DIP Episode 168 - USMLE Step 1 Rapid Review Series 11 (Integrated)

Okay, welcome. My name is Divine, I am a resident. This is episode 168 of the Divine Intervention Podcast and in this episode I'll be continuing our rapid review series for the USM list of one exam. This is going to be focused on step one but this review is I want to try out something today. I'm going to call it an integrated review. Okay, an integrated review. We're in one podcast and we'll talk about biochemistry and we'll talk about pharmacology and we'll talk about he-munk and we'll talk about GI. I will just integrate many things together with this. So let's go ahead and jump right in. So what if you get a question about a 29 year old female. She has a history of hypothyroidism and then they tell you that on physical exam she lacks like vibratory and perceptive sense in the upper and lower extremities and then they tell you that she has like a positive abinski and she also has hyperreflexia and then they give you a bunch of labs and a hemoglobin is like mine. Her plecly count is which is low obviously her plecly count is 160,000 which is normal and then her MCV is 105 and her white blood cell count is 5,100 and then so with all these pieces of information I'm giving you what's your diagnosis? What's your diagnosis? Put everything together. This person clearly has a macrosidic anemia, has problems with vibratory and perceptive sense, has hyperreflexia.

So the person is having like drosocolom symptoms, so drosocolom symptoms, upper modern neurons symptoms, macrosidic anemia. What should that tell you? Well I hope you're telling me that this person has a B-told deficiency and if you want to be a little more specific this person likely has a perinesia senemia, right? Because if you notice in the cure stem I told you that this person has a history of hypothyroidism. Well think about it, what is the most common cause of hypothyroidism in the US? It's Hashimoto's Thyroiditis and that is clearly an autoimmune disease and the thing is when you have one autoimmune disease it increases your risk of having another autoimmune disease. So this person that already has Hashimoto's Thyroiditis very likely has a pretty shes anemia. So let's talk about why we have those different findings. So obviously this person has a B-told deficiency, remember that when people have B-told deficiencies, they will lack vibratory and perceptive sensation because remember B-told deficiency causes something called a subacute combined degeneration of the cord. Okay? A subacute combined degeneration of the cord and when people have subacute combined degeneration of the cord, I mean it's literally called a combined degeneration so that means there are two pathways that don't work out so well and it's the Dorsal columns and your lateral coraco-spinal tract, the upper motor neuron part of your lateral coraco-spinal tract.

So if you have those things going on, if your Dorsal columns don't work you lose your fine touch of vibratory and perceptive sense and then if your lateral coraco-spinal tractors don't work, you have upper motor neuron symptoms for example you have things like hyperreflexia, you have muscle spasticity, you have a positive babinski, those are all things you observe in a person that has upper motor neuron symptoms and then obviously if you have a B-told deficiency you can also have amygdala blastycanemia, okay? You can also have amygdala blastycanemia because if you lack B-told you will lack the ability to produce adequate amounts of DNA because you are not able to produce adequate amounts of DNA, right? So you have like some issues with the cell division process so you get them in a galoblastic anemia that's why the MCV is elevated in this question. So what are some higher-yield things you want to keep at the back of your mind with B-told deficiency? Well what can cause a B-told deficiency on MDM exams? One thing that can cause a B-told deficiency is you see if you're vegan, right? Because if you think about it and again I'm not saying like oh by being a vegan you get a B-told deficiency, let's see if you're on a wise vegan, right? Because as a vegan you already know that you should be at least the prudent thing to do is to supplement B-told in your diet, right? Because B-told is primarily derived from animal products, right?

So you should be taking some kind of multivitamin that includes vitamin B-told and the thing is one nice thing you want to keep at the back of your mind is that your friends at the MDM again, there's only so many ways they can ask something, right? So one classic strategy the MDM uses to make questions difficult is just to give something a different name. So instead of seeing B-told on you exam you may see cobalamin as the answer choice so don't be sweet by that. So B-told because you obtain it from animal products, right? B-told tends to happen in vegans, that's one. Two, another person that can get a B-told efficiency on an MDM exam is a person that has celiac disease, okay? Or some kind of malabsorptive disorder, right? So if for example a person has like celiac disease where their terminal ilium doesn't work so well or if a person has Crohn's disease where they have again inflammation and they've torched the terminal ilium that can also cause a B-told efficiency because the thing is the terminal ilium is where B-told needs partner intrinsic factor get absorbed into the systemic circulation. So the presence terminal ilium doesn't work right that can cause a B-told deficiency. If a person also is taking a PPI that can also cause a B-told deficiency because remember you need the acidity of the you need the acidity of the stomach for you to have the ability to separate our factor from intrinsic factor that's so basically let me tell you this.

Intrinsic factor binds up with our factor so our factor is produced in the saliva and then that our factor goes down in the stomach it marries intrinsic factor and then that our factor and intrinsic factor complex they split up parts by the acidity of the stomach and then intrinsic factor like in the doodinal it pairs up with vitamin B12 and then the travel all the way to the terminal ilium and then they get reabsorbed together. So if a person has is taking a PPI right they don't have acidity in the stomach because you've been inhibited that hydrogen potassium ATP is bomb that you find at the surface of right ourselves so you're not able to establish a acidity in the stomach so that can certainly cause a B-told deficiency that's a high you'll think to keep at the back of your mind. Now one other thing you also want to remember is that B12 deficiency can be caused by prenecious anemia right like the case in this question that I highlighted because the thing is that B12 B12 I mean intrinsic factor right like you can make autoantibodies against intrinsic factor or autoantibodies against like parietal cells right and if you do those things you you'll essentially limit the ability to produce intrinsic factor and that can cause a B12 deficiency again because you don't you need intrinsic factor for B12 to be successfully reabsorbed in the GI tract.

So again if you're terminal if if you have a prenecious anemia that can cause a B12 deficiency and I think I may have made a small mistake early I don't know like my my mind just doesn't seem to agree with something I just said so actually so let me explain this I think maybe walking through things in a somewhat systematic fashion will make things a little more make things a little more useful.

So the thing is when you eat like dietary protein right let's say you eat like you know a diet that contains B12 the thing is the first thing that happens is our factor is secreted sometimes it's known as haptocory that our factor is secreted and like in the saliva right and it travels on its way you know goes all the way to the stomach but the thing is in the stomach for you to cleave B12 from dietary proteins you do actually need pepsin to make that happen so pepsin which is a stomach enzyme cleaves B12 from dietary like like the food that you consume okay so the thing is if you're taking a proton pump inhibitor right because remember pepsin is the active form of pepsinogen and remember pepsinogen comes from chief cells of the stomach the thing is if you want to convert pepsinogen to pepsin you need the acidic environment of the stomach to make that happen so if you're taking a PPI and you inhibit that hydrogen potassium and tip order that is found on the surface of the pride ourselves then you don't make an acidic environment in the stomach pepsinogen which is a zymogen never gets converted to pepsin and if that happens then pepsin will not be able to cleave vitamin B12 from the diet like the food you consume like the animal products you consume and that can cause a vitamin B12 deficiency okay so that's the mechanism that's the true so I made a small mistake earlier my apologies for that but that is the primary mechanism behind PPI's causing a vitamin B12 deficiency and this is something that has been proven in the literature but let's continue that RF factor because it's kind of high-yield and important to know so the thing is after pepsin has cleaved vitamin B12 from your dietary like whatever's right then that B12 binds to our factor again remember another name for our factor which is on your NV Me exam is Haptocory so that RF factor binds to B12 and when that RF

factor binds to B12 it protects it from the acidity of the stomach because B12 believe it or not can actually be denatured by the stomach but RF factor prevents that from happening so the thing that happens is RF factor is almost like a protecting group for B12 and those two things travel together those two things travel together to like the doorkno and then in the doorkno pancreatic enzymes okay pancreatic enzymes pancreatic enzymes cleave B12 from our factor okay and then B12 can then run free and then it can pair up with intrinsic factor that has been secreted by the parietal cells in the stomach that do that intrinsic factor just travels on its own and then pairs up with B12 and then B12 and intrinsic factor they then come together and then get reabsorbed in the terminal area so if a person has like cystic fibrosis for example or they have like chronic pancreatitis where they are not able to make pancreatic enzymes then that can certainly cause a B12 deficiency because you lose the ability to cleave B12 from our factor and if you cannot cleave B12 from our factor then B12 whenever it's like B12 is already in a relationship right and intrinsic factor does not enough to do breakups right so if B12 does not break up with our factor which happens on the tutelage of the pancreatic enzymes then you begin to have issues where intrinsic factor cannot bind to B12 and that can certainly also cause a B12 deficiency now another weird thing that can cause a B12 deficiency is this bog known as diphylobotherium lardum okay diphylobotherium lardum can consume your vitamin B12 and again that can also cause a B it's a parasite it can cause a B12 deficiency so again those are all things that can so you can see how many questions your friends at the mbimic can generate for a B12 deficiency question I mean you never knew that there's there's this there's this much that can be derived

from vitamin B12 so B12 again we've kind of talked about the different things that can happen in a person that has a B12 deficiency we talked about the subacute combined degeneration of the cork when you lose the dorsal column pathway right I mean yeah when you lose the dorsal column pathway and then you lose the lateral corticospinal tract the thing is that subacute combine degeneration of the spinal cord whenever the mbimic writes questions that details that pathology the occasionally put like two other answer choices to try to mess with people's heads and those are answer choices that deal with anterior spinal artery syndrome and answer choices that deal with tertiary syphilis so remember tertiary syphilis can cause something called tb's dorsalis where the syphilis destroys just the dorsal columns so when a person has tb's dorsalis the only symptoms they will have will be dorsal column symptoms they will not have the upper motor neurons symptoms that you get from destroying the lateral corticospinal tract because tertiary syphilis just affects affects only the the dorsal columns right so again that's something high you'd want to keep at the back of your mind now one other thing you want to you know sort of like lock down at the back of your mind as well is anterior spinal artery syndrome right so how does it classically present?

Classically on mbimics it will present in a person that has a triple A and that triple A was fixed with surgery right and then they will say that oh during the course of the surgery they were multiple the person had like multiple hypotensive episodes the thing is you abdominal aorta gives like supplies and artery known as the artery of a dhamcoids the artery of a dhamcoids supplies the anterior spinal artery for multiple segments in the spinal cord so if you infarct the artery of over dhamcoids during the fix of an abdominal leoric aneurysm then that can cause anterior spinal artery syndrome and when a person has anterior spinal artery syndrome they essentially infarcts every part of the spinal cord with the exception of the dorsal columns because the dorsal columns are supplied by the posterior spinal arteries so that's something again how you want to keep at the back of your mind on exams so why is b12 so important right why is b12 so important 12 b12 is important for many reasons and one thing that your friends at the mbimics love to test in the context of b12 is the relationship is like comparing and contrasting b12 and folic acid okay comparing and contrasting b12 and folic acid the thing is when people have a bit of deficiency their levels of homocysteine go up okay if a person also has a folic deficiency that presents homocysteine level goes up as well and we'll talk about why that is the case in a second in fact that's where I was that integrating multiple concepts are real quick homocysteine there's just so much knowledge you can build around homocysteine on mbim exams so that's kind of like a big thinna but that's a big concept I'll go with a maybe like generic like 30 40 different questions during the course of this podcast so this should be a fun podcast to listen to and then but the thing is when a person has a bit of deficiency right in bit of deficiency

you'll have elevations in your methamalonic acid because it's so happened b12 catalysis at least two reactions that we know of in the body one involves an enzyme known as methionine synthase I'll talk about that in a second but another thing that b12 catalysis is the reaction that involves converting methamaloneo coi to succino coi right remember the breakdown of the photometabolism of ochin fatty acids so b12 helps in the conversion of methamaloneo like the enzyme methamaloneo coi mutates which converts methamaloneo coi to succino coi uses b12 as a go factor so if a person has a deficiency of adding b12 methamaloneo coi would not work appropriately and if methamaloneo coi does not work appropriately that will cause an elevation in the presence I mean sorry if methamaloneo coi mutates does not work appropriately that will cause an elevation in the presence methamaloneo coi level so a methamalonic acidemia can be caused by a bit of deficiency so that's how you tell a bit of deficiency apart from a fully deficiency and remember that fully deficiency red occurs when you don't implant products and fully deficiency tends to occur more like easily than a bit of deficiency because fully you can run out of your stores within like three months it takes years for you to run out of your stores of vitamin b12 and fully try well what are the classic people that get fully deficiency people that either tear and toast diet so they're like an old person that is depressed and is not having good nutrition it can be an alcoholic one of the most common vitamin deficiencies that develops in alcoholics is a fully to a vitamin b9 deficiency they'll try to trick on you exam by seeing vitamin b12 deficiency don't choose that choose vitamin b9 deficiency because the enzyme one of the enzymes that helps you to reabsorb fully in the jujune of the digestive tract actually uses that enzyme is pois

oned by alcohol so alcoholics they tend to get a fully deficiency remember another enzyme deficiency that alcoholics tends to get tend to get not tends to get that's bad English tend to get is a vitamin b1 deficiency finding deficiency really can get like wernicic or socoph syndrome remember the tridobernicic syndrome where people get confusion and then they get ophthalmoplicia right so your ophthalmoplicia can be anything can be like lateral rectus palsy it can be like an astagmas and then they get it taxia right and then remember the thing that gets you from wernicis to corsocophs is if the person is beginning to have amnesia right so they're beginning to forget stuff or behalf confabulations or the amicin stuff up then that gets you from the realm of wernicis to corsocophs and remember that wernicis encephalopathy is reversible you can treat it with IV thiamine but corsocophs are causes is irreversible and remember many people think at least this is something you certainly want to keep at the back of your mind when being exams that the symptoms of wernicic corsocoph syndrome arise from dysfunction of the enzyme known as trasketolise remember trasketolise is the regular limiting enzyme of the non-oxidative phase of the hexos monophosphate shot which is also known as the pentosephosphate pathway and then remember the neuronatomicol association or wernicic corsocophs syndrome remember that wernicic corsocophs syndrome is associated with hemorrhagic infarctions of the mammillary bodies and if they give you a question about an alcoholic you know that comes in with like the classic wernicis symptoms on an endemic exam and then they tell you what do you do first for that patient you obviously want to give vitamin D1 or thiamine first before you give glucose right because if you give the pressing glucose then that glucose will flux through glycolysis and then that blue tha

t glyco after glycolysis you have the pyruvate dehydrogen is complex coming up coming up on that and the pyruvate dehydrogen is complex depends on vitamin D1 as a cofactor remember the pdh complex uses vitamin B1 vitamin B2 vitamin B3 and vitamin B5 as cofactors right so if you consume glucose before you give thiamine you place a need on the person's like you you put increased demand on the person's need for for thiamine and back and throw the person into or exacerbate or worsen their symptoms on wernicic corsocoph syndrome so you always give thiamine first before you give glucose and you may say oh divine this is loyal I promise you these are things that are shown up a lot on the usml is both step one step two ck step three in fact I remember during my internals actually pimped by an attendant on this very concept well thankfully that went well okay so so we said that B12 are fully deficiency can both cause elevations and homocyste well the thing is your friends are the MDM they actually really care about you knowing the different things that can raise the presence levels of homocyste and the thing is these are things that are actually not very terrible to learn if you just try to understand them right so the first thing I think that really makes sense to keep in mind is okay what is homocyste well the thing is homocyste is this ubiquitous compound that we use for a lot of stuff in the bud right we use it for a lot of stuff because you participate in a different number of reactions but the thing is that when a presence homocyste level is elevated that is not good because the thing is homocyste has very reactive soft hydro groups so it can generate a lot of free radicals and cause a lot of damage so what are the different reactions that homocyste is involved in or the first probably the most obvious one is that homocyste if you give it a methyl group it becomes methyo

nid okay if you give a methyl group to homocyste it becomes methyonid so where does that methyl group comes come from the thing is that methyl group comes from comes from full it okay that methyl group comes from fully because remember full it is a very good carrier of methyl groups in the body right so methylene tetrahydrofolate gives that methyl group to homocyste so that the homocyste can become methyonid and the thing is in that reaction that methylene tetrahydrofolate is converted to tetrahydrofolate because it's just given off its methyl group okay now the thing is in that reaction where methylene tetrahydrofolate is producing giving off the methyl group that will help you convert homocyste into methyonine the enzyme that catalyzes that reaction is known as methyonine synthase okay that enzyme is known as methyonine synthase right it's the enzyme that synthesizes methyonine well it so happens that methyonine synthase uses vitamin B12 as a cofactor okay so again make sure you keep everything straight to convert homocyste into methyonine you use methyonine synthase as the enzyme and I think another thing for methyonine synthase is like empty hFR it's like a methylene tetrahydrofolate to reduct these if I'm not mistaken so what I'm gonna call it methyonine synthase for purposes of this podcast so methyonine synthase uses B12 as a cofactor the methyl group for that reaction comes from methylene tetrahydrofolate that gets converted to tetrahydrofolate in the cause of that reaction okay so again those are all high-yield things to keep in mind for your exam so if you understand what I just said you can already see right of the bat three causes of elevated homocyste right three causes of elevated homocyste so think about it if a person has a B12 deficiency the methyonine synthase doesn't have a cofactor they'll prevent the conversion of homocysteine to methyonine your h

omocysteine levels will increase if a person has a fully deficiency then you will not have any feedstock that gives rise to methylene tetrahydrofolate okay and that you will not have any methyl donor for that homocysteine to methyonine reaction so your homocysteine levels go up alternatively if you have a mutation or a deficiency of the enzyme methyonine synthase then you literally have like no enzyme that can also cause an elevation in a person's homocyste right in fact I will talk about that separately in a second right but actually there are actually two more things that can cause elevations in a person's a homocysteine the thing is in addition to being able to be converted to methyonine another reaction that homocysteine gets involved in is its its conversion from homocysteine to cysteine okay conversion of homocysteine to cysteine and the enzyme that does that is known as CBS so CBS like the TV station although the CBS in this case stands for cysteothionine beta synthase okay cysteothionine beta synthase is the enzyme that converts homocysteine to cysteine okay the thing is it's called cysteothionine beta synthase because along the way from going from homocysteine to cysteine you have like a cysteothionine intermediate so now the thing is that CBS enzyme actually uses vitamin B6 as a cofactor okay it uses vitamin B6 as a cofactor so guess what if you have a deficiency of vitamin B6 remember another name for vitamin B6 is pyridoxyl phosphate that can also cause an elevation in homocysteine right so if for example a person is taking isonias it and they are not listening to their doctors advice and taking B6 at the same time that can elevate the person's levels of homocysteine and then if you also have a mutation or deficiency of the enzyme CBS right that can also cause elevations in homocysteine because again the homocysteine is not able to be converted to cysteine

and it so happens that there is actually a genetic disorder that literally is associated with a deficiency or mutation in CBS and that's what's known as homocysteinuria right like homocysteinuria homocysteine emia whatever you want to call it but it's a genetic syndrome where a person has elevations in homocysteine from a CBS deficiency in fact the CBS deficiency this is very high up a CBS deficiency is the most common genetic cause of elevations in homocysteine okay now remember I also talked about methyonine synthase there are actually some cases of homocysteineuria that are associated with deficiencies of methyonine synthase but the CBS deficiencies are not more common than the methyonine synthase deficiency so what are the key things you want to keep at the back of your mind with homocysteineuria well you want to keep at the back of your mind essentially you want to be able to compare and contrast this with morphine syndrome the thing is your friends at the mbmed love to see if you can differentiate between this and morphine syndrome right so the first one the first differentiating factor here is the mechanism of inheritance homocysteinuria is in herithetian and orosomor recessive fascia remember I think I may have given this shriq in one of my genetic disease in my I think my genetic disease podcast again this rule doesn't always work but it probably works like 80% of the time so it's a rule of remembering right the thing is whenever you have an enzyme deficiency enzyme deficiencies are almost always in herithet in an orosomor recessive fascia right and homocysteineuria is no exception to that rule right so homocysteineuria is almost always in herithet in an orosomor recessive fascia compare this with morphine syndrome where the mechanism of inheritance is in an orosomor dominant fascia and again that brings another most structural protein deficiencies or mutati

ons tend to be in herithet in orosomor dominant fascia for example if a person has morphine syndrome they have a mutation in fibrillin orosomor dominant inheritance fibrillin is a structural protein if a person has heridugis virus itosis right like a mutation in the enzyme spectrain and crane band 3.2 those are all structural proteins that's in herithet in an orosomor dominant fascia if a person has heridugis down low syndrome they have mutations in collagen collagen is a structural protein for many things orosomor dominant inheritance as well okay so again those are all high yield things want to keep at the back it's a high yield rule to keep in mind I mean think above a willy brand disease is a deficiency of a willy brand factor right the willy brand factor is a structural protein right it's a structural protein it helps you with adhesion step of primary hemostasis orosomor dominant inheritance as well so mutations in structural proteins in general are in herithet in an orosomor dominant fascia now so back to a story of differentiating homocystinuria from morphine syndrome right so we said that homocystinuria is in herithet in an orosomor recessive fascia morphine is inherited in an orosomor dominant fascia well and homocystinuria already said that again it's associated with the mutations in CBS since the thionine beta synthase or mthfr right so like methylene tetrahedral folid reductase which is also known as methylene synthase on the other hand in more fancy syndrome the mutation is in uh fibrilline okay remember fibrilline is a gene that comes from our chromosome 15 that's another added bit of detail that you want to keep in mind for mbimic and then remember that people that have homocystinuria right they tend to have a marphanoid habitus just like people that have morphine syndrome that also have a marphanoid habitus now people that have homocystinuria they tend

to have intellectual disability okay people that have marphans actually tend to have normal intelligence so for present has an abnormal IQ on mbimic exams that excludes the diagnosis of marphans uh marphans okay and then another key thing to keep out the back of your mind is people that have marphans their lens systems tend to be dislocated upwards contrast that with people that have homocystinuria where their lens is tend to be dislocated downwards okay so again those are all high of things to keep out the back of your mind for mbimic exams now whenever you see a person whenever you see like the term marphanoid habitus on an mbimic exam there are certain things you want to keep out the back of your mind in a differential diagnosis the first one is obviously marphan syndrome okay marphan syndrome is associated with a marphanoid habitus but again remember you'll see the other findings of marphan syndrome like mitral valve prolapse you'll see the aneurysms in the circle of willis most commonly with the anterior communicating artery right you'll see them again have all those other disorders like aortic dissection thoracic aortic aneurysms fins of that nature right another thing you should consider your differential in the presence that has a marphanoid habitus is homocystinuria again like i said intellectual disability a lot of vascula events like strokes myocardial infarctions right again intellectual disability they'll have like the lens dislocated downwards right and things of that nature a third thing you want to keep out the back of your mind with a marphanoid habitus is mm 2b remember mm 2b it's an autosomodominant disease right where a person has a mutation in a rect gene okay I remember it in mm 2b those people have again they have a marphanoid habitus they have mucosone neuromus they have fiochromocytomas and they have medallary thyroid cancer remember that calcet

onin is the tumor marker for medallary thyroid cancer okay and then another thing that can cause a marphanoid habitus on mbm exams is a inclined filter syndrome right but it'll be a guy you know that has like gynecomastia like a super tall guy has gynecomastia has a micro penis has very small testicles think about client filter syndrome under those circumstances so those are the different things you should keep at the back of your mind if you see a marphanoid habitus mentioned on your mbm exam so essentially if you understand everything i just talked about then you should know all the different things that can elevate your homocystinuria or summarize this right so if you have a B6 deficiency right so there are essentially five things that can cause a homocystin elevation if you have a B6 deficiency remember another name for B6 is parydoxyl phosphate CBS will not work so you'll not be able to convert homocystin to system so your homocystin levels will go up if you have a CBS mutation aka homocystinuria okay you won't be able to convert homocystin to system so your homocystin levels will go up as well if you have a B12 deficiency methionin synthase will not work so your homocystin level will also go up because another will convert that homocystin to methionin if you have a B9 deficiency aka a fully deficiency you'll also have issues converting homocystin to methionin because again remember fully it provides the methyl group for that reaction to go on because the difference between homocystin and methionin is a methyl group and then if you have an MTHFR deficiency aka methionin synthase deficiency or mutation that will also cause elevations in homocystin because you're not able to convert your homocystin to methionin again those are all big higher things to keep out the back of your mind for exams so what if but I mean methionin is also kind of important I mean like many

people don't think about it this way but methionin believe it or not is also a pretty great it's also a pretty great methyl donor in the body okay so the thing is methionin can actually combine with ATP and when it combines with ATP it becomes a compound known as SAM okay this adenosio methionin well SAM is a very key high-eal methyl donor in the body one key reaction your friends at the end being kind of expected to know it SAM is that SAM can be the methyl donor for the conversion of neuropinephrine to epinephrine remember the conversion of neuropinephrine to epinephrine that reaction actually happens in the adrenaline dollar okay and remember that it happens under the action of the enzyme known as PNMT okay PNMT is known as a phenol ethanolamine N methyl transferase okay it converts neuropinephrine to epinephrine right literally the difference between neuropinephrine and epinephrine is a methyl group okay is a methyl group so SAM provides the methyl group for that reaction to happen and actually just as an endocrine tying here because I'm feeling like integrating this evening the endocrine tying you want to keep at the back of your mind here is that PNMT is actually activated by cortisol that is actually one of the ways that cortisol has a permissive effect on the sympathetic nervous system okay and then really in that reaction that SAM after it gives off its methyl group and you give off like adenosine it actually reforms homocysteine and then you keep that homocysteine cycle going again now I also talked about methylene tetrahydrofolate and tetrahydrofolate well I said that methylene tetrahydrofolate after it gives off its methyl group right to methylene synthase it forms tetrahydrofolate well what are some high yield things you want to keep at the back of your mind with this folate business right remember that that methylene tetrahydrofolate can also help you i

n DNA synthesis this is one of the reasons why folate deficiency can cause megaloglastic anemia because it can mess up your DNA synthesis right because the thing is if you want to convert DUMP or deoxyredine monophosphate to DTMP or deoxythymidine monophosphate the difference between your your cell and thymine believe it or not is actually the presence of a methyl group okay that methyl group actually comes from a methylene tetrahydrofolate and the thing is in that reaction that methylene tetrahydrofolate does it gives its methyl group to DUMP to become DTMP it becomes dihydrofolate well that dihydrofolate is kind of important for reason because that I mean if you want to convert that dihydrofolate but to like the methylene tetrahydrofolate you need to convert the dihydrofolate first to tetrahydrofolate and you already you should already know the enzyme that makes that happen.

The enzyme that makes that happen is known as dihydrofolate reductis. Dihydrofolate reductis converts dihydrofolate to tetrahydrofolate and in that tetrahydrofolate can ultimately be converted back to methylene tetrahydrofolate well what is dihydrofolate reductis important?

Dihydrofolate reductis is important because it is inhibited by multiple drugs like it is inhibited by pyramethamine remember pyramethamine is combined with sulfurizing to treat toxoplasmosis in like HIV patients remember if they give you a question about a HIV patient that has multiple ring enhancing lesions in the brain right that toxoplasma gondia you can treat that with a combination of pyramethamine and sulfur diezin pyramethamine works by inhibiting dihydrofolate reductis now if a person has HIV and we have nemosis disease you will see remember that you can treat that with tri-methodramsopharmethoxazole when it so happens that the tri-methodram part of tmpsmx works by inhibiting dihydrofolate reductis as well and then if you get a question about a patient that has rheumatoid arthritis the first line agent for the treatment of rheumatoid arthritis is the demard known as methyl trexit okay methyl trexit works by inhibiting dihydrofolate reductis so there are three high old drugs on you exam that work by inhibiting dihydrofolate reductis the methyl trexit tri-methodrhym and pyramethamine okay so those are all high old things you want to keep at the back of your mind and it so happens that because if you think about it if you keep inhibiting dihydrofolate reductis you're not going to be able to regenerate active folate and you're not going to be able to make DNA so you can get a profound bone marrow suppression with that okay so one high old thing you want to keep at the back of your mind is that if a person has a profound bone marrow suppression from taking one of these folate inhibitors one thing you can actually do on an mbme exam is is to give a drug known as lucovory okay to give a drug known as lucovory lucovory is a pholinic acid analog that can be used to rescue the bone marrow in a person that has profound bone marrow suppression in the setting of taking a f

olate inhibitor classically methyl trexit on mbme exams now one thing you want to keep at the back of your mind is that lucovory is an analog of pholinic acid it is not an analog of folic acid they do this a lot both on you wrote and on mbme exams to mess up people's heads okay look of there's a difference between folic acid and pholinic acid they are not the same compound lucovory is a pholinic acid analog because believe it or not your friends at the mbme have been known to write questions where they talk about a person that is having profound bone marrow suppression from taking methyl trexit and then they tell you that oh which of the following is the rescue agents yada yada yada and then you put an answer choice that says for administration of a folic acid analog and then they will give you an answer choice that says administration of a folic acid analog you want to go ahead and pick the answer choice that says administration of a folic acid analog which is lucovory now i'd also just said that um that methanine tetrahedral folic provides the methyl group for you to go from deoxyardium monophosphate or du mp to deoxyardium monophosphate dt mp well the thing is the enzyme that actually catalyzes that reactions and enzyme known as thymidylate synthase okay thymidylate synthase right helps you literally synthesize thymidine okay so that's a high-ealthing one to keep at the back of your mind because there's actually a drug that works by inhibiting thymidylate synthase that drug is known as uh five-floor urethyl okay five-floor urethyl is a thymidylate synthase inhibitor okay and it's an anti-cancer drug because again it prevents dn-y synthesis now the thing is um many people just stop their knowledge at five f u but there's actually like a high-ealthing that your friends at the u sml exams me won't that for whatever reason i don't find in too many resources that actual

ly uh again integrates on extra knowledge with five-floor urethyl the thing is think about it if they give you a question about a hiv patients that has like no core agility and you know has like signs and symptoms of meningitis what is the bug that is likely causing them meningitis well i would hope you're telling me that that person has a cryptococcal meningitis remember right meningitis in a hiv patient the big thing you want to be thinking about is cryptococcus new formants okay if a person has cryptococcal meningitis i mean obviously you can meet the diagnosis by you know you can do like the latex particle uh latex a particle agglotination but one other thing you can actually do is i mean remember it's positive for india ink so the india ink stain is pretty good for um cryptococcus and your formants but again these days everyone does the cryptococcal latex particle agglotination uh as a so the thing is um um the way you trade crypto is actually you give amphoteric like a combination of amphotericin b and five flu cytosine okay now you i mean amphotericin b you know it's a they gostrel inhibitor right bynzer gostrel poke holes in the walls of the uh fungal membrane right uh but one thing you want to keep at the back of your mind is how those five flu cytosine work well it's again it's a biochemistry application so again this is something that your friends at the mb me want you to understand the thing is maybe not want you to understand so that you don't get the question right on the test but i mean i truly believe that the people that read these questions actually really want students to succeed but i guess that's a different conversation for a different day but the thing is that five flu cytosine is actually because think about it what is the difference between cytosine and uracel it's actually an amino group cytosine has an amino group that uracel does not have s

o the thing is if you want to convert cytosine to uracel all you need to do is deaminate cytosine and boom uracel shows up so it so happens that when you take five flu cytosine that five flu cytosine is actually converted by cytosine deaminates to five flu uracel to five f you and then that five f you then inhibits time it relates in this in whatever bulk you're trying to kill aka crypto coql uh i mean crypto coqlasa new formants okay so again these are all higher things to know so i think since this podcast you know it's probably going on for a long while 41 minutes and some seconds so i think i'm gonna maybe go ahead and stop here but again i'll try to be like you know make podcasts like this in the future where i start from one central concept and then begin to build all these networks that is really the ideal way to learn right because really if you understand everything i've just discussed in this podcast you should never ever in your life get a B12 or a full eight or a homo system question mark because i've essentially attracted from every possible angle from like the neurology angle the endocrineology angle the genetic diseases angle the biochemistry angle right i've attracted from mic the micro angle the pharmacology angle right i love making these kinds of podcasts because you can just sit down and again integrate a lot of things in a very short time frame and as i do at the end of every podcast i do offer one on one tutoring for many exams right so if you if you're taking any of these exams or you know people that are taking any of these exams and need help uh please feel free to send them my way i offer tutoring for the usmd step one step two ck step two cs and step three exams and then the pre-clinical medical exams the thirty-ecclative shelf exams uh if you're a medicine resident i offer tutoring for the internal medicine in training exam the abim interna

l medicine board exam right and if you're a college student write tutor for like gen-cam ochem physics biochem histology physiology and there's this thing i've been offering uh called a longitudinal tutoring where if you're first second or third-ecclative student i tutor you for all your class exams so i guess your show of exams if you're third year and then at the same time i tutor you for your upcoming usmd exam okay the vast majority of people have done that with have been wildly wildly wildly successful on the exams and then there's this thing i also offer which is called like a booster course um for the usmd step one it's a 20 hour course for the usmd step two ck and step three exams it's a 10 hour course and essentially the thing i don't know the circumstances is it's good for a person that is at the end of their dedicated periods or a person that feels good about their knowledge base and they just want someone to help them put everything together in a higher format uh essentially this is these sessions end up being like three to five sessions where we reveal a lot of the higher material that you're gonna see on your exam in a very like quick dirty qanny higher format and again i integrate multiple disciplines i mean if you if you listened if you just listen to this podcast you have a pretty good idea of how i integrate concepts together right so those are all things i can help you with with this uh usmd booster course if that's something you're interested in i feel free to reach out to me and then the final thing i offer if you're a met student applying to residency so like an era's application or a collection and a plan to met school so like an amca's application i'd offer like one or one advice in one or one like coaching for like you know personal statement direct letters editing editing applications mocking reviews again i've done this with tons of people a

nd again that overwhelming majority of people i've worked with have been very very very very successful right most of them have much of their first choice so again if that's something you're interested in feel free to reach out to me um again i have a lot of experience with this i've been on the admissions committee of a top two met school for a year so i've reviewed like thousands of applications so i know the kinds of things that people look out for so reach out to me if i'm interested in any of these things so i do wish you a wonderful weekend um i should be going to bed soon so i can watch the lakeers game early tomorrow morning so i'll see in the next podcast thank you and god bless you

Dietary protein $\rightarrow$ Pepsin cleavage $\rightarrow$ R-protein binding $\rightarrow$ Intrinsic factor pairing $\rightarrow$ Terminal ileum reabsorption.

Pernicious anemia (autoantibodies against intrinsic factor/parietal cells), veganism, celiac disease/terminal ileum damage, or PPI use.

Loss of sensation in the anterior spinal artery distribution, often following abdominal aortic aneurysm repair (due to injury to the artery of Adamkiewicz).

Vitamin B12 deficiency. The enzyme Methylmalonyl-CoA mutase requires B12 as a cofactor for this reaction.

Homocystinuria is typically autosomal recessive; Morprhine Syndrome is typically autosomal dominant.

Thiamine (Vitamin B1). Giving glucose before thiamine can exacerbate the deficiency by increasing demand on the already compromised metabolic pathways.

They inhibit gastric acidity, preventing pepsin from cleaving B12 from dietary proteins in the stomach.

Cystathionine beta-synthase (CBS). Deficiency leads to homocystinuria.

Leucovorin (Folinic acid analog). It bypasses the need for active folate regeneration.

Marfans typically have upwardly dislocated lens; Homocystinurics tend to have downwardly dislocated lenses.

Both cause it, but B12 deficiency also causes neurological symptoms (subacute combined degeneration).

Pyrimethamine, Trimethoprim-Sulfadiazine (TMP-SMX), and Methyltrex (Methotrexate).

Elevated homocysteine levels because the conversion of homocysteine to methionine cannot occur.

They inhibit gastric acidity, preventing pepsin from cleaving B12 from dietary proteins in the stomach.

Cystathionine beta-synthase (CBS). Deficiency leads to homocystinuria.

Leucovorin (Folinic acid analog). It bypasses the need for active folate regeneration.

Marfans typically have upwardly dislocated lens; Homocystinurics tend to have downwardly dislocated lenses.

Both cause it, but B12 deficiency also causes neurological symptoms (subacute combined degeneration).

Pyrimethamine, Trimethoprim-Sulfadiazine (TMP-SMX), and Methyltrex (Methotrexate).

Elevated homocysteine levels because the conversion of homocysteine to methionine cannot occur.