Fat-Soluble & Water-Soluble Vitamins: The Complete Clinical Reference

Why This Matters

Think of vitamins as a symphony orchestra. Each instrument plays its own part, but the magic happens in the interplay — the way vitamin D calls to K2, which signals calcium where to go, while A conducts the immune section from the wings. Remove one player and the whole performance falters. Double one without the others and you get noise instead of music.

Functional medicine doesn’t treat vitamins as isolated pills. It treats them as a biochemical network — with synergies, cofactors, genetic variability, and dose-response curves that matter enormously in clinical practice.

This reference covers both fat-soluble (A, D, E, K) and water-soluble (B-complex, C) vitamins with clinical dosing, testing, interactions, and the nuances that separate effective supplementation from expensive urine.

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Part 1: Fat-Soluble Vitamins (A, D, E, K)

Fat-soluble vitamins dissolve in fat, store in liver and adipose tissue, and carry real toxicity risk at sustained high doses. This storage capacity is a double-edged sword — you don’t need them daily, but you can accumulate them to harmful levels.

Vitamin A: The Immune Architect

Vitamin A is the guardian of epithelial barriers — skin, gut lining, respiratory tract, eyes. Without it, your first line of defense has holes in the wall.

Two forms, critically different:

• Retinol (preformed vitamin A): Found in liver, cod liver oil, egg yolks, butter. Immediately bioactive. This is real vitamin A.
• Beta-carotene (provitamin A): Found in carrots, sweet potato, leafy greens. Must be converted to retinol by the enzyme BCMO1.

Here’s what most practitioners miss: the BCMO1 SNP. Roughly 45% of people carry genetic variants that reduce beta-carotene conversion by 30-70%. These are the patients eating mountains of carrots with perfect orange skin — and still vitamin A deficient. They cannot rely on plant sources alone. Testing for this SNP through nutrigenomic panels (23andMe, Strategene) changes clinical decisions.

Clinical dosing: 5,000-10,000 IU retinol daily (maintenance). Higher doses (25,000 IU) used short-term for acute infections under supervision.

Deficiency signs: Night blindness (earliest), dry eyes, frequent infections, keratosis pilaris (bumpy skin on upper arms), poor wound healing.

Toxicity: Chronic intake above 25,000 IU retinol can cause liver damage, headaches, bone pain, birth defects. Beta-carotene does not cause vitamin A toxicity — just harmless skin yellowing (carotenodermia). Pregnant women should not exceed 10,000 IU retinol.

Best food source: One ounce of beef liver contains roughly 25,000 IU of retinol. It is the most nutrient-dense food on earth. Cod liver oil provides retinol plus D3 plus omega-3s — a three-in-one ancestral supplement.

Vitamin D3: The Prohormone That Acts Like a Hormone

Vitamin D is not really a vitamin. It’s a steroid prohormone that influences over 2,000 genes — immune regulation, calcium metabolism, mood, cancer protection, cardiovascular function. Calling it a vitamin undersells its importance by several orders of magnitude.

The pathway: Skin + UVB sunlight → cholecalciferol (D3) → liver converts to 25-OH vitamin D (what we test) → kidneys convert to 1,25-OH (active calcitriol).

Optimal testing range: 50-80 ng/mL (25-OH vitamin D). The conventional “normal” range of 30-100 ng/mL sets the bar too low. Below 50 ng/mL, immune and metabolic benefits diminish significantly.

Dosing rule of thumb: Every 1,000 IU of D3 raises blood levels approximately 10 ng/mL. A patient at 30 ng/mL targeting 60 ng/mL needs approximately 3,000 IU daily — but individual absorption varies wildly. Obese individuals often need 2-3x more (D3 sequesters in fat tissue).

Critical cofactors:

• Vitamin K2 (MK-7): Without K2, vitamin D increases calcium absorption but calcium goes to arteries instead of bones. D3 without K2 is a setup for vascular calcification.
• Magnesium: Required for every step of vitamin D metabolism. Low magnesium = impaired D3 activation. Many “vitamin D resistant” patients are actually magnesium deficient.

VDR polymorphisms: Vitamin D receptor gene variants (Fok1, Bsm1, Taq1) affect receptor sensitivity. Some patients need higher serum levels to achieve the same cellular effect. Nutrigenomic testing reveals these.

Sunshine vs supplement: 15-20 minutes of midday sun on exposed arms and legs produces approximately 10,000-20,000 IU. Latitude above 37° (above Atlanta, USA) means essentially zero D3 production October through March. Sunscreen above SPF 15 blocks 99% of D3 production. The modern indoor lifestyle has created a pandemic of deficiency.

Vitamin E: The Misunderstood Antioxidant

Most vitamin E supplements contain only synthetic dl-alpha-tocopherol — one form out of eight. This is like playing a chord with one finger. Worse, high-dose synthetic alpha-tocopherol displaces gamma-tocopherol, which is actually the more potent anti-inflammatory form.

The full family: Four tocopherols (alpha, beta, gamma, delta) and four tocotrienols. Clinical vitamin E should be mixed tocopherols with tocotrienols.

Gamma-tocopherol quenches reactive nitrogen species that alpha cannot touch. It’s the predominant dietary form (nuts, seeds, soybean oil) and the one most Americans actually need more of.

Clinical dosing: 200-400 IU mixed tocopherols with tocotrienols. Selenium and vitamin E are synergistic — both are required for glutathione peroxidase function.

Caution: High-dose alpha-tocopherol alone (>400 IU) was associated with increased mortality in the Miller 2005 meta-analysis — but this used synthetic alpha alone, not mixed natural forms. The form matters profoundly.

Vitamin K: The Calcium Traffic Controller

Vitamin K comes in two clinically distinct forms that do very different jobs:

K1 (phylloquinone): Clotting factors. Found in green leafy vegetables. This is what the “K” originally stood for — “Koagulation.” Adequate intake: 90-120 mcg.

K2 (menaquinone, MK-7): Calcium trafficking. Activates osteocalcin (puts calcium into bones) and matrix GLA protein (keeps calcium out of arteries). Found in natto (richest source — 1,000+ mcg per serving), aged cheeses, egg yolks, liver.

Clinical dosing: 200 mcg MK-7 daily. MK-7 has a longer half-life (72 hours vs 1-2 hours for MK-4), making once-daily dosing effective.

The D3-K2 synergy: Vitamin D increases calcium absorption. K2 directs where calcium goes. Taking D3 without K2 is like flooding a city with water without building canals — the calcium goes everywhere it shouldn’t.

Warfarin interaction: Vitamin K (both forms) directly opposes warfarin’s mechanism. Patients on warfarin should maintain consistent K intake rather than avoiding it entirely — wild fluctuations in K intake cause unstable INR. This requires physician coordination.

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Part 2: Water-Soluble Vitamins (B-Complex, C)

Water-soluble vitamins don’t store well — excess is excreted in urine. This means you need consistent daily intake but toxicity risk is low (with notable exceptions). It also means deficiency develops faster.

The B-Complex Family

B vitamins are the metabolic workforce. Every mitochondria in every cell needs them to produce ATP. Every neurotransmitter synthesis pathway requires at least one B vitamin. They are the unsung heroes of cellular energy.

B1 (Thiamine): The energy vitamin. Required for pyruvate dehydrogenase — the gateway enzyme from glycolysis to the Krebs cycle. Without B1, you literally cannot burn glucose efficiently.

• Benfotiamine: Fat-soluble form, 150-300mg, crosses membranes better. First-line for diabetic neuropathy, preventing advanced glycation end-products (AGEs).
• TTFD (thiamine tetrahydrofurfuryl disulfide): Another fat-soluble form with excellent tissue penetration.
• Depletion: Alcohol is the classic thief (Wernicke-Korsakoff syndrome). Also depleted by refined carbohydrates, coffee, tea (tannins), and diuretics.

B2 (Riboflavin): Mitochondrial cofactor for FAD and FMN — required in Complex I and II of the electron transport chain.

• Migraine prevention: 200-400mg daily reduced migraine frequency by 50% in the landmark Schoenen 1998 trial. One of the most evidence-based migraine interventions.
• Also required for MTHFR function — B2 deficiency impairs methylation even with adequate folate.

B3 (Niacin): The NAD+ precursor. Niacin feeds into NAD+ production, the molecule required for over 400 enzymatic reactions including DNA repair, energy production, and sirtuin activation.

• Flush niacin (nicotinic acid): 1-3g for lipid management (raises HDL 20-35%, lowers triglycerides, shifts LDL from small-dense to large-buoyant). The flush is prostaglandin-mediated and harmless though uncomfortable.
• No-flush forms: Niacinamide (good for NAD+ but doesn’t improve lipids), inositol hexanicotinate.
• Pellagra (the 4 D’s): Dermatitis, diarrhea, dementia, death. Still occurs in alcohol dependence and chronic malnutrition.

B5 (Pantothenic Acid): Coenzyme A (CoA) production — the central molecule of fat and carbohydrate metabolism. Also critical for adrenal steroid hormone synthesis. Clinical dose: 250-500mg. Often included in adrenal support formulas.

B6 (Pyridoxine vs P5P): Required for over 100 enzymatic reactions, particularly neurotransmitter synthesis — serotonin, dopamine, GABA, norepinephrine all need B6.

• P5P (pyridoxal-5-phosphate): The active coenzyme form. Some individuals have impaired conversion from pyridoxine to P5P (notably those with NBPF3 SNPs). Clinical dose: 50-100mg P5P.
• Toxicity warning: Chronic pyridoxine above 200mg can cause peripheral neuropathy (the very symptom it treats at lower doses). This is the one water-soluble vitamin with real toxicity risk. P5P form appears to carry less neuropathy risk.

B7 (Biotin): Carboxylase cofactor — gluconeogenesis, fatty acid synthesis, amino acid catabolism.

• Hair, skin, nails: 5,000-10,000 mcg for cosmetic benefit. Takes 3-6 months.
• Critical lab interference: High-dose biotin causes FALSE readings on immunoassay-based lab tests — falsely low TSH, falsely high free T4 (mimics hyperthyroidism), and false troponin readings. Discontinue biotin 48-72 hours before any blood work.

B9 (Folate): The methylation fuel. Folate donates methyl groups — critical for DNA synthesis, repair, neurotransmitter production, and homocysteine metabolism.

• Methylfolate (5-MTHF) vs folic acid: Folic acid is synthetic, requires DHFR enzyme conversion. Unmetabolized folic acid in the bloodstream may be problematic (cancer debate). Methylfolate (L-5-MTHF, Quatrefolic, Metafolin) is the bioactive form. 400-1000 mcg.
• MTHFR polymorphisms: C677T and A1298C reduce conversion of folic acid to methylfolate by 30-70%. Roughly 40% of the population carries at least one variant. These individuals need methylfolate, not folic acid.
• Neural tube defects: 400-800 mcg methylfolate started before conception. This is one of the most successful public health interventions in history.

B12 (Cobalamin): The nerve vitamin. Required for myelin synthesis, DNA production, and homocysteine/methylmalonic acid metabolism.

• Forms matter: Methylcobalamin (methyl donor, neurological), hydroxocobalamin (longer retention, detox support, cyanide binding), adenosylcobalamin (mitochondrial). Cyanocobalamin is synthetic and requires conversion — it also delivers a tiny amount of cyanide.
• Clinical dosing: 1,000-5,000 mcg sublingual or intramuscular. Sublingual bypasses absorption issues.
• Testing: Serum B12 is unreliable (can be normal with functional deficiency). MMA (methylmalonic acid) is the gold standard — elevated MMA means cellular B12 deficiency regardless of serum level. Homocysteine is also elevated in B12 deficiency but is less specific.
• Intrinsic factor: Required for B12 absorption in the ileum. Pernicious anemia (autoimmune destruction of intrinsic factor) necessitates IM injections.
• Metformin depletion: 10-30% of metformin users develop B12 deficiency (de Jager 2010). Annual MMA testing is essential for every metformin patient.

Vitamin C: The Universal Protector

Vitamin C (ascorbic acid) is the most versatile water-soluble antioxidant — collagen synthesis, immune function, adrenal steroid production, neurotransmitter synthesis, iron absorption, antioxidant recycling (regenerates vitamin E).

Humans are one of the few mammals that cannot synthesize vitamin C (a mutation in the GULO gene). A goat under stress produces approximately 13,000mg of vitamin C daily. We must get every milligram from food or supplements.

Clinical dosing:

• General health: 1-3g daily in divided doses.
• Bowel tolerance dosing (Robert Cathcart method): Increase dose by 1g every hour until loose stools, then back off by 1g. The amount tolerated before bowel tolerance increases dramatically during illness — a useful real-time indicator of tissue need.
• Liposomal vitamin C: Phospholipid-encapsulated, 2-5x higher bioavailability than standard ascorbic acid, doesn’t cause GI distress.
• IV vitamin C: Pharmacologic doses (25-100g) achieve plasma levels 100-200x higher than oral. Used in cancer adjunct therapy (Riordan protocol), sepsis (Marik protocol — debated), and severe infections. Requires G6PD screening.

Adrenal glands have the highest concentration of vitamin C in the body. Under chronic stress, vitamin C is rapidly consumed in cortisol production. Adrenal fatigue patients often need 3-5g daily.

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The Synergy Principle: IFM’s Network Approach

The Institute for Functional Medicine teaches us never to think about single nutrients in isolation. The clinical synergies:

• D3 + K2 + Magnesium + A: The bone-cardiovascular quartet
• B2 + B6 + B9 + B12: The methylation team
• C + E + Glutathione + Selenium: The antioxidant recycling network
• B1 + B2 + B3 + B5: The mitochondrial energy squad

Testing before supplementing. Personalizing forms based on genetics. Respecting synergies and antagonisms. This is what separates functional medicine nutrition from the random multivitamin approach.

Every nutrient deficiency has a root cause — is it dietary inadequacy, malabsorption, genetic conversion issues, or medication-induced depletion? Find the cause, and the treatment becomes obvious.

What would change in your practice if you tested every patient’s nutrient status before reaching for the prescription pad?