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Question 1: Aspirin-Induced Asthma
A 23-year-old man presents to an urgent care clinic for shortness of breath and wheezing. His current symptoms began 2 hours ago, but he reports similar episodes that have occurred intermittently for the last 4 months. He does have a history of childhood asthma, but prior to these latest episodes, he has had several years without symptoms and has not needed to use his albuterol inhaler. His current symptoms do not seem to be correlated to any specific activity or environmental exposure. He denies fever, productive cough, nasal congestion, rhinorrhea, and chest pain. In addition to his history of asthma, he reports having suffered a meniscus injury 5 months ago that he has been managing with over-the-counter pain relievers as needed and physical therapy. His medical history is otherwise unremarkable and he takes no other medications. He does not use tobacco products or illicit substances. Pulmonary examination reveals mild bilateral-end expiratory wheezing. Cardiac examination is unremarkable. Which of the following additional findings is likely present in this patient?
- Cobblestoning of the pharyngeal mucosa
- Increased forced expiratory volume in 1 second/forced vital capacity ratio
- Nasal polyps
- Recurrent symptoms following administration of ergonovine
The correct answer is: D
Aspirin-exacerbated respiratory disease, otherwise termed aspirin-induced asthma, is characterized by the presence of 3 features: asthma, respiratory symptoms that are exacerbated by aspirin or other NSAIDs, and nasal polyps. The symptoms seen in these patients are the result of hypersensitivity reactions to NSAIDs rather than the true allergic reactions that are seen with other forms of allergen-induced asthma. Although the exact pathophysiology is not fully understood, the current theory is that NSAID-induced inhibition of COX-1 results in a decrease in the production of thromboxane and anti-inflammatory prostaglandins. This results in an overproduction of proinflammatory leukotrienes and the development of symptoms such as wheezing and shortness of breath. Patients with aspirin-induced asthma have also been found to have low levels of prostaglandin E2, which further worsens pulmonary inflammation (prostaglandin E2 is protective for the lungs).
This patient has a history of childhood asthma that seemed to be well controlled until approximately 4 months ago. His symptoms have not been correlated to any specific activity or environmental exposure, which further suggests that this is not allergen-induced asthma. In reviewing his history, note that his symptoms began shortly after his knee injury and one should infer that he is likely using NSAIDs based on his admission to using “over-the-counter pain relievers.” As such, since the most likely diagnosis is aspirin-exacerbated respiratory disease, the most likely additional finding is the presence of nasal polyps.
Answer A: Cobblestoning of the pharyngeal mucosa is a sign of post-nasal drip and is often seen in patients with nasal congestion and rhinorrhea. Although patients with aspirin-induced asthma can complain of rhinorrhea and nasal congestion, this patient denies these symptoms, and as such, cobblestoning would be unlikely.
Answer B: Patients with a history of asthma often have a history of other atopic conditions such as eczema and allergic rhinitis. However, as stated above, this patient’s symptoms are not the result of typical allergen-induced asthma but rather are the result of a hypersensitivity reaction to NSAIDs. Urticaria is the most likely dermatologic finding that would be seen in a patient with aspirin-induced asthma.
Answer C: Asthma is an obstructive lung disease and thus is characterized by a decrease in the forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio. Restrictive lung diseases (eg, pulmonary fibrosis, asbestosis) are characterized by a normal or increased FEV1/FVC ratio.
Answer E: The ergonovine stimulation test is used to diagnose variant angina, not aspirin-induced asthma. Variant angina (also termed vasospastic angina and Prinzmetal angina) is caused by vasospasm of the coronary arteries. Patients typically present with resting chest pain and have evidence of episodic ST-segment elevation on ECG. In patients with variant angina, ergonovine administration causes vasoconstriction of the coronary arteries and will reproduce their symptoms. By contrast, remember that the methacholine challenge test is used to diagnose asthma.
Bottom Line: Aspirin-exacerbated respiratory disease (aspirin-induced asthma) is most commonly characterized by the triad of preexisting asthma, worsening of respiratory symptoms following administration of NSAIDs, and the presence of nasal polyps.
For more information, see:
First Aid for the USMLE Step 1 2019: 660.
First Aid for the USMLE Step 1 2020: 674.
There will be several situations where the USMLE will want you to infer that a patient is on a certain medication based on something within the question stem. Some commonly seen examples are included in the table below.
As you study, look for other examples where you are being asked to infer a specific medication based on details within the question stem. Understanding these associations can improve your score on the exam.
Question 2: 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?
- Blockage of voltage-dependent calcium channels in vascular smooth muscle
- Decreased production of angiotensin II
- Decreased renin secretion
- Increased cGMP-mediated arterial dilation
- Inhibition of sodium chloride reabsorption in the distal convoluted tubule
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:
- Metabolic alkalosis
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:
First Aid for the USMLE Step 1 2019: 593, 595.
First Aid for the USMLE Step 1 2020: 609.
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.
Question 3: 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?
- Abdominal pain and bloody diarrhea
- Dysarthria and tremor
- Epigastric pain that improves with meals
- Joint pain and hyperpigmentation
- Watery diarrhea
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:
First Aid for the USMLE Step 1 2019: 389.
First Aid for the USMLE Step 1 2020: 395.
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.