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PHYSICIAN’S REFERENCE

MANUAL



3rd Edition, 2007, Herbalife International, Inc.

Copyright: David Heber, M.D., Ph.D.Chairman, Herbalife Scientific and Nutrition Advisory Boards

This manual is not intended for the purpose

of preventing, diagnosing, or treating any

illness or disease. It is intended solely as a

source of information about Herbalife’s

nutritional programs. The products and

programs mentioned in this manual are

represented as foods or food supplements and

not being represented by Herbalife

International or its scientific and nutrition

advisors as being medical treatments or cures,

nor are they considered to be substitutes for

proper medical diagnosis or treatments.

This manual is intended for physicians

and health professionals as a guide to the

science of nutrition behind Herbalife’s

products and programs. The information

contained in this manual does not cover all

possible uses, actions, precautions, sideeffects, and interactions. It is not intended as

medical advice for individual problems.

Liability for individual actions or omissions

based upon the contents of this manual is

expressly disclaimed.

Please note



Dear Colleague ,

Obesity is the number one nutritional problem in the world today, yet our medical

offices are not set up to deal with this epidemic that costs the health care system over

$130 billion a year. Many of your patients with diabetes, hypertension and heart

disease could benefit from a program to achieve and maintain a healthy body weight.

Despite all the drugs and surgical options for weight management available today, the

most cost-effective method of fighting this epidemic in your office is to engage your

patients using a method that works and that works for your practice.

Herbalife International–a publicly traded company listed on the New York Stock

Exchange and a leader in nutrition and weight loss for over 27 years, with $3 billion in

revenues yearly–invites you to become an Independent Distributor. You have a built-in

referral base in the patients coming into your practice every day, and Herbalife willprovide you with a business system that will enable you to help your patients, engage

your office staff and improve the economics of your practice in three ways. First, your

patients with common co-morbidities of obesity–including diabetes, hypertension and

heart disease–may require less costly medications at their ideal weight. In today’s

capitated care environment, that can make your practice much more profitable while

increasing patient satisfaction. Second, your patients will pay your office staff for the

use of supplements that are customized to their needs based on their metabolism, and

your practice will make a reasonable profit on these products. Finally, some of your

most dedicated and successful patients will want to share their success with their

friends and family, leading to more referrals to your practice, which will now have a

reputation for expertise in weight management and nutrition.

A recent survey done in the UCLA Primary Care Network found that 50 percent

of patients in typical practices were obese with a body mass index over 30. Among these

patients, almost 60 percent had low back pain, 20 percent had high cholesterol,

20 percent had diabetes, and 5 percent had sleep apnea. Yet the average primary care

practitioner finds the busy practice environment unable to accommodate a weight-

management and nutrition program. Doctors in Herbalife was developed by Herbalife

International to meet the need for a program that works both medically and financially

for busy primary care practitioners. Doctors in Herbalife is based on concepts developed

by David Heber, M.D., Ph.D., professor of medicine and public health at UCLA* and

director of the Center for Human Nutrition at the David Geffen School of Medicine at

UCLA*. Dr. Heber is chairman of both the Scientific and Nutrition Advisory Boards at

Herbalife International and directs an international group of scientific and nutrition

advisors.

Setting up a weight-management center in your office is fast, easy and profitable.

Your patients will see results and live healthier lives. You will be increasing your

practice revenue with many possibilities for international travel as you grow your

business at home.

A Letter to Doctors from Herbalife

*Dr. Heber’s name and title are for identification purposes only. The University of California does not endorse

specific products or services as a matter of policy.



Doctors who currently use the Herbalife program design a quick and easy weight-

management program for their patients. Patients lose weight under medical supervision

while using some of the best foods and food supplement products on the market. As

patients achieve success, practice revenue grows. Your local involvement builds your

practice, and there are many international opportunities to grow and expand as

Herbalife is sold in 65 different countries worldwide.

This state-of-the-art program, offered to you by an industry leader with a history

of over 27 years in weight management and based on the best science available in

weight management and nutrition, will help you to provide a comprehensive program

to support your patients’ health while you improve the financial health of your

practice. Please feel free to email us with any further questions [email protected].

Sincerely,

..

PHYSICIAN’S REFERENCE MANUAL

Luigi Gratton, M.D., M.P.H.

Vice President,

Medical Affairs and Education

David Heber, M.D., Ph.D., F.A.C.P., F.A.C.N.

Chairman,

Scientific and Nutrition Advisory Boards



A. Philosophy and History of Herbalife International 8B. What Is the Rationale Behind Doctors in Herbalife? 9C. Cellular Nutrition 10D. Herbalife ShapeWorks® Program 11

A. History and Future of Nutritional Science and Medicine 13B. Fundamentals of Nutrition 16B.1 Fundamentals of Cellular Nutrition 16B.2 Quality of the Diet: Good vs. Bad 16B.3 Energetics and Obesity 17B.4 Protein and Its Role in Cellular Nutrition 17B.4.1 Protein Quality 17B.4.2 Protein Requirements 19B.4.3 Optimum Protein Intake 19B.4.4 Protein’s Role in Satiety 20

B.5 Fats in Cellular Nutrition 21B.5.1 Fatty Acid Structure and Classification 21B.5.2 Fatty Acids as Cellular Signals 22

B.6 Carbohydrates in Cellular Nutrition 23B.6.1 Sugars and Starches 23B.6.2 Glycemic Index and Glycemic Load 24

B.7 Functional Foods 28B.7.1 Soy Protein 28B.7.2 Phytochemical-Rich Fruits, Vegetables and Grains 28B.7.3 Beyond the Four Food Groups 32

C. Vitamins and Minerals 38C.1 Introduction 38C.2 Pregnancy and Birth Defects 38C.3 Immune Function 39C.4 Cardiovascular Disease 39C.5 Cancer 40C.6 Obesity and Diabetes 41C.7 Safety of Vitamins 42

D. Weight Management and Meal Replacement 44D.1 Definition of Obesity 44D.2 Causes of Obesity 44D.3 Body-Fat Regulation and Function as an Endocrine Organ 45D.3.1 Female Fat 45

D.3.2 Abdominal Fat 46D.3.3 Brain Centers and Body Fat 46D.3.4 Genes and Obesity 48D.4 Meal Replacements 49D.4.1 History of Meal Replacements 49D.4.2 Nutrient Composition of Herbalife Formula 1 and High-Protein/

Low-Carb Drink Mix 50D.4.3 Clinical Research on Meal Replacements 50D.4.4 Recent Research on ShapeWorks® (Abstract) 52

E. Body Composition 55E.1 Classification According to Lean-Body Mass 55E.2 RMR and Predicted Weight Loss from Lean Body Mass 56E.3 Basic Science Behind Bioimpedance 56

SECTION IINTRODUCTION

Section IIBACKGROUND

Contents



E.4 Challenges in the Clinical Use of Bioelectrical Impedance 58E.5 Future Research and Other Methods 58

F. The Safety of Caffeine and Its Effects in Weight Management 60

F.1 What is Caffeine? 60F.2 Coffee Consumption 61F.3 Caffeine Safety 61F.4 Fibrocystic Breast Disease and Caffeine Consumption 62F.5 Osteoporosis and Caffeine Consumption 62F.6 Caffeine and Blood Cholesterol 63F.7 Caffeine and Blood Pressure 63F.8 Caffeine and Heart Disease 63

G. Metabolic Syndrome and the Co-morbidities of Overweight and Obesity 64G.1 Diabesity 65G.2 Heart Disease and Hypertension 65G.3 Fatty Liver Disease and Cirrhosis 66G.3.1 Diagnosing Fatty Liver Disease 66

G.3.2 Other Causes of Fatty Liver and Liver Failure 66G.4 Cancer 67G.5 Changes with Aging in Body Fat and Chronic Disease Risk 68




SECTION I: INTRODUCTION

A.PHILOSOPHY AND HISTORY OFHERBALIFE INTERNATIONAL

Herbalife International is a unique company that has a worldwide mission of changing

people’s lives through improved lifestyles, nutritional health and weight management.

This company, now traded on the New York Stock Exchange (symbol HLF), is the

largest manufacturer of meal replacements in the world, with over 1.6 million

Distributors in 65 countries.

How did Herbalife grow to this position as an international leader in nutrition?

Herbalife was founded in 1980 by Mark Hughes. At the time, this remarkable individual

was only in his 20s, but he had the passion to bring healthy weight-loss solutions to the

world after his mother died of complications from taking diet pills.

In his first year of business, he was able to sell $1 million of meal replacements

from the trunk of his car by offering people the opportunity to both lose weight and

make money by helping others. However, the company did more than give people a

chance to make money. Mark Hughes inspired people to change for the better in many

ways. He taught them to speak in front of groups as they received recognition. He

taught them to train others to do the same job and learn business and leadership skills

in the process.

The critical issue in weight management is adherence to diet and lifestyle change.

In our best universities, the average weight loss achieved in any trial is on the order of

5 percent of initial body weight on average, with dropout rates from clinical trials of

between 20 percent and 40 percent after one year. However, in these trials there are

always individuals who do much better than the average and some who gain weightdespite being given all of the nutritional and lifestyle tools to be successful. The key

difference between those who succeed and those who fail is found in their personal

motivation and ability to change themselves.

Through hard work and person-to-person contact, Herbalife Independent

Distributors from every walk of life move up through the ranks, at first helping their

family and friends and then developing the skills to run a small business. Through

training they can reach leadership positions in the company as President’s Team and

Chairman’s Club members. These individuals with innate business skills often have little

or no formal education, or have been unsuccessful in other businesses before coming to

Herbalife. However, by combining product results, recognition and a sense of community,

Herbalife has helped countless individuals change their health status through long-lasting

weight loss and maintenance. In the process, Herbalife has developed an army of over1.6 million agents of change throughout the world, and one of the most powerful

weapons in the war against the international epidemic of obesity.

Herbalife International was acquired from the estate of Mark Hughes in 2003 by

the investment banking firms of Whitney and Golden Gate, and is led by Chairman

and CEO Michael O. Johnson, former head of Disney International, and President and

COO Gregory Probert. Chief Scientific Officer Steven Henig, Ph.D., has an over 20-year

history in the food business, which included positions with Con-Agra, Ocean Spray ®*

and POM Wonderful®†, and was a member of the Board of Directors of the International

8

Section l Introduction

*Ocean Spray® is a registered trademark of Ocean Spray Cranberries, Inc.†POM Wonderful® is a registered trademark of POM Wonderful, LLC.



Life Sciences Institute (ILSI). A prestigious Scientific Advisory Board is led by David

Heber, M.D., Ph.D., F.A.C.P., F.A.C.N., professor of medicine and public health and

director of the prestigious UCLA Center for Human Nutrition. Louis Ignarro, Ph.D.,

winner of the 1998 Nobel Prize for Physiology or Medicine, is a member of the board.

Under the leadership of Dr. Heber, Luigi Gratton, M.D., M.P.H., a clinical physician at

the University of California, Los Angeles (UCLA), administers a worldwide Nutrition

Advisory Board made up of highly qualified physicians, often with current or formerprestigious university affiliations, who work in the training of Herbalife Independent

Distributors in science-based approaches to nutrition and weight management.

B.WHAT IS THE RATIONALE BEHIND

DOCTORS IN HERBALIFE?Over the past 27 years, several hundred physicians in the United States alone, and

many others throughout the world, have discovered that they can help far more

individuals to attain and maintain a healthy lifestyle through their activities as HerbalifeDistributors than through their routine medical practice. It is very difficult to motivate

patients to achieve and maintain a healthy body weight even when you are able to take

the time to do this important job. Too often, prescriptions for drugs to lower cholesterol,

blood pressure or blood sugar take the place of lifestyle change precisely because long-

term adherence to diet and lifestyle is so problematic.

The Doctors in Herbalife initiative is meant to accelerate the Herbalife mission of

changing people’s lives by recruiting practicing doctors to be Herbalife Distributors. As

physicians, you have a constant stream of patients coming to your office who could

benefit from diet and lifestyle change. However, your education, your facilities,

reimbursement mechanisms and time constraints all make it impossible for you to

deliver this service within a traditional practice. What is rewarded is the prescription of

medications for lowering cholesterol, blood pressure and blood sugar, or referring

patients for expensive cardiovascular or bariatric surgery.

Surveys done within the UCLA Primary Care Network have shown that over

50 percent of patients are obese with BMIs of greater than 30. Among these, 58 percent

have musculoskeletal pain, such as knee or back pain. Subgroups of patients amounting

to 20 percent to 40 percent each of the total population have metabolic syndrome,

hyperlipidemia, hypertension or abnormal glucose tolerance. About 5 percent have

sleep apnea, which can be fatal. Many of these problems respond to lifestyle change,

improved nutrition and weight loss. The Diabetes Prevention Program funded by the

National Institutes of Health (NIH), demonstrated that a modest 5 percent weight loss

among individuals with impaired glucose tolerance led to a 58 percent reduction in new

cases of type 2 diabetes over a five-year period.Meal replacements work. The scientific data is presented in this manual in detail

and has appeared in the peer-reviewed medical literature. The NIH LookAHEAD trial,

examining the impact of weight loss on cardiovascular mortality in patients with

type 2 diabetes, is successfully utilizing this strategy. The Herbalife ShapeWorks®

program described in this manual applies the latest nutritional science on weight

management to provide a personalized approach based on individualizing protein

recommendations and on lean body mass. When this science-based approach is

combined with the motivational tools developed by Herbalife, successful individuals

achieve remarkable results.

Herbalife has committed to a worldwide program of outreach to the medical and

scientific communities through medical meetings and presentations at key medical





conferences. Through the Scientific and Nutrition Advisory Board and Doctors in

Herbalife, it will be possible to build an international medical alliance dedicated to

providing healthy nutrition solutions. The power of the Internet and high tech is being

coupled with the “high touch” of Herbalife Distributors worldwide to create

unprecedented efforts to prevent the spread of the international epidemics of obesity

and obesity-associated chronic diseases.

C.CELLULAR NUTRITION

Good nutrition begins at the cellular level. Not only must the nutrients be delivered,

but they must get to the appropriate cells of the body. These principles are the basis for

Cellular Nutrition. Cellular Nutrition is the overriding nutritional philosophy of

Herbalife International. A fully referenced section on Cellular Nutrition and the

Fundamentals of Human Nutrition is included in Section II of this manual.

Today, throughout the world, people are facing a lack of vital nutrients that their

cells need for good health. This occurs even in countries where overweight and obesity

are common. In the past 100 years, the human diet has changed drastically in ways that

do not fit well with our genes. Our cells are adapted to a calorie-poor environment rich

in bioactive substances from colorful fruits and vegetables, and high in dietary fiber and

healthy plant-based proteins. Our genes cannot change rapidly enough through

evolution to enable us to adjust in only the past few hundred years to a diet missing

key cellular nutrients.

For example, humans and fruit-eating bats have given up the cellular machinery

to make Vitamin C, since both our diets and those of fruit-eating bats were originally

rich in Vitamin C from plant foods. Unfortunately many individuals in the United

States go all day without eating a single piece of fruit, and so do not get enough

Vitamin C for optimum health. They often can get the tiny amount (20 milligrams)

needed to prevent scurvy from fortified foods, but not enough to get the antioxidant benefits of this essential vitamin.

Similarly, many different pathways promote retaining calories when excess food is

eaten. The key element in reaching a successful body composition is not simply eating

less but eating more of the right foods. Significant scientific evidence supports a high-

protein/low-fat diet, including meal replacements such as Herbalife’s ShapeWorks®

Formula 1, fortified (when necessary) with Performance Protein Powder, which

provides additional protein to help control hunger and support increasing muscle mass

with exercise. ShapeWorks® meal replacements taken twice a day with a healthy meal

and exercise leads to weight loss, while one meal replacement per day with two meals

and exercise can help keep weight off for life. Meal replacements work by structuring

the diet so that the healthy shake is providing better control of hunger and more

protein to support the lean body mass than do the foods normally eaten at meal time.

However, these shakes are taken in addition to at least one healthy meal per day, and

Herbalife includes a healthy, colorful meal plan recommending seven servings of fruits

and vegetables each day.

While it was generally taught in medical schools for some 20 years that the so-called

“four basic food groups” provided all the nutrition the body needed, this was not true.

Significant research, which will be reviewed in this manual, demonstrates that most

Americans are not getting what they need from their diet, and that nutritional

supplements are a useful prevention strategy for the general population.

Of course, nutritional supplements work best when combined with a healthy diet

and lifestyle. Nutritional supplements help you obtain vitamins, minerals, proteins and10



other nutrients frequently missing from modern diets. Multivitamin supplements, protein

supplements, individual mineral and vitamin supplements (provided alone or in

combination), as well as botanicals, amino acids, and other forms of supplementation, are

being used by millions of consumers around the world.

Herbalife International has been providing nutritional supplements to over

1.6 million Distributors in 65 countries and is making a positive contribution to the

lives of millions around the world. With over 27 years of experience in providing thefinest nutritional supplements available, Herbalife is changing the health of the world,

one person at a time.

D.HERBALIFE ShapeWorks® PROGRAM

Over the past 27 years, Herbalife International has become the leading global

manufacturer of meal replacements for healthy nutrition and weight management. The

goal of weight management is to achieve and maintain not only a healthy weight, butalso a healthy shape. Shape is critical to achieving the health goals of weight

management, since shape includes the concept of body-fat distribution, optimizing lean

body mass and getting into a proper level of fitness. Shape means both body shape and

“getting into shape,” and so provides a valuable tool for communicating the benefits of

a healthy diet and lifestyle, regardless of body weight.

It is not simply the weight of the body that determines health, but the quality of

the body tissues in terms of lean versus fat. Simply because an individual is overweight,

normal weight, or underweight is not neccessarily a gauge of his or her nutritional

balance. Weight loss can lead to loss of lean body mass, which occurs during

unsupplemented starvation and with hypocaloric diets that are deficient in protein.

A body of scientific research is demonstrating that increased protein provided at

about one gram per pound of lean body mass (29 percent of resting metabolic rate)provides better control of hunger and maintains lean body mass better than the usually

recommended amount of protein, which is about 15 percent of total calorie intake. In

addition to research at UCLA which forms the basis for the ShapeWorks ® program,

recent studies in Australia and in Colorado demonstrate that increased protein may

be especially useful for promoting weight loss in the pre-diabetic, insulin-resistant,

obese individual.

Many Americans take in too little protein and lead a sedentary lifestyle, resulting

in loss of muscle and increase in fat or sarcopenic obesity. Attempts at rapid weight loss

by eating less of their favorite foods results in deficiencies of multiple nutrients, which

usually includes protein. In this common condition, lean tissue is deficient and

the percentage of body fat is high (>30 percent), despite a normal Body Mass Index

(BMI). Similarly, weight lifters can be overweight with a high BMI but have a normal

body-fat percentage. Their increased weight is due to increased muscle tissue, and they

require increased protein based on their lean mass, both to control hunger and

maintain muscle.

The rate at which weight is lost is a function of how much of a calorie deficit is

created from the calories required to maintain current weight. For every 500 cal/day

deficit created through calorie restriction, increased physical activity or some

combination of the two, there will be a one-pound weight loss per week. Increased

protein intake does not make weight loss more rapid, but it does result in better

maintenance of lean body mass at the same rate of weight loss when compared to a

lower protein intake. Starvation is the extreme, in which about one pound of body


1




protein is lost for every four pounds of weight lost. With exercise and increased protein

intake during weight loss, it is possible to minimize the loss of lean body mass.

Some thin women will gain weight when given adequate protein, due to an

increase in muscle mass. They may not be happy with this, and it is their choice to

remain at a lower muscle mass. However, in order to keep their body-fat percentage in

a healthy range, these women will need to burn calories daily with aerobic exercise and

carefully watch their food intake to minimize total calorie intake. Their lower musclemass means that they will need fewer calories to maintain their tiny shape.

The ultimate secret ingredient in this program is the care that each Herbalife

Distributor provides to their customers. Herbalife International provides many

resources in the form of pamphlets, DVDs and educational materials, as well as

downloadable Web-based information, to help Distributors provide the best care for

their customers. It is our hope that this manual will help you in your efforts as a Doctor

in Herbalife Distributor.

12



A.HISTORY AND FUTURE OFNUTRITIONAL SCIENCE AND MEDICINE

The understanding of human nutrition has evolved throughout history in parallel to

the development of key sciences, including chemistry, biochemistry and physiology.

During the “Naturalistic Era” (400 BC–1750 AD), Hippocrates hypothesized about the

body’s “innate heat” and coined his famous phrase, “Let food be your medicine and

medicine be your food.” During the next 500 years, little happened in either the

development of scientific knowledge or nutritional science. However, the level of

knowledge that could be gleaned from careful clinical observation of the effects of foods

on physiological function was remarkable, as typified in the writings of Maimonides in

the 11th century.

The late 1700s ushered in the “Chemical-Analytical Era” (1750–1900), highlighted by Lavoisier’s calorimetry studies (McCollum, 1957). He discovered how food is

metabolized by oxidation to carbon dioxide, water and heat. He also invented the

calorimeter, crucial to further understanding heat energy. In the 19th century, Liebig

recognized that carbohydrates, proteins and fats are oxidized by the body, and he

calculated energy values for each. While chemists were examining the composition of

foods and metabolism, physicians were studying the mechanisms and process of

digestion–the means by which food is converted to useful, oxidizable components.

The “Biological Era” (1900–present) was founded on advances in chemistry,

biochemistry and the understanding of the metabolic pathways. In the early 20th century,

considerable research had been done on energy exchange and on the nature of foodstuffs.

Nutritional science took a leap forward, as evidenced by publication of the “laws of

nutrition” by Langworthy. Once understanding of macronutrients was developed and

better tools were developed, nutritional scientists turned their attention to the

understanding of micronutrients–vitamin and mineral nutrition (Pike and Brown, 1975).

The “Cellular Era” of the late 20th century (after 1955) focused on understanding

the functions of essential nutrients and the roles of micronutrients (vitamins and

minerals) as cofactors for enzymes and hormones, and their subsequent roles in

metabolic pathways. The roles of carbohydrates and fats in diseases such as diabetes and

atherosclerosis were discovered, and actual and potential mechanisms have been

uncovered (University of Vermont).

Today we are still in the era of Cellular Nutrition, but the coming era of “Molecular

and Cellular” is developing in the 21st century. It has been spurred on by the

sequencing of the human genome, but is not yet ready for application. Here is a glimpseof the future as Herbalife International uses its high-tech and international reach to

change lives around the world.

Observations of health and disease in the 20th century raised some new questions.

Why can some individuals consume high-fat diets and yet show no evidence of

atherosclerotic disease? Genetic differences certainly were suspected, but elucidating

and proving cellular, molecular and ultimately genetic-level mechanisms in both

healthy and unhealthy individuals proved to be a challenge. With the continuing

developments in tools that enable molecular-level exploration of cause-effect

phenomena, scientists have begun to develop hypotheses and conduct experiments to

lay the foundation for a deeper level of understanding of gene-nutrient interactions.

PHYSICIAN’S REFERENCE MANUAL A

1

Section II Background Material



Today, an emerging field of nutritional research focuses on identifying and understanding

molecular-level interaction between nutrients and other dietary bioactives with the

human genome during transcription, translation and expression–the processes during

which proteins encoded by the genome are produced and expressed.

The UCLA Center for Human Nutrition and the Mark Hughes Cellular and

Molecular Nutrition Laboratory are at the cutting edge of this new science. Continuing

and accelerating discoveries in genomics present possibilities for an ever more dynamicera of scientific investigation based on understanding the effects of nutrients in

molecular-level processes in the body, as well as the variable effects nutrients and non-

nutritive dietary phytochemicals have on each of us as individuals. We call this new era

in nutritional science the “Genetic Era,” or nutrigenomics. There is a coming revolution

in the way nutrition and diet are viewed.

Enabling science and technology platforms and techniques are essential for

development of knowledge and advancements in science. However, the ultimate result

will require both high tech and “high touch.” The latter involves behavior and lifestyle

changes best performed on an individualized basis. What do we know about behavior that

makes Herbalife such a powerful approach?

The National Weight Control Registry includes a group of more than 3,000 men and

women who have been classified as “successful losers.” Wing and colleagues and Klemstudied these individuals and found that their long-term success was due to a

combination of a healthy, low-fat diet and regular, moderate exercise. The ShapeWorks®

program is based on sound science and the latest advances in formulating a low-fat/high-

protein diet and incorporating fitness into future messaging and image. Second, we know

that our success as physicians in a clinical setting is typically poor, with up to 50 percent

dropouts at one year.

We know what the signposts of success are. They include readiness to change, and

a step-wise approach to lifestyle change. These principles were built into the successful

Herbalife programs over the last 27 years. Moreover, they have always been based on a

proven way to enhance compliance. Meal-replacement shakes organize the diet and

simplify long-term adherence. As discussed in this background section, there is significant

evidence that higher protein levels than recommended for the general population are

particularly useful in weight management, both to control hunger and maintain lean

body mass. However, these physiological principles would be useless without the proper

behavioral approach.

A Glimpse at the Future of Nutritional Medicine

• Individual genetic differences in response to dietary components

have been evident for years: lactose intolerance, alcohol dehydrogenase

deficiency, individual and population differences in blood lipid profiles and

health outcomes after consumption of high-fat diets.

• Genomic information—including proteomics and SNPs—will be usedto understand the basis of individual differences in response to dietary

patterns.

• The resulting nutrigenomic data also will provide a sound basis for

development of safe and effective diet therapies for individuals or

subgroups of the population.

• Refined models of disease mechanism based on understanding the

genome may provide new lines of research and possibly new diets. The

elaboration of physical and genetic linkage maps combined with techniques

to catalog massive databases of genetic information will uncover genes that

may interact with diet to influence disease.

SECTION II: BACKGROUND

14

A



“Personalized medicine” developed through growing knowledge of genomics has

generated a lot of well-deserved enthusiasm as an important tool for the future, but it

will require a personalized behavioral approach as well.

Who will do this? Public health officials will continue to issue vague “one size fits

all” solutions and will necessarily need to run these through the funnel of special

interests that distort nutritional advice given to the public. The drug industry, while

recognizing that nutrition may play a role, minimizes this and uses the generalgovernment guidelines in patients given drugs to ameliorate conditions driven by diet

and lifestyle, such as hypertension, hypercholesterolemia and diabetes. Food processors

marketing mainstream products will wait a long time for the products to be created and

the demand to be established.

At the present time, Herbalife International can provide you with a unique

opportunity to impact your patients and your practice using a high-tech and high-touch

approach. With the resources of a $3 billion company in 65 countries and with over

1.6 million “agents of change,” what a unique opportunity for you as a Doctor in

Herbalife to “ride the wave” of the coming advances in nutrition that will change the

way you practice medicine. You will begin to appreciate the power of the personal

touch in lifestyle change, and you can enlist the help of successful staff and patients to

help you in the mission of changing people’s lives one at a time and hundreds at a time.You will learn how you can duplicate your expertise and spread a message of health. If

you take on this challenge, you will gain satisfaction and enhance your clinical practice.

At the same time, you will be acting within the highest ethical standards of physicians

who have an obligation, not simply to prescribe drugs and surgery for the treatment of

disease, but to use the resources available to motivate and follow their patients as they

prevent disease through changes in diet and lifestyle.

REFERENCES“A History of Nutrition,” E.V. McCollum 1957 QU 145 McCol.

Nutrition; An Integrated Approach, Ruth Pike and Myrtle Brown, John Wiley & Sons, 1975, pp 4-8.“Fundamentals of Nutrition,” Course Syllabus, University of Vermont.

Biospace.com “Pharmacogenomic Medicine: Technology Outpacing the Health Care System.”

AAAS symposium on “Gene-diet Interactions in Coronary Heart Disease,” AHA press release 2/14/98.

“Attenuated hypercholesterol response to a high-cholesterol diet in subjects heterozygous for the apolipoprotein A-IV-2 allele,” Weiberget al, N Engl J Med, Vol. 331, No.11, pp 706-710.

“Attacking Heart Disease at Its Genetic Base,” Agricultural Research, 7/99.

Autism and Schizophrenia: Intestinal Disorders, Cade R et al. Nutritional Neuroscience, in press 1999.

Symposium: Interactions of diet and Nutrition with Genetic Susceptibili ty in Cancer, Journal of Nutrition, Vol. 129, 2/99, pp 550S-551S.

PHYSICIAN’S REFERENCE MANUAL A

1




B.FUNDAMENTALS OF NUTRITION

B.1 FUNDAMENTALS OF CELLULAR

NUTRITIONDiets are made up of numerous foods in varied proportions that are prepared in many

different ways, but ultimately the purpose of foods is to contribute energy to the body

to support basic cellular energy needs. How that energy is provided as foods which are

made up of the basic macronutrients–protein, carbohydrate and fat–plays a major role

in determining the impact of dietary patterns on health and disease. Within each

category of macronutrient, there are marked differences in how different food sources

are digested, absorbed and metabolized. It is critical to understand the impact of the

specific food sources of these macronutrients.

Foods can be grouped according to their content of macronutrients combined with

their traditional use in an ethnic or societal geographic cuisine. Food groupings such as

the basic four food groups [1) Grains and Cereals, 2) Fruits and Vegetables, 3) Meat,

Beans, Nuts and Cheese and 4) Dairy Products] classify foods of very different

compositions together (such as red meat and ocean-caught fish, or muffins and whole-

grain bread). However, considerations of chemical structure, digestibility, metabolism

and functionality contribute to what is called the quality of the diet overall, as well as

for individual macronutrients.

B.2 QUALITY OF THE DIET:

GOOD VS. BADThe quality of dietary macronutrients, such as the ratio of n-3 fatty acids to n-6 fatty

acids or of whole grains to refined grains, complicates the basic considerations of the

effects of diet on the incidence of chronic diseases and efforts to organize dietary

interventions designed to reduce risk. An additional and important consideration is

the presence of phytochemicals in fruits, vegetables and whole grains leading to their

designation in some cases as functional foods. The term functional food indicates the

presence of bioactive substances that affect physiology or cellular and molecular

biology.

The term quality implies that a value judgment is being leveled against a

particular food. While there is a hierarchical ranking of fats, carbohydrates and

proteins common to the disease-prevention literature, the mechanisms underlying the

differences among foods that provide protein, fat and carbohydrate to the diet are

simply analyzed in light of fundamental principles of nutrition. Taken together, these

aspects of foods contribute to the assessment of the quality of the diet. The lowest

quality foods are called “junk foods,” since they are high in energy density but low in

nutrient density (e.g., French fries). It has been said that there are no junk foods

but simply “junk diets.” Obviously, if one combines enough junk foods, it results in a

junk diet.16

B - B.2



B.3ENERGETICS AND OBESITY

Among species, smaller surface area animals such as mice burn more energy at rest per

unit body mass than large mammals such as elephants. Children have higher metabolic

rates than adults per unit body mass. Within the same species there can be significantvariations in metabolic rates. For example, the sedentary and overfed laboratory rat has

a higher metabolic rate than does the desert rat, which is better adapted to starvation

(Kalman et al., 1993). Energy efficiency may vary as well among humans. There is

evidence that the post-obese adult may have a lower metabolism than a never-obese

individual of the same size. However, the impact of excess energy is modulated by the

location of excess body fat and its effects on hormones and inflammatory cytokines.

Therefore, while energy balance is critical, it is not sufficient for an understanding of

the effects of nutrition on disease risk.

Since obesity results from an imbalance of energy intake and expenditure, certain

dietary factors have been identified as contributing to obesity. These include hidden

processed fats in foods, added refined sugars in foods and a high-glycemic-load diet rich

in refined carbohydrates. Therefore, the quality of the diet, in terms of nutrient density,can contribute to the tendency of a dietary pattern to promote the development of

obesity in genetically susceptible individuals. Low-energy density foods include all

fruits and vegetables, generally due to their high-water content. High-energy density

foods include red meats, fats, cheeses, pastries, cookies, cakes, ice cream, snack chips,

some fruit juices and refined grains.

B.4PROTEIN AND ITS ROLE IN

CELLULAR NUTRITIONProteins are involved in the growth, repair and replacement of tissue, and serve

numerous functions in the body as enzymes, antibodies, hormones, regulators of fluid

and acid-base balance, and as integral parts of most body structures, including skin,

muscle and bone. Within each cell, there is a continuous process of synthesis and

breakdown of proteins in the body, referred to as protein turnover .

The rate of protein turnover affects organ-protein mass, body size and ultimately,

the body’s protein and amino acid requirements (Matthews, 1999; Fuller, 2000). The

amino acids are the basic units in protein metabolism, and all have the same basic

structure of a central carbon atom with a hydrogen, an amino group and an acid group

attached to it. Attached to the fourth site on the carbon atom is a distinct side chain,

which defines the amino acid. Cells link these amino acids in an infinite variety to

create proteins which become metabolically essential compounds.

B.4.1PROTEIN QUALITY

There are 21 amino acids in human proteins, and 12 of these are synthesized by the

body and are, therefore, known as non-essential amino acids. The nine remaining

amino acids (histidine, isoleucine, leucine, lysine, methionine, phenylalanine,

threonine, tryptophan and valine) are either not made by the body or not made in

sufficient quantities to meet needs, and are, thus, termed essential amino acids.

PHYSICIAN’S REFERENCE MANUAL B.3 - B.4.1

1



The proper balance and sufficient intake of essential amino acids, along with an

adequate amount of nitrogen for the production of non-essential amino acids, is required

for proper protein nutriture (Berdanier, 2000).

In order to manufacture proteins, cells require all the needed amino acids

simultaneously with adequate nitrogen-containing amino groups for the manufacture

of the non-essential amino acids. The amino acid composition of a food can vary widely,

and determines the nutritional quality of the dietary protein. Foods that containessential amino acids at levels that facilitate tissue growth and repair are known as

complete proteins and are supplied in the diet from animal sources and

soy protein.

There are several ways of measuring protein quality. Most commonly, the term

biological value is used, which is a measure of the efficiency of a given protein in supporting

the body’s needs. Complete proteins have a high biological value, which is an expression

of the amount of nitrogen absorbed relative to the amount of nitrogen retained by the

body. All protein sources are compared with egg white, which provides the most complete

protein and has the highest biological value of 100, indicating that 100 percent of the

nitrogen absorbed is retained.

A low concentration of one or more essential amino acids in a food lowers its biological

value. With the exception of soy, most plant proteins are deficient in one or more essentialamino acids and are, therefore, regarded as incomplete. However, the biological value of

incomplete proteins can be improved by combining two proteins that are complementary so

that those essential amino acids lacking or deficient in one protein are provided by the other

when they are combined. In this way, the two complementary proteins together provide all

the essential amino acids in ratios ideal for human protein utilization (Kreutler and Czajka-

Narins, 1987; Lappe, 1971; Matthews, 1999). For example, the combination of corn (limited

in lysine) with beans (limited in methionine) results in a high-quality protein food

combination. Thus, the requirement for adequate essential amino acids can be met in a

vegetarian diet by mixing foods of complementary amino acid composition (Berdanier,

2000; Committee on Diet and Health, 1989; Lappe, 1971).

TABLE 1

A Few Facts on Amino Acids

There are 21 common (non-essential) amino acids and nine essential

amino acids. Essential amino acids are those that cannot be synthesized

from other amino acids, but must be consumed in the diet. The usual way

that non-essential amino acids are formed is by metabolism of other amino

acids. All amino acids have a basic structure of an alpha-amino nitrogen and

carboxylic acid. What defines their identity is the side chain denoted as “R”

in the diagram below:

R - C – C – O – O – H

NH2

Some amino acids are called conditionally essential, because they must

be consumed in the diet during growth to provide adequate growth rates,

but become non-essential in adults who are not growing. One such amino

acid is histidine, which is essential for rats that are still growing but not for

adult rats. Much of the data on essentiality of amino acids is obtained from

rats, where single amino acid elimination is a way of determining whether

a given amino acid is essential. For example, lysine and threonine cannot be


18

B.4.1



made from other amino acids by transamination and must be included in

the diet.

Essential Amino Acids Non-essential Amino Acids

Histidine Alanine

Isoleucine Arginine

Leucine Asparagine

Lysine Aspartic Acid

Methionine Cysteine

Phenylalanine Glutamic Acid

Threonine Glutamine

Tryptophan Glycine

Valine Proline

Serine

Taurine

Tyrosine

B.4.2PROTEIN REQUIREMENTS

The U.S. food supply can provide an average of 102 grams of protein per person per day

(Nationwide Food Consumption Survey, 1984). Actual daily protein consumption

ranges from 88 grams to 92 grams for men and from 63 grams to 66 grams for women

(McDowell et al., 1994). Animal products provide 75 percent of the essential amino

acids in the food supply, followed by dairy products, cereal products, eggs, legumes,

fruits and vegetables (McDowell et al., 1994). The recommended daily allowance

(RDA) for protein of high biological value for adults, based on body weight, is

0.8 grams/kilograms (National Research Council, 1989) or 0.36 grams/lb. However, the

RDA is set to meet the needs of a defined population group as a whole, rather than

indicating individual requirements. In a recent report concerning Dietary Reference

Intakes (DRI) the Acceptable Macronutrient Distribution Range (AMDR) was set at

10 percent to 35 percent of total calories from protein. The AMDR is defined as the

acceptable range of intakes for protein associated with reduced risk of chronic disease

while providing intakes of essential nutrients (Barr et al., 2003). This range was largely

set so that the intake of other macronutrients in the diet would be in an acceptable range.

There are many conditions in which extra protein is needed, including periods of

growth, pregnancy, lactation, intensive strength and endurance training, and other

forms of physical activity, and possibly in the elderly (Campbell et al., 1994).Additionally, there is recent research into the role of protein in the regulation of long-

term energy balance, maintenance of body weight and satiety (see “B.4.4: Protein’s Role

in Satiety” on page 20).

B.4.3OPTIMUM PROTEIN INTAKE

Given the variation in the needs for protein throughout the life cycle, there is an

individual optimum intake that exists based on lean body mass and activity levels.

PHYSICIAN’S REFERENCE MANUAL B.4.2 - B.4.

1

TABLE 1 (Continued)




However, optimal intakes are difficult to determine based on the existing science base in

nutrition. In 1977, Garza et al. studied a small number of healthy volunteers and found that

0.8 (grams per kilograms per day) resulted in positive nitrogen balance. Subsequent studies

in endurance athletes found that more than 1 g/kg/day was required for positive nitrogen

balance (Tarnopolsky, 2004) and studies of weight lifters indicated that more than

2 g/kg/day was needed to achieve positive nitrogen balance (Tarnopolsky et al., 1992).

Therefore, while the DRI (which is the same as the RDA) is set at 56 grams per day for menconsistent with the 1977 study, the allowable range of macronutrient intake is broad

(10 to 35 percent of total calories), enabling some individual adjustment for optimal intakes

both to control hunger and to provide support to lean tissues.

B.4.4PROTEIN’S ROLE IN SATIETY

In comparison with carbohydrate or fat, protein provides a stronger signal to the brain to

satisfy hunger. While the mechanism of action is unknown, it has been suggested that either

single amino acids or small peptides enter the brain to elicit their effects, and several amino

acids, including tryptophan, phenylalanine and tyrosine, have been theorized to affect the

hunger control mechanisms once they cross the blood-brain barrier. Small differences in the

rates at which proteins release their amino acids into the bloodstream may also affect satiety.

In subjects consuming high-protein meals, compared with high-carbohydrate meals fed ad

libitum, a voluntary reduction in energy consumption has been observed.

Researchers in the Netherlands (Westerterp-Plantenga et al., 1999) have studied the

effects of protein on hunger perceptions by studying two groups of subjects in a whole-body

energy chamber under controlled conditions for over 24 hours. Subjects were fed isocaloric

diets that were either high-protein/high-carbohydrate (protein/carbohydrate/fat, percentage

of calories 30/60/10) or high-fat (protein/carbohydrate/fat, percentage of calories 10/30/60).

Significantly more satiety was reported by subjects on the high-protein/high-carbohydrate

diet. At the same time, hunger, appetite, desire to eat and estimated quantity of food eatenwere significantly lower in this group, with less hunger both during and after the high-protein

meals. The level of protein in the diet may also impact maintenance of body weight after

weight loss. After following a very low-energy diet for four weeks, subjects who consumed a

20 percent higher intake of protein than did control subjects (15 percent versus 18 percent of

energy) showed a 50 percent lower body-weight regain, only consisting of fat-free mass, with

increased satiety and decreased energy efficiency during a three-month maintenance period

(Westerterp-Plantenga et al., 2004).

Similar studies have reported improved weight loss and fat loss in subjects consuming a

high-protein diet versus a control diet (25 percent versus 12 percent energy from protein)

ad libitum, due to a reduction in daily calorie intake of approximately 16 percent (Skov et al.,

1999) and improved utilization of body fat with maintenance of lean body mass in subjects

consuming 32 percent of energy from protein compared with control subjects who consumed

15 percent of calories as protein (Layman et al., 2003). A similar study comparing diets with

15 percent versus 30 percent of calories from protein found that while weight loss in the two

groups was similar over the six-week trial, diet satisfaction was significantly greater in those

consuming the higher-protein diet (Johnston et al., 2004).

A meta-analysis of studies (Eisenstein et al., 2002) concluded that, on average, high-

protein diets were associated with a 9 percent decrease in total calorie intake. While the role

of protein (in comparison to fat and carbohydrate) in affecting overall calorie intake and in

body-weight regulation needs further investigation, the evidence is strong that protein affects

hunger-signaling mechanisms in the brain, induces thermogenesis and contributes to the

building and maintenance of lean body mass.20

B.4.3 - B.4.4



B.5FATS IN CELLULAR NUTRITION

Fats are a subset of the lipid family, which includes triglycerides (fats and oils),

phospholipids and sterols. Fats play an extremely important role in energy balance by

enabling efficient storage of calories in adipose tissue. It is possible for the mythical

70-kilogram man to carry 130,000 calories in 13.5 kilograms of fat tissue, compared to only

54,000 calories stored as protein in an equivalent weight of lean tissue. This efficient

storage is accomplished both largely by excluding water from adipose tissues and by storing

energy in the chemical bonds of very long chain fatty acids. The typical fatty acids found

in digested and stored fat range between 16 and 22 carbons in length.

Triglycerides, the chief form of fat in the diet and the major storage form of fat in the

body, are composed of a molecule of glycerol with three fatty acids attached. The principal

dietary sources of fat are meats, dairy products, poultry, fish, nuts, and vegetable oils and

fats used in processed foods. Vegetables and fruits contain only small amounts of fat, so that

vegetable oils are only sources of fat due to processing of vegetables. The most commonly

used oils and fats for salad oil, cooking oils, shortenings and margarines in the United States

include soybean, corn, cottonseed, palm, peanut, olive, canola (low-erucic-acid rapeseed

oil), safflower, sunflower, coconut, palm kernel, tallow and lard. These oils contain varying

compositions of fatty acids which have particular physiological properties. The fats stored in

tissues reflect, to a certain extent, the fats in the diet. Humans synthesize saturated fats (e.g.,

palmitic acid) from carbohydrates, but the polyunsaturated essential fats (linoleic and

linolenic acids) must be taken in from the diet. The balance of these fats and the metabolic

products of these fats reflect short-term and long-term dietary intake. There is a statistically

significant but poor correlation between adipose tissue fatty acid profiles and dietary fatty

acid intake as measured on a food frequency questionnaire (London et al., 1991). Red blood

cell membranes change their composition in about three weeks. However, it is clearly

possible to change the amount of fatty acids in tissues (Bagga et al., 1997) and total

quantitative fatty acids can be altered by dietary intervention. The quality of fats in the dietis defined as that ratio of fatty acids that can be measured in plasma and tissues.

B.5.1FATTY ACID STRUCTURE

AND CLASSIFICATIONFatty acids are organic compounds composed of a carbon chain with hydrogens

attached at one end and an acid group at the other. Most naturally occurring fatty acids

have an even number of carbons in their chain, up to 24 carbons in length, with

18-carbon chains the most abundant fatty acids in the food supply.

Saturated fatty acids are completely saturated with hydrogens. Those fatty acids

lacking two hydrogen atoms and containing one double bond are monounsaturated

fatty acids, and polyunsaturated fatty acids contain two or more double bonds in the

carbon chain. The degree of saturation influences the texture of fats so that, in general,

polyunsaturated vegetable oils are liquid at room temperature and the more saturated

fats, most of which are animal fats, are solid. Some vegetable oils such as palm and

coconut oils are highly saturated, and liquid oils can be hydrogenated in the presence

of a nickel catalyst to produce a firmer fat.

The nomenclature of fatty acids is based on location of the double bonds: an

omega-3 fatty acid has its first double bond three carbons from the methyl end of the

carbon chain. Similarly, an omega-6 fatty acid has its double bond six carbons from the

PHYSICIAN’S REFERENCE MANUAL B.5 - B.5.1

2




methyl end. Fatty acids are also denoted by the length of the carbon chain and the

number of double bonds they contain, such that linoleic acid is an 18:2 fatty acid which

contains 18 carbons and two double bonds. The human body requires fatty acids and

can manufacture all but two essential fatty acids: linoleic acid and linolenic acid (18:3)

(see Figure 1 below).

Omega-3 fatty acids possess anti-inflammatory, antiarrhythmic and antithrombotic

properties and have been shown to reduce the risk for sudden death caused by cardiacarrhythmias and decrease mortality from all causes in patients with coronary heart

disease. Conversely, the omega-6 fatty acids, obtained in the diet primarily from

vegetable oils such as corn, safflower, sunflower and cottonseed, are proinflammatory

and prothrombotic. Fish and fish oils are the richest sources of the omega-3 fatty acids

eicosapentaenoic acid (EPA) and docosshexaenoic acid (DHA) and are also present in

algae. Green leafy vegetables, nuts, seeds and soybeans contain the omega-3 fatty acid

alpha-linolenic acid (AHA). The increased consumption in the United States of

omega-6 fats from vegetable oils and grain-fed animals has led to a drastic increase in

the ratio of omega-6 to omega-3 fatty acids in the diet from an estimated ratio of 1:1 in

early human diets to a ratio exceeding 10:1 today (Simopoulos, 2001).

B.5.2FATTY ACIDS AS CELLULAR SIGNALS

Increasing evidence from animal and in vitro studies indicates that omega-3 fatty acids,

especially the long-chain polyunsaturated fatty acids EPA and DHA, present in fatty fish

and fish oils inhibit carcinogenesis (Karmali et al., 1984; Lindner, 1991; Rose et al., 1991;

Tsai et al., 1998; Boudreau et al., 2001; Narayanan et al., 2001). Several molecular

mechanisms have been proposed for the influences on the process, including suppression

of arachidonic acid-derived eicosanoid biosynthesis (Rose, 1999; Okuyama, 1996) and

influences on transcription factor activity, gene expression and signal transduction

pathways (Bartsch et al., 1999).

The peroxisome proliferator-activated nuclear receptors (PPARa, d, g ) are activated

by polyunsaturated fatty acids, eicosanoids, and various synthetic ligands (Willson et al.,

22

B.5.1 - B.5.2

Figure 1



2000). Consistent with their distinct expression patterns, gene-knockout experiments

have revealed that each PPAR subtype performs a specific function in fatty acid

homeostasis.

Over a decade ago, PPARa was found to respond to hypolipidemic drugs, such as

fibrates. Subsequently, it was discovered that fatty acids serve as their natural ligands.

Together with the analyses of PPARa null mice, these studies established PPARa as a global

regulator of fatty acid catabolism. PPARa target genes function together to coordinate thecomplex metabolic changes necessary to conserve energy during fasting and feeding. In

the fatty acid metabolic cascade, PPARa activation up-regulates the transcription of liver

fatty acid-binding protein, which buffers intracellular fatty acids and delivers PPARa

ligands to the nucleus (Wolfrum et al., 2001). In addition, expression of two members of

the adrenoleukodystrophy subfamily of ABC transporters, ABCD2 and ABCD3, is

similarly up-regulated to promote transport of fatty acids into peroxisomes (Fourcade et

al., 2001) where catabolic enzymes promote beta-oxidation. The hepatocyte CYP4A

enzymes complete the metabolic cascade by catalyzing gamma-oxidation, the final

catabolic step in the clearance of PPARa ligands (Lee et al., 1995).

PPARg was identified initially as a key regulator of adipogenesis, but it also plays an

important role in cellular differentiation, insulin sensitization, atherosclerosis and cancer

(Rosen and Spiegelman, 2001). Ligands for PPARg include fatty acids and other

arachidonic acid metabolites, antidiabetic drugs (e.g., thiazolidinediones) and

triterpenoids. In contrast to PPARa, PPARg promotes fat storage by increasing adipocyte

differentiation and transcription of a number of important lipogenic proteins. Ligand

homeostasis is regulated by governing expression of the adipocyte fatty acid-binding

protein (A-FABP/aP2) and CYP4B1(Way et al., 2001). In macrophages, PPARg induces

the lipid transporter ABCA1 through an indirect mechanism involving the LXR pathway,

which in turn promotes cellular efflux of phospholipids and cholesterol into high-density

lipoproteins (Chawla et al., 2001; Chinetti et al., 2001).

B.6 CARBOHYDRATES IN CELLULAR

NUTRITIONAs with proteins and fats, one can consider the quality of carbohydrates based on the

source of the carbohydrates (fruits, vegetables, or whole grains versus refined grains

and simple sugars) and their digestibility (soluble versus insoluble fiber). A quantitative

approach to the analysis of dietary carbohydrate has been developed based on glycemic

index and glycemic load, as will be discussed.

B.6.1 SUGARS AND STARCHESSimple carbohydrates are present in foods as mono- or di-saccharides, and are naturally

present in such foods as fruit and milk. Glucose, fructose and galactose are the most

common monosaccharides in the human diet and combine to form the disaccharides

sucrose (glucose + fructose), lactose (glucose + galactose) and maltose (glucose +

glucose). Oligosaccharides are short chains of 3-10 sugar molecules, and the most

common ones, raffinose and stachyose, are found in beans, peas and lentils.

Polysaccharides are starches which contain more than 10 sugar molecules, found in

wheat, rice, corn, oats, legumes and tubers. Starches form long chains that are either

PHYSICIAN’S REFERENCE MANUAL B.5.2 - B.6.

2




straight (amylose) or branched (amylopectin). Amylose and amylopectin occur in a

ratio of about 1:4 in plant foods.

While there are several dietary factors that contribute to obesity, a dietary pattern

that is rich in sugars and starches is considered a risk factor for obesity, whereas a high

intake of nonstarch polysaccharides in the form of dietary fiber is considered protective

(Swinburn et al., 2004). The typical Western diet is high in refined starches and sugars

which are digested and absorbed rapidly, resulting in a high glycemic load and increaseddemand for insulin secretion. This, in turn, promotes postprandial carbohydrate

oxidation at the expense of fat oxidation. Both acute (Ludwig et al., 1999; Febbraio et

al., 2000) and short-term studies (Agus et al., 2000; Howe et al., 1996) indicate that a

dietary pattern that produces a high-glycemic response affects appetite and promotes

body-fat storage.

However, diets based on high-fiber foods that produce a low glycemic response can

enhance weight control because they promote satiety, minimize postprandial insulin

secretion, and maintain insulin sensitivity (Brand-Miller et al., 2002). This is supported

by several intervention studies in humans in which energy-restricted diets based on low

glycemic index foods produced greater weight loss than did equivalent diets based on

high glycemic index foods. Long-term studies in animal models have also shown that

diets based on high glycemic index starches promote weight gain, visceral adiposity and

higher concentrations of lipogenic enzymes than do isoenergetic diets with a low

glycemic index, which are macronutrient-controlled.

B.6.2GLYCEMIC INDEX AND

GLYCEMIC LOADConventional approaches to weight loss have focused on decreasing dietary fat, due to

its high-calorie density. However, the relationship between dietary fat and obesity has been brought into question for several reasons. Low-fat diets have been shown to

produce only modest weight loss, and prospective epidemiological studies have not

been able to consistently correlate dietary fat intake with weight. Despite a decrease in

fat consumption as a percentage of total calories and widespread availability of low-fat

and fat-free foods, obesity prevalence in the United States has risen dramatically since

the 1970s (Putnam and Allshouse, 1999). At the same time, carbohydrate consumption

has increased, and most of this increase has been in the form of refined starches and

concentrated sweets with a high glycemic index (GI) and/or glycemic load (GL).

In 1981, Jenkins et al. introduced the glycemic index as a system for classifying

carbohydrate-containing foods based upon their effect on post-prandial glycemia

(Jenkins et al., 1981). The glycemic response to the ingestion of 50 grams of available

carbohydrate from the test food is compared to the response from the ingestion of

50 grams of the reference food (glucose or white bread), and the glycemic index is

expressed as the area under the glucose response curve for the test food divided by the

area under the curve for the standard, multiplied by 100. However, the amount of

carbohydrate in 50 grams of a given food will vary depending upon the food, and this

observation led to the introduction of the concept of glycemic load. This is an

expression of the glycemic index of the food multiplied by the carbohydrate content of

the food, and takes into account the differences in carbohydrate content among foods

(Liu, 1998). Foods with a high index but relatively low total carbohydrate content, such

as carrots, have a low glycemic load. In general, fruits, non-starchy vegetables, nuts and

legumes have a low GI (see Table 2 on the following pages). One problem with the GI24

B.6.1 - B.6.2



is that it only detects carbohydrate quality, not quantity. A GI value tells you only how

rapidly a particular carbohydrate turns into sugar; it doesn’t tell you how much of that

carbohydrate is in a serving of a particular food. Both should be known to understand

a food’s effect on blood sugar. The most famous example of this is the carrot. The form

of sugar in the carrot has a high glycemic index, but the total carbohydrated content of

the carrot is low, so it doesn’t add a lot of calories.

A low glycemic load (GL) is less than 16, and this has been found to be the mostimportant variable in studies of populations and their risk of chronic disease. You are

not going to be able to eat all low GL foods, but it is important to know both the GL

and the calories that the food provides.

The problem with GL is that fatty foods which carry lots of calories have a lower

glycemic index. Fatty foods can still add calories to the diet even though they have a

low glycemic index.

TABLE 2

GLYCEMIC INDEX, GLYCEMIC LOAD AND CALORIES

The GI, GL, and total calories of foods are listed here. The GI is of foods

based on the glucose index—where glucose is set to equal 100. The other is

the glycemic load, which is the glycemic index divided by 100 multiplied by

its available carbohydrate content (i.e., carbohydrates minus fiber) in grams.

Each of these foods is equivalent to one serving size. Except as noted, each

of the GI values shown below is based on the 120 studies in the professional

literature referenced in The American Journal of Clinical Nutrition,

July 2002.

LOW GI (<55) and LOW GL (<16) FOODS

Lowest Calorie (110 calories per serving or less)

GI GL CALORIESAPPLE 40 6 75BANANA 52 12 90CHERRIES 22 3 85GRAPEFRUIT 25 5 75KIWI 53 6 45MANGO 51 14 110ORANGE 48 5 65PEACH 42 7 70PLUM 39 5 70STRAWBERRIES 40 1 50TOMATO JUICE 38 4 40Most Other Vegetables <20 <5 40NONFAT MILK 32 4 90

Moderate Calorie (110 to 135 calories per serving or less)

GI GL CALORIES

APPLE JUICE 40 12 135

GRAPEFRUIT JUICE 48 9 115

PEAR 33 10 125

PEAS 48 3 135

PHYSICIAN’S REFERENCE MANUAL B.6.2

2




TABLE 2 (Continued)

GI GL CALORIES

PINEAPPLE JUICE 46 15 130

WHOLE-GRAIN BREAD 51 14 120

SOY MILK 44 8 130

Higher Calorie (160 to 300 calories per serving)

GI GL CALORIES

BARLEY 25 11 190

BLACK BEANS 20 8 235

GARBANZO BEANS 28 13 285

GRAPES 46 13 160

KIDNEY BEANS 23 10 210

LENTILS 29 7 230

SOYBEANS 18 1 300

YAM 37 13 160

HIGH GI (>55) BUT LOW GL (<16) FOODS

All Low Calorie (110 calories per serving or less)

GI GL CALORIES

APRICOT 57 6 70

ORANGE JUICE 57 15 110

PAPAYA 60 9 55

PINEAPPLE 59 7 75

PUMPKIN 75 3 85

SHREDDED WHEAT 75 15 110

TOASTED OATS 74 15 110

WATERMELON 72 7 50

Low GI and Low Gl - But High Fat and High Calorie

GI GL CALORIES

CASHEWS 22 4 395

PREMIUM ICE CREAM 38 10 360

LOW-FAT ICE CREAM 37-50 13 220

PEANUTS 14 1 330

POPCORN (FULL-FAT) 72 16 110

POTATO CHIPS 54 15 345

WHOLE MILK 27 3 150

VANILLA PUDDING 44 16 250

FRUIT YOGURT 31 9 200+

SOY YOGURT 50 13 200+

26

B.6.2



TABLE 2 (Continued)

HIGH GI >55

HIGH GL >16

Includes Typical Trigger Foods, Many Higher Calorie

GI GL CALORIES

BAKED POTATO 85 34 220

BROWN RICE 50 16 215

COLA 63 33 200

CORN 60 20 130

CORN CHIPS 63 21 350

CORN FLAKES 92 24 100

CRANBERRY JUICE 68 24 145

CREAM OF WHEAT 74 22 130

CROISSANT 67 17 275

FRENCH FRIES 75 25 515

MAC ‘N’ CHEESE 64 46 285OATMEAL 75 17 140

PIZZA 60 20 300

PRETZELS 83 33 115

RAISIN BRAN 61 29 185

RAISINS 66 42 250

SODA CRACKERS 74 18 155

WAFFLES 76 18 150

WHITE BREAD 73 20 160

WHITE RICE 64 23 210

The intake of high GI/GL meals induces a sequence of hormonal changes,

including an increased ratio of insulin to glucagon, that limit the availability of

metabolic fuels in the post-prandial period and promote nutrient storage (Ludwig,

2002) and would be expected to stimulate hunger and promote food intake. Short-term

feeding studies have demonstrated less satiety and greater voluntary food intake after

consumption of high GI meals as compared to low GI meals (Ludwig et al., 1999), for

example, the demonstration of prolonged satiety after consumption of a low GI bean

puree vs. a high GI potato puree (Leathwood and Pollett, 1998).

Weight loss on a low-calorie, reduced-fat diet may be enhanced if the diet also has

a low GI (Slabber et al., 1994), and even when energy intake is not restricted, low GI

and/or low GL diets have been shown to produce greater weight loss than conventional

low-fat diets (Ebbeling et al., 2003). Additionally, subjects consuming a low GI dietad libitum have been reported to experience a spontaneous 25 percent reduction in

energy intake, with significant reductions in body weight and waist and hip

circumference when compared with control subjects (Dumesnil et al., 2001).

Other data suggest that low GI/GL diets may confer protection against certain

forms of cancer, cardiovascular disease and the metabolic syndrome and type 2

diabetes. In the Women’s Health Study, a high GL dietary pattern was associated with

an increased risk for colon cancer (Higginbotham et al., 2004), and data from the Iowa

Women’s study indicated that a higher GL pattern may be a risk factor for endometrial

cancer incidence in nondiabetic women (Folsom et al., 2003). In a study of 244 healthy

women, a strong and statistically significant positive association was found between


2




dietary GL and plasma C-reactive protein, a plasma marker for chronic inflammation

associated with an increased risk for heart disease (Liu et al., 2002). In large prospective

epidemiologic studies, both the GI and the GL of the overall diet have been associated

with a greater risk of type 2 diabetes in both men and women (Salmeron et al., 1997a;

Salmeron et al., 1997b).

B.7FUNCTIONAL FOODS

Functional foods contain bioactive substances and have effects on health and

physiological function beyond simply providing calories. While many of the foods

reviewed above fit this definition (e.g., n-3 fatty acids), the foods reviewed in this

section have received attention as foods and food ingredients for health.

They are contained in Herbalife® products. For example, soy protein is a major

ingredient in the ShapeWorks® Formula 1 Protein Drink Mix; Performance Protein

Powder also consists of soy protein, as well as whey protein.

B.7.1SOY PROTEIN

Soy protein is the highest-quality protein found in the plant kingdom, and it is

consumed by two-thirds of the world’s population.

Soy protein naturally contains isoflavones (primarily genistein and daidzein), which

are called phytoestrogens. They are usually found in foods linked to sugars called glycosides,

and these phytoestrogens act like very weak estrogens or anti-estrogens similar to

raloxifene. When primates have a surgical menopause induced and are given estradiol

alone or estradiol in combination with soy isoflavones, the isoflavones antagonize the

actions of estradiol in the breast and the uterus but demonstrate estrogen-like beneficial

activities in the bone, on serum lipids and in the brain. These observations are explained

by the existence of two estrogen receptors called alpha and beta. Soy isoflavones bind with

very low affinity (1/50,000 to 1/100,000 the affinity of estradiol) to the alpha-estradiol

receptor, but bind equally well to the beta-estradiol receptor (Clarkson et al., 2001).

Soy protein isoflavones have been shown to influence not only sex hormone

metabolism and biological activity but also intracellular enzymes, protein synthesis,

growth-factor action, malignant cell proliferation, differentiation and angiogenesis,

providing strong evidence that these substances may have a protective role in cancer

(Kim et al., 2002).

B.7.2PHYTOCHEMICAL-RICH FRUITS,VEGETABLES AND GRAINS

Because fruits and vegetables are high in water and fiber, incorporating them into the

diet can reduce energy density, promote satiety and decrease energy intake, while at

the same time provide phytonutrients. Few interventions have specifically addressed

fruit and vegetable consumption and weight loss, but evidence suggests that the

recommendation to increase these foods while decreasing total energy intake is an

effective strategy for weight management. Obesity, while often considered synonymous28

B.6.2 - B.7.2



with overnutrition, is more accurately depicted as overnutrition of calories but

undernutrition of many essential vitamins, minerals and phytonutrients.

This increased incidence of obesity has been associated with an increased

incidence of heart disease, breast cancer, prostate cancer and colon cancer in

comparison with populations eating a dietary pattern consisting of less meat and more

fruits, vegetables, cereals and whole grains. The intake of 400 to 600 grams/day of fruits

and vegetables is associated with a reduced incidence of many common forms of cancer,heart disease and many chronic diseases of aging (Temple, 2000; Willett, 1994;

Willett, 1995).

The common forms of cancer, including breast, colon and prostate cancer, are the

result of genetic-environmental interactions. Most cancers have genetic changes at the

somatic cell level, which lead to unregulated growth through activation of oncogenes

or inactivation of tumor suppressor genes. Reactive oxygen radicals are thought to

damage biologic structures and molecules, including lipids, protein and DNA, and there

is evidence that antioxidants can prevent this damage.

Fruits and vegetables provide thousands of phytochemicals to the human diet and

many of these are absorbed into the body. While these are commonly antioxidants,

based on their ability to trap singlet oxygen, they have been demonstrated scientifically

to have many functions beyond antioxidation. These phytochemicals can interact withthe host to confer a preventive benefit by regulating enzymes important in

metabolizing xenobiotics and carcinogens; modulating nuclear receptors and cellular

signaling of proliferation and apoptosis; and acting indirectly through antioxidant

actions that reduce proliferation and protect DNA from damage (Blot et al., 1993).

Phytochemicals found in fruits and vegetables demonstrate synergistic and

additive interactions through their effects on gene expression, antioxidation and

cytokine action. Fruits and vegetables are 10- to 20-fold less calorie dense than grains;


2Adapted from What Color Is Your Diet?, Harper-Collins/Regan Books 2001

Figure 2



provide increased amounts of dietary fiber compared to refined grains; and provide a

balance of omega-3 and omega-6 fatty acids and a rich supply of micronutrients.

Several studies have sought to characterize dietary patterns and relate these

patterns to body weight and other nutritional parameters. A prospective study of

737 non-overweight women in the Framingham Offspring/Spouse cohort explored the

relationship between dietary patterns and the development of overweight over a

12-year period. Participants were grouped into one of five dietary patterns at baseline,which included a heart-healthy pattern (low-fat, nutritionally varied); a light-eating

pattern (lower calories, but proportionately more fat and fewer micronutrients); a wine

and moderate-eating pattern; a high-fat pattern; and an empty-calorie pattern (rich in

sweets and fat, and low in fruits and vegetables). Women in the heart-healthy cluster

consumed more servings of vegetables and fruits than women in each of the other four

clusters. Over the 12-year period, 214 cases of overweight developed in this cohort.

Compared with women in the heart-healthy group, women in the empty-calorie group

were at a significantly higher risk for developing overweight (RR1.4, 95 percent CI)

(Quatromoni et al., 2002).

In another analysis of dietary patterns among 179 older rural adults, those in the

high-nutrient-dense cluster (higher intake of dark-green/yellow vegetables,

citrus/melons/berries, and other fruits and vegetables) had lower energy intakes andlower waist circumferences than those in the low-nutrient-dense cluster (higher intake

of breads, sweets, desserts, processed meats, eggs, fats and oil). Those with a low-

nutrient-dense pattern were twice as likely to be obese (Ledikewe et al., 2004). Similar

observations were reported utilizing data from the Canadian Community Health Survey

from the years 2000 to 2001. The frequency of eating fruits and vegetables was

positively related to being physically active and not being overweight (Perez, 2002).

In a controlled clinical trial, families with obese parents and non-obese children

were randomized into a comprehensive behavioral weight-management program,

which featured encouragement either to increase fruit and vegetable consumption or

to decrease intake of high-fat, high-sugar foods. Over a one-year period, parents in the

increased fruit and vegetable group showed significantly greater decreases in

percentage of overweight than in the group attempting to reduce fat and sugar (Epstein

et al., 2001).

Current NCI dietary recommendations emphasize increasing the daily

consumption of fruits and vegetables from diverse sources such as citrus fruits,

cruciferous vegetables, and green and yellow vegetables (Steinmetz and Potter, 1991).


30

B.7.2



THE SEVEN COLORS OF HEALTH AND GARDEN 7®

In addition to well-known vitamins and minerals present in fruits and

vegetables, scientists are now focusing on other bioactive substances found

in fruits and vegetables called phytonutrients (also referred to as

phytochemicals). An important property of these phytonutrients is that theyappear to work together synergistically in some studies (Erdman, 2004)

suggesting that by including a variety of different colors of fruits and

vegetables in the diet daily (including those which provide such compounds

as carotenoids, bioflavonoids and glucosinolates) may contribute to

the health benefits associated with consuming five to nine servings of fruits

and vegetables a day. The benefits of consuming diverse classes of

phytonutrients are reviewed in the popular book What Color is Your Diet?

by Dr. David Heber (Harper-Collins/Regan Books, 2001). Garden7® is based

on the philosophy of Dr. Heber’s book. In it, he recommends the

consumption of at least one serving per day from each of the color groups

discussed below (also see Figure 2 on page 29).

An interesting property of these antioxidant compounds is their

localization in specific tissues. They are transported to major organs

(e.g., lycopene to the prostate, lutein to the macular area of the retina). It

is this localization in specific tissues that makes the phytonutrients in

Garden 7® different from general antioxidants such as Vitamin E. It is in this

regard that these phytonutrients provide a special benefit to tissues in

several vital body organs, such as the heart, brain, eyes, colon,

prostate/breast, liver and skin. Furthermore, it should be noted that these

phytonutrients do not occur as isolated compounds but as mixtures with

other vitamins such as Vitamin C and Vitamin E, and where possible, Garden

7® tablets and capsules are not only derived from extracts of the

corresponding fruit (e.g., tomato) or vegetable (e.g., broccoli), but arestandardized to the key phytonutrient provided (e.g., lycopene or

glucosinolates). Therefore, Garden7® provides standardized extract capsules

and tablets of different key phytonutrients as a supplement to the diet.

Thus Garden7® contains selected beneficial phytonutrients; these specific

phytonutrients are present in quantities equivalent to those found in

approximately one-half cup of broccoli, one-half cup of spinach, one cup of

red grapes, three ounces of cranberries, one orange, one carrot, one tomato

and a clove of garlic.

The supportive and protective effects of these phytonutrients localized

in tissues where they have antioxidant and other protective effects are

based on the current knowledge base in the nutritional literature for each

of the colors. They are as follows:

Red: Lycopene and related phytonutrients from tomatoes are localized

in the prostate tissues and help support healthy prostate by protecting the

cells of the prostate. Some evidence suggests that similar protection is

provided to breast cells.

Green: Glucosinolates from broccoli support healthy liver function and

the capacity of liver cells to produce enzymes which can clear certain

poisons and drugs from the body. Good evidence is available for

glucosinolates affecting detox enzymes in gut, liver, prostate, colon and

breast (benefit of indole-carbinols). There is some evidence for


3



sulforaphane and colon health. There is also evidence for broccoli

glucosinolates inducing intestinal detox enzymes.

White-Green: Allyl sulfides from garlic support a healthy cardiovascular

system and healthy heart.Red-Purple: Polyphenols from berries, plums and cranberries localize in

the brain and help support normal memory by protecting the nerve cells in

the brain.

Yellow-Green: Lutein is concentrated in the area of the retina called the

macula, which receives the most ultraviolet light. Lutein supports healthy eyes

and vision by protecting the cells of the retina. There is evidence for

protection against age-related macular degeneration, a slow process that is

the leading cause of blindness in individuals over 65 years of age.

Orange-Yellow: Flavonoids, normally found in citrus fruits, are

localized in the cells of the colon where they provide local antioxidant

protection. There is some evidence in cells for protection of DNA by

stimulation of repair enzymes.Orange: Alpha- and beta-carotene from carrots localize in the skin

where they act as a local antioxidant to help protect the skin cells from

ultraviolet light. There is significant evidence for carotenoid accumulation

in skin (alpha- and beta-carotenes) to provide UVA/UVB protection.

B.7.3BEYOND THE FOUR FOOD GROUPS

The USDA Pyramid is the result of deliberations within the USDA which must take

into consideration economic factors related to food production and stabilization of the

food supply as well as health. The food groups are 1) Cereals and Grains; 2) Fruits and

Vegetables; 3) Meat, Beans, Nuts and Cheese; and 4) Dairy Products. There is also a

fifth group called Sweets, Fats and Oils which sits atop the USDA pyramid developed

in 1992 (see Figure 3 above).


32

B.7.2 - B.7.3

THE SEVEN COLORS OF HEALTH AND GARDEN 7® (Continued)

Figure 3 THE USDA PYRAMID

Sweets, Fats and Oils

Dairy Products

Fruits and Vegetables

Cerealsand Grains

Meats, Beans,Nuts and Cheese

4

1 3 62 5



In the current USDA Pyramid developed in 2005, the largest band to the left 1, which is

orange in color, is still Cereals and Grains (again, see Figure 3). It remains the major

recommended food group, but now the advice is to eat at least three ounces per day of

whole grain bread, cereals, rice, crackers, or pasta. The next group 2, which is the green

band, is Vegetables. Vegetables are divided into dark-green colored, orange colored, dry

beans and peas, and others. The next band 3, which is red in color, is the Fruit Group.

Depending on the number of calories you burn each day, between nine and 13 servings offruits and vegetables are recommended. However, since these are divided into two groups,

the orange band for Grains remains the predominant food group recommended. In this

sense, there was no change from the old pyramid, despite a strong push from many

scientists to put the Fruits and Vegetables together as one group to form the base of the diet.

The next group 4 is a thin yellow band for Oils, even though the recommendations

indicate most Americans get enough. They get too much of the wrong oils and fats. The

next band 5 is the blue band for Milk. One change here is that milk itself is advised at

three servings per day on average. This group does not include cheeses, cream cheese or

other products made from milk. It also recommends low-fat or nonfat milk be used.

Meats, beans, nuts, seeds, peas and eggs are members of the last group to the right 6,

which is purple in color. Lean meats are advised.

As you can see, the width of each band varies, suggesting you eat more of the good

foods within each category. Also, the figure running up the side of the pyramid

indicates for the first time the importance of exercise. The pyramid is fully described

and individualized by age, gender and calorie requirements at the Web site

www.mypyramid.gov. However, this is hardly personalized and the number of calories

recommended will promote obesity and overweight.

The new pyramid leaves in place traditional therapeutic diets which provide

suggested servings of foods in the food groups defined by the USDA, since it is

impractical to calculate specific food values for every diet plan that is individually

administered. For example, exchange diets are based on the idea that all human diets

can be simplified into protein, carbohydrate or fat exchanges. So a serving of iceberg

lettuce and a serving of spinach are equivalent, as would be a serving of grain-fed primerib and a serving of ocean-caught tuna. Also, the pyramid makes fruit juices equivalent

to whole fruits, although it takes over two oranges to make a small glass of orange juice,

which does not have the fiber of a whole orange. However, there is a large Florida

orange juice industry depending on sales of the juice that provides 160 calories per

serving as simple carbohydrate.

Ultimately, this simplification leads to the misconception that food is simply an

energy source for the body and that there are certain minimum requirements for

avoiding deficiency and promoting health.

To some extent, according to these notions, a calorie is a calorie. The body can

interconvert from one source to another, and this is a key part of our adaptation to

starvation. However, there is no genetic pressure for eating a healthful diet that avoids

the chronic diseases of aging, since these arise after the age of reproduction has passed.Therefore, the preventive properties of the diet are dissociated from its provision of

nutritional energy or calories alone. The California Cuisine Pyramid developed at UCLA

in 1997 by Dr. David Heber and his colleagues puts fruits and vegetables at the base and

then whole grains. This was the first pyramid to do so and was followed by the Mayo

Clinic Pyramid in 2001, which did the same thing. However, this idea was never

accepted by the USDA. It should be noted that fruits and vegetables in 2000 received

only 4.5 percent of the nearly $80 billion in total subsidies largely given by the USDA

to grain producers.

As our society is solving the problem of malnutrition throughout the world, we

are left with chronic diseases of aging related to too many calories relative to physical


3




activity. These diseases are also related to poor-quality diets consisting of too few

servings of fruits, vegetables and whole grains and too many servings of high-fat, high-

sugar processed foods. The latter lack naturally occurring vitamins, minerals and the

thousands of secondary plant substances (phytonutrients, or phytochemicals).

The Herbalife-recommended Pyramid is based on seven or more colorful fruits and

vegetables per day (see Figure 4 on this page). These whole fruits and vegetables provide

less than 100 calories per serving compared to an average of over 200 calories perserving of grains and cereals. Protein on the next level is provided by high-protein, low-

fat shakes which can be made with fresh or frozen fruits to help meet the fruit and

vegetable requirements. In addition, lean meats and fish round out this level. Getting

your protein from beans and rice, or beans and corn, can result in too many calories. Soy

protein found in Herbalife shakes can provide the protein at about half the calories.

While grains are not mandatory (since there is carbohydrate included in Herbalife

shakes), it is possible to have one to three servings per day of whole-grain bread. A

serving is reduced on our pyramid to one-half cup of rice, pasta or potato so that you are

getting 125 calories per serving, which is more comparable to the 100 calories or less

found in fruits and vegetables. The top of the Herbalife-recommended Pyramid has herbs

and spices rather than sweets, fats and oils. The vertical organization of this pyramid is

clearer and less confusing than the vertical bands of the current USDA Pyramid. Back in1992, the food industry fought the original pyramid and recommended a bowl with

bands because it did not like the idea of a hierarchy of foods. The current USDA Pyramid

with vertical bands gave the food industry what it wanted–more confusion for the

consumer. Herbalife teaches consumers how to build a healthy diet, and recognizes that

supplements and exercise are also needed daily for good health.

Why worry about the composition of the diet? The premise is simple: Diet is a

major etiologic factor in chronic disease. Dietary chemicals change the expression of

one’s genes and even the genome itself. Genetic variation may explain the reason two

people can eat exactly the same diet and respond very differently. Nutritional genomics

emphasize the interactions at a cellular and molecular level studied through systems

biology. Herbalife® products provide not only a balance of macronutrients, but also

vitamins and minerals critical to health, as will be reviewed in the next section.

34

B.7.3

Figure 4 HERBALIFE-RECOMMENDED PYRAMID

HerbsandSpices

Grains

Protein

ColorfulFruits and

Vegetables



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C.VITAMINS AND MINERALS

C.1 INTRODUCTIONThere is still controversy about vitamins in the newspapers and medical journals in this

country, which reflects the poor state of nutrition education in our medical schools.

Studies in which vitamins are compared to drugs are publicized as showing that

vitamins have no benefit. Additionally, many physicians and other healthcare

providers are not familiar with the significant body of scientific studies supporting the

use of vitamins and minerals.

The majority of Americans do not meet through their diets the recommended

daily allowance of many of the vitamins and minerals that are critical to promoting

health and preventing disease. Vitamin supplementation has been shown to prevent

neural tube defects and improve immune function, and other studies suggest that

generous intakes of vitamins and minerals may reduce the risk of coronary heart

disease, cancer and osteoporosis. Optimal intakes of vitamins and minerals from a

combination of food and supplements are important goals in efforts at heath promotion

and disease prevention.

There are three scientific arguments supporting the use of vitamins and mineral

supplements. First, use of these supplements can help bring consumption of vitamins

and minerals up to recommended levels. Second, there may be benefits of vitamins and

minerals in maintaining optimal health and preventing disease at levels above the

recommended intakes. Finally, adequate micronutrient intake can be beneficial in

reducing the risk of birth defects and may help reduce the risk of some chronic diseases.

These concepts are grounded in evidence provided by a large number of studies,

including laboratory studies, population studies and a small number of clinical trials.Additional research looking at dosing levels, targeted populations and long-term effects

is now underway.

C.2PREGNANCY AND BIRTH DEFECTS

One out of every 30 babies born in the United States has a serious birth defect. Each

year, some 3,000 pregnancies are affected by what is called a neural tube defect (NTD),

such as spina bifida (in which an opening in the spinal cord does not close) or

anencephaly (in which a baby is born without a brain).

Since 1980, more than a dozen studies have looked at the role of folic acid in

reducing the incidence of neural tube defects. Perhaps the most important, the 1991

United Kingdom Medical Research Council (UKMRC) randomized clinical trial, found

that folic acid use could reduce the relative risk of NTD by more than 70 percent (MRC

Vitamin Study Research Group). The United States Public Health Service (USPHS) drew

on this data to issue recommendations on folic acid the following year. It said that

women capable of becoming pregnant should take 400 micrograms (or millionths of a

gram) of folic acid daily, which is the amount contained in a daily multivitamin The

Food and Drug Administration (FDA) followed this advisory with orders requiring all

products made with “enriched” grain to contain additional folic acid, and approved the

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use of health claims for products that contain significant amounts of the vitamin. The

Centers for Disease Control and Prevention (CDC) suggest that the consumption of

supplemental folic acid could significantly reduce that number even beyond what has

been achieved to date with the fortification of “enriched” grain products—to the extent

that about 80 percent of these birth defects could be prevented.

Educational programs soon emerged, targeting women of childbearing years,

healthcare professionals, women’s groups and policy makers. Surveillance studiesconducted in China, Canada and the United States have shown that fortification programs

have dramatically lowered the prevalence of NTD. More and more women of childbearing

age have become familiar with the need for folic acid; the percentage of women between

ages 18 and 45 who heard about folic acid grew by more than 50 percent between 1995

and 2000. However, only 10 percent knew the correct dose and only one-third actually

consumed the vitamin daily. Thus, although at least part of the folic acid message is

reaching targeted women, not all are benefiting from that information.

C.3IMMUNE FUNCTION

Diet and nutritional status are two of the key factors affecting the body’s immune

response. Recent studies show that multivitamin use, in concert with a good diet, is a

cost-effective tool to enhance immunity, reduce the incidence of infection, and improve

overall quality of life. Immune status is relatively easy to test, because unlike in

cardiovascular disease or cancer, established and accepted measures of immune

function are available. In randomized clinical trials conducted by Dr. Ranjit Chandra in

Newfoundland, Canada, micronutrients have been shown to enhance the response of

lymphocytes and natural killer cells; increase production of interleukin-2; and reduce

the duration of infection and the time spent on antibiotics. These studies demonstrate

that inadequate micronutrient intakes are associated with poorer immune responses

and an increased incidence of infection, and that consumption of a multivitamin canhelp eliminate this deficit.

C.4CARDIOVASCULAR DISEASE

Elevated levels of homocysteine are a major risk factor for coronary disease and

ischemic stroke. Indeed, people with the highest homocysteine levels have a nearly

two-fold increase in the risk of coronary heart disease (CHD), compared to those with

normal levels. This risk is comparable to that associated with smoking or high

cholesterol. Folate is essential to homocysteine metabolism, and a number of studies

have established the link between folate intake and CHD. Contributions to loweringhomocysteine levels are also made, though to a lesser degree, by Vitamins B6 and

B12. Low-serum folate levels were associated with an increased risk of fatal CHD in

studies from Canada (Morrison et al., 1996) and Europe (Robinson et al., 1998),

while in the United States, higher intake of folate and Vitamin B6 reduced that risk

(Rimm et al., 1998). Homocysteine-lowering therapy with folate and B complex was

also found to decrease the incidence of death, nonfatal heart attacks and other

adverse events following coronary angioplasty (Schnyder et al., 2002). This finding

was confirmed in a large, case-control study from Sweden, which showed that use of

a multivitamin supplement reduced the risk of a myocardial infarction by 21 percent

PHYSICIAN’S REFERENCE MANUAL C.3 - C.4

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in men and 34 percent in women, suggesting that consumption of folate and B

complex may aid in the primary prevention of heart attacks (Holmquist et al., 2003).

Additional studies are now in progress to further clarify the relationship between

these vitamins and coronary disease.

Vitamins C and E are essential, well-established antioxidants, and researchers

have investigated whether these micronutrients have a role to play in heart disease

prevention. To date, some studies have found a mild effect for higher-dose Vitamin Cusers (Osganian et al., 2003), while others have failed to establish a relationship

(Kushi et al., 1996). Similarly, the Nurses’ Health Study found that women taking

modest amounts of Vitamin E had a 44 percent reduction in the incidence of heart

disease (Stampfe et al., 1993) and that higher doses (400 to 800 IU) reduced the rate

of second heart attacks in heart patients (Stephens et al., 1996). However, other well-

controlled trials found no effect (Rapola et al., 1997; Yusuf et al., 2000).

Since these studies were done in individuals who already had heart disease, it is

difficult to account for the many different factors which may have caused their heart

disease and made them different from one another. Therefore, when these people

were assigned by chance to get the placebo or vitamin supplements, the results may

have been more related to the individual profiles of those assigned to the two arms

of the study rather than to whether the vitamins were having an effect. Researchersassumed that such differences are overcome by large numbers, but this may not be

true in the case of a complex disease such as heart disease, with so many different

factors involved. While it would be of great interest to conduct a prevention study in

otherwise healthy individuals, such a study would require huge numbers and be

prohibitively expensive.

C.5CANCER

Folic acid deficiency may contribute to the development of cancer by interfering with

normal gene processes. Thus, there has been much recent interest in the effects of

folate supplementation on cancer prevention. Both the Nurses Health Study and the

Health Professionals Follow-up Study found that long-term (15 years in the former,

10 in the latter) folate consumption significantly reduced the risk of colorectal cancer.

Studies done by Dr. Ed Giovannucci and his team at the Harvard School of Public

Health found that in women who use alcohol and have low blood folate levels,

supplementation helped lower the elevated risk of breast cancer associated with

drinking (Zhang et al., 1999). Ongoing trials continue to explore the effects of folate

supplementation, especially in users of alcohol, where the interaction appears to be

very strong.

Vitamin E has been investigated in connection with a number of major cancers,

including breast, lung, colon and prostate. Only in the latter does it appear to have asignificant effect across several studies. In the ATBC trial, researchers found that 400

mg of Vitamin E reduced the incidence of, as well as mortality from, prostate cancer

in male smokers (Albanes et al., 1995). This association has since been confirmed,

both in non-smokers and smokers. On the strength of this evidence, the National

Cancer Institute (NCI) is conducting a primary prevention trial (called the “SELECT

trial”) of selenium and vitamin E versus a placebo for prostate cancer prevention in

25,000 normal men.

An editorial in The New York Times suggested that no cancer patients should take

Vitamin C or Vitamin E, but it was based on a misinterpretation of two basic findings.

The first is that Vitamin C is concentrated by cancer cells, which the author of the

40

C.5



editorial assumed meant that the cancer cell used this Vitamin C to stimulate tumor

cell growth. Dr. David Golde of the Sloan-Kettering Cancer Center in New York

discovered that Vitamin C is taken up by the glucose transport proteins in tumor cells.

Before the tumor cell can take up Vitamin C through the glucose transport system, it

must be oxidized to a form called dehydroascorbate. This form of Vitamin C is taken up

and then trapped in the cell when it is converted back to Vitamin C inside the cell by

reducing enzymes. But the concentrations required to do this do not occur in humanswho take Vitamin C by mouth; to reach these concentrations, Vitamin C would have

to be given by vein. This would never happen in someone taking vitamin

supplements. The experiments that resulted in the caution on Vitamin E were

performed in animals that were made Vitamin E deficient and compared to normal

Vitamin E status animals. Because it is not possible to make humans deficient in

Vitamin E, this study also has no relevance to supplements of Vitamin E in humans

with cancer.

The consumption of various carotenoids, such as lycopene, lutein and beta carotene,

may reduce the risk of lung cancer by one-third, but pure beta-carotene at high doses of

30 mg may elevate it, particularly in smokers. Calcium supplementation, too, may protect

against osteoporosis and the development and recurrence of colon polyps, which are a

precancerous change in the colon (Baron et al., 1999; Bonithon-Kopp et al., 2000), butsome data suggest that in extremely high doses (greater than 1,500 mg per day total),

calcium may increase the risk of prostate cancer (Chan et al., 2000; Giovannucci et al.,

1998). Data in the latter study suggested that taking Vitamin D with calcium may reduce

any negative effects while maintaining the colon cancer protection. Also, no man should

get less than the recommended dietary allowance, which is 1,000 mg per day of calcium.

Cancer is a collection of heterogeneous conditions with complex causes and histories, and

there is much more research that needs to be done on the use of vitamins and minerals

for cancer prevention.

C.6 OBESITY AND DIABETESWhile most of the population fails to consume adequate levels of micronutrients,

the problem is particularly severe for the obese. There is evidence that overweight

men and women with high cholesterol levels who are on diets do not achieve the

RDA of most essential vitamins and minerals, due to lower micronutrient intake, lack

of adherence and over-restriction of foods (Gryzbek et al., 2002). This nutritional

deficiency clearly compromises their health status. Research conducted on people

with type 2 diabetes has shown that those taking a multivitamin supplement had a

lower incidence of infections and infection-related absenteeism than did those

receiving placebo (Barringer et al., 2003). While a relatively small study, the

magnitude of the differences in infection-incidence noted over one year in diabeticpatients were remarkable. Those who took a placebo had a 93 percent incidence over

one year of infectious episodes while those taking a multivitamin had an incidence of

only 17%. These findings deserve further research in larger populations, as the

implications are significant. In a study of people at risk for diabetes, investigators

reported that males who took beta-carotene supplements improved their glucose

metabolism, as did women who consumed Vitamin E (Ylonen et al., 2003). While

dieting has important implications for nutritional intake in all populations, it may

play an even more essential role in those who are overweight and those with either

metabolic syndrome or adult-onset diabetes mellitus.

PHYSICIAN’S REFERENCE MANUAL C.6

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C.7SAFETY OF VITAMINS

The consumption of Vitamin A above 25,000 IU per day (daily value = 5,000 IU) canclearly cause skeletal birth defects–and this amount is only five times the RDA.

Pregnant women should not consume more than 2,500 IU of Vitamin A per day to

avoid any possibility of problems. A few recent studies suggest that long-term

consumption in excess of 5,000 IU/day Vitamin A may be associated with decreased

bone mineral density and an increased risk of osteoporosis (Promislow et al., 2000). On

the other hand, insufficient intake also may accelerate the loss of bone mineral density.

Thus, there is a narrow window of optimal Vitamin A intake in adults. It is recommend

that a multivitamin that contains about 2,500 IU of preformed Vitamin A, or 5,000 IU

of Vitamin A, be used, of which at least 50 percent comes from beta-carotene.

As noted previously, high calcium intakes (above 1,500 mg/day) have been

associated with an increased risk of prostate cancer (Giovannucci et al., 1998). Also, an

antioxidant supplement combining Vitamins C and E, selenium and beta-carotene wasfound to reduce the protective effects of a lipid-lowering agent and niacin in 160

patients with heart disease and low HDL cholesterol levels (Brown et al., 2001),

although a larger trial of 20,000 patients, using a supplement of Vitamin C, Vitamin E

and beta-carotene, reported that the antioxidant combination did not inhibit the

protective effects of the lipid-lowering drug (Heart Protection Study Collab. Group).

It is important to realize that the safety of vitamins and minerals is often decided

by government committees reviewing reports of adverse effects to determine an

arbitrary “tolerable upper limit.” In some countries in the world, any vitamins in

amounts above the recommended dietary allowance are considered medicines. There

are ongoing discussions on the safety of vitamins and strong opinions based on limited

data, often from inconclusive meta-analyses, which combine different studies.

Herbalife® products contain safe levels of vitamins and minerals, and the product line

undergoes constant review. Reformulation is done if the science or regulatory

interpretation of science changes in local markets throughout the world. This explains

the difference in the various formulations of similar products in different countries.

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C.7



Albanes D, Heinonen OP, HuttunenJK, Taylor PR, Virtamo J, Edwards BK,Haapakoski J, Rautalahti M, HartmanAM, Palmgren J, et al. “Effects ofalpha-tocopherol and beta-carotenesupplements on cancer incidence inthe Alpha-Tocopherol Beta-Carotene

Cancer Prevention Study.” Am J ClinNutr. 1995;62(6 Suppl):1427S-1430S.

Baron JA, Beach M, Mandel JS et al.“Calcium supplements for theprevention of colorectal adenomas.” N Engl J Med. 1999;340:101-107.

Barringer TA, Kirk JK, Santaniello AC,Foley KL, Michielutte R. “Effect of amultivitamin and mineral supplementon infection and quality of life. Arandomized, double-blind, placebo-controlled trial.” Ann Intern Med.

2003;138(5):365-71.

Bonithon-Kopp C, Kronborg O,Giacosa A, Rath U, Faivre J. “Calciumand fibre supplementation in

prevention of colorectal adenomarecurrence: a randomised interventiontrial.” European Cancer PreventionOrganisation Study Group. Lancet.

2000;356(9238):1300-6.

Brown BG, Zhao XQ, Chait A, FisherLD, Cheung MC, Morse JS, Dowdy AA,Marino EK, Bolson EL, Alaupovic P,Frohlich J, Albers JJ. “Simvastatin andniacin, antioxidant vitamins, or thecombination for the prevention ofcoronary disease.” N Engl J Med. 2001Nov 29;345(22):1583-92.

Chan JM, Pietinen P, Virtanen M,Malila N, Tangrea J, Albanes D,Virtamo J. ”Diet and prostate cancerrisk in a cohort of smokers, with a

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Giovannucci E, Rimm EB, Wolk A,Ascherio A, Stampfer MJ, Colditz GA,

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Graham IM, Daly LE, Refsum HM,Robinson K, Brattstrom LE, et al.“Plama homocysteine as a risk factorfor vascular disease.” The EuropeanConcerted Action Project. JAMA. 1997;277(22):1775-1781.

Gryzbek A, Klosiewicz-Latoszek L,Targosz U. “Changes in the intake ofvitamins and minerals by men andwomen with hyperlipidemia andoverweight during dietetic treatment.”Eur J Clin Nutr. 2002;56:1162-1168.

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Holmquist C, Larsson S, Wolk A, deFaireU. “Multivitamin supplements areinversely associated with risk ofmyocardial infarction in men andwomen.”–Stockholm Heart EpidemiologyProgram (SHEEP). J Nutr. 2003;133:2650-2654.

Kushi LH, Folsom AR, Prineas RJ, MinkPJ, Wu Y et al. “Dietary antioxidantvitamins and death from coronary heart

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Michaud DS, Feskanich D, Rimm EB,Colditz GA, Speizer FE, Willett WC,Giovannucci E. “Intake of specificcarotenoids and risk of lung cancer in 2prospective US cohorts.” Am J ClinNutr. 2000;72(4):990-7.

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Persad VL, Van den Hof MC, Dube JM,Zimmer P. “Incidence of open neuraltube defects in Nova Scotia after folicacid fortification.”CMAJ. 2002;167(3):241-5.

Promislow JH, Goodman-Gruen D,Slymen DJ, Barrett-Connor E. “Retinolintake and bone mineral density in theelderly: the Rancho Bernardo Study.”J

Bone Miner Res. 2002;17(8):1349-58.

Rapola JM, Virtamo J, Ripatti S,Huttunen JK, Albanes D, Taylor PR,Heinonen OP. “Randomised trial ofalpha-tocopherol and beta-carotenesupplements on incidence of majorcoronary events in men with previousmyocardial infarction.” Lancet. 1997;349(9067):1715-20.

Rimm EB, Willett WC, Hu FB,Sampson L, Colditz GA et al. “Folateand vitamin B6 from diet andsupplements in relation to risk ofcoronary heart disease amongwomen.” JAMA. 1998;279(5):359-364.

Robinson K, Arheart K, Refsum H,Brattstrom L, Boers G et al. “Lowcirculating folate and vitamin B6concentrations: risk factors for stroke,peripheral vascular disease, andcoronary artery disease.” EuropeanCOMAC Group. Circulation. 1998;97(5):437-443.

Schnyder G, Roffi M, Flammer Y, PinR, Hess O. “Effect of homocystein-lowering therapy with folic acid,vitamin B12 and vitamin B6 on clinicaloutcome after percutaneous coronaryintervention.” The Swiss Heart Study:A Randomized Controlled Trial. JAMA.

2002;288:973-979.

Stampfer M, Hennekens C, Manson J,

Colditz G, Rosner B et al. “Vitamin Econsumption and the risk of coronaryartery disease in women.” N. Eng J

Med. 1993; 328(20):1444-1449.

Stephens NG, Parsons A, Schofield PM,Kelly F, Cheeseman K et al.“Randomised controlled trial ofvitamin E in patients with coronarydisease: Cambridge Heart AntioxidantStudy (CHAOS).” Lancet. 1996;347(9004):781-786.

“Summary of notifiable diseases—United States, 2000.” MMWR Morb

Mortal Wkly Rep. 2002 Jun 14;49(53):i-xxii, 1-100

Ylonen K, Alfthan G, Groop L,

Saloranta C, Aro A, Virtanen SM.“Dietary intakes and plasmaconcentrations of carotenoids andtocopherols in relation to glucosemetabolism in subjects at high risk oftype 2 diabetes: the Botnia DietaryStudy.” Am J Clin Nutr. 2003;77(6):1434-41.

Yusuf S, Dagenais G, Pogue J, Bosch J,Sleight P. “Vitamin E supplementationand cardiovascular events in high-riskpatients.” The Heart Outcomes PreventionEvaluation Study Investigators. N Engl J

Med. 2000;342(3):154-60.

Zhang S, Hunter DJ, Hankinson SE,Giovannucci EL, Rosner BA, ColditzGA, Speizer FE, Willett WC. “A

prospective study of folate intake andthe risk of breast cancer.” JAMA. 1999;281(17):1632-7.


4

REFERENCES




D.WEIGHT MANAGEMENT AND

MEAL REPLACEMENT

D.1DEFINITION OF OBESITY

Obesity is the most common nutritional disorder in the United States. In the world at-

large, the number of overnourished people is now equivalent to the number of

undernourished individuals–both at 2.1 billion.

Obesity is defined as Excess Body Fat minus Not Excess Body Weight (see section

E: “Body Composition” on pages 55 through 59). However, on average, body weight is

a useful surrogate, and body-mass index is used to follow the obesity epidemic and its

association with diseases since, as a practical matter, it is difficult to measure bodycomposition on tens of thousands of individuals.

D.2CAUSES OF OBESITY

The most common causes of obesity are overeating and underactivity. There is evidence

for differences in metabolism, making some individuals more efficient in hanging onto

calories, but the most common reasons for differences in the tendency to gain or lose

weight relate to age, height, sex and weight. Therefore, obesity results from common

genetic predisposition, but is expressed only when there is excess energy available

for storage.

Energy In = Energy Out + Energy Stored

However, energy out is largely related to body composition in terms of lean tissue

rather than fat tissue. So a man who is 74 inches tall might burn 2,200 calories per day,

while his wife at 62 inches tall burns only 1,200 calories per day due to differences in the

amount of lean-body mass they each have. Is it any wonder that the woman in this case

will lose weight more slowly than her husband if both are on the same diet of 1,000

calories per day?Despite these individual differences in energy needs and expenditure, it is clear that

the modern diet contains too many calories per bite to enable the normal weight-

regulatory mechanisms in the body to operate properly. This is illustrated by a rat

experiment. If pellets with more oil are fed to a rat, the rat will eat fewer pellets and

maintain a normal weight. If fat is removed from the pellets, the rat will eat more pellets

and still maintain its weight. On the other hand, if the rat is fed what is known as a

“cafeteria diet” (made up of peanut butter, salami and chocolate chip cookies), the rat will

lose all control of its homeostatic mechanisms and become as large as genetically obese

rodents. Mankind, by analogy, adapted to low-nutrient density diets and is no longer able

to maintain normal body fat on the high-fat, high-sugar diets of modern times.44

D - D.2



D.3BODY-FAT REGULATION AND

FUNCTION AS AN

ENDOCRINE ORGANBody fat is a vital organ, just like the heart, liver, kidney or skin. It has nerves, blood

vessels and fat cells, and this organ secretes hormones and small proteins that affect

energy balance, fat storage and metabolism. The function of body-fat organs depends

on where they are located in the body. Each of the body-fat organs in the lower body

as female fat and in the upper body in both men and women, has special functions with

regard to the uptake and release of fatty acids and in terms of the hormones they

secrete and to which they respond. There is emerging evidence that leptin comes from

both lower- and upper-body fat, whereas adiponectin comes from abdominal fat.

D.3.1 FEMALE FATThe fat on women’s hips and thighs provide the energy mothers need to provide milk

to their newborn babies. This fat responds to female hormones, and in every menstrual

cycle right after ovulation there is a one-thousand-fold increase in the blood levels of

the female hormone, progesterone. So when women believe they are gaining small

amounts of weight in addition to being bloated–they are correct. The body is preparing

for pregnancy by developing the fat organ in the hips and thighs, and it grows much

more if a woman becomes pregnant due to the large amounts of estrogen and

progesterone produced by the placenta. A considerable number of calories must be

stored, since breast-milk production normally requires about 500 calories per day.

The main factor accounting for female obesity is weight gain after pregnancy.Women typically gain between 30 and 40 pounds during pregnancy. If they do not

breast-feed or diet in the six months after delivery, the weight gained during pregnancy

is not lost. The next pregnancy starts at a higher weight, and more weight is gained

with the second pregnancy–and so forth. Understanding how this fat accumulates can

help women lose this fat after delivering their children and can lead to prevention of

obesity.

Just as women are born with different-shaped bodies, women are born with

different-sized hip and thigh fat organs. There is nothing wrong with that body of fat,

except that our modern society has labeled it as bad. This was never the case prior to

the past four decades, women with lower body fat were considered attractive, and

biology reflected what was desirable. There is a disconnect between women’s genetics

and what is considered attractive by many people. However, there has been a backlash.

For instance, full-figured women have begun speaking out about the attractiveness of

larger women, and full-figured models have been appearing more and more in

billboards and in fashion magazines. A key message is that there needs to be more

tolerance of different body shapes in our society.

Finally, this fat tends to be more resistant to diet and exercise, and there are many

women who starve themselves trying to lose this fat. Some even lose too much fat in

their faces and chests to look healthy. It is important to be aware of their appropriate

target weight and shape if they have more fat in the hips and thighs than in the

upper body.

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D.3.2ABDOMINAL FAT

The fat in the middle of the body surrounds the intestines and has special properties

both in terms of the substances released into the bloodstream by this fat and in the

hormones to which this fat responds. Both men and women can accumulateabdominal fat. There are some women who have only upper-body fat, and never

accumulate much lower-body fat. Then there are also women who accumulate both

upper- and lower-body fat.

Those women with upper-body fat have higher male hormone levels than do

women with lower-body fat. They are three times more likely to get breast cancer and

about nine times more likely to get diabetes than women with lower-body fat.

This fat is designed to store a limited amount of fat for the purpose of surviving

short periods of starvation. It secretes a number of substances called cytokines to fight

infection. When malnourished, humans are more susceptible to infections. Therefore,

it makes sense that abdominal fat should work to protect against such infections.

This fat also responds to the stress hormone cortisol. This stress hormone comes

from the adrenal gland. In a disease called “Cushing’s syndrome,” there isoverproduction of cortisol by the adrenal glands with a resulting increase in this fat

organ in the middle of the body. There is an enzyme called 11-betahydroxysteroid

dehydrogenase which can convert cortisone to cortisol. In mice genetically altered to

produce more of this enzyme, they accumulate fat only in the abdomen and not in

other fat pads.

Abdominal fat is easier to lose with dieting than lower-body fat. It is often the

first fat to be lost in those with both upper- and lower-body fat.

D.3.3 BRAIN CENTERS AND BODY FATThe fat cells make leptin, a hormone named for the Greek word for “thinning.” It was

first discovered in a mutant line of obese mice who made a defective version of this

normal hormone. These mice develop about 60 percent of their body weight as fat tissue.

When normal mice had their circulation merged with these obese mice, they corrected

the abnormality and the mice lost weight. Leptin is sensed in a part of the brain called the

Arcuate nucleus of the hypothalamus, where it is one of many different signals to the

brain. Leptin deficiency is extremely rare, but there is a village in Turkey where a family

has this deficiency. Dr. Julio Licinio at UCLA, recently treated this family with leptin, and

they lost large amounts of weight, going from massively obese to a normal size. Leptin

has other effects. It both reduces food intake and increases physical activity. It also inhibits

new blood-vessel formation, another way it may inhibit new fat-tissue growth in

genetically obese mice.

Insulin is the feeding hormone and goes up after eating. It pushes fats into fat cells

for storage and amino acids into muscle. It also stores some sugars as starch in the liver

and muscle. Insulin comes from cells in the pancreas and goes up together with leptin in

response to nutrients such as glucose and amino acids. Insulin is transported into the

brain. For the last 30 years, Dr. Daniel Porte at the University of California, San Diego,

has championed the theory that obesity is due to a lack of insulin action in the brain.

Using primates, he has demonstrated that high levels of insulin in the blood are associated

with reduced insulin action in the brain.

Leptin levels change in the opposite direction to another peptide–neuropeptide Y,46

D.3.2 - D.3.3



or NPY. When leptin goes down, NPY increases in the brain. NPY has the opposite effect

to leptin, and it increases food intake.

New insights into the complex regulation of food intake, metabolism and energy

homeostasis have refined the understanding of the pathophysiology of malnutrition.

Studies in rodents have demonstrated that the adaptation to starvation is far better

developed than the adaptation to overnutrition both in the short term and long term.

Long-term signals associated with body-fat stores are provided by leptin andinsulin. The concentration of leptin in the blood is highly correlated with total fat mass.

Excess body fat results in increased leptin production from fat cells, while decreases in

body fat that occur with dieting cause leptin and insulin concentrations to decrease,

triggering responses that aim to conserve body fat. These circulating hormones also

modulate short-term signals that determine meal initiation and termination. Signals

that provide short-term information about hunger and satiety include gut hormones

such as cholecystokinin, ghrelin, and peptide YY3-36. Vagal afferent nerves within the

gastrointestinal tract also provide short-term signals in response to distension,

macronutrients, pH, tonicity and hormones. The neural and hormonal signals are then

integrated within specific regions of the hypothalamus and brainstem.

Anorexigenic (appetite-suppressing) signals are generated by a-melanocyte-

stimulating hormone, a peptide derived from proopiomelanocortin which derives its

name from its actions in skin pigmentation through interaction with the melanocortin 1

receptor. This hormone reduces food intake and increases energy expenditure through

the melanocortin 4 receptor in the hypothalamus. Deletion of the melanocortin 4

receptor gene in animals results in obesity, hyperphagia and reduced energy

expenditure. Deletion of the related melanocortin 3 receptor gene results in obesity due

to reduced energy expenditure without hyperphagia.

Antagonism of anorexigenic melanocortin signals is caused by orexigenic

(appetite-stimulating) peptides such as agouti-related protein and neuropeptide Y.

Agouti-related protein antagonizes the interaction between a-melanocyte-stimulating

hormone and the melanocortin 4 receptor. Neuropeptide Y, found in the arcuate

nucleus of the hypothalamus, is a member of the pancreatic polypeptide family andincreases during food restriction, acting to increase food intake. Neuropeptide Y

decreases expression of the gene encoding proopiomelanocortin. Neuropeptide Y also

decreases the synthesis of thyrotropin-releasing hormone and increases the synthesis of

melanin-concentrating hormone, another orexigenic peptide.

Ghrelin is a 28-amino-acid, acetylated peptide secreted by oxyntic cells in the

stomach fundus. Ghrelin is named for its ability to stimulate growth hormone

secretagogue receptors to increase the release of growth hormone from the pituitary.

Circulating levels of ghrelin increase before meals and decrease after eating. Ghrelin

increases food intake through the stimulation of ghrelin receptors on hypothalamic

neuropeptide Y-expressing neurons and agouti-related protein-expressing neurons.

Peptide YY3-36 (PYY) is secreted after meals in proportion to the calories ingested

by endocrine L cells lining the distal small bowel and colon. The initial release of PYYafter eating occurs through neural mechanisms before ingested nutrients arrive in the

distal small intestine and colon. Subsequently, PYY is released in response to direct

intestinal stimulation by nutrients, especially lipids and carbohydrates. PYY decreases

food intake in both lean and obese individuals through inhibition of gut motility. This

function is referred to as the “ileal brake” and results from the actions of vagal afferent

neurons that ascend from the intestinal tract to the hindbrain and interact with

humoral receptors in the hypothalamus. PYY inhibits NPY-expressing neurons and

AgRP-expressing neurons through inhibitory neuropeptide Y2 receptors. This results in

disinhibition of neighboring proopiomelanocortin-expressing neurons, resulting in

decreased food intake.

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Following gastric bypass surgery for obesity, hunger diminishes, circulating

concentrations of ghrelin decrease and circulating concentrations of PYY increase. This

suppression of hunger may contribute to long-term weight maintenance of reduced

body weight in these patients.

Since ghrelin signals hunger and PYY signals satiety, some investigators have

conducted studies in transgenic mice to examine whether these hormones can be

manipulated to affect body composition. Experimental knockouts of the ghrelin gene,AgRP, and NPY gene and a double knockout of the AgRP and NPY genes are not

associated with any obvious effects on food intake or energy metabolism. On the other

hand, inactivating mutations of the genes encoding leptin or the leptin receptor and the

melanocortin 4 receptor result in obese phenotypes. Consistent with the hypothesis

that humans and mice are better adapted to starvation than overnutrition, it is evident

that the orexigenic peptides are so critical to survival that the absence of one peptide is

compensated for by the actions of others. However, the orexins also communicate

widely throughout the brain, with such regions as those involved in satiety (brainstem)

and sleep/wakefulness. Indeed, the orexin knock-out mouse exhibits typical features of

narcolepsy in addition to hypophagia. An important role of the orexins might be to

integrate a variety of behaviors related to feeding or fasting, including emotional

changes, reward responses and sleep/alertness.

Insulin-like growth factor I (IGFI)/somatomedin C stimulates amino acid uptake

and protein synthesis while inhibiting lipolysis. IGF peptides in serum are associated

with IGF binding proteins (IGFBPs), a family of six polypeptides thought to modulate

storage, transport and action of the IGFs. As noted above, IGFI secretion parallels GH

secretion with age. During starvation, this linkage is broken. In the presence of elevated

GH levels, IGFI levels remain low, and the concentration of IGFI inhibitors in the

circulation is increased.

As if this were not enough, the fat tissue makes other hormones, including

omentin, vasofatin and resistin, that have effects on the breakdown of nutrients by the

body. Some of the hormones made in abdominal fat are not secreted into the

bloodstream and are presumed to regulate the functions of cells within the abdominalfat.

The take-home lesson from all of this is that maintaining body weight in the face

of starvation is a very important and basic function maintained by overlapping groups

of hormones produced in various parts of the body, but the fat organs have a lot to

do with transmitting to the brain the state of nourishment. The fat in the body is

regulated. It is clearly possible to change it through diet and lifestyle, but the many

attempts to “fool Mother Nature” by changing one part of the system have

not succeeded.

D.3.4 GENES AND OBESITYObesity is the result of an interaction of genes and environment. Nonetheless, the total

number of individuals with rare genetic defects account for only 5 percent of all cases

of obesity. Some of these disorders are fascinating and involve multiple problems in

mental functioning, reproduction, vision and facial appearance.

The majority of the obese population is simply well-adapted to starvation.

Research on the genes involved in familial obesity have so far shown up some

70 associations with parts of the human genome. However, it is unlikely that this search

will uncover any single unique target that accounts for a significant percentage of48

D.3.3 - D.3.4



obesity cases. Rather, most experts suggest any one defect may contribute about

2 percent to the tendency to gain weight. Somehow the cumulative effects of multiple

genes are what tip the balance towards gaining weight.

On the other hand, it is the sedentary lifestyle of the current age which combines

with the high-fat, high-sugar, and high-starch diet to unmask the genes for obesity. It

is generally believed that the very obese (those over 100 pounds overweight or with a

BMI >40) have the greatest genetic programming for obesity. In the last 10 years, whenobesity has doubled, the number of people with severe obesity has increased four-fold

according to a recent Rand study.

However, beyond obesity in general shape is also genetic. Identical twins reared

apart not only have similar body weights but photographs of their fat distribution show

almost identical pockets of fat. So, the body’s shape is genetically determined, but it can

be altered significantly with diet and lifestyle changes.

D.4MEAL REPLACEMENT

D.4.1HISTORY OF MEAL REPLACEMENTS

The late Dr. Ernst Drenick, a UCLA obesity specialist, was featured in a Life magazine

article in the 1960s about starvation as a treatment for severe obesity. The only problem

was that an individual would lose muscle at a proportion of one pound for every four

pounds of weight lost with this method.

Protein-modified fasting (also known as “very low calorie dieting”) was developed

clinically by Dr. Victor Vertes at the Cleveland Clinic in the late 1970s. By this method,which was validated by the scientific studies of Dr. George Blackburn and Dr. Vernon

Young at the Massachusetts Institute of Technology (MIT), an individual could take in

enough protein to restore what was being lost. It worked to some extent and was safe

as long as the individual consumed high-quality proteins and had their blood tested

every week. The amount of calories in this diet was extremely low–in the range of 375

to 400 calories per day.

Satisfying physical hunger to some extent with a liquid meal was the basis of the

Opti-Fast diet, which was provided through hospitals beginning in the late 1970s. In

1977, the late Dr. Morton H. Maxwell brought this method of dieting to Los Angeles at

the Risk Factor Obesity Clinic, which is still in operation today at UCLA. This clinic

collects data on all the patients enrolled and includes a multidisciplinary team of

psychologists, exercise physiologists, nurses and dieticians who meet weekly. The

emotional support provided by this center has led to miraculous results, with patients

losing large amounts of weight safely, and effectively maintaining their weight loss

for years.

In the late 1970s, the very low-calorie Cambridge diet was sold to people door-to-door

without medical monitoring and caused about 80 deaths around the country, mostly in

women with less than 40 pounds to lose. These women lost muscle protein from their

hearts because they had small protein reserves. The massively obese patients did better

because they could draw down their huge protein reserves. Since the heart is both a

muscle and an electrical generator that regulates its own beating, the muscle loss in

these women resulted in fatal heart attacks as their hearts stopped beating. Due to this

PHYSICIAN’S REFERENCE MANUAL D.3.4 - D.4.

4




bad publicity, doctors avoided having much to do with diets such as this, leaving it to

specialists like Dr. Maxwell, who developed centers like the one at UCLA, to carry on

quietly saving thousands of lives over the years.

In the 1970s and 1980s, research probed into how these diets worked from a

nutritional viewpoint, and this research led ultimately to the development of high-

carbohydrate/low-fat/low-protein meal replacement shakes that were sold over the

counter. These shakes were different from VLCD shakes in that they did not requiremedical supervision when incorporated into diets at greater than 1,000 calories per day.

At about this time, Mark Hughes founded Herbalife in 1980 and began what

would grow into the largest distribution method for meal replacements, in the world

over the next 27 years, as the effectiveness of meal replacements were immediately

evident to him. It would take the next 20 years after Herbalife’s founding for the

scientific evidence that meal replacements work to be published in peer-reviewed

journals and be accepted by the scientific community.

D.4.2NUTRIENT COMPOSITION OFHERBALIFE FORMULA 1 AND

HIGH-PROTEIN/LOW-CARB DRINK MIXNot all meal replacements are alike. Some taste better than others. The first meal

replacements used a lot of sugar and very little protein to optimize taste. Since high-

protein diets came into fashion, some have more protein and less sugar, but much

more fat. When a meal replacement is packaged in a can, there is a limit to how much

protein can be engineered into the liquid without having it settle out. One of the

strategies for getting more protein is to add more fat. However, if the meal

replacement has more than 5 grams of fat, under FDA rules, its manufacturer can no

longer make any health claims. Some of the high-protein drinks contain 10 grams offat, which is 90 calories of fat in a 270-calorie high-protein drink.

Herbalife’s ShapeWorks® Formula 1 contains high-quality soy protein, low

amounts of fat and a moderate amount of carbohydrate, together with vitamins,

minerals and a proprietary herbal blend.

Note: To be classified as a meal replacement a shake must provide at least 170

calories. Therefore, a high-protein/low-carb drink mix is classified as a nutritional

protein snack in the ShapeWorks® program. In order to be easily duplicated by patients

helping other patients, VLCD at levels below 1,000 calories per day is not part of the

ShapeWorks® or Doctors in Herbalife program. This minimizes the amount of medical

testing needed to safely administer this plan.

D.4.3CLINICAL RESEARCH ON MEALREPLACEMENTS: AN ACCOUNT BYDR. DAVID HEBER

Throughout the 1980s, meal replacements were being sold over-the-counter, and

advertising raised the awareness of the public about the existence of meal replacements.

At about this time, I started my research with meal replacements. I had seen the results in

my clinic, but in the late 1980s I started to document the effects on blood pressure,50

D.4.1 - D.4.3



cholesterol and blood sugar in diabetics and non-diabetics overweight and obese patients.

In 1994, I supervised a study of more than 300 patients at six medical centers in

the United States. They were paid $25 a week and given a can of the powdered meal

replacement each week. They mixed the powder with milk and drank a shake twice a

day for weight loss, together with a reasonable dinner, providing about 1,200 calories

per day. The results were amazing. Men lost 24 pounds in 12 weeks on average. Women

lost 12 pounds in 12 weeks, but by 24 weeks both men and women had lost an averageof 17 pounds. In 1994, I published these results in a paper entitled “Clinical Evaluation

of a Minimal Intervention Meal Replacement Regimen for Weight Reduction” in The

Journal of the American College of Nutrition.

In the late 1990s a series of studies were done which demonstrated the impact of

meal replacements on blood pressure, cholesterol, triglycerides, blood sugar and sleep

disorders. Our own unit at UCLA conducted key studies showing that meal

replacements were safe and effective when used for type 2 diabetes with obesity (what

I call “diabesity”). In these studies, weight loss with meal replacements led to reduction

or elimination of expensive medications used to treat high-blood sugar in these diabetes

patients after a relatively modest weight loss of about 5 percent of body weight. This

amount of weight loss in a study called the “Diabetes Prevention Program” prevented

58 percent of new cases of diabetes over five years in people who had high-blood sugars(but had not yet developed diabetes) and was better at prevention of diabetes than a

drug approach.

However, the most striking study was done by Dr. Herwig Ditschuneit at the

University of Ulm in Germany. In most American studies, we lose between 20 percent

and 40 percent of participants in research studies by the end of one year. This is not

because we lose track of them; studies have shown that volunteers in weight-loss

research studies are always looking for the “magic bullet” and tend to abandon these

studies in mid-stream. Given the strict overseeing of Human Subjects Protection

Committees at UCLA and elsewhere, it is no longer possible to provide strong monetary

incentives linked in any way to continued participation in research. This is now

considered unethical as it is viewed as forcing the patient to participate in the research.

We do have to pay for parking and provide them with monetary compensation for their

participation not linked in any way to attending sessions in the research study. So we

can hand out some goodies, such as pedometers and provide theater tickets and

lotteries for gifts, and that’s about it.

I bring this up because Dr. Ditschuneit kept 75 percent of his patients on his study

for four years and proved that meal replacements were not just effective for weight loss

but also for weight maintenance. He couldn’t leave the patients on two meal

replacements a day for four years, so the study had an interesting design. For the first

twelve weeks, volunteers were randomly assigned to either try to cut down on eating

their favorite foods to reach a target of 1,200 calories per day or follow a meal

replacement plan at the same number of calories, which involved drinking two meal

replacements a day and eating a healthy dinner. At the end of twelve weeks, the groupthat tried to cut down on their favorite foods lost a pound or two on average, but the

meal replacement group lost 14 pounds. At that point both groups were told to have

one meal replacement a day. By the end of four years, the group that consumed two

meal replacements a day for twelve weeks and then one a day for four years lost

10 percent of their body weight. The group who started the meal replacements after

12 weeks and had one per day for four years lost 5%. There were also significant

changes in some of the risk factors for obesity-associated diseases, such as glucose and

insulin levels, with larger changes in the group that lost 10 percent of body weight

compared to the group that lost 5 percent of body weight (see Figure 5 on page 52). A

statistician at UCLA analyzed the data, and the results were published in The American

Journal of Clinical Nutrition.


5




As a result of all this research, meal replacements are now an accepted method of

weight-loss treatment. The National Institutes of Health is sponsoring a multi-million dollar

trial on the effects of weight loss on heart disease in type 2 diabetes patients over five years.

Based on some of our research at UCLA and that of others, they have chosen to include

meal replacements as a nutritional intervention option in one arm of the study.

D.4.4RECENT RESEARCH ON

SHAPEWORKS® (ABSTRACT)The ShapeWorks® plan is simple and is based on the meal replacement strategy

described below:

THE PLAN TO LOSE WEIGHT

Replace two meals a day with portion-controlled, low-calorie,

nutritionally balanced mealsSnacks between meals (fruit and vegetables) to reduce severe hunger

Physical activity and emotional support

THE PLAN TO MAINTAIN WEIGHT LOSS

Replace one meal a day with portion-controlled, low-calorie meal and

eat two well-balanced meals

Physical activity and emotional support

If weight gain occurs, restart the weight-loss plan until excess

weight is lost

52

D.4.3 - D.4.4

Figure: Weight loss over four years using a meal replacement twice a day for twelve weeks (solid triangles) compared tocutting back on favorite foods (solid squares). Until the end of the study at four years, one meal replacement per day was

used by both groups (body weight in solid circles). Weight in pounds on the vertical scale is plotted against time in months

on the horizontal scale. Figure adapted from reference 2: Flechtner-Mors M, Ditschuneit HH, Johnson TD, Suchard MA,

Adler G. “Metabolic and weight loss effects of long-term dietary intervention in obese patients: four-year results.” Obes

Res. 2000 Aug;8(5):399-402.

Figure 5



Unlike other meal-replacement plans, ShapeWorks® allows patients to personalize

their protein intake. They can choose to take adequate protein to prevent nutritional

deficiency, which is the U.S. RDA of 56 grams for men and 46 grams for women, or

they can choose to take 1 gram of protein per pound of lean body mass as determined

by body composition (see section E: “Body Composition” on pages 55 through 59).

To test the safety and effectiveness of this approach, 100 obese patients were

recruited for study at the UCLA Center for Human Nutrition. At three months, theamounts of weight lost in each of the two groups was equivalent, but there was more

lean-body mass retained by the high-protein group. Clearly, compliance in this research

setting was not affected by the higher protein and masked the satiety benefits. That is,

psychology trumps physiology in weight management, and the nature of this double-

blind study made it impossible to influence behavior. Since it is known that people

overeat even when they are not hungry, the equivalent weight loss is not surprising.

The retention of increased lean-body mass is significant.

Shown in Figure 6 above is the result of bioelectrical impedance determinations at

three months. While weight losses were equivalent, the higher-protein group lost

significantly more body fat by three months and hence retained more lean-body mass

on average. The amounts of weight lost by both groups were typical of the experience

with meal replacements in clinical trials and clearly is much less significant than what

is seen in individuals with higher levels of compliance. The study design retains all

subjects in both groups regardless of compliance level and this minimizes the average

weight losses seen.

Recent studies done in Seattle and published in The American Journal of Clinical

Nutrition confirm the findings of equivalent weight losses with increased retention of

lean-body mass. The higher-protein, low-fat, lower-carbohydrate approach of

ShapeWorks® is a state-of-the-art, science-based program that provides your patients

the finest in nutrition and weight-management support.


5

Figure 6




REFERENCES

Flechtner-Mors M, Ditschuneit HH, Johnson TD, Suchard MA, Adler G. “Metabolic and weight loss effects of long-termdietary intervention in obese patients: four-year results.” Obes Res. 2000 Aug;8(5):399-402.

Hensrud DD “Dietary treatment and long-term weight loss and maintenance in type 2 diabetes.” Obes Res. 2001 Nov;9 Suppl4:348S-353S.

Yip I, Go VL, DeShields S, Saltsman P, Bellman M, Thames G, Murray S, Wang HJ, Elashoff R, Heber D. “Liquid mealreplacements and glycemic control in obese type 2 diabetes patients.” Obes Res. 2001 Nov;9 Suppl 4:341S-347S.

Bowerman S, Bellman M, Saltsman P, Garvey D, Pimstone K, Skootsky S, Wang HJ, Elashoff R, Heber D. “Implementationof a primary care physician network obesity management program.” Obes Res. 2001 Nov;9 Suppl 4:321S-325S.

Ashley JM, St Jeor ST, Perumean-Chaney S, Schrage J, Bovee V. “Meal replacements in weight intervention.” Obes Res. 2001Nov;9 Suppl 4:312S-320S

Heymsfield SB, van Mierlo CA, van der Knaap HC, Heo M, Frier HI. “Weight management using a meal replacement strategy:meta and pooling analysis from six studies.” Int J Obes Relat Metab Disord. 2003 May;27(5):537-49.

Weigle DS, Breen PA, Matthys CC, Callahan HS, Meeuws KE, Burden VR, Purnell JQ. A high-protein diet induces sustainedreductions in appetite, ad libitum caloric intake, and body weight despite compensatory changes in diurnal plasma leptin andghrelin concentrationsAm J Clin Nutr. 2005 Jul;82(1):41-8.

54



E.BODY COMPOSITION

E.1 CLASSIFICATION ACCORDING TO

LEAN-BODY MASS

Obesity = Excess Body Fat

(Body Fat > 20% in men, > 30% in women)

Sarcopenic Obesity Normal Obesity Hypermuscular Obesity

(reduced lean mass) (proportionate) (increased lean mass)

Increased lean mass as well as fat mass is seen in obese individuals. One study reported that

lean tissue in obese children was increased compared to non-obese peers (Forbes, 1964).

Another study, using total body potassium, found increased lean tissue in obese adults

(Drenick et al., 1966). Yet another study measured the body composition of 104 obese and

normal weight women by densitometry (Webster et al., 1984). This reported that the excess

body weight of the obese over non-obese women consisted of 22 percent to 30 percent lean

and 70 percent to 78 percent fat tissue. Forbes and Welle examined data on lean body mass

in obese subjects collected in their laboratory or published in the literature (Forbes and

Welle, 1983). Their own data demonstrated that 75 percent of the obese population had a

lean-to-height ratio that exceeded 1 standard deviation (SD) and that more than half

exceeded 2 SD. A review of the literature supported these observations and determined that

the lean body mass could account for approximately 29 percent of excess weight in obesepatients. A proportionate increase of lean-body mass of approximately 25 percent is

considered normal. Deviations both above and below this amount of lean mass are observed

on clinical grounds based on various etiologies listed in Table 3 below. An example of data

collected in the UCLA High Risk Breast Cancer Clinic is shown in Table 4 on page 56.

PHYSICIAN’S REFERENCE MANUAL E - E.1

5

TABLE 3

Etiologies of Sarcopenic and Hypermuscular Obesity

Sarcopenic Obesity

Chronic Use of Corticosteroids

Prolonged Inactivity or Bed Rest

Hypogonadism

HypopituitarismNeuromuscular Diseases

Menopause and Age-Related Hypogonadism

Genetic

Hypermuscular Obesity

Childhood Onset Severe Obesity

Use of Anabolic Androgens

Hyperandrogenism in Females

Athletics (e.g., football, wrestling, weight lifting)

Genetic




E.2RMR AND PREDICTED WEIGHT LOSS

FROM LEAN-BODY MASSLean-body mass is clinically important for two reasons. First, lean-body mass predicts

energy expenditure and, thereby, the predicted rate of weight loss on a given calorically-

restricted diet (Lohman et al., 1987). Secondly, lean-body mass can be used to diagnose

increased or decreased lean-body mass. In the first instance, the increased lean-body mass

can be used to calculate a more appropriate target weight than would be predicted from

ideal body-weight tables. In those subjects with reduced lean-body mass, a program of

aerobic and heavy resistance training can be initiated to provide for an increase in lean-

body mass and energy expenditure. In both markedly obese individuals and individuals

with decreased lean-body mass, there is a linear relationship (Sterling-Pasmore Equation)

of lean-body mass to energy expenditure (ca. 13.8 Kcal/day/lb lean-body mass). This

represents approximately 90 percent of total energy expenditure in a sedentary obese

individual, and provides a good clinical estimate of maintenance calories.

E.3BASIC SCIENCE BEHIND

BIOIMPEDENCEThe principle behind bioelectrical impedance analysis is that the fat tissues of the body

do not conduct electrical impulses as well as lean tissues, such as muscle, which are 70

percent water. While there are many ways to measure bioimpedance, the most widelyaccepted method involves the placement of four skin paste electrodes similar to those

used to obtain electrocardiograms. These are placed at set points on one arm and one

leg. By separating the electrodes a known distance based on the height of the individual

which is provided to the computer in the analyzer, it is possible for the bioimpedance

analyzer to quantitatively measure the electrical characteristics of the body. This can

then be used to calculate lean-body mass and fat mass as described in the following:

This type of circuit has a frequency-dependent impedance based on the resistance

and capacitance (reactance) of the circuit elements, which are fat and lean tissue in this

case. As the frequency is increased the circuit acts more like a simple resistor, and

56

E.1 - E.3

TABLE 4

Body Mass and Percent Body Fat in Women

at Increased Risk of Breast Cancer

(From Heber et. al., The American Journal of Clinical Nutrition, 1996)

n=28 Age Wt. Ht. BMI Body Fat(yr) (lbs) (in) (wt/ht2) ( % )

Mean

+ SD 36.8+6.4 137.8+1.9 65.3+2.7 22.9+3.1 34.6+4.8

(nl < 27) (nl 22-28%)



electricity travels through the circuit easily. At low frequencies it acts more like a

capacitor until at 0 Hz (cycles/sec) there is no circuit flow and the impedance

approaches infinity. All bioimpedance analyzers use an equation such as the one shown

below. The Biodynamics impedance analyzer, in particular, uses four sets of equations

to be able to predict lean-body mass with different constants for different body types.

LBM = (A X Ht2) + (B X Wt) + (C X Age) + (D X R) + E

Where: LBM = lean-body massHt2 = the height squared in units the machine reads

either centimeters or inchesWt = weight in pounds or kilogramsAge = age in years, since lean-body mass tends to

decrease with ageR = bioimpedance in ohms

The reactance is not used, but by convention the bioimpedance is readat 50 Hz. Some variable frequency machines are available which claim torepresent extracellular and intracellular water by measuring impedance atdifferent frequencies.

Data Provided By a Manufacturer on Correlation With

Underwater Weighing (Bioanalogics, Inc.)

Clinical Results Men WomenPercent Body Fat 4.3-37.1 12.0-45.5R correlation 0.98 0.96SEE (% body fat) 1.50% 1.62%Sample Size 198 226

PHYSICIAN’S REFERENCE MANUAL E.3

5

The impedance meter is a simple electrical circuit with the following

characteristics:




E.4CHALLENGES IN THE CLINICAL USE

OF BIOELECTRICAL IMPEDANCEDuring the first week of caloric restriction, there is a loss of body weight in excess of

the loss of lean and fat tissue due to a diuresis. If patients are measured at their first

visit and then weekly thereafter, it is possible to find that patients are apparently

gaining fat as they lose weight using bioelectrical impedance. Since lean-body mass is

assessed based on both body water and muscle, the loss of water leads to an apparent

decrease in lean-body mass, which in most cases, exceeds the loss of fat in the first week

of dieting leading to an increase in percent body fat (Yang, 1988). The bioelectrical

impedance measurement is most useful at the first visit for assessing type of obesity

(usual, decreased lean mass, increased lean mass, or fat maldistribution), and not useful

for multiple serial determinations. In fact, the machine is not accurate enough to pick

up small changes; therefore, it is advised to delay repeating the measurement until the

patient has reached a weight close to target weight.

A second potential problem is overemphasis on the quantitative accuracy of body-fat estimation. Small changes cannot be measured using this device. It is important to

stress this fact to patients. The changes observed in percent fat often do not impress

patients as much as the ratio of the absolute change in fat mass in pounds compared to

changes in lean mass.

E.5FUTURE RESEARCH ANDOTHER METHODS

There should be standards set for calibrating machines from different manufacturers.There are a number of laboratories that have multiple methods for measuring body

composition, including total body potassium, underwater weighing, TOBEC, DEXA

and deuterium dilution. Each of these has drawbacks and strong points, but none is the

“gold standard.” The only perfect method is carcass analysis, and that can be done only

once. Table 5 on this and the following page shows the methods and the principles

underlying their determination. They correlate with one another but do not give the

exact same measurements of body composition.

TABLE 5

TOTAL BODY POTASSIUM

Detects natural K 39 decay in body from potassium assumed to be in

muscle. Assumes potassium concentration of muscle is constant–not

always true in malnutrition. Body fat attenuates signal so poor

in obesity.

DEXA

Scan X-ray absorptiometry of body on scan table. Assumes density of

muscle and fat different.

58

E.4 - E.5



TABLE 5 (Continued)

TOBEC

Body passes through magnetic field weakening it proportional to

conductivity of the body. Uses magnetic field for bioimpedance.

(Similar problems to bioimpedance).

UNDERWATER WEIGHING

Weight underwater compared to land is a function of body density.

Air trapped in lungs affects density.

DEUTERIUM DILUTION

Exact volume of deuterium diluted into the body water. Water

volume not exactly equivalent to lean tissues (similar problems to

bioimpedance).

BOD POD

Air displacement in a closed chamber with scale in the seat (similarproblems to underwater weighing).

REFERENCES

Garrow JS, Webster J. Quetelet’s Index (W/H2) as a measure of fatness.Int J Obes 1985;9:147-153.

Forbes GB. Lean body mass and fat in obese children.Pediatrics 1964;34:308-314.

Drenick EJ, Blahd WH, Singer FR, et al. Body potassium content in obese subjects and postassium depletion duringprolonged fasting. Am J Cl in Nutr 1966;18:278-285.

Webster JD, Hesp R, Garrow JS. The composition of excess weight in obese women estimated by body density, total bodywater, and total body potassium. Human Nutrition: Clinical Nutrition 1984;38C:299-306.

Forbes GB, Welle SL. Lean body mass in obesity. Int J Obesity 1983;7:99-107.

Segal KR, Van Loan M, Fitzgerald PI, Hodgson JA, Van Italie, TB. Lean body mass estimation by bioelectrical impedanceanalysis: a four-site clinical validation study. Am J Cl in Nutr 1988;47:7-14.

Durnin JVGA, Womersley J. Body fat assessed from total body density and its estimation from skinfold thicknesses:measurements on 481 men and women aged 16 to 72 years. Br J Nutr 1974;32:77-92.

Lukaski HC, Bolonchuk WW, Hall CB, Sider WA. Validation of a tetrapolar bioelectrical impedance method to assesshuman body composition. J Appl Physiol 1986;60:1327-1332.

Lohman TG, Going SB, Golding L et al. Interlaboratory bioelectrical resistance comparison. Med Sci Sports Exerc

1987;19:539-545.

Yang M-U. Body composition and resting metabolic rate in obesity.In: Obesity and Weight Control (Frankle RT and YangM-U, eds.) Aspen Publishers, Rockville , 1988 pp.71-96.

Gray DS. Changes in bioelectrical impedance during fasting. Am J Cl in Nutr 1988;48:1184-1187.

PHYSICIAN’S REFERENCE MANUAL E.5

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F.SAFETY OF CAFFEINE AND ITS

EFFECTS IN WEIGHT MANAGEMENTThe information that follows is taken from the International Food Information Council

Publication of January 2003. It clearly states the answers to the most common questions

about caffeine in Herbalife® products.

Caffeine is one of the most comprehensively studied ingredients in the food

supply. There is considerable knowledge of this compound, with centuries of safe

consumption in foods and beverages. However, some questions and misperceptions

about the potential health effects associated with this ingredient still persist. Weight

management studies by Dulloo et al. published in The New England Journal of Medicine

indicate that coffee, in addition to its effects on stimulating mental alertness, can

increase energy expenditure by approximately 2 percent per day, which is about

40 calories in an individual expending 2,000 calories per day. Beyond these

physiological effects, taking caffeine can help dieters through the low-energy periods of

the day, aiding in compliance.

The benefits for weight management were recently described by Westerterp-

Plantenga and co-workers in a research study.

F.1WHAT IS CAFFEINE?

Caffeine is a naturally occurring substance found in the leaves, seeds or fruits of at least

63 plant species worldwide. Caffeine, also known as trimethylxanthine, coffeine, theine,

mateine, guaranine, methyltheobromine and 1,3,7-trimethylxanthine, is a xanthine

alkaloid found naturally in such foods as coffee beans, tea, kola nuts, Yerba maté, guarana

berries and (in small amounts) cacao beans. For the plant, caffeine acts as a natural

pesticide since it paralyzes and kills insects that attempt to feed on the plant.

Caffeine’s main pharmacological properties are: a stimulant action on the central

nervous system with psychotropic effects and stimulation of respiration, a stimulation of

the heart rate and a mild diuretic effect.

The most commonly known sources of caffeine are coffee, tea, some soft drinks and

chocolate. The amount of caffeine in food products varies depending on the serving size,

the type of product and preparation method. With teas and coffees, the plant variety also

affects caffeine content.

60

F - F.1

Chemical Structure of Caffeine



Coffee is the chief source of caffeine in the United States. An 8 oz cup of drip-brewed

coffee typically has 85 milligrams (mg) of caffeine; an 8 oz serving of brewed tea has 40

mg; soft drinks that contain caffeine have an average of 24 mg per 8 oz serving; and an

ounce of milk chocolate has just 6 mg.

F.2 COFFEE CONSUMPTIONPublished data shows the per capita consumption level of caffeine for the average adult

is approximately 200 mg daily. The average child consumes much less caffeine–only

one-quarter of the caffeine consumed by adults.

For children and young adults, the primary sources of caffeine are tea and soft

drinks, while for adults, caffeine intake is mostly from coffee.

Foods and beverages derived from cocoa beans, kola nuts and tea leaves often

contain some caffeine. Caffeine is also added to some foods and beverages for flavor. It

contributes to the overall flavor profile of those foods in which it is added.

F.3CAFFEINE SAFETY

In 1958, the U.S. Food and Drug Administration (FDA) classified caffeine as “Generally

Recognized As Safe” (GRAS). In 1987, the FDA reaffirmed its position that normal

caffeine intake produced no increased risk to health. In addition, both the American

Medical Association and the American Cancer Society have statements confirming the

safety of moderate caffeine consumption.

What constitutes a normal amount of caffeine depends on the individual. Caffeine

sensitivity depends on many factors, including the frequency and amount of regular

intake, body weight and physical condition.

Numerous studies have shown that moderate amounts of caffeine–about

300 milligrams per day–are safe for most adults. Children consume about 35 to 40 mg

daily.

Depending on the amount of caffeine ingested, it can be a mild stimulant to the

central nervous system. Although caffeine is sometimes characterized as “addictive,”

moderate caffeine consumption is safe and should not be classified with addictive drugs

of abuse. Often, people who say they are “addicted” to caffeine tend to use the term

loosely, not unlike saying they are “addicted” to work or television.

When regular caffeine consumption is stopped abruptly, some individuals may

experience mild symptoms such as headache, fatigue or drowsiness. These effects are

usually only temporary and will end in a day or so.

Moderate amounts of caffeine are safe for most people. Some individuals may besensitive to caffeine and will feel effects at smaller doses than do individuals who are

less sensitive. Pregnancy and aging all may affect an individual’s sensitivity to caffeine.

There is no evidence that the caffeine in beverages is dehydrating. Any diuretic

effect is more than likely compensated for by the total amount of fluid provided by

the beverage.

Research has found no evidence to suggest the use of caffeine at the levels in

foods and beverages is harmful. As with all foods and beverages, parents should use

common sense in giving their children normal servings of caffeinated foods

and beverages.

PHYSICIAN’S REFERENCE MANUAL F.1 - F.3

6




There is no evidence to show that caffeine is associated with hyperactive behavior.

In fact, most well-conducted scientific studies show no effects of caffeine-containing

foods–or any food or beverage, in general–on hyperactivity or attention deficit disorder

in children.

Scientific evidence suggests that children are no more sensitive to the effects of

caffeine than adults.

Most physicians and researchers today agree that it is perfectly safe for pregnantwomen to consume caffeine.

Daily consumption of up to 300 mg per day (approximately two to three 8 oz cups

of brewed coffee) has been shown to have no adverse consequences during pregnancy.

However, it is wise for pregnant women to practice moderation in consumption of all

foods and beverages.

The weight of scientific research indicates that moderate caffeine consumption

does not affect fertility, or cause adverse health effects in the mother or the child.

Caffeine-containing foods and beverages, in moderation, can be enjoyed while

breastfeeding. Studies have shown that although caffeine is passed to the infant

through breast milk, the amount is minute and has no effect on the infant.

Both the American Academy of Pediatrics and researchers of a review published

in The American Journal of Clinical Nutrition confirm that caffeine consumption at usualamounts has no effect on the infant.

F.4FIBOCYCSTIC BREAST DISEASE AND

CAFFEINE CONSUMPTIONFibrocystic breast disease (FBD) is a condition characterized by multiple cysts that can

be felt throughout the breast and usually associated with pain and tenderness.

Approximately 50 percent to 90 percent of women experience symptoms of FBD,

which include cyclic breast pain and tenderness. There is no relationship between FBD,which is extremely common (occurring in up to 70 percent of normal women before

menopause), and breast cancer. The condition improves or disappears in the majority

of women after menopause.

Both the National Cancer Institute and the American Medical Association’s

Council on Scientific Affairs have stated there is no association between caffeine intake

and fibrocystic breast disease. Research has shown that caffeine does not cause or

worsen the symptoms of fibrocystic breast disease. A worldwide investigation of

100,000 deaths due to breast cancer found no relationship between caffeine intake and

the development of this disease.

F.5 OSTEOPOROSIS AND

CAFFEINE CONSUMPTIONOsteoporosis is a disease of the bone characterized by a decrease in bone density and

the development of weak and brittle bones, which are more prone to fracture. While it

is not exclusively a women’s disease, osteoporosis occurs most frequently in women.

Risk factors include inadequate calcium intake, high-protein intake, smoking,

inadequate exercise, small body frame, low-estrogen levels and age. In addition,

Caucasian and Asian women are at higher risk for osteoporosis than women of most

other ethnic groups.62

F.3 - F.5



A recent study of post-menopausal women demonstrated that caffeine intake is

not associated with any change in bone density.

Several other recent, well-controlled studies have concluded that consuming

moderate amounts of caffeine do not increase a woman’s risk of osteoporosis.

F.6 CAFFEINE ANDBLOOD CHOLESTEROL

There is no evidence linking caffeine to changes in blood cholesterol. Consumption of

coffee as typically prepared in the United States does not effect blood cholesterol levels.

Studies from Scandinavia using boiled, unfiltered coffee have found an adverse effect

on blood cholesterol, but this preparation method is rarely used in the United States.

F.7 CAFFEINE AND BLOOD PRESSURECaffeine does not cause chronic hypertension or any persistent increase in blood

pressure. Some individuals sensitive to caffeine may experience a slight rise in blood

pressure, usually not lasting more than several hours.

Studies show any rise in blood pressure is modest and less than that normally

experienced when climbing stairs. However, individuals with high blood pressure

should consult their physician about caffeine intake.

F.8 CAFFEINE AND HEART DISEASEThere have been over 100 studies that have examined whether a relationship exists

between exposure to caffeine and blood pressure, cardiac arrythmia or coronary heart

disease. Most of this research has led to the conclusion that ingestion of moderate

amounts of caffeine is not associated with any increase in cardiovascular disease risk.

REFERENCES

Westerterp-Plantenga S, Lejeune MPGM, Kovacs EMR. “Body Weight Loss and Weight Maintenance in Relation to HabitualCaffeine Intake and Green Tea Supplementation.”Obes Res. 2005;13:1195-1204.

PHYSICIAN’S REFERENCE MANUAL F.5 - F.8

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G.METABOLIC SYNDROME AND

THE CO-MORBIDITIES OF OVERWEIGHT

AND OBESITYThe risk of age-adjusted relative risk of diabetes mellitus increases above a Body Mass

Index (BMI) of 27, which is overweight but not obese. Measures of body fat in these

women would likely indicate higher than normal amounts of body fat and increased

abdominal fat which is the primary depot involved in insulin resistance and the

progression of diabetes.

So, here is an example where waiting to see the blood sugar rise before initiating

treatment is closing the barn door after the horse has run away. Identifying patients prior

to the development of diabetes is one way to deal with this problem. For this reason, the

diagnostic category called “Dysmetabolic Syndrome X,” or simply Metabolic Syndrome,

has been developed with the following diagnostic criteria:

THREE OF THE FIVE SPECIFIC CRITERIA BELOW:

• Blood Pressure > 140/90

• Fasting Blood Sugar > 110 mg/dl

• Waist circumference > 35" in women, 40" in men

• Triglycerides (fasting) > 150 mg/dl

• HDL Cholesterol (fasting) < 50 mg/dl in a woman or

< 40 mg/dl in a male

As the BMI increases, the risks of hypertension, coronary heart disease and

cholelithiasis increase gradually. However, the risk of type 2 diabetes mellitus increases

much more rapidly so that relative risks of diabetes with obesity are in the 40 to 100

fold range compared to the 4 to 6 range for other obesity-associated diseases.

64

G

OBESITY - ASSOCIATED TYPE 2 DIABETES

Overweight or Obesity with Genetic Predisposition

Excess Adipokines Impaired ß Cell Function Endothelial Cell Dysfunction

Multistep Process ofAtherogenesis

Insulin Resistance andDeclining Insulin Levels withImpaired Glucose Tolerance

Type 2 Diabetes CVD Complications

Insulin Resistance andHyperinsulinemia with Normal

Glucose Tolerance andDyslipidemia



G.1DIABESITY

The strong correlation of diabetes and obesity is not merely a coincidence but highlights

the common underlying pathophysiology of obesity causing the progression of a

metabolic syndrome which results in type 2 diabetes. Type 2 diabetes is the cause ofabout 50 percent of all renal failure in the United States and in the next 10 years it is

estimated that 70 percent to 80 percent of all heart disease will occur in patients with

“diabesity,” or type 2 diabetes with obesity. Since diabetes mellitus is defined as an

elevation in blood-sugar levels (>126 mg/dl fasting or >200 mg/dl 2 hours post-

prandial), researchers have identified the metabolic syndrome as a disorder which has

different criteria than type 2 diabetes but is believed to be the precursor disease which

lasts for eight to 10 years prior to the onset of diabetes mellitus.

The development of type 2 diabetes mellitus in association with obesity is a global

epidemic that is estimated to result in the vast majority of new cases of heart disease in

the coming decades, with an estimated 300 million diabetic patients worldwide by the

year 2025.

Dietary modification and enhanced physical activity are the most effective methodsto prevent or delay the onset of type 2 diabetes mellitus (T2DM) as illustrated by the

Da Qing Impaired Glucose Tolerance Study, the Finnish Diabetes Prevention Study, and

the Diabetes Prevention Program. Progression to T2DM in both of the latter studies was

reduced by 58 percent with a modest lifestyle and diet intervention.

The progression of glucose intolerance to T2DM involves a period of insulin

resistance and progressive beta-cell failure as demonstrated in the landmark studies of

Drenick and Johnson at UCLA in 1970. However, the tendency for the pancreatic b-cell

to fail in the presence of chronic insulin resistance may be genetically determined.

Progressive beta-cell failure is related to the high-secretory demands placed on the beta

cell by insulin resistance.

G.2HEART DISEASE AND

HYPERTENSIONObesity is related to the pathogenesis of heart disease through multiple pathways including

hypertension, increased clottability of the blood, and dyslipidemia which is an abnormality

of lipid metabolism in which there is overproduction of triglycerides with a depression of

“good” HDL cholesterol and normal or increased “bad” LDL cholesterol.

The hypertension that is seen in obesity is related to the hyperinsulinemia and

increased secretion of catecholamines. These patients have elevated renin and angiotensinlevels and the drugs of choice for hypertension in these patients are called angiotensin

converting enzyme (ACE) inhibitors. Weight loss will also reduce blood pressure, but the new

guidelines for these patients suggest that lifestyle and diet be used to lower blood pressure

to less than 135/85 along with medications. Only 5 percent of all hypertension is due to

salt sensitivity, but this disorder does occur. Salty foods will increase blood pressure in

patients where obesity is the primary problem. However, low-salt diets have relatively little

effect on blood pressure in these patients. A diet rich in calcium and fruits and vegetables,

which supply potassium, will lower blood pressure significantly, compared to a usual diet

as shown in the Dietary Approaches to Stop Hypertension (DASH) study, funded by the

National Institutes of Health (NIH). Restricting salt had a small but significant additional

effect beyond the DASH diet alone.

PHYSICIAN’S REFERENCE MANUAL G.1 - G.2

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G.3FATTY LIVER DISEASE AND

CIRRHOSIS

The increased incidence of obesity has been paralleled by an increase in metabolicsyndrome in the same cohort of patients. The net consequence of insulin resistance in

a large majority of these obese individuals is hepatic steatosis, which, over time in a

proportion of these patients, progresses to steatohepatitis and cirrhosis.

G.3.1DIAGNOSING FATTY LIVER DISEASE

Despite the increased awareness among physicians regarding its presence, the diagnostic

process has been hampered by the lack of sensitive and specific population-based

screening tests. Liver biopsy remains the gold standard for diagnosis as well as for gradingand staging of the disease process, but its precise role in the process of diagnosis continues

to be debated. Moreover, because laboratory testing is routine, an abnormal serum

transaminase or alkaline phosphatase in patients without clinical symptoms is not

uncommon. Although liver function tests are critical in recognizing the presence of liver

disease and its specific diagnosis, the interpretation of the tests may be confusing and

difficult (Knight, 2005). Furthermore, not all persons with one or more test abnormalities

actually have liver disease.

Abnormal liver enzymes may also be present in the absence of symptoms and signs

of liver disease. A good clinical history and physical examination are mandatory. If a

systematic approach is adopted, based on additional non-invasive serological tests and

imaging procedures covering the most frequent liver diseases, the cause is often apparent.

The clinician should be aware of nonhepatic diseases that can cause abnormal liver

enzymes, such as thyroid disorders and occult celiac disease. In those patients in which

no explanation can be found at the time of the initial evaluation for these abnormal liver

enzymes, there is a high probability of non-alcoholic fatty liver disease. The risks and

benefits of a liver biopsy in this setting should be carefully considered, as it only seldom

alters management (Verslype, 2004).

G.3.2OTHER CAUSES OF FATTY LIVER

AND LIVER FAILUREFatty liver disease has traditionally been classified as alcoholic and nonalcoholic. While

the gross and histologic appearance of the liver are similar in these conditions, the

pathophysiologic processes and clinical features of the two conditions are not identical.

The histologic spectrum of nonalcoholic fatty liver disease (NAFLD) includes both hepatic

steatosis and steatohepatitis. The causes of fatty liver include: 1) Metabolic syndrome,

which is the most common cause; 2) Alcohol-induced liver disease (very common);

3) Rare Metabolic Diseases including abetalipoproteinemia, Weber-Christian Syndrome

and lipodystrophy; 4) Drugs, including amiodarone, tamoxifen, antiretroviral therapies;

5) Hypothyroidism; and 6) Unknown cause (idiopathic).66

G.3 - G.3.2



The global emergence of obesity as an epidemic has made fatty liver disease a public

health problem in the Western world and in emerging economies where obesity is

becoming more prevalent. At the same time, the number of cases of idiopathic liver

disease have increased. While there are documented cases of toxic liver disease due to a

limited number of herbal products as well as what appear to be allergic reactions, the

practice of ascribing idiopathic cases to herbal hepatoxicity is not warranted in the

absence of particular criteria including the identification of the hepatotoxic ingredient,and proof of its hepatotoxicity. Given the prevalence of use of herbal medicines and the

increasingly common occurrence of liver disease worldwide, there have been a number

of misclassifications of liver disease as being due to herbal toxicity.

G.4CANCER

Cancer is due to accumulation of DNA mutations that confer a growth advantage and

invasive properties on clones of cells. A variety of external factors, including nutrients in

the environment interacting with genetic susceptibility, influence the accumulation of

mutations in cells. Nutrition is important at every stage of carcinogenesis from initiation

to promotion to progression and metastasis.

The primary risk factor for cancer is aging. All data demonstrating nutritional

influence utilize age-adjusted cancer incidence. Through primary prevention as well as

nutritional effects on patients with early treated cancer, the hope is to reduce the duration

of morbidity as well as lengthen survival. This has not yet been demonstrated in clinical

trials, but is the ultimate goal of research in nutrition and cancer.

International correlation data in the late 1960s demonstrated a relationship of age-

adjusted breast cancer incidence to dietary fat intake. This correlation marked a dietary

pattern rather than a specific effect of dietary fat. Later studies pinpointed a correlation

with meat-protein rather than vegetable-protein intake. Migration data also demonstrate

that individuals moving from a high-risk to a low-risk country, or vice versa, take on therisk of the country to which they migrate within one generation.

International correlation data also show a relationship of adult height to the age-

adjusted rate of breast cancer. Adult height is a marker of pre-pubertal nutrition. With an

increase in childhood obesity incidence in a country, there is a concomitant increase in

adult height. The incidences of obesity and obesity-related cancers have increased in

Japan in the last 20 years as has adult height. There is evidence that childhood obesity

confers a lifelong increased risk of common forms of cancer.

There is significant evidence that major forms of cancer are affected by diet and

lifestyle. Obesity is a risk factor for common forms of cancer including breast, prostate,

colon, uterine, kidney, gallbladder and pancreatic. Ad lib intake of excess calories in

animal models has also been associated with enhanced tumorigenesis for breast, colon

and skin cancer. Since laboratory animals tend to develop obesity with age, the preventiveeffects of calorie reduction in animals are likely to be analogous to the prevention and

treatment of obesity in humans by either reduction in caloric intake or an increase in

physical activity.

PHYSICIAN’S REFERENCE MANUAL G.4

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G.5CHANGES WITH AGING IN BODY

FAT AND CHRONIC DISEASE RISKAll of the chronic diseases discussed above increase in incidence with aging. With age

there is a reduction in lean-body mass in both men and women. The decrease is

associated with reduced calorie requirements and increased risk of developing common

forms of cancer. The reduced muscle mass may be associated with increased insulin and

reproductive hormone levels in some aging individuals. Lean-body mass decreases with

aging in males as they tend to become less active. There may also be age-related

decreases in hormones mediating muscle growth and maintenance. These changes in

body composition affect the levels of sex hormones, insulin and growth factors which

may affect chronic diseases, including diabetes, cardiovascular disease and common

forms of cancer. Efforts at diet and lifestyle change with aging to prevent chronic

diseases, including cancer, need to include interventions to maintain or increase lean

body mass.

REFERENCES

Knight JA. “Liver function tests: Their role in the diagnosis of hepatobiliary diseases.”J Infus Nurs. 2005 Mar-Apr;28(2):108-17.

Verslype C. “Evaluation of abnormal liver-enzyme results in asymptomatic patients.” Act Clin Belg. 2004 Sep-Oct;59(5):285-9.

SECTION I: BACKGROUND

68

G.5




Notes

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