E1
1. A 34-year-old woman has new-onset hypertension. Initial blood pressure (BP) was 158/98 mm Hg. Her serum potassium level is 2.7 mEq/L. Initial hormone screening shows a plasma aldosterone (PA) of 55 ng/dL (normal [nl] 1–16) and a plasma renin activity (PRA) of 0.1 ng/mL/hr (nl 0.15–2.33). What is the probable diagnosis, and what is the next step?
Primary aldosteronism (Conn’s syndrome)
hypertension and spontaneous hypokalemia.
Initial screening confirms with significantly elevated PA, suppressed PRA, high PA/PRA ratio
Confirmatory testing with saline infusion or oral salt-loading test to assess suppressibility of PA often the recommended next step.
However, the 2016 Endocrine Society Guideline Committee on Primary Aldosteronism recommended that confirmatory testing is not needed when all three of the following are present: spontaneous hypokalemia, suppressed PRA, PA > 20 ng/dL
The next step, therefore, is to establish whether the cause is an aldosterone-producing adenoma or bilateral adrenal hyperplasia with abdominal computed tomography (CT)
Her abdominal CT scan showed a 2-cm left adrenal cortical adenoma with < 10 Hounsfield Units (HU).
Adrenal vein sampling (AVS) may be needed at this point if an accurate diagnosis is not apparent, but the 2016 guidelines also recommend that AVS is not needed if all three of the following are present: age < 35 years, , PA markedly elevated,, unilateral cortical adenoma on imaging study. This patient also meets these criteria.
The treatment for this aldosterone-producing adrenal adenoma is surgery.
Spironolactone and or eplerenone should be given to control BP and to normalize the serum potassium preoperatively
6. A 38-year-old nurse presents in a stuporous state; the blood glucose level is 14 mg/dL. Additional blood is drawn, and the patient is quickly resuscitated with intravenous (IV) glucose. Further testing on the saved serum reveals the following: serum insulin = 45 mcU/mL (nl < 22); C-peptide = 4.2 ng/mL (nl 0.5–2.0); and proinsulin = 7 pmol/L (nl < 5). A sulfonylurea screen yields negative results. What is the probable diagnosis, and what are the next steps in management?
insulinoma
hyperinsulinemic hypoglycemia.
The differential diagnosis includes insulinoma, surreptitious insulin injection, and oral sulfonylurea ingestion.
The elevated serum C-peptide and proinsulin levels are most consistent with an insulinoma.
After an appropriate localizing procedure, surgical removal is the treatment of choice
11. A 45-year-old man has a 4-year history of worsening hypertension, which has not yet been controlled with three antihypertensive medications. Serum potassium had been 3.7 mEq/L when his hypertension was first discovered. There is no family history of hypertension. His medications include the following: lisinopril 40 mg daily; amlodipine 10 mg daily; and hydrochlorothiazide (HCTZ) 25 mg daily. His vitals are as follows: BP 165/95 mm Hg and pulse 72 beats per minute. Physical examination results are normal. Recent laboratory values are as follows: sodium (Na) 144 mEq/L; potassium (K) 2.5 mEq/L; and creatinine 1.1 mg/dL. Morning, seated PA was 24 ng/dL (nl 1–21), and PRA was < 0.6 ng/mL/hr (nl 0.6–4.3). PA after a 2-L saline infusion was 21 ng/dL ( non suppression) What do you recommend next for evaluation and subsequent treatment?
Primary aldosteronism (Conn’s syndrome)
bilateral adrenal hyperplasia
strongly suggested by the presence of resistant hypertension (uncontrolled on a three-drug regimen that includes a thiazide diuretic) and easily induced (thiazide diuretic) hypokalemia.
Initial screening confirms this through the following findings: significantly elevated PA, suppressed PRA, and a high PA/PRA ratio.
Confirmatory testing with a saline infusion (or oral salt-loading test) to assess suppressibility of PA was indicated according to the 2016 Endocrine Society Guideline Committee on Primary Aldosteronism (confirmatory testing is not needed when all three of the following are present: spontaneous hypokalemia, suppressed PRA and PA > 20 ng/dL); this patient had easily induced but not spontaneous hypokalemia.
The next step, therefore, is to establish whether the cause is an aldosterone-producing adenoma or bilateral adrenal hyperplasia with an abdominal CT scan; abdominal CT showed bilateral but asymmetrical adrenal enlargement with the left side being significantly larger than the right.
The next step should be AVS because he does not meet the criteria for not needing AVS (all three of the following must be present: age < 35 years, PA markedly elevated, and unilateral cortical adenoma on imaging study).
AVS did not show significant lateralization, indicating that the most likely underlying disorder in this patient is bilateral adrenal hyperplasia (idiopathic hyperaldosteronism).
The management for this condition is the use of an aldosterone receptor antagonist (spironolactone with or without eplerenone) and the use of other antihypertensive medications, as needed, to adequately control his BP. Aldosterone receptor antagonist therapy should be titrated until the serum potassium is normal without a need for potassium supplements and PRA is in the upper end of the reference range
16. A 29-year-old woman has asymptomatic hypercalcemia. Her mother and one of her sisters also have hypercalcemia and have had failed neck explorations for presumed parathyroid tumors. Further testing results are as follows: serum Ca = 11 mg/dL (nl 8.5–10.2); P = 3 mg/dL (nl 2.4–4.5); creatinine = 0.9 mg/dL; intact PTH = 66 pg/mL (nl 10–65); 25-hydroxyvitamin D = 42 ng/mL (nl 30–100); 24-hour urine Ca = 13 mg (nl 100–300); and creatinine = 1100 mg. What is the probable diagnosis, and what is the recommended management?
FHH
The vast majority of patients with hypercalcemia and a mildly elevated serum PTH level have primary hyperparathyroidism. However, in this case, the very low urinary calcium excretion and family history of unsuccessful parathyroid surgeries point to a suspected diagnosis of familial hypocalciuric hypercalcemia (FHH).
The diagnosis is confirmed by finding a Ca/creatinine clearance ratio (urine Ca × serum creatinine/serum calcium × urine creatinine) of < 0.01.
This autosomal dominant disorder results from heterozygous inactivating mutations of the calcium sensor receptor gene. The mutant sensor receptors, present in parathyroid and renal tubular cells, have a raised threshold for calcium recognition. The result is a raised physiologic equilibrium, in which hypercalcemia coexists with mild elevations of PTH and low urinary calcium excretion.
The disorder causes no morbidity and does not require treatment
21. A 70-year-old man presents complaining of a 1-year history of weakness, weight loss, and hand tremors. He has been treated with amiodarone for nearly 3 years for paroxysmal atrial flutter. Laboratory tests show the following: TSH < 0.01 mU/L (nl 0.5–5.0); free T 4 = 3.35 ng/dL (nl 0.8–1.8); and the RAIU was 2.7% at 6 hours and 4.1% at 24 hours. Thyroid scan showed patchy tracer uptake. Color doppler shows increased blood flow. What is the likely diagnosis, and what is the best treatment plan?
amiodarone-induced thyrotoxicosis (AIT), occurs in up to 10% of patients using amiodarone, which has a very high iodine content. There are two subtypes but it can be very difficult to determine which type is present and in fact, there can be mixed cases with features of both types.
type 1 AIT results from iodine overload - usually occurs in patients with underlying goiters or nodules; RAIU is low but may be detectable and color Doppler studies show increased flow - treated with methimazole, although lithium and perchlorate may also add benefit
type 2 AIT results from amiodarone-induced thyroid follicular damage (thyroiditis) - more often seen in patients without underlying goiters or nodules- RAIU is very low (often < 1%), and color Doppler studies show decreased flow. Serum interleukin-6, when available, is often elevated in type 2 AIT - responds better to steroid therapy.
Mixed or refractory cases may require both methimazole and steroids, plasmapheresis, or thyroidectomy
26. A 52-year-old woman complains of a 1-year history of progressive fatigue, puffy eyes, dry skin, and mild weight gain. She had acromegaly treated with transsphenoidal surgery and radiation therapy 10 years ago. Physical examination showed normal visual fields, mild periorbital edema, and dry skin. Laboratory testing revealed the following: GH = 1.2 ng/mL (nl < 2.0); insulin-like growth factor-1 (IGF-1) = 258 ng/mL (nl 182–780); TSH = 0.2 mU/L (nl 0.5–5.0); and free T 4 = 0.3 ng/dL (nl 0.8–1.8). What is the most likely cause of this patient’s symptoms, and what treatment do you recommend?
central hypothyroidism
caused by pituitary damage from the combined effects of surgery and radiation treatment of her pituitary tumor 10 years earlier.
Such a lengthy delay in the development of this condition is not uncommon.
The most common conditions that cause central hypothyroidism are tumors, surgery, radiation, hemorrhage, infections, infiltrative disorders, and trauma affecting the hypothalamus or pituitary gland.
Medications that have been shown to suppress thyroid-releasing hormone (TRH) or TSH production include opioids, glucocorticoids, mitotane, and bexarotene; use of these medications may cause central hypothyroidism.
Metformin has also been reported to suppress TSH secretion and may interfere with thyroid test interpretation but, as yet, has not been implicated in causing de novo central hypothyroidism.
The diagnosis of central hypothyroidism is based on the presence of symptoms of thyroid hormone deficiency, a low serum free T 4 , and a low or low-normal serum TSH.
Treatment consists of levothyroxine replacement in doses sufficient to relieve symptoms and to maintain the serum free T 4 level in the mid-normal or upper-normal range.
Because TSH secretion is impaired, the serum TSH level cannot be used to monitor this patient’s response to therapy.
Assessment of her pituitary–adrenal axis with a cosyntropin stimulation test and plasma ACTH level is also indicated
31. A 68-year-old man presents with complaints of a 10-year history of progressive pain in the shins, knees, and left arm. He also notes progressive hearing loss. Physical examination reveals tenderness above the left elbow and enlarged, bowed shins. Bone scan shows intense uptake in both tibias and the left humerus. Skeletal radiography shows enlargement, with multiple focal lytic and sclerotic areas, in the tibias and the distal left humerus. Laboratory evaluation reveals: serum Ca = 9.8 mg/dL (nl 8.5–10.5); and alkaline phosphatase = 966 U/L (nl 25–125). What is the probable diagnosis, and what treatment recommendations would you give?
Paget disease
Bone pain and deformity, reduced hearing, and markedly elevated serum alkaline phosphatase levels suggest a diagnosis of Paget’s disease.
Intense radioisotope uptake on bone scanning supports this diagnosis, and the characteristic findings on skeletal radiography confirm it.
Treatment options include analgesics, IV bisphosphonates (zoledronic acid preferred), subcutaneous denosumab and calcitonin.
A single infusion of zoledronic acid, 5 mg intravenously, will likely reduce symptoms and serum alkaline phosphatase levels for an extended period
2. A 32-year-old business executive develops amenorrhea. She has not recently lost weight but states that her job is very stressful. Evaluation reveals the following laboratory results: serum estradiol = 14 pg/mL (nl 23–145); luteinizing hormone (LH) = 1.2 mIU/mL (nl 2–15); follicle-stimulating hormone (FSH) = 1.5 mIU/mL (nl 2–20); prolactin = 6.2 ng/mL (nl 2–25); thyroid-stimulating hormone (TSH) = 1.2 mU/L (nl 0.5–5.0); and negative result on serum pregnancy test. Magnetic resonance imaging (MRI) of her pituitary gland shows normal results. What is the probable diagnosis, and what is the best management approach?
hypothalamic amenorrhea
This patient has secondary amenorrhea with low estradiol and gonadotropin levels.
These results are most consistent with hypothalamic amenorrhea, which may occur in women who exercise excessively, have very low body weight, or have stressful jobs.
The disorder results from reduced gonadotropin-releasing hormone (GnRH) pulse frequency in the hypothalamus. Treatment consists of stress management and, if menses do not resume, estrogen replacement therapy
7. A 28-year-old woman presents with amenorrhea. Her menses started at age 13 years and have been regular since age 16 years. She has type 1 diabetes mellitus (T1DM). Further tests show the following: estradiol = 15 pg/mL (nl 23–145); LH = 78 mIU/mL (nl 2–15); FSH = 92 mIU/mL (nl 2–20); prolactin = 12 ng/mL (nl 2–25); TSH = 1.1 mU/L; the pregnancy test yields negative results. What is the most likely diagnosis, and how would you treat her?
POI
secondary amenorrhea, with low estradiol and elevated gonadotropin levels.
In a patient with another autoimmune disease (T1DM), the most likely diagnosis is premature ovarian insufficiency (POI) caused by autoimmune ovarian destruction.
Hormone replacement therapy is the treatment of choice
12. A 25-year-old woman presents with a rounded face, prominent supraclavicular adiposity, and purplish striae in the axillae. The results of hormone testing are as follows: 24-hour urine cortisol = 318 mcg (nl 10–50); after 1 mg of dexamethasone at bedtime, morning serum cortisol = 28 mcg/dL (nl 5–25); and baseline morning plasma adrenocorticotropic hormone (ACTH) = 65 pg/mL (nl 10–80). After an 8-mg oral bedtime dose of dexamethasone, the morning serum cortisol is 3 mcg/dL. What is the probable diagnosis, and what are the next steps for evaluation and management?
Cushing’s disease
pituitary adenoma producing ACTH
Cushingoid features and significantly elevated urinary cortisol excretion confirm the diagnosis of Cushing’s syndrome.
Endogenous Cushing’s syndrome is most often caused by ACTH-secreting pituitary adenomas (65%–80%), ectopic ACTH production by nonpituitary tumors (10%–15%), and cortisol-producing adrenal adenomas (10%–15%).
The normal plasma ACTH level, which is inappropriate for the elevated serum cortisol level, and serum cortisol suppression with high-dose dexamethasone are most consistent with a pituitary adenoma (Cushing’s disease).
This should be confirmed with MRI of the pituitary gland and, unless a pituitary adenoma ≥ 7 mm in size is identified, inferior petrosal sinus sampling should follow.
Transsphenoidal surgical removal is the treatment of choice.
When surgery does not result in remission, treatment options include repeat surgery, radiation therapy, and medical therapy with ketoconazole, metyrapone, or pasireotide to reduce cortisol production or mifepristone to block cortisol tissue action
17. A 39-year-old human immunodeficiency virus (HIV)–positive man with Pneumocystis jiroveci pneumonia (PJP) has the following serum thyroid hormone values: free T4 = 0.8 ng/dL (nl 0.8–1.8); total T3 = 22 ng/dL (nl 90–200); TSH = 0.5 mU/L (nl 0.5–5.0). What is the most likely endocrine diagnosis, and what is the best management approach?
nonthyroidal illness syndrome ( sick euthyroid or euthyroid sick syndrome)
The very low T3, low-normal TSH are most consistent with the euthyroid sick syndrome (nonthyroidal illness syndrome).
This is not a primary thyroid disorder but is, instead, a set of circulating thyroid hormone abnormalities that occur in the presence of nonthyroidal illnesses; it is corrected when the underlying illness resolves.
Treatment of the condition with thyroid hormone administration is not currently recommended, although this remains controversial
22. A 20-year-old man presents with failure to enter puberty. He has small, soft testes, no gynecomastia, normal visual fields, and decreased sense of smell. Laboratory evaluation is as follows: serum testosterone = 40 ng/dL (nl 300–1000); LH = 2.0 mIU/mL (nl 2–12); FSH = 1.6 mIU/mL (nl 2–12); prolactin = 7 ng/mL (nl 2–20); and TSH = 0.9 mU/L (nl 0.5–5.0). MRI of the pituitary gland shows normal results. What is the probable diagnosis, and what is the recommended treatment?
idiopathic hypogonadotropic hypogonadism (IHH) - Kallmann’s syndrome when it is accompanied by anosmia.
The disorder is caused by deficiency of GnRH and may be X-linked, autosomal dominant, autosomal recessive, or sporadic. The X-linked form results most commonly from mutations of the Kal-1 gene, which encodes anosmin, a neural cell adhesion protein that is critical for the scaffolding for GnRH neuron migration from the olfactory placode to the hypothalamus during embryonic development. In addition to GnRH deficiency, this mutation causes maldevelopment of the olfactory lobe, resulting in anosmia. Mutations in fibroblast growth factor 8 (FGF8) or its receptor, FGFR1, or in the Kisspeptin/KissR system have also been found to underlie some cases of IHH.
Androgen therapy is indicated to promote appropriate masculinization. When desired, these patients can also become fertile by receiving treatment with GnRH or gonadotropin preparations
27. A 32-year-old woman complains of deep pain in both thighs. She was diagnosed as having type 1 diabetes mellitus at age 20 years. She currently has two to three bowel movements each day. Her menses are regular. Her diet is well balanced, with adequate calcium intake, and she takes a multivitamin. Physical examination results are normal. Laboratory studies show the following: serum Ca = 8.2 mg/dL (nl 8.5–10.5); P = 2.3 mg/dL (nl 2.5–4.5); alkaline phosphatase = 312 U/L (nl 25–125); PTH = 155 pg/mL (nl 11–54); and 25-hydroxy vitamin D = 7 ng/mL (nl 30–100). Explain the findings in this patient, and suggest a probable underlying diagnosis and treatment plan.
vitamin D deficiency
Her biochemical profile of hypocalcemia, hypophosphatemia, elevated alkaline phosphatase, and significant secondary hyperparathyroidism suggests vitamin D deficiency, which is confirmed by the low serum 25-hydroxy vitamin D level.
The elevated serum alkaline phosphatase suggests that the vitamin D deficiency has been sufficiently severe and prolonged to result in osteomalacia.
Lactose intolerance can cause chronic diarrhea but seldom results in vitamin D and calcium malabsorption.
Celiac disease (gluten-sensitive enteropathy), which occurs with increased frequency in patients with T1DM, should be suspected. The diagnosis can be confirmed through measurement of tissue transglutaminase antibodies or small bowel biopsy. The treatment is elimination of gluten (wheat, rye, barley, oats) from the diet and supplementation with calcium and vitamin D.
32. A 19-year-old man has been experiencing fatigue, muscle weakness, and dizziness for the past 3 weeks. This morning he fainted when he went outdoors to exercise. His BP is 95/60 mm Hg, and his pulse is 110 beats per minute. His skin is cool, dry, and tanned. His thyroid feels normal. Laboratory testing shows the following: hematocrit = 36%; glucose = 62 mg/dL; Na = 120 mmol/L; K = 6.7 mmol/L; creatinine = 1.4 mg/dL; and blood urea nitrogen (BUN) = 36 mg/dL. What endocrine disorder should be considered and evaluated?
adrenal crisis
Hyponatremia with hyperkalemia always suggests primary adrenal insufficiency. Fatigue, weakness, hypotension, tanned skin, anemia, azotemia, and hypoglycemia are also consistent with this diagnosis.
The most common cause is autoimmune destruction of the adrenal glands.
The diagnosis is made by finding a basal serum cortisol level < 3 mcg/dL or by a cosyntropin stimulation test that shows a low basal serum cortisol level and failure to increase to at least 18 mcg/dL after ACTH administration.
During an adrenal crisis, however, there is no time to wait for test results. When this diagnosis is suspected, blood should be drawn for serum cortisol measurement (if a diagnosis of adrenal insufficiency is not already established) and then treatment started with IV fluids and glucocorticoids.
The recommended treatment regimen for an adrenal crisis is the following: IV normal saline (1 L over 1 hour, then guided by clinical evaluation) and hydrocortisone (Solu-Cortef) 100 mg IV immediately, then a 200 mg/24-hr infusion for 24 hours, followed by a 100 mg/24 hr infusion for 24 hours.
Precipitating conditions should also be actively sought and treated. After that the patient should be transitioned to an oral replacement regimen of glucocorticoids (hydrocortisone or prednisone) and, usually a mineralocorticoid (fludrocortisone)
3. A nulliparous 48-year-old woman presents with symptoms of thyrotoxicosis. She has a modest, nontender goiter and no exophthalmos. She takes no medications or supplements and has had no recent radiology procedures. The following results are found on thyroid evaluation: TSH < 0.1 mU/L; free thyroxine (T 4 ) = 3.5 ng/dL (nl 0.8–1.8); thyroglobulin = 35 ng/mL (nl 2–20); erythrocyte sedimentation rate (ESR) = 10 mm/hr; and 24-hour radioactive iodine uptake (RAIU) = 1% (nl 20%–35%). What is the likely diagnosis, and what are your management recommendations?
thyroiditis
thyrotoxicosis with a low RAIU.
The differential diagnosis includes postpartum thyroiditis, painless thyroiditis, subacute thyroiditis, factitious thyrotoxicosis, and iodine-induced thyrotoxicosis.
She has never been pregnant and denies medication use and recent iodine exposure.
The nontender gland, elevated thyroglobulin, and normal ESR are most consistent with painless thyroiditis.
A transient (1–3 months) thyrotoxic phase followed by a transient (2–6 months) hypothyroid phase is expected before the condition resolves; 20% of patients, however, remain hypothyroid. If symptomatic, the thyrotoxic phase is best treated with beta-blockers, and the hypothyroid phase can be managed, if necessary, with temporary levothyroxine replacement
8. A 34-year-old woman presents with a milky breast discharge, amenorrhea, headaches, fatigue, and weight gain. Laboratory evaluation reveals the following: prolactin = 58 ng/mL (nl 2–25); free T 4 = 0.2 ng/dL (nl 0.8–1.8); and TSH > 60 mU/L (nl 0.5–5.0). The pituitary gland is observed to be enlarged on MRI. What is the cause of her elevated prolactin, and what is the most appropriate treatment?
primary hypothyroidism
The patient has moderately increased serum prolactin levels, pituitary enlargement, and severe primary hypothyroidism. Her entire clinical picture is most likely explained solely by the hypothyroidism, which is well known to cause secondary hypersecretion of prolactin and pituitary enlargement resulting from thyrotroph hyperplasia. All abnormalities should resolve after adequate thyroid hormone replacement is established
18. An 18-year-old female has not yet begun menstruating. She has a height of 56 inches, a small uterus, and no breast development. The results of hormone tests are as follows: estradiol = 8 pg/mL (nl 23–145); LH = 105 mIU/mL (nl 2–15); FSH = 120 mIU/mL (nl 2–20); prolactin = 14 ng/mL (nl 2–15); and TSH = 1.8 mU/L (nl 0.5–5.0). What is the probable diagnosis, and what are the management options?
Turner syndrome
Primary amenorrhea, short stature, low serum estradiol, and elevated gonadotropins are most consistent with a diagnosis of Turner’s syndrome.
This disorder, characterized by ovarian dysgenesis, is associated with a 45XO karyotype.
These patients should be given hormone replacement therapy with estrogen and progesterone.
Growth hormone (GH) therapy should be considered because it improves longitudinal growth and final height
23. A 40-year old man is brought to the emergency department with sudden onset of inability to stand. He endorses recent muscle aches and weakness. His past medical history and family history are negative. He is a naturalized citizen originally from Korea. He takes no medications. His vitals are as follows: BP = 124/68 mm Hg, P = 88; height = 5 feet 6 inches; weight 142 lb. Physical examination findings are as follows: bilateral flaccid leg weakness (0/5); bilateral proximal arm weakness (3/5); reduced reflexes; thyroid: diffuse goiter; eyes: lid lag, no proptosis. Laboratory testing results are as follows: Serum potassium drawn during the episode was 2.1 mEq/L, TSH < 0.01 mU/L (nl 0.45–4.5); free T4 2.52 ng/dL (nl 0.8–1.8). What is his likely diagnosis, and what do you recommend next?
thyrotoxic periodic paralysis (TPP).
TPP is a potentially fatal complication of hyperthyroidism that occurs as a sporadic (noninherited) disorder predominantly in Asian males. Episodes of mild-to-severe muscle weakness or paralysis associated with severe hypokalemia result from sudden intracellular shifts of potassium caused by thyrotoxicosis-induced increased sensitivity of Na-K-ATPase (adenosine triphosphatase) pump activity. TPP attacks are treated acutely with potassium supplementation (oral or IV) and can be prevented by successful treatment of the hyperthyroidism.
28. A 31-year old woman is referred for abnormal results on thyroid tests that had been ordered to evaluate fatigue, insomnia, and headaches for the past 6 months. Vitals: BP 132/73 mm Hg; P = 72; height = 5 feet 8 inches; weight = 139 lb. Physical examination results are as follows: normal except for a diffuse goiter and warm moist skin; eyes appear normal. Laboratory tests are reviewed and repeated: TSH = 4.74 and 5.04 mU/L (nl 0.45–4.5); and free T4 2.91 and 2.82 ng/dL (nl 0.8–1.8). What is the differential diagnosis, and what do you recommend next?
TSH-producing pituitary adenoma
Elevated or normal serum TSH levels in the presence of elevated serum free T4 levels are clearly inappropriate.
The following causes of inappropriate TSH levels should be considered: thyroid hormone resistance syndromes, TSH-producing pituitary tumors, human antimouse antibodies (HAMA), macro-TSH, and high-dose biotin supplements.
The patient was asked about biotin supplements, and she confirmed that she was not taking them. HAMA testing was negative.
The alpha-subunit (ASU) was measured; ASU was elevated at 1.4 ng/mL and the ASU/TSH molar ratio was > 1.0.
This prompted MRI evaluation, which showed a 2.4-cm pituitary tumor that abutted, but did not displace, the optic chiasm.
Transsphenoidal surgery was performed, and the tumor stained heavily for TSH and ASU. Final diagnosis: TSH-producing pituitary adenoma
33. A 72-year old woman is found to have elevated serum calcium on preoperative laboratory examinations before elective surgery, prompting a referral to you. She reports noting recent fatigue and “fuzzy thinking.” Past medical history: gastroesophageal reflux disease (GERD), osteopenia. Medications: calcium carbonate 2000 mg four times daily (“maybe more often”). Vitals: BP 139/80 mm Hg; P = 82; height = 5 feet 5 inches; weight = 142 lb. Physical examination results are normal. Further laboratory testing reveals the following: Ca = 14.1 mg/dL; creatinine = 7.1 mg/dL; CO 2 = 37 mEq/L; and P = 2.7 mg/dL. More tests were ordered: PTH < 1 pg/mL (nl 10–65); PTHrp < 1 pmol/L (nl 0–3); 25-hydroxy vitamin D = 35 ng/mL (nl 30–100); and venous pH = 7.54. What is the most likely cause of her hypercalcemia, and what treatment options are available?
Milk alkali syndrome
triad of hypercalcemia, metabolic alkalosis, and renal insufficiency
associated with the ingestion of calcium and absorbable alkali, most commonly calcium carbonate.
Alkalosis occurs because the calcium-induced diuresis results in volume depletion, which stimulates renal bicarbonate absorption (contraction alkalosis).
Milk alkali syndrome is the third most common cause of hypercalcemia after primary hyperparathyroidism and hypercalcemia of malignancy.
Treatment is hydration and stopping calcium, alkali, and vitamin D intake until the biochemical abnormalities resolve. Dialysis may be needed in some cases
4. A 38-year-old man has coronary artery disease, xanthomas of the Achilles tendons, and serum lipid profile as follows: cholesterol = 482 mg/dL; triglycerides (TG) = 125 mg/dL; high-density lipoprotein (HDL) cholesterol = 42 mg/dL; and low-density lipoprotein (LDL) cholesterol = 415 mg/dL. What is the probable diagnosis, and what are the management options?
heterozygous familial hypercholesterolemia.
Significant elevations of total cholesterol and LDL cholesterol, normal TG, tendon xanthomas, and premature coronary artery disease are most consistent with a diagnosis of heterozygous familial hypercholesterolemia.
Genetic mutations resulting in deficient or dysfunctional LDL receptors (LDLRs) are the most common cause.
Less common monogenic hypercholesterolemia disorders include apolipoprotein B (apo-B) mutations that produce a defective apo-B that cannot bind to LDLRs, proprotein convertase subtilisin-like kexin type 9 (PCSK9) mutations that cause accelerated LDLR degradation, LDLR adaptor protein 1 mutations that prevent normal clustering of LDLR in cell surface clathrin-coated pits, and adenosine triphosphate (ATP)–binding cassette G5 or G8 (ABCG5/8) mutations that cause abnormal cellular transport of cholesterol and plant sterols (sitosterolemia).
The recommended criteria for diagnosing heterozygous familial hypercholesterolemia are the following: LDL > 190 mg/dL (adults) or > 160 mg/dL (children) plus premature coronary artery disease, or history of a similarly affected first-degree relative, or the identification of a genetic defect.
Aggressive lipid lowering with a combination of statins and PCSK9 inhibitors is often required for satisfactory LDL control; ezetimibe and bile acid resins may be added, if needed. In many cases, LDL apheresis is also indicated (see
14. A 52-year-old man has a personal and family history of early coronary artery disease, minimal alcohol consumption, and no xanthomas on examination. He has the following results on serum testing: cholesterol = 328 mg/dL; TG = 322 mg/dL; HDL = 35 mg/dL; LDL = 229 mg/dL; apo-B = 178 mg/dL (nl 60–130), apo-E genotype = E3/E3 (normal), TSH = 2.1 mU/L (nl 0.1–4.5); and glucose = 85 mg/dL. What is the probable diagnosis, and what are the treatment options?
familiar combined dyslipidemia
This patient has elevations of both serum cholesterol and TG and no detected disorders that cause secondary dyslipidemia.
The differential diagnosis is familial combined hyperlipidemia and familial dysbetalipoproteinemia.
The elevated apo-B level and the normal apo-E phenotype are most consistent with familial combined hyperlipidemia;
E2/E2 apo-B phenotype is characteristic of familial dysbetalipoproteinemia.
The top treatment priority is LDL reduction with use of a statin. After the LDL cholesterol level is brought to the individualized-goal level, persistent TG elevations can be addressed with further dietary medication and weight loss and the possible addition of a fibrate, niacin, or fish oils
19. A 62-year-old woman presents for evaluation of recent nephrolithiasis and low back pain. Her estimated calcium intake is 800 mg/day, and she takes no vitamins. Her physical examination is unremarkable. Spinal radiography shows a compression fracture of the second lumbar vertebra (L2). Laboratory evaluation shows the following: serum Ca = 13.0 mg/dL (nl 8.5–10.5); P = 2.3 mg/dL (nl 2.5–4.5); albumin = 4.4 g/dL (nl 3.2–5.5); intact PTH = 72 pg/mL (nl 11–54); and 24-hour urine Ca = 312 mg (nl 100–300). What is the most likely diagnosis?
primary hyperparathyroidism
Hypercalcemia, hypophosphatemia, and elevated serum PTH levels are characteristic of primary hyperparathyroidism.
Hyperparathyroidism is usually caused by a solitary parathyroid adenoma, but familial cases and those associated with multiple endocrine neoplasia (MEN) syndromes more often have four-gland hyperplasia.
Surgical indications include serum calcium levels > 1 mg/dL above the normal range, urinary calcium excretion > 400 mg/24 hr, renal impairment, osteoporosis, age < 50 years, or symptoms related to hyperparathyroidism.
Observation alone or bisphosphonate therapy may be appropriate for patients with mild, asymptomatic disease or only mild bone loss. This patient should be referred for parathyroid surgery
24. A 32-year-old man presents with complaints of impotence and intermittent retroorbital headaches for the past year. He is adopted and does not know his natural family history. He has bitemporal visual field loss, but his examination is otherwise normal. Laboratory tests reveal the following: serum calcium = 11.8 mg/dL (nl 8.5–10.5); P = 2.5 mg/dL (nl 2.5–4.5); albumin = 4.8 g/dL (nl 3.2–5.5); intact PTH = 58 pg/mL (nl 11–54); prolactin = 2650 ng/mL (nl 0–20); testosterone 72 ng/dL; LH 2.1 mIU/mL (nl 2–12); and FSH = 1.1 mIU/mL (nl 2–12). What is the likely diagnosis, and how should this be further evaluated?
prolactinoma
manifesting as impotence, headaches, bitemporal hemianopsia, secondary hypogonadism, and a significantly elevated serum prolactin level.
Hypercalcemia with an elevated serum PTH level indicates that he also has hyperparathyroidism.
MEN 1 syndrome, which consists of hyperparathyroidism, pituitary tumors, and pancreatic endocrine tumors, results from an inherited mutation in the Menin gene.
This patient should be screened for a gastrinoma by ordering a fasting serum gastrin and for insulinoma by measuring serum glucose, insulin, C-peptide, proinsulin, and beta-hydroxybutyrate after an overnight fast or during a prolonged supervised fast.
After pituitary imaging studies, he should be treated with a dopamine agonist, transsphenoidal surgery, or both, and subsequently with parathyroid surgery
29. A 42-year-old man presents for evaluation of a skin rash that has recently developed. He has a history of T2DM. He drinks two to three alcoholic beverages several nights each week. Physical examination shows eruptive xanthomas (red papules with golden crowns) all over his body, most prominently on the buttocks, thighs, and forearms. Laboratory studies reveal the following: glucose = 310 mg/dL; hemoglobin A 1c (HbA 1C ) = 12.9%; cholesterol = 1082 mg/dL; and TG = 8900 mg/dL. Discuss the cause, risks, and treatment of this lipid disorder.
This patient has severely elevated serum TGs.
This condition usually results from the combination of an inherited disorder (familial hypertriglyceridemia or familial combined hyperlipidemia) with a secondary cause of TG elevation (uncontrolled diabetes mellitus, excess alcohol use).
His LDL cholesterol cannot be assessed until the serum TG levels are < 400 mg/dL.
He is at high risk of developing acute pancreatitis because of the severely elevated TG levels; acute pancreatitis has a 3% to 5% mortality rate in this setting.
The priority, therefore, is to quickly lower his serum TG level to < 1000 mg/dL. This goal can be achieved most effectively with a temporary very-low-fat (< 5% fat) diet, blood glucose control, and discontinuation of alcohol. TG levels will fall by about 20% to 25% a day on this regimen.
A fibrate or fish oil (or both) should then be added, and he should be advised to follow an American Heart Association diet.
Diabetes management must also be improved and further alcohol intake discouraged.
TG-lowering medications are ineffective when serum TG levels exceed 1000 mg/dL because the enzyme lipoprotein lipase is saturated at this level. The only currently effective intervention for serum TG levels above 1000 mg/dL is the very-low-fat diet, as described above.
Consider plasmapheresis to prevent pancreatitis
34. A 38-year old woman is referred for hyperthyroidism. She has recently been experiencing anxiety, fatigue, insomnia, thinning hair, and brittle nails. Medications: vitamins, multiple supplements. Vitals: BP 122/78 mm Hg; P = 66; height = 5 feet 4 inches; weight = 145 lb. Physical examination results are as follows: thyroid: normal; eyes: normal; hair: normal; and nails: normal. Repeat evaluation: TSH = 0.05 mU/L (nl 0.45–4.5); free T 4 = 3.6 ng/dL (nl 0.8–1.8); TRabs = positive; RAIU = 18%; and scan: homogeneous uptake. What is her likely diagnosis, and what do you recommend next?
biotin use
lab interference
The patient was asked about her intake of vitamins and supplements; her list included a hair-and-nail treatment that contained high amounts of biotin.
She was asked to stop the supplements temporarily, and 3 days later, her thyroid test results were normal. This is a case of biotin interference in hormone assays, with results mimicking Graves’ disease.
Biotin is a component of the reagents for immunoassays of some hormones, such as TSH, T4, T3 , TRAb, PTH, cortisol, and others.
patients who take high doses of biotin supplements, a common over-the-counter treatment for hair loss and brittle nails, can cause falsely and significantly elevated serum levels of free T4 , free T3 , PTH, cortisol, estradiol, and dehydroepiandrosterone sulfate (DHEAS) for several hours or longer after biotin ingestion
TSH levels can be low, high, or normal, depending on which assay is used.
Measurement of these hormones after at least an 8-hour (preferably 2–3 days) abstinence from biotin corrects the anomaly in this laboratory value
5. A 28-year-old man presents with complaints of infertility. He is found to have small, firm testes and gynecomastia. Laboratory testing shows the following abnormalities: testosterone = 171 ng/dL (nl 300–1000); LH = 88 mIU/mL (nl 2–12); and FSH = 95 mIU/mL (nl 2–12). What is the likely diagnosis, and what is the recommended treatment?
Klinefelter’s syndrome.
hypergonadotropic hypogonadism.
The small, firm testes and gynecomastia are most consistent with a diagnosis of Klinefelter’s syndrome.
These patients usually have a 47XXY karyotype, but mosaic patterns are also common. Androgen replacement therapy is the treatment of choice
10. A 19-year-old man presents with excessive thirst and urination. Laboratory evaluation shows the following: serum glucose = 88 mg/dL; sodium = 146 mmol/L; osmolality = 298 mOsm/kg; and urine volume = 8800 mL/24 hr. A water deprivation test is performed: it shows a urine osmolality of 90 mOsm/kg, with no response to water deprivation, and an increase in urine osmolality to 180 mOsm/kg after the administration of vasopressin. What is the likely diagnosis, and what are your treatment recommendations?
central DI
The differential diagnosis of polyuria and polydipsia with maximally dilute urine includes central diabetes insipidus, nephrogenic diabetes insipidus, and primary polydipsia.
The lack of response to water deprivation and the > 50% increase in urine osmolality after administration of vasopressin are most consistent with central diabetes insipidus.
This may be caused by inflammatory or mass lesions in the hypothalamus but is often idiopathic.
MRI of the pituitary–hypothalamic region should be performed.
The treatment of choice is intranasal or oral desmopressin
15. A 58-year-old man reports recently developed diabetes mellitus, weight loss, and a skin rash that is most prominent on the buttocks; a dermatologist suspects this to be necrolytic migratory erythema and performs biopsy and histopathologic analysis to confirm this. What is the probable underlying diagnosis, and what are the therapeutic options?
glucagonoma
migratory erythema
Diabetes mellitus, weight loss, and necrolytic migratory erythema are virtually diagnostic of a glucagon-secreting pancreatic neuroendocrine tumor (glucagonoma).
The diagnosis can be confirmed with the finding of a significantly elevated serum glucagon level.
After appropriate localizing procedures, treatment options include surgery for localized disease, somatostatin analogues (octreotide LAR, lanreotide) to reduce glucagon secretion, hepatic-directed therapies (partial resection, hepatic artery embolization), chemotherapy (streptozotocin/doxorubicin), everolimus (an inhibitor of mTOR [mechanistic target of rapamycin]), sunitinib, and other vascular endothelial growth factor receptor (VEGF-R) inhibitors, and peptide receptor radioligand therapy with use of radiolabeled somatostatin analogues, such as 177-Lu DOTATATE, 90-Y edotreotide, or 90-Y DOTA tyr3-octreotide.
Chronic anticoagulation to reduce the increased risk of thromboembolic events and supplementation with zinc and amino acid infusions to reduce the skin rash and improve quality of life should also be considered
20. A 32-year-old woman presents with recent-onset fatigue, palpitations, profuse sweating, and emotional lability. She gave birth to her second child 8 weeks ago. Her pulse is 100 beats per minute, and she has mild lid retraction, a fine hand tremor, and a slightly enlarged, nontender thyroid gland. She is not breast feeding her child. Laboratory tests are as follows: TSH < 0.03 mU/L (nl 0.5–5.0); free T4 = 3.8 ng/dL (nl 0.8–1.8); and RAIU < 1% at 4 and 24 hours (10-30%) What is the probable diagnosis, and what treatment do you recommend for her?
postpartum thyroiditis
Postpartum thyrotoxicosis is most often caused by Graves’ disease or postpartum thyroiditis.
RAIU will distinguish the two, being high in Graves’ disease and low in postpartum thyroiditis.
RAIU is contraindicated in patients who are breast feeding; in those cases, measurement of TSH receptor antibodies (TRAbs) is often useful, being positive in Graves’ disease and negative in postpartum thyroiditis.
This patient has postpartum thyroiditis, a condition caused by lymphocytic inflammation with leakage of thyroid hormone from the inflamed gland. There is often a thyrotoxic phase (lasting 1–3 months) followed by a hypothyroid phase (lasting 2–6 months) and eventual return to euthyroidism, although nearly 20% of patients remain permanently hypothyroid.
Treatment consists of beta-blockers, if necessary, for symptom control in the thyrotoxic phase, and levothyroxine, if necessary, for symptom control in the hypothyroid phase and for those who remain permanently hypothyroid
25. A 45-year old man presented to his primary care provider with progressive dyspnea on exertion. Laboratory testing revealed hypercalcemia, prompting a referral to you. Past medical history: hepatitis C. Medications: interferon, ribavirin. Dietary Ca: 600 mg/day. He takes no supplements. He smokes half a pack of cigarettes per day and drinks one to two beers per day. Physical examination results are normal except for diffuse rales in all lung fields. Laboratory testing results are as follows: Ca = 12.4 mg/dL; creatinine = 1.2 mg/dL; carbon dioxide (CO 2 ) = 23 mEq/L; and P = 5.9 mg/dL. Additional laboratory examinations yielded these results: PTH < 1 pg/mL; PTH-related peptide (PTHrp) < 1 pmol/L; 25-hydroxy vitamin D = 34 ng/mL (nl 30–100); 1,25-dihydroxy vitamin D 186 pg/mL (nl 15–75). Chest radiography showed hilar adenopathy and diffuse interstitial disease; biopsy revealed noncaseating granulomas. What is the most likely cause of his hypercalcemia and what treatment options are available?
sarcoidosis
Hypercalcemia associated with low serum PTH levels and high 1,25-dihydroxy vitamin D levels is most often caused by granulomatous disorders or lymphomas. In these cases, the granulomatous tissue or lymphoma expresses high levels of 1-alpha-hydroxylase that converts circulating 25-hydroxy vitamin D into 1,25-dihydroxy vitamin D in high concentrations, resulting in 1,25-dihydroxy vitamin D–mediated hypercalcemia. The most common cause of 1,25-dihydroxy vitamin D–mediated hypercalcemia is sarcoidosis (∼50% of cases), followed by lymphoma (∼17%), granulomatous infections (∼8%), other granulomatous diseases (∼4%), and idiopathic cases (∼3%).
Treatment for the hypercalcemia consists of hydration and glucocorticoids; if these measures do not reduce serum calcium sufficiently, ketoconazole or hydroxychloroquine can be added
30. A 26-year-old woman requests to be tested for a type of thyroid cancer that has recently been found in her mother and two of five siblings. She notes that she has had intermittent headaches and palpitations for the past year. Her BP is 164/102 mm Hg. She has a 1-cm, left-sided thyroid nodule without associated lymphadenopathy. Laboratory testing shows the following results: serum Ca = 11.2 mg/dL (nl 8.5–10.5); P = 2.4 mg/dL (nl 2.5–4.5); albumin = 4.5 g/dL (nl 3.2–5.5); intact PTH = 55 pg/mL (nl 11–54); calcitonin = 480 pg/mL (nl 0–20); and 24-hour urine metanephrines = 1788 mcg (nl 0–400). Discuss her diagnosis and management.
MCT
The thyroid nodule, elevated serum calcitonin, and family history make medullary carcinoma of the thyroid (MCT) likely.
Hypertension, headaches, palpitations, and high urinary metanephrines indicate a probable pheochromocytoma.
She also has hyperparathyroidism.
MEN type 2A (MEN 2A) consists of MCT, pheochromocytoma, and hyperparathyroidism. It is an autosomal dominant syndrome that results from a germ-line mutation in the Ret gene.
After initiation of alpha-blocker therapy and blood pressure control, treatment should consist of removal of the pheochromocytoma(s), followed by removal of the abnormal thyroid and parathyroid glands.
Screening at-risk family members for the Ret/MCT oncogene should also be performed