What’s up fellow AMBOSSians! I’m Dr. Zeb, here to get the most of this question with you
in the next 7 minutes by covering test-taking strategies, high-yield concepts, and bonus
questions at the end. I know you’re busy studying, so let’s jump right in!
We first need to determine our task by reading the lead-in.
“Which of the following is the most likely cause of this patient's hypercalcemia?”
Alright, now I’m primed for a pathophysiology question. Now, in a real clinical setting,
it’s important to focus on the patient's history and examination before jumping to diagnostics!
But, for timed board questions, I like to read the sentence before to
look for confirmatory findings or even a diagnosis if I’m lucky to save time.
“An x-ray of the chest shows bilateral hilar lymphadenopathy.”
OK, bilateral hilar lymphadenopathy is an important clue that should
narrow down our differentials to which conditions?
That’s right! Sarcoidosis, infections, typically fungal, like histoplasmosis,
blastomycosis, or coccidioidomycosis (tuberculosis is usually unilateral!),
mediastinal tumors like lymphoma, and even some pneumoconioses, so dust
inhalation diseases like silicosis or berylliosis. So now it’s time to put on our thinking caps and
break out those illness scripts! Which of these differentials is associated with hypercalcemia?
Definitely sarcoidosis! But actually, any chronic granulomatous disease, including lymphomas,
and even some systemic fungal infections or pneumoconioses could cause it as well.
So let’s look for any additional features to help narrow down the diagnosis.
“A 35-year-old woman with hypertension comes to the physician
because of a 4-month history of progressive fatigue, shortness of breath, constipation,
and a nonproductive cough. Current medications include hydrochlorothiazide and a multivitamin.”
So to continue our clinical reasoning:
So far, we have two nonspecific findings: hypertension controlled by
a thiazide diuretic and worsening fatigue One sign of hypercalcemia: constipation
Remember: Too much CAlcium = too little CA-CA.
Two respiratory symptoms: shortness of breath and cough
And I’m also paying attention to the age and sex - these often provide important
clues to a condition. And that’s it.
There’s no history of travel, occupation, or other exposure to
indicate pneumoconiosis or an infectious cause. There are no additional constitutional symptoms
such as weight loss, low-grade fever, and night sweats to indicate cancer.
Now, the info in the stem alone doesn’t rule out these conditions. But for exam purposes,
if it was important for ruling in a condition, in other words, a pertinent positive,
then the NBME would have included it.
So, as a systemic disorder that affects the lungs, is associated with hypercalcemia,
and occurs most often in younger to middle-aged women, we can hypothesize that
sarcoidosis is the most likely diagnosis. And if you think back on your pathology,
you’ll remember that chronic sarcoidosis is characterized by noncaseating granulomas.
Hey bro, want some cheese? No thanks, I’m a noncaseating granuloma.
These granulomas harbor activated macrophages that produce 1-alpha hydroxylase.
This enzyme is responsible for converting calcidiol (or 25-hydroxyvitamin D) to the
metabolically active calcitriol also known as 1,25-dihydroxyvitamin D,
or 1,25-dihydroxycholecalciferol, or geeze, how many names does this vitamin have?
Normally, this happens in the kidneys.
Calcitriol then increases intestinal and renal calcium absorption.
Hey, Noncaseating!
What do you call vitamin D whose on trial for kidnapping calcium?
What?
Calci-trial
But in sarcoidosis, it occurs ectopically in activated macrophages,
which can ultimately lead to hypercalcemia.
If you ever need any help with clinical reasoning, I recommend utilizing the key
terms or attending tip in AMBOSS questions in practice mode. Fighting through the question
with the help of these tools will make the content more memorable than just guessing.
Now that we’ve answered the question, let’s see if we can find a match.
Whallah, there it is!
To save time and my nerves, I would normally mark it and move on
because it matched our reasoning, so we don’t have to rule out other options.
But let’s say you weren’t 100% sure, or you’re reviewing.
When reviewing questions, it’s important to briefly reflect and connect concepts to strengthen
your knowledge and identify any gaps, so you’ll be more prepared for similar questions on exam day.
Let’s do that now: Parathyroid hormone-related protein production:
This is a good consideration since it can also cause hypercalcemia,
particularly as a paraneoplastic syndrome of squamous cell carcinomas. If you remember,
PTH and PTH-related protein increase serum calcium by triggering its resorption from bone
and kidney and activating 1α-hydroxylase to create more calcitriol.
Although this patient has symptoms that could match squamous cell lung cancer,
(coughing!)
we’d expect a solitary hilar nodule in the x-ray instead.
With this patient’s hypertension, chronic kidney disease would be a good differential to consider.
But what happens to calcitriol and phosphate with chronic kidney disease? That’s right,
renal calcitriol production is impaired, meaning less calcium absorption, and reduced phosphate
excretion leads to an excess serum phosphate that binds circulating calcium. So we’d actually
expect hypocalcemia - not hypercalcemia. As for the last 3, you’d be right to
consider them as causes of hypercalcemia. A parathyroid adenoma induces hypercalcemia
by excess PTH, as we just spoke about with PTH-related protein.
Although quite rare and not high yield, vitamin A toxicity from excessive
supplementation could disrupt calcium homeostasis, leading to hypercalcemia.
As for thiazides, in the early distal convoluted tubule,
they inhibit sodium-chloride cotransporters,
which leads to a loss of sodium and an increase in renal calcium resorption to compensate.
But none of these explain the respiratory symptoms or bilateral hilar lymphadenopathy.
Also, thiazide-induced hypercalcemia is usually milder, so less than 11.5 mg/dL.
Continuing our reflective practice, let’s briefly consider what other questions could
appear on the exam for a stem like this. Other correct options could be:
Elevated calcitriol
Compensatory decreased PTH
or hyperphosphatemia
We could have been asked for sarcoidosis histopathology, such as:
noncaseating granulomas,
asteroid bodies,
or Schaumann bodies
They could have asked about a further sarcoidosis finding like
uveitis or skin lesions
Or even the diagnosis of sarcoidosis itself.
Ectopic 1-alpha-hydroxylase production is also the cause of hypercalcemia induced by
other chronic granulomatous diseases like Tb as well as lymphomas. So in reality,
we could have answered the question correctly without even diagnosing sarcoidosis,
but hey, hopefully, you learned or reinforced something useful.
Any of these concepts could appear on your exam,
so when you study, try to actively recall like this to be even more prepared.
You can read more about sarcoidosis & differentials in this AMBOSS article:
Let us know in the comments below if you have any other ideas for a good lead-in question.
So to recap, the key takeaways of this question are:
1. Formulate differentials for hypercalcemia and know their pathophysiology.
2. Know that chronic granulomatous conditions like sarcoidosis and lymphomas induce hypercalcemia
by expressing ectopic 1-alpha-hydroxylase, an enzyme that converts calcidiol to calcitriol,
which increases calcium absorption.
3. Identify sarcoidosis based on respiratory symptoms,
signs of hypercalcemia such as constipation, and bilateral hilar lymphadenopathy.
Alright, that’s it for this video,
for another high yield topic that you’ll definitely see on Step 1.
Let us know in the youtube comments if you found this video helpful and would like to see more.
If we get enough interest, I’d be happy to continue them.
Remember, hard work pays off, so keep it up, stay positive - you’ve got this.