaired by mutation.

Examples are biotin in some types of multiple carboxylase deficiencies, and vitamin B1with some forms of lactic acidosis. In fact, the vitamin-responsive inborn errors are

among the most successfully treated of all genetic diseases. The vitamins used are

remarkably nontoxic, generally allowing the safe administration of amounts several times

greater than those required for normal nutrition.

PHENYLKETONURIAA CASE

A 41/2-year-old girl was admitted to a hospital because of retardation of development andpossible neurological problem. She began to sit up at 1 year of age and could use a few words.She learned to walk at the age of 2 years but did not develop further in language ability andgradually lost the few words she had acquired. She was stiff-legged and hypertonic. She hadbeen hyperactive and noisy, frequently banging her head on the wall, slapping her face,voluntarily falling down, biting her tongue, and screaming. There had been no episodes ofunconsciousness or convulsions.

Physical examination revealed an above normal weight child with extensive red scalingdermatitis of the forearm and legs and the characteristic odor of phenylacetic acid. She wasextremely hyperactive and her attention span was short. She grated her teeth together nearlycontinually and frequently uttered unrecognizable cries but no words. She responded toattention but did not play with toys or feed herself.

Neurological examination showed that her muscular tone was somewhat increasedgenerally and reflexes were hyperactive. No objective evidence of sensory impairment wasapparent. Electroencephalogram showed no seizure discharges. The usual blood and urineexaminations were normal. Fasting serum phenylalanine was 42 mg/dl (normal 0.52 mg/dl).Acidified urine developed green color on addition of ferric chloride (positive for PKU).

She was placed on artificial formula diet containing all of the amino acids in adequateamounts except phenylalanine. Her urinary phenylalanine fell promptly from 14 to about 3 mg/mg creatinine, and serum phenylalanine came down to 20 mg/dl. During the next 2 weeks, herurinary ketoacids and serum phenylalanine continued to fall but her weight also declined.Phenylalanine in an oral dose of 90 mg/day was started on the 13th day, but the dose wasincreased to 500 mg/day in order for growth to resume. During the first few weeks of herdietary regimen, she showed some improvements in behavior. There was moderate decrease inhyperactivity and increase in attention span. She also engaged in activities of her own choosingfor periods as long as 15 to 20 min. The dermatitis disappeared after the first week of the dietand her skin remained clear during her stay in the hospital. She was discharged after 13 weekson this diet.

Fundamentals of Nutrition 13

On a natural home diet, serum phenylalanine rose to 30 mg/dl and phenylpyruvic aciduriaand dermatitis recurred. She continued to grow normally during the following 22 months.

This case of PKU was one of the first to be investigated for the possible salutary effect ofphenylalanine restriction in the diet. PKU is characterized by reduced activity of phenylalaninehydroxylase (less than 2% of normal activity). The disease manifests between the third and sixthmonths of age and is characterized by mental retardation, abnormal electroencephalogram,dermatitis, hyperactivity, and reduced attention span. Although the exact pathogenesis of mentalretardation in PKU is unknown, the accumulation of phenylalanine or its metabolites up to 5 to10 times normal levels, or the deficiency of tyrosine or its products, or a combination of the two,cause irreversible damage to the central nervous system. High phenylalanine appears to interferewith decarboxylation of dihydroxyphenylalanine (DOPA) and 5-hydroxy tryptophan, whichcould impair neurotransmitter synthesis. This effect causes hyperactivity, short attention span,and dermatitis, which can be reversed by reducing serum phenylalanine levels, as was seen withthis case.

In PKU, phenylalanine levels are elevated and tyrosine levels tend to be depressed. Therational therapy, therefore, is to reduce phenylalanine to just enough for growth requirementsand increase tyrosine intake to the level required for growth. Tyrosine becomes a dietaryessential amino acid for patients with PKU. The estimated requirement for infants less than 6months of age is 140 mg/kg of body weight/day. This drops with time to 70 mg at 2 years andabout 20 mg/kg of body weight/day with maturity. The diet should be started as soon aspossible, preferably by the time the child is 3 weeks old. The diets effectiveness is remarkable.In almost every case, it can prevent the devastating array of symptoms described above.

DEFINITIONS

Allele An alternative form of a gene that may occupy a given locus.

Autosomes All chromosomes other than the X and Y chromosomes.

Chromosome A highly ordered structure composed of DNA and proteins that carries

the genetic information. In humans, there are 46 chromosomes ordered

in pairs.

Dominant allele An allele that is expressed when present at only a single copy (i.e., it

dominates over the other allele present).

Gene A sequence of nucleotides that represent a functional unit of

inheritance.

Heterozygous The two alleles are different.

Homozygous Both alleles at a locus are the same.

Locus Position of a gene on a chromosome.

Mutation A permanent heritable change in the sequence of DNA.

Recessive allele An allele that is only expressed when homozygous.

X-Linkage The distinctive inheritance pattern of alleles at loci on the X

chromosome.

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Introduction to Clinical Nutrition14

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S. M. Kleiner. Water: An essential but overlooked nutrient. J. Amer. Diet. Assoc. 99: 200, 1999.

L.G. Leksell and M. Rundgren: Regulation of water intake. Annu. Rev. Nutr. 2: 73, 1982.

C.A. Monturo: Enteral access device selection. Nutr. Clin. Pract 5: 207, 1990.

J.M. Saavedra and J.A. Perman: Current concepts in lactose malabsorption. Annu. Rev. Nutr. 9: 475,

1989.

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N.S. Scrimshaw and V.R. Young: The requirements of human nutrition. Sci. Am. 235: 50, 1976.

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1978.

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Fundamentals of Nutrition 15

2Digestion of Carbohydrates, Lipids,and Proteins

I. INTRODUCTION

Our normal food is a mixture of complex plant and animal materials that is composed

largely of carbohydrates, fat, protein, vitamins, and minerals. The bulk of these ingested

nutrients consists of large polymers that must be reduced to simpler components before

they can be absorbed and thus made available to all the cells in the body. The

disintegration of naturally occurring foodstuffs into assimilable forms in the gastro-

intestinal tract constitutes the process of digestion and involves enzymes. The gastro-

intestinal tract is important both in terms of maintaining the nutritional status of the gut

as well as providing nutrients to maintain nutritional status and homeostasis of the whole

organism. The majority of the enzymes involved in the digestive process are hydrolases

(i.e., they split bonds of esters, glycosides, or peptides by the addition of water). The

powerful hydrolytic enzymes of the digestive tract catalyze the degradation of large

molecules present in food (e.g., starch or protein) into small molecules that can be

readily absorbed such as glucose or amino acids. The digestive tract is under neuro-

logical and hormonal control. Fear, anger irritation, worry, all may exert unfavorable

influences in the digestive system, while the thought, smell, and presence of food cause

secretion and motility necessary for digestion. Both types of changes are controlled via

the nervous system of the body. Several areas of the digestive tract secrete hormones,

which act as chemical messengers on other areas of the digestive tract to control the

process of digestion.

We take food by mouth where it is homogenized, mixed, and lubricated by saliva

secreted by salivary glands. One constituent of human saliva is amylase, which catalyses

the hydrolysis of starch. Approximately 1.5 L of saliva is secreted daily. From the

mouth, the food contents pass via the esophagus (a straight muscular tube about 25 cm

long) to the stomach. The stomach consists of three anatomically and functionally

distinct regions: (a) the fundus, an upper portion; (b) the body, the central portion and

(c) the antrum, a constricted portion just before entry into the small intestine. The

body that makes up approximately 8090% of the stomach contains parietal cells and

chief cells. In the stomach, the food contents come in contact with gastric juice with a

17

pH V 2. Gastric juice contains hydrochloric acid, mucins, and the enzymes pepsin andlipase. Hydrochloric acid is secreted by parietal cells and pepsin by the chief cells.

Chyme, the acidic food content in the stomach, is intermittently introduced into the

small intestine. The small intestine is divided into three sections: (a) the duodenum,

which receives chyme from the stomach and the secretions from the gall bladder and

the pancreas; (b) the jejunum; and (c) the ileum. Bile is formed and secreted

continually by hepatocytes. Bile flows from the liver into the gallbladder, where it

is concentrated, stored and emptied into the duodenum when the partially digested

contents of the stomach enter the duodenum. The alkaline content of pancreatic (about

1.5 L/day) and biliary secretions (0.5 L/day) neutralizes the acid of the chyme and

changes the pH to the alkaline side necessary for the optimum activity of pancreatic

and intestinal enzymes. Most of the breakdown of food is catalyzed by the soluble

enzymes and occurs within the lumen of the small intestine; however, the pancreas is

the major organ that synthesizes and secretes the large amounts of enzymes needed

to digest the food. Secreted enzymes amount to about 30 g/day of protein in a

healthy adult. The pancreatic duct joins with the common bile duct to form

the ampulla of Vater; thus, pancreatic juice and bile empty into the duodenum at

the same point.

When fat and digestion products of protein reach the small intestine, the duodenal

and jejunal mucosa release cholecystokinin, a peptide hormone (Table 1). It stimulates

the secretion of pancreatic juice rich in enzymes and also stimulates the contraction of

the gall bladder and secretion of bile. The presence of acidic food in the small intestine

causes the release of another peptide hormone, secretin, by the duodenal and jejunal

mucosa; this stimulates secretion of pancreatic juice rich in bicarbonate and potentiates

the action of cholecystokinin on the pancreas. The secretion of gastric juice is under the

control of the hormone gastrin, a heptadecapeptide, and its release is stimulated by the

presence of food in the stomach. Gastrin is secreted by the antral region of the gastric

mucosa and by the duodenal mucosa. The main function of gastrin is to stimulate the

secretion of hydrochloric acid into the stomach, but it also stimulates pepsin secretion

and increases the motility of the gastric antrum. Gastric inhibitory peptide (GIP)

consists of 43 amino acid residues. Its secretion by the K cells of the duodenum and

jejunum is stimulated by the presence of glucose and lipids in the duodenum. GIP

stimulates secretion of insulin and inhibits gastric secretion and motility. In addition to

TABLE 1 Gastrointestinal Hormones

Hormone Site of secretion Biological action

Gastrin (34 aminoacids)

Gastric antrum; stimulatedby the presence of food inthe stomach

Increased secretion ofhydrochloric acid, pepsin

Secretin (27 aminoacids)

Duodenum, jejunum; stimulatedby the presence of acid induodenum

Increased secretion ofpancreatic juice rich inbicarbonate

Cholecystokinin (33amino acids)

Duodenum, jejunum; stimulatedby the presence of digestionproducts of fat and protein inthe duodenum

Increased secretion ofpancreatic juice rich inenzymes; increasedcontraction of gallbladder

Introduction to Clinical Nutrition18

these hormones, there are several others (e.g., epidermal growth factor) of possible

gastrointestinal significance. The discussion of their effects is beyond the scope of

this chapter.

At the low pH of the gastric juice, proteins are denatured and this allows the

polypeptide chains to unfold and makes them more accessible to the action of proteolytic

enzymes. Some digestion of protein occurs within the lumen of the stomach, and the acid

environment also destroys most of the microorganisms swallowed or ingested with food.

This protective action against many and varied microorganisms that accompany normal

food intake constitutes the bodys first and major defense against food-borne infection. It

also aids in maintaining qualitative stability in the intestinal flora distal to the stomach.

The absence of hydrochloric acid is termed achlorhydria. Achlorhydria may occur in

pernicious anemia and in a number of other conditions. An average of 22.5 L/day of

gastric juice is secreted, but the volume is reduced in atrophy of the gastric glands. The

intestinal bacterial concentration increases in hypochlorhydria (i.e., abnormally small

amounts of hydrochloric acid in the stomach) and may affect the absorption of some

nutrients by bacterial binding or metabolizing of nutrients. The bulk of digestion occurs

distal to the second (descending) part of the duodenum. The final result of the action

of digestive enzymes is to reduce the nutrients to forms that can be absorbed

and assimilated.

There is little absorption of nutrients from the stomach although alcohol can be

absorbed to a significant extent by this organ. Even water passes through the stomach to be

absorbed subsequently in the intestine. The main organ for the absorption of nutrients is

the small intestine, which has sites for the absorption of specific nutrients.

In the newborn baby, the length of the small intestine is about 200 cm. It

elongates and grows in diameter with age and by adulthood, the length is 700800

centimeters. The morphology of the intestine ideally meets the need for maximum

surface area for digestion and absorption of nutrients. The luminal surface of the small

intestine is so organized that the area available for contact with intestinal contents is

greatly amplified by visible spiral or circular concentric folds with villi lined by

absorptive columnar epithelial cells. The apical surface of each epithelial cell, in turn, is

covered by microvilli that form the brush border of each epithelial cell of the villus.

The result of this folding is that the intestinal surface of an adult human covers an

estimated area of 300 m2, or about 600 times greater than its external surface area. The

mucosal cells of the small intestine and stomach have a life of about 34 days. The

cells are sloughed off from the tips of the villi and are replaced by new ones. This

amounts to 2030 g protein/day, which is reclaimed as amino acids after hydrolysis in

the lumen.

About 9095% of the ingested foodstuffs along with water are absorbed in the small

intestine. The unabsorbed residue then enters the large intestine, which is about 1.5 m

long. The major functions of the large intestine are absorption of water, sodium, and other

electrolytes present in the residue, and temporary storage of unabsorbed contents and their

elimination. The semiliquid intestinal contents gradually become more solid. During this

period bacterial activity on the residual matter takes place with the production of: (a) gases

including ammonia, carbon dioxide, methane, and hydrogen, (b) lactic and acetic acid, and

(c) certain substances such as indoles and phenols that may have toxic properties. The

human gastrointestinal tract contains at least 150 different species of bacteria. Most are

anaerobic. There are few bacteria in the lower regions of the small intestine and very large

population in the large intestine. Bacteria can have desirable or undesirable effects on

Digestion of Carbohydrates, Lipids, and Proteins 19

metabolism. They synthesize various vitamins and some, e.g., biotin and vitamin K can be

absorbed and utilized by the hosts. They can be harmful by utilizing valuable nutrients so

preventing their absorption and by producing toxic compounds that damage the mucosa.

Bacteria may also metabolize bile acids to carcinogenic compounds.

II. CARBOHYDRATES

A. Digestion and Absorption

From a quantitative point of view, carbohydrate is the major group of chemical substances

metabolized by man and most animals. Approximately 50% by weight of the American

diet or 400500 g/day for the average American male is carbohydrate. About 60% of the

total digestible carbohydrate is in the form of starch largely derived from cereal grains and

vegetables such as corn and potatoes. The other 40% is supplied in