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

Management

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.

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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

Mastocytosis

  • 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

Management

  • 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.

Amenorrhea

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!

7/24 (HUP): thyroid physiology and amiodarone-induced thyroiditis

Thanks to Dr. Caitlin White for guiding us through the case of an elderly man with aortic stenosis and atrial fibrillation who was found to have amiodarone-induced thyrotoxicosis.

First, a framework for hyperthyroidism. Causes of hyperthyroidism can be divided into those that lead to:

A) autonomous thyroid hormone production (hot nodule, Graves, etc): increased uptake on radioactive iodine uptake scan (I123)
B) destructive thyroiditis (leading to leakage into the bloodstream of stored thyroid hormone- Hashimoto’s, viral, amiodarone, etc): no uptake on I123 scan
C) Extrinsic thyroid hormone production: struma ovarii, exogenous thyroid hormone intake, etc

An important bit of physiology to know if you want to understand the thyroid:

The thyroid produces T4 (and T3) in a 14:1 ratio, but mostly T4 is deiodinated in the periphery into the biologically active T3.

Wolff-Chaikoff effect: the thyroid is tightly autoregulated so that it doesn’t suddenly produce a huge amount of thyroid hormone just because of swings in your dietary iodine intake (ex: seafood). Thus, the Wolf-Chaikoff effect is characterized by a transient stoppage in thyroid hormone synthesis after a high iodine load. Your thyroid ‘escapes’ from this in 1-2 weeks and returns to normal.

Jod-Basedow phenomenon: in a thyroid with underlying autonomous thyroid hormone production (Graves, toxic multinodular goiter), normal regulatory mechanisms (ie the Wolf-Chaikoff effect, above) are bypassed, and the autonomous thyroid overproduces thyroid hormone possibly leading to hyperthyroidism. This can happen after an iodinated contrast load…or amiodarone exposure, for example.

Amiodarone-induced thyroid dysfunction

An average normal iodine intake for an adult is 0.2-0.3 mg/day. In contrast, one 200mg dose of amiodarone has 6mg of iodine (about 30x the dietary intake!). Amiodarone is lipophilic and can be slowly released from fat stores long after the drug is stopped, meaning thyroid dysfunction can occur even if you’re not on the drug.

Patients can get either hypothyroidism or hyperthyroidism from amiodarone. It is idiosyncratic, and the risk of its effect on the thyroid cannot be predicted based on how long the person has been taking amiodarone (ie you can run into thyroid issues at any time).

There are two flavors of amiodarone-induced thyroiditis (AIT):

Type I AIT: characterized by increased T4 and T3 production, usually due to pre-existing ‘thyroid autonomy’, ie Graves’ disease or toxic nodule which uses the amio/iodine load to churn out more thyroid hormone.
Rx: methimazole (preferred; risk of agranulocytosis) or PTU (less preferred except in 1st trimester pregnancy, due to risk of liver failure). Stop amiodarone.

Type II AIT: caused by direct destructive effect of amiodarone on the thyroid, leading to a destructive thyroiditis. In this case, hyperthyroidism is caused by leakage of stored thyroid hormone into the bloodstream (not increased synthesis, as in type II). Most common in the US.
Rx: prednisone. Stop amiodarone.

You can continue amiodarone in patients with amiodarone-induced hypothyroidism (but not hyperthyroid).

 

A few other thyroid pearls

Suspicious of thyroid pathology? Start with a TSH. If normal, the only reason to get T4/T3 is concerned for pituitary pathology or critical illness- otherwise, you’re done.

  • TSH high: check a total T4 +/- free T4 (a calculated assay that supposedly accounts of protein binding abnormalities but doesn’t always do so perfectly).
  • TSH low: check both total T4 and T3.

 

NB: you’ll sometimes see patients come in on Armour- or Nature thyroid, which is dessicated pig thyroid. The problem is that pig thyroid has a T4:T3 ratio of 4:1, so there’s much more T3 than the human thyroid (14:1 ratio); since T3 is the biologically active hormone, there’s a higher risk of hyperthyroid symptoms.

Common thyroid function derangements

TSH T4 T3 Abnormality
Primary hypothyroid
TSH secreting adenoma
NORMAL ↑TBG from estrogen (preg, OCP); thyroid hormone resistance
NORMAL Subclinical hypothyroidism; recovery from nonthyroidal illness; HAMA
↑↑ Thyrotoxicosis
NORMAL NORMAL OR ↓ Subclinical hyperthyroidism; nonthyroidal illness; exogenous meds (dopamine, steroids)
Central hypothyroidism

References

  1. Loh, K.-C. 2000. Amiodarone-induced thyroid disorders: a clinical review. Postgraduate Medical Journal. PMC1741517

 

7/10 PPMC Report: DM Foot Ulcers

Today Tariq presented a fascinating case of a gentleman with neuropathy and c/f gas gangrene of his right foot.

This lead us on to a discussion about diabetic foot ulcers and a new perspective/respect for what they mean for our patients.

PEARLS:

  1. DM foot ulcer infections are POLYMICROBIAL – so keep things broad!
  2. The risk of death at 5 years for a patient with a diabetic foot ulcer is 2.5x as high as the risk for a patient with DM who does NOT have a foot ulcer. (1)
  3. Mortality after a DM-related amputation exceeds 70% at 5 years for all patients with diabetes. (1)

Take a glance over the NEJM article I was quoting from during report (and here) for a GREAT summary!

References:

  1. Armstrong DG, Boulton AJM, Bus SA. “Diabetic Foot Ulcers and Their Recurrence.” NEJM 2017;376:2367-75. http://www.nejm.org/doi/full/10.1056/NEJMra1615439

7/5 PPMC Report: Adrenal Insufficiency

Today we discussed a case of autoimmune primary adrenal insufficiency presenting in a 24 yo F as N/V, hypotension and hyponatremia.
PEARLS For evaluation of HYPONATREMIA: 
HypoNa
1. Useful to get Serum Osm (and calculate your own!), UOsm, UNa.
2. The VOLUME STATUS EXAM is crucial! While many “classic” physical exam findings associated with hypovolemia are not useful in isolation, in summation they are likely much better. Remember to check for axillary sweat (+LR 2.8, -LR 0.6, sensitivity 50%, specificity 82%).(1)
For ADRENAL INSUFFICIENCY:
1. If suspected don’t be afraid to give a dose of hydrocortisone early! It lasts approximately 24 hours, so try to draw a random cortisol level/ACTH, Aldo/Renin level ahead of time. The crisis level dosing of hydrocort (100-200mg) should provide enough mineralocorticoid activity that you don’t need to think about adding fludrocort.
2. You can do a cosyntropin test ANYTIME — no need to wait for a specific time of day. Two cortisol/ACTH measurements (a baseline and 60 minutes after administration) are all you really need. THE PENN LAB HAS DIFFERENT CUT OFF POINTS FOR NORMAL THAN OTHER LABORATORIES — so check your “normal” ranges closely.
3. To confirm diagnosis of autoimmune send of “adrenal antibodies” in PennChart. Patients should likely get CT A/P to evaluate for adrenal hemorrhage, granulomatous disease, metastases, and an infectious work up.
4. Patients with primary adrenal insufficency should be maintained on hydrocort and fludrocort as outpatients. They need to DOUBLE or even TRIPLE their meds when they get a cold/ill for any reason. We do NOT trend ACTH in these patients, we treat based on symptoms!
5. There are tons of risk factors that put you at higher risk for adrenal insufficiency (2) is an excellent short read if you want to learn a bit more!
References:
1. McGee S, Abernethy WB, Simel DL. The rational clinical examination. Is this patient hypovolemic? JAMA. 1999 Mar 17;281(11):1022-9.
2. Bornstein, SR. Predisposing Factors for Adrenal Insufficiency. NEJM. 2009;360;2328-39.

7/3 at HUP: inpatient management of diabetes

Thanks to Dr. Cardillo for an awesome overview of inpatient diabetes management- too many pearls to count but here are some selected ones:

  1. When starting someone de novo on insulin, use either a weight-based regimen (0.2U/kg for basal only or 0.5U/kg for basal+bolus) or use their correction insulin use as a guide
  2.  Basal/bolus regimens should be approximately balanced in a 50/50 ratio, eg 30U lantus/10U aspart with each meal is balanced; but 80U lantus/5U aspart QAC is not
  3. C-peptide is produced along with insulin and is a marker of beta-cell function; it can be used to assess for insulin activity, but it has to be drawn when the patient is not glucose ‘toxic’, nor when they’re hypoglycemic (as their insulin secretion will be suppressed no matter what during hypoglycemia)
  4. 70/30 is 70% NPH/30% aspart; it is given twice daily, with the bigger dose (~2/3) given in the morning in order to cover both breakfast and lunch, and the smaller dose (~1/3) given before dinner. To convert to basal/bolus, add up the total daily dose of NPH, make 50% basal and split up the remaining 50% as prandial doses
  5. Steroid effect on sugars depends on half life: dexamethasone (24h) > prednisone/methylprednisolone (~12h) > hydrocortisone (~8h). So if giving dexamethasone, have a lower threshold for starting a basal insulin especially if pre-existing DM, while with prednisone or hydrocort, may be able to get away with prandial insulin alone.
  6. Dosing insulin w/ TPN: add up 24h correction, then add it to TPN bag as regular insulin (be mindful of dextrose calories in bag and make sure to decrease insulin dose accordingly)
  7. Continuous TEN: avoid basal insulin (risk of hypoglycemia if TEN stopped). Give either q6h regular or q4h aspart. TEN is held during dialysis and also before and after certain meds (warfarin, synthroid, etc) so make sure insulin orders are held for that period.
  8. Insulin pump: to convert to hospital-delivered insulin, add up total basal dosing and give 80%. Pump site has to be changed every 2-3 days. If they don’t have supplies for change, have to give non pump insulin.
  9. U500 is an ultraconcentrated (5x) formulation of insulin; it is given 2-3x per day and used only for very insulin resistant patients who need huge doses