HY Arrows PDF

MEHLMANMEDICAL HY ARROWS  MEHLMANMEDICAL.COM YouTube @mehlmanmedical Instagram @mehlman_medical MEHLMANMEDICAL.COM 2  MEHLMANMEDICAL.COM HY Arrows It is to my observation that if a stude...

MEHLMANMEDICAL HY ARROWS  MEHLMANMEDICAL.COM YouTube @mehlmanmedical Instagram @mehlman_medical MEHLMANMEDICAL.COM 2  MEHLMANMEDICAL.COM HY Arrows It is to my observation that if a student ever fails the USMLE Step 1, his or her concept of arrows (i.e., should a hormone, electrolyte, etc., be ­, ¯, or «) is always terrible. I consider this one of the most important pieces of content I’ve created to date. It comprises 168 HY arrow questions. I would say that >90% of the arrow questions I discuss in this document are essential to merely pass USMLE Step 1. Maybe about the other 10% are more difficult but important enough that I included them. I have only included the concepts I view as the highest yield for the exam. I’m aware some students might go through this PDF and say, “Oh but Mike, you could have also included arrow questions on x, y, and z.” And my response is, yes, we could by all means sit together in a conference room with a whiteboard and draw up, e.g., 300+ potential arrow questions. But I want to reiterate that the purpose of this document is not to be a massive agglomeration of questions just for the sake of it. The value of this document is specifically in the fact that it’s highly potent and concise despite there being a broad range of testable material for USMLE. I considered adding a table to contents to this document, as some students might prefer to jump to certain subject areas, but after starting one, I decided it was better to omit it in order to not give away some answers, essentially. MEHLMANMEDICAL.COM 3  MEHLMANMEDICAL.COM 1. Patient has high aldosterone. What are the arrows (i.e., ­ or ¯) for serum Na+, K+, pH, bicarb, and CO2? MEHLMANMEDICAL.COM 4  MEHLMANMEDICAL.COM - ­ Na+, ¯ K+, ­ pH, ­ bicarb, ­ CO2. - Remember that all arrows go the same direction as aldosterone, except for potassium, which is the opposite. - Aldosterone upregulates the sodium-potassium ATPase pump on the basolateral membrane of the cortical collecting duct in the kidney. This causes Na+ reabsorption and K+ secretion. Water follows sodium; this will function to increase volume status and blood pressure. - Aldosterone also upregulates an apical H+-ATPase pump. If protons are kicked out into the urine, the patient develops metabolic alkalosis (i.e., bicarb goes up). - CO2 is acidic. If we have a metabolic alkalosis, we want to retain acidic CO2, so we slow respiratory rate – i.e., metabolic alkalosis with respiratory compensation. MEHLMANMEDICAL.COM 5  MEHLMANMEDICAL.COM 2. Patient has low aldosterone. What are the arrows (i.e., ­ or ¯) for serum Na+, K+, pH, bicarb, and CO2? MEHLMANMEDICAL.COM 6  MEHLMANMEDICAL.COM - ¯ Na+, ­ K+, ¯ pH, ¯ bicarb, ¯ CO2. - Remember that all arrows go the same direction as aldosterone, except for potassium, which is the opposite. - Decreased aldosterone would mean metabolic acidosis (normal anion gap in this case) with respiratory compensation. - I will go into more detail on different things as we move along. However for starters, you knowing the above arrows for high versus low aldosterone is paramount for USMLE, which is why I started this way. MEHLMANMEDICAL.COM 7  MEHLMANMEDICAL.COM 3. Patient is given lisinopril. What change will this cause (i.e., ­ or ¯) in renin, angiotensin I, angiotensin II, and aldosterone? MEHLMANMEDICAL.COM 8  MEHLMANMEDICAL.COM - ­ Renin, ­ angiotensin I, ¯ angiotensin II, ¯ aldosterone. - Lisinopril is an ACE inhibitor. This will decrease cleavage of AT I into AT II in the lungs. AT II and aldosterone will go down as a result. - Lower aldosterone will cause reduced fluid status, which will cause renin secretion to go up to compensate. This will lead to increased angiotensin I production (renin cleaves hepatically synthesized angiotensinogen into AT I in the plasma). - Another way to think of it is: if you block the step between AT I and AT II, substrates on the left go up; products on the right go down. MEHLMANMEDICAL.COM 9  MEHLMANMEDICAL.COM 4. Patient is given valsartan. What change will this cause (i.e., ­ or ¯) in renin, angiotensin I, angiotensin II, and aldosterone? MEHLMANMEDICAL.COM 10  MEHLMANMEDICAL.COM - ­ Renin, ­ angiotensin I, ­ angiotensin II, ¯ aldosterone. - Valsartan is an angiotensin II receptor blocker (ARB). - Unlike with ACE inhibitors, there is no inhibition of the synthesis of AT II. - Since the AT II receptors are blocked, aldosterone synthase activity in the zona glomerulosa of the adrenal cortex goes down. - Lower aldosterone causes lower fluid status, so renin goes up to compensate. This in turn leads to more angiotensinogen cleavage into angiotensin I. - More angiotensin I is then cleaved into angiotensin II in the lungs. MEHLMANMEDICAL.COM 11  MEHLMANMEDICAL.COM 5. Patient is given spironolactone. What change will this cause (i.e., ­ or ¯) in renin, angiotensin I, angiotensin II, aldosterone, and K+ levels? MEHLMANMEDICAL.COM 12  MEHLMANMEDICAL.COM - ­ Renin, ­ angiotensin I, ­ angiotensin II, ­ aldosterone, ­ K+. - Spironolactone is an aldosterone receptor antagonist. Blocking aldosterone receptor will cause all substrates to increase. - Since aldosterone causes potassium secretion from the blood into the urine, blocking aldosterone receptors can cause hyperkalemia. - High potassium can also be caused by ACE inhibitors and ARBs, since they decrease aldosterone. - It should be noted that spironolactone is anti-androgenic and can cause gynecomastia. There is less risk of this with eplerenone. MEHLMANMEDICAL.COM 13  MEHLMANMEDICAL.COM 6. If a patient is given enalapril, what will happen (i.e., ­, ¯, or «) to left ventricular afterload, systemic arteriolar diameter, renal afferent arteriolar diameter, and renal efferent arteriolar diameter? MEHLMANMEDICAL.COM 14  MEHLMANMEDICAL.COM - ¯ LV afterload, ­ systemic arteriolar diameter, « afferent diameter, ­ efferent diameter. - AT II is a potent vasoconstrictor. Not only does it increase aldosterone synthase activity in the zona glomerulosa of the adrenal cortex, but it also constricts peripheral arterioles. - ACEi (e.g., enalapril) and ARBs decrease afterload on the LV by relieving the constrictive effects of AT II on peripheral arterioles. - Some students will get pedantic about potential minor effects of AT II on the afferent arterioles. This will get you questions wrong on USMLE. Do not over-think things. The exam assesses AT II as a potent vasoconstrictor at the efferent arterioles. This increases filtration fraction and maintains GFR in the setting of reduced renal blood flow. - AT II will constrict (i.e., ¯ diameter) of efferent arterioles. Therefore ACEi/ARBs ­ diameter. MEHLMANMEDICAL.COM 15  MEHLMANMEDICAL.COM 7. 32F + abdominal bruit + BP of 160/100. What are the arrows (i.e., ­ or ¯) for Na+, K+, pH, bicarb, and CO2? MEHLMANMEDICAL.COM 16  MEHLMANMEDICAL.COM - ­ Na+, ¯ K+, ­ pH, ­ bicarb, ­ CO2. - Diagnosis is fibromuscular dysplasia (FMD), which is tunica media proliferation, generally in women 20s-50s. This results in decreased renal perfusion à renin secretion by JGC à RAAS activation. - This is not the same as renal artery stenosis, which is due to atherosclerosis. The vignette will instead be a patient with, e.g., intermittent claudication, Hx of CABG, or many years of smoking. MEHLMANMEDICAL.COM 17  MEHLMANMEDICAL.COM 8. 74M + hyperpigmentation of the forearms + eosinophils 23% + 6-month Hx of fatigue + BP 100/60. What are the arrows (i.e., ­ or ¯) for Na+, K+, pH, bicarb, CO2, and ACTH? MEHLMANMEDICAL.COM 18  MEHLMANMEDICAL.COM - ¯ Na+, ­ K+, ¯ pH, ¯ bicarb, ¯ CO2, ­ ACTH. - Patient has Addison disease (primary hypoadrenalism). I’ve seen it in young and old patients on NBME. Most commonly, the etiology is autoantibodies against 21-hydroxylase in the adrenal cortex. - Patients with Addison disease have ¯ aldosterone and ¯ cortisol. - ¯ cortisol results in ¯ negative feedback at hypothalamus and anterior pituitary à ­ CRH and ACTH secretion. POMC is precursor to both ACTH and a-MSH. The latter (as well as ACTH to some extent) causes hyperpigmentation. - In Addison, the adrenal gland itself is the location of the pathology, so aldosterone and cortisol are low. In secondary hypoadrenalism (i.e., ¯ ACTH production by the anterior pituitary), only cortisol is low; in the latter case, there is nothing wrong with the adrenal gland, so AT II can still ­ aldosterone synthesis without a problem. - Eosinophilia is common in adrenal insufficiency. This is HY, especially on 2CK IM Qs. Don’t go chasing stool ova and parasites. Cortisol can function to sequester eosinophils in the spleen. MEHLMANMEDICAL.COM 19  MEHLMANMEDICAL.COM 9. 45M + one-year Hx of fatigue and darkening of skin of forearms + BP 100/60; exogenous ACTH is administered and shows marginal increase in cortisol levels. Prior to administration of ACTH, what are the arrows (i.e., ­, ¯, or «) for this patient’s serum ACTH, eosinophils, Na+, K+, pH, bicarbonate, and CO2? MEHLMANMEDICAL.COM 20  MEHLMANMEDICAL.COM - ­ ACTH, ­ eosinophils, ¯ Na+, ­ K+, ¯ pH, ¯ bicarbonate, ¯ CO2. - This patient has Addison disease. The ACTH stimulation test is used to diagnose, which will show a very marginal increase in serum cortisol, thereby demonstrating the patient has adrenal insufficiency (i.e., unable to adequately make cortisol in response to ACTH). - Healthy patients will demonstrate a robust increase in serum cortisol in response to exogenous ACTH. - Patients with Addison have low serum cortisol and aldosterone. Low cortisol means less negative feedback at the hypothalamus and anterior pituitary, leading to increased CRH and ACTH levels. - Eosinophilia is a common finding in Addison disease. This is especially prevalent in 2CK-level IM Qs. Once again, do not go chasing stool ova and parasites. - Low aldosterone means less sodium reabsorption, as well as less potassium and proton secretion in the cortical collecting duct of the distal kidney. Retention of protons means serum bicarb is low. - CO2 is low because the patient will have metabolic acidosis, so it is blown off as compensation. MEHLMANMEDICAL.COM 21  MEHLMANMEDICAL.COM 10. 39F + 20-year-Hx of rheumatoid arthritis managed with NSAIDs, prednisone, methotrexate, and infliximab. She has Cushingoid appearance. What are the arrows (i.e., ­, ¯, or «) for her ACTH and cortisol levels? MEHLMANMEDICAL.COM 22  MEHLMANMEDICAL.COM - ¯ ACTH, ¯ cortisol. - Students get this question wrong all of the time. - Prednisone is not the same as cortisol. It is merely a cortisol (i.e., glucocorticoid) analogue. - Prednisone will induce negative feedback at the hypothalamus and anterior pituitary, causing a reduction in CRH and ACTH. - Because ACTH is low, the adrenal gland is under-stimulated, and endogenous cortisol production decreases. - Students erroneously assume cortisol must be high if a patient is Cushingoid in appearance. The ¯ for ACTH and cortisol in the setting of exogenous glucocorticoids is exceedingly high-yield for USMLE. - If the USMLE tells you the patient is on prednisone, that makes the question easy. They will sometimes say a Cushingoid patient with an autoimmune disease, e.g., SLE, IBD, RA is “managed with multiple medications,” and just assume you can infer he/she is on prednisone. - Not hard now that we discussed it. But students fuck this up a lot. MEHLMANMEDICAL.COM 23  MEHLMANMEDICAL.COM 11. 13M + three days ago treated for meningococcal septicemia + now has BP of 80/50. What are the arrows (i.e., ­, ¯, or «) for serum aldosterone, cortisol, ACTH, K+, Na+, HCO3-, pH, and CO2? MEHLMANMEDICAL.COM 24  MEHLMANMEDICAL.COM - ¯ Serum aldosterone, ¯ cortisol, ­ ACTH, ­ K+, ¯ Na+, ¯ HCO3-, ¯ pH, and ¯ CO2. - Diagnosis is Waterhouse-Friderichsen syndrome, which is hemorrhagic necrosis of the adrenal glands secondary to meningococcal septicemia. Both the zona glomerulosa (aldosterone-producing layer) and zona fasciculata (cortisol-producing layer) are affected. The zona reticularis (androgen-producing layer) could in theory be affected, but don’t worry about that here. - Cortisol normally functions to upregulate a1-receptors on arterioles. Catecholamines (norepinephrine and epinephrine) agonize these receptors and cause vasoconstriction, thereby maintaining blood pressure. If cortisol is low, then NE and E can’t do their job, so BP is low. - If the USMLE asks which drug to give in this setting (following the administration of normal saline), the answer = hydrocortisone, which is a cortisol analogue. If you give NE, it won’t significantly increase BP since a1-receptors aren’t being expressed adequately due to the low cortisol. - Low aldosterone would in theory cause low BP from less fluid retention, but in the case of W-F syndrome, the low BP is more an acute effect of ¯ cortisol, resulting in ¯ a1-receptor expression. - Low aldosterone causes high potassium, low sodium, low bicarb, and low pH (metabolic acidosis). CO2 then goes down to compensate (we want to blow off CO2 since it’s acidic). - ACTH is high since there is less cortisol exerting negative feedback at the hypothalamus and anterior pituitary. MEHLMANMEDICAL.COM 25  MEHLMANMEDICAL.COM 12. 31M + Cushingoid appearance + serum ACTH levels undetectable + serum cortisol high; if high-dose dexamethasone is administered, what will happen (i.e., ­, ¯, or «) to his ACTH and cortisol levels? MEHLMANMEDICAL.COM 26  MEHLMANMEDICAL.COM - « ACTH, « cortisol. - Dexamethasone is a cortisol analogue that is capable of exerting negative feedback at the hypothalamus and anterior pituitary. Given to healthy individuals, the result is suppression of ACTH and cortisol levels. - This patient has undetectable ACTH and high serum cortisol. Giving exogenous dexamethasone, if anything, would only further suppress ACTH by inducing negative feedback at the hypothalamus and anterior pituitary. Because levels are already undetectable, they will not go lower (on NBME). - Low serum ACTH in the setting of high serum cortisol means the diagnosis is Cushing syndrome secondary to primary adrenal cortical secretion. This is most likely due to an adenoma, but could also be diffuse cortical hyperplasia. - Cushing syndrome = how the patient looks/presents; can refer to any cause of Cushingoid presentation (i.e., exogenous glucocorticoids, ACTH-secreting tumor of anterior pituitary, cortisol- secreting tumor of adrenal cortex, small cell bronchogenic carcinoma secreting ACTH). - Cushing disease = ACTH-secreting tumor of anterior pituitary. - Low-dose dexamethasone = yes or no test only for Cushing syndrome; doesn’t tell us etiology. - If low-dose dex is administered and patient’s cortisol goes down, he/she does not have Cushing syndrome. If cortisol does not go down, then yes, he/she has Cushing syndrome; we don’t know the cause, but yes, he/she has Cushing syndrome. o Failure of cortisol suppression with low-dose dex; high-dose dex administered + patient’s cortisol goes down; answer = Cushing disease (anterior pituitary tumor secreting ACTH). Only Cushing disease will suppress with high-dose dex. o Failure of cortisol suppression with low-dose dex; high-dose dex administered + patient’s cortisol goes not go down; answer = either primary adrenal secretion (i.e., adenoma or hyperplasia), or small cell bronchogenic carcinoma secreting ACTH. We know that because cortisol did not go down with high-dose dex, the cause of our Cushing syndrome cannot be Cushing disease. o Patient has high ACTH; failure of cortisol suppression with low-dose dex; high-dose dex administered + patient’s cortisol goes not go down; answer = small cell bronchogenic carcinoma secreting ACTH. MEHLMANMEDICAL.COM 27  MEHLMANMEDICAL.COM o Patient has low ACTH; failure of cortisol suppression with low-dose dex; high-dose dex administered + patient’s cortisol goes not go down; answer = primary adrenal (cortisol- secreting tumor or diffuse hyperplasia). - If a patient is on exogenous glucocorticoids, we do not do dexamethasone suppression test because the Cushing syndrome is clearly due to the exogenous steroids. We use the dexamethasone suppression test to identify endogenous causes of Cushing syndrome. MEHLMANMEDICAL.COM 28  MEHLMANMEDICAL.COM 13. 45F + Cushingoid in appearance + serum ACTH levels high + serum cortisol high; MRI of the brain shows a mass; if high-dose dexamethasone is administered, what will happen (i.e., ­, ¯, or «) to ACTH and cortisol levels? MEHLMANMEDICAL.COM 29  MEHLMANMEDICAL.COM - ¯ ACTH, ¯, cortisol. - Since the patient’s diagnosis is Cushing disease (i.e., ACTH-secreting tumor of the anterior pituitary), she will experience successful suppression of cortisol with high-dose dexamethasone. - Only Cushing disease will suppress with high-dose dex. - In contrast, if the patient had high ACTH due to small cell bronchogenic carcinoma, neither ACTH nor cortisol would suppress with high-dose dex. MEHLMANMEDICAL.COM 30  MEHLMANMEDICAL.COM 14. 50M + Cushingoid appearance + proximal muscle weakness + successful ability to maintain upward gaze for 60 seconds + serum ACTH levels high + serum cortisol high; if high-dose dexamethasone is administered, what will happen (i.e., ­, ¯, or «) to his ACTH and cortisol levels? MEHLMANMEDICAL.COM 31  MEHLMANMEDICAL.COM - « ACTH, « cortisol. - The patient has both Lambert-Eaton and Cushing syndromes secondary to small cell bronchogenic carcinoma. - Since the etiology for his Cushing syndrome is not Cushing disease, ACTH and cortisol will not suppress. - Patients with Lambert-Eaton can maintain upward gaze for 60 seconds; patients with myasthenia gravis cannot (this detail shows up a lot on NBMEs). MEHLMANMEDICAL.COM 32  MEHLMANMEDICAL.COM 15. 35F + central obesity with purple striae + adrenal mass visualized on CT of the abdomen. What are the arrows (i.e., ­, ¯, or «) for this patient’s serum ACTH, cortisol, and urinary potassium? MEHLMANMEDICAL.COM 33  MEHLMANMEDICAL.COM - ¯ Serum ACTH, ­ cortisol, ­ urinary potassium. - This patient has Cushing syndrome due to a cortisol-secreting adenoma of the zona fasciculata. - Serum ACTH is suppressed due to negative-feedback in the setting of high cortisol. - Chronically high glucocorticoid levels can cause potassium wasting at the distal kidney similar to aldosterone. Patients with Cushing syndrome can sometimes have hypokalemia. - Do not start psychoanalyzing questions and thinking aldosterone is high just because the patient has hypokalemia. I make a point about hypokalemia in Cushing syndrome just so you’re not confused if you get a K+ of 3.0 (NR is 3.5-5.0) in a patient with Cushingoid presentation. MEHLMANMEDICAL.COM 34  MEHLMANMEDICAL.COM 16. 28F + gave birth one week ago via C-section in which she lost a lot of blood + now has fatigue + difficulty breastfeeding postpartum; what are the arrows (i.e., ­, ¯, or «) for serum prolactin, ACTH, TSH, and aldosterone? MEHLMANMEDICAL.COM 35  MEHLMANMEDICAL.COM - ¯ Prolactin, ¯ ACTH, ¯ TSH, ­ aldosterone. - These exact arrows are from a retired Step 1 NBME exam. I agree it’s weird that they assess an ­ for aldosterone in this case, but it’s not my opinion. It’s on NBME. - Diagnosis is Sheehan syndrome. The pituitary doubles in size during pregnancy in order to produce more prolactin à greater oxygen demand. If patient loses a lot of blood during parturition, she is at risk of ischemic infarction à decreased production of pituitary hormones. - Patient’s fatigue implies hypothyroidism (¯ TSH here means secondary hypothyroidism). - The patient will not have hyperaldosteronism as a result of Sheehan syndrome. In other words, the patient is not going to have an overt Conn syndrome-type of picture (i.e., ­ Na+, ¯ K+, ­ pH, ­ bicarb) in the vignette. It is likely the case the USMLE wants you to know that aldosterone would be ­ relative to its theoretical baseline because ACTH is ¯. In other words: - ACTH à increases cortisol à upregulates a1 receptors on systemic arterioles à increases blood pressure; without this effect, blood pressure is lower, thereby providing impetus for aldosterone to increase. Once again, it’s on a retired Step 1 NBME. I’m not disagreeing that this seems like an unusual arrow to ask. MEHLMANMEDICAL.COM 36  MEHLMANMEDICAL.COM 17. 40M + recent weight gain + pituitary mass visualized on MRI + point tenderness over a vertebra at L1 + compression fracture visualized on x-ray + slight muscle weakness. What are the arrows (i.e., ­, ¯, or «) for prolactin, ACTH, and serum K+? MEHLMANMEDICAL.COM 37  MEHLMANMEDICAL.COM - « Prolactin, ­ ACTH, ¯ K+. - Point tenderness over a vertebra on USMLE = compression fracture = osteoporosis. - Cushing disease can present as mere osteoporosis and weight gain in a patient with a pituitary adenoma. Do not confuse this with avascular necrosis of the femoral head, which can also occur in Cushing disease. - This is not a prolactinoma, so prolactin will be unchanged. Prolactin can cause impotence in men, amenorrhea in women, and galactorrhea in both genders. - Serum potassium is sometimes decreased in patients with Cushing syndrome due to the fractional mineralocorticoid effects (i.e., function like aldosterone) of glucocorticoids at the kidney. - All glucocorticoids will have fractional mineralocorticoid effects, some more than others. - Fludrocortisone (often given to treat Addison) is a glucocorticoid with high mineralocorticoid effect. - Endogenous cortisol, as well as exogenous prednisone, hydrocortisone, and dexamethasone all have very minor mineralocorticoid effect (i.e., they do not function similarly to aldosterone). In spite of this, chronically elevated levels can lead to reduced serum potassium. MEHLMANMEDICAL.COM 38  MEHLMANMEDICAL.COM 18. What are the arrows (i.e., ­, ¯, or «) for serum sodium, urinary osmolality, and urinary specific gravity if vasopressin (anti-diuretic hormone; ADH) is high? MEHLMANMEDICAL.COM 39  MEHLMANMEDICAL.COM - ¯ Serum sodium, ­ urinary osmolality, ­ urinary specific gravity. - ADH causes the insertion of aquaporins in the medullary collecting duct of the distal kidney. This results in increased free water reabsorption. Think of this process as diluting out serum sodium, while simultaneously making the urine more concentrated. - Urinary osmolality refers to your concentration of solutes within the urine. The urine is becoming more concentrated because free water is being pulled out. - Urinary specific gravity is another way of measuring concentration/diluteness of the urine. This variable shows up a lot, particularly in 2CK Qs. If urinary specific gravity is ­, the urine is concentrated; if it is ¯, the urine is dilute. - Patients will have elevated ADH in the setting of dehydration and syndrome of inappropriate secretion of ADH (SIADH). MEHLMANMEDICAL.COM 40  MEHLMANMEDICAL.COM 19. What are the arrows (i.e., ­, ¯, or «) for serum sodium, urinary osmolality, and urinary specific gravity if vasopressin (anti-diuretic hormone; ADH) is low? MEHLMANMEDICAL.COM 41  MEHLMANMEDICAL.COM - ­ Serum sodium, ¯ urinary osmolality, ¯ urinary specific gravity. - If ADH is low, there is less aquaporin insertion in the medullary collecting duct of the distal kidney, and therefore less reabsorption of free water. The serum sodium will not be diluted out by free water, so the serum tonicity is greater. - Urine osmolality and specific gravity are reduced because the urine is more dilute. - Central diabetes insipidus (DI) is a condition of excessive urination due to decreased production of ADH by the hypothalamus (of defective storage by the posterior pituitary). - In nephrogenic DI, ADH levels are high due to insensitivity to ADH at the kidney. Serum sodium will remain high, resulting in continual secretion of ADH by the hypothalamus. This is different from SIADH, since in nephrogenic DI, the high levels of ADH are appropriate given the increased serum sodium. MEHLMANMEDICAL.COM 42  MEHLMANMEDICAL.COM 20. 45M + long history of smoking + recent weight loss + confusion; what are the arrows (i.e., ­, ¯, or «) in this patient for serum sodium, urinary osmolality, and urinary specific gravity? MEHLMANMEDICAL.COM 43  MEHLMANMEDICAL.COM - ¯ serum sodium, ­ urinary osmolality, ­ urinary specific gravity. - The patient has SIADH secondary to small cell bronchogenic carcinoma (i.e., his vasopressin is high). - Mental status change can occur with low or high serum sodium. - HY small cell lung cancer paraneoplastic syndromes: o SIADH (ADH secretion). o Cushing syndrome (ACTH secretion). o Lambert-Eaton syndrome (pre-synaptic voltage-gated Ca2+-receptor antibodies). o Neurologic/cerebellar dysfunction (Anti-Hu/-Yo antibodies). - HY squamous cell lung cancer paraneoplastic syndrome: o Hypercalcemia often presenting as urolithiasis (PTH-related peptide; i.e., PTHrp, secretion). MEHLMANMEDICAL.COM 44  MEHLMANMEDICAL.COM 21. 17M + was in car accident 6 weeks ago in which he witnessed his father pass away + since incident has heard voices telling him to drink a lot “to cleanse himself of the evil spirits.” What are arrows (i.e., ­, ¯, or «) in this patient for serum sodium, urinary osmolality, and urinary specific gravity? MEHLMANMEDICAL.COM 45  MEHLMANMEDICAL.COM - ¯ serum sodium, ¯ urinary osmolality, ¯ urinary specific gravity. - The patient has psychogenic polydipsia (i.e., drinking too much) secondary to schizophreniform disorder (psychosis 1-6 months in duration). - In patients who drink too much, ADH will be low in order to permit the micturition of free water (thereby causing dilute urine), however serum sodium will be low, not high, because the ADH is appropriately low (i.e., we want ADH to be low if our serum is too dilute from water consumption). - USMLE could also give a bodybuilder who drinks gallon jugs of water. MEHLMANMEDICAL.COM 46  MEHLMANMEDICAL.COM 22. 30M + hospitalized for the past week due to motorcycle accident in which he incurred head trauma; urinary output is 800 mL/hour. What are arrows (i.e., ­, ¯, or «) in this patient for serum sodium, urinary osmolality, and urinary specific gravity? MEHLMANMEDICAL.COM 47  MEHLMANMEDICAL.COM - ­ serum sodium, ¯ urinary osmolality, ¯ urinary specific gravity. - This patient has central diabetes insipidus secondary to head trauma. - Students should be aware that USMLE Qs can give central DI or SIADH secondary to head trauma or meningitis. - This patient has high urinary output, indicating central DI with dilute urine, rather than SIADH with concentrated urine. MEHLMANMEDICAL.COM 48  MEHLMANMEDICAL.COM 23. 24F + bipolar disorder + mildly tremulous + increased urinary output. What are arrows (i.e., ­, ¯, or «) in this patient for tonicity of her proximal convoluted tubule (PCT), juxtaglomerular apparatus (JGA), and medullary collecting duct (MCD) in comparison to her serum tonicity? MEHLMANMEDICAL.COM 49  MEHLMANMEDICAL.COM - « PCT, ¯ JGA, ¯ MCD. - USMLE Step 1 loves this combo of variables. - This patient has nephrogenic diabetes insipidus secondary to the lithium she takes for her bipolar disorder. Lithium causes tremor and nephrogenic DI, among many adverse effects. - The USMLE will ask the arrow combination for PCT, JGA, and MCD in a variety of patient vignettes. What you need to know is this: - The PCT is always isotonic no matter what. - The JGA is always hypotonic no matter what. o The JGA, which technically bridges the early-distal convoluted tubule (early-DCT) with the afferent arterioles of the kidney, is considered to be located at the early-DCT (top of thick ascending limb of loop of Henle) for USMLE Qs. Since there is massive ion reabsorption in the thick ascending limb (i.e., notably high concentrations of Na+/K+/2Cl- symporters), the urine will always be dilute at the early-DCT. - The MCD will be hypotonic in DI (both central and nephrogenic) and psychogenic polydipsia. - The MCD will be hypertonic in SIADH and dehydration. MEHLMANMEDICAL.COM 50  MEHLMANMEDICAL.COM 24. 32F + marathon runner + currently 10 miles into a run + has not had anything to drink. What are the arrows (i.e., ­, ¯, or «) in this patient for tonicity of her proximal convoluted tubule (PCT), juxtaglomerular apparatus (JGA), and medullary collecting duct (MCD) in comparison to her serum tonicity? MEHLMANMEDICAL.COM 51  MEHLMANMEDICAL.COM - « PCT, ¯ JGA, ­ MCD. - This patient has dehydration from being on a long run. - The PCT is always isotonic no matter what. - The JGA is always hypotonic no matter what. - The MCD will be hypertonic in SIADH and dehydration. - The MCD will be hypotonic in DI (both central and nephrogenic) and psychogenic polydipsia. - Not super hard now that we’ve discussed it. Very important question for USMLE Step 1. MEHLMANMEDICAL.COM 52  MEHLMANMEDICAL.COM 25. 47F + has been taking large doses of ibuprofen the past 25 years. What are the arrows (i.e., ­, ¯, or «) for this patient’s urine volume and urine osmolality in response to exogenous administration of ADH? MEHLMANMEDICAL.COM 53  MEHLMANMEDICAL.COM - « urine volume; « urine osmolality. - Correct, the USMLE will be this vague with the stem, and these are the arrows they want. - Patient has analgesic nephropathy secondary to long-term NSAID use. - Analgesic nephropathy is a broad, umbrella term that can be used to refer to any renal disease caused by NSAIDs. - USMLE wants you to know that nephrogenic diabetes insipidus can be caused by NSAIDs. - Insensitivity to ADH at the kidney means there will be no change in urine volume or osmolality to exogenous ADH since endogenous ADH is already maximally high. - ADH will normally increase urine osmolality and decrease urine volume due to its upregulation of aquaporins in the medullary collecting duct that function to reabsorb free water. MEHLMANMEDICAL.COM 54  MEHLMANMEDICAL.COM 26. 24M + receives intravenous infusion of mannitol. What are the arrows (i.e., ­, ¯, or «) for this patient’s ADH and serum osmolality as an immediate result of this infusion? MEHLMANMEDICAL.COM 55  MEHLMANMEDICAL.COM - ­ ADH, ­ serum osmolality. - Mannitol is a sugar alcohol. Infusion will cause immediate increase in serum osmolality since we are increasing the solute concentration of the serum (i.e., there’s more “stuff” now in the serum). - An increase in serum osmolality will trigger ADH release, which in turn will reabsorb more free water in the medullary collecting duct of the kidney to help re-dilute the serum back to original osmolality. o ­ serum tonicity + osmolality à ­ ADH release à dilutes serum back to normal. o ¯ serum tonicity + osmolality à ¯ ADH release à concentrates serum back to normal. - Mannitol is an osmotic diuretic that acts by exerting oncotic pressure within the PCT and thin descending limb of the loop of Henle, thereby helping to facilitate tubular water retention and diuresis. It is the answer on 2CK forms for how to reduce intracranial pressure in patients who are already being hyperventilated (low CO2 reduces cerebral perfusion). - Avoid mannitol in patients with heart failure, since initial increases in plasma volume due to higher serum osmolality will transiently increase preload on the heart. MEHLMANMEDICAL.COM 56  MEHLMANMEDICAL.COM 27. In primary vs secondary hyperthyroidism, what are the arrows (i.e., ­, ¯, or «) for TSH, T3, and T4? MEHLMANMEDICAL.COM 57  MEHLMANMEDICAL.COM - Primary hyperthyroidism: ¯ TSH, ­ T3, ­ T4. - Secondary hyperthyroidism: ­ TSH, ­ T3, ­ T4. - Primary hyperthyroidism traditionally refers to Graves disease, toxic adenoma, and toxic multinodular goiter. It can also refer to transient thyroiditis (deQuervain, postpartum, or drug-induced). Don’t worry, I’ll elaborate on what you need to know for these HY DDx as we move forward in this PDF. - Secondary hyperthyroidism could refer to a TRH- or TSH-secreting tumor. - There is a retired Step 1 NBME Q where they give you a two-line stem where they say TSH and T4 are elevated, then they ask for whether it’s primary or secondary hypo- vs hyperthyroidism; answer is secondary hyperthyroidism. Not difficult. But I’m just making a point that the NBME has asked this point-blank without any type of substantive vignette or disease application. MEHLMANMEDICAL.COM 58  MEHLMANMEDICAL.COM 28. In primary vs secondary hypothyroidism, what are the arrows (i.e., ­, ¯, or «) for TSH, T3, and T4? MEHLMANMEDICAL.COM 59  MEHLMANMEDICAL.COM - Primary hypothyroidism: ­ TSH, ¯ T3, ¯ T4. - Secondary hypothyroidism: ¯ TSH, ¯ T3, ¯ T4. - Primary hypothyroidism traditionally refers to Hashimoto and iodine deficiency. TSH is high because of decreased negative feedback at the hypothalamus and anterior pituitary by T3 and T4. - Secondary hypothyroidism is typically seen in Sheehan syndrome. Yes, Sheehan is classically ¯ prolactin, but NBME has also assessed TSH as decreased as well. MEHLMANMEDICAL.COM 60  MEHLMANMEDICAL.COM 29. 33F + exophthalmos + tremulousness + type I diabetes mellitus; what are the arrows (i.e., ­, ¯, or «) for TSH, T3, T4, and radioiodine (131I) uptake into the thyroid gland? MEHLMANMEDICAL.COM 61  MEHLMANMEDICAL.COM - ¯ TSH, ­ T3, ­ T4, ­ 131I uptake. - Diagnosis is Graves disease. Exophthalmos (proptosis) is only seen in Graves disease. - Mechanism is autoimmune production of thyroid-stimulating immunoglobulin (TSI). - TSI is structurally similar to TSH and will agonize the TSH receptor (type II hypersensitivity). - Relevance of type I diabetes is that “autoimmune diseases go together” – i.e., if a patient has one autoimmune disease (i.e., SLE, RA, IBD, etc.), there is increased risk of another. HLA associations are very loose on USMLE. Do not try to overthink based on specific HLAs. This will get you Qs wrong. - Uptake of iodine into the thyroid gland signifies that the thyroid gland is producing thyroid hormone. In Graves, the uptake is diffusely increased. If uptake is increased in one area only, the answer is toxic adenoma. If uptake demonstrates multiple areas of uptake in an elderly patient, the answer is toxic multinodular goiter. - If a patient has hyperthyroidism but decreased uptake, the answer is thyroiditis of some kind (i.e., drug-induced, deQuervain, or postpartum). In thyroiditis, the patient can be either hypo- or hyperthyroid; in the event he/she is hyperthyroid, the mechanism is increased release of thyroid hormone due to inflammation of the gland; the gland itself is not producing (which is why uptake is low, not high). MEHLMANMEDICAL.COM 62  MEHLMANMEDICAL.COM 30. 19F + menstrual periods heavier and longer past 6 months + low mood + HR 60 + ­ hepatic AST + ­ total cholesterol + ­ serum creatine kinase + mom has pernicious anemia; what are the arrows (i.e., ­, ¯, or «) for TSH, T3, T4, and radioiodine (131I) uptake into the thyroid gland? MEHLMANMEDICAL.COM 63  MEHLMANMEDICAL.COM - ­ TSH, ¯ T3, ¯ T4, ¯ 131I uptake. - Diagnosis is Hashimoto thyroiditis (chronic lymphocytic thyroiditis). - Mechanism is mixed antibody- (anti-thyroperoxidase [aka anti-microsomal], anti-thyroglobuin) and T cell-mediated destruction of the thyroid gland. - Uptake is diffusely decreased, or will be described as “patchy uptake” in a stem where the patient clearly has Hashimoto. - Descriptors such as brittle hair, dry skin, constipation, and cold intolerance are too easy for many USMLE Qs. Don’t rely on these as a crutch. - Students need to be aware of menstrual irregularities, bradycardia, dysthymia/depression, hepatic transaminitis, dyslipidemia, and myopathy (increased CK) as important parts of the disease. - 2CK IM Qs in particular will give findings such as high AST (or ALT) and CK in a patient with bradycardia and fatigue and expect you to know that is Hashimoto. - Hashimoto is the most common cause of hypothyroidism in Western countries. Iodine deficiency is the most common cause worldwide. MEHLMANMEDICAL.COM 64  MEHLMANMEDICAL.COM 31. 24M + tremulous + heat intolerance + HR 92 + tender thyroid; what are the arrows (i.e., ­, ¯, or «) for TSH, T3, T4, and radioiodine (131I) uptake into the thyroid gland? MEHLMANMEDICAL.COM 65  MEHLMANMEDICAL.COM - ¯ TSH, ­ T3, ­ T4, ¯ 131I uptake. - This is one of the most common incorrectly answered Qs on USMLE. - Diagnosis is deQuervain (subacute granulomatous thyroiditis; or just subacute thyroiditis). - Mechanism is viral infection followed by a painful/tender thyroid. There is inflammation of the thyroid gland, which causes the spacing between the cells to increase slightly, allowing for the release of pre-formed thyroid hormone into the blood. The gland is not over-producing thyroid hormone. This is why uptake is not increased. - Viral infections are often asymptomatic, so most deQuervain vignettes will not mention the viral infection. - Subacute granulomatous thyroiditis can be either hypo- or hyperthyroid. The key detail you need to know is that uptake is always decreased even if the patient is hyper-. - DeQuervain vignettes will almost always be given as hyperthyroidism because the USMLE wants to specifically assess that you know uptake is decreased. If they give you hypo-, of course you’ll select decreased for uptake. - Decreased uptake applies to all thyroiditis conditions (i.e, deQuervain, drug-induced, and postpartum). MEHLMANMEDICAL.COM 66  MEHLMANMEDICAL.COM 32. 40F + palpable thyroid nodule + biopsy shows amyloid demonstrating apple-green birefringence with Congo red stain under polarized light. What are the arrows (i.e., ­, ¯, or «) for TSH, T3, T4, and radioiodine (131I) uptake into the thyroid gland? MEHLMANMEDICAL.COM 67  MEHLMANMEDICAL.COM - « TSH, « T3, « T4, « 131I uptake, OR ­ TSH, ¯ T3, ¯ T4, ¯ 131I uptake. - Diagnosis is medullary thyroid carcinoma. Serum calcitonin will also be elevated. - Patients with thyroid carcinoma (i.e., papillary, follicular, medullary, anaplastic) will be either euthyroid or hypothyroid; they will not be hyperthyroid. - If the patient has a thyroid nodule and is hyperthyroid, the diagnosis is toxic adenoma. Adenomas are non-malignant tumors (i.e., they do not have metastatic potential). Carcinomas have metastatic potential. - It should be noted that on 2CK FM Qs, choose “palpation of thyroid gland” before “check serum TSH” if the patient requests thyroid cancer screening. - If patient with nodule has normal or high TSH (i.e., euthyroid or hypothyroid), do ultrasound before fine-needle aspiration. This is assessed on the new 2CK Free 120, where ultrasound is correct over FNA for evaluation of thyroid nodule. It had long been pushed in resources that ultrasound is always wrong. But this is on Free 120. - 2CK IM Q gives euthyroid patient with nodule where FNA is the answer, but ultrasound not listed. - So my conclusion (based on NBME/Free 120 content, not my opinion) is: for eu- or hypothyroid patient with thyroid nodule, ultrasound is correct over FNA if both are listed. If ultrasound isn’t listed but FNA is, FNA is correct. - If patient has low TSH (i.e., hyperthyroid), do radioiodine (131I) uptake scan, not ultrasound. - Since carcinomas are non-secretory of thyroid hormone, if a patient is hyperthyroid, we’re not concerned about carcinoma, which is why we don’t go the USS then FNA route. We just do uptake to better see if the patient’s etiology for hyperthyroidism is Graves (diffuse), toxic adenoma (single nodular uptake), or toxic multinodular goiter (multifocal nodular uptake). MEHLMANMEDICAL.COM 68  MEHLMANMEDICAL.COM 33. Patient is injecting triiodothyronine (T3). What are the arrows (i.e., ­, ¯, or «) for TSH, T3, T4, and radioiodine (131I) uptake into the thyroid gland? MEHLMANMEDICAL.COM 69  MEHLMANMEDICAL.COM - ¯ TSH, ­ T3, ¯ T4, ¯ 131I uptake. - This is a “hard” question. - Diagnosis is factitious (or surreptitious) thyrotoxicosis. - Remember, T4 is converted to T3, but T3 is not converted to T4. - Triiodothyronine is T3. Thyroxine is T4. - If we inject T3, we will suppress TSH due to negative feedback. In turn, the thyroid gland will be under-stimulated, so uptake is low. The thyroid gland will often be described as “small and non- palpable.” Since the thyroid gland will be under-stimulated (we don’t need production if we’re injecting it), production of T4 will be reduced. - This arrow combo for T3 injection is on one of the retired Step 1 NBMEs. - “But Michael, what about T4 injection then?” à Ok, go to the next question. MEHLMANMEDICAL.COM 70  MEHLMANMEDICAL.COM 34. Patient is injecting levothyroxine (T4). What are the arrows (i.e., ­, ¯, or «) for TSH, T3, T4, and radioiodine (131I) uptake into the thyroid gland? MEHLMANMEDICAL.COM 71  MEHLMANMEDICAL.COM - ¯ TSH, ­ T3, ­ T4, ¯ 131I uptake. - T4 is converted to T3, so if we inject T4, we will also have high T3. - High T3 and T4 cause suppression of TSH, which in turn leads to decreased iodine uptake into the thyroid gland. - Remember, T3 is not converted to T4. If we inject triiodothyronine, T3 will be high, but T4 will be low because we’re not able to produce it if we shut off the thyroid gland. - It is not sufficient to merely ask, “If patient injects thyroid hormone, what will the arrows be?” We need to specify whether it’s T3 or T4 we’re injecting. - Some students might say, “Wait, if TSH is low, and that’s the reason our 131I uptake is low, then why isn’t uptake low in Graves disease for instance. Cuz isn’t TSH low in Graves?” à TSH is low in Graves, but don’t forget that the mechanism for that disease is TSI production, which mimics TSH, thereby stimulating the gland to make thyroid hormone. - In the case of toxic adenoma and toxic multinodular goiter, even though TSH is low, uptake is high because those conditions are tumorous, where the gland is autonomously producing and secreting thyroid hormones without the need for TSH. MEHLMANMEDICAL.COM 72  MEHLMANMEDICAL.COM 35. 50M + routine screening by family practitioner reveals subclinical hypothyroidism. What are the arrows (i.e., ­, ¯, or «) for TSH, T3, and T4? MEHLMANMEDICAL.COM 73  MEHLMANMEDICAL.COM - ­ TSH, « T3, « T4. - In subclinical hypothyroidism, the patient will be asymptomatic (hence subclinical) and will have normal T3 and T4, despite an elevated TSH. - Most patients with subclinical do not need to be treated. - Step 3 wants you to know that you treat if TSH >10, patient is pregger, or anti-Hashimoto Abs are +. MEHLMANMEDICAL.COM 74  MEHLMANMEDICAL.COM 36. 54M + recovering in hospital from ARDS secondary to pancreatitis + currently being weaned from a ventilator. This is all the Q says and they want you to pick the arrows (i.e., ­, ¯, or «) for TSH, T3, T4, and rT3. MEHLMANMEDICAL.COM 75  MEHLMANMEDICAL.COM - « TSH, « T4, ¯ T3, ­ rT3. - This is where a lot of students say wtf? Relax. - Diagnosis is euthyroid sick syndrome (or sick euthyroid syndrome). - Vignette will either be patient being weaned from a ventilator, or a patient who’s had recent major trauma or surgery. - Etiologies are manifold, but one proposed mechanism is that in times of stress (usually acute), spikes in cortisol and other inflammatory mediators can inhibit peripheral conversion of T4 to T3. This causes T3 to go down. - T4, however, rather than being detectable in excess, is converted to an inactive form of thyroid hormone called reverse T3 (rT3), so rT3 is high. - T4 is therefore still in the normal range, as is TSH (presumably because T4 is normal). - Call it weird all you want, but USMLE asks this. This is one of the most “underrated” thyroid diagnoses, as students will often have heard of it but then disregard it, thinking it’s minutiae and probably won’t show up. à Bad fucking idea. Euthyroid sick syndrome is important for USMLE. - Do not confuse the arrows for this condition with subclinical hypothyroidism (­ TSH, « T3, « T4). MEHLMANMEDICAL.COM 76  MEHLMANMEDICAL.COM 37. 25F + G1P0 + 10 weeks’ gestation + pregnancy progressing uneventfully. What are the arrows (i.e., ­, ¯, or «) for TSH, T3, free T4, total T4, and free/total T4 ratio? MEHLMANMEDICAL.COM 77  MEHLMANMEDICAL.COM - « TSH, « T3, « free T4, ­ total T4, ¯ free/total T4 ratio. - USMLE wants you to know that estrogen causes increased thyroid-binding globulin (TBG) production by the liver. TBG is the protein carrier molecule for thyroid hormone in the blood. - Free T4 is the physiologically active form of thyroid hormone. T4 protein-bound to TBG (99%) has minimal effect. Free T4 + TBG-bound T4 = total T4. - TBG will mop up free T4, causing free T4 to transiently decrease and TSH to rise (less negative feedback). This rise in TSH will stimulate more production of T4 by the thyroid gland, making total T4 go up. The absolute amount of free T4 will increase back to normal, thereby suppressing TSH back to normal. But the total amount of T4 is now increased – i.e., free T4 is normal again, but TBG-bound T4 is higher. This means the free/total T4 ratio has decreased. - T3 is normal because free T4 is normal. Free T4 is peripherally converted to T3. I’ve never seen anything about “free T3” on NBME material and I wouldn’t worry about it. - A student might say, “Wait, but why are you giving the above bold arrows if you just gave me all sorts of transient changes in the arrows based on TBG?” à It’s because the bold arrows are what the USMLE wants. Pregnant women who are euthyroid will have normal free T4 and increased total T4, and their TSH will be normal. The changes due to TBG rising are likely synchronous and slow enough that the patient’s arrows stay as the bold ones. MEHLMANMEDICAL.COM 78  MEHLMANMEDICAL.COM 38. 2M + recently diagnosed with thyroid-binding globulin deficiency. What are the arrows (i.e., ­, ¯, or «) for TSH, T3, free T4, total T4, and free/total T4 ratio? MEHLMANMEDICAL.COM 79  MEHLMANMEDICAL.COM - « TSH, « T3, « free T4, ¯ total T4, ­ free/total T4 ratio. - The USMLE does not expect you to be intimately aware of some obscure condition called thyroid- binding globulin deficiency. The reason they ask about this is because the arrows for pregnancy are super high-yield. - In pregnancy, since TBG is high, this ultimately results in high total T4 despite a normal free T4. So if the student is very aware of those arrows for pregnancy, then he/she can easily infer, “Well, if our TBG merely is low, rather than high, then total T4 must be low while free is same. Sort of like pregnancy but just the opposite direction.” MEHLMANMEDICAL.COM 80  MEHLMANMEDICAL.COM 39. 25F + G1P1 + gave birth 8 weeks ago + no complications with pregnancy or labor; no past medical Hx; four-day Hx of tremulousness, tachycardia, and heat intolerance. What are the arrows (i.e., ­, ¯, or «) for TSH, T3, T4, and radioiodine (131I) uptake into the thyroid gland? MEHLMANMEDICAL.COM 81  MEHLMANMEDICAL.COM - ¯ TSH, ­ T3, ­ T4, ¯ 131I uptake. - Diagnosis is postpartum thyroiditis. This patient is hyperthyroid, but the condition can present as hypo- as well. - Same as with deQuervain (subacute granulomatous) and drug-induced thyroiditis, uptake is low even if the patient is hyper-. - These arrows have nothing to do with the TBG-related ones seen during pregnancy. - With thyroiditis conditions, there is merely increased spacing between the cells of the thyroid gland due to inflammation, allowing thyroid hormone to leak out into the blood. The gland itself is not excessively producing thyroid hormone. Then we have negative feedback causing low TSH, and in turn less stimulation of the thyroid gland, which is why uptake is low. MEHLMANMEDICAL.COM 82  MEHLMANMEDICAL.COM 40. 40F + taking lithium for bipolar disorder + complains of increased thirst and heat intolerance. What are the arrows (i.e., ­, ¯, or «) for TSH, T3, T4, radioiodine (131I) uptake, tonicity of the medullary collecting duct compared to serum, and serum ADH levels? (6 arrows) MEHLMANMEDICAL.COM 83  MEHLMANMEDICAL.COM - ¯ TSH, ­ T3, ­ T4, ¯ 131I uptake, ¯ tonicity of medullary collecting duct, ­ ADH. - Patient has drug-induced thyroiditis and nephrogenic diabetes insipidus secondary to lithium. - Similar to deQuervain and postpartum thyroiditis, the patient can be either hyper- or hypothyroid. Because this is thyroiditis, uptake is low, even if the patient is hyper-. - In nephrogenic diabetes insipidus, sensitivity to ADH at the kidney is reduced, leading to decreased aquaporin insertion at the medullary collecting duct and urine that is dilute (hypotonic compared to serum). - ADH is high, not low, because the hypothalamus and posterior pituitary function just fine; the hypothalamus will increase production of ADH to compensate for lack of receptor sensitivity at the kidney. In central DI, ADH is low. MEHLMANMEDICAL.COM 84  MEHLMANMEDICAL.COM 41. Patient with primary hypo- vs hyperparathyroidism. What are the arrows (i.e., ­, ¯, or «) for Ca2+, PO43- and PTH? MEHLMANMEDICAL.COM 85  MEHLMANMEDICAL.COM - Primary hypoparathyroidism: ¯ Ca2+, ­ PO43-, ¯ PTH. - Primary hyperparathyroidism: ­ Ca2+, ¯ PO43-, ­ PTH. - Primary hypoparathyroidism is classically due to thyroid surgery that leads to removal of or damage to the parathyroid glands. It is also due to DiGeorge syndrome. - Primary hyperparathyroidism is usually due to a PTH-secreting adenoma, but can also be due to diffuse four-gland hyperplasia. - Parathyroid hormone (PTH) functions to increase serum calcium in three main ways: o 1) Pulls calcium out of the bone and puts it in the blood. § PTH binds to osteoblasts, which will then express RANK-L on their cell surface, which will bind to RANK receptor on the surface of osteoclasts. Osteoclasts then resorb (break down) bone. The calcium enters the blood, increasing serum calcium. o 2) PTH increases renal reabsorption of calcium. § PTH causes Ca2+ reabsorption at the late-DCT of the kidney by increasing expression of an apical calcium channel. o 3) PTH upregulates 1a-hydroxylase. § PTH upregulates 1a-hydroxylase in the PCT of the kidney, which converts inactive 25-OH-vitamin D3 (calcidiol) into active 1,25-(OH)2-D3 (calcitriol). § 1,25-(OH)2-D3 then goes to the small bowel, where it increases absorption of both calcium and phosphate. - PTH decreases serum phosphate by inhibiting its reabsorption in the PCT of the kidney. o PTH causes the downregulation of apical PCT phosphate transporters. o If PTH is low, we don’t get downregulation of these transporters, too much phosphate is reabsorbed, and serum PO43- goes up. MEHLMANMEDICAL.COM 86  MEHLMANMEDICAL.COM 42. 24M + 2-hour Hx of shooting groin pain + family Hx of thyroid cancer. What are the arrows (i.e., ­, ¯, or «) for Ca2+, PO43-, PTH, and TSH? MEHLMANMEDICAL.COM 87  MEHLMANMEDICAL.COM - ­ Ca2+, ¯ PO43-, ­ PTH, « TSH. - Diagnosis is MEN 2A. - MEN 1 = parathyroid adenoma (or hyperplasia), pituitary adenoma, pancreatic adenoma. - MEN 2A = parathyroid adenoma (or hyperplasia), pheochromocytoma, medullary thyroid carcinoma. - MEN 2B = Marfanoid body habitus, mucosal neuromas, pheochromocytoma, medullary thyroid carcinoma. - Shooting flank or groin pain suggests urolithiasis (nephro- vs ureterolithiasis, respectively) secondary to hypercalcemia. - Family Hx of thyroid cancer in his patient suggests medullary carcinoma, considering patient also has hypercalcemia (hyperparathyroidism). - Patients with thyroid carcinoma are usually euthyroid or hypothyroid. - Serum calcitonin will be increased in patients with medullary thyroid carcinoma. MEHLMANMEDICAL.COM 88  MEHLMANMEDICAL.COM 43. 25F + total thyroidectomy one week ago for treatment of papillary thyroid carcinoma; examination shows twitching of masseter with stimulation. What are the arrows (i.e., ­, ¯, or «) for Ca2+, PO43-, and PTH? MEHLMANMEDICAL.COM 89  MEHLMANMEDICAL.COM - ¯ Ca2+, ­ PO43-, ¯ PTH. - Thyroidectomy can result in removal of or damage to the parathyroid glands, resulting in decreased PTH secretion and, in turn, hypocalcemia. Phosphate goes up because there is increased renal reabsorption (PTH normally downregulates apical PCT phosphate transporters, thereby promoting excretion). - Twitching of the masseter with stimulation is called Chvostek sign of hypocalcemia. - Hypocalcemia causes “up” findings – i.e., muscle tetany and hyperreflexia. - Trousseau sign of hypocalcemia is carpopedal spasm with blood pressure cuff inflation (i.e., twitching of the hand/wrist). The USMLE can give you either Chvostek or Trousseau sign when Ca2+ is low. - Hypercalcemia, in contrast, causes “down” findings – i.e., muscle flaccidity and hyporeflexia. - Do not confuse Trousseau sign of hypocalcemia with Trousseau and Troisier signs of malignancy. - Troisier sign of malignancy is a palpable left supraclavicular lymph node sometimes seen in visceral malignancy (aka Virchow node). - Trousseau sign of malignancy is migratory thrombophlebitis classically seen in head of pancreas adenocarcinoma (but can be other adenocarcinomas, such as bronchogenic). MEHLMANMEDICAL.COM 90  MEHLMANMEDICAL.COM 44. 44M + chronic alcoholic + serum calcium 7.8 mg/dL (NR 8.4-10.2); appropriate dose of IV calcium gluconate is administered; new serum level is measured at 7.9 mg/dL. What are the arrows (i.e., ­, ¯, or «) for Ca2+, PO43-, PTH, and Mg2+? MEHLMANMEDICAL.COM 91  MEHLMANMEDICAL.COM - ¯ Ca2+, ­ PO43-, ¯ PTH, ¯ Mg2+. - Alcoholics are susceptible to hypomagnesemia as a result of dietary deficiency (EtOH is 7kcal/g, so they fill up on alcohol). - Low magnesium can cause hypocalcemia and hypokalemia nonresponsive to supplementation (i.e., you give calcium or potassium for low serum levels, but the serum levels do not appreciably rise). - Basal levels of magnesium are required for proper functioning of the parathyroid gland, so low magnesium can cause low PTH secretion. - Patients with hypomagnesemia may indeed have completely normal serum levels for calcium, phosphate, and PTH, but if we are forced to choose arrows, we would choose a Ca2+/PO43-/PTH combo that reflects low PTH secretion. - The Step 2 exam will often just say an alcoholic has low calcium or potassium nonresponsive to supplementation, and then the next best step in management is “check serum magnesium levels.” This isn’t hard at all. But some students will be like “Oh wow.” MEHLMANMEDICAL.COM 92  MEHLMANMEDICAL.COM 45. 47M + 5-yr Hx of recurrent duodenal ulcers + impotence + reduced tendon reflexes. What are the arrows (i.e., ­, ¯, or «) for Ca2+, PO43-, PTH? MEHLMANMEDICAL.COM 93  MEHLMANMEDICAL.COM - ­ Ca2+, ¯ PO43-, ­ PTH. - This patient has MEN 1. - MEN 1 = parathyroid adenoma (or hyperplasia), pituitary adenoma, pancreatic adenoma. - MEN 2A = parathyroid adenoma (or hyperplasia), pheochromocytoma, medullary thyroid carcinoma. - MEN 2B = Marfanoid body habitus, mucosal neuromas, pheochromocytoma, medullary thyroid carcinoma. - Recurrent duodenal ulcers, or any mention of a jejunal or ileal ulcer, almost always = Zollinger-Ellison syndrome (gastrinoma) on USMLE. (Otherwise we’re talking about H. pylori) - Impotence is frequently how prolactinoma presents in men. Galactorrhea may also be seen. - Hypercalcemia can cause reduced tendon reflexes and muscle weakness. MEHLMANMEDICAL.COM 94  MEHLMANMEDICAL.COM 46. 2M + cleft lip + absent thymic shadow + recurrent viral and Pneumocystis infections + harsh systolic murmur auscultated at left sternal border. What are the arrows (i.e., ­, ¯, or «) for Ca2+, PO43-, PTH, T cell levels, and B cell levels? MEHLMANMEDICAL.COM 95  MEHLMANMEDICAL.COM - ¯ Ca2+, ­ PO43-, ¯ PTH, ¯ T cell levels, « B cell levels. - Diagnosis is DiGeorge syndrome. - Mechanism is most frequently 22q11 deletion, resulting in agenesis of the 3rd and 4th pharyngeal pouches. - The 3rd pouch becomes the thymus + two inferior parathyroids. - The 4th pouch becomes the two superior parathyroids. - Tetralogy of Fallot and truncus arteriosus are common heart defects. - Agenesis of the parathyroid glands à primary hypoparathyroidism à low calcium + high phosphate. - DiGeorge is characterized by T cell deficiency. Recurrent viral, fungal, and protozoal infections are characteristic. - Absent thymic shadow = T cell deficiency à DiGeorge. - Scanty lymph nodes/tonsils = B cell deficiency à Bruton agammaglobulinemia. - If Q says kid has both absent thymic shadow and scanty lymph nodes/tonsils à answer = SCID. MEHLMANMEDICAL.COM 96  MEHLMANMEDICAL.COM 47. 66F + long-standing Hx of type II diabetes + serum creatinine of 4.3 mg/dL (NR 0.7-1.2) + blood urea nitrogen 67 mg/dL (NR 12 is considered high. 8-12 is normal. - The high anion-gap metabolic acidoses for Step are MUDPILES à Methanol toxicity, Uremia (renal failure), DKA, Phenformin (weird drug you don’t need to know), Iron tablets/Isoniazid, Lactic acidosis, Ethylene glycol toxicity, Salicylates (aspirin). - CO2 is acidic, so we blow this off to compensate in the setting of metabolic acidosis. MEHLMANMEDICAL.COM100  MEHLMANMEDICAL.COM 49. 70M + chronic renal failure. What are the arrows (i.e., ­, ¯, or «) for his serum K+, PO43-, and HCO3-? MEHLMANMEDICAL.COM101  MEHLMANMEDICAL.COM - ­ Serum K+, ­ PO43-, ¯ HCO3-. - Potassium is elevated in renal failure mostly due to impaired distal renal secretion (normally performed by aldosterone). - Phosphate is elevated mostly due to impaired inhibition of reabsorption in the PCT. Normally, PTH will downregulate apical PCT phosphate reabsorption transporters, enabling phosphate to be micturated. - Sodium can be variable in renal failure. MEHLMANMEDICAL.COM102  MEHLMANMEDICAL.COM 50. 50F + renal insufficiency due to granulomatosis with polyangiitis. What are the arrows (i.e., ­, ¯, or «) for 24,25-(OH)2-vitamin D3, fecal Ca2+, and 1,25-(OH)2-vitamin D3? MEHLMANMEDICAL.COM103  MEHLMANMEDICAL.COM - ­ 24,25-(OH)2-vitamin D3, ­ fecal Ca2+, ¯ 1,25-(OH)2-vitamin D3. - In the PCT of the kidney, we normally have inactive 25-OH-D3 à active 1,25-(OH)2-D3 via 1a- hydroxylase under the action of PTH. - In renal insufficiency, this process is disrupted, so 1,25-D3 levels decrease, and 25-D3 levels rise. - If we are forced to choose an arrow for inactive 25-D3, it would be ­, since it is not converted sufficiently to 1,25-D3, however, 25-D3 can be converted to another inactive storage form called 24,25-(OH)2-vitamin D3. - For all intents and purposes, on USMLE, think of 24,25-D3 and 25-D3 as the same. If 25-D3 builds up, then so does 24,25-D3. - The caveat is: 24,25-D3 is not converted directly to 1,25-D3. Only 25-D3 is converted to 1,25-D3. - Since active 1,25-(OH)2-vitamin D3 causes absorption of calcium in the small bowel, if there is reduced 1,25-D3 synthesis, then less calcium is absorbed, and more ends up in the feces. Call it weird/unusual all you want, but USMLE asks this variable on some of the retired Step 1 NBMEs. MEHLMANMEDICAL.COM104  MEHLMANMEDICAL.COM 51. 35F + parathyroid adenoma. What are the arrows (i.e., ­, ¯, or «) for urinary Ca2+, serum Ca2+, and urinary cAMP? MEHLMANMEDICAL.COM105  MEHLMANMEDICAL.COM - ­ Urinary Ca2+, ­ serum Ca2+, ­ urinary cAMP. - Some students will immediately think there’s an erratum here. There’s not. Relax. - In primary hyperparathyroidism, PTH will be high. PTH functions to reabsorb calcium in the late-DCT of the kidney, so in theory, you’d think urinary calcium would be low, not high. Sounds logical. - However, even though more Ca2+ is indeed reabsorbed in the late-DCT, since serum Ca2+ is high in primary hyperparathyroidism, more calcium is filtered through the glomerulus to begin with. So even though more is reabsorbed distally, the urinary calcium is still high because we had more to start with. - PTH causes increased urinary cAMP. This is a weird variable that you should be aware of. PTH acts through G-a-s G-proteins, where adenylyl cyclase activity and, in turn, cAMP are increased. MEHLMANMEDICAL.COM106  MEHLMANMEDICAL.COM 52. 22M + asymptomatic + has mutation in calcium-sensing receptor at parathyroid glands that results in reduced sensitivity of the receptor. What are the arrows (i.e., ­, ¯, or «) for serum Ca2+ and PTH? MEHLMANMEDICAL.COM107  MEHLMANMEDICAL.COM - ­ Serum Ca2+, ­ PTH. - The calcium-sensing receptors at the parathyroid glands are negative feedback receptors. That is, when calcium binds, PTH secretion is suppressed as a result. - If the calcium-sensing receptors demonstrate attenuated sensitivity, then there is also diminished ability to adequately suppress PTH in the setting of elevated calcium levels. Therefore, PTH will demonstrate inappropriately high secretion. - High PTH will cause serum calcium to be high. MEHLMANMEDICAL.COM108  MEHLMANMEDICAL.COM 53. 24M + asymptomatic + diagnosed with familial hypocalciuric hypercalcemia on biochemical screening. What are the arrows (i.e., ­, ¯, or «) for serum Ca2+, urinary Ca2+, parathyroid calcium-sensing receptor sensitivity, and renal calcium-sensing receptor sensitivity? (4 arrows) MEHLMANMEDICAL.COM109  MEHLMANMEDICAL.COM - ­ Serum Ca2+, ¯ urinary Ca2+, ¯ parathyroid Ca2+-sensing receptor sensitivity, ¯ renal Ca2+-sensing receptor sensitivity. - As the name of the condition implies, for familial hypocalciuric hypercalcemia (FHH), serum calcium will be high and urinary calcium low. - The condition is caused by slightly decreased (not absent) sensitivity of the calcium-sensing receptors at both the parathyroid glands and kidneys, resulting in a slightly higher setpoint for calcium levels in the blood, that may be variable depending on the patient. - Most patients are asymptomatic, and PTH is often higher end of normal, or slightly elevated. Patients do not experience signs of bone resorption sometimes seen in patients with primary hyperparathyroidism. - In primary hyperparathyroidism, despite increased distal renal reabsorption of calcium, urinary calcium is still high because serum calcium is high, so more calcium will be filtered through the glomerulus. In other words, if the urine starts off with more calcium, the amount urinated out is still higher despite increased reabsorption. The calcium-sensing receptors in the renal PCT and loop of Henle function normally and can sense the high calcium, thereby decreasing paracellular reabsorption (unrelated to PTH’s effect in the DCT); this allows for greater calciuresis (urination of calcium). - In familial hypocalciuric hypercalcemia, calcium-sensing receptors in the renal tubules (unrelated to PTH) have decreased sensitivity. Therefore, the tubules interpret urinary calcium to be low and will increase reabsorption in the PCT and loop of Henle to compensate, thereby decreasing calciuresis (less urinary calcium). In other words, in FHH, the kidney thinks, “Fuck, we must have low serum calcium since I can’t sense it, so I goin’ reabsorb more so we can retain our calcium.” MEHLMANMEDICAL.COM110  MEHLMANMEDICAL.COM 54. 30F + parathyroid adenoma + is administered a drug called cinacalcet, which is a calcimimetic that potentiates the effects of calcium at calcium-sensing receptors at the parathyroid glands. What are the arrows (i.e., ­, ¯, or «) for the expected changes in serum Ca2+, serum PO43-, urinary Ca2+, and PTH as a result of administration of this drug? MEHLMANMEDICAL.COM111  MEHLMANMEDICAL.COM - ¯ Serum Ca2+, ­ serum PO43-, ¯ urinary Ca2+, ¯ PTH. - Cinacalcet agonizes the calcium-sensing receptors at the parathyroid glands. This will cause a suppression of PTH secretion and a resultant reduction in serum calcium and elevation in phosphate. - Urinary calcium is normally elevated in primary hyperparathyroidism. When PTH decreases and serum calcium falls, urinary calcium will also decrease. - Although PTH increases reabsorption of calcium in the late-DCT, it must be reiterated that high serum calcium in primary hyperparathyroidism causes more calcium to be filtered through the glomerulus in the first place, meaning that, despite increased reabsorption by the distal kidney, more calcium will still be left in the urine to be micturated out. - When PTH levels return to normal and normocalcemia is attained, urinary calcium will also decrease. MEHLMANMEDICAL.COM112  MEHLMANMEDICAL.COM 55. 22M + bony nodules on forearms + round cheeks + shortened 4th and 5th metacarpals. In response to the administration of exogenous PTH, what will be the change (i.e., ­, ¯, or «) in serum Ca2+, serum PO43-, and urinary cAMP? MEHLMANMEDICAL.COM113  MEHLMANMEDICAL.COM - « Serum Ca2+, « serum PO43-, « urinary cAMP. - The diagnosis is pseudohypoparathyroidism, which is characterized by a defective PTH receptor, and therefore insensitivity to PTH. - There are different types of pseudohypoparathyroidism. The USMLE will give you type I, which presents with what is referred to as the Albright hereditary osteodystrophy phenotype (i.e., shortened 4th + 5th metacarpals, round face, and bony abnormalities). Osteoma cutis (nodules of subcutaneous ossification) can be seen (on retired NBME Q). - In pseudohypoparathyroidism type I, there is no response to exogenous PTH, so we will not see any changes in serum calcium, serum phosphate, or urinary cAMP. - Normally, exogenous PTH would cause an increase in serum calcium, a decrease in serum phosphate, and an increase in urinary cAMP. - Patients with pseudohypoparathyroidism will have low serum calcium, high serum phosphate, and high serum PTH levels. That is, the calcium and phosphate levels appear as though the patient has low PTH, when in reality there is just insensitivity to it. PTH goes up due to decreased negative feedback at the calcium-sensing receptors at the parathyroid glands, since serum calcium is low. MEHLMANMEDICAL.COM114  MEHLMANMEDICAL.COM 56. 16F + bony nodules on forearms + round cheeks + shortened 4th and 5th metacarpals; what are the arrows (i.e., ­, ¯, or «) for serum Ca2+, urinary Ca2+, serum PO43-, and PTH? MEHLMANMEDICAL.COM115  MEHLMANMEDICAL.COM - ¯ Serum Ca2+, ¯ urinary Ca2+, ­ serum PO43-, ­ PTH. - The diagnosis is pseudohypoparathyroidism type I, presenting with the Albright hereditary osteodystrophy phenotype. - Insensitivity at PTH receptor causes low serum calcium, high serum phosphate, and high serum PTH (due to decreased negative feedback at the Ca2+-sensing receptors since serum Ca2+ is low). - Urinary calcium is low because serum calcium is low, so less is filtered through the glomerulus into the urine to begin with, even though insensitivity to PTH means less distal renal reabsorption. MEHLMANMEDICAL.COM116  MEHLMANMEDICAL.COM 57. 70F + chronic renal failure; serum electrolytes show evidence for tertiary hyperparathyroidism. What are the arrows (i.e., ­, ¯, or «) for serum Ca2+, serum PO43-, and PTH? MEHLMANMEDICAL.COM117  MEHLMANMEDICAL.COM - ­ Ca2+, ­ PO43-, ­ PTH. - In order to understand tertiary hyperparathyroidism, let’s first review secondary hyperparathyroidism: - Patients with renal failure will initially develop secondary hyperparathyroidism, where calcium is low, phosphate is high, and PTH is high. Calcium is low due to failure of reabsorption at the late-DCT of the kidney and because of decreased synthesis of activated vitamin D3 (leading to decreased small bowel absorption). Phosphate is high due to failure to downregulate PCT reabsorption pumps (i.e., more pumps reabsorb phosphate). PTH is high because calcium is low (less negative feedback). - Tertiary hyperparathyroidism results from hyperplasia of the parathyroid glands in patients with long- standing secondary hyperparathyroidism, such that even if the renal failure is brought under control and serum calcium is brought back into the normal range, PTH continues being autonomously secreted at higher basal levels than prior to the renal disease, effectively resetting the body’s setpoint for calcium homeostasis. - This causes a rise in serum calcium in a patient with renal failure. This should immediately raise a red flag for tertiary hyperPTH, since renal failure patients will almost always have low, not high, calcium. - Even though the parathyroid glands will be hyper-secreting PTH, this is not primary hyperparathyroidism, since the etiology for the high PTH was not idiopathic adenoma or hyperplasia. - Phosphate is high, not low, because the patient has renal failure. Phosphate is always high in renal failure. Even though PTH is high, remember that the kidney can’t downregulate the PCT reabsorption pumps the way they’re supposed to. MEHLMANMEDICAL.COM118  MEHLMANMEDICAL.COM 58. 9M + alopecia + determined to have rare condition characterized by an inactivating mutation in his vitamin D receptors. What are the arrows (i.e., ­, ¯, or «) for serum Ca2+, PTH, and 24,25-(OH)2-vitamin D3? MEHLMANMEDICAL.COM119  MEHLMANMEDICAL.COM - ¯ Serum Ca2+, ­ PTH, ¯ 24,25-(OH)2-vitamin D3. - The Step 1 NBME wants you to know the findings for vitamin D receptor insensitivity. - Since vitamin D causes intestinal absorption of calcium, serum calcium will be low. The low calcium causes PTH to go up (due to decreased negative feedback). - The NBME doesn’t ask about phosphate levels for this condition, possibly because whilst vitamin D deficiency will ordinarily cause low phosphate (due to decreased intestinal absorption), it is possible that in patients with chronically elevated PTH in the setting of a vitamin D receptor mutation, phosphate might be variable. - Recall that inactive 25-OH-D3 can be converted to another inactive storage form called 24,25-D3. If PTH is high, then 1a-hydroxylase activity is high, so there will be less 25-D3 available to be shunted to 24,25-D3. The NBME mentions 24,25-D3 levels as “undetectable” in the setting of vitamin D receptor mutation. This also means if USMLE asks you for merely the 25-OH-D3 levels, choose a down arrow. - The NBME gives normal serum levels for 1,25-(OH)2-D3. This might sound weird, since if there’s a mutation in the vitamin D receptor, then theoretically more 1,25-D3 should be produced to compensate. This explains the low 24-25-D3, but perhaps in patients with this condition, 1,25-D3 is often normal, rather than elevated. MEHLMANMEDICAL.COM120  MEHLMANMEDICAL.COM 59. 50M + 60-pack-yr Hx of smoking + 10-kg weight loss past 2 months + recently treated for kidney stone + coin lesion visualized on chest x-ray. What are the arrows (i.e., ­, ¯, or «) for serum Ca2+, serum PO43-, and PTH? MEHLMANMEDICAL.COM121  MEHLMANMEDICAL.COM - ­ Serum Ca2+, ¯ serum PO43-, ¯ PTH. - The diagnosis is squamous cell carcinoma of the lung with paraneoplastic parathyroid hormone- related peptide (PTHrp) secretion. This is not the same as endogenous PTH. - PTHrp exerts very similar physiologic effects as PTH, causing high serum calcium and low phosphate. - PTH secretion by the parathyroid glands will be suppressed in this setting due to the high serum calcium. - NBME will give you lung cancer + high serum calcium + low serum PTH, with the answer being squamous cell carcinoma of the lung. The low PTH will throw some people off. But this is not weird. PTH is not the same as PTHrp (which will be up-arrow). MEHLMANMEDICAL.COM122  MEHLMANMEDICAL.COM 60. 58F + blood in the urine + left flank pain + 10-kg weight loss past two months + occasional headaches and blurry vision + renal ultrasound shows a heterogenous mass in the left kidney. What are the arrows (i.e., ­, ¯, or «) for serum Ca2+, serum PO43-, PTH, and hemoglobin? MEHLMANMEDICAL.COM123  MEHLMANMEDICAL.COM - ­ Serum Ca2+, ¯ serum PO43-, ¯ PTH, ­ hemoglobin. - Diagnosis is renal cell carcinoma (RCC). - USMLE wants you to know that RCC, similar to squamous cell carcinoma of the lung, can secrete PTHrp à therefore high calcium and low phosphate. - Endogenous PTH is suppressed due to the high calcium. Once again, PTHrp and PTH are different. - RCC can also secrete erythropoietin (EPO), causing secondary polycythemia. This can lead to hyperviscosity syndrome characterized by headache, blurry vision, and Raynaud phenomenon. - For USMLE, smoker + flank pain + red urine + high calcium + high hematocrit = RCC. MEHLMANMEDICAL.COM124  MEHLMANMEDICAL.COM 61. 6F + 10th percentile for weight and height + bowing of the tibias + family recently immigrated to the US from Ireland. What are the arrows (i.e., ­, ¯, or «) for serum Ca2+, serum PO43-, and PTH? MEHLMANMEDICAL.COM125  MEHLMANMEDICAL.COM - ¯ Serum Ca2+, ¯ serum PO43-, ­ PTH. - Diagnosis is rickets (vitamin D deficiency in children). In adults, the condition is called osteomalacia. - Calcium and phosphate are both low because vitamin D is needed for intestinal absorption of both. - PTH goes up because calcium is low (decreased negative feedback). - It should be noted that in vitamin D deficiency caused by renal failure, phosphate is high, not low, because the effect of the renal failure on phosphate levels wins over the mere vitamin D deficiency. In renal failure, the kidney cannot downregulate the PCT phosphate reabsorption channels, thereby increasing absorption. - Never choose low phosphate in renal failure, even though vitamin D3 activation is low. - Renal failure + low vitamin D: o ¯ serum Ca2+, ­ serum PO43-, ­ PTH. - No renal failure + low vitamin D (i.e., rickets/osteomalacia): o ¯ serum Ca2+, ¯ serum PO43-, ­ PTH. MEHLMANMEDICAL.COM126  MEHLMANMEDICAL.COM 62. 77F + bone densitometry shows bone density of hips and vertebrae >2.5 standard deviations below the mean for 20-yr-old women. What are the arrows (i.e., ­, ¯, or «) for serum Ca2+, serum PO43-, PTH, and 1,25-(OH)2-vitamin D3? MEHLMANMEDICAL.COM127  MEHLMANMEDICAL.COM - « Serum Ca2+, « serum PO43-, « PTH, « 1,25-(OH)2-vitamin D3. - Diagnosis is osteoporosis. All laboratory findings will be normal. - Students often get this question wrong, assuming, e.g., calcium must be low, but serum findings are completely normal for most patients. - USMLE question will often be in graph form, with calcium on the x-axis and PTH on the y-axis, with letters at different locations. The correct answer here is simply the letter in the normal range for both calcium and PTH. MEHLMANMEDICAL.COM128  MEHLMANMEDICAL.COM 63. 68F + bone densitometry shows bone density of hips and vertebrae >2.5 standard deviations below the mean for 20-yr-old women. What are the arrows (i.e., ­, ¯, or «) for osteoblast activity, osteoclast activity, and RANK-L activity? MEHLMANMEDICAL.COM129  MEHLMANMEDICAL.COM - ¯ osteoblast activity, ­ osteoclast activity, ­ RANK-L activity. - Cytokine activity at bone (namely IL-1 and -6) stimulates RANK-L activity à stimulates osteoclasts à decreased bone density. - Estrogen normally functions to suppress cytokine activity à preserves bone density. - Osteoblasts build bone; osteoclasts resorb (break down) bone. - USMLE wants the above three arrows for osteoporosis. - Some students have asked about ALP in this setting. ALP is reflective of osteoblast activity. If osteoblast activity is increased (e.g., hyperparathyroidism, Paget disease), ALP is always high on USMLE. In contrast, if osteoblast activity is low, ALP activity can be normal or low. MEHLMANMEDICAL.COM130  MEHLMANMEDICAL.COM 64. 74M + favorite hat does not fit him the way it used to + fell and hit his head in the bathroom + non- contrast CT of head shows no bleeding but reveals heterogenous mixed osteoblastic and -clastic areas in the occipital region. What are the arrows (i.e., ­, ¯, or «) for serum Ca2+, serum PO43-, PTH, and alkaline phosphatase (ALP)? MEHLMANMEDICAL.COM131  MEHLMANMEDICAL.COM - « Serum Ca2+, « serum PO43-, « PTH, ­ ALP. - Diagnosis is Paget disease of bone, which is characterized by increased bone turnover and mixed areas of osteoblastic and -clastic predominance. - USMLE wants you to know that Paget causes an isolated increase in serum ALP. Calcium, phosphate, and PTH are normal. This is how it will be for 9/10 questions. - I’ve seen one 2CK-level NBME Q where ALP was normal, but the rest of the vignette was obvious for Paget. - ALP levels reflect osteoblast activity. Since there is increased bone turnover, ALP is increased. - Patients are often diagnosed incidentally, as with this patient, who had a non-contrast CT looking for a bleed, but it was discovered that he has mixed -blastic and -clastic areas of bone. Next best step in management on 2CK is “check serum ALP levels.” - Patients can often get high-output cardiac failure, with an S3 heart sound accompanied by a high, not low, ejection fraction. This is due to AV fistulae that develop within bone. MEHLMANMEDICAL.COM132  MEHLMANMEDICAL.COM 65. 68F + metastatic breast cancer. What are the most likely arrows (i.e., ­, ¯, or «) for serum Ca2+ and PTH? MEHLMANMEDICAL.COM133  MEHLMANMEDICAL.COM - ­ Serum Ca2+, ¯ PTH. - Once metastases seed at bony locations, cytokine activity causes lysis of the bone and release of calcium into the blood. Hypercalcemia is common in the setting of metastatic malignancy (not limited to breast). - PTH is suppressed due to the high calcium. MEHLMANMEDICAL.COM134  MEHLMANMEDICAL.COM 66. 67M + one-month Hx of mid-back pain + serum protein electrophoresis shows an IgG M protein spike + nephrotic syndrome + renal biopsy shows apple-green birefringence with Congo red stain + S4 heart sound. What are the most likely arrows (i.e., ­, ¯, or «) for serum Ca2+, PTH, and ESR? MEHLMANMEDICAL.COM135  MEHLMANMEDICAL.COM - ­ Serum Ca2+, ¯ PTH, ­ ESR. - The diagnosis is multiple myeloma. - Serum calcium is high due to lytic lesions of bone. This will cause suppression of PTH (negative feedback at calcium-sensing receptors). - Elevated ESR wi