Episode 85: This begins the audio series with the Cross-Synaptic learning approach. USMLE topics are taught while universal principles are pointed out that refer to other topics or physiologic processes. These lectures will be saved online in the MMC and are expected to be completed in 2014.


Cross-Synaptic Learning approach for the USMLE Step 1

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USMLE Step 1 Endocrine Disorders

Primary vs Secondary vs Tertiary:

Cross-Synaptic Principle of “Structural” Learning Process. These correlate to the processes type of information and the graphical content study approach taught in the MMC Exam Prep modules.

  • Hashimotos = destruction of the thyroid gland = PRIMARY hypothyroidism (the gland screws up the hormone)
  • Hypopituitarism and hypothyroidism = SECONDARY hypothyroidism (no TSH to stimulate)
  • Hypothalamic Dz = Sarcoidosis destroying TRH: TERTIARY (no TRH)
  • Example: adenoma on parathyroid producing PTH leading to hypercalcemia = primary hyperparathyroidism
  • Example: have hypocalcemia/vit D def, and asked the parathyroid to undergo hyperplasia, that is called SECONDARY hyperparathyroidism
  • Example: what if after a long time PTH keeps being made = tertiary hyperparathryroidism (rare)


Overactivity vs underactivity of glands:

Cross-Synaptic Learning Principle of “Interference Tests”. These refer to a physicians alteration of the ‘natural’ (or in this case unnatural) process. Other areas include ECT and the use of adenosine in supra ventricular tachycardia.

Stimulation test: if pt has underactive gland, would use stimulation test to see if the gland is working.

Supression test: if pt has overactive gland, would use suppression test to see if gland will stop working.

Most of the time, things that cause overactivity, we CANNOT suppress them. There are 2 exceptions where we suppress them, and they deal with overactivity in the pituitary gland

1)prolactinoma can be suppressed bc it can prevent the tumor from making prolactin; bromocriptine suppresses it (dopamine analog – normally, women do not have galactorrhea bc they are releasing dopamine, which is inhibiting prolactin (therefore dopamine is an inhibitory substance – bromocriptine is also used for treating parkinson’s because bromocriptine is a dopamine analog (which is what is missing in parkinsons dz)

2) Pituitary Cushings: b9 tumor in the pitiuitary that is making ACTH – you CAN suppress it with a high dose of dexamethasone. These are the only two exceptions for a tumor making too much stuff. (There is no way to suppress a parathyroid adenoma making PTH, or an adrenal ademona making cortisol, or a an adrenal tumor from synthesizing aldosterone – these are AUTONOMOUS).

Example: pt with hypocortisolism – lets do an ACTH stimulation test – will hang up an IV drip and put in some ACTH; collecting urine for 17 hydroxycorticoids (metabolic end product of cortisol) and nothing happens – so what is the hypocortisol due to? Addison dz – gland was destroyed – therefore, even if you keep stimulating it, you will not be making cortisol.

Example: Let’s say after a few days you see in an increase in 17 hydroxycorticoids, then what is the cause of hypocortisolism? Hypopituitarism – in other words, it’s atrophic bc its not being stimulated by ACTH, but when you gave it ACTH over a period of time, it was able to regain its function. So, with that single test, you are able to find cause of hypocortisalism. Can also look at hormonal levels – ie Addison’s causing hypocortisalism, what would ACTH be? High; if you have hypopituitarism causing hypocortisalism, what would ACTH be? Low.


MCC in adults = nonfunctioning pituitary adenoma (within sella turcica – in the sphenoid bone, hence surgery is transphenoidal surgery, where the expanded sella turcica is). Pit Adenoma – usually nonfunctioning and destroys the normal pituitary over time as it grows, leading to hypopituitarism.

Sheehans (postpartum necrosis)

Example: have a pregnant woman, has abruptio placenta and goes in to hypovolemic shock, but get out; doing fine and breast feeding baby at home, but suddenly stops breast milk production – dx? Postpartum necrosis – therefore she has infarcted her pituitary (coagulation necrosis), and this is residual pitiuatary (This is not liquefactive necrosis because the pituitary is not part of the brain).

The mechanism is ischemia and coagulation necrosis. Pregnant woman have a pituitary gland two times the normal size. Prolactin is being synthesized – but a pregnant woman does not have galatorrhea bc the estrogen and progesterone inhibit release. So, the moment you give birth, the inhibitory effect is released and start having galactorrhea. This is the 2nd MCC hypopit in adult.

MC in kids = craniopharnygioma

Rathke’s pouch origin – this is part of the embryological development of the pituitary gland – pieces of it remain and can become neoplastically transformed into a craniopharygioma. Its not a malignant tumor, but a b9 tumor in a bad place. It is MC supra-sellar – (above the sella) – and it goes down and destroys the pituitary, but likes to go forward and bumps into optic chiasm, leading to bitemporal hemianopsia, leading to visual field defect.

Example:: child with headaches and visual field defect – do a schematic of it and will ask what the cause is – craniopharyngioma – tumor of rathke’s pouch origin.

Growth Hormone

When you have a tumor that is expanding in the sella turcica, different releasing factors (hormones) decrease in a certain succession. The first thing that is destroyed is gonadotropin. So, in a woman, what would  happen? She would have amenorrhea (secondary amenorrhea). What if I were a man (what is the analogous condition)? Impotence; impotence is to a male as amenorrhea is to a female. Impotence = failure to sustain an erection during attempted intercourse. The next thing that goes is growth hormone (which has 2 functions: 1) increases aa uptake and 2) involved in gluconeogenesis (hormone that produces bone and tissue growth is insulin like growth factor-1, which is present in the liver – aka somatomedins; so, GH release will stimulate the liver to release IGF-1 to cause growth of bones linearly and soft tissue); an adult with the loss of growth hormone will not get smaller, but will have the effects of lack of growth hormone: will start to lose muscle mass and will have fasting hypoglycemia bc GH is normally gluconeogenic. So, its not there and not contributing is func to glucogngeogenesis, leading to hypoglycemia. What would you see in a child? Pituitary Dwarfism. Would see hypoplasia (incomplete development of something). So, pit dwarfisim is an incompletely developed child, but everything looks normal. What is the best stimulation test to see if you are GH or IGF-1 defecient? Sleep. You grow when you sleep – exactly at 5 am (that’s when GH comes out). So, the best test is sleeping, then checking blood at 5 am (if it isn’t your def).Why is histidine and arginine deficient? They are essential to normal growth of a child bc they stimulate growth hormone. These are basic aa’s. This is why wt lifters buy arg/his supplements. So, best test is sleep, followed by measuring arg and his levels. The third hormone to go is TSH, which leads to hypothyroidism (therefore low TSH and low T4 – cold intolerance, brittle hair, fatigue, delayed reflexes). The next thing that goes is ACTH , leading to hypocortisalism. Will be fatigue will a low cortisol level. Will also lead to hypoglycemia bc cortisol is gluconeogenic. That last thing to lose is prolactin.

Diabetes Insipidus

Central (lacking ADH) vs Nephrogenic (kidney doesn’t respond to ADH)

Central: one of the common causes is car accident, leading to head trauma. The head is shifted and stalk is severed. One of the first things that goes is ADH bc it is made in the supraopitic paraventricular nucleus of the hypothalamus. In the same nerve it is made in, it goes down the stalk and is stored in the POSTERIOR pituitary. So, if you sever that stalk, you sever the connection and leads to ADH def. Also def in all the releasing factors that are made in the hypothalamus that stimulate the pituitary, leading to hypopituitarism (eventually – but initially will have s/s of DI = polyurea and thrist).

Nephrogenic: have ADH, but doesn’t work on the collecting tubule to make it permeable to free water. Other polyurea’s (DM – mech = osmotic diuresis, polydipisia – mech = drink too much water (psychological problem), hypercalcemia leads to polyurea). Constantly diluting, but will never be able to concentrate urine; SIADH is the exact opposite, where ADH is always there, and will constantly concentrating, and will not be able to dilute. In DI, constantly diluting urine, losing free water, and will never be able to concentrate the urine. So, you are losing all the water, and serum Na will go up, correlating with an increased plasma osmolality (bc most of plasma osmolality is Na).

To test: restrict water – in a normal person, if you restrict water, the plasma osmolality will go up to 292 (the upper limit of normal for the osmolality), 750 urine osmolality – what does that mean? Pt is concentrating the urine. So, if you are depriving a normal pt of water, it should concentrate the urine; water is being retained get into the ECF to get the serum Na into normal range.

Example: pt restricted water and have a 319 and 312 plasma osmolality (which is elevated). So, they have hypernatremia. If you look at urine osmolality, it is 110 and 98. So you know that have DI. So, how do you distinguish central from nephrogenic? Give them ADH (aka vasopressin). So, you give it to them and see what happens to urine osmolality.

If it increases greater that 50% from the baseline: then it’s central.

It its less than 50% it’s nephrogenic. So, gave ADH to first guy and it urine osmolality change to 550, indicating that he has central DI. For the second pt, ADH was given, but only a lil increase in urine osmalality, indicated nephrogenic DI.


What is cheapest way for screening for acromegaly? Ask for an old pic of the pt 10 years ago. Gigantism in kid bc epiphyses haven’t fused, therefore an excess in GH and IGF-1 lead to an increase in linear growth. Bad dz bc can die from cardiomyopathy. So, they have excess GH and excess IGF-1. So, what if you’re an adult with acromegaly? Will not get taller bc the epiphyses have fused, but bones will grow wider. One of the bones in the head that does that is the frontal bones, so they stick out. So, get a gorilla like increase in the frontal lobe (bc it increases size of the sinuses), so the hat size will increase. Your hands get bigger, feet get bigger, and every organ in the body gets bigger. Also, you produce a cardiomyopathy, which leads to death.


Men do not get galactorrhea bc we don’t have enough terminal lobules to make the milk. So, if a male has a prolactinoma, do not expect him to have galactorrhea. This has many causes. When woman comes in with it, make sure you ask what drug they are on – bc there are many drugs that can stimulate prolactin synthesis.

Example:: OCP’s, hydralazine, Ca channel blockers, psychotropic drugs. Primary hypothyroidism can also be a cause, therefore get a TSH level. Why? Bc if you have hashimoto’s, not only is TSH increased, but you also have increased TRH. TRH is used as a stimulation test for prolactin. So, you must rule out hypothyroidism in a woman with galactorrhea (so in this case, there is nothing wrong with the pituitary, but the thyroid, leading to galactorrhea). So, must r/o hypothyroidism. If all this is ruled out and pt has high prolactin level, dx is prolactinoma (any time there is a prolactin level over 200 it is always a prolactinoma). When pts have prolactinoma, why do they develop amenorrhea? Bc prolactin has a negative feedback on GnRH. So, this is a cheap birth control pill for the first three months after pregnancy bc mom is breast feeding, and the high prolactin levels are feeding back on the pituitary on GnRH.


Thyroid studies – do NOT have to know resin T3 uptake and T4 indexes; 3 things need to know: T4, TSH, I 131 uptake. If TSH is normal, the thyroid is normal. If TSH is decreased, pt has hyperthyroidism or hypopituitarism. If TSH is increased, have high primary hypothyroidism.  Thyroid binding globulin is the binding protein for thyroid hormone.

What is the binding protein for—

  • cortisol? Transcortin;
  • calcium? Albumin;
  • Fe? Transferrin;
  • Cu? Ceruloplasmin; what % of binding sites occupied? 30%).

3 of 9 binding sites on TBG are occupied by thyroid hormone. Free T4 level. When we measure total T4 level, there is free T4 and bound T4. The free T4 is the part that is metabolically active and is converted to T3. This part is doing all the work (that part that is bound is not). What happens if you are on an OCP with an increase of estrogen? TBG and transcortin increase. So, increased syn TBG, and is immediately 1/3 occupied (9 sites on TBG, and 1/3 occupied by T4, so that is 3 T4’s). Bc everything is in equilibrium, the thyroid senses that it lost 3 T4’s and replaces them immediatetly. So, has the FREE T4 altered? No. So what is the TSH? Normal. What is the T4? Increased (but the free hormone level and TSH not altered). So, an increase T4 with a normal TSH means the pt is on estrogens. This is true for any woman on estrogen or any pregnant women. So, the total T4 is elevated bc increased TBG (not be increased free hormone level) and it automatically has 3 sites occupied by T4). Same is true for cortisol – if pt is pregnant or on OCP, cortisol is elevated but do not have signs of cushings. Why? Bc transcortin is increased bc estrogen increasing the synthesis of it, so there is more cortisol bound to it, but the free cortisol levels are still normal.

Example:: if football player/wt lifter, assume pt is on anabolics. They work the opposite. Anabolics break down proteins that you normally would use for other things to build up and put them into muscle. The proteins it likes to go after is binding proteins. So, when they are on anabolics, thyroid binding globulin is decreased bc the aa’s that you would have used to make the binding protein are instead utilized to make muscles stronger. So, they won’t work if you are not working aa supplements.

Example: pt on anabolics, so less TBG being synthesize bc proteins being used elsewhere (muscles). The same number of site are occupied, but missing TBG. So, free T4 is the same, but missing TBG. So, if a person has a low T4 with a TSH, they are on anabolic steroids. If a woman has a high T4 and a normal TSH, what is she on? Estrogen. If a person has high T4 and low TSH, what do they have? Hyperthyroidism. If pt has low T4 and increased TSH, what do they have? Primary hypothyroidism. Do not need resin T3 uptake to make these dx’s. I 131 uptake is a radioactive test (remember that thyroid hormone is tyrosine with iodine on it). (What are other things involved with tyrosine? Melanin, tyrosine tyrosinase, dopamine – goes into the golgi apparatus and becomes melanin, phenylalanine, dopamine, dopa, NE, epi (catecholamines), if you put iodides on tyrosine you have thyroid hormone). So, with hyperthyroidism (ie graves), thyroid gland will be making more thyroid hormone. Would we need more iodide to do this? Yes. So, if you gave a pt radioactive iodide, will there be increased uptake of radioactive iodide in that overactive gland? Yes. So, will have increased I131 uptake. What if I were taking excess thyroid hormone to lose weight – what would that do to my TSH level? Suppress it. So, when that pt is taking too much hormone, the gland has atrophied. So, if you have a radioactive I 131, would there be an increased uptake? No bc is has atrophied. So, radioactive I 131 is the main way to distinguish whether a person has true evidence of hyperthyroidism (GLAND is making too much thyroid hormone) vs someone that is  surreptitiously/purposely/unknowingly taking too much thyroid hormone and producing hyperthyroidism. I 131 is the best test to distinguish these two types of hyperthyroidism. So, if its increased, pt has graves (gland is using it); if its decreased, pt is taking thyroid hormone.

Example:: pt from wt loss clinic – they are taking thyroid hormone, so they will lose wt at the expense of hyperthyroidism.

Slide: midline cyst – dx? Thyroglossal cyst. Remember that the thyroid gland was originally at the base of the tongue and migrates down the midline to the current location.

Slide: cyst in anolateral portion of neck – dx? Branchiocleft cyst (know all branchiocleft derivatives – esp the one in the head area).

Thyroiditis (inflammation of the thyroid). The only imp one is Hashimoto’s.

Grave’s Dz – exophalmos Unique to Grave’s Dz – excess GAG’s deposited in orbital fat, and pushing the eye out (pathonomognic for graves); apathetic graves OLD people with graves dz have heart prob with atrial fib. They get heart manifestations. So, any pt with atrial fib, must get a TSH level to rule out graves.

s/s hyperthyroidism: heat intoleranc, sinus tachy, atrial fib, brisk reflexes, diarrhea, systolic HTN, hypercalcemia, increased bone turnover (all symptoms are adrenergic – they are all catecholamine things – why? T4 increases the synthesis of beta receptors (catecholamines are cousins of Thyroid hormone and they work together. All the symptoms are adrenergic. What is the INITIAL Rx of graves? Beta blockers (blocking adrenergic response, then give PTU to stop the gland from making it – can stop all the symptoms with beta blocker except one – sweating) so, thyroid studies on graves pt: T4 is high, TSH is low, I 131 is HIGH In hyperthyroidism, want to always look at the face and will see periorbital puffiness, which is seen a lot bc of GAG’s (also in vocal cords, leading to hoarseness, tibial area leading to nonpitting edema).

Mitral Valve Prolapse also has an increase in GAGs bc dermatan sulfate is responsible for causing excess and redudency of the valve). Also seen in Hashimotos. Graves is due to IgG Ab against TSH receptor, causing it to synthesize too much. What type of HPY rxn is this? Type II (Ab against the receptor); MG is also type II HPY (have Ab against receptor which is destroying the receptor). In hashimoto’s thyroiditis, they also have an IgG against the receptor, except instead of activating the gland, it inhibits it. So, in Hashimoto’s and Graves, these are both autoimmune dz’s but at opposite ends of the spectrum. One as stimulatory IgG while the other has an inhibibitory one. So, an overlying symptom that they both have is pretibial myxedema and GAG deposition. Where do you see a decrease in GAG’s (ie metabolism of GAG’s)? Lysosomal storage dzs – Hurlers, Hunters – need lysosomal enzymes for breaking down dermatan sulfate, etc…

s/s hypothyroidism – weakness (MC) bc all pts with hypothyroidism have proximal muscle myopathy, so they cannot get up out of chairs , serum CK’s are elevated. Also have brittle hair, course skin, slow mentation, periorbital puffiness, delayed reflex, diastolic HTN Slide: bx of thyroid gland in Hashimotos’s – no follicle, but do see germinal follicle bc there is autoimmune destruction of the gland. There are  cytotoxic T cells that destroying it, and are synthesizing Ab’s (IgG Abs, hence you see the germinal follicles), and therefore looks like a lymph node). Will see a low T4, high TSH, low I 131 (not necessary to do this test).

Example: pt on estrogen – what will happen to T4? Increase TSH? Normal (no need for I 131 – this is bad bc babies thyroid would take it up and its thyroid would take it up and leads to cretinism) thyroid hormone is responsible for brain growth in the first year, so it imp to do thyroid hormone screens to avoid cretinism (will be severly MR bc brain depends on thyroid hormone for development).

Example: Grave’s dz – T4 high, TSH, low, I 131 high

Example: pt on anabolic steroids – T4 low, TSH normal

Example: Hashimotos – T4 low, TSH high, I 131 low

Example: factitious (taking too much thyroid hormone and have hyperthyroidism) – T4 high, TSH low, I 131 low (main factor that distinguishes from graves)


Anytime thyroid is big. Lots cysts.

MCC goiter = Iodine def

Most often due to low iodide levels, so they have hypothyroidism or borderline hypothyroidism, so the glands are getting rev’d up, T4 goes up and TSH goes down (so TSH will be stimulating it, then not, then it is, etc..). Rx of choice – thyroxine. Sometimes have a nodule – nodules that develop in the thyroid gland get hemorrhaged. There is sudden increase in hemorrhage due to cyst. Dx with FNA. Then, give thyroid hormone and many times these things will get smaller. In this country, we iodinize salt, so don’t see much. However, some places people have iodine poor diets – ie Great Lakes in Chicago area, Britain; when they get graves dz, due to increase in T3 bc they are iodide def and do not have enough iodine.

Cold nodule vs Hot Nodule

Means if nodule is taking up I 131 or not. If it does not, there is an area of lucency, and therefore cold. If it is hot, there will be a black dot. Why? Bc if the nodule is autonomously making thyroid hormone, what is the TSH? Decreased. If the TSH is decreased, would that suppress the normal portion of the thyroid? Yes, so it undergo atrophy and not take it up, leading to black dot (wouldn’t see anything else). What is chance that a cold nodule is malignant in a woman? 15-20%. Most cold nodules in an older woman are benign. Most are cysts. A small % is follicular adenoma. Any cold nodule in a MAN is cancer until proven otherwise. Any cold nodule in a child is cancer until proven otherwise. Any PERSON that has been exposed to radiation and has a cold nodule has CANCER (papillary carcinoma of the thyroid – radiation exposure in head/neck area).

Cancers of the thyroid

Need to bx (cannot tell if malignant just by looking at it) – this is true for follicular adenoma, something b9, multinodular goiter. Done with FNA.

1. Papillary cancer would show up with a cold nodule, and has Psammoma bodies. Papillary carcinomas mets to cervical lymph nodes next to them. They commonly do this, and have a good prognosis. This is the only assoc with radiation. Annie orphan nuclei.

2. Follicular cancer – 2nd MC type, invades vessels. Do not go to lymph nodes. Spread hematogenously, therefore often go to lungs and bone.

3. Medullary carcinoma – some cases are sporadic and other cases have AD relationship; assoc with MEN syndromes (multiple endocrine neoplasia I, IIa, IIb) Pink stain – stain with congo red and see polarized apple green birefringence = amyloid A (which came from calcitonin); what is the tumor marker? Calcitonin (which is the screening test of choice)

Example: where would the cancer be located in the body where the tumor marker is converted into amyloid? Medullary carcinoma of the thyroid

MEN I – pit tumor, parathyroid adenoma, pancreatic tumor (usually Zolinger Ellison, leading to peptic ulcer).

MEN IIa – medullary carcinoma, pituitary , pheochromocytoma

MEN IIb – medullary carcinoma, pheochromocytoma, mucosal neuroma How do you screen? Ret protooncogene (unique to coding for receptors in this syndrome).

Prognosis (best to worst): Papillary>Follicular>Medullary


Pt can have tetany with a normal total Ca. Ca is bound and free – it’s the free Ca that is metabolically active (which is true for ANY hormone – the part that is bound is totally metabolically inactive). So, who does Ca interact with? PTH So, if Ca is low, the PTH is high, and if Ca is high, PTH is low. Roughly 1/3 of the binding sites in albumin are occupied by Ca. So, in other words, roughly 40% of the total Ca is bound to  albumin. 47% is ionized Ca floating around and the rest is phosphate and sulfates. The ionized Ca is the metabollicaly active form. MCC overall of hypocalcemia = hypoalbuminemia. Have low albumin level, therefore decreased level, and less of albumin binds Ca. So, before you look at PTH levels, look at albumin levels – if that is low, this is the cause of hypocalcemia. This is not affecting the free hormone level, just that albumin is decreased. This the same as TBG being decreased, leading to decreased T4.

Alkalosis (resp or metabolic): have decreased H ions, and pH is increased. What are the acidic aa’s? Glutamate, Aspartate. Why are they acidic? Have COOH groups (as opposed to basic aa’s , which have more basic NH groups). The reason why albumin is such a great binder of Ca is bc it has the most negative charges in the body, bc it has the most acidic aa’s in it. So, if you have an alkalotic state the COOH groups become COO “-“ groups. Bc if you have less H ions, its COO”-“. So, albumin has MORE of a negative charge in an alkalotic state, which means it can bind more Ca. So, where does it get it from? Ionized free Ca (so a bunch of ionized free Ca binds to the the albumin). However, we have NOT altered the total, just took it. It doesn’t affect the total, but it DOES decrease the ionized Ca level, leading to TETANY. So, total is the same, but the ionized level has decreased. What is the mech of tetany?

Have threshold for the AP before the nerve is stimulated. Then you have a resting membrane potential. So, a decreased ionized Ca level will lower the threshold for activating the nerve and muscle. If its -60 for normal threshold. Pt is partially depolarized, therefore doesn’t take a lot to activate the muscle or the nerve (which is the mech of tetany) – so you are lowering the threshold. In hypercalcemia, the opposite occurs and you are increasing the threshold, so it takes more ionized Ca to activate the nerve. PTH on y axis and Ca in x axis – ht of square = PTH and width = Ca.

Low serum Ca, low PTH = primary hypoparathyroidism

MCC = previous thyroid surgery

Example: pt goes in to remove thyroid cancer (these days they autotranplant it to the arm)

Example: newborn with cyanosis, irritable and xray of chest shows not anteriormediastinum shadow – dx? DiGeorge – hypoparathyroidism and no thymus

Example: low Ca, high PTH = secondary hypoparathyrodism – so whatever is causing the hypocalcemia is causing a compensatory increase in PTH (called secondary hypoparathyrodism – the MCC of this is renal failure bc these pts have hypovitaminosis D, which decreases Ca and increases PTH). So, any decrease in Ca with cause a compensatory increase in PTH.

Example: high Ca, high PTH = primary hyperparathyroidism = gland is not obeying negative feedback. This is MCC hypercalcemia is a community; If pt is in a hospital, MCC hypercalcemia = mets to bone (malignancy induced). Most hypercalcemia pts are asmptomatic; if they ARE symptomatic, they have stones (Ca stones, which is the MC symptomatic presentation for hypercalcemia). Labs: increased Ca, increased PTH, low phosphate (normally PTH increases Ca reabsorption and decreased phophorus reabsorption). Almost always over 50 yo

Example: high Ca, low PTH = all other causes except primary hyperparathyroidism. MC due to malignancy. Can PTH like peptide cause hyperCa? Yes (so if you measure PTH it will be normal). Squamous cell of the lung, renal adenocacinoma, or mets to bone (breaking bone down), sarcoidsis (leading to hypercalcemia), multiple myeloma (leading to hypercalcemia) all will have LOW PTH. So, what is the ez’est way to determine hyperCa in a pt? PTH level (if its high, its primary hyperparathyroidism; if its low, its all the causes – ie malignancy).


Cushing Syndrome

PURPLE striae, obesity, thin extremities. MCC = pt on long term steroid therapy (ie pts with renal transplants, pt on immunosuppressant, Lupus). If this is excluded, need to think of 3 sources: pituitary Cushings, adrenal Cushings, ectopic Cushings. Which of the three will have the highest ACTH levels? Ectopic (small cell carcinoma). Which would have the lowest ACTH levels? Adrenal. Why? Bc its making cortisol, which would suppress the ACTH. Pit Cushings is usually a b9 tumor making ACTH.

There are 2 good screening tests for Cushings (when you have excluded the fact that they are not on steroids). The screening tests are: 24 hr urine test for free cortisol. This is looking for cortisol in the urine, not attached to any protein (so it’s free). It must mean that you have a lot of excess of it to have that much of it in your urine. This is the BEST screening test for Cushings. This test distinguishes Cushing’s syndrome from Cushingoid obesity.

Example: see obese pt with Cushing’s symptoms and you think they have Cushings; however, get a 24 hr urine cortisol test and it’s normal. If it’s increased, they truly have Cushings – in other words, they have 99% sens and specificity. They will ask about dexmeth suppression test (low vs high dose). What is dexamethasone? It’s a cortisol analog. If you give dexamethasone to a normal person, it will suppress ACTH. If you suppress ACTH, the cortisol levels with be low, indicating the cortisol levels are suppressible. So, what happens when you give a LOW dose of dexamethasone in a pt with Cushings – will you suppress their cortisol? No. So, you see a lack of suppression. Therefore pt has cushing’s. However the LOW dose just tells you pt has Cushings, not what kind they have, so it just a screening test (if you did a 24 hr cortisol urine level, it would be positive). Remember that there are two endocrine dz’s that you CAN suppress – PITUITARY Cushings and prolactinoma. So, if you give high dose of dexamethasone, you are able to suppress the ACTH release by the pituitary and cortisol goes down. It will not be suppressed in adrenal and ectopic Cushings (small cell). [Read last sentence if you get a long question]

Example: for one of these, they will describe Cushings, and ask about dexmeth suppression – first thing to do is look at high dose suppression – if its suppressed, its automatically pituitary cushings (not a hard question!) So, why do the pts look like this? Pt has hypercortisolism, which is gluconeogenic. So, need substrates for gluconeogenesis – main substrate is aa from muscles. Where are the muscles located? Arms and legs – so pt will get a break down of muscle in the extremities, which is why they have thin arms and thin legs. Then will get alanine transaminated and get pyruvate. So, will always have thin arms and extremities. Bc it is gluconeogenic, what will the glucose be? High. What does that do to insulin release? Increases it. What does insulin do to fat? Increases fat storage. What part of the body have the most adipose? Face and trunk. So, you are getting an increase in deposition of TG in the face and trunk and back. So, the thin extremities is due to breaking down muscle for aa’s in gluconeogenesis. The moon facies, buffalo hump and truncal obesity is due to increase in insulin and fat deposition. The stretch marks are due to obesity, and they are purple bc cortisol decreases collagen synthesis. Will get structurally weaker  collagen. Its like purpura within the stretch mark (like senile purpura). Break down the vessels bc increase in cortisol.

Example: Trousseau’s sign – sign of tetany; this pt has HTN, hypernatremia, hypokalemia, and metabolic alkalosis – dx? Primary aldosteronism. (have tetany bc alkalosis – neg charges on albumin are increased, and ioninzed Ca level decreases). Aka Conn’s syndrome

Adrenal Medulla tumors

MC in adults = pheochromocytoma (b9, HTN) (so, adult, HTN, tumor in adrenal medulla = pheo); have unstable HTN – anxiety, sweat a lot; get a 24 hr urine test for VMA and metenephrine (these are metabolic endproducts of NE an Epi (so, anxious, sweating, HTN). Are there assoc with pheochromocytoma? Yes – MEN IIa and MEN IIb, neurofibromatosis (ie pt with neurofibromatosis with HTN – what test you get? VMA and metanephrine 24 hr urine, bc high assoc with pheo). MC in kids = neuroblastoma (MALIGNANT).

Both of these are from renal medulla, both are neural crest origin, both produce HTN. Pheo = adults ; neuro – kids

Waterhouse Friderichsen Syndrome

N. menigitidis

Example:: 12 yo, gram “-“ diploccocus, high fever, nuchal rigidity, spinal tap found neutrophils and gram “-“, kid then ‘crashed’ – started to get petechial lesions all over the body, hypovolemic shock, died, on autopsy both adrenal glands are hemorrhaged – Dx? Waterhouse Freidrickson

MCC meningitis from 1 month to 18 yrs of age = N meningitidis. It is the ONLY meningitis with petechial lesions (and they always mention this). So, if they give meningitis and petechia, know is N  meningitis. If they are hypovolemic, they hemorrhaged their adrenals and went into hypvolemic shock, also, they have no cortisol or mineralocorticoids.

Cause of hypocortisolism that is chronic = Addison’s dz

MCC Addisons = autoimmune destruction of the gland (used to be TB due to autoimmune destruction). The entire adrenal cortex is destroyed, therefore the mineralocorticoids and glucocorticoids are low. So, there is low cortisol with HIGH ACTH.

What does that do to melanocytes? Increases them, leading to hypigmentation in the mouth and elsewhere. There is NO aldosterone. There are 2 pumps (Na/K pump and proton/K pump).

Are you gonna lose Na? Yes – which will lead to hyponatremia and HYPERkalemia (peaked T waves).

Will you be able to get rid of the protons in the urine? No – therefore will have metabolic acidosis. So, you have hyponatremia, hyperkalemia, metabolic acidosis, hyperpigmentation.

Example: ambiguous genetalia – what is first step in management? C’some analysis – have to find out what the genetic sex is. It’s XX. So, pt has ambiguous genetalia, female, phenotypically cannot tell, so it’s female pseudohermaphrotide – (play odds) – adrenogenital syndrome due to 21 hydroxylase def. 17 hydroxylase is responsible for 17 ketosteriods (include DHEA, androstenedione, and are weak androgens). Androstenedione can be converted into testosterone and testosterone into dihydrotestosterone. 17 hydroxycorticoids are 11 deoxycortisol and cortisol.

So, if you have an increase in 17 hydroxycorticoids, this is an increase in 11 deoxycortisol and cortisol. If you have an increase in 17 ketosteroids, (17, KS) it’s an increase in DHEA and androstenedione. When you have an enzyme def, things prox to the block increase and things distal to the block decrease.


Cross-Synaptic Learning Principle of “Enzyme Deficiencies”. THis is similar to aldehyde dehydrogenase deficiency and alcohol tolerance.

With 21 hydroxylase def, decrease mineralcorticoids and glucocortiocoids and increase androgens, lead to ambiguous genetalia (excess androgens), lose salt, high ACTH, therefore hyperpigmented

With 11 hydroxylase def – decreased cortisol, decreased aldost, but increased 11 deoxycorticosterone (weak mineralcoricoid), increased 17 hydroxy’s and 17 ketos – lil girl will have ambiguous genitalia, lil boy will have precocious puberty (excess androgens), HTN.

17 hydroxylase def – no androgens, increased in mineralocorticoids (HTN), so if it’s a lil boy he won’t have test and will look like a female bc no development (no external genitalia bc no 17 keto’s, test, or dihydrotest). In a lil girl – she will be underdevoped.

Islet cell tumors Only 2 to know: Insulinomas and ZE syndrome

ZE: making too much gastrin, leads to peptic ulcers.

Insulinoma: is pt injecting or do they really have insulinoma?

When you break proinsulin down into insulin, you release C peptide, so for every insulin molecule that is released, there is C peptide that is released with it. So, if you inject human insulin into yourself, and produce a low glucose level and C peptide will be SUPPRESSED. If you have a islet cell tumor, glucose will be low, insulin will be high and C peptide will be INCREASED. Don’t confuse with C-reactive protein from inflammation.

Example: pts that have access to insulin get this (Drs, nurses, pharmacists)

Diabetes Mellitus

Type 1

  • Absolute insulin deficiency
  • Antibodies against islet cells
  • DKA
  • HLA relationship
  • Insulin used (always)

Type 2

  • Family history of diabetes
  • Obesity
  • Amyloid in islet cells
  • Hyperosmolar non-ketotic coma
  • Insulin used when eventually pt get resistant to SFU

PATHOGENESIS: 2 mechanisms:

1) Osmotic Damage

Tissue has to have aldose reductase: only 2 have them:

a) Lens, glucose

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