2/22 VA report: hypocalcemia (mechanisms and management)

Thanks to MK Hannan for giving an outstanding intake report yesterday on a 61 year old alcoholic with a h/o RCC s/p nephrectomy who presented with hypocalcemia.


  • Serum [Ca] is governed by the actions of PTH and Vitamin D on the bones, gut and kidneys
  • Calcium itself regulates its own metabolism via calcium-sensing receptors (CaSR) in the parathyroid gland (inhibits PTH secretion) and kidney (promotes urinary Ca excretion)
  • Serum calcium is transported partly bound to albumin (~45%); small anions such as phosphate and citrate (15%); and partly in the free/ionized state (‘iCal’: 40%)

Acute signs of hypocalcemia

  • Neuromuscular irritability (tetany): paresthesias, muscle twitching, Trousseau/Chvostek’s, bronchospasm, seizures
  • Cardiac: prolonged QT, heart failure (decreased inotropy), hypotension
  • Papilledema

Diagnosis: consider sending off PTH level (most important), BMP, iCal, Vit D level

PTH-related causes of hypocalcemia

  1. PTH absent (ie low PTH): postsurgical, hypo- OR hypermagnesemia (<0.8 or >5), autoimmune parathyroid destruction or Abs to parathyroid CaSR, s/p XRT, infiltrative (very rare)
  2. PTH ‘ineffective’ (ie high PTH): Vit D deficiency or resistance, end-stage CKD (via decreased calcitriol production and hyperphosphatemia), malabsorption (ex: celiac causing Ca malabsorption), pseudohypoparathyroidism
  3. PTH ‘overwhelmed’: osteoblastic metastases (breast, prostate), pancreatitis, sepsis, massive blood transfusions (via citrate), rhabdomyolysis (via increased serum phosphate)

Drugs that can cause hypocalcemia: EDTA, citrate, bisphosphonates, cisplatin, foscarnet (Phos-based Ca chelator)

Management of hypocalcemia

  • Mg repletion (goal >2)
  • Vitamin D repletion (50K units Vit D2 or D3 x 6-8 weeks)
  • Oral calcium w/ goal 1-2g of  elemental calcium daily, goal Ca 8-8.5 (low end of nl)
    • Many oral supplements like Ca carbonate contain only 40% elemental Ca; so a 1250mg pill contains ~500mg elemental Ca. Ca citrate is ~20% elemental Ca.
  • Ca gluconate can be given IV in acute situations

1/18 PPMC Report: Hypoglycemia

Today we discussed a case of a 40 y/o M with no significant PMH who had spells of confusion, diaphoresis, blurry vision and paresthesias and was ultimately found to be profoundly hypoglycemic.

We reviewed the basic ways in which the healthy body manages glucose homeostasis:


Keeping it simple, if there is an increase in circulating glucose, the pancreas senses this and its beta cells secrete insulin, which has the following effects:

  • stimulates the liver and skeletal muscle to store glucose as glycogen
  • stimulates tissue cells to take up glucose
  • inhibits gluconeogenesis and ketogenesis in the liver

These actions reduce circulating glucose levels, store glucose for later use, and inhibit use of alternative metabolic fuels when glucose is present.

Conversely, when there is a decrease in circulating glucose, the alpha cells of the pancreas secrete glucagon, which has the following effects:

  • stimulates glycogenolysis, or breakdown of glycogen into glucose
  • stimulates gluconeogenesis, or production of glucose (in the liver)
  • stimulates ketogenesis, or production of ketones (in the liver)

Together these actions mobilize stored glucose, create new glucose, and then create ketones to be used as an alternative metabolic fuel when glucose is scarce.

Pathologic hypoglycemia should be suspected in the presence of Whipple’s Triad:

  1. Symptoms consistent with hypoglycemia
  2. Low plasma glucose while symptomatic
  3. Relief of symptoms once glucose level is raised

Our basic differential for hypoglycemia includes the following:

  • Drug/toxin
    • Exogenous insulin
    • Insulin secretagogues (ex: sulfonylureas – not insulin-sensitizing agents!)
    • EtOH
      • Inhibits gluconeogenesis but not glycogenolysis, so EtOH only causes hypoglycemia after long periods of drinking without oral intake – after glycogen stores are depleted
    • Long list of other culprits (commonly in association with insulin or underlying hepatic/renal dysfunction)
  • Endogenous hyperinsulinism
    • Beta cell secretagogue
    • Beta cell tumor (insulinoma)
    • Functional beta cell disorder (hypertrophy and hyperfunction)
      • Nesidioblastosis
      • Post-gastric bypass hypoglycemia
    • Insulin autoimmune hypoglycemia
      • Antibodies to insulin receptor or to insulin (usually in patients on insulin)
      • Ab-insulin complex circulates and dissociates in an unregulated fashion, which can cause relative hyperinsulinemia and resulting hypoglycemia
      • Or antibody can stimulate insulin receptors and mimic downstream effects (similar to Grave’s disease and TSH-R stimulating Abs)
  • Other
    • Sepsis – cytokine-accelerated glucose utilization
    • CKD – unclear pathophysiology, probably related to increased insulin sensitivity (since insulin is renally-cleared) and inhibition of gluconeogenesis
    • Hepatic failure – impaired gluconeogenesis
    • Adrenal insufficiency – partly related to loss of cortisol-induced gluconeogenesis and epinephrine-induced hyperglycemia
    • Non-islet tumors – usually related to incompletely processed IGF2
    • Malnourishment
    • Critical illness

Workup is most informative when the patient is hypoglycemic! You can challenge a patient with a 72 hour fast if symptoms present during fasting, or a mixed-meal challenge if symptoms are post-prandial. Check these labs:

  • Insulin level: make sure to check which types of insulin are detected on your assay. Elevated insulin level in the setting of hypoglycemia is inappropriate.
  • Proinsulin and C-peptide level: Proinsulin is cleaved into active insulin and C-peptide, so these will both be elevated in cases of endogenous hyperinsulinemia.
  • Beta hydroxybutyrate: insulin is antiketogenic, so in cases of inappropriately elevated insulin, switching metabolic pathways is impaired and BOHB is not elevated
  • Glycemic response to glucagon: insulin is antiglycogenolytic, so excess insulin inhibits breakdown of glycogen in the liver. Insulin-mediated hyperglycemia patients will thus be able to respond to glucagon (which promotes glycogenolysis) by releasing glucose since they still have glycogen stores. In a normal patient, by the end of a fast most glycogen will be depleted so response is diminished.
  • Sulfonylurea screen and anti-insulin antibody test

During hypoglycemic episodes, the following lab patterns can be observed:

  1. Non-insulin dependent:
  • insulin – low
  • c-peptide and proinsulin – low
  • BOHB – high
  • Glycemic response to glucagon – low

2. Exogenous insulin:

  • insulin – markedly elevated
  • c-peptide and proinsulin – low
  • BOHB – low
  • Glycemic response to glucagon – high

3. Endogenous insulin

  • insulin – high
  • c-peptide and proinsulin – high
  • BOHB – low
  • Glycemic response to glucagon – high
  • Check sulfonylurea screen and anti-insulin Abs if this pattern is detected

If labs are consistent with an endogenous insulin source, various imaging modalities are available to evaluate for insulinoma, which was the diagnosis for our patient. Surgical resection/enucleation is usually the best treatment option, but anatomy and other comorbidities can make this complicated in certain cases!





HUP report 1/3: Hyperthyroidism and Polyendocrine Syndrome

For today’s case, we presented a 24 year old male with no significant history who presented to the ED for 2 months of post-prandial nausea, weight loss, and loose stools.  He had seen GI doctors outside of our system and already had negative imaging, EGD/Colo, and intestinal biopsies.  His initial work-up in the ED revealed hyperthyroidism (TSH 0.01, tT4 16.07, tT3 2.13).  This is consistent with relatively mild disease (T4 and T3 < 2x ULN), and when Endocrinology was consulted, they were concerned that this level of hyperthyroidism did not explain his symptoms and that not all of his symptoms were consistent with hyperthyroidism at all.  A full endocrinologic work-up was pursued, and he was found to have autoimmune adrenal insufficiency as well (Addison’s disease).  This combination of hyperthyroidism and Addison’s disease clinched the diagnosis of polyendocrine syndrome type 2.  The key teaching points from the conference are as follows:

  1. Hyperthyroidism should be suspected when patients complain of symptoms such as jitteriness, diarrhea, palpitations, and weight loss; nausea is not a common feature.  Further history should be sought to look for signs of Graves disease (ex. Ophthalmoplegia), thyroiditis (pain), or masses.  A differential for hyperthyroidism is noted below, TSH-depended is crossed out because we know this patient has an appropriate TSH response to primary hyperthyroidism.CaptureAs you consider this diagnosis, the approach to narrowing your differential should follow the below algorithm.  Note that the TRAb and TSI antibodies can both be used for diagnosis and following response to therapy in Grave’s; our faculty expert prefers TRAb in her clinical practice.Capture
  2. Diagnosis of adrenal insufficiency should start with an am Cortisol.  If that value is > 12 you have ruled out AI, if it is < 3 then you have diagnosed AI; if it is between 3 and 12, then you should proceed with ACTH-stimulation to see if a value > 12 can be obtained with ACTH stimulation.  Once these first line tests are complete, you can differentiate primary and secondary dysfunction with an ACTH level. (As a contrast, hypercortisolism/Cushing is diagnosed with one of 3 options: midnight salivary cortisol, 24 hour urinary cortisol, or 1mg Dex supression test)
  3. The polyglandular syndromes are rare disorders.  They should be suspected when a patient presents with a rare endocrinologic presentation (such as Addision’s disease), but not when a patient presents with a common endocrinologic disorder (such as hyperthyroidism) unless the story is not adding up (as was the case here).  Details of the polyglandular syndromes are listed below.Capture

11/13 Presby report: sulfonylurea toxicity, loop diuretics

Thanks to Dan Kim for giving a great talk (and to the audience of contributing lots of great learning points!) on a middle aged woman who presented with hypoglycemia after taking a dose of her sulfonylurea.

Recall that sulfonylureas work by inhibiting the ATP-sensitive potassium channel in pancreatic beta cells; this leads to increased endogenous insulin release. Long acting sulfonylureas (ie glyburide) are more likely than short-acting agents (glipizide, glimepiride) to cause hypoglycemia.

Screen Shot 2017-11-13 at 1.19.18 PM.png

Symptoms of hypoglycemia; remember that it can mimic virtually any neurologic condition

When thinking about hypoglycemia, it helps to think in terms of whether the patient is ill-looking or not


  • drugs (insulin or insulin secretagogue, alcohol, ?others)
  • Sepsis/critical illness
  • Hormone deficiency (cortisol, glucagon or epinephrine)

Seemingly well-appearing

  • Endogenous hyperinsulinism
    • insulinoma
    • post-gastric bypass hypoglycemia
    • antibodies to insulin or insulin receptor
  • Surreptitious/factitious hypoglycemia


Sulfonylurea toxicity is generally a clinical diagnosis based on history. There are sulfonylurea assays that can be sent, but they generally take too long to result and are thus of limited use

Management of sulfonylurea toxicity

  • D50
  • D5 or D10 gtt
    • should not be used as monotherapy for sulfonylurea toxicity, as it will cause transient hyperglycemia that triggers insulin release and further episodes of hypoglycemia
  • Octreotide
    • works by decreasing insulin release from beta cells
    • Give for the first 24h, and then stop; can restart if hypoglycemia recurs
  • Glucagon
    • NB: very short acting, so should only be used as a temporizing measure while getting IV access or some other longer-acting source of glucose

Activated charcoal can be used within 2-3h of the ingestion, but hemodialysis has not been shown to be effective. Diazoxide, an older drug which also inhibits pancreatic insulin release, used to be used, but is less effective than octreotide and can cause hypotension.


We talked briefly about the threshold effect with loop diuretics:

Screen Shot 2017-11-13 at 1.55.05 PM.png

The inflection point where the blue line takes off is the ‘threshold’, and is largely determined by the rate at which the diuretic gets to its site of action. HF patients show resistance at any given diuretic dose due to Na reabsorption at other segments of the nephron. Brater 1983.

Lastly, this study compared bolus vs continuous infusion of lasix in patients with ADHF, and found that there was no real difference between the two dosing strategies. However, keep in mind that this was part of a research setting, where even bolus doses were probably timed perfectly. In real life, doses may be given late (ie beyond the point that the previous dose is effective), so continuous diuretic infusion may still have a role in clinical practice.


  1. Oh S et al. Loop Diuretics In Clinical Practice. Electrolyte Blood Press 2015.
  2. Felker et al. Diuretic Strategies in Patients with Acute Decompensated Heart Failure. NEJM 2011.
  3. Brater DC, Day B, Burdette A, et al. Kidney Int 1984; 26:183.

10/5 HUP Report: Graves’ Disease

Today we talked about workup and management of hyperthyroidism. Here is a review of some of the high yield facts we discussed:


How to examine the thyroid

  • Ask patient to flex neck slightly
  • Place three middle fingers on neck below chin, near midline
  • Locate upper edge of thyroid cartilage (Adam’s apple)
  • Move inferiorly until you reach the cricoid cartilage
  • The first two rings of the trachea are located below the cricoid cartilage, and the thyroid isthmus is here
  • Palpate the isthmus, then palpate the lobes by moving out laterally
  • Size –> diffuse enlargement likely Grave’s, thyroiditis
  • Masses/consistency
  • Thrill/bruit –> likely Grave’s
  • Tenderness –> inflammation
  • Ask the patient to stick out tongue
    • Mass that elevates with tongue protrusion is thyroglossal duct cyst
  • Ask the patient to swallow to feel for symmetric elevation of thyroid
    • Asymmetric elevation can indicate unilateral mass

Low TSH that is NOT Hyperthyroidism

  • Central HYPOthyroidism –> low TSH, low/normal thyroid hormones
  • Nonthyroidal illness, especially receiving glucocorticoids or dopamine –> low TSH, low/normal T4, low T3 (conversion inhibited)
  • Recovery from hyperthyroidism treatment (TSH lags behind normal thyroid hormones)
  • Biotin –> low TSH, high thyroid hormones (artifact from assay)
  • Pregnancy
  • Subclinical hyperthyroidism

Hyperthyroidism – Ddx

  • De-Novo thyroid hormone synthesis in thyroid
    • TSH-induced
    • Grave’s Disease
    • Toxic multinodular goiter and focal toxic adenoma
    • Amiodarone-induced –> can cause increased synthesis (usually underlying toxic nodule) OR can cause destructive thyroiditis (can also cause hypothyroidism)
    • Germ cell tumors secreting hCG (structural similarity with TSH)
  • Independent of increased thyroid hormone synthesis in thyroid
    • Exogenous thyroid hormone
    • Struma ovarii
    • Thyroiditis – with pain
      • DeQuervain’s (subacute granulomatous)
      • Radiation
      • Traumatic
    • Thyroiditis – without pain
      • Subacute lymphocytic thyroiditis (AKA silent or painless thyroiditis)
      • Postpartum thyroiditis
      • Fibrous (Riedel’s) thyroiditis — Usually HYPOthyroid or euthyroid
      • Chronic autoimmune thyroiditis (Hashimotos)

Grave’s Disease

  • Distinguished by presence of orbital manifestations and thyroid stimulating immunoglobulin
  • If patient has ophthalmopathy, thyroid exam diffusely enlarged without nodules, and labs consistent with hyperthyroidism, this is clinically diagnostic of Grave’s
  • If uncertain, then check thyroid receptor Ab –> can be negative early in disease
  • If Ab negative and high clinical suspicion, can check radioactive iodine uptake (should be diffusely increased) or ultrasound for vascularity


Unless there is a contraindication, all patients presenting with symptomatic hyperthyroidism should be started on a beta-blocker to reduce adrenergic effects, and usually a cardioselective agent with daily dosing is preferred (atenolol). The hyperthyroidism can be treated with thionamides (PTU or methimazole; major side effects are agranulocytosis and hepatic toxicity), radioactive iodine ablation (may transiently worsen ophthalmopathy), or surgery.

10/4 HUP Report: Systemic Mastocytosis

Today we discussed a case of a 37 year old male with history of recurrent and progressive episodes of hypotension and flushing, who was ultimately diagnosed with systemic mastocytosis. Here are some facts from our report!


Differential for Hypotension and Flushing (not comprehensive!)

  • Anaphylaxis
  • Mastocytosis
  • Endocrine tumors
    • VIPoma
    • Pheochromocytoma
    • Carcinoid
    • Medullary thyroid cancer
  • Idiopathic capillary leak syndrome
  • Medication overdose (niacin, PDE5 inhibitor, calcium channel blocker, ACE inhibitor)
  • Toxin – scromboidosis


  • Distinguished between cutaneous and systemic forms — WHO classification belowmastocytosis


  • Clinical features of flushing and hypotension with involvement of the cardiovascular, gastrointestinal, and nervous systems in the absence of urticaria, angioedema, and upper-airway involvement suggest systemic mastocytosis
  • Symptoms result from mast cell mediators or direct organ infiltration
    • GI –> abdominal pain, emesis; acute abdomen and negative ex-lap
    • Recurrent anaphylaxis –> can be allergy/IgE mediated or nonspecific trigger
    • Neuropsychiatric –> depressive symptoms (wide range)
    • Musculoskeletal –> osteoporosis, pathologic fractures, lytic or sclerotic bone lesions
    • Cardiac –> epicardial coronary vasospasm from supraphysiologic histamine levels (called allergic angina, Kounis syndrome, hypersensitivity coronary syndrome)
  • Elevated total tryptase when patient is asymptomatic supports the diagnosis
    • Total tryptase is preformed in mast cell granules — surrogate for mast cell burden
    • B-tryptase is released during mast cell activation
    • Both will be elevated if measured during acute symptoms
    • Total tryptase will remain elevated and B-tryptase will normalize when asymptomatic in mastocytosis
  • Confirm dx with BMBx/aspirate
      • Associated with clonal hematologic neoplasm of non-mast cell lineage in 30-40% of cases
        • Determines prognosis
        • Often share KIT mutation and cytogenetic abnormalities with the mast-cell proliferation, indicating an origin from a common precursor cell
      • Need to exclude myeloid neoplasm with FIP1L1PDGFRA rearrangement
        • response to specific targeted therapies, such as imatinib mesylate, that are ineffective in systemic mastocytosis


  • Aggressive systemic involvement or mast cell leukemia should be treated with cytoreductive therapy
    • First line is midostaurin (multikinase/TKI inhibitor)
    • Allogeneic stem cell transplant (if response to chemotherapy) can be curative, but high rates of post-transplant complications
  • If associated heme neoplasm, treat that process
  • Indolent mastocytosis should be treated with symptomatic management, trigger avoidance, and anaphylaxis preparedness
    • H1 and H2 blockade
    • Montelukast
    • Disodium cromoglycate (inhibits release of mediators from mast cells)
    • EpiPen x 2


Murali MR, Castells MC, Song JY, et al. Case records of the Massachusetts General Hospital. Case 9-2011. A 37-yearold man with flushing and hypotension. NEngl J Med 2011;364:1155-65.







8/10 PPMC Report: Secondary Amenorrhea

Today we discussed the case of a 31 yo F with PMH of ?PCOS presenting with difficulty conceiving after attempting for 3 years.

First of all — the PPMC report team agreed that three years was too long! She should be referred for work up after 1 year (or 6 months if >35yo) of attempting to conceive (sex ~2x weekly) without resultant pregnancy.

We discussed the Rotterdam criteria to diagnose PCOS (2003).

Two out of three of the below:

  1. Oligo/anovulation
  2. Clinical/biochemical signs of hyperandrogenism
  3. Polycystic ovaries on US (>12 follicles)

WITHOUT other causes of hyperandrogenism present.

We reviewed the other causes of hyperandrogenism (…and when to go looking for them) including tumor (ovarian/adrenal), congenital adrenal hyperplasia, Cushing’s disease and acromegaly.


Following the above workup algorithm, our patient had hypogonadotropic hypogonadism and an MRI which demonstrated a pituitary mass. Given her presentation with hyperandrogenism, the PPMC report team went back and ordered a Cushing’s and Acromegaly work up which demonstrated elevated IGF-1 which did not suppress with a glucose load — diagnosing this patient with acromegaly 2/2 a hyperfunctioning pituitary adenoma!