Free USMLE Step 1 Sample Questions

The following three USMLE Step 1 sample questions from TrueLearn’s SmartBank test some of the high-yield material you’re sure to see on exam day. Each question is followed by an authoritative answer explanation, complete with rich visuals, a focused Bottom Line statement, and supporting references (including page numbers from First Aid for the USMLE Step 1). Finally, each question also includes a unique TrueLearn Insight. 

TrueLearn Insights are where our expert author team provides Step-wise strategies and tables to help you master the exam. Inspired by our authors’ own experience studying and tutoring for Step 1, they address common student struggles through detailed insider advice. As a supplement to our thorough answer explanations, TrueLearn Insights provide added value not available from any other USMLE question bank.  

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First Step 1 Sample Question: Anemia

A 65-year-old woman presents to the office with generalized fatigue for the last 4 months. She used to walk 1 mile each evening but now gets tired after 1-2 blocks. She has a history of Crohn disease and hypertension for which she receives appropriate medications. She is married and lives with her husband. She eats a balanced diet that includes chicken, fish, pork, fruits, and vegetables. She rarely drinks alcohol and denies tobacco use. Her vital signs are within normal limits. A physical examination is unremarkable. Laboratory studies show the following:

• Hemoglobin: 9.8 g/dL
• Hematocrit: 32%
• Mean corpuscular volume: 110 μm3
• Platelets: 180,000/mm3
• Leukocytes: 5200/mm3

The patient is prescribed oral vitamin B12 supplementation and advised to return to the clinic for follow-up in 1 month. Laboratory studies performed at that time show persistent anemia with a serum hemoglobin of 9.5 g/dL. Which of the following is the most likely cause of this patient’s anemia?

The patient is prescribed oral vitamin B12 supplementation and advised to return to the clinic for follow-up in 1 month. Laboratory studies performed at that time show persistent anemia with a serum hemoglobin of 9.5 g/dL. Which of the following is the most likely cause of this patient’s anemia?

A. Chronic blood loss
B. Complement mediated destruction of red blood cells
C. Decreased release of iron from macrophages due to chronic inflammation
D. Dietary deficiency of folate
E. Impaired intestinal absorption of vitamin B12
F. Pancreatic insufficiency

Answer

When approaching anemia questions on the USMLE, start by evaluating the mean corpuscular volume (MCV) as this will allow one to narrow down the list of possible answers. Here, the patient has an MCV > 100 μm3, pointing toward a macrocytic anemia. Common causes of macrocytic anemia include:

• Vitamin B12 deficiency
• Folate deficiency
• Orotic aciduria
• Alcoholism
• Liver disease

After evaluating the MCV, possible correct answers include dietary folate deficiency and impaired intestinal absorption of vitamin B12. Although this patient’s anemia did not improve with supplementation with vitamin B12, that does not rule out vitamin B12 deficiency as a cause of her anemia. This is because the absorption of vitamin B12 requires several key aspects, including:

1. Adequate dietary intake of vitamin B12
2. Binding of B12 with intrinsic factor (produced by parietal cells within the gastric mucosa)
3. Successful absorption of vitamin B12 in the small intestine (particularly at the ileum)

Vitamin B12 deficiency can develop if any of these steps are impaired. In this case, the patient’s history of Crohn disease should raise suspicion that impaired intestinal absorption of vitamin B12 is the cause of her anemia. Crohn disease can occur anywhere within the gastrointestinal tract, except for the rectum, but most commonly involves the ileum and small intestine. As a result of ileal damage, patients may have impaired absorption of vitamin B12. In these cases, oral supplementation with vitamin B12 will be ineffective as the ileal damage will still prevent sufficient absorption. A similar finding would be expected in cases where patients are lacking intrinsic factor (eg, pernicious anemia, post gastrectomy). 

Historically, the Schilling test would have been used to assess whether vitamin B12 deficiency was due to a dietary deficiency or malabsorption. This test involved four distinct phases:

• Phase 1: The patient is given radiolabeled vitamin B12 to drink or eat. Several hours later, urine is collected and examined for the presence of radiolabeled vitamin B12. The presence of radiolabeled vitamin B12 in the urine implies that the patient is able to absorb vitamin B12 and, thus, is suggestive of a dietary deficiency as the underlying etiology. 
• Phase 2: If radiolabeled vitamin B12 did not appear in the urine, then the patient is given another dose of radiolabeled vitamin B12 and intrinsic factor. If radiolabeled vitamin B12 now appears in the urine, then it suggests a lack of intrinsic factor as the underlying etiology.
• Phase 3: The patient is given radiolabeled vitamin B12 and antibiotics. If radiolabeled vitamin B12 now appears in the urine, then bacterial overgrowth is the likely underlying etiology.
• Phase 4: The patient is given radiolabeled vitamin B12 and pancreatic enzymes. If radiolabeled vitamin B12 now appears in the urine, then pancreatic insufficiency is the likely etiology. If radiolabeled vitamin B12 is still not in the urine, then this is suggestive of ileal disease. 

The Schilling test is no longer routinely used in the clinical setting. However, it may still appear on the USMLE.

Did you get it right? The correct answer was E.

Further Explanation

Answer A: Chronic blood loss can result in iron deficiency anemia. However, iron deficiency anemia is a form of microcytic anemia and would have an MCV < 80 μm3. Iron deficiency anemia should not be considered in a patient who has evidence of macrocytic anemia.

Answer B: Complement mediated destruction of red blood cells is the pathophysiology of paroxysmal nocturnal hemoglobinuria, which is a form of hemolytic anemia and thus would be a normocytic anemia. On laboratory studies, normocytic anemias have an MCV of 80-100 μm3.

Answer C: Anemia of chronic disease occurs as chronic inflammation impairs the release of iron from macrophages and decreases the intestinal absorption of iron. It is most commonly seen with conditions such as lupus, rheumatoid arthritis, and chronic kidney disease. Here, anemia of chronic disease should be eliminated as a possible answer because it typically presents as either a normocytic (most common) or microcytic anemia.

Answer D: Dietary deficiency of folate can result in a macrocytic anemia. However, folate is found in leafy green vegetables. Given that this patient eats a balanced diet with fruits and vegetables, folate deficiency is much less likely than vitamin B12 deficiency secondary to deficient intestinal absorption.

Answer F: Pancreatic insufficiency can result in either a normocytic anemia (due to vitamin E deficiency) or a macrocytic anemia (due to vitamin B12 deficiency). If pancreatic insufficiency were the cause of this patient’s vitamin B12 deficiency, than oral supplementation would not be expected to improve the anemia. However, this patient has no underlying history that would suggest she has pancreatic insufficiency. Causes of pancreatic insufficiency include chronic pancreatitis (often due to alcoholism and recurrent episodes of acute pancreatitis) and cystic fibrosis. Given her history of Crohn disease, impaired intestinal absorption of vitamin B12 is much more likely.

Bottom Line: Vitamin B12 deficiency can be seen in patients with Crohn disease due to impaired intestinal absorption of vitamin B12. In these cases, oral supplementation with vitamin B12 will not result in an improvement of their anemia or symptoms.

TrueLearn Insight

Make sure that you are comfortable differentiating among the different types of vitamin deficiency that can result in anemia. These topics are frequently tested together on the USMLE. 

Second Sample Question: Hydrochlorothiazide Mechanism Of Action

A 57-year-old African American man comes to the office for follow-up regarding elevated blood pressures. Two months prior, the patient was diagnosed with hypertension due to an elevated blood pressure at multiple office visits. Since then, he has attempted to manage his blood pressure with dietary changes and exercise. Despite a 2.3-kg (5-lb) weight loss during this time, his blood pressure is 150/90 mm Hg on arrival and 152/88 mm Hg on repeat 10 minutes later. He has been tracking his blood pressure at home and notes that his systolic blood pressure ranges between 140 and 160 mm Hg. Given his persistent hypertension, pharmacologic intervention is initiated. Six weeks later, the patient returns to the clinic for follow-up evaluation. He notes that his blood pressures have improved, and his systolic blood pressure now ranges between 125 and 135 mm Hg. Serum laboratory studies are ordered and show the following:

Which of the following best describes the mechanism of action of the pharmacologic agent most likely responsible for this patient’s laboratory findings?

1. Blockage of voltage-dependent calcium channels in vascular smooth muscle
2. Decreased production of angiotensin II
3. Decreased renin secretion
4. Increased cGMP-mediated arterial dilation
5. Inhibition of sodium chloride reabsorption in the distal convoluted tubule

Explanation

The correct answer is: E

Thiazide diuretics such as hydrochlorothiazide are frequently used in the outpatient treatment of hypertension, especially in African American patients, as they have been shown to be especially beneficial in this population. Thiazides work by inhibiting sodium chloride reabsorption in the early part of the distal convoluted tubule (DCT) that serves to diminish the diluting capacity of the nephron and induces diuresis. 

Thiazide diuretics have many adverse events, many of which involve electrolyte imbalances and metabolic disturbances. By inhibiting sodium reabsorption in the DCT, use of thiazide diuretics can result in hyponatremia, as was seen in this patient. In addition, calcium is reabsorbed within the DCT, and thiazide diuretics are known to enhance calcium reabsorption at these transporters. As such, thiazide diuretics will cause a decrease in calcium excretion and can cause hypercalcemia (as was also seen with this patient’s laboratory studies). For this reason, thiazide diuretics can also be used to treat patients with recurrent nephrolithiasis due to calcium-containing stones. However, they should not be used in patients with preexisting hypercalcemia. 

Additional adverse events of thiazide diuretics include:

1. Hyperglycemia
2. Hypokalemia
3. Hyperuricemia
4. Metabolic alkalosis
5. Hyperlipidemia
6. Orthostasis 

As such, it is important to schedule a patient for follow-up laboratory studies after initiating treatment with a thiazide diuretic. Also note that, in both clinical practice and on the USMLE, patients may have none, one, or multiple of these aforementioned adverse events.

Answer A: Dihydropyridine calcium channel blockers, such as amlodipine, are often used in the treatment of hypertension as they cause vascular smooth muscle relaxation via blockage of voltage-dependent L-type calcium channels. Although they are calcium channel blockers, they are not associated with the development of hypercalcemia or hypocalcemia. Adverse events of these drugs include peripheral edema, weight gain, flushing, dizziness, and gingival hyperplasia.

Answer B: Angiotensin-converting enzyme (ACE) inhibitors, such as lisinopril, are frequently used in the outpatient treatment of hypertension. They are often used in patients with diabetes as these drugs are also nephroprotective in this population. Adverse events of ACE inhibitors include a dry cough, angioedema, and hyperkalemia. They are not associated with hypercalcemia.

Answer C: Beta-blockers are often used in the treatment of hypertension as they decrease both cardiac output and renin secretion. Beta-blockers decrease renin secretion via beta-1 receptor blockade of the juxtaglomerular apparatus cells. Beta-blockers do not cause hypercalcemia. Adverse events of beta-blockers include bradycardia, heart block, sedation, fatigue, exercise intolerance, erectile dysfunction, dyslipidemia (metoprolol only), and asthma or chronic obstructive pulmonary disease exacerbations (nonselective beta-blockers only).

Answer D: Hydralazine is an arterial dilator that may be used in the outpatient treatment of hypertension. Hydralazine causes vasodilation via increased cGMP, which results in smooth muscle relaxation. Given that its main effect is arterial dilation, use of hydralazine can result in rebound tachycardia. Additional adverse events include drug-induced lupus, fluid retention, headache, and angina. Hydralazine does not cause hypercalcemia.

Bottom Line: Thiazide diuretics are frequently used in the outpatient treatment of hypertension and work by inhibiting sodium chloride reabsorption in the distal convoluted tubule in order to induce diuresis. Thiazides also decrease calcium excretion and, as such, can result in the development of hypercalcemia.

For more information, see:

• Mechanism of action of diuretics: UpToDate
• First Aid for the USMLE Step 1 2019: 593, 595.
• First Aid for the USMLE Step 1 2020: 609.

TrueLearn Insight

Tip #1: If you struggle with multistep questions such as this, you can try working backwards from the answer choices. Here, you could have converted each answer to the medication whose mechanism of action it was describing. From there, you would ask yourself: (1) Would this be used to treat hypertension, and (2) could it cause hypercalcemia? Make sure to take advantage of this being a multiple-choice test and learn to work backwards on 2-step and 3-step questions. 

Tip #2: The USMLE will frequently ask you questions about a medication without telling you what that medication is. Instead, you will need to identify it based on things like: what is it being used for or what laboratory changes and adverse events developed after using it. Make sure to know the medications that you would use for the treatment of common conditions such as hypertension, diabetes, and dyslipidemia.

Third Sample Question: Primary Sclerosing Cholangitis Risk Factors

A 40-year-old man presents for magnetic resonance cholangiopancreatography (MRCP) as part of ongoing evaluation for fatigue. He notes several other additional symptoms but is unsure if these are related, given that they have been present for many years. Laboratory studies had been ordered by his primary care physician and were remarkable for elevated alkaline phosphatase and direct bilirubin. He occasionally drinks a glass of wine or beer with dinner but denies tobacco or intravenous drug use. MRCP is performed and reveals a series of strictures and dilations in the intrahepatic and extrahepatic biliary ducts. This patient most likely has a history of which of the following additional symptoms?

1. Abdominal pain and bloody diarrhea
2. Dysarthria and tremor
3. Epigastric pain that improves with meals
4. Joint pain and hyperpigmentation
5. Watery diarrhea

Explanation

The correct answer is: A

The MRCP findings seen in this patient are indicative of PSC, a form of biliary tract disease that results in concentric bile duct fibrosis of both the intrahepatic and extrahepatic bile ducts. Biliary fibrosis impairs the flow of bile, resulting in an increase in direct (conjugated) bilirubin and alkaline phosphatase on labs. Given that most patients are asymptomatic, PSC is often discovered incidentally due to the evaluation of these abnormal LFTs. When present, common symptoms include fatigue, jaundice, right upper quadrant pain, and steatorrhea.

MRCP or ERCP are useful for making a diagnosis and will demonstrate alternating strictures and dilations (“beading”) of the intrahepatic and/or extrahepatic bile ducts. A biopsy is useful for determining a definitive diagnosis and will show an inflammatory infiltrate as well as concentric bile duct fibrosis. 

PSC is most common in male patients with a history of inflammatory bowel disease (most commonly ulcerative colitis); as such, this patient could have noted a prior history of abdominal pain and bloody diarrhea.

Answer B: Wilson disease is caused by an autosomal recessive mutation in the hepatocyte copper-transporting ATPase and results in decreased copper excretion into bile. Subsequent copper accumulation can affect the liver, brain, cornea, and kidneys. In the brain, copper frequently deposits in the basal ganglia and causes symptoms such as dysarthria, dystonia, tremor, and parkinsonism. Wilson disease is not a risk factor for PSC.

Answer C: The presence of epigastric pain that improves with meals is suggestive of a duodenal ulcer. Duodenal ulcers are commonly caused by Helicobacter pylori but may also be found in patients with a gastrinoma (Zollinger-Ellison syndrome). PSC does not increase the risk of duodenal ulcers.

Answer D: Hereditary hemochromatosis is caused by an autosomal recessive mutation that results in increased absorption of iron by enterocytes and symptoms secondary to iron deposition. Patients are frequently approximately 50 years of age and may complain of joint pain, new-onset type 2 diabetes mellitus, hyperpigmentation (“bronze diabetes”), loss of libido, hepatomegaly, jaundice, and cardiomyopathy. Hereditary hemochromatosis is not a risk factor for PSC.

Answer E: In patients with PSC, biliary fibrosis impairs bile flow and can result in fat malabsorption and the presence of steatorrhea. As a result of impaired fat absorption, patients are at risk of developing deficiencies in the fat-soluble vitamins (vitamins A, D, E, and K) and may present with associated symptoms. Watery diarrhea is not seen in patients with PSC.

Bottom Line: Primary sclerosing cholangitis (PSC) most commonly occurs in males with a history of ulcerative colitis. Diagnostic features of PSC include increased alkaline phosphatase and direct (conjugated) bilirubin on labs and imaging that shows dilation and strictures within the intrahepatic and/or extrahepatic bile ducts.

For more information, see:

• Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis: UpToDate
• First Aid for the USMLE Step 1 2019: 389.
• First Aid for the USMLE Step 1 2020: 395.

TrueLearn Insight

Make sure to understand the key differences between primary biliary cirrhosis and primary sclerosing cholangitis. Students frequently struggle to differentiate between these two pathologies on the USMLE exams.