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25-year-old (Female) with Fatigue

by Mohammad Hajighasemi-Ossareh, MD, MBA

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    00:01 Okay, guys. Super complex but important question, so let’s focus in.

    00:07 A 25-year-old woman visits her physician with the complaint of progressive fatigue.

    00:14 She has noticed that over the past six months she has been feeling increasingly tired at the end of each day.

    00:23 She also feels weaker than before.

    00:26 She has no recollection of similar instances in the past.

    00:30 Her past medical history is insignificant except for the fact that she has been a strict vegan for the last five years.

    00:40 Her vital signs are stable. On physical examination she is visibly pale.

    00:45 A pre-visit blood test was done last week, the report of which shows a hemoglobin of 9.7 with a MCV of 110.

    00:56 The serum levels of which of the following will most likely aid in the physician’s treatment plan.

    01:03 Answer choice A: Succinyl CoA.

    01:07 Answer choice B: Homocysteine.

    01:11 Answer choice C: Ferritin.

    01:14 Answer choice D: Folate, or Answer choice E: Methylmalonic acid.

    01:21 Now take a moment to come to the answer by yourself before we go through it together.

    01:28 Okay, let’s go right into the question characteristics -- this is a juicy good question.

    01:34 Now, this question is family medicine.

    01:37 You’re gonna have people come into the clinic having this kind of complaints, bread and butter family.

    01:42 Now this is a two step question.

    01:45 The first thing we gotta figure out is what’s going on with the patient? What’s the clinical diagnosis? And then we have to figure out what blood test could we used to try to then prove or figure out really our diagnosis here.

    01:59 Of course, the stem here is required because we really have to fish through the clinical symptoms to figure out the diagnosis of the patient and then from there leap one more step forward to figure out which lab test to order. Now, let’s first figure out the diagnosis.

    02:17 We have a young otherwise healthy female patient coming to us and her chief complaint is progressive fatigue.

    02:24 She tells us that for the last six months she’s been tired at the end of each day.

    02:29 Now fatigue, boy, let me tell you, that is a very broad differential diagnosis.

    02:35 This could be sleep disorder, endocrine disorder, a nutrition deficiency, an autoimmune disorder, a viral infection, a cardiovascular or pulmonary problem or even malignancy, AKA anything can make you tired, you know that just from common sense.

    02:55 So really here, it’s tough and the fact that she tells us on top of fatigue, she has generalized weakness, really doesn’t help anything. It just keeps making it more vague and confusing so that doesn’t really help.

    03:07 We have a tired and someone whose generally weak so broad symptoms is still a broad differential diagnosis but she tells us that she’s been a strict vegan for the last five years.

    03:22 Now that really is something we're gonna have to harp on, something you have to be thinking about when reading the question stem, the fact that she’s been a strict vegan for the last five years kind of hints that there’s likely a nutritional deficiency.

    03:37 Now, we know that the typical nutritional deficiencies in patients who were vegan or carry the vegan diet is a B12 deficiency, a calcium deficiency, an iron deficiency and also a zinc deficiency.

    03:53 Now, the physical exam and blood test are actually suggestive of a megaloblastic anemia, although how did I figure that out? Well, the question stem tells us that she’s visibly pale, that means anemia and we’re also told the hemoglobin is 9.7.

    04:09 Well, for a female, 12-14 is a normal range, for a male, 14-16 so 9.7 definitely anemic so that’s also supported - so low hemoglobin, being told on the exam that she’s pale, that can tell you that she’s anemic and the MCV or Mean Corpuscular Volume for her is a 110, normal is 80-96, some people just memorize 80-100, and that’s fine, anything over a hundred is megaloblastic so here she has a megaloblastic anemia.

    04:43 Now, the typical causes of a megaloblastic anemia are going to be a vitamin B12 deficiency or a folate deficiency classically.

    04:53 Now, vitamin B12 deficiency is more likely, given that the patient has a vegan diet but don’t go around assuming things cuz that’s how you get messed up on USMLE.

    05:05 It’s not possible to exclude folate deficiency with this question so we really at this point still have a differential diagnosis of vitamin B12 deficiency or folate deficiency, we can’t just say B12 blindly based on the vegan comment, but we can narrow it down to B12 and folate.

    05:27 So now that we have a narrow differential, let’s try to look through the answer choices of what laboratory test we have to see what even works to figure out the answer.

    05:37 Now, we have to figure out a marker that’s specific for either B12 or folate deficiency.

    05:44 Now, we have to then delete things that would not be related to what telling us about B12 or folate or things that would tell us about both of them, that’s the strategy that we're gonna use when eliminating answer choices.

    05:58 So let’s look at Answer choice B, Homocysteine.

    06:01 Well, that level tells you about both B12 and folate, so you can get rid of that.

    06:06 It doesn’t help narrow the differential, and also answer choice C, ferritin, well, that measure iron levels and we’re not worried about the iron, we’re worried about the megaloblastic anemia and the B12 or folate, so we can get rid of that as well so that leaves us, at this point, having eliminated two already.

    06:25 Now, what are appropriate markers that we can be hunting for? Well, for vitamin B12 what you want to look for is methylmalonic acid, now that’s very viable.

    06:36 Now, if you look at Answer choice A, succinyl CoA, well, this is actually subtle.

    06:42 It’s also involved in the reaction with vitamin B12 but it’s actually not clinically used as a marker as it’s quickly utilized in the citric acid cycle so we don’t use that clinically, it’s not clinically relevant and that could be excluded as well.

    06:59 And then for folate, the only lab test we have for that is a folate level which is Answer choice D, but now that we can say, okay, I can check a folate level or I can check a methylmalonic acid level both are there.

    07:15 So now I’m gonna say that elimination technique didn’t really helped me, what do I need to do? I need to go back to the clinical picture and now I can say, okay, they’ve given me no new information, elimination strategy of the answer choices brought me down to Answer choices D and E, folate and methylmalonic acid and now I have to say, okay, patients that have a vegan diet, what are their deficiencies, okay - B12, calcium, iron, and zinc, I gotta now say, the best answer choice I got is Answer choice E, methylmalonic acid, so that’s the answer choice, methylmalonic acid as a precursor for us to test B12 levels to find out the megaloblastic anemia cause in this vegan diet patient.

    08:03 Now, I hope you really appreciated the complexity of that thought we went through because it was really a tie, two for two, folate or methylmalonic acid but ultimately we eliminated, came down to those two and then with confidence at the end, knowing we had done a fair job of elimination picked the vegan diet as the last data point for tipping when picking our answer choice.

    08:28 So now let’s go through some of the other answer choices, discuss them a little further to learn more about them.

    08:33 Now, let’s start with the right answer which is Answer choice E, methylmalonic acid.

    08:38 Now, the clinical vignette as we said describes vitamin B12 deficiency but we also mentioned that B12 and folate can both cause megaloblastic anemia and if you were to look at the levels of methylmalonic acid, they tell you about the presence of vitamin B12 and they don’t quite tell you anything about folate levels.

    09:00 Now, B12 deficiency can be caused by other causes other than a vegan diet.

    09:06 You need to think about, it’s either gonna be due to either lack absorption of the vitamin as in patients that have pernicious anemia which is a deficiency in intrinsic factor.

    09:17 They could have blind loop syndrome, they could have an infection called diphyllobothrium latum, which actually gets rid of your B12.

    09:25 They could have Crohn’s disease, pancreatitis or even ileal resection -- recall that B12 is absorbed in the ileum, and that is going to be causing B12 deficiency and of course, being a strict vegan can also cause B12 deficiency.

    09:40 Now, the symptoms you need to be looking out for in a patient who has this type of anemia is going to be dyspnea, fatigue and weakness -- very general complaints.

    09:53 And if you were to look at a slide of a blood smear, you would see megaloblastic, basophilic, and polychromatic erythroblast that are prominent in the reticular and finely dense chromatin will also be seen.

    10:08 Now, when looking at a question stem, you also need to pay attention to neurological complaints in a patient with B12 deficiency.

    10:17 Now, patients with B12 deficiency can have several neurological deficits including the most common peripheral neuropathy, that’s like bread and butter, you gotta memorize that. B12 peripheral neuropathy, that’s like peanut butter and jelly -- don’t forget it.

    10:33 Now, other causes that go along with the neurological complaints of a B12 deficiency are also gonna be urinary and fecal incontinence and rarely dementia.

    10:45 Now, sometimes or even seeing the question stem, that there has been a change in the color of their tongue and what they are trying to get out there is with B12 deficiency, you can also have glossitis or stomatitis.

    10:59 Now, remember, both B12 and folate can cause a megaloblastic anemia and that’s defined as having an MCV or Mean Corpuscular Volume greater than a 100.

    11:12 Now, if you were to measure a homocysteine level that would be elevated in both B12 and folate deficiency, that’s a classic trick they try to do on the USMLE and also in your wards, people try to get that, that, oh let’s check the homocysteine -- no, I don’t want to do that because that’ll be high in both folate and B12, it won’t help me.

    11:34 Now, starting folate therapy can actually help improve anemia in patients that have B12 deficiency but to actually treat the neurological complaints of some of the B12 deficiency, you need to replenish the B12. Now, B12 deficiency is actually confirmed by looking at the increased levels of methylmalonic acid also called MMa. Now, methylmalonic acid is a diagnostic test for vitamin B12 deficiency and it’s also the most sensitive test.

    12:06 Now look at the image here of we’re looking at the role of vitamin B12 employing energy from fats and proteins.

    12:14 If you look at our image, we can see that vitamin B12 is a co-factor for the conversion of methylmalonyl-CoA to Succinyl-CoA by the enzyme methlymalonyl-CoA mutase, that’s the B12 what we’re gonna need it.

    12:33 So B12 is used in converting animal fats and animal proteins down to Succinyl-CoA to enter the Kreb cycle to give you ATP, and that’s why patients with B12 deficiency have weakness and fatigue, they are low on energy. So that’s explaining why methlymalonic acid works.

    12:54 Now, let’s look at our other answer choices to show why they’re wrong and how we could have eliminated them.

    12:59 Now, Answer choice A, Succinyl-CoA and we can see Succinyl-CoA here in our diagram and that’s actually the end product of the action of methlymalonyl-CoA mutase on methylmalonic acid.

    13:13 Now, this reaction like we said, uses vitamin B12 as a co-factor and the succinyl-CoA will enter into the citric acid cycle to give you succinate and that’s how we’re gonna get energy, but the key point here, is that succinyl-CoA is not used clinically to diagnose vitamin B12, it’s not a thing.

    13:34 Now, Answer choice B, homocysteine like we said, that’s an amino acid and B12 is used to convert homocysteine to methionine with the help of folic acid.

    13:46 Now because both B12 and folic acid are helping here, homocysteine is going to be elevated in either B12 or folate deficiency, not one.

    13:58 Now, let’s look at Answer choice C, ferritin.

    14:01 Now this is commonly used when assessing a microcytic anemia that is the MCV is less than 80 and a decrease ferritin level is indicative of an iron deficiency.

    14:14 If it’s normal or increased that can be even seen in anemia of chronic disease.

    14:19 There are other microcytic anemia such as sideroblastic anemia or thalassemia in which the level of ferritin will actually be normal, but also something I want you guys to know, take it to both USMLE and the wards, is that ferritin is also an acute phase reactant as seen in inflammatory disorders.

    14:42 And then let’s look here at Answer choice d, folate. And like we said, a decrease in the serum folate levels confirms the presence of a folate deficiency but based on neurological symptoms you won’t see that in folate deficiency but you’ll see it in B12 that can help you clinically kind of isolate between the B12 and folate complaints in another questions stem.

    15:07 And since in this question, methylmalonic acid was ultimately what we went for, we can then say folate to really is a non-neurological clinical complaint and that’s how you can figure out which one to pick.

    15:20 Now, let’s reviews some last high-yield facts regarding vitamin B12 deficiency.

    15:26 So vitamin B12 deficiency is low blood levels of vitamin B12, recall that vitamin B12 is also called cobalamin, now very important, this is why you have to care about these patients, vitamin B12 is not produced by the body, you got it, you take it in, so, but why do we care? Well, vitamin B12 is required as an enzyme and co-enzyme for both DNA synthesis and energy extraction from both protein and fats in the pathway we had discussed.

    15:59 Now, the symptoms of deficiency really depend on the extent of the B12 deficiency.

    16:05 If it’s mild, you can have some fatigue and some anemia that is microcytic anemia, but if it’s moderate, that’s when you start to notice neurological complaints in which you can have neuropathy, you can start to have, if it’s very severe, urinary or fecal incontinence, you can also have decrease sensation and decrease reflexes and if it’s severe deficiency, you can have dementia or even reduced heart function or even psychosis.

    16:36 Now, the causes of deficiency is either going to be due to lack of intake because you didn’t eat it cuz you have like a vegetarian diet or impaired absorption which is going to be due to having ileal resection, pancreatitis, intrinsic factor deficiency also called pernicious anemia, etc.

    16:56 Now the diagnosis is made on an elevated serum methylmalonic acid also called MMA, and if again, if we look at our diagram, we see that vitamin B12 is used to convert methlymalonyl-CoA to Succinyl-CoA so if there’s a deficiency, we’ll have an elevation in MMA or methylmalonic acid and that’s what we’re going to measure.

    17:18 Now, the treatment here is directed at the reversing the cause of the B12 that is if they have some kind of underlying absorption problem, we have to fix it, and of course supplementing with vitamin B12.


    About the Lecture

    The lecture 25-year-old (Female) with Fatigue by Mohammad Hajighasemi-Ossareh, MD, MBA is from the course Qbank Walkthrough USMLE Step 2 Tutorials.


    Author of lecture 25-year-old (Female) with Fatigue

     Mohammad Hajighasemi-Ossareh, MD, MBA

    Mohammad Hajighasemi-Ossareh, MD, MBA


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    Questions review
    By Irina P. on 29. September 2021 for 25-year-old (Female) with Fatigue

    This is an excellent explanation! I like how you split the question into "molecules". Thank you!