United States Medical Licensing Examination Step 1

A 6-month-old infant presents with hepatomegaly, hypoglycemia after short fasts, lactic acidosis, hyperuricemia and hyperlipidemia. Muscle strength is normal. Liver biopsy shows markedly increased glycogen with normal structure. Which enzyme is most likely deficient?

1. Glucose-6-phosphatase correct Correct. Von Gierke disease (type I). Without glucose-6-phosphatase the liver cannot release free glucose from either glycogenolysis or gluconeogenesis, so fasting hypoglycemia is severe and early, and the blocked pathway diverts substrate to lactate, urate and triglyceride.
2. Branching enzyme Andersen disease presents with cirrhosis and failure to thrive from abnormally branched glycogen. The biopsy here shows structurally normal glycogen.
3. Muscle glycogen phosphorylase McArdle disease affects muscle only: exercise intolerance, cramps, myoglobinuria and a flat lactate response to exercise. Liver and blood glucose are normal.
4. Debranching enzyme Cori disease gives milder fasting hypoglycemia with abnormally structured glycogen and, importantly, normal lactate because gluconeogenesis is intact.
5. Lysosomal acid alpha-1,4-glucosidase Pompe disease, which pumps up the heart: cardiomegaly, hypotonia, early death. Blood glucose is characteristically normal because cytoplasmic glycogen handling is intact.

The point: Sort glycogen storage diseases by organ and by whether lactate rises. Type I: liver, severe fasting hypoglycemia, HIGH lactate. Type III: milder, normal lactate. Type V: muscle only. Type II: heart.

Source: USMLE Content Outline — biochemistry and nutrition NBME / FSMB (USMLE programme) · tier 0, exam blueprint / regulator

A 58-year-old man is started on a new antihypertensive. Two weeks later he develops a dry, persistent cough. Serum potassium has risen from 4.1 to 5.2 mEq/L and creatinine from 0.9 to 1.1 mg/dL. Which mediator most directly explains his cough?

1. Histamine Mediates immediate hypersensitivity, urticaria, bronchospasm, flushing, not the delayed dry cough of ACE inhibition.
2. Prostaglandin E2 Contributes to airway sensitization in some models, but the mediator ACE inhibition directly spares is bradykinin. Switching to an ARB resolves the cough precisely because ARBs do not affect bradykinin metabolism.
3. Aldosterone Also reduced, which is why potassium rose. It has no role in generating the cough reflex.
4. Angiotensin II Reduced, not increased, by the drug. Reduced angiotensin II explains the blood pressure fall and the potassium rise, not the cough.
5. Bradykinin correct Correct. ACE (kininase II) degrades bradykinin as well as converting angiotensin I to II. Inhibiting it lets bradykinin and substance P accumulate in the airway, producing the dry cough in roughly 5 to 20% of patients and, rarely, angioedema.

The point: ACE inhibitor cough and angioedema are bradykinin-mediated; the hyperkalemia and creatinine rise are angiotensin-mediated. Switch to an ARB for the cough, the potassium effect persists because it is on-target.

Source: USMLE Content Outline — pharmacology NBME / FSMB (USMLE programme) · tier 0, exam blueprint / regulator