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HYPERTHYROIDISM (THYROTOXICOSIS)     See Thyroid Storm | Graves’ disease | Thyroiditis |   Thyrotoxic_paralysis (Mayo 2005)

   DX  | LAB  | SX  | RX  |  Diff-Dx                                                                                                               REF:  ACP PIER 2006
More than 80% of the hyperthyroidism cases are caused by Graves’ disease.

Screening Tests:   TSH

* Patients with a low or undetectable TSH and an elevated FT4 have overt hyperthyroidism.
* Patients with a low or undetectable TSH and a normal FT4 have subclinical hyperthyroidism and
have increased risk for atrial fibrillation and osteoporosis.

Diagnostic Approach to Thyrotoxicosis

Classification of Thyrotoxicosis Based on Serum TSH screening test
in patients with symptoms of thyrotoxicosis or conditions associated with thyrotoxicosis

  1. Suppressed TSH
    • Elevated 24 hr RAIU (>30%)
      • Graves' disease
      • Toxic MNG - multinodular goiter
      • AFTN - autonomously functioning thyroid nodule
      • HCG - producing tumor (human chorionic gonadotropin)
    • Normal 24 hr RAIU (15-30%)
      • Toxic MNG - multinodular goiter
      • AFTN - autonomously functioning thyroid nodule
      • Mild Graves' disease
    • Suppressed 24 hr RAIU (<15%)                        | See  Thyroiditis.htm  
      • Subacute thyroiditis
      • Silent thyroiditis
      • Surreptitious T4 or T3 usage
      • Consider central hypothyroidism
  2. Normal TSH - Thyroid disease unlikely
  3. Elevated TSH  
    • Consider discordant TSH secretion
    • Thyroid hormone resistance
    • TSH- producing pituitary tumors

Classification of Thyrotoxicosis Based on Radioactive Iodine Uptake            

  1. High RAIU = radioactive iodine uptake                            
    • Common causes
    • Uncommon causes
      • HCG-mediated (choriocarcinoma)
      • TSH-secreting pituitary tumor
      • Amiodarone-induced hyperthyroidism (non-thyroiditis)
  2. Low RAIU = radioactive iodine uptake                                   See  Thyroiditis.htm

Laboratory and Other Studies for Thyrotoxicosis     

  • TSH if Suspected thyrotoxicosis
  • FT4 if Suppressed TSH
  • FT3 or T3 if Suppressed TSH, normal FT4
  • Thyroglobulin & ESR if Suspected thyroiditis
  • TSH-receptor antibodies  if Euthyroid Graves' ophthalmopathy, Assessing remission during antithyroid drug therapy in Graves' disease; Assessing neonatal risk in pregnant patients with Graves' disease
  • Thyroid peroxidase antibodies  if Confirming Hashimoto's thyroiditis and autoimmune thyroid disease in general (including Graves' disease); Assessing risk for drug-induced thyroid dysfunction and postpartum thyroiditis
  • Thyroglobulin antibodies (anti-Tg antibodies) if Excluding thyroglobulin antibody interference in serum thyroglobulin measurement in patients with thyroid cancer
  • Thyroid hormone antibodies (anti-T4 and anti-T3 antibodies) if Investigation of incongruous thyroid hormone and TSH results (spuriously high FT4 and FT3) in patients with Hashimoto's thyroiditis
  • RAIU = radioactive iodine uptake if Confirmed biochemical thyrotoxicosis
  • Thyroid scan if Confirmed biochemical thyrotoxicosis
  • Whole body scan if Suspected struma ovarii
  • Color Doppler ultrasonography if Differentiating Graves' disease from destruction-induced thyroiditis
  • HCG if Choriocarcinoma

Use radioactive uptake and other imaging tests to determine the etiology of hyperthyroidism.

  • Obtain an RAIU measurement to distinguish between causes of thyrotoxicosis with a low or high incorporation of iodine into thyroid hormone.
  • Obtain 123I or 99Tc scanning to look for AFTN or multinodular goiter.
  • Consider using thyroid ultrasound to document AFTN size and to determine change in dominant nodules within a multinodular goiter over time.
  • Consider ultrasound-guided fine needle aspiration biopsy on nonfunctional nodules >1 cm in TMNG or any nodule with suspicious characteristics on ultrasound in patients with Graves' disease.


   DX  | LAB  | SX  | RX  |  Diff-Dx   
Consider hyperthyroidism (Thyrotoxicosis) in patients with the following history & physical signs.

HISTORY in Thyrotoxicosis       

Nervousness 99%, Increased sweating 91%, Heat intolerance 89%, Palpitations 89%, Fatigue 88%, Weight loss 85%, Weight gain 5-10%, Tachycardia 82%, Dyspnea 75%, Weakness 70%, Leg swelling 65%, Eye complaints 54%, Hyperdefecation 33%, Menstrual irregularity 22%, Emotional lability 30-60%

PHYSICAL EXAM in Thyrotoxicosis  

  • Tachycardia 100%, Goiter 100%, Skin changes 97%, Tremor 97%, Bruit 77%, Eye signs 30-45%, Atrial fibrillation 10%, Splenomegaly 10%, Gynecomastia 10%

HISTORY specific to subacute thyroiditis                 See  Thyroiditis.htm

  • Neck pain 91%, Radiation to ears 64%, Sore throat 36%, Malaise 84%, Recent upper respiratory illness 18%, Anorexia 18%, Myalgias 12%, Nervousness 46%, Perspiration 46%

PHYSICAL EXAM specific to subacute thyroiditis

  • Thyroid firm in consistency 100%, Bilateral thyroid enlargement 45%, Appearing acutely ill 50%, Fever 57%, Eye signs 11%


PHYSICAL EXAM specific to Graves' disease  

  • Ophthalmopathy - Refers to soft tissue inflammation, proptosis, extraocular muscle dysfunction, and optic neuropathy; stare and lid lag are nonspecific findings in thyrotoxicosis.
  • Diffuse thyroid enlargement  - Rare nodular forms of Graves' disease (Marine-Lenhart variety) exist
  • Graves' dermopathy  - Localized myxedema may occur anywhere in the body but is most frequently seen in the pretibial region and the hands
  • Thyroid acropachy  - Soft tissue enlargement of the fingers with clubbing
  • Vitiligo and premature hair graying  - Suggestive of organ-specific autoimmunity
  • Thyroid bruit - there was one case in which a large autonomous nodule was associated with a bruit, presumably resulting from compression of the ipsilateral carotid artery


   DX  | LAB  | SX  | RX  |  Diff-Dx   
Differential Diagnosis or Causes of Hyperthyroidism (Thyrotoxicosis)       

Elevated FT4, suppressed TSH

  • Graves' disease  - Thyroid scan homogeneous
  • Toxic multinodular goiter - Thyroid scan heterogeneous
  • Autonomous “hot” nodules  - “Hot” focus on scan
  • Subacute thyroiditis - No visible thyroid uptake on scan       |    See Painful subacute thyroiditis
  • Postpartum thyroiditis  - May be followed by hypothyroid phase
  • Surreptitious/iatrogenic  - May involve LT4 or LT3 ingestion
  • Struma ovarii  - Increased pelvic uptake on whole body scan
  • TSH-producing pituitary tumor  - Alpha-subunit elevated; flat response on TRH stimulation
    TSH excess due to TSH-secreting pituitary adenomas or pituitary resistance to thyroid hormone is a very rare cause of hyperthyroidism; clinical suspicion of hyperthyroidism is important because TSH measurement alone is misleading. (TSH concentration is normal or high.)
  • Hyperemesis gravidarum  -  increased HCG, nuclear medicine testing contraindicated
  • Choriocarcinoma, testicular tumor  - marked increased HCG
  • Amiodarone-induced -  Two distinct types of thyrotoxicosis
  • Metastatic thyroid cancer  - Prior thyroidectomy in most patients

Normal FT4, suppressed TSH

  • Subclinical thyrotoxicosis  - RAIU may be high normal
  • Recent thyrotoxicosis - After treatment for Grave's disease
  • Central hypothyroidism - FT4 may be low or normal
  • Recovery from thyroiditis - TSH may be low, normal, or elevated
  • Corticosteroid therapy - Suppressive effect on thyroiditis
  • Nonthyroidal illness - TSH may be low, normal, or elevated
  • Dopamine therapy - Suppressive effect on thyroiditis

Causes of Hyperthyroidism (Thyrotoxicosis)        

A. Common causes:

  1. Graves' disease  (diffuse toxic goiter)   - High RAIU = radioactive iodine uptake
  2. Toxic multinodular goiter (Plummer's disease)
  3. Toxic uninodular goiter (toxic adenoma)
  4. T3 toxicosis

B. Less common causes:

  1. Excess thyroid hormone intake (factitious thyrotoxicosis)
  2. Thyroiditis:   - Low RAIU = radioactive iodine uptake
    a. Subacute
    b. Hashimoto's thyroiditis
    c. Silent
  3. Hyperthyroidism due to exogenous iodide (Job Basedow phenomenon)

C. Uncommon causes:

  1. Metastatic follicular thyroid carcinoma
  2. Malignancy: lymphoma, other met to thyroid, other malignancy with circulating thyroid stimulators: testicle embryonal Ca, ChorioCa & hydatidiform mole, other malignancy
  3. Pituitary: TSH producing pit. tumor, acromegaly, selective pituitary resistance to thyroid hormone
  4. Struma ovarii with hyperthyroidism   - marked increased HCG

D. Disorders that can simulate thyrotoxicosis:

  1. Pheochromocytoma   - elevated 24 h uriine metanephrines
  2. Acromegaly
  3. Mitral valve prolapse
  4. Chronic pulm. disease
  5. Diabetes mellitus
  6. Hepatic cirrhosis
  7. Myeloproliferative disorders
  8. Drugs stimulant effects

Causes of Thyrotoxicosis  (Thyrotoxicosis) based on Increased Thyroid Hormone Production        

Dependent on Increased Thyroid Hormone Production

  1. Dependent on increased occupancy of the TSH receptor by:
    • Thyroid-stimulating immunoglobulin (TSI): Graves' disease , Hashitoxicosis
    • Human chorionic gonadotropin (hCG): Hydatiform mole, Choriocarcinoma
    • Thyroid-stimulating hormone (TSH): TSH-producing pituitary tumor
  2. Autonomous overproduction of thyroid hormone (independent of TSH)
    • Toxic adenoma (TSH receptor mutant)
    • Toxic multinodular goiter
    • Follicular cancer (rare)
  3. Jod-Basedow effect (excess iodine-induced hyperthyroidism)

Independent of Increased Thyroid Hormone Production

  1. Increased thyroid hormone release
    • Subacute granulomatous thyroiditis (painful)
    • Subacute lymphocytic thyroiditis (painless)
  2. Nonthyroidal source of thyroid hormone
    • Thyrotoxicosis factitia
    • "Hamburger" thyrotoxicosis
    • Ectopic production by:
      • Ovarian teratoma (struma ovarii)
      • Metastasis of follicular cancer

      REF:   Goldman: Cecil Textbook of Medicine, 22nd ed., 2004  

   DX  | LAB  | SX  | RX  |  Diff-Dx   
Disorders or Complications Caused or Aggravated by Thyrotoxicosis      
  • Bone and mineral: Osteoporosis, Hypercalcemia, Hyperphosphatemia
  • Cardiac:  Atrial dysrhythmia, Arial fibrillation, Premature atrial contractions, Congestive heart failure
  • Respiratory:  Dyspnea due to respiratory muscle fatigue
  • Neuromuscular: Myopathy, Myasthenia gravis, Periodic paralysis
  • Psychiatric disturbance: Psychosis, Anxiety disorder
  • Reproductive:  Amenorrhea, Infertility, Spontaneous abortion


   DX  | LAB  | SX  | RX  |  Diff-Dx   
Thyroid Storm      

Recognize the manifestations of thyroid storm before it is too late.

  1. Thermoregulatory: Severe hyperpyrexia
  2. Central nervous system: Confusion, Agitation, Delirium, Psychosis, Extreme lethargy, Coma, Seizure
  3. Gastrointestinal/hepatic: Diarrhea, Nausea and vomiting, Abdominal pain, Unexplained jaundice
  4. Cardiovascular: Tachycardia, Atrial dysrhythmia, Thromboembolic events, Congestive heart failure

Recognize the precipitants of thyroid storm

  1. Rapid rise in thyroid hormone levels Thyroid surgery
    • Withdrawal of antithyroid drugs
    • Radioiodine therapy
    • Thyroid palpation
    • Iodinated contrast dyes
    • Massive thyroid hormone overdose
  2. Acute or subacute nonthyroidal illness Nonthyroid surgery
    • Infection
    • Stroke
    • Pulmonary embolism
    • Parturition (labor)
    • Diabetic Ketoacidosis
    • Emotional stress
    • Trauma

Initiate prompt intensive four-prong treatment for thyroid storm and impending thyroid storm:

  1. Therapy against the thyroid
    • Inhibition of new hormone synthesis:  Propylthiouracil, methimazole
    • Inhibition of thyroid hormone release: Iodine (saturated solution of potassium iodide [SSKI], Lugol's solution, Ipodate)
  2. Therapy against  the peripheral effects of thyroid hormone
    • Blocking T4-to-T3 conversion: Propylthiouracil, Corticosteroids (dexamethasone > hydrocortisone), Propranolol, Iopanoic acid
    • Beta-adrenergic blockade:  Propranolol
    • Removal of excess thyroid hormone (rarely required):  Plasmapheresis, Charcoal plasma perfusion
  3. Treating systemic decompensation
    • Treatment of hyperthermia:   Acetaminophen, Cooling blankets
    • Correction of dehydration: Intravenous fluid
    • Correction of nutritional deficit :Glucose, thiamine
    • Supportive care: Corticosteroids, Vasopressors
    • Treatment of congestive heart failure
    • Intensive care unit monitoring:  Consider in all cases
  4. Treating the precipitating event
    • Treatment depends on cause Empiric antibiotics not recommended in the absence of evidence for infection

Drugs Used in Thyroid Storm

  • Anti-thyroid drugs:  Inhibits thyroid hormone synthesis

    Propylthiouracil  (PTU)  Load PO 600-1000 mg; then 200-250 mg q 4 -6h - Propylthiouracil preferred   or
    Methimazole (Tapazole) PO 20 mg q 4 h - Propylthiouracil preferred
  • Beta-BLockers:
    Consider invasive monitoring if used in patients in congestive heart failure

    Propranolol PO 60-80 mg q 4 h, or  
    Esmolol (IV infusion) 250-500 ug/Kg IV loading dose, then 50-100 ug/kg·min continuous infusion
  • Iodine
    Do not start until 1 hr after starting antithyroid drugs

    Iopanoic acid 500-1000 mg qd.  Blocks T4-to-T3 conversion. 
    Saturated solution of potassium iodide 5 drops q 6 h.  Blocks thyroid hormone release and new hormone synthesis 
    Lugol's Solution 8 drops q 6 h.  
  • Lithium carbonate 300 mg q 6 h .
    Adjust dose to maintain therapeutic range; questionable benefit beyond iodine.
  • Hydrocortisone 300 mg IV loading followed by 100 mg q 8 h Also decreases T4-to-T3 conversion.
    * Equivalent doses of dexamethasone are also efficacious


Therapy of Hyperthyroidism
- the type of treatment being determined by the cause & type of hyperthyroidism, the age & preference of the patient,
  the size of the goiter or nodule, and the presence of coexisting conditions.
  • Thyroidectomy or subthyroidectomy
    Permanent scar; Permanent hypothyroidism likely; Potential injury to parathyroids and recurrent laryngeal nerve
  • 131I radiation therapy 10-30 mCi         hyperthyroidism_radioiodineRx2011
    RAI therapy for Graves' disease is safe and effective. Hypothyroidism occurs over time in about 75% of patients.
    Permanent hypothyroidism likely; Requires delay in pregnancy (6-12 months) and breast feeding; May precipitate new or worsened ophthalmopathy;
    Slight risk of thyroid storm after treatment
    * Select radioiodine as primary therapy for thyrotoxicosis due to Graves' disease, toxic multinodular goiter, or autonomously functioning thyroid nodules and in patients failing to achieve a remission after a course of antithyroid drugs.
  • Anti-thyroid drugs:    
    Adverse drug effects; Low cure rate (approximately 33%-50%)
    * Use antithyroid drugs for primary therapy of thyrotoxicosis, for attainment of euthyroidism in preparation for thyroidectomy, and for use in conjunction with radioiodine therapy in selected patients.
    To inhibit new thyroid hormone production:
    Use methimazole (Tapazole), 10 to 40 mg once daily for most patients, or 5-10 mg PO tid, up to 20 mg tid.
    Use propylthiouracil (PTU) 100-150 mg tid , up to 200-400 mg tid if needed for patients with allergy to methimazole (except agranulocytosis), who are pregnant or breast feeding, or have severe thyrotoxicosis or thyroid storm.
    As primary therapy, use antithyroid drugs alone for 12 to 18 months
    Monitor for hepatic dysfunction and agranulocytosis.

    * Propylthiouracil associated with liver failure, death
       6-4-2009 FDA Alert
    Propylthiouracil carries the risk of serious liver injury, including liver failure and death, in adult and pediatric patients, the FDA said last week in a safety alert.
    [Posted 06/04/2009] FDA notified healthcare professionals of the risk of serious liver injury, including liver failure and death, with the use of propylthiouracil in adult and pediatric patients. Reports to FDA’s Adverse Event Reporting System (AERS) suggest there is an increased risk of hepatotoxicity with proplythiouracil when compared to methimazole. FDA has identified 32 (AERS) cases (22 adult and 10 pediatric) of serious liver injury associated with propylthiouracil use. Although both proplythiouracil and methimazole are indicated for the treatment of hyperthyroidism due to Graves’ disease, healthcare professionals should carefully consider which drug to initiate in a patient recently diagnosed with Graves’ disease. Physicians should closely monitor patients on propylthiouracil therapy for symptoms and signs of liver injury, especially during the first six months after initiation of therapy. Propylthiouracil should not be used in pediatric patients unless the patient is allergic to or intolerant of methimazole, and there are no other treatment options available.
    [06/04/2009 - Healthcare Professional Sheet - FDA]

  • Supportive medications:
    Beta blockers as Propranolol or Atenolol provide symptomatic relief, when necessary, in all types of hyperthyroidism.
    Consider anti-inflammatory therapy in patients with thyrotoxicosis due to thyroiditis, as Prednisone 40-60 mg/d, rapid relief of thyroiditis pain, for thyroiditis only. 
    Naproxen PO 500 mg bid for thyroiditis only.

Potential Indications for Thyroidectomy in Patients with Thyrotoxicosis

  • Large goiter  -Radioiodine is less effective in this setting, although repeated treatments are ultimately effective.
  • “Cold” nodule in Graves' disease -  Nodules with indeterminate biopsies or inaccessible to biopsy are best addressed surgically.
  • Active ophthalmopathy  - Antithyroid drugs are preferred until eye disease is quiescent; thyroidectomy may be used in patients with antithyroid drug allergy.
  • Patient aversion to radioiodine  - Applies to patients with antithyroid drug failure or allergy.
  • Toxic adenoma  - A large adenoma or radiotracer uptake in the extranodular portions of the thyroid makes radioiodine problematic due to a persistent cosmetic defect and hypothyroidism, respectively.
  • Pregnancy with allergy to antithyroid drugs  - Patients with progressive thyrotoxicosis and a history of a major side effect from antithyroid drugs.
  • Refractory thyroiditis  - Refractory amiodarone thyroiditis, rare cases of non-remitting subacute thyroiditis.