Master Biochemistry & Nutrition
for USMLE Step 1

What the USMLE Step 1 Tests in Biochemistry & Nutrition

USMLE Step 1 Biochemistry & Nutrition tests the application of molecular and metabolic principles to clinical scenarios. Candidates must identify enzyme deficiencies (e.g., G6PD, phenylalanine hydroxylase) from presenting features like hemolytic anemia or intellectual disability. They must interpret laboratory values (e.g., elevated ammonia, lactate, or homocysteine) and link them to specific disorders (e.g., urea cycle defects, mitochondrial disease). Nutritional questions require knowledge of vitamin deficiency syndromes (e.g., beriberi, pellagra, scurvy) and their treatment, including dosing of thiamine for Wernicke encephalopathy or niacin for pellagra. Candidates must also calculate nitrogen balance, interpret BMI cut-offs (e.g., obesity ≥30 kg/m²), and apply dietary management for conditions like phenylketonuria (PKU) or glycogen storage diseases. The exam emphasizes clinical reasoning—e.g., choosing between biotinidase deficiency and holocarboxylase synthetase deficiency based on age of onset and urine organic acids.

High-Yield Concepts

• Glycogen Storage Diseases (GSD): GSD type I (von Gierke): glucose-6-phosphatase deficiency → fasting hypoglycemia, lactic acidosis, hyperuricemia, hepatomegaly. GSD type V (McArdle): muscle phosphorylase deficiency → exercise intolerance, myoglobinuria, 'second wind' phenomenon. GSD type II (Pompe): acid alpha-glucosidase deficiency → cardiomegaly, hypotonia, death by age 1 (infantile form).
• Lysosomal Storage Diseases: Tay-Sachs: hexosaminidase A deficiency → cherry-red spot, progressive neurodegeneration, no hepatosplenomegaly. Gaucher: glucocerebrosidase deficiency → hepatosplenomegaly, bone pain, 'Gaucher cells' (crumpled paper cytoplasm). Niemann-Pick: sphingomyelinase deficiency → cherry-red spot, hepatosplenomegaly, foam cells.
• Vitamin Deficiency Syndromes: Thiamine (B1): beriberi (wet: high-output heart failure; dry: peripheral neuropathy) and Wernicke encephalopathy (ataxia, ophthalmoplegia, confusion) — treat with 100 mg IV thiamine before glucose. Niacin (B3): pellagra (dermatitis, diarrhea, dementia) — treat with nicotinamide 100 mg PO TID. Cobalamin (B12): pernicious anemia (macrocytic anemia, neuropathy, subacute combined degeneration) — treat with IM hydroxycobalamin 1000 mcg daily for 1 week, then weekly.
• Urea Cycle Defects: Ornithine transcarbamylase (OTC) deficiency: X-linked, presents with hyperammonemia (≥200 μmol/L), respiratory alkalosis, coma. First-line: IV sodium phenylacetate and sodium benzoate (Ammonul), arginine supplementation, hemodialysis if severe. Avoid protein intake acutely.
• Amino Acid Metabolism Disorders: Phenylketonuria (PKU): phenylalanine hydroxylase deficiency → elevated phenylalanine, musty odor, intellectual disability. Newborn screen mandatory; treat with phenylalanine-restricted diet (e.g., low-protein formula) and tetrahydrobiopterin (BH4) in responsive patients. Maple syrup urine disease (MSUD): branched-chain alpha-ketoacid dehydrogenase deficiency → sweet-smelling urine, ketosis, encephalopathy; treat with dialysis and dietary restriction of leucine, isoleucine, valine.
• Mitochondrial Disorders: MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, Stroke-like episodes): mitochondrial DNA mutation (often A3243G) → elevated lactate, seizures, migraine. Diagnosis: muscle biopsy shows ragged-red fibers. No cure; supportive care (e.g., coenzyme Q10, L-carnitine, avoid valproate).
• Nutritional Assessment and Management: BMI: underweight <18.5, normal 18.5–24.9, overweight 25–29.9, obesity ≥30 kg/m². Nitrogen balance = protein intake (g)/6.25 – (urinary urea nitrogen + 4 g). Negative balance indicates catabolism. For refeeding syndrome: monitor phosphate, magnesium, potassium; start feeding at 10–20 kcal/kg/day and supplement thiamine.
• Hemoglobinopathies and Porphyrias: Sickle cell disease: Glu6Val mutation in beta-globin → HbS polymerization, vaso-occlusive crises. Treat with hydroxyurea (increases HbF), transfusion, folic acid. Acute intermittent porphyria: PBG deaminase deficiency → abdominal pain, neuropsychiatric symptoms, red urine; avoid barbiturates, sulfonamides, estrogen; treat with IV hemin and glucose.

Common Traps in Biochemistry & Nutrition Questions

• Confusing galactosemia (galactose-1-phosphate uridylyltransferase deficiency) with lactose intolerance; galactosemia presents with cataracts, hepatomegaly, and E. coli sepsis in neonates.
• Assuming all hyperammonemia is due to urea cycle defects; consider organic acidemias (e.g., propionic acidemia) which also cause metabolic acidosis.
• Forgetting that vitamin K deficiency leads to elevated PT (factor II, VII, IX, X) but normal PTT; treat with 10 mg IV vitamin K.
• Misidentifying which GSD presents with hypoglycemia (type I, III, VI, IX) vs. which present with exercise intolerance (type V, VII).
• Using oral vitamin B12 for pernicious anemia; must be IM due to lack of intrinsic factor.
• Thinking that biotin deficiency is rare; it occurs in raw egg consumption (avidin) or long-term TPN without biotin supplementation.

How to Revise Biochemistry & Nutrition for the USMLE Step 1

Focus on linking enzyme deficiencies to specific clinical and lab findings. Prioritize high-yield disorders: GSDs, lysosomal storage diseases, urea cycle defects, and vitamin deficiencies. Questions often present as a clinical vignette with a key lab value (e.g., elevated ammonia, lactate, or urine organic acids) requiring you to identify the enzyme defect and treatment. Memorize classic presentations: cherry-red spot (Tay-Sachs, Niemann-Pick, Sandhoff), hepatomegaly without splenomegaly (GSD I), splenomegaly without hepatomegaly (Gaucher). For nutrition, know BMI cut-offs, refeeding syndrome management, and vitamin deficiency treatments with doses. Practice interpreting newborn screen results and linking to dietary management. Questions are often 'first-order' but require precise recall of specific enzyme names, inheritance patterns, and therapeutic interventions.

Practise it: MedLumen has 30 Biochemistry & Nutrition questions for the USMLE Step 1, each with a full explanation and references.