September 2001 Issue | Jesse L. Hanley, MD

 


 

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Welcome to Functional Medicine Update for September 2001, a month in which we continue our focus on the promotion of healthy aging. This month I want to emphasize some simple things we all do and the way we communicate with patients. We can implement specific information into programs to provide tremendous benefit in promoting healthy aging and reducing the incidence and risk of diseases of aging, including heart disease, cancer, diabetes, and arthritis.

Is healthy aging a realistic objective or an empty promise? That question is related to the whole of functional medicine, which tries to implement successful, cost-effective ways to improve health and function throughout the life cycle. The best answer to that question may be found in a recent British Medical Journal paper on the topic of healthy aging, which asks if it is a realistic or futile goal.

One of the modern medicine’s greatest accomplishments seems to be the ability to enable people in our culture to live longer, on average, than any previous culture of which we are aware. We can look at increasing life expectancy, often hailed as one of the greatest achievement of the 20th century as a justification for the 20th century medical model, from different perspectives. It is true that more elderly people are alive at the start of the 21stcentury than ever before. It is also true that one can now expect to live, on average, some 20 years longer than if he or she had been born at the beginning of the last century.

Does that translate to absolute success in medicine? There’s where the question gets a little more complicated.

Living Longer Lives—In Health or Disability?

First, as Ivan Illich pointed out in his book, Medical Nemesis, factors other than medicine may be contributing to these changes in morbidity and mortality. Socialization, hygiene, sanitation, and nutrition—factors related to community health patterns and practices—may also contribute. Second, we must ask about the health of people in their 70s, 80s, and 90s. Are they held together with the equivalent of baling wire and bubble gum in the form of polypharmacy? Or are they functional human beings who can enjoy the opportunities the wisdom of later life can bring? There is great concern about disability as we grow older as a population, even as life expectancy increases.

As the BMJ article points out, concerns about caring for the growing number of older people has dominated discussion almost to the exclusion of a search for strategies that might improve the overall health of these individuals. This negative focus is fueled in part by a misunderstanding of health in old age. Certainly, older people in general have poorer health than younger people, due in part to higher disease rates in old age. This incidence should not be assumed to be a natural consequence of aging, however. The incidence of heart disease increases with age, for example, but this does not mean that aging itself is a cause of heart disease. Nor does it mean heart disease is inevitable in old age. In fact, by any known biological mechanism, we should not assume that any of the major chronic diseases that cause premature death is a natural consequence of aging.

Disease Not Inevitable with Aging

We often assume we are going to get sick as we get old. We tend to believe either that illness is a natural consequence of our bodies’ wearing out or that we are genetically programmed to get heart disease, cancer, or diabetes. That model is highly contestable. No definitive study exists in any of the world’s literature that indicates any of those degenerative diseases is an inevitable consequence of aging. The absence of such data should change our whole perspective about view healthy aging.

According to the BMJ article, the crucial distinction between the effects of age alone and the effects of disease to be reinforced in the minds of both the public and health professionals. Laying to rest the pervasive misconception that all the ills of old age are attributable to age would represent a major breakthrough in health care for older people. It would change our perception and allow us to focus on ways to deliver programs to improve health in aging, which is not a focus of medicine today.

Compression of Morbidity

Evidence is beginning to emerge that morbidity can be compressed into the last phase of life, and healthy aging may be achievable. The BMJ article refers to the alumni study by James Fries et al. at Stanford University’s School of Medicine. That study showed those individuals who chose a life of nonsmoking, controlled body weight-to-height ratio, regular exercise, and good nutrition had a longer life expectancy, 6.7 years on average. Even more important, they compressed morbidity and were not chronically ill or disabled until the very last phase of their lives. These practices extended both the quantity and the quality of their lives.

Dr. Fries incurred powerful criticism when he initially proposed, in his 1980 NEJM article on compression of morbidity, rectangularization of the survival curve, and natural death. Many people in medicine said if people live longer, they are just going to be sicker and it’s going to cost the healthcare system more. Instead, Fries showed that by practicing the right things they didn’t get sicker; they were able to extend their health and promote healthy aging.

In concluding the BMJ article, the author suggests the health sciences are starting to emphasize matching a person’s lifestyle and environment to his or her genes. By so doing, practitioners can construct a program for an individual that is likely to lead to healthy aging, compressed morbidity, and reduced disability, as they move toward a natural death.

The aging of the population, according to this article, is a success story. Although much debate has focused on how to care for the growing number of old people, an equally important target should be finding ways to maintain health and minimize disability through the promotion of healthy aging. A public health and medical approach to this objective is overdue, according to the article.

Functional medicine focuses on understanding the connection of the individual’s genome to his or her environment to promote a functional status over years of living that gives rise to high outcome of function, compression of morbidity, and lowered disability. Let me take this esoteric discussion to the reality of a clinical case history. Dr. David Jones, former Functional Medicine Update COM, winner of the second Linus Pauling award in functional medicine, and president of the Institute for Functional Medicine, provided us with the following case history from his clinical experience. I think this case exemplifies the concept of healthy aging from the point of view of the functional medicine practitioner.

The patient is an 83-year-old white male widower who was found wandering in the streets by local police who knew him. He and his car were transported back to his home. According to neighbors and friends, he had recently become more confused. They feared he was unable to care for himself. His personal hygiene and cleanliness had worsened over the last few months, and his cooking and eating patterns had deteriorated. He was on his way toward needing some type of care. He had experienced no recent acute illnesses and was taking no long-term prescription medications, but he had complained of pain in his feet when he walked.

Functional Declines at Age 83

The patient’s son, contacted by phone, reported his father had generally been able to care for himself. His diet consisted mainly of prepared foods, either canned goods or TV dinners. The only long-term medications he took was OTC ibuprofen for a chronic left hip arthritis. He took no nutritional supplements. The son had noticed, however, that his father’s memory had decreased in the last few years and he had recently seemed somewhat disoriented in telephone conversations. He had been thinking of moving his father into HUD housing, in order to be nearer to him and to be able to watch over him more closely. His father had resisted moving.

Before retirement, the patient had worked in the lumber industry. He had smoked a pack of cigarettes every day for 70 years. He had been evaluated in the past for claudication and vertigo. He had refused lifestyle intervention changes, either in connection with smoking cessation or dietary changes. He was an average man who was pretty tough and independent. He had no need for “darned doctors.” He wasn’t going to change his lifestyle and was going to behave as he saw fit. Now, however, at age 83 his functional capability was significantly impaired. Dependency and institutional care seemed imminent. Quality of life was being lost, and his morbidity was increasing.

A Medical Puzzle

A review of systems revealed the patient had disorientation problems but no recent problems with vision, cough, fever, chills, chest pain, muscle weakness, frequent falls, intolerance of heat or cold, incontinence of bowel or bladder. He admitted to chronic hearing problems. He said he had been in good health

On exam, he appeared disheveled, slightly lethargic, mildly confused, oriented to person and place only. He said his mind was not working as well as it had in the past. He had no obvious physiological dysfunction that would lead to a clearcut diagnosis. Carotids were normal. Thyroid was not enlarged. Heart function was normal. Chest, abdomen, extremities, and neurologic exam revealed no significant abnormalities. Laboratory values showed a normal chem screen, except for a slightly elevated fasting blood sugar. Thyroid-stimulating hormone (TSH) was normal. A CT scan showed internal capsule infarcts on the left with moderate atrophy and no evidence of hemorrhage. What do you do in a case like this?

B Vitamin Insufficiency?

In the traditional model, his son might have moved him to an institution and provided him with the best care available in that setting. From a functional medicine perspective, however, we might ask, what could produce a functional neurological problem in the absence of any overt pathology? Could it be what Dr. John Lindenbaum described from his work as a neurologist in New York, published in the NEJM, and told us about as a COM on FMU years ago? Could a functional vitamin B12 and/or folate insufficiency be contributing to the patient’s problem?

Lab testing of his CBC, vitamin B12, serum folate, homocysteine and serum methylmalonic acid (MMA) levels would reveal if there was any evidence through these metabolite assays of a functional insufficiency with regard to the folate cycle. This would be a uniqueness related to his diet, his genes, his age, and how they interface to control the folate cycle biochemistry and physiology, which we have discussed on so many levels in previous issues of FMU.

Functional B12 Insufficiency

Lab results revealed a slightly elevated MCV. His serum vitamin B12 level, at 191, was within the normal range of 150-840. His serum folate was 10.2; anything greater than 3 is considered in the normal range. His homocysteine, however, was 12.1. According to Dr. Kilmer McCully’s work, anything above 8 is considered elevated. His MMA level was also elevated. Clearly, there was evidence of a functional vitamin B12 and possibly folate insufficiency.

After he had been given folate orally and B12 by 1000 mcg intramuscular injection, along with a B complex oral supplement for three weeks, his clinical condition improved so that both he and his son noticed it. Within two months, the patient could drive himself to his office. He was walking confidently, but still with a small shuffle. He had no difficulty turning around. He had significant gait disturbances prior to the onset of this B12 and folate therapy. He still had a slight tremor in his hands, but he was more alert and communicative after two months on the intramuscular B12 and oral folate therapy.

Restoring Quality of Life

Continuing on over the course of several more months, his clinical condition improved. He eventually did move to be closer to his son, but he maintains his independence and is not institutionalized.

If we talk about compression of morbidity, extension of the health span, and promotion of healthy aging, this is a great case history. A simple therapy produces a remarkable outcome by asking the right questions and not just assuming that people lose their memory as they get older. That may be a statement of fact in a suboptimal gene/environment matched population. However, if you ask the right questions in the matched environment with genes, the outcome may be very different.

We might wonder how much genetic variation there is. Almost everyone has 10 fingers and 10 toes, 2 eyes and a nose. In many respects, apart from our skin and hair color and the shapes of various parts of our anatomy, we look pretty much the same. Are we really that different when it comes down to it? When we studied individuals in school, we talked about the 70 kg, statistically average human. That must represent most of us, right? That must be how we respond to our environment through this average anatomy and physiology.

A recent report in Science magazine, based on research at Genaissance Pharmaceuticals of New Haven, Connecticut, identified an astounding variation at the genetic level in 82 unrelated people from four racial backgrounds—white, black, Asian, and Hispanic. This landmark study supports the biochemical heterogeneity at the physiological level Dr. Roger Williams and Dr. Linus Pauling described 50 years ago with their concepts of biochemical individuality and molecular medicine. In this Genaissance pharmaceutical work, researchers studied 313 genes out of 30,000 identified in the human genome. They found, on average, a given person can inherit 14 versions of each gene from his or her parents—14 haplotypes. We have much more genetic variation at the biochemical level, the physiological level, than we ever speculated on before the deciphering of the code of the human genome.

Vast Genetic Variations

According to Dr. Gerald Vovis, chief technology officer at Genaissance, “We’ve looked at the largest number of individuals and diverse populations that’s ever been done. The most surprising finding that came out of here was the fact that we found an enormous amount of variation within these genes which had not been known before.”

Genetic differences may help explain why people respond differently to various medications. Atypical side effects from drugs may not be atypical. They may be typically reproducible, given an individual’s physiological propensity for metabolizing drugs based on genetic uniqueness. Pharmacogenetics is a discipline that will change pharmacy dramatically. Possessing a certain variation of a given gene could determine whether a particular environmental substance, food, or medication causes benefit or harm to a particular individual. We hope to harness knowledge of an individual’s genetic makeup to tailor disease treatment to that specific person, according to Dr. Vovis. It sounds like the discussions we have been having in FMUand its predecessors for years.

Genetic Variations by Geographic Area

According to Dr. J. Claiborne Stephens, lead author of the study published in Sciencemagazine, if the study is accurate, “The functional complement of the human genome is going to be a repertoire of something like 400,000 to 500,000 gene versions.” Individuals may have mixes and matches of those variations that give them their unique metabolic thumbprint, to use a graphic metaphor.

“What we didn’t see was any variation that really defined what might be considered to be an ethnic group,” Dr. Vovis continued. “What we did see, however, was that different versions of a gene may be present at higher frequencies in one group of a geographical origin over another.” This is much more important apparently than differences in ethnicity. These are fascinating constructs related to how people respond to the same principles in their diet, lifestyle, and environment.

Single-Gene Disorders

As the British Medical Journal article pointed out, we are learning a lot from single-gene disorders that help us understand other complex chronic diseases of aging. As we study the simplest cases, things like thalassemias or sickle cell anemia, these single-gene disorders show great genetic variation. They are not just “off” or “on” switches. They can be seen in different ways with different genetic polymorphisms with different severity.

This certainly holds true for Gilbert’s syndrome, a basic glucuronidation defect related to the detoxification of bile. It is not just whether one has Gilbert’s or not; there are multiple variants based on different exons and introns that can be mutated. The result is varying effects in the way a person responds to his or her environment, with stress or sleep deprivation, or high-sugar diets, and how these factors are ultimately expressed as the jaundice of Gilbert’s.

The Genotype/Phenotype Connection

We are starting to see a profound merging between the studies of Dr. James Fries on compression of morbidity with individualized therapy designed around a genotype/phenotype connection and how that influences healthy aging. This is what functional medicine is all about. It sounds very sophisticated.

We have to understand that the choices people make over the course of their lives will influence how their genes are expressed and how the phenotype, or their outcome and performance and function, is established. We don’t need to know as clinicians all the specifics and eccentricities of this topic to generate information that is of importance to the patient and to communicate that information. Simple things often have very profound influence

Mitochondrial DNA is one part of the genetic information we carry. Constitutive mitochondrial defects are inborn errors of mitochondrial DNA that can be quite serious and can produce metabolic disorders of infancy, like Kearns-Sayre syndrome Leber’s hereditary optic neuropathy, or some of the neurologic and musculoskeletal problems and ocular problems. Those very serious mutational injuries are passed on through the maternal germ cells to the fetus and are manifest as very serious problems in the child.

More commonly, however, are the acquired mitochondrial injuries, things we collect along the road of life, which can damage our mitochondria. It might be a consequence of exposure to a toxic heavy metal like lead, cadmium, or mercury. It could be the influence of a xenobiotic chemical or the influence of a chronic stress reaction or increases the expression of nuclear factor k B, which increases oxidative stress in the cells. All of these things could induce mitochondrial DNA mutation.

Collecting Mitochondrial Injuries along the Road of Life

We might ask if people collect more injurious mutations in their mitochondria as they age, than in their nuclear DNA. Mitochondria are the site where most of the oxygen is utilized in the body and where many oxidants are produced. These oxidants include hydroxyl radical, superoxide, and peroxynitrite. The greatest potential risk of genetic injury is at the mitochondrial genome, and the mitochondrial repair enzymes for DNA damage are much less efficient than those for nuclear DNA.

What do we know about mitochondrial DNA damage? A recent paper in Free Radical Biology & Medicine describes how mitochondrial damage is associated with aging. It opens the door for developing lifestyles to reduce the risk of accumulating induced mitochondrial injuries. This is a comprehensive, ground-breaking study of the phenotype and genotypic alterations in aging individuals. It looks at ragged red fibers from histochemical data and at genetic markers for mitochondrial DNA injury at ages up to 40 years and then after 40 years.

Molecular Analysis Study

Molecular analysis in this study showed the existence of a 4977-based pair deletion of mitochondrial DNA and a 7436-based pair deletion of mitochondrial DNA in individuals younger than age 40. This occurrence appears to be set and does not seem to change with age, suggesting that some of these may be constitutive, but relatively innocuous. They don’t appear as serious molecular diseases. After age 40, however, there is growing frequency of a new mitochondrial DNA deletion mutation, revealed by long extension polymerase chain reaction. This is a specific 10422-based pair deletion of mitochondrial DNA. Although it has a very low frequency of occurrence. During the course of aging from 40 to 70 years of age, on average, it is seen to double in its frequency.

This may suggest an induced mitochondrial injury caused by factors associated with the nature of life, the nature of aging. Some individuals in molecular gerontology feel these mitochondrial injuries are the seat of biological aging and are trying to find the variables and factors that increase the risk to these mitochondrial DNA damages, and also what are those factors that help protect against them.

Mutant Mitochondria

The first level we can come to in our understanding of that is that oxidative injuries, or substances that increase the rate of production of injurious oxidants, will increase the rate of mitochondrial DNA damage and increase the potential collection of these mutant mitochondria.

A corollary is the existence of agents that help protect mitochondria. These agents include the redox-active substances within mitochondria, the coenzyme Q10, the vitamin E, the lipoic acid, the flavonoids, substances that help keep electrons on the wire, so to speak, and prevent these oxidants from having a deleterious effect on mitochondrial DNA. Therefore, the authors of this study point out, after age 40 the phenotypic and genotypic mitochondrial alterations appear in human skeletal muscle and seem to increase with age. We can begin to implement this concept of healthy aging at the cell biological or at the physiological level to help defend mitochondria against injury, thus minimizing one of the sources of loss of function and increasing risk of cardiac or malignant or insulin resistance problems.

Study Difficulties

Let me add a parenthetical comment. How does one actually study, in a double-blind, placebo-controlled intervention trial, the influence in specific individuals of agents that influence mitochondrial function over years of living? Try to imagine the type of study that would have to be done. It is beyond my ability to envision the analysis, the size and length of the study, the control of the study to unequivocally define the role of nutrients in an individual on mitochondrial dysfunction and its relationship to age-related diseases over the course of 40 oar 50 years of living. These very difficult questions defy definitive, unequivocal answers.

We may have to move toward information obtained from animal work, epidemiological work, cell culture work, and limited intervention trials, all of which are consistent with the underlying science. We will never get completely unequivocal answers that are so incontrovertible as to be above criticism. First we have to look at safety. Then we need to establish efficacy based on a variety of different pieces of information. Patient history, patient outcome, and things we learn from good history-taking and understanding and communicating with our patients will help guide us in understanding the outcome from some of these intervention trials. It is important to look closely at the patient, integrate his or her history, antecedents, triggers and mediators, signs and symptoms into the assessment methodology of this model. That is the functional medicine approach. Dr. Jesse Hanley, our COM, will describe this process from her 20 years of experience as a clinician later in this month’s FMU.

To illustrate why I believe this perspective is so important, and how it is restructuring the practice of medicine today, I go back to the B12 and folate story. A recent Journal of the American Medical Association featured two papers that, at first, seem to be unconnected. If we take a broader view, however, they may reveal an interesting relationship.

The first of these papers is titled “Impact of Folic Acid Fortification of the US Food Supply on the Occurrence of Neural Tube Defects.” This retrospective study looked at the impact of daily consumption of 400 m g of folic acid before conception and during early pregnancy on the appearance of neural tube defects (NTDs), the most common birth defect in our society. Before food fortification, an estimated 29 percent of the US women of reproductive age women were taking a supplement containing 400 m g of folate daily. Beginning in 1996 and moving to 1998 with mandatory compliance, grain products were supplemented with folic acid to raise folate intake in the population at large. This study sought to compare the incidence of spina bifida and anencephaly before October 1995 through December 1996) with the incidence after mandatory fortification with folate (October 1998 through December 1999).

A 30-Year Learning Curve

In examining the prevalence of NTDs reported on birth certificates, the researchers found they decreased from 37.8 per 100,000 live births before fortification to 30.5 per 100,000 live births conceived after mandatory folate acid fortification. This represents a 19 percent decline in the most common birth defects in Western countries. Until recently, this birth defect was considered to be of unknown origin, despite a 1970 Lancet article in which Dr. John Smithells had suggested NTDs might be a consequence of insufficiency of folate and vitamin B12.

It took 30 years for this concept to weave its way into public health measures. How many NTD babies born during that period of time might have been spared the occurrence of this defect in the phenotype? Their genes were just fine; it was a phenotypic development problem in utero,resulting from suboptimal periconceptional folate status in the mother. The folic acid supplement study concluded that a 19 percent reduction in NTD defect births occurred after folic acid fortification of the US food supply. Other factors may have contributed, but the strong association with the timing of folic acid supplementation confirms what Dr. Smithells told us more than 30 years ago.

Folate and Cervical Dysplasia

Folate’s effects go beyond NTDs. Dr. Charles Butterworth, Jr., another investigator in the 1970s, also examined the role of folate intake on cervical dysplasia in women. Dr. Butterworth, a medical school professor at the University of Alabama, observed that low folate status seemed to be correlated with increased prevalence of cervical dysplasia. Colleagues criticized his work as being uncontrolled. You could not define this variable with specificity. Dr. Butterworth published a number of papers in JAMA, looking at oral contraceptive-supplemented women with low plasma folate. He showed they had a much higher level of cervical dysplasia, and folic acid intervention helped reduce this incidence and correct the epithelial dysfunctions in these women. Resistance to those conclusions continued, however, because the dominant belief was that the dysplasia was a virally induced through papillomavirus and was not a nutrition problem at all.

This story assumes new importance in the context of the year 2001. First of all, some women may have genetically higher-than-average requirements for folate, as revealed in a gene polymorphism called methylenetetrahydrofolate reductase. This polymorphism, at least in its heterozygous form, may occur in as many as 20 to 30 percent of women. These women who require high levels of folate to support their folate cycle are those who, in the absence of adequate folate intake for their genetic need, may have a much higher incidence of cervical dysplasia. They also seem likely to give birth to children with Down syndrome or spina bifida, both NTD defects. This story crosses many medical specialties and various medical issues.

HPV Infection and Folate Insufficiency

Another recent paper in the Lancet discussed the association between cervical dysplasia and human papillomavirus infection in young women. This paper is titled “Natural History of Cervical Human Papillomavirus Infection in Young Women: a Longitudinal Cohort Study.” Its findings suggest that attempts to exploit the association between cervical neoplasia and HPV infection to improve effectiveness of cervical screening programs might be undetermined by the limited inferences that can be drawn from the characterization of a women’s HPV status at a single point in time and the short lead time gained by its detection.

Other variables seem to work with HPV infection to create the increasing prevalence of cervical dysplasia and perhaps even cervical cancer. Could one of those variables be folate status and vitamin B12 status, as Dr. Butterworth suggested? In fact, he did a study of HPV in women. By looking at titers to HPV in their blood and examining the prevalence of cervical dysplasia in relation to their folate status, he showed the two work together. HPV infection and folate insufficiency together dramatically increase the risk of dysplasia.

HPV and LSIL

A paper that appeared in same JAMA issue as the paper describing the impact of folic acid fortification of the US food supply on the occurrence of NTDs is titled “Risks for Incident Human Papillomavirus Infection and Low-Grade Squamous Intraepithelial Lesion Development in Young Females.” This paper is unconnected to the paper on folic acid supplementation in this journal. One could make a connection, however, by knowing the whole history of this field over the last 30 years. The authors of this paper conclude the results indicate distinct risks for HPV and low-grade squamous intraepithelial lesions (LSIL). In addition, most HPV-infected women in the study did not develop LSIL. Biological risks other than HPV infection seem to amplify the appearance in the phenotype of this condition.

The authors suggest tobacco smoking is one such risk. Tobacco smoking have is another risk factor for lowering folate status. They did not look specifically at folate status in this particular paper, which surprises me. If they had looked at Butterworth’s work, with which I’m sure they are familiar, they would have realized they should have inspected that variable as well. A virus in combination with other factors leads to poor gene expression, poor phenotypic outcome. Folate status and its relationship to the folate cycle is an important variable in this equation

To illustrate why I believe this perspective is so important, and how it is restructuring the practice of medicine today, I go back to the B12 and folate story. A recent Journal of the American Medical Association featured two papers that, at first, seem to be unconnected. If we take a broader view, however, they may reveal an interesting relationship.

The first of these papers is titled “Impact of Folic Acid Fortification of the US Food Supply on the Occurrence of Neural Tube Defects.” This retrospective study looked at the impact of daily consumption of 400 m g of folic acid before conception and during early pregnancy on the appearance of neural tube defects (NTDs), the most common birth defect in our society. Before food fortification, an estimated 29 percent of the US women of reproductive age women were taking a supplement containing 400 m g of folate daily. Beginning in 1996 and moving to 1998 with mandatory compliance, grain products were supplemented with folic acid to raise folate intake in the population at large. This study sought to compare the incidence of spina bifida and anencephaly before October 1995 through December 1996) with the incidence after mandatory fortification with folate (October 1998 through December 1999).

A 30-Year Learning Curve

In examining the prevalence of NTDs reported on birth certificates, the researchers found they decreased from 37.8 per 100,000 live births before fortification to 30.5 per 100,000 live births conceived after mandatory folate acid fortification. This represents a 19 percent decline in the most common birth defects in Western countries. Until recently, this birth defect was considered to be of unknown origin, despite a 1970 Lancet article in which Dr. John Smithells had suggested NTDs might be a consequence of insufficiency of folate and vitamin B12.

It took 30 years for this concept to weave its way into public health measures. How many NTD babies born during that period of time might have been spared the occurrence of this defect in the phenotype? Their genes were just fine; it was a phenotypic development problem in utero,resulting from suboptimal periconceptional folate status in the mother. The folic acid supplement study concluded that a 19 percent reduction in NTD defect births occurred after folic acid fortification of the US food supply. Other factors may have contributed, but the strong association with the timing of folic acid supplementation confirms what Dr. Smithells told us more than 30 years ago.

Folate and Cervical Dysplasia

Folate’s effects go beyond NTDs. Dr. Charles Butterworth, Jr., another investigator in the 1970s, also examined the role of folate intake on cervical dysplasia in women. Dr. Butterworth, a medical school professor at the University of Alabama, observed that low folate status seemed to be correlated with increased prevalence of cervical dysplasia. Colleagues criticized his work as being uncontrolled. You could not define this variable with specificity. Dr. Butterworth published a number of papers in JAMA, looking at oral contraceptive-supplemented women with low plasma folate. He showed they had a much higher level of cervical dysplasia, and folic acid intervention helped reduce this incidence and correct the epithelial dysfunctions in these women. Resistance to those conclusions continued, however, because the dominant belief was that the dysplasia was a virally induced through papillomavirus and was not a nutrition problem at all.

This story assumes new importance in the context of the year 2001. First of all, some women may have genetically higher-than-average requirements for folate, as revealed in a gene polymorphism called methylenetetrahydrofolate reductase. This polymorphism, at least in its heterozygous form, may occur in as many as 20 to 30 percent of women. These women who require high levels of folate to support their folate cycle are those who, in the absence of adequate folate intake for their genetic need, may have a much higher incidence of cervical dysplasia. They also seem likely to give birth to children with Down syndrome or spina bifida, both NTD defects. This story crosses many medical specialties and various medical issues.

HPV Infection and Folate Insufficiency

Another recent paper in the Lancet discussed the association between cervical dysplasia and human papillomavirus infection in young women. This paper is titled “Natural History of Cervical Human Papillomavirus Infection in Young Women: a Longitudinal Cohort Study.” Its findings suggest that attempts to exploit the association between cervical neoplasia and HPV infection to improve effectiveness of cervical screening programs might be undetermined by the limited inferences that can be drawn from the characterization of a women’s HPV status at a single point in time and the short lead time gained by its detection.

Other variables seem to work with HPV infection to create the increasing prevalence of cervical dysplasia and perhaps even cervical cancer. Could one of those variables be folate status and vitamin B12 status, as Dr. Butterworth suggested? In fact, he did a study of HPV in women. By looking at titers to HPV in their blood and examining the prevalence of cervical dysplasia in relation to their folate status, he showed the two work together. HPV infection and folate insufficiency together dramatically increase the risk of dysplasia.

HPV and LSIL

A paper that appeared in same JAMA issue as the paper describing the impact of folic acid fortification of the US food supply on the occurrence of NTDs is titled “Risks for Incident Human Papillomavirus Infection and Low-Grade Squamous Intraepithelial Lesion Development in Young Females.” This paper is unconnected to the paper on folic acid supplementation in this journal. One could make a connection, however, by knowing the whole history of this field over the last 30 years. The authors of this paper conclude the results indicate distinct risks for HPV and low-grade squamous intraepithelial lesions (LSIL). In addition, most HPV-infected women in the study did not develop LSIL. Biological risks other than HPV infection seem to amplify the appearance in the phenotype of this condition.

The authors suggest tobacco smoking is one such risk. Tobacco smoking have is another risk factor for lowering folate status. They did not look specifically at folate status in this particular paper, which surprises me. If they had looked at Butterworth’s work, with which I’m sure they are familiar, they would have realized they should have inspected that variable as well. A virus in combination with other factors leads to poor gene expression, poor phenotypic outcome. Folate status and its relationship to the folate cycle is an important variable in this equation.

Prognostic Value of Altered Estrogen Metabolism in Breast Cancer

Over the years, we have described many other examples of genetic variability in the promotion of healthy aging. One such example is altered estrogen metabolism. Women respond to their own estrogens in different ways, depending on the way they metabolize estrogen into its hydroxylated metabolites, the 2-hydroxylated metabolites, the 16-hydroxylated metabolites, and the 4-hydroxylated metabolites. Estrone, estradiol, or estriol may not be the metabolite with the most dramatic effect on cellular physiology in the woman’s breast, uterus, or endometrium. It may be the metabolites of estrogen, the 2-hydroxy estrones, the 2 methoxyestradiols, the 16-hydroxy estrone or estradiol compound, and the 4-hydroxy compounds.

We call the 4s and the 16s the “flame dancers.” They promote oxidative stress. They are genotoxic and also highly mitogenic, creating a lot of cell division and cell cycling. Alteration in the way a woman modifies or metabolizes estrogen may be very important. A woman’s unique genes determine the way she metabolizes these estrogens of estrone and estradiol through the pathways, and various factors influence the expression of her genes. A number of nutrients influence gene expression and help control the expression of enzymes that manufacture the 2-hydroxylated, the 16-hydroxylated, or the 4-hydroxylated compounds in the body. Indole-3-carbinol plays an important role, along with rosemary terpenes, in upregulating the expression of the enzymes involved in the 2-hydroxylation, the favorable, friendly estrogen, versus lowering the 16-hydroxylation patterns. Isoflavones from kudzu, the Oriental plant, also favorably influence 2, 4, and 16 hydroxylation patterns.

Predicting Breast Cancer

A recent abstract in the Annals of Surgical Oncology showed the ratio of 2-hydroxylated estrogen to 16-hydroxylated estrogen, in either urine or serum, was useful in identifying women who may be at risk for breast cancer. Comparing women with benign breast disease to those with normal breast tissue architecture and those who have cancer showed different ratios of 2- to 16-hydroxylated estrogens. This finding suggests this ratio could be a prognostic marker for women for whom diet or their lifestyle modification could reduce the risk or concern about breast cancer. Ratios above 2 in the urine (the 2-hydroxy estrogens to the 16-hydroxy estrogen ratio greater than the number 2 ) indicate women with low risk. Women with ratios below 2, with increasing reduction below 2, say down to 1.3, are those with node-positive, estrogen-positive breast cancers. As the 2-hydroxylated estrogen goes down in the urine and the 16-hydroxylated estrogen goes up, it indicates increasing imbalance of estrogen metabolism and more mitogenic concern.

A paper presented at the 37th American Society of Clinical Oncology meeting in May of 2001 dealt with the same theme. It showed the prognostic value of the 2- to 16-hydroxylated estrogens, both in serum and urine, was a prognostic marker for individuals. It indicates something about the way a woman metabolizes her own estrogen, the uniqueness of her body. If she goes on Premarin or estrogen replacement therapy, or if she is put on hormone replacement therapy, what is her body’s own metabolic outcome from those particular interventions? How does that translate into healthy aging? These new tools allow us to examine that gene environment or gene phenotype connection. We know that nutritional variables like indole-3-carinol, rosemary, and kudzu isoflavones will favorably modify this ratio. These are some clinical examples of the important role of basic science in shaping the new medicine around healthy aging.


INTERVIEW TRANSCRIPT

Jesse L. Hanley, MD

JB: Once again, welcome to the Clinician of the Month section of FMU. This month’s guest is Dr. Jesse Lynn Hanley, a medical doctor in the Malibu area of California. She has been focusing on integrative medicine in her private practice, combining traditional Chinese medicine with Western and nutritional medicine. She is a functional medicine practitioner in every sense of the term. Dr. Hanley received her medical agree from the Abraham Lincoln School of Medicine in Chicago, Illinois, and has been in practice almost 20 years.

Dr. Hanley, welcome to Functional Medicine Update. Could you describe some of the “Aha!” experiences you have had in your years of practice as an integrated functional medical doctor, in comparison to the more traditional routes of your colleagues?

JH: I am delighted to join you this morning. Thank you, Jeff. You have been one of my teachers. I’ve been listening to your updates for over 15 years, with all the wonderful guest clinicians. They’ve helped me to see and stay focused.

I was a very sick child, so my first teacher was my own illness. I realized shortly after I picked my head up and looked in the mirror and said that I was sick and tired of being sick and tired, that it’s actually easy to be healthy. I started studying everything I possibly could about health, which eventually led me to medical school and helped me to know, when I’m sitting there with patients, that it is actually possible to be healthy.

Choosing Health

People make choices every day. Whether they realize it or not, they may sometimes make 100 choices a day that can make a difference in their lives. Unfortunately, in our culture, we’re told over and over again that it’s hard to be well; it’s hard to change. I focused on healthy people to see how easy it is. In the past 20 years, I’ve sat and listened to people talk about their illnesses, patients who had seen from 5 to 25 other doctors and been told there was nothing to do, or that the only solution was drugs.

I would look and listen, take long and careful histories, and discover patterns in their lives that were setups for the problems they were bringing to me. It was the unraveling of the pattern that would give them back the power in their life. People want to be powerful in their health, and they love it when their doctor helps them be powerful and does not just admonish them and tell them what to do, but helps them to be a partner in the human process.

Creating a Healing Partnership

JB: You have a tremendous ability to link with patients to build a team and create a relationship for successful healing. Many practitioners have not developed that skill and maintain what is called a “clinical distance,” separating themselves from their patients. Is this an inherent skill, or have you had to work on it? Have you sometimes gotten too close to patients? In other words, what advice would you give other clinicians for building this relationship, which would help them create more motivation/compliance and behavior change in their patients?

JH: When I started practicing medicine, I realized I wanted to treat people the way I wanted to be treated and could never find in doctors I sought out. I realized I wanted to be listened to and considered as part of the relationship. I’ve learned over the years, and, the medical literature reflects this over and over again, that when patients feel listened to and cared about, they’re more likely to participate, and they’re more likely to tell more than a superficial story. Since I feel my job is to search for true causes, I need to hear what’s really going on inside of patients and their insights as well.

The only problem I can think of is other people’s perceptions that doctors should never have patients as their friends. I realized years ago that if none of my patients were my friends, I would never have any friends because once people knew me, they were pretty much my patients. For the doctors listening, I think it’s important to find a few patients or take a few hours each week and start trying a different way to be with people. I dedicated myself to making time for every new patient. I’ve spent a minimum of an hour with every new patient who comes to see me, so they know me and my intent, and I know them. They are comfortable telling me about the parts of their souls and their past that give me a clear picture. I am trying to find out how, in advance of hitting the iceberg, I can help them steer their Titanic with just a little bit of a change in direction. One of the simplest little things may make the most difference. It takes listening for a while to do that. People really appreciate it. I still get phone calls and letters from people from the past 20 years.

Tailoring the Message to the Patient

JB: That’s a beautiful message. I imagine some of your patients may not want to hear you talk from a perspective of science, while others want to get into the nuts and bolts, look under the hood, and talk about anatomy and physiology. How do you find that balance between integrating science and knowing when to use it and how not to use that language?

JH: It’s so simple. When I listen, a patient will give me all the clues. I find it works very well for me always to be educating people along the way. They give me feedback on what they do and do not want to know. It’s very clear to me that people seek out the kinds of doctors who do functional and integrative medicine because they know we want them to be well, but they want to be treated with respect and want to be a part of the therapeutic relationship. They don’t want another doctor who knows about natural healing just to give them a bunch of bottles and jars and new regimens and not understand. They want to be a functional part of the healing relationship. They often come in to me with the answers. Whether they found them on line or from introspection, they come in with the answers and need some help knowing that they’re making good choices.

Tired of Being Tired

JB: Let’s talk about your extraordinary new book, Tired of Being Tired. I want to compliment you on that. You are able to take very complex topics and demythologize them and communicate them in a way that is engaging and understandable to the average reader. Congratulations on a wonderful book. In the book you talk about rescue, repair, and rejuvenate for individuals with chronic tiredness and a sense of exhaustion. How do you implement this rescue/repair/rejuvenate program?

JH: After 20 years of listening to people, I began to realize that the old naturopathic construct of adrenal dysfunction/adrenal burnout really is at work. It is an epidemic in the United States. Most of the maladies that end in “-itis,” a lot of the immunosuppression and depression, osteoporosis and infertility issues, and the dramatic increase in diabetes and heart disease have to do with the extreme cultural and nutritional demands we are putting on our adrenals.

When I help people focus on that aspect, I tell them their adrenals are like batteries in their body and they’re managing the charge. When they’re not eating, when they’re living on stimulants—sugars and caffeine and other nutrition-deficient substances that give them a rush and leave them dependent on drugs—they’re spending their inheritance. I teach them the simple things you’ve talked about and taught all the physicians who have been listening to your updates for years. I have put it in ways that people can understand. I think we did a decent job in this book. People start to get well, whether it’s colitis, or recurrent infections. I’ve even seen people routinely turn around type 2 diabetes, which is 90 percent of the diabetes in this country.

Adrenal Burnout and Sex Hormone Dysfunction

JB: When you talk about your various therapeutic approaches in the book, they make sense, from both a phenomenological and mechanistic perspective. One example is the depletion effect on the adrenals, which are kind of a master stress thermostat, and how that can influence the function of other parts of the body. You discussed this in reference to the sex steroid hormones—estrogen, progesterone, and testosterone. What clinically have you seen in the relationship between adrenal burnout symptoms and the other sex hormone-related dysfunctions?

JH: The path to adrenal burnout has five stages: driven, dragging, losing it, hitting the wall, and the most dangerous stage, burned out. In the first four stages, the demand on the adrenals causes them usually to hypertrophy. Since cortisol, cortisone, and adrenaline are such survival hormones, the body preferentially increases the function of the layers of adrenals that produce cortisone at the cost to DHEA and the sex steroid hormones. So we see a decline in them.

I began to wonder if it actually may not be natural for DHEA to decline with age. It may be that stress and the demands on our adrenals in our culture have caused that. We see vibrant people in their later years who still have good levels of DHEA without supplementing. A lot of the illnesses we see in this country have to do with excess cortisol in the first four stages, which causes immunosuppression and increases the risk for diabetes and insulin dysregulation, depression, and binge eating. It’s very much like when people take prednisone. The effects are the chronic elevation of cortisol and cortisone. By bringing that back into balance, doing the simple things we’ve all learned about, adrenals begin to repair. Human bodies are amazing in their ability to repair and recharge if we give them the chance. That’s what I teach people in my practice, and in my book. The good news is I’ve seen it over and over again, even in people in their 70s.

Inappropriate Hormone Supplementation

JB: That suggests that practitioners who don’t understand this adrenal component, at least at the clinical level, may jump in at an inappropriate level and begin to add back hormones without first addressing the underlying cause.

JH: I agree. Some people need supplementation temporarily or permanently. You can’t know that for sure, but I think it’s important to start with the basics. I always talk to my patients about the basic foundation, healing the foundation. It can start with nutrition. Nutrition is something we’re making decisions about all day. If people want energy, they have to put fuel in their tank. I teach them to eat real food, and I find it painfully humorous when they ask me what real food is.

We’ve gone to great lengths in the book to help people see what chemicals are in foods and what refining has done to diminish the value of food and increase the potential for the epidemic of burnout. It is a stress to our bodies, which means it’s a demand and an expense to our adrenals to be constantly trying to manage our energy and our blood sugar with non-food. The first thing I do is to teach people to eat real meals, to bring balance back into their meals. I talk about snacks. When people go back to eating balanced meals, which means complex carbohydrates and protein and a little fat in every meal, and eating every couple of hours, they have more energy and crave fewer stimulants, even caffeine. They also start to lose weight if they’re overweight, because their metabolic fire begins to burn more heartily. I teach people about deep breathing because we all know that we hold our breath when we’re stressed and that oxygen helps any fire burn more cleanly, as well as calms the system and makes it a less stressed system.

Clinical Assessment of Burnout

JB: In the assessment of adrenal burnout, how much do you rely on clinical presentation, and how much does laboratory work, like salivary hormones, or other lab variables, play a role in your assessment of the severity, frequency, and duration of these problems?

JH: In the first years, the clinical laboratory was more important. Over the years, however, it has become easy to diagnose and obvious. I often let a patient’s pocketbook determine how much testing I do, and his or her ability to recognize the situation. Unfortunately, I often hear about physicians who are new on the path who order every test in the book instead of being more discriminating, using their wisdom.

I was taught in medical school (I think these are the words of William Osler), “You can learn just about everything you need to know about a patient in the history.” Most people come to me with a lot of laboratory work. I really enjoy the 24-hour saliva test. They are far superior, I’ve found over the years, to the 8 am or 4 pm serum cortisol test. It’s a much better picture of the rhythm that goes on throughout a person’s day. Sometimes it’s not that the elevation of cortisol or cortisone is so severe, it’s the dysregulation. And it’s the chronic elevation that adds up to cause the problem. Sometimes it’s immune suppression and sometimes it’s the rest of the hormonal imbalances that are created.

Measuring Blood Pressure

JB: When Dr. John Tintera talked about adrenal exhaustion some 50 years ago, playing off the Hans Selye model of general adaptation syndrome, he discussed the role of differential standing and sitting blood pressure measurements in assessing some of the adrenal insufficiencies. Do you find clinically that it has any value?

JH: Absolutely. Sometimes people come in and tell me they get dizzy when they stand up. That’s another soft sign; people can even come in with some of their own self-diagnoses. I think it’s one good piece of information that our adrenals are dragging and can’t keep up with the demand. Again, part of what I try to explain to people is that we are born with an inheritance; the medical texts call it our organ reserve. When we are running on empty and living on caffeine, other stimulants and nutritionally depleted food, we’re spending our inheritance. What the world calls it now is premature aging.

Hormone Replacement

JB: You talked earlier about patients who may have pushed their reserves a little too far. To get them back on track, you have to fill in the potholes, so to speak, and do at least some temporary hormone replacement. How do you see the use in practice of DHEA, progesterone, estrogen, or testosterone. What role do they play for you in some of these cases?

JH: It depends on the person and the situation. In a perimenopausal woman with luteal phase defects, whose progesterone levels are deficient, I often supplement with natural progesterone, and I do prefer the transdermals. Often the low-dose transdermals of 2 to 3 percent are plenty to use from midcycle to menses. But knowing that progesterone is sometimes depleted because the demand for its downstream substrate cortisone is so great, I’ll also work on helping that person learn how to calm. Sometimes, as I said earlier, something as simple as deep breathing will improve her nourishment and take some of the stress off. Using vitamin B5. Vitamin B5 is also helpful in getting the adrenals to function better.

Pantothenic Acid

JB: Many people don’t know much about vitamin B5, pantothenic acid. Roger Williams, the father of the concept of biochemical individuality, discovered this vitamin. Would you share your experience with pantothenic acid supplementation and the doses required for repletion.?

JH: Vitamin 5, pantothenic acid, is an incredibly safe vitamin. I’ve used doses up to 3,000 to 4,000 mg/day in people with arthritis and allergies, and in children. I usually recommend that people start out by adding 500 mg/day up to 500/per meal. It improves energy by assisting the Krebs cycle and going into the acetyl CoA part, as well as the adrenal hormones, and it works with other vitamins like vitamin C for the adrenals.

As you’ve been so eloquent in saying over the years, we can bring out the best of our genes, or the worst of our genes, and our nutrition influences that. Vitamin B5 influences the way the adrenal genetics are manifested. It helps the adrenals repair and regenerate. The beauty is that they do and they can. I’ve seen it repeatedly, and I’ve seen people as young as age 30, to whom I’ve had to give DHEA for chronic fatigue, who within a year of following programs such as like those we have in the book, no longer need the DHEA because their body repairs.

DHEA

JB: DHEA is an interesting androgen and estrogen precursor hormone, going into etiocholanolone testosterone, later to be aromatized to estrogen. What dose do you normally start with, and how do you know whether the patient may be a DHEA candidate?

JH: Whenever I’m giving hormone replacement, clear hormones, I’ll always do saliva or serum testing. And I always follow it with saliva or serum testing. If people are using sprays or sublinguals, we can’t use saliva, of course, and then we have to use serum. The timing of the testing is important. It needs to be consistent. If people are doing serum testing, it’s usually 2-3 hours after a dose, and if we’re doing saliva testing, it’s best, I believe 4-6, hours after dosing.

I find that rather than do the shotgun approach which I think too many doctors have started to do, which is to give them everything at once, it is best to give one hormone at a time, along with a nutritional program, and watch how they repair. Perhaps in 4-6 weeks, if necessary, I add whatever else seems like the next most critical. But often, if people are doing the basics and get the most pivotal hormone they need, which is usually, in women, progesterone, or DHEA, and in men usually testosterone or DHEA, the rest will repair. I use naturopathic adrenal extracts. I’ve used glandulars. I’ve used vitamins and I’ve used herbs to help adrenals to repair, as well as getting people to eat and reduce the stresses so that their adrenals aren’t on such constant demand.

Getting Started in Patient-Centered Functional Medicine Practice

JB: Newcomers to this field may be wondering where to start. We’ve talked about food, supplements, exercise, relaxation therapy, life management, and behavioral components. How does one begin down this road if he or she hasn’t engaged in this conversation with patients in the past? Can you help them get started?

JH: I think that by listening to people we often hear where and what their greatest need is. It is pretty easy to assume in the U.S. that it’s nutrition, and learning what good nutrition is. I talk about it extensively in the book. Getting people started on a very basic program of eating real food, balanced meals, getting a good multiple vitamin started for them, will probably help 60 percent of people within two weeks. That’s a great place where I think all physicians can begin. Often, once you do that, and the patient returns and gives you some feedback about what is or isn’t working, it helps to clear the picture to see where to go next.

Often, the lab tests are beginning to come in and you can see what the adrenal function is, what the other hormone levels are, and how the patient’s body is handling the majority of the supplements and nutrients that we’ve given. But I’m clearly in favor of multiple vitamins because they’re very much like food in that they give our bodies a chance to pick and choose what it needs. When food had the nutrients over 50 years ago, our body would pick and choose from the foods we ate instead of being so concerned about can we have vitamin E with vitamin C. Our body knows, I believe, how to do that best.

Back to Simplicity in Medicine

JB: As you look forward, having now had a couple of decades of real-world clinical experience with complex chronically ill patients, where do you see this field going? What tools or techniques will become part of this 21st century medicine?

JH: I have a feeling that in a way, it’s going backward to simplicity. A lot of the things in my book are basic information like mom and grandma used to teach us, and by going back to the basics, we’re going to have good strong healthy bodies. Implementing nutrition and understanding that nutrition changes everything about our health is important, unlike we were taught in medical school. It makes a huge difference. It is the single most important thing I think any doctor can learn.

Implement simple things, like teaching people to take deep breaths. I gave almost everybody in my practice breathing lessons. Sometimes I give them a little sticky to put on their dashboard or their telephone or computer so they would remember to take deep breaths during the day, which helps people stop and pay attention so they can participate in the healthcare relationship. Those simple things are turning out to be extremely powerful and empowering to the patient, instead of always looking for drug deficiencies.

A Scientific and Patient-Centered Approach

JB: Dr. Hanley, as a clinician who has found an effective way to relate to patients in creating positive behavior change, you have provided our listeners with some valuable insights. Your book, Tired of Being Tired, does a good job of codifying this and providing understandable patient approaches. It also ties well into a non-scientific focus to create a context where real healing can occur. I can put a lot of polysyllabic scientific words behind what good sense has proven over generations to work. That is what you’ve done so beautifully, combining the two. Again, my compliments and thanks for making what is really very complex seem so simple.

JH: Thank you, Jeff. I know that as the physicians who are listening start to implement the simple things, they’re actually going to watch their patients get healthy, and then the joy of being a doctor returns.

Affirmation for the Future

JB: That’s a wonderful affirmation for going forward. I thank you. We’ll be back in touch to find out how all of our travels evolve.

JH: Thank you very much.


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