560I Functional Nutrition

Amino acid substitutions/deletions in protein primary structures that can affect structure and function.

Toxicants may also change cell structural components or may block enzyme active sites.

Intervention to restore nutrient levels promotes normal cellular and tissue function.

e.g. statins, SSRIs - can exacerbate underlying nutrient insufficiencies or toxic effects

More than 400. Phenylalanine hydroxylase.

GTP cyclohydrolase. It is involved in the formation of BH4 (tetrahydrobiopterin) which is a required coenzyme for PAH.

Lack of enzyme activity will manifest the same. However, differences may arise in the age of onset and severity of outcome (more severe effects are usually only seen with genetic alterations).

Fat soluble vitamins protect against lipid peroxide formation via oxidative stress. May need to evaluate PUFAs, since this scenario may indicate elevated levels of these easily-oxidized FA in membranes.

B1, B2, B3, B5, lipoic acid

Formiminoglutamate evaluates folate status. Folate deficiency can be ONE cause of elevated homocysteine. FIGLU.

Folic acid is not an essential nutrient, nor does it generally occur in foods. The correct term is 'folate deficiency.

tetrahydrofolate.

Serum calcium is very tightly regulated by PTH (from parathyroid, when Ca++ falls) and calcitonin (from thyroid parafollicular cells, when Ca++ rises).

Stomach - failure of HCl output. Supplementation of trace elements without HCl doesn't effectively correct the issue. Properly timed pH shifts are required for delivery of elemental salts for absorption in the small intestine.

Free amino acids and small peptides from dietary protein.

Gln converts to Glu when specimen analysis is delayed or warmed.

Hcys can be transulfurated to (eventually) form glutathione or methylated to form methionine. Excess oxidative stress can pull hcys into the transfulfuration pathway, leaving less availability for methionine, and subsequent methylation factors like SAMe.

Protein synthesis, by far.

GI tract, liver.

Assymetric dimethylarginine

Inhibits nitric oxide synthase.

Hypertension due to lack of NO to induce vasodilation.

Converts dopamine to norepinephrine in the adrenal medulla and brain. Requires Copper (as Cu++) and vitamin C.

Normally, gly and ser can be easily interconverted and tend to move up or down together on the profile. If not, the glycine cleavage system may be suspected - possible genetic or toxicant interruption of that system would prevent degradation. Can cause non-ketotic hyperglycinemia. Since the glycine cleavage system is a major source of single carbons for THF pathways, multiple biosynthetic and methylation defects may result.

B6, Mn, folate

Low levels of amino acids in profiles govern amounts added for each. Usual dosing is a rounded teaspoon twice daily.

If related to imbalanced brain neurotransmitter function may respond to amino acids that act directly as receptor agonists (Lys, Gly, Tau) or serve as precursors to neurotransmitters (Phe).

The greatest elevation is usually ornithine (substrate).

Categorized according to chain length within each greater category or desaturation leel or PUFA omega double bond position.

Arachidonic acid

Arachidonic acid. Superior binding of the n-3 FA to desaturase enzymes tends to suppress the desaturation of linoleic and GLA to form AA.

Largely LDL particles, since usually done in a fasting state.

(In order of abundance) evening primrose , safflower, grape seed, sunflower and hemp.

Peroxisomes. VLCFA intermediates cannot be processed in mitochondria, so has to be transported into peroxisomes in order to generate DHA. Thus infants born to women deficient in DHA take a long time to develop their own DHA levels from dietary precursors.

Simultaneous binding of a PUFA and vitamin A (as 9-cis-retinoic acid) is required to activate PPAR. Deficiency of Vit A or PUFAs may impact fundamental cellular response to energetic or immunological stressors.

Highly diverse. Central role in 2 processes that broadly impact cellular function: 1. cell membrane properties that affect membrane-bound protein complexes and receptors in all tissues. 2. formation of the dominant eicosanoid precursors, GLA and AA.

Low levels of n-3 PUFAs (especially EPA) along with elevated AA

Arachidonic acid

Metabolic syndrome aka syndrome X, prediabetes, hyperinsulinemia, dysinsulinemia. Insulin stimulates endogenous FA synthesis.

Etiology of adrenoleukodystrophy is lack of peroxisome activity required for oxidation and clearance of VLCFA. Those FA accumulate massively, producing chronically progressive neuropathic symptoms.

Zn++

Borage contains GLA only. Evening primrose contains less GLA but is high in LA.

Fish oil. Decrease CHO intake.

Elevated adipate, suberate and ethylmalonate

Ascribe high levels of citrate, aconitate and isocitrate to ammonia when (a) only citrate, aconitate and isocitrate are found high, or (b) orotate is concurrently elevated.

N-methyl-D-aspartic acid (a class of ionotropic glutamatergic neuron receptors).

It is those receptors that are agonized by quinolinic acid and potentiated by picolinic acid resulting in potential glutamate toxicity in neurons.

Elevated p-hydroxyphenyllactic acid (marker for tumor growth) and the concomitant elevated cell division rate stimulation that tends to produce systemic oxidative stress.

Failure of the reciprocal regulation between transmethylation and transulfuration of Hcys can impair up-regulation of hepatic glutathione synthesis as the major response to oxidative stress, leading to exacerbated and prolonged cellular (esp. mitochondrial) damage from oxidant effects. 8OHdG is a marker of DNA damage due to oxidative stress.

Urinary glucarate is a marker for increased hepatic detoxification activity (it is a by-product of pathways leading to glucuronic acid formation). Oral glucarate salts decrease enterohepatic recirculation of carcinogens. See p.365

Elevated AHB indicates up-regulated hepatic glutathione synthesis, and that process demands flow of HCys into L-Cys to form glutathione. Thus low plasma HCys can signal a late-stage of chronic glutathione depletion where total body sulfure amino acid availability is failing to keep up with demand.

Elevated benzoate can be due to either (a) failure of hepatic clearance by hippurate formation (impaired detox) or (b) bacterial action on dietary polyphenols releasing benzoate (which exceeds liver clearance capacity). Elevated hippurate indicates scenario (a), low/normal hippurate indicates scenario (b).

Arabinose is a 5-C sugar found in grapes and other fruits/veg. It is a substrate for growth of some bacteria. Arabinitol is the corresponding sugar alcohol that is formed by conversion of dietary CHO by intestinal Candida species. It serves as a biomarker for overgrowth, including severe, invasive cadidiasis.

Branched-chain keto acids (a-ketoisocaproate, a-ketoisovalerate, and a-keto-b-methylisovalerate. This is due to genetic abnormalities reducing the activity of branched-keto acid dehydrogenase.

Cofactors B1, B2, B3, B5, lipoic acid may help. But if the SNPs relate to severe alterationsin the enzyme binding sites for the cofactors, supplementation may have no effect.

FIGLU (for folate) and MMA (for B12).

Cheer up!! You're going to do great...!

B6 impairs this pathway - deficiency elevates primarily xanthurenate, but also kynurenic acid/kynurenate. In a B6 sufficient state, Inflammation activates this pathway in the brain leading to products quinolinate and picolinate (since brain does not have enzymes to complete the conversion to nicotinic acid).

Glycine is required in the kidney to sustain reformation of glutathione. Lack of glycine is one reason why the critical gamma-glytamyl pathway is truncated prior to executing the GSH reconstruction, causing release of the glutamic acid moiety as pyroglutamate.

The mitochondrial membrane is selectively permeable, regulated by transport proteins. Thus specific TCA cycle intermediates can easily leave and their levels do not become elevated.

Smoking can increase urinary glucarate levels, indicating activity of hepatic detoxification.

Progressively lowering sulfate indicates chronic toxicant challenge/oxidative stress. Pyroglutamate elevation indicates that glutathione losses may be a contributing factor. Glutathione support is indicated via GSH or precursors (Cys, Met, Gly, and related amino acids. Tau, Ser, Thr may be helpful in restring GSH status.

Cys - Gly - Glu

Decline in stomach acid output with age, likely associated with underlying metabolic changes tied to nutrient insufficiencies and toxic effects.

Zinc, biotin (for protein synthesis suport), B complex, iron, CoQ10 for mitochondrial activity.

Protein and major/trace elements.

Abnormal commensal bacterial distributions.

Decreased digestion of dietary components (esp protein) resulting instimulation of certain bacteria that metabolize amino acids.

Decreased absorption of dietary components stimulates microbe growth due to availability of growth substrate.

Lactulose-mannitol (lactulose is normally poorly-absorbed, mannitols is normally well-absorbed) evaluates intestinal permeability. However, it does not also answer the question about whether macromolecules from food are regularly permeating the intestinal barrier and producing immunological responses - serum IgG4 would do that.

IgG1 class antibodies are those that are first produced in reaction to food components penetrating intestinal barriers. IgG1-food complexes are degraded by complement systems. However, complement proteins do not recognize IgG4-food complexes, so they remain in circulation much longer (days to weeks).

Ammonuria indicated by elevated orotate suggests the bacteria genera capable of high ammonia production, including clostridia, enterobacter and Bacillus.

Threshold models presume nil response below the threshold for positive responses. Hormesis models predicts (or allows) negative responses in the regions below the threshold for positive responses.

Smoking below the threshold for increasing cancer incidence might produce lower risk via mechanisms such as induction of hepatic detoxification systems that lower total body estrogen exposure.

When a patient with a high body burden of a toxic element starts DMSA therapy, loses on a given day may be offset by release of the element from deep stores such as bone over a time interval longer than the urine collection during therapy. The DMSA can act to stimulate mobilization of old pools with slow turnover.

Glutathione. This explains the potential for uncontrolled oxidative stress and organ failure due to overdosing of drugs like acetaminophen that produce high demand for hepatic glutathione conjugation.

Lack of sulfur compound precursors is hampering sulfoxidation and probably impairing maintainance of glutathione reserves. Causative factor is most likely mercury, which is causing DNA damage.

Glycine for glycine conjugation (phase II reaction). The reaction also requires Coenzyme A, so high rates of reaction can drain pantothenic acid reserves. So pantothenate would also help.

Urophorphyrin decarboxylase catalyzes a series of 4 decarboxylation reactions. After each step the product must dissociate from the enzyme and re-associate in a new confirmation that places the next carboxyl group at the active site. Mercury binds strongly to the enzyme such that the product of the third decarboxylation (pentacarboxyporphyrinogen) has difficulty reentering the site, causing it to accumulate and spill into urine. The prior step also backs up, causing hexacarboxyporphyrinogen to spill also. Meanwhile, the excess pentacarboxyporphyrinogen is converted to precoproporphyrin.

Symptom-free until biotransformation systems are stressed; then noticeable symptoms appear. Elevated bilirubin indicates difficulty with glucuronidation.

Phase I products tend to become even more toxic than their precursors.

Zinc and copper in superoxide dismutase (cytosolic). Manganese in superoxide dismutase (mitochondrial). Selenium in glutathione peroxidase.

Selenium, B2 (as FAD) and B3 (as NADPH).

Removing oxygen radicals.

Because balanced intake of all of the antioxidants is superior to individual supplementation because of the demonstrated codependence.

Melatonin. It's roughly twice as effective as vitamin E for protection against the peroxyl radical.

Good levels of fat-soluble vitamins should indicate protection against oxidative stress especially in cell membranes, where oxidative stress without adequate protection would lead to elevated lipid peroxides. It would be important to evaluate membrane FA components, since it may be that levels of easily-oxidized PUFAs are elevated.

Did you consider them? Basically, just understand that the body uses a full and diverse array of cell regulators to achieve homeostasis in spite of dramatic fluctuations in daily habits and circumstances.

There is a danger of overuse because they are part of a delicate balancing system.

Gigantism, acromegaly, other malformations.

Depends on age. In young children - growth failure. In adults - metabolic syndrome, osteoporosis, muscle wasting, impaired quality of life, increased cardiovascular events.

Palpitations, heat intolerance, nervousness, insomnia, breathlessness, increased bowel movements, light/absent menstrual periods, fatigue, fast heart rate, trembling hands, weight loss, muscle weakness, warm/moist skin, hair loss, staring gaze.

Fatigue, weakness, weight gain, hair loss, cold intolerance, muscle cramps, constipation, depression, irritability, memory loss, abnormal menstruation, decreased libido, pale/dry skin, coarse/dry hair, puffy face, hoarse voice, elevated blood cholesterol.

May be an early indicator of depression.

Low levels of sex hormones testosterone and estrogen. DHEA also has immune-modulating effects and prevents stress-induced damage to the hippocampus, as in Alzheimer's Disease.

Blocks insulin action (so increased blood sugar), suppresses immune system, increased protein breakdown. May cause greater urinary losses of B-vitamins, lowered mineral status and reuced absorption of calcium, and a greater need for vitamins C and E.

Adrenal insufficiency, showing lowest cortisol in morning.

Cushing's syndrome.

Decreased sIgA in chronic stress.

May simulate immune response. Increased breast cancer risk. Increased prostate cancer growth. SYmptoms include anxiety, difficulty sleeping, irritability. Breast fibroids or cysts.

Breast cells will not mature properly. Menopausal symptoms.

Increased free estrogen (via increased sulfatase activity), urinary incontinence, decreased coordination, slowed reflexes, impaired memory and reasoning skills, increased risk for diabetes. Possibly migraines. Possibly chronic fatigue.

Vitamin C

High cortisol, possibly metabolic syndrome, T2DM and cardiovascular disease.

Increased risk for growth of prostate cancer cells.

Drugs are metabolized/cleared via detoxification enzymes. Thus SNPs in phase I CYP enzymes or phase II enzymes may alter the patient's clearance rates of that drug.

Specifies location (base number 677) and nucleotide replacement (cytosine to thymine) that is present.

The CYP3A4 and CYP2E variants required for 16a-hydroxyestrone formation are present at 35% and 4% respectively.

All steps including DNA transcription, RNA translation and protein function are potentially impacted by environmental factors.