hello everyone and welcome to our session on high yield biochemistry for the usmle step one my name is ethan plotzker and i'm excited to be leading this session with you all today so one of the high steel topics that we're going to dive right into is vitamins you're guaranteed essentially at least a couple of questions about vitamins on your exam so with that let's get started the first vitamin to look out for is thiamine also called b1 so one of the ways this is commonly tested in the clinical context is through the avenue of beriberi there's two kinds of beriberi wet and dry so wet berry berry is essentially the same as dry berry berry except what berry berry has the addition of something called high output heart failure essentially the heart becomes dilated and cardiac output is increased that's on top of dry berry berry which typically involves damaged nerves and muscle atrophy around the body so if you see someone who maybe is malnourished and they're having muscle wasting and nerve issues that is one of the things to definitely consider then we get to warnicky encephalopathy warnicky is characterized by a couple of common symptoms which you can memorize via the mnemonic can obear also because one of the risk factors for thiamine deficiency is alcoholism so can o beer c stands for confusion the a for ataxia the n for nystagmus the o for ophthalmoplegia and beer just reminds you that alcoholism is a risk factor so if you see someone who presents to the ed a lot of times they'll say that the eyes aren't able to look in one consistent direction as a way of tipping you off to the nystagmus maybe they smelled alcohol one of the things to consider definitely is warnicky encephalopathy korsakoff syndrome is similar but what marks korsakoff syndrome is something called confabulation contabulation is essentially when people forget certain periods of recent time in their lives and they fill it in with details that didn't actually happen so for instance you could have a person who comes to the ed and when asked how they got there they were apparently brought on a magic carpet of course they weren't brought on a magic carpet but that is their way of filling in the details that they don't know and they're not trying to fake anything they're just trying to fill in the details because they themselves don't know when you combine warnicky korsakoff syndrome one of the things that the usmle loves to test is what exact part of the brain which anatomical structure is damaged and that is the medial dorsal nucleus of the thalamus or the mammillary bodies um and with warranty corsaikov syndrome you have all of the symptoms of wernicke and the confabulation of corsicoff so the can of beer symptoms of wernicke and then the confabulation of corsicoff and those are essentially the high yield points for thymine or b1 next we get to niacin or vitamin b3 so a deficiency of niacin which is also a very high yield think to know for the step exams for all of them is something called pellagra or the 3ds those d's are dermatitis diarrhea dementia and some people add a fourth d which is death the dermatitis typically presents like in the picture on the right here with that necklace sort of appearing distribution of skin irritation and that is a very commonly tested image on these step exams one of the ways that a niacin deficiency can manifest is with something called hearten up disease so for this we have to go back into a little bit of biochemistry so with heart enough disease you lack the transporters in the proximal renal tubules and with that you can't reabsorb the neutral amino acids one of the neutral amino acids is tryptophan which coincidentally tryptophan is a main component of niacin so in heart enough disease you can't reabsorb tryptophan in the kidney and you urinate it out that can lead to a niacin deficiency or eventually pellagra because you simply don't have the ingredients needed to make the niacin that's a very commonly tested um pathology on the step exams the symptoms as i was saying mainly the things to know are the dermatitis diarrhea and dementia potentially death becomes that severe again it's important to know that tryptophan is a main constituent of niacin but it's also important to know what niacin itself is needed so niacin is needed to to act as one of the main ingredients in the molecules nad plus and nadp plus both of those play important roles in energy production in both glycolysis and the tca cycle they're involved in redox reactions and which nad plus and nadp plus are converted to nadh and nadph respectively and those eventually can fuel onto the electron transport chain so it's clear that niacin plays some pretty important roles and thus is a very testable vitamin for the step exams i'm going to skip a bit ahead to the next high-yield vitamin which is folate b9 one of the things to know is that folate comes primarily from leafy green vegetables things like spinach kale stuff like that um it's also important to know that it plays a really big role in pregnancy the folate is needed to promote neural tube closure in embryos and fetuses so if you don't have folate the babies can have neural tube defects that's why in pregnancy you have to usually supplement with folate also with a folate deficiency you can get a macrocytic anemia which as a little bit of hemank you are going to have over six lobes in your red blood cells and they're going to have an mcv of over a hundred for the labs you're going to want to check the methyl malonic acid and the homocysteine levels so with this case the methylmalonic acid is going to be normal but the homocysteine levels are going to be elevated and that's going to be in contrast to one of the other vitamin deficiencies we're going to see in a bit one other thing to know for folate is just generally about the functions that it does in the body so folate composes primarily among other things tetrahydrofolate which plays a pretty important role in methylation reactions so that involves moving one carbon from one molecule to another and it's also it also plays a big role in um making nitrogenous bases so things like uh deoxyfibronucleotides and ribonucleotides one of the last things they like to test is where folate is absorbed in the gut and that primarily is the jejunum so the main takeaways for this is that folate is involved in methylation reactions plays a role in the neural tube for pregnancy and a defect or deficiency rather can lead to a macroacidic anemia next we come to copa lemon or a vitamin b12 so a b9 and b12 deficiency can look pretty similar and that's because if you have a deficiency in both that can lead to the megaloblastic anemia like you see on the screen there's that red blood cell with um over six lobes present still there are certain ways to tell it apart so with a b12 deficiency unlike a b9 deficiency one of the things that you're going to have is something called subacute combined degeneration that's going to generally manifest in a lot of neuropathic symptoms so what you're going to have is weakness um you're gonna have sort of tingling and numbness in your hands and feet maybe you are gonna be a bit clumsier than normal that's what people describe it's a general loss of proprioception in the extremities so if you have that along with the elevated mcv that would suggest a b12 deficiency for the lab results so unlike before with the benign deficiency when you have the elevated homocysteine levels but the normal methylmalonic acid levels here you would have an elevation of both so that would be an elevation of both the homocysteine and the methylmalonic acid and that's just because these vitamins are involved in different enzymes and processing different substrates so overall things can accumulate on the back end one of the other high-yield facts that's tested for cobalamin or b12 is what food products provided so that primarily is going to be animal products any kind of meat things like that and where it's stored is in the liver and b12 can be stored in the liver for years so it's typically a little bit rare to see someone who has a b12 deficiency due to a lack of meat in their diet eventually if after years and years of not consuming animal products it's possible sure but the usmle typically won't test it in that fashion with a beach pulp deficiency one of the things they typically will test is pernicious anemia where you get antibodies that kind of destroy the ability of b12 to work and be absorbed one of the ways they will test the deficiency of b12 is through something called pernicious anemia where you get antibodies against something called intrinsic factor and then you have less b12 absorption our next vitamin is vitamin c also called ascorbic acid so vitamin c plays a pretty important role in the production of collagen and with that it does hydroxylation so attaches an oh group to proline and lysine residues on collagen and with that it can stabilize the triple helix of the molecule when you don't have that kind of stabilization that can lead to a bunch of different symptoms and sequelae which collectively could be known as scurvy so one of the things you can have is corkscrew hairs and that's just because you don't have um the stabilization of the structural components in the hair one of the next things is easy bleeding and bleeding into joint spaces and one of the ways that the usmle test writers like to trick students is to make them um think that patients have hemophilia rather than vitamin c leading to the bleeding into joint spaces the bleeding into joint spaces is typical of both a vitamin c deficiency and hemophilia but the difference is for vitamin c deficiency it's because you don't have the strength of the vessels required because you have a deficiency in collagen and then that leads to the bleeding otherwise something called the tea and toast diet leads to vitamin c that's because vitamin c is typically found among other things in citrus fruits and if patients especially elderly patients are only having tea and toast as it's usually called they can develop a vitamin c deficiency and if they come to the office with those corkscrew hairs with easy bleeding petechia bleeding into joint spaces all those things might clue you into a deficiency of that vitamin next we come to retinol or vitamin a so vitamin a plays a really important role in vision and that's because the opsins which are photoreceptor proteins in the eye are based they're composed of vitamin a in part so you need vitamin a to see one of the other ways that vitamin a is important is that it can be used in acne treatment and the primary way that the vitamin a works is it promotes re-epithelialization and turnover of keratinocytes which can help clear the skin of acne one of the commonly tested enzyme deficiencies on the usmle is a vitamin a deficiency so with that you get a whole range of symptoms so you get things called beto spots because vitamin a among other things is needed for normal um differentiation of carotenocytes if you don't have vitamin a you can get things like metaplasia and dysplasia so the plateau spots like you can see in the image on the right on the eye can develop you can also develop night blindness which means you just simply can't see at night and also dry and scaly skin interestingly vitamin a can be used to treat a certain kind of hematologic cancer and they love testing this and that cancer is called apml that's acute promyelocytic leukemia for that you would need a form of vitamin a called atra which is all trans retinoic acid of course vitamin a is retinol and it can come in different flavors and forms so if you have all trans retinoic acid you would use that to treat the apml next we come to vitamin d so vitamin d is interesting it plays a lot of important roles in the body especially when it comes to calcium homeostasis there's different forms of the vitamin so there's d2 which is ergocalciferol and d3 which is cholecalciferol the important thing to know about vitamin d is that it's usually not absorbed in an activated form it has to be activated in the kidneys via hydroxylation so you get 125 oh d3 or that is the activated form of vitamin d where it can exert its effects on calcium homeostasis typical foods that it comes from are things like dairy products and in the environment it often comes from sunlight or rather sunlight promotes the reaction that is used to activate vitamin d a deficiency of vitamin d and kids can lead to rickets and in adults it can lead to osteomalacia and then of course as i was saying it has a pretty important role in calcium homeostasis so i want to spend some more time on that because they do test that a lot if you have elevated parathyroid hormone decreased calcium or decreased phosphate all of these things will lead to an increase in the activation of vitamin d that 125 oh form because vitamin d is going to want to increase the absorption of calcium so things like an elevated pth which would suggest that you don't have enough calcium in the body are going to want to increase vitamin d also when you have the activated form of vitamin d that 125 oh2 d3 product that's going to feed back more upstream and it's going to stop the production of further vitamin d because or else you could be at risk for having too much calcium so those are the high yield points of vitamin d to know next we have tocopherol or vitamin e this may not be the highest yield vitamin but they do test it occasionally and i would want you guys to get it if it came up so it functions primarily as an antioxidant taking care of free radicals in the body things like that a deficiency of vitamin e is going to lead to hemolytic anemia so you would be able to see on a blood smear the red blood cells that have burst but also to differentiate it from other conditions you would have a hemolytic anemia alongside that subacute combined degeneration-like presentation so if you have a patient who looks like they have a b12 deficiency they have the numbness and tingling in their hands and feet but they also have a hemolytic anemia so for instance they don't have an mcv of something like 120. that would make you want to think of a vitamin e deficiency instead of a beach bulb deficiency our last vitamin is vitamin k so vitamin k is it plays a really important role in a lot of clotting functions and also it has interaction with a lot of different commonly used drugs like warfarin so vitamin k is activated by an enzyme called epoxide reductase this is the enzyme that warfarin inhibits so if you block the epoxide reductase by warfarin you don't have vitamin k and you reduce the clotting functions of the blood which is how orphan works vitamin k is needed for modification of glutamate residues most importantly through gamma carboxylation it's also important to know which factors vitamin k inhibits so it inhibits factors 2 7 9 and 10. so that's both the intrinsic and extrinsic coagulation pathways one of the other things to know for vitamin k is that newborns need an injection of it so vitamin k is in part synthesized by intestinal flora and when newborns are worn they don't have the intestinal flora that can make that vitamin k so if a baby is born for instance at home and isn't in the hospital to get the injection of vitamin k they could potentially bleed out later on because they don't have the vitamin that helps with clotting in the blood so new boards need a vitamin k injection one of the other high yield things to know just overall is that the fat soluble vitamins are vitamins a d e and k um all those are absorbed in similar manners as opposed to the water soluble vitamins and they do test that as well our next topic is the fructose metabolism disorders so first we come to essential fructoseria so this one as opposed to hereditary fructose intolerance is a bit milder the typical symptoms are a result of the disease process itself so with this condition you have a defect of fructokinase so with that you don't have um fructose being phosphorylated and then trapping it inside the cells so fructose can go inside and outside of cells as it wishes that leads to fructose in the urine which is essentially the only symptom of essential fructoseria and besides that it's a generally benign condition that's in contrast to hereditary fructose intolerance so with this condition you have a deficiency of aldolase b and what aldolase b does is it converts fructose 1-phosphate to dihydroxyacetone phosphate or d-hap and glyceraldehyde or gap so because of that you get an increase in fructose 1-phosphate in the cells you typically get the symptoms after having things that have fructose so for instance any kind of sweet or fruit so the symptoms and why they're present all ties back into the pathogenesis so when you have hereditary fructose intolerance and you have trapping of the fructose-1-phosphate inside the cell because the phosphate traps it inside the cell that leads to a lack of available phosphate because all the phosphate is bound up in the fructose 1-phosphate because of that you disrupt glycogenolysis and gluconeogenesis and because of that you can get symptoms of hypoglycemia jaundice and vomiting so it is a relatively severe disease and the main treatment for it is just changing things in the diet um so you want to decrease your intake of fructose and molecules that compose fructose like sucrose and generally staying away from those foods so you don't have the increase of fructose 1-phosphate inside the cells our next topic is the galactose metabolism disorders so with a galactokinase deficiency this is a little bit similar to essential fructose area and that you don't have the enzyme required for the phosphorylation of the sugar in question so here you can't convert galactose to galactose 1-phosphate so the galactose will accumulate in the blood and urine as i said before the galactokinase deficiency is a bit more severe than the essential fructoseria and that just manifests with a couple of actual symptoms so one of them is cataracts in the eye another is an inability to track objects and never developing a social smile around others which is a bit of a weird presentation but it can be a giveaway on an exam then we come to classic galactosemia which is an enzyme deficiency of galactose-1-phosphate urinal transferase for the presenting symptoms these typically come after the infant has galactose which is often present in breast milk so once the baby starts breastfeeding this can manifest in symptoms if they have the condition the symptoms typically involve cataracts an enlarged liver jaundice and just overall failure to thrive one of the commonly tested infections in patients with classic lactosemia is e coli sepsis in neonates and the treatment as with hereditary fructose intolerance is changing your diet so you want to not have galactose in your diet and other things that include galactose such as lactose next we come to the glycogen storage diseases which are all very high yield and you are essentially guaranteed to have a question on one of these our first one is von gierke disease or type 1. the enzyme that's deficient is the glucose 6-phosphatase enzyme so glucose 6-phosphatase is going to remove as phosphatases do remove the phosphate from the molecule and without the phosphatase you are left with g6p just kind of stuck there because you can't remove the phosphate the presenting symptoms can be remembered because they all have a g in them so things like gout fasting hypoglycemia and increased glycogen in the kidneys and liver for the classic labs you also can get elevated um urate levels elevated triglycerides and elevated blood lactate levels so that entire picture on a step exam stem would probably clue you into vonger disease the treatment as before you're probably seeing a theme by now is dietary changes so what you want to do is avoid certain sugars that can lead to exacerbations of the condition so you want to give cornstarch orally as often as you can because by giving that you can keep the gluconeogenesis and glycogenolysis going for pompe disease which is type 2 that's a deficiency in alpha 1 4 glucosidase and one of the most unique organs affected in this condition is the heart so if they mention that the patient has things as young and has maybe a cardiomyopathy and can't really tolerate any sort of exercise uh that can be indicative of pompe disease also they can present with generalized hypotonia of the muscle so low tone and overall difficulty breathing cory disease is type 3 and it's similar to the van gear disease type one but it's a bit not as severe so unlike in von gierke disease here you have normal blood lactate levels and your deficient enzyme is the de-branching enzymes which remove bits of glucose from glycogen when you have a deficiency of the de-branching enzymes you are left with a collection of these things called limit dextrins in the cells the organs that are primarily affected are the liver and the muscle and it can lead to a mild hypoglycemia because you are impairing the process of glycogenolysis uh in cory disease you aren't affecting gluconeogenesis because this condition only affects the debranching enzymes our next one is mcardle disease which is also called type 5. the deficient enzyme is glycogen phosphorylase primarily in skeletal muscle and for your labs you're going to have an elevated creatinine kinase for your symptoms you're going to have muscle cramping and myoglobin area during physical activity but one of the main signs that can kind of give this away on an exam is something called the second wind phenomenon so with that you have exhaustion after exercise but then you get a second wind and that's because of improved blood flow and fatty acid delivery and all those things together kind of give a picture of mcardle disease our next topic is lysosomal storage diseases so some general facts about the lysosomes they are essentially the cells trashcan they function at a low ph so they are acidic and they use a collection of digestive enzymes so like proteases and light bases to digest molecules that are no longer needed in the cells when you have an issue then with the lysosomes you get an accumulation of those abnormal metabolic products which can lead to issues so our first condition is metachromatic leukodystrophy the enzyme deficiency in this case is aerosulfatase a and it's primarily characterized by demyelination and the central and peripheral nervous systems and overall that leads to things like ataxia memory loss and dementia the substrate that builds up because aerosulfates a is deficient is cerebroside sulfate and it's good to keep in mind the inheritance pattern for all these diseases so this one is autosomal recessive that's the case for most of them if you happen to forget on the exam which condition is which inheritance pattern i would go with autosomal recessive unless you are confident of the ones that differ which we'll get to in a bit our next one is tastex so here you have a deficiency of hexosaminase a and the typical finding is a red spot on the macula called a cherry red macula you also can see onion skin lysosomes on pathology and other symptoms are just developmental delay and otherwise death in early childhood the substrate that accumulates because you are deficient in the hexostamidase a is the gm2 ganglioside and one of the things to know about taysacs is how to differentiate it from another disease which we'll get to soon called neiman pick because they do present very similarly tay sachs has a lack of hepatosphenomegaly so you're going to have a normal sized liver and spleen in this case tay sachs is pretty common or relatively common and ashkenazi jews and it is autosomal recessive neiman pick disease so the enzyme deficiency here is stingomyelinase and that leads to an accumulation of stingomyelin as i was saying before the presentation can be very similar to taysacs you even have that same cherry red macula but here you do have hepatosplenomegaly if you were to look at some of the macrophages and just cells under microscopy you would see that they have um are filled with lipids those can be called foam cells and the inheritance pattern is autosomal recessive fabry disease the enzyme deficiency is alpha galactosidase a the substrate that accumulates because of the enzyme deficiency is ceramide trihexose and here you have a typical triad you're going to want to commit to memory so you're going to have peripheral neuropathy so just general um tingling and numbness in your hands and feet angiocaratomas which you can see an example of on the screen on the right i would know that picture in case they test an image of it and hypohidrosis so just an inability to sweat or just an impairment of overall sweating patients with vapor disease can have kidney or heart issues later in life and this is one of the conditions that uh deviates from the norm of things being autosomal recessive here it is excellent recessive next we have goshare disease and the enzyme deficient is glucose cerebrosidase the substrate that's accumulated is glucose cerebroside and these symptoms are a bit different from others which makes it a bit easier to spot so you have hepatophonomegaly which is nonspecific but you also have cytopenias so a lac in one or many blood cell lines and a vascular necrosis often of the femur if you have tissue paper cells on microscopy as shown to the right that can be also indicative of gaucher disease and it is autosomal recessive um as many of the other conditions are next we have craba disease and the deficient enzyme is galactose cerebrosidase so this does sound similar to the enzyme deficient and go share disease called glucose cerebrosidase so just make sure that you don't confuse them the substance that accumulates is galactose three birth sides and the typical findings are optic nerve atrophy so eventual blindness and globoid cells which you could see on the right like the many of the other conditions it is autosomal recessive next we come to hunter and hurler syndromes these are called the mucopolysaccharidosis and they have some commonalities but they're also a little bit different so let's start with hunter disease so it's a bit less severe than hurler disease and it's a lack of the enzyme hydronate to sulfatase which leads to a collection of heparin sulfate it is excellent recessive that's the other excellent recessive disease besides fabry disease and here you have preserved vision contrast to hurler disease where you have things like clouding of the corneas which can impair vision you also can get aggression and just intellectual disability one of the common findings on a physical exam is gargoyle-like facies as well and here it's a lack of alpha-l-hydronidase so the enzymes sound similar but they will often put both of those enzymes in the potential answer choices so make sure you can differentiate the two and um it is a little more recessive some other metabolic diseases so our first one is cystenuria here you get a defect with reabsorption of a couple of key amino acids these are cysteine ornithine lysine and arginine they're called together the cola amino acids just because of the first letters of each name and the test used to diagnose it primarily is the sodium cyanide nitro press scientist one of the main symptoms that it presents with is kidney stones because when you don't reabsorb these enzymes they can precipitate out in the urine and obstruct the flow of urine and as a quick review um you would see hexagonal cystine stones on microscopy the treatment for cystenuria is alkalinizing the urine making it more basic with things like potassium citrate that's going to help make the amino acids more soluble because when you make the urine more alkaline the acids can dissolve in it more easily and you also want to have a diet low in methionine and you also want to just generally hydrate well now we have homocystinuria and here you can have two main deficient enzymes so one of them is cystothionine beta synthase the other is methionine synthase so that can lead to a collection of different sort of substrates if you don't have the methionine synthase you get an increase in homocysteine and if you don't have cystothionine synthase you also get an increase in homocysteine levels marfan syndrome can be a bit similar to homocysteine urea because in both conditions they have the marfanoid habitus they can have lens dislocation and cardiovascular effects the main difference for homocysteine urea that's good to know is that you have the lens dislocating in a different direction so in marfan disease the typical lens dislocation is up and out it's supralateral for homocysteineuria the lens dislocation is infraomedial so it's down and in and that's one of the typical ways they try to get students to tell apart those two conditions the treatment is with b6 and cysteine so if you have b6 that can strengthen the function of the enzyme cystothianine synthase because it uses b6 as a cofactor as you can see on the screen it's paradoxine dependent for treating with cysteine it just supplies the downstream sort of substrate that's lacking then we come to phenylketonuria which is a deficiency of one of two enzymes so the first enzyme is phenylalanine hydroxylase the second is tetrahydrobiopterin so there are typical symptoms that present with pku one of the common ones is um skin that is hypopigmented you also can have a weird off-putting musty body odor and overall intellectual disability and one of the things that's good to know for pku is that tyrosine becomes essential as an external cofactor because phenylalanine is used to make tyrosine if you don't have the enzyme that converts phenylalanine into tyrosine you have to get it from somewhere else so the treatment becomes to supply with tyrosine the other treatment in general is just to avoid foods that have phenylalanine they make specialized foods on the market for these patients and patients should usually subsist on those to avoid flare-ups of their disease next we come to maple syrup urine disease which is so named because of how the disease presents the urine tends to look like maple syrup as you can see on the right the enzyme deficiency is alpha keto acid dehydrogenase which as a pearl of knowledge um that requires thiamine or vitamin b1 b1 is needed for a lot of dehydrogenase activity so if you see dehydrogenase and they ask which vitamin to is needed to supply that sort of enzyme go with b1 the defect is that you can't break down branched amino acids so things like valine and isoleucine so those will accumulate in the blood the symptoms are besides the presence of the dark brown urine you just get things like vomiting and poor feeding next we come to the high-yield genetic abnormalities and this is actually our last topic so trisomy 13 is tau syndrome as a quick review a trisomy is three copies of one chromosome so in the human body there are the regular human body there are 46 chromosomes per cell and you have two copies of each so two of chromosome one two of chromosome two and so on and then you also have the sex chromosomes which would be xx or xy with trisomy 13 instead of having two copies of the 13th chromosome you'd have three so the symptoms are holopresent cephaly um a cleft lip and palate cuticlasia which is kind of marked by um a defect in the calvarium you also can have an omphalocele in the abdomen rocker bottom feet polydactyly a severe developmental delay and further labs which can be used to predict this you could have a low beta hcg pappa in the first trimester but of note these do normalize by the second trimester and the prognosis for this condition is usually very poor children often die in the first year unfortunately our next condition is trisomy 18 or edward syndrome and the high yield symptoms for this are rocker bottom feet clenched fists with overlapping fingers that's a main one developmental delay or intellectual disability a prominent occiput or back of the head micrognathia and for your labs you would have a low beta hcg and pappa in the first trimester and then in the second you would have low beijing hgg estriol afp and inhibit a so essentially everything is low our last condition is trisomy 21 or down syndrome um it's the most common trisomy and unlike trisomy 13 and 18 um people can live for long lives with tristan 21 the symptoms are hypotonia cardiac defects especially of the endocardial cushions that can lead to things like a complete atrioceptal defect and one of the commonly tested things is a change in the facial structure so you have epicanthal folds a protruding tongue upslanting palpebral fissures and things like that and lastly these patients are at elevated risk of things like hersprung disease um alzheimer's disease that's because the amyloid protein is coded for on chromosome 21 so if you have an extra chromosome you have even more of that protein and also the blood cancers aml and all and that's the end of the high yield topics in biochemistry if you have any questions feel free to reach out and i'm looking forward to hearing from you all thank you