KAPLAN USMLE STEP 1 EXAM PRACTICE | COMPREHENSIVE STUDY GUIDE |
ADVANCED TESTBANK WITH PRACTICE QUESTIONS & ANSWERS | LATEST
UPDATE 2026/2027
TABLE OF CONTENTS
i. Biochemistry, Molecular Biology & Genetics
ii. Immunology & Hematology
iii. Microbiology & Infectious Disease
iv. General Pathology & Neoplasia
v. Pharmacology & Therapeutics
vi. Cardiovascular, Pulmonary & Renal Systems
vii. Gastrointestinal, Endocrine & Reproductive Systems
viii. Neurology, Behavioral Science & Biostatistics
ix. Anatomy, Physiology & Integrated Clinical Correlation
INTRODUCTION
This comprehensive Kaplan USMLE Step 1 practice set is designed around the
foundational biomedical sciences and integrated clinical reasoning emphasized on
USMLE Step 1. The questions target advanced application rather than isolated
memorization, requiring interpretation of mechanisms, laboratory findings,
pathology, pharmacodynamics, physiology, genetics, microbiology, and anatomy.
The difficulty ranges from advanced to extremely challenging, with realistic clinical
vignettes and plausible distractors intended to test discrimination between closely
related concepts. Students should expect questions requiring multi-step reasoning,
identification of underlying mechanisms, prediction of treatment effects,
recognition of classic disease patterns, and integration of basic science with clinical
presentations. This set is intended as a study and review resource for high-level
Step 1 preparation.
Question 1
A 24-year-old woman presents with recurrent episodes of severe muscle pain and
weakness after prolonged exercise. Laboratory studies obtained after an episode
show markedly elevated creatine kinase and myoglobinuria. She reports that
symptoms usually begin after several minutes of intense activity but improve if she
,briefly rests and then resumes exercise. During prolonged fasting, she has no
symptoms. A muscle biopsy demonstrates accumulation of glycogen with
abnormally short outer branches. Which enzyme deficiency most likely explains this
patient's condition?
A. Acid maltase
B. Branching enzyme
C. Muscle glycogen phosphorylase
D. Lysosomal acid lipase
🔴 Correct Answer: C. Muscle glycogen phosphorylase
🔵 Explanation: Muscle glycogen phosphorylase deficiency causes McArdle disease,
characterized by exercise intolerance, muscle cramps, rhabdomyolysis, and the
"second-wind" phenomenon after brief rest. The liver can maintain blood glucose, so
fasting hypoglycemia is not characteristic. Acid maltase deficiency causes Pompe
disease, while branching-enzyme deficiency causes Andersen disease.
Question 2
A newborn develops severe hypoglycemia, metabolic acidosis, hyperuricemia, and
hepatomegaly shortly after prolonged fasting. Laboratory evaluation demonstrates
excessive hepatic glycogen accumulation with normally structured glycogen. Which
metabolic defect is most likely responsible?
A. Deficiency of glucose-6-phosphatase
B. Deficiency of lysosomal acid α-glucosidase
C. Deficiency of muscle glycogen phosphorylase
D. Deficiency of branching enzyme
🔴 Correct Answer: A. Deficiency of glucose-6-phosphatase
🔵 Explanation: Glucose-6-phosphatase deficiency causes von Gierke disease.
Inability to convert glucose-6-phosphate into free glucose impairs both glycogenolysis
and gluconeogenesis, producing severe fasting hypoglycemia, lactic acidosis,
hyperuricemia, hyperlipidemia, and hepatomegaly.
Question 3
,A 7-year-old boy has recurrent infections with encapsulated bacteria. Laboratory
testing shows absent mature B cells and markedly decreased levels of all
immunoglobulin classes. T-cell numbers and function are normal. Genetic testing
identifies a mutation affecting a cytoplasmic tyrosine kinase required for B-cell
maturation. Which cellular process is directly impaired?
A. Class switching mediated by activation-induced cytidine deaminase
B. V(D)J recombination mediated by RAG proteins
C. Pre-B-cell receptor signaling
D. Somatic hypermutation of immunoglobulin variable regions
🔴 Correct Answer: C. Pre-B-cell receptor signaling
🔵 Explanation: Bruton's tyrosine kinase is essential for signaling through the pre-B-
cell receptor during B-cell development. Its absence causes X-linked
agammaglobulinemia, with profound depletion of mature B cells and
immunoglobulins but preserved T-cell function.
Question 4
A 5-year-old child presents with recurrent bacterial and fungal infections, chronic
diarrhea, and failure to thrive. Laboratory studies show severe lymphopenia
affecting both T and B cells. The infant's newborn screening records demonstrate
markedly decreased T-cell receptor excision circles. Which developmental process is
most directly defective?
A. Rearrangement of immunoglobulin heavy-chain constant regions
B. Rearrangement of antigen receptor variable regions
C. Complement C3 synthesis
D. Neutrophil oxidative burst
🔴 Correct Answer: B. Rearrangement of antigen receptor variable regions
🔵 Explanation: Severe combined immunodeficiency can result from defective V(D)J
recombination, commonly involving RAG1 or RAG2. Failure of antigen receptor gene
rearrangement prevents normal development of functional T and B lymphocytes. T-
cell receptor excision circles are reduced because normal thymic T-cell development is
impaired.
Question 5
, A 32-year-old man develops hemolytic anemia after receiving trimethoprim-
sulfamethoxazole. Peripheral blood smear demonstrates Heinz bodies and bite cells.
Which biochemical abnormality most directly predisposes this patient to the
observed hemolysis?
A. Reduced production of ATP by erythrocytes
B. Reduced regeneration of reduced glutathione
C. Impaired synthesis of spectrin
D. Defective β-globin chain production
🔴 Correct Answer: B. Reduced regeneration of reduced glutathione
🔵 Explanation: Glucose-6-phosphate dehydrogenase generates NADPH in the
pentose phosphate pathway. NADPH maintains glutathione in its reduced form,
protecting erythrocytes from oxidative damage. G6PD deficiency therefore
predisposes to oxidant-induced hemolysis, Heinz bodies, and bite cells.
Question 6
A 58-year-old man develops progressive exertional dyspnea and fatigue.
Echocardiography reveals severe concentric left ventricular hypertrophy. He has a
history of poorly controlled hypertension. Which change in ventricular myocytes is
primarily responsible for the increased wall thickness?
A. Addition of sarcomeres in series
B. Addition of sarcomeres in parallel
C. Increased compliance caused by sarcomere loss
D. Replacement of myocytes by adipose tissue
🔴 Correct Answer: B. Addition of sarcomeres in parallel
🔵 Explanation: Chronic pressure overload produces concentric hypertrophy through
addition of sarcomeres in parallel, increasing myocyte width and ventricular wall
thickness. Chronic volume overload instead produces eccentric hypertrophy through
addition of sarcomeres in series.
Question 7
A 67-year-old man with chronic obstructive pulmonary disease has an arterial blood
gas showing pH 7.37, PaCO₂ 60 mm Hg, and HCO₃⁻ 34 mEq/L. Which renal
ADVANCED TESTBANK WITH PRACTICE QUESTIONS & ANSWERS | LATEST
UPDATE 2026/2027
TABLE OF CONTENTS
i. Biochemistry, Molecular Biology & Genetics
ii. Immunology & Hematology
iii. Microbiology & Infectious Disease
iv. General Pathology & Neoplasia
v. Pharmacology & Therapeutics
vi. Cardiovascular, Pulmonary & Renal Systems
vii. Gastrointestinal, Endocrine & Reproductive Systems
viii. Neurology, Behavioral Science & Biostatistics
ix. Anatomy, Physiology & Integrated Clinical Correlation
INTRODUCTION
This comprehensive Kaplan USMLE Step 1 practice set is designed around the
foundational biomedical sciences and integrated clinical reasoning emphasized on
USMLE Step 1. The questions target advanced application rather than isolated
memorization, requiring interpretation of mechanisms, laboratory findings,
pathology, pharmacodynamics, physiology, genetics, microbiology, and anatomy.
The difficulty ranges from advanced to extremely challenging, with realistic clinical
vignettes and plausible distractors intended to test discrimination between closely
related concepts. Students should expect questions requiring multi-step reasoning,
identification of underlying mechanisms, prediction of treatment effects,
recognition of classic disease patterns, and integration of basic science with clinical
presentations. This set is intended as a study and review resource for high-level
Step 1 preparation.
Question 1
A 24-year-old woman presents with recurrent episodes of severe muscle pain and
weakness after prolonged exercise. Laboratory studies obtained after an episode
show markedly elevated creatine kinase and myoglobinuria. She reports that
symptoms usually begin after several minutes of intense activity but improve if she
,briefly rests and then resumes exercise. During prolonged fasting, she has no
symptoms. A muscle biopsy demonstrates accumulation of glycogen with
abnormally short outer branches. Which enzyme deficiency most likely explains this
patient's condition?
A. Acid maltase
B. Branching enzyme
C. Muscle glycogen phosphorylase
D. Lysosomal acid lipase
🔴 Correct Answer: C. Muscle glycogen phosphorylase
🔵 Explanation: Muscle glycogen phosphorylase deficiency causes McArdle disease,
characterized by exercise intolerance, muscle cramps, rhabdomyolysis, and the
"second-wind" phenomenon after brief rest. The liver can maintain blood glucose, so
fasting hypoglycemia is not characteristic. Acid maltase deficiency causes Pompe
disease, while branching-enzyme deficiency causes Andersen disease.
Question 2
A newborn develops severe hypoglycemia, metabolic acidosis, hyperuricemia, and
hepatomegaly shortly after prolonged fasting. Laboratory evaluation demonstrates
excessive hepatic glycogen accumulation with normally structured glycogen. Which
metabolic defect is most likely responsible?
A. Deficiency of glucose-6-phosphatase
B. Deficiency of lysosomal acid α-glucosidase
C. Deficiency of muscle glycogen phosphorylase
D. Deficiency of branching enzyme
🔴 Correct Answer: A. Deficiency of glucose-6-phosphatase
🔵 Explanation: Glucose-6-phosphatase deficiency causes von Gierke disease.
Inability to convert glucose-6-phosphate into free glucose impairs both glycogenolysis
and gluconeogenesis, producing severe fasting hypoglycemia, lactic acidosis,
hyperuricemia, hyperlipidemia, and hepatomegaly.
Question 3
,A 7-year-old boy has recurrent infections with encapsulated bacteria. Laboratory
testing shows absent mature B cells and markedly decreased levels of all
immunoglobulin classes. T-cell numbers and function are normal. Genetic testing
identifies a mutation affecting a cytoplasmic tyrosine kinase required for B-cell
maturation. Which cellular process is directly impaired?
A. Class switching mediated by activation-induced cytidine deaminase
B. V(D)J recombination mediated by RAG proteins
C. Pre-B-cell receptor signaling
D. Somatic hypermutation of immunoglobulin variable regions
🔴 Correct Answer: C. Pre-B-cell receptor signaling
🔵 Explanation: Bruton's tyrosine kinase is essential for signaling through the pre-B-
cell receptor during B-cell development. Its absence causes X-linked
agammaglobulinemia, with profound depletion of mature B cells and
immunoglobulins but preserved T-cell function.
Question 4
A 5-year-old child presents with recurrent bacterial and fungal infections, chronic
diarrhea, and failure to thrive. Laboratory studies show severe lymphopenia
affecting both T and B cells. The infant's newborn screening records demonstrate
markedly decreased T-cell receptor excision circles. Which developmental process is
most directly defective?
A. Rearrangement of immunoglobulin heavy-chain constant regions
B. Rearrangement of antigen receptor variable regions
C. Complement C3 synthesis
D. Neutrophil oxidative burst
🔴 Correct Answer: B. Rearrangement of antigen receptor variable regions
🔵 Explanation: Severe combined immunodeficiency can result from defective V(D)J
recombination, commonly involving RAG1 or RAG2. Failure of antigen receptor gene
rearrangement prevents normal development of functional T and B lymphocytes. T-
cell receptor excision circles are reduced because normal thymic T-cell development is
impaired.
Question 5
, A 32-year-old man develops hemolytic anemia after receiving trimethoprim-
sulfamethoxazole. Peripheral blood smear demonstrates Heinz bodies and bite cells.
Which biochemical abnormality most directly predisposes this patient to the
observed hemolysis?
A. Reduced production of ATP by erythrocytes
B. Reduced regeneration of reduced glutathione
C. Impaired synthesis of spectrin
D. Defective β-globin chain production
🔴 Correct Answer: B. Reduced regeneration of reduced glutathione
🔵 Explanation: Glucose-6-phosphate dehydrogenase generates NADPH in the
pentose phosphate pathway. NADPH maintains glutathione in its reduced form,
protecting erythrocytes from oxidative damage. G6PD deficiency therefore
predisposes to oxidant-induced hemolysis, Heinz bodies, and bite cells.
Question 6
A 58-year-old man develops progressive exertional dyspnea and fatigue.
Echocardiography reveals severe concentric left ventricular hypertrophy. He has a
history of poorly controlled hypertension. Which change in ventricular myocytes is
primarily responsible for the increased wall thickness?
A. Addition of sarcomeres in series
B. Addition of sarcomeres in parallel
C. Increased compliance caused by sarcomere loss
D. Replacement of myocytes by adipose tissue
🔴 Correct Answer: B. Addition of sarcomeres in parallel
🔵 Explanation: Chronic pressure overload produces concentric hypertrophy through
addition of sarcomeres in parallel, increasing myocyte width and ventricular wall
thickness. Chronic volume overload instead produces eccentric hypertrophy through
addition of sarcomeres in series.
Question 7
A 67-year-old man with chronic obstructive pulmonary disease has an arterial blood
gas showing pH 7.37, PaCO₂ 60 mm Hg, and HCO₃⁻ 34 mEq/L. Which renal
