A Functional Biochemical Mechanism Against Disease Biology Essay

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Human development and physiology depends on a myriad of biochemical-physiological processes, many of which are co-dependent and interrelated. The rate and extent of many reactions are dependent on the enzymatic activity which, at the same time, depends on the bioavailability of micronutrient co-factors such as vitamins and minerals. In order to achieve a healthy physiological state, the organism needs that biochemical reactions occur at a certain rate. To achieve this state it is required that metabolic reactions reach full velocity and completion, which can be considered an optimal metabolic equilibrium. A combination of genetic makeup, erroneous dietary patterns, trauma, diseases, toxins and environmental stressors will often elevate the demand of nutrients in order to reach this optimal metabolic equilibrium. Metabolic Correction is a functional biochemical/physiological concept that explains how improvements in cellular biochemistry can help the body achieve metabolic or physiological optimization. Brilliant minds (such as Roger J. Williams, Linus C. Pauling, Jeffrey Bland and Bruce N. Ames) have contributed in a fundamental way to our understanding of the importance of micronutrients to attain the healthy state. The concept of Metabolic Correction is becoming increasingly important due to the presence of genetic variants that affect the rate of enzymatic reactions causing metabolic disturbances that favor or promote the diseases states. The decreasing nutritional value of our food, the increased demand for certain nutrients caused by growth, development, diseases and medications induce nutrient depletion. These nutrient insufficiencies are causing enormous cost due to an increase in morbidity and mortality. In summary, Metabolic Correction improves enzymatic function that enhances biological functions, thus contributing to health improvement and wellbeing. The purpose of this manuscript is to describe and introduce the concept of Metabolic Correction as a functional mechanism against disease contributing to disease prevention, physiological regeneration and health.

Nutrition, Metabolism and Physiologic Function

Basic micronutrients are required to operate metabolism effectively. They are needed for energy, fat, protein and carbohydrate metabolism. These metabolic activities also require over forty micronutrients (1). In addition, two essential fatty acids (omega-3 and omega-6) and approximately eight essential amino acids are also needed for this process (2). Likewise, other important nutrients such as: Coenzyme Q10, Acetyl L Carnitine and lipoic acid, must be considered in our quest for physiological optimization (3). Virtually, every metabolic pathway requires these micronutrients for their completion.

The optimal concentration of every nutrient will facilitate physiological functionality. Many individuals do not function at 100 % efficiency; nevertheless they do not present any detectable disease or considerable symptoms but if supplied with the needed substances in optimum concentrations, physiology will improve providing for disease prevention and improved physiology. Optimal concentration of nutrients needed may be variable among individuals. Certain individuals have a greater need for certain nutrients. Individual needs may vary extensively according to particular physiological requirements (4, 5). This variation could be caused by: digestive problems, malabsorption, food sensitivities, difficulty in the metabolism of certain amino acids, fatty acids, complex carbohydrates, low levels of neurotransmitters precursors and other causes [1].

The best possible state of health is achieved by reaching a metabolic equilibrium. The array of critical functions of vitamins, minerals and other nutrients at the cellular level, and especially their role as cofactors in enzyme reactions is mostly unrecognized or unappreciated by most health professionals. The whole significance of micronutrients in human metabolism has not been completely elucidated, simply due to the high complexity of cellular processes. Nevertheless, we know that critical enzymes require metals as copper, zinc, manganese, selenium, and vitamins as the B-complex; as an integral part of their functional molecular structure or as part of their mechanism of action (6). Enzymes play a critical role in regulating and orchestrating the velocity of the plethora of vital biochemical reactions that take place in living organisms.

Metabolic nutrition is generally recognized as the study of how diet and nutrition affects the body's physiology. Nutrition, in general, is a very complex science but its importance is relatively easy to understand. Aside from starvation, there are three levels of nutrition: poor, fair and good. Poor nutrition is manifested as severe underdevelopment of the young as well as deficiency diseases such as beri-beri, scurvy, pellagra, rickets, kwashiorkor and all illness defined combinations and variations of these afflictions (1). Fair nutrition is good enough to prevent the well defined deficiencies but not good enough to promote good health and proper development. This second-rate nutrition is, unfortunately, the kind which we have been taught to regard as satisfactory (7). Good nutrition is the one that provides the needed energy in addition to high quality protein, carbohydrates, fats and the necessary vitamins and minerals. The concept of a balanced diet was developed to prevent deficiency diseases, based on the knowledge that an appropriate mixture of food items will provide the minimum requirements of the nutrients needed by the body. This supposedly good nutrition may not be enough to reach the physiological optimization needed to achieve excellent health. Food by itself may not provide sufficient micronutrients for preventing deficiency (8).

Inadequate dietary intakes of vitamins and minerals are widespread, most likely due to excessive consumption of calorie-rich, nutrient poor, refined food (1). Caloric excess often accompanies sub-optimal intake of micronutrients. This is the Hidden Hunger Concept (9). Hidden hunger is defined as high caloric consumption but with a low micronutrient density that results in subclinical deficiency or nutrient insufficiency. These inadequate intakes may produce metabolic disruptions (10). Episodic shortages of micronutrients were common during evolution. Natural selection favors short term (emergency) survival at the expense of long term health (10). Short term survival was achieved by allocating scarce micronutrients by triage (10). As micronutrients become scarce, a triage mechanism for allocating scarce micronutrients is activated. This triage means, prioritization of the use of relatively scarce nutrients to the most fundamental life preserving functions. In metabolic reactions, enzymes involved in ATP synthesis would be favored over DNA repair enzymes; as well as over production of immune system components and neurological chemicals. When there is a lack of synergistic components of the metabolic network, an array of negative metabolic repercussions arise, such as accumulation of metabolic by-products (such as homocysteine); leading eventually to loss of the healthy physiological equilibrium and accelerating the disease state (1, 5).

Concept of Metabolic Correction

The Metabolic Correction Concept provides the biochemical explanation of the utilization of nutrients as enzymatic cofactors, precursor molecules, regulator molecules and metabolites for preventive and therapeutic purposes against disease (11). Metabolic Correction is a functional biochemical/physiological concept that clarify how improvements in cellular biochemistry help the body achieve metabolic or physiological optimization. Figure 1 illustrates this concept.

Figure 1 illustrates the concept of Metabolic Correction.

Food provides macro and micro-nutrients that are required for the production of energy, precursors of functional and structural molecules necessary for healthy metabolism, tissue repair and detoxification. However, the presence of genetic variants, diseases, contaminants and medications can increase the demand for certain nutrients. If the demand goes beyond tissue storage, then a co-factor insufficiency arises. Co-factor insufficiencies will create a decrease in specific enzymatic activity. Decreases in enzymatic activity could then impact energy production, tissue repair, biosynthesis of bioactive molecules and detoxification, all of which will alter homeostasis of the healthy physiological state.

High prevalence of a genetic polymorphism of the enzyme that converts folic acid to the physiologically active 5-methylolate, results in elevated levels of homocysteine. In this situation, elevated homocysteine levels are reduced (metabolic by-product that is a risk factor for inflammation, cardiovascular disease, stroke, blood clot formation, dementia and Alzheimer's disease among others) by 5-methylfolate, pyridoxal-5-phosphate, methylcobalamin and betaine (12,13). Hispanics have shown a relatively high prevalence of this functional polymorphism (i.e., MTHFR C677-T, a.k.a. rs1801133) on the gene encoding the enzyme methylene-tetrahydrofolate reductase (MTHFR) (14-16). MTHFR catalyzes the conversion of 5, 10-methylenetetrahydrofalate to 5-methyltetrahydrofolate (physiologically active form), a co-substrate for homocysteine (Hcy) remethylation to methionine (17). Pyridoxal-5-phosphate, methylcobalamin and betaine also play a role in this important biochemical reaction (4). This polymorphism, presents changes (errors) in DNA nucleotides a C→T missense mutation (cytosine to thymidine) at position 677 of the MTHFR cDNA, leading to a valine substitution at amino acid 222, encoding a thermolabile enzyme with reduced activity that results in elevated levels of the metabolic by-product Hcy (i.e., hyperhomocysteinemia) (18, 19).

Hcy is considered is a potentially toxic amino acid and a cardiovascular (CV) risk factor as well as several other degenerative diseases. It is postulated that the methylation of Hcy to Methionine could result in reduction of adverse CV events, strokes, blood clot formation, peripheral neuropathy, dementia and Alzheimer's disease.

History of the Metabolic Correction

Visionary and extraordinarily knowledgeable scientists became the pioneers (Medical Mavericks) that provided the groundbreaking basis of what we call Metabolic Correction (20). Their innovative scientific contributions have substantially advanced our understanding of Molecular Nutritional Biochemistry and especially how it can influence (revert) the pathological or disease state.

In 1947, Dr. Roger J Williams contributed to the evolution of the understanding of the molecular origin of disease with the development of the concept of Biochemical Individuality (21). He described anatomical and physiological variations among people and how they related to their individual responses to the environment and their particular physiology. He coined and gained recognition for the term biochemical individuality and how it relates to differing nutritional needs for optimal function among different people.

Molecular medicine was a term used in 1949 by two-time Nobel laureate in chemistry and peace, Dr. Linus C. Pauling, in his landmark article on the mechanism of the cause of sickle cell anemia (22). Dr. Pauling defined a new perspective on the origin of disease based upon the recognition that specific mutations of the genes can create an altered molecular environment and therefore the modified physiological function associated with specific diseases.

In 1950, Dr. Roger J. Williams coined the term Genetotrophic Disease to describe diseases which resulted from genetically determined nutritional metabolic needs not being met by the individual and which result in poor gene expression (23). Patients with genetotrophic conditions have increased needs of one or more nutrients in order to achieve normal physiologic functioning. These genetotropic conditions, which seem to be clinically associated with some functional genetic polymorphisms on genes encoding key components of the altered metabolic pathways, respond dramatically when enough of the required nutrients are provided. Genetotrophic disease is related with less common conditions that improve dramatically with the addition of certain nutrients or combinations. Examples of this can include muscular dystrophy, allergies, mental diseases, cardiovascular diseases, arthritis, multiple sclerosis and cancer (24). Many chronic diseases can be conceived as subtle polymorphism-associated Genetotrophic diseases, as long as nutrient(s) supplementation fills a specific metabolic need that improves the patient's condition. With this new concept, Dr. Williams opened the eyes of the research and medical communities that expression of genes (probably through epigenetic mechanisms) and, therefore, phenotypic functions are modifiable through altered diet and nutritional status. He pointed out that human biochemical variation in function was of much greater relevance than nutrition and medicine recognized prior to his publications (24).

Between the 1950's and 1960's, Dr. Henry Turkel was the first to clinically demonstrate that nutrition and supplementation can modify genetic programming with his scientific work with Down's syndrome (25). Dr. Turkel was probably also the first clinician to use Metabolic Correction as therapy when he got rid of harmful gene expressions in mentally retarded children by removing accumulated metabolic by-products with nutrition and high dose supplements improving cognition, physical health and physical appearance of these children (25).

In 1973, Dr. Bernard Rimland, used an enhanced B complex formula with extra B5 and B6, plus Vitamin C and iron to help emotionally disturbed children. Out of 190 severely disturbed children, 164 showed some improvement over 90 days (26).

In 1980, Dr. Ruth Flinn Harrell and her colleagues gave a comprehensive vitamin and mineral supplement to a group mentally retarded children. Over a period of only four months, the supplemented children increased their IQ's by 5.0 to 9.6 points. The un-supplemented children showed no significant change. These gains are highly significant, especially as they were achieved with a mixture of different retardation syndromes, including Down's syndrome (27).

The word Orthomolecular was introduced by Dr. Linus C. Pauling in Orthomolecular Psychiatry in his seminal article published in the journal Science in 1968 (28). Dr. Pauling defined Orthomolecular Psychiatry as the treatment of mental disease by the provision of the optimum molecular environment for the mind, especially the optimum concentrations of substances normally present in the body. He later broadened this definition to other diseases to name it Orthomolecular Medicine, which he defined as the preservation of good health and the treatment of disease by varying the concentrations of substances normally present in the human body required for health (11). The adjective orthomolecular describes the idea of the right molecule in the right concentration. The key in orthomolecular medicine is that genetic factors influence not only the physical characteristics of individuals, but also their biochemical milieu. Biochemical pathways of the body have significant genetic variability and diseases such as atherosclerosis, cancer, schizophrenia or depression are associated with specific biochemical abnormalities (high homocysteine, reduced oxidative phosphorylation, increased kryptopyrrole, decreased serotonin) which are causal or contributing factors of the illness. Several arguments support the thesis that "optimum" molecular concentrations of substances may not be achieved solely by dietary means. The need for essential nutrilites (vitamins, essential amino acids, and essential fatty acids) may differ for each individual from the (average) daily amounts recommended for the general population (1, 10).

Dr. Jeffrey S. Bland created the concept of Functional Medicine in 1991, which is a form of personalized medicine that deals with primary prevention and underlying causes of disease, instead of just the symptoms. Functional medicine is anchored by an examination of core clinical imbalances that underlie various disease conditions. Those imbalances arise as environmental inputs such as diet, nutrients (including air and water), toxins, exercise and trauma, together with a unique set of genetic predispositions, attitudes, psychological stress and beliefs. The core clinical imbalances that arise from malfunctions include: hormonal and neurotransmitter; oxidation-reduction and mitochondropathy; detoxification and biotransformation; immune; inflammatory; digestive absorptive; and microbiological and structural imbalances from cellular membrane function to the musculoskeletal system. Improving balance is the precursor to restoring health and it involves much more than treating the symptoms (11). Functional medicine is dedicated to improving the management of chronic disease by integrating the interventions at multiple levels to address these core clinical imbalances and to restore each patient's functionality and health. Functional medicine is not a unique and separate body of knowledge. It is grounded in scientific principles and information widely available as evidence based medicine today, combining research from various disciplines into highly detailed yet clinically relevant models of disease pathogenesis and effective clinical management. Dr. Bland published a landmark book in 1999 entitled "Genetic Nutritioneering", in which, he explains how proper nutrition and supplementation can modify genetic expression to create the best possible health outcomes (29).

Later, in 2006, Dr. Bruce N. Ames presented his Triage Theory of optimal nutrition (3) that states that the human body prioritizes the use of vitamins and minerals when it is getting an insufficient amount of them to be able to keep functioning. Triage means deciding which patients to treat when faced with limited resources. When faced with limited nutritional resources, the human body must decide which biological functions to prioritize in order to give the total organism and the species the best chance to survive and reproduce. Under such limited scenario, the body will always direct nutrients toward short-term health and survival capability, totally away from regulation and repair of cellular DNA and proteins that optimizes health and increases longevity. Dr. Ames's research demonstrated how bodily insults accumulated over time as a result of vitamin and mineral insufficiencies, which can lead directly to age-related diseases. The triage hypothesis states that the risk of degenerative diseases (associated with aging, including cancer, cognitive decline, and immune dysfunction), can be decreased by ensuring adequate intake of micronutrients (10, 30-33). While short-term deficiencies or insufficiencies are common, they are often not taken seriously by mainstream physicians.

Metabolic Correction is a functional term introduced by Dr. Michael J. Gonzalez and Dr. Jorge R. Miranda-Massari in 2011 (34) to describe the mechanism of how nutrients are capable of correcting biochemical disruptions that promote a variety of disease states. Metabolic Correction embraces all previously described biochemical/physiological concepts to explain how improvements in cellular biochemistry may help the body achieve metabolic or physiological optimization. Metabolic Correction intervenes with impaired biochemical reactions that are associated with the disease state that result in lack of well being. In other words, Metabolic Correction is a fine tuning of the cellular physiology to improve function; therefore preserving health, preventing and reverting physiological disruptions.

Reasons to use Metabolic Correction

Unmet nutritional needs. Unmet nutritional needs could arise from poor nutritional habits, but can also occur due to Inferior nutritional value of food and lack of availability of nutrient dense foods [10]. We need to eat a wide variety of foods in order to obtain the required nutrients to attain the healthy state. Today's foods are not as nutritious as those eaten in the past, which posses a big problem. The nutritional value of foods that people eat seems to be greatly inferior to the listed values given in food tables. A study looking into this issue showed declines in protein by 6%, calcium by 16%, phosphorus by 9%, iron by 15%, riboflavin by 38%, and vitamin C by 20% (35 [i] ). There is a dilution effect, in which yield-enhancing methods like fertilization and irrigation may decrease nutrient concentrations, an environmental dilution effect. Recently, evidence has emerged that genetically based increases in yield may have the same result, a genetic dilution effect. Modern crops that grow larger and faster are not necessarily able to acquire nutrients at the same, faster rate, whether by synthesis or by natural soil. A report pointed out that US and UK Government statistics show a decline in trace minerals of up to 76% in fruit and vegetables over the period 1940 to 1991 (36). Moreover consumption of organic foods decreases the unhealthy intake of pesticides, herbicides, chemical fertilizers, antibiotics and hormones. In fact, organic fruits and vegetables remain the most nutrient-dense, toxic free foods. This information demonstrates the need for a further increase in the consumption of fruits and vegetables in order to get the same nutritional benefits as in the past. Also Americans, on average, do not even come close to the recommendations to limit added sugars, refined carbohydrates, added fats and oils [10].

Adverse side effects of medication and iatrogenic deaths. More than 100,000 deaths are reported annually due to medication properly prescribed and taken as directed (37, 38). The incidence of serious and fatal adverse side effects in US hospitals is extremely high, these are frequent and more so than generally recognized. Fatal adverse side effects appear to be the fourth leading cause of death in the USA (38). The cost of medication related mortality and morbidity in the USA is exceedingly high and continues to increase. One of these adverse effects is unrecognized and untreated medication induced nutrient depletion. Drug-induced nutrient depletion is usually a slower process that can lead over time to a diversity of health problems that also increase health costs (39). If drug therapy is required, providing Metabolic Correction can compensate for nutrient depletion, and improve metabolic disturbances that may lead to reduction in medication dose, thus reducing adverse side effects and improving therapeutic outcome (34).

Compensate for the increased demand of nutrients due to the disease state and toxins. Toxins like drugs, alcohol, tobacco, environmental contaminants and metabolic by-products can accumulate over time and can be an important contributor to chronic disease. The human body detoxifies these harmful substances through biochemical reactions that require a number of nutrients (vitamins, minerals, amino acids and other co-factors) in sufficient amounts to work effectively. Exposure to alcohol, tobacco and environmental toxins can create an increased metabolic demand for nutrients to allow detoxification (40). Therefore, lacking sufficient amount of any of these nutrients should be avoided in order to prevent toxicity and chronic disease (41, 42).

Burns lead to loss of protein and essential nutrients (43). Surgery increases the need for zinc, vitamin C and other nutrients involved in cellular-tissue repair (44). Broken bones need calcium, magnesium and vitamin C and D for healing (45). Infections challenge the immune system and places high demand on nutritional resources such as zinc, B-complex vitamins and vitamin C (46). Chronic Fatigue and Fibromyalgia syndromes represent a process with a common end point, mitochondrial dysfunction. Nutritional support has been implicated as an important treatment modality in restoring adequate energy production that allows muscle relaxation and pain relief. A similar nutritional demand is present when exposed to chemical, physical and emotional stress. Stress can generate many symptoms and diseases, mediated by changes in immune function, hormonal response, and biochemical reactions, which then influence body functions in our digestive tract and our cardiovascular, neurological, or musculoskeletal systems. It results in a wide variety of health problems. Also, chronic diseases sufferers are at higher risk of interaction of drugs and nutrients due to their prescription regimen. Close to 33% of gene mutations result in decreased enzyme binding affinity for corresponding coenzymes which includes vitamins and minerals. There are many genetic defects (inborn or acquired), so it is likely that many people have higher genetic requirements for many micronutrients (28, 30).

Biochemical Mechanism of Metabolic Correction:

Molecular Concentrations and Rate of Reaction: Dr. Ames Km Concept

The majority of the chemical reactions that take place in living organisms are catalyzed by enzymes. The mechanisms of enzyme-catalyzed reactions in general involve: (1) the formation of a complex between the enzyme and a substrate and (2) the breakdown of this complex to form the product of the reaction. The rate determining step is usually the breakdown of the complex to form the product. Under conditions such that the concentration of the complex corresponds to equilibrium with the enzyme and the substrate, the rate of the reaction is given by the Michaelis-Menten equation (28). The higher the Michaelis Constant (Km), the lower the coenzyme binding affinity.

The Km is a measure of the binding affinity of an enzyme for its ligand. The Km is defined as the concentration of ligand required to fill half of the ligand binding sites. In other words, the substrate concentration at which the reaction rate is half of the maximal metabolic rate.

The rate of an enzyme-catalyzed reaction is approximately proportional to the concentration of the reactant, until concentrations that largely saturate the enzyme are reached. The saturating concentration is larger for a defective enzyme with decreased combining power for the substrate than for the normal enzyme. For such a defective enzyme the catalyzed reaction could be made to take place at or near its normal rate by an increase in the substrate concentration. This mechanism of action of gene mutation is only one of several that lead to disadvantageous manifestations that could be overcome by an increase in the concentration of enzymatic cofactors. These binding problems may result in metabolic inefficiency with the accumulation of metabolic by-products. In general, this is the Law of Mass Action as the vitamin and mineral concentration increases, enzyme efficiency increases. These considerations obviously suggest a rationale for Metabolic Correction where you provide the required cofactors in the amount needed to improve function. This increased enzyme efficiency may allow a genetic defect to be overcome. This biochemical activity follows the chemical principle of Le Chatlier, which states that when stress is applied in an equilibrium situation; it will move to the direction to minimize stress. In this case, there is an unfavorable equilibrium of active enzyme that with the addition of the necessary nutrients will be moved toward a more physiologically favorable metabolic state (47).

Many human genetic diseases due to defective enzymes can be remedied or ameliorated by the administration of high doses of the vitamins component of the corresponding coenzyme, which can partially restore the enzymatic activity (30). Several single nucleotide polymorphisms in which the variant amino acid reduces coenzyme binding and thus enzymatic activity can be remedied by raising cellular concentrations of the cofactor through high dose nutrient therapy. Close to 33% or greater of the mutations in a disease gene are responsive to high concentrations of a nutrient cofactor (48-50).

Inadequate intakes of vitamins and minerals from food may lead to DNA damage, mitochondrial decay, and other pathologies (10). Dr. Ames suggests that evolutionary allocation of scarce micronutrients by enzyme triage is an explanation of why DNA damage is commonly found in micronutrient deficiency (10). Also, Motulsky has argued that many of the common degenerative diseases (such as cardiovascular disease and cancer) are the result of the imbalance nutritional intake with genetically determined needs (51, 52).

As an example, Folic acid and Vitamin B12 have an important function in the maintenance of nuclear and mitochondrial genome integrity. Both in-vivo and in-vitro studies with human cells show that deficiency of these vitamins causes an array of problems in the nuclear and mitochondrial DNA which can be minimized with increased folate and cobalamin concentrations. In order to acquire the protective effect of these vitamins, they are needed in concentrations that are obtained at intake levels above the current recommended dietary intakes of Folate (> 400 µg/day) and Vitamin B12 (>2µ/day) (53).

Chromosome breaks lead to mutations that precede tissue damage and disease. Many types of physiological impairments due to inadequacy of vitamins and minerals can lead to suboptimal organ-system function including poor drug metabolism, insufficient neurotransmitter production and impaired immune defenses (6). Chronic vitamin-mineral undernutriture may reduce immune competency and central nervous system efficiency; while increases morbidity related to the increases in degenerative diseases. This approach to optimize health by improving enzyme efficiency and thereby metabolism and physiology, is the basis of Metabolic Correction (11).

An example of Metabolic Correction is that high dose B vitamins can counteract a poor Km. As many as one-third of mutations in a gene result in the corresponding enzyme having an increased Km (decreased binding affinity) for a coenzyme, causing a lower rate of reaction (30, 31). About 50 different human genetic diseases due to a poorer binding affinity of the mutant enzyme for its coenzyme can be remedied by feeding high dose B vitamins, which raise levels of the corresponding coenzyme; many polymorphisms also result in a lowered affinity of enzyme for its coenzyme (30) and thus may be in part remediable. Vitamins also have certain influences on metabolism which are not related to co-enzyme effects. Vitamins can have effects upon a specific cellular organelle, hormone or supra-molecular structure within a cell that may optimize its function (6).

To summarize, Metabolic Correction has two important biological actions: 1) Optimization of cellular function by improving enzymatic efficiency and 2) Producing a pharmacological effect to correct abnormal cell function due to biochemical disarray occasioned by the disease process. An optimum intake of micronutrients and metabolites, which varies with age, environmental factors and genetics, should tune up metabolism and markedly increase health at a modest cost, particularly for the poor, obese, and elderly (32).

Stages of Nutrient Insufficiency:

A nutrient deficiency is a physiological state in which a depletion of a nutrient is associated with the impairment of certain biochemical reactions and lack of well-being. A marginal deficiency or insufficiency refers to the early stage of the deficiency or an early shortage of the needed nutrient to cover all the necessary biochemical pathways to optimize physiology to be able to reach the healthy state.

In order to better understand the nutrient depletion in the body, we can divide the process in five stages. 1) Depletion stage or preliminary deficiency stage: In which the body stores are gradually depleted of the necessary cofactors. 2) Biochemical stage or secondary deficiency stage: In which the functional enzymes are decreased and the body manifest a decline in function due to the lack of necessary cofactors. 3) Physiological stage or tertiary deficiency stage: In which enzyme activity is sufficiently impaired to affect immune and behavioral parameters. Personality changes and decrease in the resistance of disease occur. This is accompanied by a variety of non-specific symptoms such as loss of appetite, depression, irritability, anxiety, insomnia, somnolence; in which the person may not be sufficiently ill to seek medical attention but his general health is not optimal. 4) Clinical stage or semi-final deficiency stage: In which classical clinical deficiency disease is manifested. 5) Anatomical stage or final deficiency stage: In which death of the individual will occur without any nutritional intervention. Suboptimal intake of vitamins just barely above levels causing vitamin deficiency is a risk factor for chronic diseases and common in the general population, especially in the elderly (54-56).


Nutrient deficiency or insufficiency diseases are the end product of a long and complex series of nutrient depletion reactions. Deficiencies in these micronutrients may not be severe enough to create immediate clinical symptoms, but the long-range implications could lead to an increased risk of diseases. This lack of needed cofactors may present without specific symptoms or some vague non-specific symptoms such as lethargy, irritability, insomnia and difficulty in concentration. Also, lack of co-factors may affect the body's ability to resist and revert disease, its ability to recover from exercise, surgery, disease and the ability of the brain to function at a high level. Detecting and treating disease at its earliest stages of cellular biochemical abnormality, rather than waiting for clear clinical symptoms appears to be cost effective and of benefit to the patient. Authors propose to abandon outdated paradigms of nutrient intake merely to prevent deficiencies and expand the concept to prevent and treat chronic diseases through the achievement of the optimal health status with Metabolic Correction.