Presented byCam Roessner, PharmD Student

An Impending Storm: Graves’ Disease Thyrotoxicosis

May 5, 2015

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•Outline the etiology, pathophysiology, clinical presentation, and complications of hyperthyroidism/thyrotoxicosis

•Review alternatives for the treatment of thyrotoxicosis secondary to Graves’ disease

•Understand the evidence and rationale behind the common treatment modalities for Graves’ disease and be able to identify the medication-related needs of patients with Graves’ disease thyrotoxicosis

Learning Objectives

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• Introduction to Patient Case•Hyperthyroidism Background•Goals of Therapy & Drug Therapy Problems▫DRP #1 – Symptomatic management▫DRP #2 – Graves’ treatment▫DRP #3 – Thyroidectomy pre-treatment▫DRP #4 – Thionamide adverse effects

•Case Resolution and Monitoring•Summary•References

Presentation Outline

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• History of Presenting Illness▫40 year old LL with a 3-4 month history of tremor, diaphoresis, heat intolerance, ♀

palpitation, 12 lb. unintentional weight loss, irregular menses, and insomnia

• Past Medical History▫Hyperthyroidism (× 1 month)▫Cesarean section (× 2)

• Social and Family History▫Ex-smoker (quit 1 year ago)▫2 sisters with hypothyroidism

Patient Case

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•Medications▫Propylthiouracil (PTU) 150mg PO tid

Switched from MMI 6 days before admission▫Atenolol 50mg PO bid

Increased from once daily 6 days before admission

•Past Medications▫Methimazole (MMI) 30mg PO daily

No response after 1 month trial Patient developed bilateral rash, skin peeling and arthralgia of hands

Patient Case

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Patient CaseSystem Relevant Labs, Vital Signs, and Physical Examination Findings

CNS & Psych A & O × 3, anxious mood, restless, insomnia

HEENT lid lag/thyroid stare, enlarged thyroid with bruit

CVS BP 144/75mmHg, HR 114, ECG – sinus tachycardia, ECHO – normal, JVP 1cm, palpitations

Resp RR 20, 97% on room air, Ø crackles, Ø wheezeGI Ø NVD, abdomen soft and non-tender, ALT = 51

Renal Scr 38umol/L, eGFR 128mL/minEndo free T4 > 100pmol/L (10.0 – 25.0pmol/L)

free T3 > 50pmol/L (3.5 – 6.5pmol/L)TSH = 0.04mU/L (0.5 – 4.0mU/L)PTH = 4ng/L (7 – 37ng/L)

Autoantibodies:TSH-receptor antibody (TRab) = 90IU/L (negative)

Heme & Electrolytes Neut 1.2 10E9/L (2.0 – 9.0 10E9/L) Ca2+ = 2.77 (2.10 – 2.55mmol/L)MSK & Integument tremor, palmar erythema, proximal muscle weakness, hyperreflexia, arthralgia of hands

Miscellaneous Temp 37.7ᵒC, heat intolerant

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•Thyrotoxicosis secondary to Graves’ disease

Patient Diagnosis

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Differential Diagnosis of Thyrotoxicosis and an Overview of Graves’ disease

Hyperthyroidism and Thyrotoxicosis

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•Hyperthyroidism▫Disorders that result from sustained overproduction and release of

hormone by the thyroid itself•Thyrotoxicosis▫Refers to the physiologic manifestations of excessive quantities of the

thyroid hormones▫Not necessarily associated with the thyroid gland (i.e. thyroid hormone

ingestion, known as thyrotoxicosis factitia)

Definitions

Mandel, S. J., Larsen, P. R., & Davies, T. E. (2011)

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•Toxic adenoma•Toxic multinodal goiter•Thyroid carcinoma •TSH-secreting pituitary adenoma• Iodine-induced hyperthyroidism•Drug-induced hyperthyroidism•Graves’ Disease

Thyrotoxicosis – Differential Diagnosis

Robert James Graves1796-1853

NEJM, 358(24), 2594-2605Marino, M., Vitti, P., & Chiovato, L. (2010)

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•Composed of a T and B cell-mediated immune process•Autoantibodies, TSH-receptor antibodies or Thyroid-stimulating

antibodies (TRabs or TSabs) are capable of stimulating thyroid hormone production independent of natural TSH secretion

•Thyroid hypertrophy, increased vascularity, and unregulated thyroid hormone (↑↑T3 and ↑T4) secretion result

•Graves’ is thought to be caused by a complex interplay of genetic, hormonal, and environmental factors (infection, stress, smoking, iodine)

Graves’ disease – Etiology and Pathophysiology

Marino, M., Vitti, P., & Chiovato, L. (2010)

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• Thyroid – Symmetrically enlarged thyroid with thrill or bruit• Skin – Warm, moist, with palmar erythema, friable hair, and soft nails•Cardiovascular – Tachycardia, palpitations, and arrhythmias (premature

beats to atrial fibrillation) are common•GI – Increased appetite, increased liver enzymes, diarrhea•Nervous System – Insomnia, irritability, restlessness, decreased

concentration, fine tremor, thyrotoxic stare/lid lag (autonomic hyperstimulation of the upper eyelid)

Graves’ disease – Clinical Presentation

Marino, M., Vitti, P., & Chiovato, L. (2010)

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Thyrotoxic stare (left) and an enlarged non-nodular thyroid gland (right) are common findings in Graves’ disease, however they are non-specific and can occur in other thyrotoxic states.

Thyrotoxic Stare & Enlarged Thyroid Gland

Marino, M., Vitti, P., & Chiovato, L. (2010)

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Graves’ Ophthalmopathy

http://www.webmd.com/eye-health/graves-ophthalmopathy

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•Muscles – Weakness and easy exhaustion•Skeletal – Increased bone remodeling and osteoporosis depending on

the duration of disease and coexistence of other risk factors•Heme – Mild leukopenia (separate from effects of thionamides)•Reproductive – Oligomenorrhea or amenorrhea in women (severe

thyrotoxicosis) and gynecomastia in men•Metabolic – Heat intolerance and weight loss

Graves’ disease – Clinical Presentation

Marino, M., Vitti, P., & Chiovato, L. (2010)

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•Autoantibodies▫TRab – Positive

Very sensitive and specific with 98% of untreated patients with Graves’ disease positive for TSH-receptor antibodies

Confirms the diagnosis if there is uncertainty on presentation

• Lab Abnormalities▫TSH – Undetectable or low▫Free T3 (FT3) – Elevated▫Free T4 (FT4) – Elevated

Graves’ Disease

Marino, M., Vitti, P., & Chiovato, L. (2010)

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A Step-wise Approach

Drug Therapy Problems and Treatment Options

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•DTP #1 – Patient LL requires drug therapy for the symptomatic treatment of thyrotoxicosis

•DTP #2 – Patient LL requires drug (or non-drug) therapy for the treatment of hyperthyroidism

•DTP #3 – Patient LL requires additional drug therapy for the rapid attainment of a euthyroid state (pretreatment) prior to thyroidectomy

•DTP #4 – Patient LL requires reassessment of her thionamide medication due to the occurrence of adverse effects

Drug Therapy Problems

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•Patient LL requires drug therapy for the symptomatic treatment of thyrotoxicosis• Thyrotoxicosis leads to increased β-adrenergic binding sites•β-blockers• Evidence exists for the use of propranolol, atenolol, or metoprolol in the

symptomatic treatment of thyrotoxicosis in patients with Graves’ disease•Role• Used to manage symptoms while hyperthyroidism is being treated with

thionamides, iodine, or both +/- surgery or radioactive iodine

Drug Therapy Problem #1

Internal Medicine (Tokyo, Japan), 51(17), 2285-2290 The American Journal of Medicine, 93(1), 61-68

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•Data• Patients symptoms include tachycardia (HR 114), palpations, tremor, and anxiety

•Assessment• In addition to PTU, β-blocker indicated, effective and safe for the treatment of

symptoms of thyrotoxicosis•Plan• Atenolol 50mg PO bid• Option to increase to 100mg BID if patient is still tachycardic

Symptomatic Management

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•Patient LL requires drug (or non-drug) therapy for the treatment of hyperthyroidism• Treatment options for the remission of Graves’ disease:

1. Thionamides (aka Antithyroid Drugs)2. Radioactive iodine (I-131)3. Thyroidectomy

Drug Therapy Problem #2

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• Methimazole is 10-15x more potent than PTU• PTU blocks peripheral conversion of T4 to T3

(more so at >600mg/d)• Carbimazole is the prodrug of methimazole

• Competitively inhibit the incorporation of iodine into T4 and T3 precursor known as thyroglobulin

• Do not have an effect on preformed thyroid hormone, therefore the effects are seen once T3 and T4 stores are depleted (1-6 weeks)

• Euthyroidism is usually achieved in 6-12 weeks• Can be used as the sole treatment modality

(12-24 months), as an adjuvant to radioiodine, or for the attainment of euthyroidism before surgery

• High relapse rate of 50-70% most often occur within 3-6 months of drug discontinuation

Thionamides

Farwell, A. P., & Braverman, L. E. (2006)

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•Graves' Hyperthyroidism: Treatment with Antithyroid Drugs, Surgery, or Radioiodine – A Prospective, Randomized Study▫All 3 treatments were equally effective in establishing a hypothyroid

state with subsequent T4 supplementation at 12 months▫Radioactive iodine took “a few weeks” longer to achieve a hypothyroid

state – generally achieved in 2-6 months▫Rates of relapse back to hyperthyroidism:

Thionamides > radioactive iodine > surgery

Graves’ Treatment Options

The Journal of Clinical Endocrinology and Metabolism, 81(8), 2986-2993

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Graves’ Treatment Plan•Data• Patient is still hyperthyroid with no signs of improvement despite 4 weeks

treatment with methimazole 30mg once daily•Assessment• Inadequate response with 4 weeks of thionamide treatment and unlikely to

respond to thionamides alone•Plan• Switch from methimazole to PTU• Surgery (near total/ total thyroidectomy)

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•Patient LL requires additional drug therapy for the rapid attainment of a euthyroid state (pretreatment) prior to thyroidectomy• Surgeries include subtotal, near-total, and total thyroidectomy• Bleeding, injury to the laryngeal nerve, and hypoparathyroidism are potential risks• Mortality and morbidity from surgery are reduced when the metabolic state of

the thyroid gland is normalized and vascularity is reduced before surgery• How is this done promptly?• Thionamides• Inorganic Iodide• Plasmapheresis?

Drug Therapy Problem #3

Mandel, S. J., Larsen, P. R., & Davies, T. E. (2011)

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•Oldest treatment for disorders of the thyroid•Blocks thyroid hormone release, inhibits thyroid hormone synthesis

(Wolff-Chaikoff effect), and decreases the size and vascularity of the gland

•The thyroid will “escape” the WC effect by decreasing iodine uptake into the gland within 1-2 weeks of initiating treatment

•Role▫Used for 7-10 days prior to surgery to help attain a normal metabolic

(euthyroid) state and reduce thyroid vascularity

Iodide

Farwell, A. P., & Braverman, L. E. (2006)The Journal of Clinical Endocrinology and Metabolism, 92(6), 2182-2189

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•Benefit of short-term iodide supplementation to antithyroid drug treatment of thyrotoxicosis due to Graves’ disease11

▫Patients were randomized to receive either:1. methimazole 30mg daily2. methimazole 30mg daily+ potassium iodide 50mg tablet daily (38.2mg iodide)3. methimazole 15mg 4. methimazole 15mg + potassium iodide 50mg tablet daily

▫Potassium iodide was discontinued when FT4 normalized

Iodide Evidence

Clinical Endocrinology, 72(6), 845-850

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•Results▫Normal FT4 at 2 weeks:

MMI 30mg vs. MMI 30mg + KI 50mg: 29% vs. 59% (P < 0.05) MMI 15mg vs. MMI 15mg + KI 50mg: 27% vs. 54% (P < 0.05)

▫Normal FT4 at 4 weeks: MMI 30mg vs. MMI 30mg + KI 50mg: 71% vs. 78% (P < 0.5839 NSS) MMI 15mg vs. MMI 15mg + KI 50mg: 50% vs. 73% (P < 0.0758 NSS) 3 patients from each MMI + KI group had increased FT4 after discontinuation of

KI 50mg but levels normalized after continuing MMI

Iodide Evidence

Clinical Endocrinology, 72(6), 845-850

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Iodide Evidence

Clinical Endocrinology, 72(6), 845-850

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Case report of a 33 year old female with Graves’Baseline FT4 > 77.0pmol/L

1. Treatment with propranolol + potassium iodide × 10 days

(ATD agranulocytosis)Pre-plasmapheresis FT4 >77.0pmol/L

2. Plasmapheresis × 3Post-plasmapheresis FT4 23.2pmol/L*

3. Near-total thyroidectomy

• Plasmapheresis can be used to dramatically reduce circulating thyroid hormone levels

• Removal of thyroid hormones is possible because a large proportion bind to serum proteins

• Fresh frozen plasma or colloid/albumin combination can replace the removed plasma

Plasmapheresis

International Journal of Clinical Practice, 58(6), 554-558

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•Data▫Patient is hyperthyroid and awaiting correction prior to thyroidectomy

•Assessment▫Attaining euthyroidism and reduced vascularity prior to surgery will reduce risk of

intra/postoperative thyroid storm and intraoperative blood loss▫ Iodide and plasmapheresis will also expedite the process

•Plan▫ Lugol’s solution 5% iodine (6.3mg iodine/drop) 3 drops PO tid for 9 days pre-

thyroidectomy Given after PTU to prevent the iodine being used for thyroid hormone synthesis

▫Plasmapheresis × 2

Thyroidectomy Pre-treatment

The Journal of Clinical Endocrinology and Metabolism, 92(6), 2182-2189

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Plasmapheresis Response

15-Apr-15 16-Apr-15 17-Apr-15 18-Apr-15 19-Apr-15 20-Apr-15 21-Apr-15 22-Apr-150

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20

30

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50

60

70

80

90

100

110Plasmapheresis 1

Plasmapheresis 2

Free T3 and T4 Concentrations

Free T4 Concentration Free T3 Concentration

pmol

/L

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•Patient LL requires reassessment of her thionamide medication due to the occurrence of adverse effects▫Incidence of minor adverse effects with thionamides is 5-25% ▫Adverse effects include:

Mild leukopenia (12% - also directly a result of Graves’) Agranulocytosis (approx. 0.2%) Pruritic maculopapular rash (5%) Arthralgias (5%) Severe hepatitis (high dose PTU)

Drug Therapy Problem #4

Sherman, S. I., & Talbert, R. L. (2008)

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•Data▫Patient experiencing arthralgia of hands and feet (3-4/10) starting shortly after

initiation of methimazole and continuing after switch to PTU – autoimmune cause ruled out

•Assessment▫Arthralgia likely a minor adverse reaction secondary to thionamides▫Resolution can occur during treatment or following discontinuation

•Plan▫Naproxen 500mg PO bid (while on PTU and experiencing arthalgias)▫Discontinue PTU pre-thyroidectomy

Thionamide Adverse Effects

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•Near-total thyroidectomy following normalization of FT4/FT3•Patient was transferred to a post-op unit and discharged the day after

surgery•No complications during surgery•Home medications following thyroidectomy:

1. Vitamin D 2000IU daily2. Levothyroxine 100mcg PO once daily (1.6mg/kg × 63kg)3. Calcium carbonate 2500mg (1000mg elemental calcium) PO tid at

6:00, 14:00, and 22:00 – do not take with meals

Case Resolution

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•Scheduled for follow-up with endocrinologist 3 weeks post-surgery•Efficacy▫Symptoms of thyrotoxicosis – HR, palpitations, sweating, anxiety, insomnia,

stare, tremor, palmar erythema, muscle weakness▫Normalization of thyroid hormone – TSH 0.5 – 4.0mU/L, FT4 10-25pmol/L▫Relapse (patient will self-monitor)

•Adherence▫Symptoms of hypocalcemia and hypothyroidism post-surgery

Monitoring

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•Safety▫Symptoms of hypocalcemia – paresthesia, muscle twitches and cramps▫Symptoms of hypothyroidism – Fatigue, constipation, dry skin, weight gain▫Surgical complications – hematoma, vocal cord damage, hypocalcemia▫Adverse effects of medications

Thionamides – agranulocytosis, rash, arthralgia (improving?) β-blocker – bradycardia, fatigue, hypotension Iodide – hypersensitivity, metallic taste, GI upset, nausea Levothyroxine – over-supplementation (hyperthyroid symptoms)

Monitoring

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•Graves’ disease is a common cause of thyrotoxicosis involving TSH-receptor antibody mediated stimulation of thyroid hormone release

•Multiple treatment options exist, therefore the choice of therapy will be reliant on disease severity, patient-dependent factors (i.e. pregnancy, age, comorbidities), and patient preference

•Medications play a prominent role in the treatment of Graves’ disease, even if surgery is the elected procedure, and reemphasizes the importance of pharmacist-mediated care for these patients

Summary

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•About hyperthyroidism in cats?▫Evaluation of Thyroid-Stimulating Hormone, Total Thyroxine, and Free Thyroxine

Concentrations in Hyperthyroid Cats Receiving Methimazole Treatment▫Effect of thyroid volume on radioiodine therapy outcome in hyperthyroid cats▫Worldwide prevalence and risk factors for feline hyperthyroidism: A review▫Concurrent diseases in hyperthyroid cats undergoing assessment prior to

radioiodine treatment▫Thyroid scintigraphy findings in 2096 cats with hyperthyroidism

Questions?

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1. Mandel, S. J., Larsen, P. R., & Davies, T. E. (2011). Thyrotoxicosis. In S. Melmed, K. S. Polonsky, H. M. Kronenberg, & P. R. Larsen, William's Textbook of Endocrinology (pp. 362-405). Philadelphia: Elsevier.

2. Brent, G. A. (2008). Clinical practice. graves' disease. The New England Journal of Medicine, 358(24), 2594-2605. doi:10.1056/NEJMcp0801880; 10.1056/NEJMcp0801880

3. Marino, M., Vitti, P., & Chiovato, L. (2010). Graves' Disease. In J. L. Jameson, L. J. De Groot, D. M. de Kretser, L. C. Giudice, A. B. Grossman, S. Melmed, G. C. Weir, Endocrinology: Adult and Pediatric (pp. 1439-1464). Philadelphia: Elsevier.

4. Tagami, T., Yambe, Y., Tanaka, T., Tanaka, T., Ogo, A., Yoshizumi, H., et al. (2012). Short-term effects of beta-adrenergic antagonists and methimazole in new-onset thyrotoxicosis caused by graves' disease. Internal Medicine (Tokyo, Japan), 51(17), 2285-2290.

5. Geffner, D. L., & Hershman, J. M. β-Adrenergic blockade for the treatment of hyperthyroidism. The American Journal of Medicine, 93(1), 61-68.doi:10.1016/0002-9343(92)90681-Z

6. Farwell, A. P., & Braverman, L. E. (2006). Thyroid and Antithyroid Drugs. In L. L. Brunton, J. S. Lazo, & P. L. Keith, Goodman and Gilman's The Pharmacological Basis of Therapeutics (pp. 1511-1540). New York: McGraw-Hill.

References

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7. Torring, O., Tallstedt, L., Wallin, G., Lundell, G., Ljunggren, J. G., Taube, A., et al. (1996). Graves' hyperthyroidism: Treatment with antithyroid drugs, surgery, or radioiodine--a prospective, randomized study. thyroid study group. The Journal of Clinical Endocrinology and Metabolism, 81(8), 2986-2993. doi:10.1210/jcem.81.8.8768863

8. Takata, K., Amino, N., Kubota, S., Sasaki, I., Nishihara, E., Kudo, T., et al. (2010). Benefit of short-term iodide supplementation to antithyroid drug treatment of thyrotoxicosis due to graves' disease. Clinical Endocrinology, 72(6), 845-850. doi:10.1111/j.1365-2265.2009.03745.x; 10.1111/j.1365-2265.2009.03745.x

9. Erbil, Y., Ozluk, Y., Giris, M., Salmaslioglu, A., Issever, H., Barbaros, U., et al. (2007). Effect of lugol solution on thyroid gland blood flow and microvessel density in the patients with graves' disease. The Journal of Clinical Endocrinology and Metabolism, 92(6), 2182-2189. doi:10.1210/jc.2007-0229

10. Ozbey, N., Kalayoglu-Besisik, S., Gul, N., Bozbora, A., Sencer, E., & Molvalilar, S. (2004). Therapeutic plasmapheresis in patients with severe hyperthyroidism in whom antithyroid drugs are contraindicated. International Journal of Clinical Practice, 58(6), 554-558.

11. Sherman, S. I., & Talbert, R. L. (2008). Thyroid Disorders. In J. T. Dipiro, R. L. Talbert, G. C. Yee, G. R. Matzke, B. G. Wells, & L. M. Posey, Pharamcotherapy, A Pathiophysiologic Approach (pp. 1243-1263). New York: McGraw-Hill.

12. Sundaresh, V., Brito, J. P., Wang, Z., Prokop, L. J., Stan, M. N., Murad, M. H., et al. (2013). Comparative effectiveness of therapies for graves' hyperthyroidism: A systematic review and network meta-analysis. The Journal of Clinical Endocrinology and Metabolism, 98(9), 3671-3677. doi:10.1210/jc.2013-1954; 10.1210/jc.2013-1954

References

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Diagnostic Criteria for Thyroid StormDiagnostic Parameter Points *Temperature (° F)

99-99.9 5

100-100.9 10

101-101.9 15

102-102.9 20

103-103.9 25

≥104.0 30

Central Nervous System Effects

Absent 0

Mild (agitation) 10

Moderate (delirium, psychosis, extreme lethargy)

20

Severe (seizures, coma) 30

Gastrointestinal-Hepatic Dysfunction

Absent 0

Moderate (diarrhea, nausea/vomiting, abdominal pain)

10

Severe (unexplained jaundice) 20

Cardiovascular Dysfunction

Tachycardia (beats/min)

90-109 5

110-119 10

120-129 15

130-139 20

≥140 25Congestive Heart Failure

Absent 0

Mild (pedal edema) 5

Moderate (bibasilar rales) 10

Severe (pulmonary edema) 15

Atrial Fibrillation

Absent 0

Present 10

Precipitating Event

Absent 0

Present 10

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ThionamidesProperty Methimazole PropylthiouracilRelative potency >10 (up to 50) 1Administration route Oral OralAbsorption Almost complete Almost completeBinding to serum proteins Negligible 75%Serum half-life (hours) 4-6 1-2Duration of action (hours) >24 12-24Transplacental passage Low LowLevels in breast milk Low LowerInhibition of type I deiodinase No Yes

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Treatment OptionsTreatment Modality Advantages Disadvantages

Radioiodine Definitive treatment of thyrotoxicosis Rare, mild, and transient side effects No surgical risks Easy to perform Fast Low cost

Delayed control of thyrotoxicosis Lower efficacy in large goiters Radiation hazard in young patients (?) Possible appearance of ophthalmopathy Worsening of a preexisting ophthalmopathy Possible requirement of glucocorticoids to prevent appearance of worsening of ophthalmopathy

Thyroidectomy Definitive treatment of thyrotoxicosis No radiation hazards Removal of large goitersFast

Hypoparathyroidism (0.9%-2%) Recurrent laryngeal nerve damage (0.1%-2%) Bleeding/infections/anesthesia complications Scarring High cost

Thionamides No radiation hazards No surgical risks No permanent hypothyroidism

Frequent relapses Requires frequent testing Side effects and adverse reactions

Brent GA. N Engl J Med 2008;358:2594-2605.

Brent GA. N Engl J Med 2008;358:2594-2605.

Brent GA. N Engl J Med 2008;358:2594-2605.