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E. Tell her that everything is normal and discharge her from your clinic.


The important point to remember for this question is that an empty sella may be normal. This patient does not present any indication of pituitary dysfunction. The history of blood loss at the time of delivery may suggest Sheehan syndrome (hemorrhagic necrosis of the pituitary), but one of the most sensitive indicators of pituitary dysfunction is ovulation. This patient was able to get pregnant 6 more times; the hypothalamic-pituitary-ovarian axis must be working properly. She does not have Sheehan syndrome, but her obstetrical history offers another clue. Her 7 pregnancies have most likely caused her empty sella. With pregnancy, the pituitary enlarges and has a greater blood flow. This produces an upward pressure on the diaphragm covering the top of the sella, which stretches and expands the diaphragm. After pregnancy, the pituitary returns to a normal size with a normal blood flow, but the diaphragm is acellular and remains stretched. With each subsequent pregnancy, the diaphragm becomes progressively more stretched. This allows the diaphragm to bulge downward and into the sella under the pressure of the CSF fluid above it. In some cases, the diaphragm has become so loose that the CSF fluid displaces the majority of the pituitary to the periphery of the sella. A CT of the head will fail to identify pituitary tissue, and the term "empty sella" will be used. In actuality, the sella is not empty, but contains CSF fluid and normal pituitary tissue that has been pushed to the periphery. The pituitary tissue can work perfectly normally in this environment.

It is inappropriate to refer her to a neurosurgeon. Pituitary exploration may disrupt the normal functioning of her existing pituitary tissue and result in the development of hypopituitarism. While there is no evidence of pituitary dysfunction, the abdominal striae may trick some people to suspect Cushing syndrome, but there is no mention of hyperglycemia, hypokalemia, or the typical body habitus. Stretch marks are a common occurrence, especially following pregnancy. The typical stretch marks associated with Cushing syndrome are broad and appear purplish from the coloration of underlying tissue.

D. Begin dexamethasone 4 mg IV and order an ACTH stimulation test.


There is a strong suspicion that this patient has adrenal insufficiency and is having an adrenal crisis. She is hypovolemic with a hyperkalemic metabolic acidosis. The hypotension responded well to saline fluids. The thin body habitus and loss of axillary and pubic hair imply a chronic adrenal insufficiency. The flight delay may have caused stress for some reason that she was not able to cope with because of the adrenal insufficiency. This may have been what tipped her over the edge. Whether she really has an adrenal crisis or not is not the issue. It is more important to begin treatment than it is to prove your suspicion. The treatment is to give her intravenous glucocorticoids as soon as possible. But which glucocorticoid should you give? Remember, you do not yet have proof of the adrenal insufficiency. You can start treatment based on a suspicion, but you must also pursue a diagnosis. The diagnostic workup begins with an ACTH stimulation test. To do this, order a baseline serum cortisol level, administer 1 ampule of ACTH, and repeat the cortisol level 30 minutes later. The important thing to remember is that the assay for cortisol will cross-react with most other glucocorticoids and also pick up prednisone, methylprednisolone, and especially hydrocortisone since it is cortisol under a different name. If any of these are administered, how will you know what her endogenous production of cortisol really is? The solution is to administer a glucocorticoid that does not interfere with the cortisol assay, such as dexamethasone. She needs a glucocorticoid to save her life; begin dexamethasone immediately. If her adrenal function proves to be okay, you can easily stop the steroid. To check her adrenal function, check for her response to ACTH. If the cortisol level is greater than 20 μg/dL, her adrenal reserve is intact and you can stop the dexamethasone. If the ACTH stimulation test shows adrenal insufficiency, stop the dexamethasone and switch her to hydrocortisone. This is the actual cortisol molecule, and it has an advantage over the other glucocorticoids. Hydrocortisone (cortisol) is primarily a glucocorticoid, but it also has some mineralocorticoid activity that will help with her electrolytes.

The other answers are incorrect because a glucocorticoid other than dexamethasone should not be used for the above reasons. Hypothyroidism is unlikely, so starting thyroxine is not indicated. Once her adrenal crisis has resolved, you can reevaluate her.

B. Primary adrenal insufficiency


This case demonstrates several clues that should lead you toward primary adrenal insufficiency. He has a thin body habitus, decreased body hair, hyperkalemic metabolic acidosis, and a low glucose. This constellation of findings should always make you suspect adrenal insufficiency. The appropriate action is to start dexamethasone while you wait for the results of an ACTH1-24 (cosyntropin) stimulation test. A normal person will have a stimulated cortisol level exceeding 20 mg/dL. His cortisol comes back low, which confirms your diagnosis. Now you must decide between primary and secondary disease. The answer is in the question. How many elderly people in Philadelphia have a good tan in the middle of winter? Yes, he could frequently visit the neighborhood tanning salon, and he could have returned recently from an extended vacation in the Caribbean. But most likely, the well-tanned skin represents hyperpigmentation resulting from elevated levels of melanocyte-stimulating hormone (MSH). ACTH and MSH are derived from POMC. His tan most likely represents the hyperpigmentation associated with excess ACTH production in an attempt to overcome the primary adrenal insufficiency. It would be appropriate to switch him from dexamethasone to hydrocortisone (cortisol) because the latter has mineralocorticoid actions. Remember that a person with primary adrenal insufficiency also loses his mineralocorticoid (aldosterone) production.

There is no such thing as pseudo adrenal insufficiency; his clinical presentation is opposite to what you would expect from someone abusing glucocorticoids; and although hypothyroidism could explain his fatigue, it doesn't explain the rest of his presentation.
A 25-year-old woman comes to see you for irregular menses and difficulty getting pregnant. She denies unusual stress or any recent changes in her health. Her periods were regular until 8 months ago. She briskly walks 1 mile 4 days per week and has been dieting for 1 year. Her weight has decreased 47 pounds during the previous year. Your physical examination shows a small thyroid nodule and somewhat brisk deep tendon reflexes.

You order a series of tests and have her return in 3 weeks to discuss the results, which are as follows:

Na+ 140 mEq/L (135-143 mEq/L)
K+ 4.0 mEq/L (3.5-5.0 mEq/L)
Cl- 104 mEq/L (100-109 mEq/L)
HCO3- 24 mEq/L (22-30 mEq/L)
Urea nitrogen 9 mg/dL (8-18 mg/dL)
Creatinine 0.8 mg/dL (0.6-1.2 mg/dL)
Glucose 85 mg/dL (65-110 mg/dL)
Ca+2 9.9 mg/dL (8.5-10.5 mg/dL
FT4 1.9 ng/dL (0.7-1.5 ng/dL)
TSH 0.01 mU/L (0.5-5.0 mU/L)

Pelvic ultrasound was normal.

Nuclear medicine thyroid scan showed mildly enlarged thyroid with generally diffuse uptake, except for a 1.5 cm cold nodule.

Nuclear medicine thyroid uptake was 40% (normal 10-35%).

Which of the following recommendations should be given to her at this time?
A) PTU 100 mg every 8 hours with follow-up in 2 months.
B) Begin oral contraceptives and repeat the thyroid tests in 6 months.
C) Ultrasound-guided biopsy of her thyroid nodule.
D) Surgical resection of her thyroid, followed by thyroxine replacement.
E) Radioactive iodine ablation of the thyroid gland, avoid getting pregnant for at least 6 months, and biopsy the nodule if it still exists after the ablation.

D. Surgical resection of her thyroid, followed by thyroxine replacement.


She is hyperthyroid due to Graves disease but also has a cold nodule. The best treatment option in someone with Graves disease complicated by a cold nodule is surgical resection, followed by appropriate thyroxine replacement. This will take care of both the Graves disease and the cold nodule. Even though most cold nodules are benign, any cancer that may be present is most likely to occur in a cold nodule. Radioactive iodine ablation is an excellent treatment option for Graves disease, but it will not have any effect on the cold nodule because cold nodules do not take up iodine, by definition. Thus, after ablation her nodule will still be present and will have to be biopsied, but now the architecture is altered, and the biopsy and any necessary nodule resection may be more difficult. Surgical resection will also give this patient a faster return to euthyroidism and probable return to regular menses and fertility. Granted, this is a difficult question with several possible treatment plans. However, this scenario is one of the reasons to refer a patient with Graves disease for surgical resection. The vast majority of cases are treated with radioactive iodine ablation.

PTU will address the hyperthyroidism, but will not address the cold nodule. An ultrasound-guided biopsy is not a bad choice, but you must still address the hyperthyroidism after the nodule has been taken care of. If the nodule is benign, then you can proceed to the ablation. If the nodule is not benign, then you will have to refer her for surgical resection anyway. Again, radioactive iodine ablation will address the Graves disease, but will not address the cold nodule. Waiting 6 months to examine the nodule could cause unacceptable advancement of any malignancy that may be present. Starting oral contraceptives will not address any of her problems.

Remember: Any woman receiving a radioactive iodine ablation must avoid pregnancy for a minimum of 6 months. Also, since oral contraceptives are less effective in a woman who is hyperthyroid, she must use two forms of birth control or avoid sex altogether. The dose for a thyroid scan and uptake is considerably smaller, and no special precautions are required after the scan and uptake. Though the fetus is probably safe when exposed to the small dose used in scans, pregnant women should never receive radioactive iodine because of the potential threat to the fetus.

E. High dietary intake of iodine


This question requires you to know what factors influence a radioactive iodine uptake test. A high uptake (> 35%) signifies a greater than usual uptake of radioactive iodine by the thyroid. The most common cause of high uptake in this country is Graves disease. Other causes of a high uptake include iodine deficiency (common in other parts of the world), hot nodules (if hot enough), toxic multinodular goiter (sometimes), high levels of β-HCG (it resembles TSH and can activate TSH receptors when present in very high concentrations such as seen with molar pregnancy, choriocarcinoma, and some cases of germ-cell tumors), and a pituitary tumor secreting TSH.

A low uptake (< 5%) signifies a less-than-usual uptake of radioactive iodine by the thyroid. Causes of a low uptake include Hashimoto thyroiditis (most common), other causes of thyroiditis (e.g., subacute, postpartum, radiation, and amiodarone-induced), thyroid-suppressive drugs (e.g., propylthiouracil, methimazole, and lithium), iodine excess, ectopic thyroid tissue (struma ovarii), lack of a thyroid gland (radioablation or surgical removal), and expired radioactive iodine (extremely unlikely because of several quality assurance steps).

The patient in this question probably has Graves disease because of an elevated FT4 in the face of an undetectable TSH and a symmetrical goiter with homogeneous uptake. The uptake in Graves disease is normally greater than 35%. His thyroid is undoubtedly taking up iodine at a much higher rate than normal. However, the thyroid gland does not discriminate between radioactive iodine and non-radioactive iodine (cold iodine). Some patients take iodine supplements (e.g., kelp pills), and this excess cold iodine competes with the radioactive iodine. Thus, less radioactive iodine is taken up by the thyroid while greater amounts of cold iodine are being taken up. This results in a lower uptake than expected. High intake of iodine can be verified by checking a 24-hour urine for iodine.

The other choices are incorrect. Hyperthyroid Hashimoto thyroiditis (aka hashitoxicosis) can present with hyperthyroidism, symmetrical goiter, and suppressed TSH, but the uptake is low (< 5%). His uptake is too high for thyroiditis. Expired radioactive iodine is extremely unlikely. Low dietary intake of iodine would enhance the uptake, not suppress it. His scan is homogeneous, which argues against hot nodules.

C. Do a cosyntropin stimulation test.


This is a case of secondary hypothyroidism. The teaching point is to recognize that she likely also has secondary adrenal insufficiency and it is important to make the diagnosis and treat adrenal insufficiency before starting thyroid hormone. Starting IV levothyroxine is wrong because you would not give IV T4 to an elderly individual, especially one who might have adrenal insufficiency. Beginning hydrocortisone is wrong because you would not give hydrocortisone until it has been confirmed that the patient actually has adrenal insufficiency.

This question requires you to understand Schmidt syndrome. And this question tests your ability to consider the entire presentation and not to focus on the obvious. Of course she is clinically and biochemically hypothyroid, but don't miss the other possible issue. She has several clues that raise the possibility of adrenal insufficiency: thin body habitus, not gaining weight despite being hypothyroid, low blood pressure, and a hint of hyperkalemic metabolic acidosis. The blood pressure is not unusual for a woman, but hypothyroidism usually raises diastolic blood pressure. The blood pressure alone is not diagnostic of adrenal insufficiency, but it is highly suggestive when taken in context with her other findings. The glucose is also normal, but how many of your patients have a fasting glucose this normal?

The board examination is not likely to give you an obvious case of adrenal insufficiency, so be suspicious whenever you encounter a high-normal potassium with a somewhat low bicarbonate. It is imperative to recognize a possible case of Schmidt syndrome (combination of hypothyroidism and adrenal insufficiency) because the patients die soon after starting thyroid hormone replacement unless they begin glucocorticoid replacement. If you ever have any suspicion that a patient may have adrenal insufficiency, you must begin steroids and work up the patient. The standard test is an ACTH1-24 (cosyntropin) stimulation test. Because dexamethasone is the only available glucocorticoid that does not interfere with the cortisol assay, the patient must be started on dexamethasone until the results of the test are available.

If she truly has adrenal insufficiency, it should be treated with hydrocortisone because it also has some mineralocorticoid activity. Once she takes her first steroid pill, she can begin thyroxine.

B. He has Klinefelter syndrome and should start testosterone, 100 mg IM weekly.


This question tests your knowledge of Klinefelter syndrome and other causes of hypogonadism. He has Klinefelter syndrome, which is characterized by very small and fibrotic testes. The genotype is 47,XXY, and hence a Barr body (condensed chromatin seen in female cells due to an inactive X chromosome) can be seen in these men. They often have gynecomastia and poor social skills. They are not able to produce normal amounts of testosterone. The treatment is testosterone replacement, which is often done with weekly injections. One important point to remember is that the arm span is normal (arm span - height < 5 cm or 2½ inches).

He does not have Kallmann syndrome because such patients have an increased arm span (arm span - height > 5 cm or 2½ inches); testes that are larger than seen in Klinefelter syndrome, although they are still small; a normal genotype (46,XY) and no Barr bodies; usually no gynecomastia; have adequate social skills; and have an impaired sense of smell. Primary hypogonadism due to a postpubertal mumps infection would result in small soft testes, but they will be larger than seen in either Klinefelter or Kallmann syndrome. He clearly has primary hypogonadism and cannot have hypogonadotropic hypogonadism because the gonadotropic hormones LH and FSH are elevated, trying to compensate for the primary defect. He also does not have complete testicular feminization because these 46,XY individuals develop as phenotypical women but without a uterus or full introitus.

B. Begin thyroxine 50 µg per day and check lipids, TSH, FT4, and anti-thyroid antibodies in 2-3 months.


This patient may very well have subclinical hypothyroidism. By definition, the diagnosis is very difficult and easily missed: The FT4 is normal and the TSH may be normal or minimally elevated. This diagnosis is important because of the implications. Positive anti-thyroid antibodies contribute to the diagnosis of subclinical hypothyroidism and increase the risk of transforming into overt hypothyroidism in the future. Patients with subclinical hypothyroidism and a TSH>10 mU/L should be treated regardless of symptoms. For TSH between 5-10 mU/L, patients should be treated if they have symptoms of hypothyroidism. The Rotterdam study clearly showed that women ≥ 55 years of age with subclinical hypothyroidism have a significantly elevated risk of myocardial infarction and aortic atherosclerosis. Nevertheless, a clear benefit from treatment has not yet been published. However, hypothyroidism is well known to cause an elevated LDL, and her LDL is 175 mg/dL. Even though she is not symptomatic for hypothyroidism, her elevated TSH >10 mU/L in conjunction with her elevated LDL are both factors in your decision to treat with thyroxine supplementation.

It is premature to begin statin drug therapy, since treatment of hypothyroidism often reduces LDL levels. Starting a low-dose trial of thyroxine is very appropriate in this case. Since her anti-thyroid antibodies (anti-TPO) are positive, I would continue her thyroxine therapy even if the LDL does not improve. If the LDL remains elevated, you should consider statin therapy. A year-long revisit is too prolonged a follow-up to address both the lipid disorder and subclinical hypothyroidism. And finally, her likelihood of having an ovarian or uterine cancer in this post-menopausal patient without symptoms or an abnormal pelvic exam is very low. Therefore, the indication for a pelvic ultrasound is unnecessary.

E. Begin non-radioactive iodine (Lugol's solution) immediately.


The patient is clearly hyperthyroid based on clinical symptoms and biochemical testing. It is unclear if he has Graves' disease versus a toxic multinodular goiter as a radioactive uptake scan is not available at this time. Iodine preparations such as Lugol's solution and potassium iodide cause immediate inhibition of preformed thyroid hormone secretion. These iodine preparation are not indicated in this situation as should he have a toxic multinodular goiter, the iodine would provide addition substrate for new hormone synthesis, potentially worsening any hyperthyroidism. Should Lugol's solution be given, it is only recommended at least one hour AFTER thionamide (such as PTU) administration.

Elective surgery should ideally be postponed to correct hyperthyroidism in order to prevent the precipitation of thyroid storm. Though his surgery can be postponed for a short period of time to give the thyroid treatments a chance to start working, he needs the surgery soon. Sending him home with a suprapubic catheter until he is euthyroid is not a good option in this case. Therefore, your best strategy is to address his hyperthyroidism in anticipation of immediate surgery. PTU will decrease synthesis of new thyroid hormone, with the goal of decreasing hyperthyroidism in the post-operative period as it takes a few days to start working. A β-blocker will help control his symptoms of hyperthyroidism. A good choice would be a β-blocker that can be given IV and rapidly titrated during surgery, such as esmolol. Because he has A-fib, he must be suspected of having an atrial thrombus; therefore, he should be anticoagulated because he may revert to a normal rhythm once he becomes euthyroid. This can be done with a heparin product before surgery, which can be stopped preoperatively, and with warfarin after surgery.

C. Encourage weight-bearing exercises.


This question requires you to know the recommendations for preventing glucocorticoid-induced osteoporosis. Glucocorticoids directly weaken bone by stimulating bone resorption and inhibiting bone formation. They have a negative impact on calcium by decreasing gastrointestinal absorption and increasing renal excretion. This in turn may increase PTH, which will further weaken bones. Nevertheless, calcium and PTH levels generally remain within normal limits, suggesting that the main problems are the direct effects of glucocorticoids on bone.

The following are recommended by the American College of Rheumatology for preventing glucocorticoid-induced osteoporosis in patients starting prednisone equivalents at least 5 mg daily for 3 months or less:

Modify lifestyle
Weight-bearing exercises
Calcium 1.5 g daily
Vitamin D 800 units daily
Oral bisphosphonates (caution in premenopausal women)
The following are recommended by the American College of Rheumatology for treating glucocorticoid-induced osteoporosis in patients receiving prednisone equivalents at least 5 mg daily for at least 6 months:

Modify lifestyle
Weight-bearing exercises
Calcium 1.5 g daily
Vitamin D 800 units daily
Monitor BMD and treat T-scores of -1 or less
Monitor for hypogonadism and consider replacement therapy if needed
Bisphosphonates if T-score is -1 or less or fracture occurs (caution in premenopausal women)
Treat with calcitonin if other drugs are contraindicated.
The patient in this question should not be told to consume 4 g of calcium daily, and vitamin D of 100 units daily is too small of a dose. She cannot take bisphosphonates because they are contraindicated in someone with a history of esophageal stricture. She should get some sun exposure as well.

C. Vitamin A intoxication


This question requires you to know that hypercalcemia may be due to vitamin A intoxication. This patient has hypercalcemia and osteopenia, along with chronic ingestion of large doses of vitamins. The lack of an elevated level of 1,25(OH)2-vitamin D rules out an excess of this particular hormone, while an elevated level of 25(OH)-vitamin D indicates that he is ingesting an excess of this particular hormone. However, we are less interested in excess 25(OH)-vitamin D because it has limited activity and presents a problem only when at markedly high levels. His mild elevation of 25(OH)-vitamin D is too little to explain his hypercalcemia. The enzyme that converts 25(OH)-vitamin D into 1,25(OH)2-vitamin D (1α-hydroxylase) is regulated by PTH and will protect a person from developing high levels of 1,25(OH)2-vitamin D.

Another hormone with a well-recognized role in calcium homeostasis is PTH. This patient's PTH level is appropriate in the setting of hypercalcemia. A low PTH would indicate hypoparathyroidism only in the setting of low calcium. Primary hypoparathyroidism is not a cause of hypercalcemia. Because his PTH is low, renal excretion of phosphate is not being stimulated and the level of phosphate is elevated. There is no reason to suspect thiazide diuretics. His blood pressure and volume status are normal, and his potassium is high-normal. There is no reason to attribute his hypercalcemia to thiazide diuretic use. Increased dietary calcium intake rarely causes hypercalcemia and would not explain the patient's osteopenia. The only other choice is vitamin A excess.

Vitamin A excess is an uncommon cause of hypercalcemia, but it can be seen with chronically high ingestion of vitamin A, usually at levels 10-fold greater than the recommended daily allowance. For reasons unknown, high levels of vitamin A cause calcium resorption from bone. Vitamin A excess may also cause muscle and bone pain, hepatic dysfunction, dry skin, nausea, headache, fatigue, ataxia, alopecia, hyperlipidemia, and irritability.

A. Check serum IGF-1 and 24-hour urine cortisol.


Whenever a pituitary incidentaloma is discovered, two main questions must be answered. One, is the mass inhibiting secretion of any pituitary tumors? Two, is the tumor secreting something? Let's review the inhibiting scenario first. Many pituitary tumors do not appear to secrete anything and are called null cell tumors. With the advent of sensitive assays, it has been learned that some of these null-cell tumors actually do secrete. They may be secreting α-chains or gonadotrophins (LH or FSH), which rarely cause symptoms. After all, what man is going to complain about larger testes or a higher sperm count? However, some of these tumors get large enough that they inhibit secretion of pituitary hormones because of a mass effect. In this patient, the tumor is a microadenoma (< 10 mm) and is too small to inhibit secretion.

The other scenario is one of excess secretion. Does the pituitary tumor secrete any hormones? Remember the main 6 anterior pituitary hormones: ACTH, LH, FSH, GH, TSH, and PRL. A fishing expedition to test all hormones is not recommended. Instead, evaluate the patient for signs or symptoms that may point toward a particular excess such as galactorrhea or loss of libido (PRL); amenorrhea (LH, FSH); weight loss, hyperdefecation, tachyarrhythmia, or heat intolerance (TSH); hypertension, hypokalemia, or alkalosis (ACTH). These findings can be very subtle or even absent in the case of a new tumor or a very small one. If your evaluation does not point toward a particular hormone, then check the adrenal and thyroid axes. A screening test for the adrenal axis is a 24-hour urine for cortisol; a value < 70 μg is normal. The thyroid axis can be checked by a TSH and T4 drawn at any time of the day.

You are cautioned to check one more hormone. A small tumor may be secreting GH. The effects of over-secretion of GH take many years to become evident, and many more years usually transpire before it is recognized. These patients develop acromegaly and its many serious complications. Though GH is pulsatile, its effect on IGF-1 is not. Measure a random IGF-1 in any patient with a pituitary incidentaloma. In this patient, the central obesity and hypertension may indicate hypercortisolism (Cushing syndrome). Order a 24-hour urine for cortisol and don't forget to check the IGF-1 level.

"Refer him to a neurosurgeon for transsphenoidal resection of the pituitary mass" is incorrect because there are no reasons to refer this patient for surgery at this time.

"Return to your clinic in a few weeks to recheck blood pressure" is incorrect because the pituitary tumor must be evaluated and his blood pressure management must be followed.

"Discharge him from your clinic on a drug to treat hypertension and encourage him to stop riding motorcycles" is incorrect because, once again, the pituitary tumor must be evaluated.

"Check an ACTH stimulation test, TSH, and a total testosterone" is incorrect because hyposecretion of ACTH, secondary hypothyroidism, and secondary hypogonadism are not suspected.
A woman with Type 1 diabetes comes to your office. She has been followed by another physician but hasn't been feeling right and wants to try a different physician. She heard that you are the best internist in town. She is 50 years old and has had diabetes for 35 years. She has retinopathy (being followed by an ophthalmologist) and mild microalbuminuria. Her medications include NPH insulin 15 units every morning and 60 units at bedtime; a rapid-acting insulin analogue 6-12 units with each meal, which she adjusts depending on the pre-meal capillary glucose level; an ACE inhibitor every evening; and aspirin 81 mg daily. Her glucometer log shows glucose levels generally okay except for the morning fasting glucose, which is elevated. The physical examination is unremarkable except for some retinal microaneurysms. She has her most recent laboratory tests from last week, which are generally okay. The HbA1c is 5.8%. She is very proud of her HbA1c and reports that her other physician had been increasing the evening NPH in an attempt to lower the morning fasting glucose, which has been steadily high despite increasing the evening insulin. She reports to you that she has been experiencing terrible, vivid nightmares during the night and often wakes up in a cold sweat, but attributes this to a scary movie that she saw 2 months ago.

Which of the following is the most appropriate action to take at this time?
A) Reduce her evening NPH insulin and follow closely.
B) Begin an anxiolytic to help her nightmares.
C) Add an insulin sensitizer to reduce her insulin needs.
D) Increase the evening NPH insulin again to reduce the morning fasting glucose levels.
E) Switch her to 70/30 insulin mix twice daily.

A. Reduce her evening NPH insulin and follow closely.


Her symptoms of vivid nightmares and waking in a cold sweat are compatible with nocturnal hypoglycemia. The most likely explanation for the early morning hyperglycemia is that the nocturnal hypoglycemia is causing the contra-insular hormones (glucagon, cortisol, growth hormone, and epinephrine) to be secreted. Many Type 1 diabetics lose the ability to secrete glucagon in response to hypoglycemia, but the remaining hormones are unaffected. These hormones will raise the glucose level. However, insulin-deficient persons such as this patient do not have the ability to make their own insulin to control the hyperglycemic effect of the contra-insular hormones, and her morning fasting glucose levels are elevated. Every patient taking insulin needs to perform self-monitoring of their blood glucose levels. They should check their glucose before and 2 hours after every meal, at bedtime, and in the middle of the night around 3 a.m. Of course it's impractical to constantly check glucose levels this often on a daily basis. One alternative is to have patients check their glucose level twice every day, choosing different times each day so that the log book will have some numbers at each time point. The 3 a.m. glucose level should be checked at least once each month, but doesn't need to be checked much more frequently—unless the patient is having evidence of nocturnal hypoglycemia or has changed the insulin regimen. Once this patient no longer has hypoglycemia, the insulin can always be carefully and slowly increased.

It is inappropriate to begin an anxiolytic rather than decreasing the insulin. Hypoglycemia can be life-threatening. Increasing her evening insulin further could be fatal. There is no evidence that she has insulin resistance in addition to her insulin deficiency, and adding an insulin sensitizer is inappropriate. Switching her to a 70/30 premix is also inappropriate. The goal of treating a Type 1 diabetic is to replace the insulin in a physiologic way. Her insulin regimen is already physiologic by offering basal coverage with NPH twice daily and bolus coverage with a rapid-acting insulin analog with each meal.
A. Dexamethasone + fludrocortisone and order an ACTH stimulation test.


The problem list:

Hypotension in a tanned male with sparse hair
Hyponatremia and hyperkalemia
Prerenal state
Anion gap = 10
This case is straightforward primary adrenal insufficiency (Addison's), but the question asks you indirectly about methods of diagnosis. The patient is tan because of an elevated ACTH level in response to inadequate cortisol production by the adrenal. The adrenal cortex is abnormal (because of tumor or vascular damage), and aldosterone is also deficient, causing the hyponatremia and hyperkalemia. (In cases where the defect is in the pituitary and ACTH is not formed [secondary adrenal insufficiency], patients are not tanned, and they do not have the sodium and potassium derangements because the adrenal secretes aldosterone perfectly fine.)

Clearly, the option to address only the thyroid gland is wrong. The answer with hydrocortisone instead of dexamethasone and fludrocortisone asks you to 1) differentiate between methods of diagnosis; and 2) include treatment for the comorbid mineralocorticoid deficiency. This question is included specifically to teach you about ACTH-stimulation tests and query whether you understand that primary adrenal disease includes both aldosterone and glucocorticoid deficiencies. Empiric therapy should include dexamethasone if you plan to try to diagnose Addison's with an ACTH-stimulation test, because every steroid except dexamethasone cross-reacts with the assay. The fludrocortisone replaces the missing mineralocorticoids.

Patients who are clearly hypothyroid should never receive thyroid replacement if they are also adrenally insufficient (Schmidt syndrome) until after cortisol has been replaced. If you give thyroid replacement first, patients can die quickly due to an inability to respond to the increased metabolic demand. The clinical scenario in this question, however, gives no indication that the patient has comorbid hypothyroidism.

B. Begin antithyroid medication now and postpone the surgery until he is euthyroid or nearly so.


This question requires you to understand the dangers of hyperthyroidism in a patient going into surgery. This patient has signs of hyperthyroidism, which is verified by laboratory tests. In a patient with hyperthyroidism, any kind of surgery can trigger a severe uncompensated hyperthyroidism (thyroid storm), which can be fatal. Treatment of the hyperthyroidism should be initiated before the surgery takes place. The question of whether to postpone the operation is a little more problematic and depends on whether the surgery is emergent, urgent, or routine. Obviously, if the surgery is an emergency and cannot be postponed, ask the anesthesiologist to administer iodine to inhibit thyroid hormone synthesis (this can be administered as intravenous radiocontrast agents), β-blockers to block the adrenergic effects of hyperthyroidism, and glucocorticoids to protect from the stress of hyperthyroidism and to inhibit the conversion of T4 to T3. If the surgery is routine and can be delayed, as in this case, the patient should be started on antithyroid medications, and the operation should be postponed until the patient is rendered euthyroid or nearly euthyroid. An operation that is urgent, but not emergent, can be postponed for a limited amount of time. During this interval, begin antithyroid medications (PTU or methimazole), iodide, and β-blockers. Though the patient will probably not be euthyroid before surgery, his hyperthyroidism will at least be lessened in severity and may protect him from developing thyroid storm.
A 47-year-old woman comes to your clinic complaining of night sweats and marked mood swings. She says that she is experiencing the same unbearable symptoms of menopause that her mother experienced and she wants relief. She routinely exercises, and she has already tried the diet changes recommended in the lay press. She had a hysterectomy 20 years ago due to a complication of childbirth. There is no family history of breast cancer or thromboembolic disease. You agree with her that she is most likely experiencing marked symptoms of menopause. She asks about hormone replacement therapy because her mother got relief from it. You review the recent evidence against it and discuss other options with her, but she insists on trying hormones. You give her some literature, refer her for a mammogram, ask the lab to measure FSH, and schedule a follow-up appointment. The mammogram is negative, and the FSH confirms menopause. She still wants to try hormone therapy, so you start her on low-dose estrogen.

She comes back in three months and reports feeling much better and thanks you for the estrogen. You remind her that hormone therapy can increase her risk of death, but she still wants the hormone therapy. It has been almost five years since you last checked her lipids, so you ask her to return in 3-4 months for fasting lipids. The HDL and non-HDL cholesterol are acceptable, but the triglycerides have markedly increased from 107 mg/dL to 820 mg/dL.

Which of the following should be done at this time?
A) Stop treating her symptoms despite her preferences.
B) Hold the estrogen and resume once the triglycerides are normal again.
C) Continue the estrogen and recheck lipids in 6-12 months.
D) Switch from oral estrogen to a transdermal patch.
E) Switch from estrogen to black cohosh from her local health food store
A patient of yours comes to the clinic for his routine follow-up. He is 47 years old and has Type 2 diabetes. He is moderately obese, has mild hypertension treated effectively with an ACE inhibitor, and has hypercholesterolemia treated with a statin. Before you started the statin, his LDL-cholesterol was 170 mg/dL. His glycemic control has been difficult, and he is currently taking a thiazolidinedione, metformin, and a rapid-acting secretagogue, all at the maximum dose allowed. Despite 3 drugs, his glycemic control has worsened during the past 6 months along with his weight. He states that he is tired of watching his diet and admits to gaining 21 pounds in the last 6 months. The blood pressure today is 126/74. The physical examination is unchanged; his feet are fine.

LABORATORY 6 months ago (fasting):

Na+ 140 mEq/L (135-143 mEq/L)
K+ 4.0 mEq/L (3.5-5.0 mEq/L)
Cl- 107 mEq/L (100-109 mEq/L)
HCO3- 24 mEq/L (22-30 mEq/L)
Urea nitrogen 11 mg/dL (8-18 mg/dL)
Creatinine 1.0 mg/dL (0.6-1.2 mg/dL)
Glucose 102 mg/dL (65-110 mg/dL)
HbA1c 8.5% (4.9-6.2%)
TChol 169 mg/dL
LDL 92 mg/dL
HDL 38 mg/dL
Triglycerides 195 mg/dL
Random urine microalbuminuria screen is 12 μg/mg (< 30 μg/mg).

LABORATORY today (fasting):

Na+ 139 mEq/L (135-143 mEq/L)
K+ 4.1 mEq/L (3.5-5.0 mEq/L)
Cl- 105 mEq/L (100-109 mEq/L)
HCO3- 24 mEq/L (22-30 mEq/L)
Urea nitrogen 12 mg/dL (8-18 mg/dL)
Creatinine 1.0 mg/dL (0.6-1.2 mg/dL)
Glucose 179 mg/dL (65-110 mg/dL)
HbA1c 10.2% (4.9-6.2%)
TChol 198 mg/dL
LDL 98 mg/dL
HDL 36 mg/dL
Triglycerides 320 mg/dL

Random urine microalbuminuria screen is 17 μg/mg (< 30 μg/mg).

Which of the following is the best choice to address the hypertriglyceridemia?
A) Discontinue his oral agents for glycemic control and switch him to insulin.
B) Stop the statin and begin a fibrate.
C) Add a fibrate and another statin to his current statin.
D) Add an α-glucosidase inhibitor to his diabetic regimen.
E) Continue his statin and add a second statin.

A. Discontinue his oral agents for glycemic control and switch him to insulin.


This question requires you to know that triglyceride levels are very dependent upon glycemic control. This patient has gained a significant amount of weight, and his insulin resistance has worsened to the point that he is not controlled on the combination of a thiazolidinedione, metformin, and a rapid-acting secretagogue, despite taking the maximum allowable doses. At this point, he must be switched to insulin. His triglyceride level was much better 6 months ago when his glycemic control was better. It is safe to assume that the increase in triglyceride levels is due to his worsening control. This scenario is commonly seen with diabetic patients. Before specifically targeting his triglyceride levels, his glycemic control must first be improved.

Adding a fibrate to a statin is controversial. Though some physicians do it, the combination is not approved by the FDA at the time of this writing. A fibrate could certainly be used once the statin was discontinued, but a fibrate is not as good an agent at lowering LDL cholesterol. His LDL was 170 mg/dL in the past. It is unlikely that his LDL will remain controlled once he has been switched from a statin to a fibrate. An α-glucosidase inhibitor is expected to lower HbA1c by about 0.5 percentage points. This will not provide enough control for his hyperglycemia. Adding a second statin will not help the situation. If anything, this will increase his risk of an adverse event.

C. Ret-proto-oncogene (RET)


This question requires you to know the usefulness of the ret-proto-oncogene in cases of medullary thyroid cancer. Medullary thyroid cancer may be sporadic or familial. The biggest issue with familial disease is identifying family members who may be at risk. The preferred test is the ret-proto-oncogene. Hundreds of mutations have been identified. Though some mutations seem to be associated only with sporadic disease and some with familial disease, there is a tremendous degree of overlap—and few mutations can virtually eliminate familial disease. However, if the patient has an identifiable mutation, all first-degree relatives should be tested. Any family member with the same mutation either already has or will develop medullary cancer. These patients require a thyroidectomy regardless of age. Even her 2-year-old son would need surgery if he has the mutation. But if the patient has a mutation and a family member does not, then that family member has no risk and need not be
tested again.

A problem develops when no ret-proto-oncogene mutation can be documented in the index case. An older test utilized for screening family members was the pentagastrin-stimulated calcitonin level. This test detects only existing medullary thyroid cancer, and all first-degree relatives had to be tested periodically for much of their lives. (This test is not currently available because pentagastrin is no longer being manufactured.)

The other tests listed in the question do not help in identifying family members at risk
You are asked to see a woman recently hospitalized for a hip fracture and found to have hypocalcemia. She is 75 years old and has been in poor health for quite some time. She lives alone and is reluctant to leave her house. Her granddaughter does the shopping and laundry for her, but admits that her grandmother doesn't eat very much. Her only medication is hydrochlorothiazide 50 mg every morning for mild hypertension; she rarely goes to her internist for scheduled appointments. When you examine her, you find a frail-looking elderly woman with moderate dementia. She has a right hip fracture that she attributes to falling down the steps to her front door. The orthopedic surgeon is currently deciding whether to operate. In the meantime, full DVT precautions are in place. Her labs, including the additional tests ordered by you, come back as the following:

Na+ 142 mEq/L (135-143 mEq/L)
K+ 3.6 mEq/L (3.5-5.0 mEq/L)
Cl- 105 mEq/L (100-109 mEq/L)
HCO3- 28 mEq/L (22-30 mEq/L)
Urea nitrogen 22 mg/dL (8-18 mg/dL)
Creatinine 1.2 mg/dL (0.6-1.2 mg/dL)
Glucose 86 mg/dL (65-110 mg/dL)
Calcium 7.6 mg/dL (8.9-10.5 mg/dL)
Phosphate 1.8 mg/dL (2.5-4.5 mg/dL)
Magnesium 2.9 mg/dL (1.4-2.5 mg/dL)
25-OH-vitamin D 6 μg/L (10-55 μg/L)
1,25-(OH)2-vitamin D 12 ng/L (18-62 ng/L)
Intact PTH 81 pg/mL (10-65 pg/mL)

Bone density at hip z-score is -2.8 SD.

Which of the following is the most likely cause of her hypocalcemia?
A) Hypermagnesemia
B) Vitamin D deficiency
C) Primary hyperparathyroidism
D) Thiazide diuretic
E) Hypophosphatemia
You are asked to see a 68-year-old woman who became dizzy and fell last week. She reports becoming shaky, sweaty, and slumping to the floor while shopping at about 11:30 a.m. She recovered after lying on the floor for several minutes and eating candy. She takes calcium and multivitamins. Past medical history includes a Billroth II for ulcers in 1962, C-section, and penicillin allergy. She had met a friend for breakfast at a donut shop that morning. Her usual breakfast consists of a boiled egg, brown toast and butter, and fruit. She generally eats a late-morning snack, and a meat-containing salad and hard roll for lunch at 1 p.m. She occasionally has similar, milder episodes, but in the past 10 years has had very few such episodes. She runs 3 miles three times weekly, does yoga daily, and works out with free weights twice weekly. She has no cardiac history, and her parents are still alive in their late 80s, as are their siblings. Physical exam reveals BP 116/78 and P 68. Musculature in upper arms and calves is well developed and delineated. Other than well-healed surgical scars on the abdomen, the exam is physiologic.

The above is a prelude to asking you to identify "Whipple's triad."

Which of the following comprise Whipple's triad?
A) Symptoms of hypoglycemia, pancreatic lesion, and low serum glucose
B) High serum glucose, symptom relief with insulin, and symptoms of hyperglycemia
C) Symptoms of hypoglycemia, pancreatic lesion, and high serum glucose
D) Symptoms of hypoglycemia, low serum glucose, and symptom relief with glucose
E) Low serum glucose, abdominal pathology, and symptom relief with glucose

A. Swimming-induced amenorrhea


This question requires you to know some of the many causes of secondary amenorrhea and what type of exercise does not cause amenorrhea.

This is a young, physically active woman who stopped having her usual periods. Many things can cause secondary amenorrhea, including all incorrect choices mentioned in the list of possible answers. However, it is important to note that exercise-induced amenorrhea is typically accompanied by a calorie deficit low BMI. In addition, swimmers in general are less likely to develop secondary amenorrhea compared to runners and dancers.

Don't forget the most common cause of secondary amenorrhea is pregnancy!

Over 60% of women with secondary amenorrhea have hyperandrogenism. PCOS is one of the most common endocrine disorders and is a diagnosis of exclusion. 2 out of 3 criteria must be met: (1) hyperandrogenism (2) oligomenorrhea/amenorrhea (3) polycstic ovaries on ultrasound. Given the patient's amenorrhea and acne, she should also undergo work up for an androgen-secreting tumor and late-onset congenital adrenal hyperplasia.

Elevated LH and FSH in the setting of secondary amenorrhea means that the patient has loss of negative feedback due to premature ovarian failure (POF). Decreased FSH and LH in the amenorrheic woman tell you that the pituitary is not making the hormones, either because the pituitary itself or the hypothalamus is diseased or because of excessive negative feedback from another source such as exogenous steroids. This state is called "hypogonadotropic hypogonadism,"

C. Continue the current management.


The initial laboratories reveal hyperosmolar hyponatremia with an elevated anion gap. The sodium corrects into normal range when considering the hyperglycemia.

To correct sodium for hyperglycemia, increase the sodium by 1.6 for each 100 increment in glucose over 100:

Measured glucose - Normal glucose = 700 - 100 = 600, or 6 increments over 100.

6 x 1.6 = 9.6. To correct the sodium, add 9.6 to the measured sodium (128) = 137.6 = Normal.

Anion gap = 128 - 98 - 7 = 23. (Although controversial, consensus is to use the measured serum sodium concentration when calculating the anion gap.)

The repeat labs show correction of the anion gap, but the patient remains hyperglycemic. New anion gap = 136 - 105 - 19 = 12. Therefore, the acidosis has resolved, but hyperglycemia is still present.

The question next queries if you know when to change the IVF to a dextrose-containing fluid. The patient's blood glucose is 375, and recommendations state that the fluids should be supplemented with dextrose when the serum glucose concentration is < 200 mg/dL. Therefore, none of the answers that suggest changing the fluids or stopping the fluids is correct. Because the patient's high anion gap has resolved and the glucose has lowered by > 70 mg/dL, the rate of insulin infusion is adequate, and increasing the insulin rate is unnecessary. Current management should be continued until the blood glucose is < 200 mg/dL, at which time dextrose-containing fluids should be substituted, and the insulin infusion should be titrated to a blood glucose of 100-200 mg/dL. Once the glucose is 100-200 mg/dL, and the anion gap remains in the normal range, the IV insulin is continued until the patient is able to eat. At that time, give a subcutaneous injection of regular insulin, continue the infusion for 1-2 hours after the injection, and allow the patient to eat. Titrate the regular insulin to the blood sugar and initiate long-acting insulin when the insulin infusion is discontinued.

D. Check TSH.


This patient has signs and symptoms of hypothyroidism. The next test that should be ordered is a TSH level, which is expected to be markedly increased. The obvious evidence for hypothyroidism includes feeling tired, moving slowly, talking slowly, and dry skin. But don't overlook the galactorrhea, pituitary mass, and mildly elevated prolactin level. At first glance, this can be mistaken for a prolactinoma, but a prolactinoma of this size (macroadenoma) should be associated with prolactin levels > 200 ng/mL. A prolactin level < 100 ng/mL should always prompt you to look elsewhere―in this case, the thyroid. Some other causes of a mildly elevated prolactin that have been ruled out include pregnancy and excessive nipple stimulation. The pituitary mass in this patient is most likely not a tumor. It is a pseudotumor composed of TSH-secreting cells (thyrotrophs), which have hypertrophied in response to TRH stimulation. TRH also stimulates the secretion of prolactin; hence the elevated levels.

"Start bromocriptine" and "refer her to a neurosurgeon" are incorrect because it is important to rule out a thyrotroph pseudotumor first prior to any therapeutic intervention. It would be inappropriate to treat with bromocriptine or surgery. "Look for an unknown non-pituitary cancer" is incorrect because the described clinical scenario does not suggest any reason to look for a non-pituitary cancer. "Recheck the prolactin in 6-12 months" is incorrect because, although rechecking the prolactin level would be appropriate at some time in the future, her hypothyroidism must be addressed first.

E. Add an ACE inhibitor or an angiotensin-receptor blocker (ARB).


The random urine screen indicates microalbuminuria. Normal albumin excretion is < 30 mg/day, microalbuminuria is 30-300 mg/day, and macroalbuminuria is > 300 mg/day. Collecting an accurate 24-hour urine is difficult and problematic. Fortunately, creatinine excretion is somewhat consistent when adjusted for standard body surface area. This has led to use of the albumin:creatinine ratio in a random spot urine as a surrogate marker. A normal ratio is < 30 μg/mg, microalbuminuria is 30-300 μg/mg, and macroalbuminuria is > 300 μg/mg. If the ratio is only slightly above normal, it is best to repeat the random urine or to ask for a 24-hour urine to better quantitate the albumin excretion. In addition, any urinary tract infection must be completely resolved before checking for albuminuria. His ratio is well within the range of microalbuminuria, and there is no suspicion of a urinary tract infection. Once a diabetic has microalbuminuria, the patient must be treated. The goal of treatment is to slow the progression of the nephropathy in an attempt to prevent end-stage renal disease. Several studies have shown that an ACE inhibitor is an excellent drug for this purpose, and some recent studies have shown that ARBs may be just as beneficial. The best course of action for this patient is to begin one of these drugs.

The patient is certainly doing a good job by watching his diet, consistently walking, and losing weight. He should be praised for this, but he also needs treatment for the nephropathy. There is no reason to increase his statin, since the LDL is less than 100 mg/dL (goal). A calcium-channel blocker may be useful for hypertension, but is not the initial drug of choice in diabetics with nephropathy. Likewise, a diuretic can be useful for blood pressure control, but is not the i nitial drug of choice in a diabetic with nephropathy