Macronutrients, Micronutrients, Vitamin Deficiencies & Vitamin Toxicities

Foundations and mechanisms

Macronutrients: energy yield, essentiality, and metabolic roles

Nutrition can be divided into macronutrients, required in gram quantities for energy and structure, and micronutrients, required in milligram or microgram quantities as cofactors, hormones, antioxidants, or structural ions. Energy balance is governed by intake versus expenditure: basal metabolic rate, thermogenesis, and physical activity. Approximate caloric yields are carbohydrate 4 kcal/g, protein 4 kcal/g, fat 9 kcal/g, and ethanol 7 kcal/g. In adults, a normal BMI is 18.5–24.9 kg/m²; underweight is <18.5, overweight 25–29.9, and obesity ≥30.

Nutrient class	Core mechanisms	High-yield essential components
Carbohydrates	Glucose is obligatory fuel for erythrocytes and a major fuel for brain; glycogen stores buffer fasting for approximately 12–24 hours.	Dietary fiber lowers LDL by binding bile acids; soluble fiber slows glucose absorption.
Proteins	Provide amino acids for enzymes, transporters, receptors, immunoglobulins, and oncotic proteins. Nitrogen balance reflects protein synthesis minus breakdown.	Essential amino acids include PVT TIM HALL: phenylalanine, valine, threonine, tryptophan, isoleucine, methionine, histidine, arginine, leucine, lysine.
Lipids	Major energy store; required for membranes, myelin, steroid hormones, bile acids, eicosanoids, and absorption of fat-soluble vitamins.	Essential fatty acids: linoleic acid omega-6 and α-linolenic acid omega-3.

Minimum adult protein requirement is approximately 0.8 g/kg/day; requirements increase in growth, pregnancy, burns, trauma, infection, and postoperative states. Negative nitrogen balance occurs in starvation, glucocorticoid excess, sepsis, malignancy, and severe burns. In prolonged fasting, insulin falls and glucagon, epinephrine, cortisol, and growth hormone promote glycogenolysis, lipolysis, ketogenesis, and muscle proteolysis. The brain adapts to ketone utilization after several days, reducing but not eliminating protein catabolism.

Micronutrients: absorption, transport, storage, and biochemical function

Vitamins are organic compounds not synthesized in sufficient quantity. Fat-soluble vitamins are A, D, E, and K; they require bile salts and pancreatic enzymes for micellar absorption in the small intestine, travel in chylomicrons, and are stored in liver and adipose tissue. Therefore, deficiencies occur with fat malabsorption, cholestasis, pancreatic insufficiency, cystic fibrosis, celiac disease, and bariatric surgery, whereas toxicities are more likely because storage is substantial.

Water-soluble vitamins include the B-complex vitamins and vitamin C. They generally have limited storage and are excreted renally, so deficiency may develop rapidly with poor intake, alcoholism, dialysis, or increased metabolic demand. Important exceptions are vitamin B₁₂, stored in the liver for approximately 3–5 years, and folate, with stores lasting approximately 3–4 months.

Vitamin	Principal biochemical role	Mechanistic deficiency theme
A	Retinal for phototransduction; retinoic acid regulates epithelial gene transcription.	Impaired vision in dim light and squamous metaplasia.
D	Steroid hormone increasing intestinal Ca2+ and phosphate absorption; suppresses PTH.	Defective mineralization: rickets or osteomalacia.
E	Lipid-soluble antioxidant protecting membranes from free radicals.	Oxidative injury to RBCs and neurons.
K	γ-carboxylation of glutamate residues on factors II, VII, IX, X and proteins C and S.	Bleeding with elevated PT/INR; factor VII falls earliest due to short half-life.
B1 thiamine	TPP cofactor for pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, branched-chain ketoacid dehydrogenase, transketolase.	Impaired ATP generation, especially in brain and heart.
B12/folate	DNA synthesis via one-carbon metabolism; B12 also converts methylmalonyl-CoA to succinyl-CoA.	Megaloblastic anemia; only B12 deficiency increases methylmalonic acid.
C	Hydroxylation of proline and lysine in collagen; antioxidant; enhances nonheme iron absorption.	Defective collagen cross-linking and bleeding gums.

Core numerical anchors and classification principles

Deficiency syndromes are classified by cause: inadequate intake, malabsorption, impaired activation, increased requirement, excess loss, or drug antagonism. Examples include isoniazid causing B₆ deficiency, methotrexate and trimethoprim antagonizing folate metabolism, warfarin antagonizing vitamin K epoxide reductase, and anticonvulsants accelerating vitamin D catabolism.

• Vitamin D status: serum 25-hydroxyvitamin D is the best screening marker. Deficiency is commonly <20 ng/mL, insufficiency 20–29 ng/mL, and sufficiency ≥30 ng/mL; toxicity is often associated with levels >150 ng/mL and hypercalcemia.
• Folate recommendations: adults require about 400 mcg dietary folate equivalents/day; pregnancy requires 600 mcg/day. Neural tube defect prevention typically uses 400 mcg/day before conception and early pregnancy.
• Vitamin B₁₂: adult RDA is approximately 2.4 mcg/day. Absorption requires gastric acid release from food, binding to R protein, pancreatic protease transfer to intrinsic factor, and ileal uptake.
• Iodine: adult requirement is approximately 150 mcg/day; pregnancy requires about 220 mcg/day. Iodine is necessary for thyroid hormone synthesis.

Vitamin toxicities follow mechanism-specific patterns. Vitamin A excess activates nuclear retinoid receptors, causing hepatotoxicity, pseudotumor cerebri, alopecia, dry skin, and teratogenicity. Vitamin D excess increases intestinal calcium absorption and bone resorption, causing hypercalcemia, nephrolithiasis, and tissue calcification. Vitamin B₆ toxicity, classically at high chronic doses often >100–200 mg/day, causes sensory neuropathy. Thus, Step 1 questions often hinge on whether a nutrient is stored, where it is absorbed, which cofactor reaction fails, and which laboratory metabolite accumulates.

Clinical assessment and investigations

Clinical presentation and initial nutritional assessment

Nutritional disorders should be suspected when abnormal intake, absorption, metabolism, or losses produce characteristic changes in growth, body composition, epithelial integrity, neurologic function, hematopoiesis, or bone mineralization. On Step 1, the key task is often to connect a clinical syndrome to the deficient or toxic nutrient and then select the confirmatory laboratory marker.

Begin with anthropometrics. Body mass index (BMI) is calculated as weight in kg/height in m². Adult categories are: underweight <18.5, normal 18.5–24.9, overweight 25–29.9, obesity class I 30–34.9, class II 35–39.9, and class III ≥40 kg/m². In children, use age- and sex-adjusted percentiles; failure to thrive is commonly suggested by weight-for-age or weight-for-length <5th percentile or crossing down ≥2 major percentile lines. Unintentional weight loss is clinically significant when >5% in 1 month, >7.5% in 3 months, or >10% in 6 months.

Physical examination emphasizes patterns: protein-energy malnutrition causes muscle wasting, loss of subcutaneous fat, edema, hair changes, dermatitis, and impaired wound healing. Marasmus is primarily total calorie deprivation with severe wasting and little edema; kwashiorkor is protein deficiency with hypoalbuminemia, edema, fatty liver, “flaky paint” dermatitis, and hair depigmentation. Cheilosis, glossitis, neuropathy, petechiae, night blindness, bone pain, and bleeding diathesis should prompt targeted micronutrient evaluation.

Differential diagnosis by syndrome

Presentation	High-yield nutritional causes	Important mimics
Megaloblastic anemia, hypersegmented neutrophils	Vitamin B12 deficiency, folate deficiency	Myelodysplasia, hydroxyurea, methotrexate, zidovudine
Microcytic anemia	Iron deficiency, copper deficiency	Thalassemia, anemia of chronic disease, lead poisoning, sideroblastic anemia
Neuropathy or encephalopathy	B1, B6, B12, vitamin E deficiency; B6 toxicity	Diabetes, alcohol toxicity, hypothyroidism, uremia, Guillain-Barré syndrome
Bone pain, fractures, tetany	Vitamin D deficiency, calcium deficiency, phosphate deficiency	Chronic kidney disease, hypoparathyroidism, malignancy, osteogenesis imperfecta
Bleeding, petechiae, poor wound healing	Vitamin C deficiency, vitamin K deficiency	Platelet disorders, liver disease, DIC, vasculitis

Core investigations and interpretation

Basic screening includes CBC with indices, reticulocyte count, comprehensive metabolic panel, magnesium, phosphate, calcium, liver tests, PT/INR, fasting glucose or HbA1c, lipid panel, urinalysis, and inflammatory markers when indicated. Albumin has a long half-life of approximately 20 days and reflects inflammation, hepatic synthesis, renal/GI losses, and hydration more than acute intake. Prealbumin has a shorter half-life of approximately 2 days but is also decreased by inflammation and increased by renal failure; neither should be used alone to diagnose malnutrition.

Nutrient problem	Best test or classic lab pattern	Interpretation threshold / mechanism
Iron deficiency	Ferritin, transferrin saturation, TIBC	Ferritin <15 ng/mL is highly specific; <30 ng/mL commonly used clinically. Low iron, high TIBC, low transferrin saturation <15–20%; ferritin may be falsely normal/high in inflammation.
Vitamin B12 deficiency	Serum B12, methylmalonic acid, homocysteine	B12 <200 pg/mL suggests deficiency. Both methylmalonic acid and homocysteine rise because B12 is needed for methylmalonyl-CoA mutase and methionine synthase.
Folate deficiency	RBC folate, homocysteine	Homocysteine increases, methylmalonic acid remains normal. RBC folate better reflects tissue stores than serum folate.
Vitamin D deficiency	Serum 25-hydroxyvitamin D	25-OH vitamin D reflects body stores. Deficiency often <20 ng/mL; insufficiency 20–29 ng/mL; toxicity usually >150 ng/mL with hypercalcemia, suppressed PTH, nephrolithiasis.
Vitamin K deficiency	PT/INR	PT prolongs first because factor VII has the shortest half-life, approximately 4–6 hours; PTT may prolong later.
Vitamin A deficiency/toxicity	Serum retinol; eye findings	Deficiency causes night blindness, xerophthalmia, Bitot spots. Toxicity causes headache, hepatotoxicity, alopecia, pseudotumor cerebri, teratogenicity.
Vitamin C deficiency	Clinical diagnosis; plasma ascorbate if needed	Impaired proline/lysine hydroxylation weakens collagen: perifollicular hemorrhage, corkscrew hairs, gingival bleeding, poor wound healing.
Thiamine deficiency	Clinical; erythrocyte transketolase activity	Causes Wernicke encephalopathy, beriberi, lactic acidosis. Give thiamine before glucose in high-risk patients to avoid worsening ATP failure.

Targeted testing in malabsorption and special risk states

When multiple deficiencies coexist, think of malabsorption: celiac disease, pancreatic insufficiency, cholestatic disease, inflammatory bowel disease, short bowel, bariatric surgery, chronic alcoholism, or medications. Celiac screening uses IgA anti-tissue transglutaminase plus total IgA; IgA deficiency can cause false negatives, so IgG-based tests may be needed. Fat malabsorption causes deficiencies of vitamins A, D, E, and K; steatorrhea is supported by increased fecal fat, and cholestasis reduces bile salt-mediated micelle formation.

Assess refeeding syndrome risk in severely malnourished patients, especially BMI <16 kg/m², negligible intake for >7–10 days, or substantial alcohol use. Carbohydrate reintroduction increases insulin, driving phosphate, potassium, and magnesium intracellularly. The hallmark is hypophosphatemia, often <2.5 mg/dL and severe <1.0 mg/dL, causing weakness, rhabdomyolysis, respiratory failure, arrhythmias, and hemolysis.

Finally, interpret vitamin levels in context. Acute-phase responses can lower measured retinol, iron, and zinc independent of stores, while renal failure elevates methylmalonic acid. Water-soluble vitamin toxicities are uncommon except pyridoxine, in which chronic high intake can cause sensory neuropathy. Fat-soluble vitamins accumulate in adipose and liver, making toxicity more likely with chronic excess supplementation.

Management, pharmacology and procedures

General principles of nutritional support

Management begins by identifying the route, urgency, and specific nutrient deficit or excess. If the gastrointestinal tract is functional, enteral nutrition is preferred because luminal nutrients maintain villous architecture, stimulate bile flow, preserve gut-associated lymphoid tissue, and reduce bacterial translocation. Parenteral nutrition is reserved for severe ileus, bowel obstruction, high-output fistula, short bowel syndrome, severe malabsorption, or inability to use the gut for approximately 7 days in a well-nourished patient or sooner in severe malnutrition.

Strategy	Typical indication	Key complications
Oral diet plus supplements	Mild deficiency, intact swallowing and absorption	Nonadherence, excess fat-soluble vitamin intake
Nasogastric/nasoenteric tube	Short-term feeding, usually <4–6 weeks	Aspiration, sinusitis, tube displacement
PEG or jejunostomy tube	Long-term enteral nutrition	Infection, leakage, buried bumper, aspiration
Total parenteral nutrition	Nonfunctional gut	Catheter sepsis, thrombosis, hyperglycemia, cholestasis, fatty liver, electrolyte shifts

Total parenteral nutrition contains dextrose, amino acids, lipid emulsion providing essential fatty acids, electrolytes, trace elements, and vitamins. Glucose is commonly monitored with a target near 140–180 mg/dL in hospitalized patients. Lack of lipid for more than 2–4 weeks may cause essential fatty acid deficiency with scaly dermatitis, alopecia, thrombocytopenia, and impaired wound healing.

Refeeding syndrome: acute prevention and treatment

Refeeding syndrome occurs when carbohydrate reintroduction raises insulin, driving phosphate, potassium, and magnesium into cells. Hypophosphatemia impairs ATP and 2,3-BPG production, causing weakness, rhabdomyolysis, respiratory failure, hemolysis, seizures, and heart failure. High-risk patients include those with BMI <16 kg/m², little or no intake for >10 days, significant weight loss, alcoholism, eating disorders, or baseline low phosphate, potassium, or magnesium.

• Give thiamine 100 mg IV or PO before glucose, then daily for at least 5–7 days.
• Begin calories slowly, often 10 kcal/kg/day; in extreme starvation, start near 5 kcal/kg/day.
• Monitor phosphate, potassium, magnesium, and glucose at least daily initially; severe cases require more frequent checks.
• Replete electrolytes aggressively; phosphate replacement is central because severe hypophosphatemia is the hallmark.

High-yield deficiency treatment

Deficiency	Classic associations	Treatment principle
Thiamine, vitamin B1	Wernicke encephalopathy: confusion, ophthalmoplegia, ataxia; alcoholism; bariatric surgery	Suspected Wernicke: 500 mg IV three times daily for 2–3 days, then 250 mg IV/IM daily for 3–5 days; always give before glucose.
Niacin, vitamin B3	Pellagra: dermatitis, diarrhea, dementia; carcinoid syndrome; Hartnup disease	Niacinamide 300 mg/day in divided doses; treat underlying tryptophan malabsorption or excess serotonin synthesis.
Pyridoxine, vitamin B6	Isoniazid therapy, sideroblastic anemia, seizures, peripheral neuropathy	Prophylaxis with isoniazid: 25–50 mg/day; excess B6 itself can cause sensory neuropathy.
Folate, vitamin B9	Megaloblastic anemia without neurologic deficits; neural tube defects	1 mg PO daily for deficiency. Pregnancy prevention: 400–800 mcg/day before conception; 4 mg/day if prior neural tube defect.
Cobalamin, vitamin B12	Megaloblastic anemia plus neurologic deficits; pernicious anemia; ileal disease	1000 mcg IM weekly for 4 weeks, then monthly, or high-dose oral 1000–2000 mcg/day if absorption is adequate.
Vitamin C	Scurvy: bleeding gums, perifollicular hemorrhage, corkscrew hairs, poor wound healing	100–500 mg/day orally; improvement in fatigue and gingival symptoms is often rapid.
Vitamin D	Rickets, osteomalacia, hypocalcemia, secondary hyperparathyroidism	Cholecalciferol 50,000 IU weekly for 6–8 weeks or 6000 IU/day, then maintenance 800–2000 IU/day; add calcium if intake is low.
Vitamin K	Bleeding, elevated PT/INR; newborns, malabsorption, antibiotics	Newborn prophylaxis: 0.5–1 mg IM phytonadione. Adult deficiency: oral or IV vitamin K depending on severity.
Iron	Microcytic anemia, low ferritin, high TIBC	Oral elemental iron approximately 40–65 mg once daily or every other day; vitamin C enhances absorption, calcium and PPIs reduce it.

Vitamin toxicities and follow-up

Fat-soluble vitamins A, D, E, and K accumulate in adipose tissue and liver, so toxicity is more likely than with most water-soluble vitamins. Management is primarily discontinuation of supplements plus supportive care. Vitamin A toxicity causes headache, skin desquamation, hepatotoxicity, pseudotumor cerebri, and teratogenicity; isotretinoin is therefore contraindicated in pregnancy. Vitamin D toxicity causes hypercalcemia with stones, bone pain, constipation, polyuria, and neuropsychiatric symptoms; treatment includes stopping vitamin D/calcium, IV isotonic saline, and in severe cases calcitonin or bisphosphonates. Vitamin E excess can impair platelet aggregation and antagonize vitamin K–dependent clotting, increasing bleeding risk. Niacin used pharmacologically for dyslipidemia can cause prostaglandin-mediated flushing, hyperglycemia, hyperuricemia, and hepatotoxicity; aspirin before dosing reduces flushing.

Follow-up is guided by mechanism: repeat CBC and reticulocyte response for anemia, electrolytes during refeeding, 25-hydroxyvitamin D and calcium after vitamin D therapy, and neurologic recovery after B₁₂ or thiamine replacement. After Roux-en-Y gastric bypass or other malabsorptive procedures, patients require lifelong multivitamins plus monitoring for thiamine, B₁₂, iron, calcium, vitamin D, folate, copper, and fat-soluble vitamin deficiencies.

Exam controversies and advanced synthesis

Population supplementation: benefit is context-dependent, not universal

For USMLE Step 1, the key principle is that vitamin supplementation prevents or treats deficiency states; it does not reliably improve outcomes in nutritionally replete adults. Large randomized trials have repeatedly shown that antioxidant supplementation may be neutral or harmful, especially when given pharmacologically rather than physiologically.

Intervention/trial	High-yield result	Step 1 implication
ATBC and CARET: beta-carotene in smokers/asbestos exposure	Increased lung cancer risk in high-risk smokers	Avoid assuming “antioxidant = protective”; beta-carotene can be harmful in smokers
SELECT: vitamin E 400 IU/day ± selenium	Vitamin E increased prostate cancer risk; selenium did not prevent prostate cancer	Fat-soluble vitamin excess can be harmful despite normal intake requirements
AREDS/AREDS2	Antioxidant/zinc formulation slowed progression of intermediate age-related macular degeneration; beta-carotene removed in AREDS2 due to smoker risk	Benefit is disease-specific, not generalizable to all patients
Folic acid fortification	Reduced neural tube defects; standard preconception dose is 400 mcg/day	Folate prevents failed neural tube closure before many pregnancies are recognized

Guideline-style thresholds and common examination traps

Nutrition questions often test thresholds rather than nuanced subspecialty debates. Know the biochemical logic behind the cutoffs. Vitamin D status is assessed by 25-hydroxyvitamin D, not 1,25-dihydroxyvitamin D, because 25-OH vitamin D reflects body stores and has a longer half-life of about 2–3 weeks. A commonly used deficiency threshold is <20 ng/mL; 20–29 ng/mL is often called insufficiency, but the clinical significance is controversial. The Institute of Medicine target for most adults is approximately ≥20 ng/mL, whereas some endocrine guidelines use ≥30 ng/mL.

Nutrient	Key number	Major toxicity threshold/consequence
Vitamin A	RDA: ~700–900 mcg RAE/day	Teratogenicity; hepatotoxicity; pseudotumor cerebri. Avoid high-dose retinoids in pregnancy.
Vitamin D	RDA: 600 IU/day adults; 800 IU/day older adults	Hypercalcemia, nephrolithiasis; toxicity usually with chronic intake >10,000 IU/day
Vitamin B6	Needed for transamination and neurotransmitter synthesis	Sensory neuropathy with chronic high doses; upper limit often cited as 100 mg/day
Folate	Pregnancy prevention dose: 400 mcg/day; high-risk prior NTD often 4 mg/day	Can mask hematologic signs of B12 deficiency while neurologic injury progresses

Viva-level integration: deficiency patterns are mechanistic

A rigorous approach is to connect clinical findings to biochemical function. Thiamine is a cofactor for pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, branched-chain alpha-ketoacid dehydrogenase, and transketolase. Deficiency impairs aerobic glucose metabolism, causing lactic acidosis and neuronal energy failure. This explains Wernicke encephalopathy: confusion, ophthalmoplegia, and ataxia. In malnourished or alcohol-use patients, give thiamine before glucose because carbohydrate loading increases thiamine demand.

Vitamin B12 and folate both impair thymidylate synthesis when deficient, causing megaloblastic anemia with hypersegmented neutrophils. Distinguish them biochemically: B12 deficiency increases methylmalonic acid and homocysteine; folate deficiency increases homocysteine only. B12 deficiency causes neurologic disease through impaired conversion of methylmalonyl-CoA to succinyl-CoA, leading to abnormal fatty acid incorporation into myelin, classically subacute combined degeneration of dorsal columns and lateral corticospinal tracts.

Refeeding syndrome: high-yield physiology, not just clinical trivia

Refeeding syndrome occurs when a chronically malnourished patient receives calories, especially carbohydrates. Insulin secretion shifts phosphate, potassium, and magnesium into cells. The hallmark is hypophosphatemia, which reduces ATP and 2,3-BPG, causing weakness, hemolysis, respiratory failure, arrhythmias, and heart failure. High-risk patients include those with negligible intake for >5–10 days, anorexia nervosa, alcoholism, cancer cachexia, or prolonged fasting. Step 1 questions usually emphasize prevention conceptually: slow caloric advancement, electrolyte repletion, and thiamine replacement before carbohydrate load.

Common pitfalls

• Fat-soluble vitamins—A, D, E, K—are more likely to accumulate and cause toxicity; water-soluble vitamins are generally excreted, but B6 and niacin are important exceptions.
• Niacin treats dyslipidemia mechanistically by decreasing hepatic VLDL synthesis, but outcome benefit is limited in the statin era; toxicities include flushing via prostaglandins, hyperglycemia, hyperuricemia, and hepatotoxicity.
• Zinc excess can cause copper deficiency by inducing intestinal metallothionein, which binds copper and prevents absorption; this produces anemia, neutropenia, and neurologic dysfunction.
• Vitamin K deficiency prolongs PT first because factor VII has the shortest half-life, about 4–6 hours.
• Protein-energy malnutrition: marasmus is total calorie deficiency with wasting; kwashiorkor is protein deficiency with edema due to hypoalbuminemia and oxidative stress.