Hyperthyroidism

Hyperthyroidism

ACKNOWLEDGEMENTS:

Thanks to Dr. Ronald M. Goldenberg, MD, FRCPC, FACE, Staff Endocrinologist, North York General Hospital, ON Canada; Endocrinologist & Medical Co-Director, LMC Endocrinology Centres, Toronto, ON Canada, and Dr. William Semchuk, M.Sc., Pharm.D., FCSHP., Manager, Clinical Pharmacy Services, Regina Qu’Appelle Health Region 14, Regina, SK Canada for their expertise with the initial review of this topic.

Definition

Hyperthyroidism:

  • A group of diseases caused by excessive synthesis and secretion of thyroid hormone by the thyroid gland

Thyrotoxicosis:

  • A hypermetabolic state that results from excess thyroid hormone and can occur in the presence or absence of hyperthyroidism. The resulting clinical manifestations are a consequence of the high concentration of thyroid hormone in the tissues

Thyrotoxic crisis/ thyroid storm:

  • Rare but life-threatening exacerbation of hyperthyroidism, usually precipitated by acute illness or surgery

Etiology

The most common cause of thyrotoxicosis is Graves’ disease in which thyrotropin receptor antibodies (TRAbs) binds to and stimulates thyroid stimulating hormone receptors (TSHR) on the thyroid cells and results in increased production of T3 and T4.

The following table document causes of thyrotoxicosis and hyperthyroidism.

Epidemiology

  • Prevalence of hyperthyroidism:
    • Approximately 1.3% and increasing
  • Age predominance:
    • Graves’ disease (diffuse toxic goiter): 20-40 years
    • Toxic multinodular goiter (TMNG) is the primary cause of hyperthyroidism in elderly patients
  • Incidence:
    • Increases with age; highest being in the white population and in iodine deficient areas
    • Among women = 0.38/1000/year
  • Common in smokers

Ref: Franklyn JA, Boelaert K. Thyrotoxicosis. Lancet 2012; 379: 1155-66

Pathophysiology

1-Image-Pathophysiology-Normal physiology-Hyperthyroidism

  • Thyroxine (T4) is a prohormone and is present in higher concentrations than T3
  • T3 is biologically active through interaction with specific nuclear receptors that are present in nearly all tissue
  • T3 regulates energy production and metabolic rates; it has profound effects on cardiac, hepatic and neuromuscular functions, as well on fetal and postnatal growth and development
  • Thyroid hormone concentration is regulated by negative feedback of circulating free hormone primarily on the anterior pituitary gland and to a lesser extent on the hypothalamus

General pathological mechanisms leading to thyrotoxicosis and hyperthyroidism:

  • Inappropriate thyroid stimulation by trophic factors
  • Continuous activation of thyroid hormone synthesis and secretion, resulting in independent release of increased thyroid hormone
  • Preformed thyroid hormone is released in excessive amounts; due to abnormal autoimmune, infectious, chemical, or mechanical insults
  • Extrathyroidal source of thyroid hormone; which may be endogenous (e.g. struma ovarii, metastatic thyroid cancer) or exogenous (e.g. factitious thyrotoxicosis)

Specific pathological mechanisms; involved in conditions associated with hyperthyroidism

Clinical Presentation

Elderly may have few symptoms (apathetic hyperthyroidism) or only present with weight loss or atrial fibrillation.

Heat Intolerance and weight loss are common.

1-Image-Symptoms-Systems and effects-Hyperthyroidism

Differential Diagnosis

See “Etiology” as well.

  • Euthyroid hyperthyroxinemia
  • Panic attacks
  • Anxiety
  • Mania
  • Malignancy
  • Diabetes mellitus
  • Pregnancy
  • Menopause
  • Pheochromocytoma
  • Plummer-Vinson syndrome
  • Weight loss due to cancer
  • Retrobulbar tumor

Investigation and Workup

History:

Detailed history includes:

  • Palpitation
  • Anxiety/ nervousness
  • Increased perspiration
  • Abrupt mood changes
  • Heat/cold intolerance
  • Menstrual irregularities in females
  • Weight changes
  • Family history of any autoimmune disease

Physical examination:

Obtain vital signs, body weight, and perform local thyroid examination.

– Thyroid (anterior neck) examination:

  • Size/ symmetry
  • Nodularity
  • Presence or absence of tenderness

– Ophthalmologic examination:

Approximately 50% of patients with hyperthyroidism may have associated mild thyroid ophthalmopathy, and may present with:

  • Conjunctival edema
  • Poor lid closure
  • Extraocular muscle dysfunction causing diplopia
  • Proptosis

– Dermatologic examination:

  • Non-pitting edema
  • Erythema
  • Thickening of skin without pain or itching

– Diagnostic approach in hyperthyroidism:

Laboratory studies:

Patients with low serum TSH and high free T4 and/or T3 concentrations are hyperthyroid.

– Complete blood count

– TSH level

  • If TSH normal – unlikely to be hyperthyroidism
  • Suppressed in hyperthyroidism
  • Hyperthyroidism with TSH less than 0.3 mU/L (or undetectable) with normal free T4 estimates and normal total T3 or free T3 estimates, usually indicative of subclinical disease

– Serum free T4 and T3

  • May be used to confirm diagnosis
  • Elevated free T4 and/or T3 level
  • In Graves’s (or nodular) associated hyperthyroidism T3 > T4

– ECG/Holter monitor

Specific to Grave’s Disease (GD)

– TSH receptor antibodies: Results are valuable during

  • Pregnancy
  • After recent iodine load

GD is an autoimmune disorder in which thyrotropin receptor antibodies (TRAbs) stimulate the TSH receptor, increasing thyroid hormone production.

– Orbital imaging

  • Evaluate other causes of ophthalmopathy

Imaging:

– Radionuclide uptake:

  • Can help distinguish hyperthyroidism from other causes of thyrotoxicosis)

– Thyroid scan I-123 or Technetium scintigraphy:

May help determine the etiology of hyperthyroidism.

  • Diffuse uptake in Grave’s disease
  • Focal in toxic nodules
  • Evaluation of suspicious nodules

– Ultrasound with fine needle aspiration of suspicious nodules

– Pituitary MRI: Rule out pituitary adenoma

Treatment

  • Assessment of disease severity and underlying cause as determined by history, physical and investigations
  • Factors that are important to consider in the choice of treatment:
    • Pregnancy
    • Breastfeeding
    • Planning pregnancy
    • Presence of ophthalmopathy
    • Patient’s age
  • Obtain CBC and LFTs before the initiation of antithyroid medication.

Supportive care:

Regardless of etiology, beta blockers may be started as soon as in laboratory confirmed thyrotoxicosis, except in patients with significant history of asthma; where it is contraindicated.

Note: Calcium channel blockers (verapamil and diltiazem) may be used for rate control in patients intolerant to beta blockers, or in whom it is contraindicated.

Management of overt hyperthyroidism due to Graves’ disease:

Patients should be treated with any of the following modalities i.e.

  • 131I therapy ( radioactive iodine)
  • Antithyroid drugs (ATDs)
  • Surgery

Typically in North America, physicians prefer radioactive iodine, while in Europe and Japan ATD’s/or surgery is preferred. However, the long-term quality of life following any one of the treatment modality is the same.

1-Image-Teatment-Factors and contraindications -Hyperthyroidism

  1. 131I therapy in the management of Graves’ disease is commenced as shown in the table:
  2. Antithyroid drugs in the management of Graves’ disease as shown in the table:
  3. Thyroidectomy in the management of Graves’ disease as shown in the table:

Management of thyroid nodule in patients with Graves’ disease:

Thyroid nodule larger than 1-1.5 cm should always be evaluated prior to radioactive iodine therapy in GD. The occurrence of thyroid cancer is approximately ≤2% in GD.

Following steps are recommended on discovery of a thyroid nodule:

  • Any nonfunctioning or hypoactive nodule should be considered for fine needle aspiration
  • If pathology is suspicious or confirms malignancy, surgery is advised after normalization of thyroid function

Management of thyroid storm associated complication:

Thyroid storm is a life-threatening disorder characterized by involving multiple systems with high mortality if not treated immediately and aggressively.

Criteria for thyroid storm has been defined by Burch- Wartofsky score; is solely based on clinical and physical assessment, which covers the following factors:

  • Body temperature
  • Central nervous effects
  • Hepatic and gastrointestinal symptoms
  • Cardiovascular dysfunction

Treatment comprises of:

  • Provide immediate IV fluids, oxygen, ventilatory support, and ICU monitoring if needed
  • Aggressive cooling with cooling blankets; followed by acetaminophen 15 mg/kg every 4 hrs, orally or rectally is administered in hyperthermia
  • Administer antithyroid drugs to block the synthesis of new hormone; methimazole (MMI) 60-80 mg/day, or propylthiouracil (PTU) 500-1000 mg loading dose, then 250 mg every 4 hourly
  • Beta-blockers (propranolol 60-80 mg every 4 hrs); it blocks T4 to T3 conversion and also used in patients with congestive cardiac failure (CCF)
  • Iodine (SSKI) 5 drops (0.25 ml or 250 mg) PO every 6 hrs, to block thyroid hormone release and new hormone synthesis
  • To further block the conversion of T4-T3, and avoid adrenal insufficiency; administer hydrocortisone 300 mg IV loading dose followed by 100 mg every 8 hrs

Management of overt hyperthyroidism due to TMNG or TA:

Treatment is focused to achieve rapid and sustained euthyroid state, there are two main treatment modalities recommended.

  • 131I therapy
  • Thyroidectomy

Note: Sometimes lifelong ATDs are the best choice for elderly patients who are in nursing homes, have increased surgical risk and are with limited life expectancy. The treatment requires frequent monitoring (every 3 months).

  1. Factors and contraindications influencing the decision to choose particular modality:
  2. 131I therapy in the management of overt hyperthyroidism due to TMNG or TA is commenced as shown in the table:
  3. Thyroidectomy to manage TMNG or TA as shown in the table:

Management of subclinical hyperthyroidism:

Subclinical hyperthyroidism is defined by low TSH less than 0.3 mU/L (or undetectable) with normal free T4 estimates and normal total T3 or free T3 estimates.

  • Usually, an incidental finding during a routine physical or sometimes signs and symptoms suggest the possibility of hyperthyroidism to the physician
  • Once the results are confirmed by repeating the labs, determine the cause of low TSH by excluding other causes of decrease TSH levels such as:
    • Pituitary and hypothalamic disease
    • Euthyroid sick sinus syndrome
    • Drugs e.g. dobutamine, dopamine and steroids
    • Pregnancy: First trimester
    • Factitial TSH suppression e.g. excessive thyroid hormone ingestion
  • In elderly TMNG is probably the most common cause of SH
  • Patients with GD rather than a TMNG as the cause of SH may be more likely to spontaneously revert
  • It is important to diagnose SH; because there is 2.8 folds risk of atrial fibrillation in individuals over the age of 60 yrs, likewise post-menopausal females with SH have increased risk of fractures

Who to Treat according to the age and TSH levels:

  • Individuals who are >65 years with TSH <0.1 mU/L should be treated; while 0.1-0.5 mU/L should be considered for therapy
  • Individuals aged <65 years with TSH < 0.1 mU/L with heart disease, osteoporosis and hyperthyroid symptoms should be treated while with TSH 0.1-0.5 mU/L with heart disease, menopausal females and hyperthyroid symptoms should consider treatment
  • Individuals with aged <65 years and asymptomatic may consider treatment with TSH <0.1 mU/L

Treatment of subclinical hyperthyroidism will depend on its cause. In the case of clinical evidence for underlying Graves’ disease (goiter, ophthalmopathy, positive TSH (receptor antibodies), low-dose thiourea therapy with methimazole could be considered as well as radioiodine.

Management of hyperthyroidism in pregnancy:

  • If GD is diagnosed during 1st trimester of pregnancy, PTU is recommended treatment. Measure TRAb at diagnosis and if elevated repeat at 22-26 weeks of gestation; if thyroidectomy indicated then perform in 2nd trimester
  • If it is diagnosed after 1st trimester methimazole is recommended; if surgery indicated it should be done in 2nd trimester
  • Diagnosed and treated females prior pregnancy; should switch to PTU from methimazole if pregnancy is confirmed
  • Once in remission after stopping ATDs, TRAb monitoring is not required
  • If previous treatment with radioiodine or surgery, TRAb are measured initially and if high then repeat 22-26 weeks of gestation

Management of Graves’ ophthalmopathy (GO):

Graves’ ophthalmopathy is defined as an inflammation of the orbital and periorbital soft tissues effecting on the eye; such as pain, itching, chemosis, retraction of the eyelids, and proptosis associated with hyperactivity of thyroid gland.

Approximately 50% of Graves’ hyperthyroidism presents with Graves’ ophthalmopathy, and 5% tend to suffer from severe disease.

Assessment of the disease activity is calculated by a clinical activity score (CAS)**. The score ranges from 0-10 and also predicts response to anti-inflammatory therapy. GO is considered active if the CAS ≥3.

The severity of disease is graded as follows:

  • Mild GO: Features of GO, having very mild effects on daily life, insufficient to justify treatment
  • Moderate to severe GO: Features having significant effects on daily life but without sight threatening GO; sufficient to justify treatment with immunosuppressive (inactive disease) or surgical intervention (if inactive disease)
  • Sight threatening GO: patients with dysthyroid optic neuropathy and/or corneal breakdown, requiring immediate intervention

** Ref: Mourits MP, Koornneef L, Wiersinga WM, et al. Clinical criteria for the assessment of disease activity in Graves’ ophthalmopathy: a novel approach. Br J Ophthalmol. 1989;73:639-644.

Therapeutic approaches to GO include:

  • Local measures
  • Corticosteroids
  • Orbital radiation
  • Surgery

Since quality of life may not be significantly improved by these measures, it is important to prevent development and/or progression of GO by identifying and treating of risk factors as follows:

  • High pretreatment T3 and TRAb levels: Achieve euthyroid state as soon as possible
  • Smokers: Advised to stop
  • Radioiodine- induced hypothyroidism should be corrected

In patients receiving RAI for hyperthyroidism, use of glucocorticosteroids may help prevent the development of GO.

Use of glucocorticoids for prevention of Graves’ ophthalmopathy in patients receiving radioactive iodine (RAI) for Graves’ hyperthyroidism:

Management of drug induced thyrotoxicosis:

More than one mechanism can be induced by a single drug. Medications which may interfere and affect thyroid function to cause hyperthyroidism or thyrotoxicosis involve following mechanisms:

  • Iodine induced
  • Destructive thyroiditis
  • Thyroid autoimmunity

9-Image-Treatment-Management of drug induced thyrotoxicosis-Hyperthyroidism

Management of destructive thyroiditis:

Destructive thyroiditis results from the subacute release of preformed thyroid hormone, and is self-limited.

Common causes include:

  • Subacute thyroiditis
  • Painless thyroiditis (including postpartum thyroiditis, amiodarone-associated destructive thyroiditis, and lithium-associated thyroiditis)
  • Acute thyroiditis- referred to suppurative thyroiditis or thyroid abscess, is usually euthyroid, occasionally may present as destructive thyrotoxicosis

a) Patients with mild symptomatic subacute thyroiditis are treated with:

  • Beta-blockers
  • Non-steroidal anti-inflammatory drugs (NSAIDs)

Note: Non-responders may require steroids for moderate to severe symptoms.

b) Patients with painless thyroiditis treated with:

  • Beta-blockers for symptoms of thyrotoxicosis
  • ATD has no role because new thyroid hormone synthesis is already low in these patients
  • In severe cases, corticosteroids may be used

c) Patients with acute thyroiditis:

  • Cause is usually bacterial infection requiring systemic antibiotics
  • In the presence of abscess drainage is required
  • Beta blocker is given for supportive therapy in case of thyrotoxicosis
  • No role of ATD

Management of unusual causes of thyrotoxicosis:

As discussed earlier there are other uncommon causes that may cause hyperthyroidism or thyrotoxicosis.

10-Image-Treatment-Management of unusual causes of thyrotoxicosis-Hyperthyroidism

MEDICATIONS:

Radiopharmaceutical, Antithyroid agent

  • ➣ Sodium iodide I131

Mechanism:

  • Destroyed the overactive thyroid gland; brings back to normal function
  • Small amount is used for diagnostic purpose by measuring the uptake by the thyroid gland
  • Larger doses of sodium iodide I131 are used in certain thyroid cancer to destroy the remaining thyroid tissues after surgery

Doses:

Sodium Iodide I131

Graves’ disease

  • Typically (10-15 mCi) is a sufficient single dose to achieve hypothyroid state

Toxic multinodular goiter (TMNG)

  • Activity of radioiodine should be calculated according to the size of the goiter to deliver 150-200 µCi per gram of tissue corrected for 24 hrs RAIU

Toxic thyroid adenoma (TA)

  • Approximately 10-20 mCi, or calculated on the bases of nodule size using 150-200 µCi per gram corrected for 24-hour RAIU

Thionamides, Antithyroid agent

  • ➣ Propylthiouracil (PTU)
  • ➣ Methimazole (MMI)

Mechanism

  • Inhibits the conversion of iodide to iodine by binding to thyroid peroxidase
  • Thus blocks synthesis of thyroxine and triiodothyronine
  • Does not inactivate already formed, circulating and exogenous thyroid hormones

Doses:

Propylthiouracil (PTU)

  • 50-150 mg PO TID; once the thyroid functions return to normal; it is maintained 50 mg PO TID

Thyroid storm

  • Initial 500-1000 mg, then 250 mg every 4 hourly

Methimazole (MMI)

  • Start 10-20 mg/day PO daily; maintenance dose: 5-10 mg once daily

Thyroid storm

  • 60-80 mg/day

Drug induced thyrotoxicosis

  • 20-40 mg daily

Beta-adrenergic blocking agents

β1 selectivity

  • ➣ Atenolol
  • ➣ Metoprolol

Nonselective

  • ➣ Nadolol
  • ➣ Propranolol

Mechanism:

  • Blocks response to beta-adrenergic stimulation
  • β1-selective beta-blocker inhibits β-adrenergic receptors within the myocardium at normal doses
  • But can inhibit β-adrenergic receptors within bronchial and vascular smooth muscle at higher doses
  • Nonselective beta-blocker inhibits β-adrenergic receptors within the myocardium and within bronchial and vascular smooth muscle
  • Decrease heart rate and cardiac output
  • Decrease renin release

Doses:

β1-selective:

Atenolol

  • 25-100 mg/day PO once daily or BID; Max 200 mg/day

Esmolol

Thyrotoxicosis/thyroid storm

  • IV pump 50-100 mcg/kg/min

Metoprolol

  • 25-50 mg PO QID

Nonselective:

Nadolol

  • 40-160 mg/day once daily

Propranolol

  • Oral: 10-40 mg TID-QID
  • Intravenous: 1-3 mg single dose

Thyroid storm

  • Oral: 60-80 mg every 4 hrs
  • Intravenous: 0.5-1 mg over 10 minutes every 3 hrs

Calcium channel blocking agents (CCBs)

Non-dihydropyridine

  • ➣ Diltiazem
  • ➣ Verapamil

Mechanisms:

  • Blocks the inward movement of calcium by binding to the L-type calcium channels in the heart and in smooth muscle of the peripheral vasculature
  • This decreases intracellular calcium leading to a reduction in muscle contraction
  • Significant reduction in afterload but not preload

Doses:

Diltiazem

  • 120 mg PO every 8 hrs

Verapamil

  • 40-80 mg/day PO every 8 hrs

Non-steroidal anti-inflammatory drugs (NSAIDs)

  • ➣ Ibuprofen
  • ➣ Aspirin

Mechanism:

  • Prostaglandins are believed to be a common factor in the production of pain, fever, and inflammation
  • These drugs inhibit cyclooxygenase-1 and 2 (COX-1 and 2) enzymes
  • This results in decreased formation of prostaglandin precursors

Doses:

Ibuprofen

  • 1200 to 3200 mg/day in divided doses

Aspirin

  • 2600 mg/day in divided dose

Glucocorticoids

  • ➣ Methylprednisolone
  • ➣ Prednisone

Mechanism:

  • Decreases inflammation and the normal immune response through multiple mechanisms, such as
  • Inhibition of macrophage accumulation in inflamed areas
  • Decreases permeability of capillary wall and edema formation
  • Stabilizes leukocyte lysosomal membranes
  • Also suppresses adrenal function in higher doses

Doses:

Hydrocortisone

Thyroid storm

  • 300 mg IV loading dose followed by 100 mg every 8 hrs

Prednisone

Subacute thyroiditis

  • 40 mg/day PO for 1-2 weeks; followed by gradual taper over 2-4 weeks or longer, depending upon clinical response

Antithyroid agent; Expectorant

  • ➣ Saturated solution of potassium iodide (SSKI)

Mechanism:

  • Decreases viscosity of mucus by increasing respiratory tract secretions
  • Inhibits thyroid hormone synthesis and release
  • Also blocks or reduces accumulation of radioactive iodine in the thyroid gland
  • Antifungal activity is not known exactly

Doses

Saturated solution of potassium iodide (SSKI)

Thyroidectomy Graves’ disease

  • Potassium iodide 5-7 drops (0.25-0.35 mL), or saturated solution of potassium iodide (SSKI); 1-2 drops (0.05-0.1 mL) PO TID mixed in water for 10 days prior to surgery should be given

Thyroid storm:

  • 5 drops (0.25 mL or 250 mg) PO every 6 hrs

Note: Do not start until 1 hour after antithyroid drugs

Pipeline Agents

Pending new data.

Physician Resources

1. Tips for Patient Care

  • Educate about importance of drug therapy compliance and surveillance for hyperthyroidism
  • Avoid circumstances leading to stress
  • Educate patient about thyrotoxic crisis
  • Include family or social support in lifestyle modification
  • Appreciate lower starting doses of drugs in elderly, debilitated and pregnant patients
  • Obtain CBC/LFTs before the initiation of medication and during the first 3 months of therapy with thioamides
  • Repeat thyroid test at least once a year after patient become euthyroid
  • Consider concurrent risk factors and disease states with the prescribed therapy
  • Amiodarone and lithium may induce hyperthyroidism
  • Use beta-blockers with caution in patients with asthma and COPD
  • Radioactive iodine (131I) therapy is contraindicated during pregnancy
  • Propylthiouracil remains preferable to methimazole during pregnancy
  • Women of childbearing age with hyperthyroidism should achieve good control prior to conception
  • Cigarette smoking is a risk factor for the development and progression of Graves’ ophthalmopathy
  • Radioactive iodine therapy and thyroidectomy may induce hypothyroidism
  • Usually, it takes 3-4 weeks for patient to be euthyroid after the initiation of therapy
  • Prognosis is good with appropriate treatment

2. Scales and Table

References

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