Tuesday, January 8, 2008

Chapter 7, Part 1

Chapter 7: Biochemical Individuality and Genetic Uniqueness
This chapter is made up of two articles (this paper summarizes the first):

Functional Medicine and Biochemical Individuality: A Paradigm Shift in Medicine
Development of the Knowledge Base in Biochemical Individuality


Functional Medicine and Biochemical Individuality: A Paradigm Shift in Medicine

Changing scientific paradigms typically meet resistance from “normal science,” e.g. Edward Jenner and vaccination, Ignaz Semmelweis and O.W. Holmes for handwashing (!), Alexander Fleming for penicillin/antibiotics, Kilmer McCully for the role of homocysteine and inflammation in atheroscerosis. Yesterday's well accepted theories are often subsequently discarded.

Chronic disease affects 125 million Americans, but our current medical approach fails to systematically and effectively diagnose and treat its underlying causes, found in the complex interaction of genes, lifestyle and environment. Moreover, treatment according to the current paradigm of disease management may be causing harm to the tune of an estimated $200 billion. The predominance of randomized controlled trials, the lack of publication of negative medical trials, pharmaceutical marketing to physicians and patients, conflicts of interest in medical research, and the control and funding of post-graduate medical education by pharmaceutical companies all create a bias in favor of the primacy of pharmaceutical treatments to the detriment of nutrition and lifestyle interventions.

The old paradigm follows a single-invader, single-disease, single-drug model. The new paradigm focuses on optimizing function and enhancing health by understanding the complex functioning of the human being, assessing and treating the cause of dysfunction rather than suppressing symptoms. Diagnostic groups, identifying “what the patient has” are useful but only a first step, leading to two questions:

Does this person have an unmet individual need?
Does this person need to be rid of something toxic, allergic, or infectious?


In our modern, hygienic, industrialized society chronic disease has long since replaced acute illness as the dominant problem, and the developing medicine begins to address the following errors:


That diseases are entities and can cause symptoms.
That each patient's diagnostic and treatment options can be based on the determination of averages.
In the framework of chronic illness the one-disease/one-treatment multiplies
causes beyond necessity (a la Occam's razor.
Medicine is the only field claiming scientific basis in which general systems theory, that everything is interconnected, has not become the acknowledged basis for medical etiology.


We need a unifying theory of health and disease, comprehending the underlying mechanisms of disease and aging, illuminated by the light of genomics, proteomics, metabolomics, and nutrigenomics.


Example of the new paradigm: Nutrients beyond deficiency diseases.

One disease may have multiple causes, and one initiating factor may cause multiple diseases. Two examples: cardiovascular disease (CVD) and celiac disease. CVD is characterized by atherosclerotic plaque, but may be caused by insulin resistance, folate deficiency, hyperhomocysteinemia, occult infection, heavy metal toxicity, inherited dyslipidemia, stress, or other factors that increase inflammation. Diagnosis and treatment of these conditions vary and requires identifying the correct etiology.

Case 1: 56 yo male with CVD, status post angioplasty x2, CABG, receiving “standard of care” treatment, went on to suffer a stroke. Functional analysis showed elevated homocysteine. Genetic test showed a single nucleotide polymorphism (SNP) in a gene for a folate reduction enzyme. As a result of this enzyme dysfunction extraordinary amounts of folate intake was required to facilitate coenzyme activity. After appropriate nutritional intervention, the patient's homocysteine level retuned to normal and he experienced no further progression of atherosclerosis.

Case 2: 57 yo male who described himself as in general good health (planning a mountain climbing expedition), was nevertheless on 15 different prescription meds for colitis, asthma, alopecia areata, and hypertension. These were all correctly prescribed for symptoms by different specialists that he saw. Yet no one investigated the underlying pathway, noting the common inflammatory component in his symptoms. He was found to have celiac disease, undiagnosed for 40 years. By eliminating gluten from his diet he was able to discontinue most of his medications within 6 months, lose 25 pounds, stabilize his BP, be free of asthma symptoms, normalize bowel function, and regrow his hair. According to the New England Journal of Medicine, immune mediated gluten sensitivity can cause: anemia, osteoporosis, autoimmune diease, thyroid deficiency, schizophrenia, and psoriasis.

The Diverse Role of Nutrients

Vitamins continue to be defined in terms of single deficiency diseases, e.g. pellagra (niacin), beri beri (thiamine), scurvy (vit C), rickets (vit D). Accordingly the dietary reference intake (DRI) is calculated as the minimal amount to prevent single deficiency disease. However greatly increased amounts of these may be required by individuals in the polymorphic population for optimal health. For example, vitamin D deficiency is not only associated with rickets, but with heart disease, MS, polycystic ovary, depression, epilepsy, type 1 diabetes, and cancer. Folate deficiency is implicated in neural tube defects, CVD, dementia, depression, colon and breast cancer. Magnesium plays a role in over 300 enzyme reactions.

However, there remains a bias against the use of vitamins in treating diseases. One reason why is that the desired outcome is the absence of problems not of a defined dysfunction. Pharmaceuticals are designed to alter pathology, whereas nutrients help to restore normal function by optimizing biological functions, most through coenzyme activity in biochemical reactions.

There are 30K genes in the human genome with 3M variations. The most common is the SNP, which occurs in about 1:1000 base pairs (!). The frequency of a specific polymorphism is stable in the population. The SNP leads to unique biochemical needs, and ⅓ of these affect coenzyme binding sites for vitamins and other nutrients and consequently play a role in disease/dysfunction.

Constant clinical question: “What does this individual need which he/she has failed to get?

In many cases a single nutrient catalyzes hundreds of biochemical reactions. Suboptimal conditions lead to cellular or molecular dysfunction, which may not rise to the level of a distinctive disease. Optimum functioning my require doses of a specific nutrient hundreds of times the DRI. The result is long latency deficiency disease that are epidemic in our population: CVD, cancer, osteoporosis, neurodegenerative disease, immune dysfunction. Yet in the prevailing paradigm nutrition is seen as a secondary focus: “something best left to dietitians.” (!!!)

Long-latency disease

Recommended nutrient intake has been based on prevention of index deficiency diseases, but the assumption that they are also adequate for optimal functioning of the whole organism overlooks two important facts:

There are long-term consequences of lesser degrees of deficiency that may
operate through similar mechanisms as the index disease.
There may be very
different mechanisms involved in the development of long-latency deficiency
diseases.



Research in nutrition faces a controversy in the belief that double-blind randomized controlled trials (RCTs) are the gold standard methodology in all scientific studies. It has been suggested that observational research is better suited to infer causality in nutrition studies. It is a reasonable assumption that higher nutrient levels are needed than the minimum required to prevent deficiency diseases, and the burden of proof is actually on those who assert that the minimum levels are adequate generally. The pre-agricultural diet may be a better guide, and this would have featured: high protein intake, low glycemic index, high calcium intake, high folic acid intake, and alkaline ash residue and high vitamin D input.

For example, vitamin D is associated with prevention of rickets and osteoporosis, but increasing vitamin D to the upper levels of the reference range reduces osteoporotic fracture risk by ⅓. Also serum 25(OH) vitamin D concentrations are inversely associated with prostate and squamous cell cancers. This may be due to the fact that people with low sun exposure or increased skin pigmentation may be less able to make calcitrol (biologically active 1,25-dihydroxyvitamin D in an amount adequate to control cell proliferation and reduce oncogenesis. Much higher levels than current reference values may be necessary for cancer prevention.

Nutrigenomics: An Organizing Principle of the New Paradigm

Nutrients hold great potential because they function within the genetic and evolutionary necessities of the cell, and their role in prevention of long-latency diseases may be less dramatic than their role in preventing index deficiency diseases, but it is more frequently relevant to daily clinical practice. Patients often worry about the dangers of medications, making seeing a doctor a calculated risk that the danger of the disease will outweigh the danger of the medication. The promise of nutrigenomics is in the primary role of nutrients in maintaining the function of the integrated complexity of the body. The shift is away from disease treatment to disease prevention. Nutrigenomics is an advance on the scale of quantum mechanics and the theory of relativity and has the potential to radically change our approach to health and disease.

Principles:

Nutrients act on the genome directly or indirectly to alter gene expression or
structure.
Under certain circumstances and in certain individuals diet can be a serious disease risk factor.
Some diet-regulated genes are likely to play a role in the onset, incidence, progression, or severity of chronic diseases.
The degree to which diet influences the balance between healthy and disease states may depend on individual genetic makeup.
Dietary intervention based on knowledge of nutritional requirement, nutritional status, and genotype can be used to prevent, mitigate or cure chronic disease.

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