creation date: 2025-07-01 23:02
tags: Pathologies
Hyperthyroidism
Background
Definitions
Hyperthyroidism is a thyroid disorder characterized by excess thyroid hormone production.
Primary hyperthyroidism: thyroid gland overproduces T3/T4 (TSH suppression by feedback)
Secondary hyperthyroidism: pituitary gland (overproduces TSH, overstimulating T3/T4 secretion)
Overt hyperthyroidism: low or suppressed TSH with elevated T3 and/or elevated T4
Subclinical hyperthyroidism: low or suppressed TSH with normal levels of T3 and T4
Thyrotoxicosis is often used interchangeably but actually refers to excess thyroid hormone exposure to tissues. Hyperthyroidism can lead to thyrotoxicosis.
Etiology
The three most common causes of hyperthyroidism are:
- Graves disease
- Toxic multinodular goiter
- Toxic adenoma
Other less common causes include:
- Iodine-induced hyperthyroidism
- TSH-secreting pituitary adenomas
- Conditions relating to high hCG levels
- Choriocarcinomas and hydatiform moles in females
- Germ cell tumours in males
- Ectopic thyroid in struma ovarii
- Extensive metastasis from functionally differentiated thyroid carcinoma
- Drug-induced thyroiditis
- Amiodarone
- Lithium
- Tyrosine kinase inhibitors
- Interferon-alpha
- Immune checkpoint inhibitor therapy
- Other thyroiditis
- Hashitoxicosis
- Painless thyroiditis
- Painful subacute thyroiditis
- Suppurative thyroiditis
- Riedel thyroiditis
- Factitious thyroiditis
Pathogenesis
Pathophysiology of hyperthyroidism depends on the etiology and variant. Common etiologies are briefly discussed here.
Graves disease
- Autoimmune process with antibodies against TSH receptor
- Antibodies stimulate TSH receptor causing production of T3 and T4
- Trophic effect leads to thyroid growth
Toxic multinodular goiter (TMNG) - Initial phase of development of nodules (years)
- Mutations to TSH receptor causes constitutive activation of cAMP pathway resulting in thyroid autonomy (production without need for TSH)
- Larger nodules correlated to development of hyperthyroidism
Toxic adenoma - Like TMNG but with solitary nodule
Iodine-induced hyperthyroidism (Jod-Basedow Phenomenon) - Typically iatrogenic due to excessive iodine intake through diet or iodine-containing medication (eg. contrast media or amiodarone)
- Normally, organification of iodine is self-regulating (Wolff-Chaikoff effect) but in the Jod-Basedow phenomenon (pre-existing thyroid disease), excess thyroid hormone is produced when there is excess iodine
Amiodarone-induced thyroiditis (risk if use >24 hr)
Type 1: - Thyroid hormone production secondary to excess iodine exposure from amiodarone in the setting of pre-existing thyroid disease (Jod-Basedow)
- Pre-existing disease usually latent Graves or TMNG
Type 2: - Destructive thyroiditis due to direct toxic effect of amiodarone on the thyroid follicular cells
Thyroiditis - Inflammation or destruction of the thyroid follicular cells
- Results in transient increase in circulating thyroid hormones
- Clinical manifestation varies based on etiology of thyroiditis
- Typically occurs over several weeks before depleting and hypothyroid phase begins
In the case of factitious thyroiditis, exogenous thyroid hormone is in circulation whether unintentional (due to accidental overuse) or intentional (as the side effect of weight lost creates potential for abuse).
Clinical Presentation
Signs & Symptoms
Overt hyperthyroidism typically have a dramatic constellation of symptoms. The classic ones include:
- Heat intolerance
- Tremor
- Palpitations
- Anxiety
- Weight loss despite normal or increased appetite
- Increased frequency of bowel movements
- Shortness of breath
Specific findings by organ systems:
Skin
- Warm and sometimes erythematous (increased blood flow)
- Smooth (decrease in keratin layer)
- Sweating
- Onycholysis
- Hyperpigmentation
- Pruritis and hives (primarily with Graves disease)
- Vitiligo and alopecia areata (associated with autoimmune disorders)
- Infiltrative dermopathy (pretibial myxedema; Graves disease only)
Eyes - Stare sign and lid lag (due to sympathetic overactivity)
- Thyroid eye disease (Graves disease only)
- Inflammation of extraocular muscles and orbital fat
- Manifest as proptosis, impaired eye muscle function, and periorbital and conjunctival edema
Cardiovascular
- Increased cardiac output (increased contractility and increased peripheral oxygen demands)
- Elevated heart rate
- Pulse pressure widened
- Decreased peripheral vascular resistance
- Systolic hypertension is common
- Atrial fibrillation
Metabolic/endocrine - Bone resorption causing increased porosity of cortical bone and reduced volume of trabecular bone
- Low serum total and HDL cholesterol
- Hyperglycemia due to antagonism of insulin action (although insulin secretion is increased as well to a lesser extent)
- Lower total serum cortisol (can be misleading of ACTH stimulation testing)
- Altered estradiol and LH levels can result in amenorrhea in women
- Conversion of testosterone to estradiol can result in gynecomastia, reduced libido, and erectile dysfunction in men
Respiratory - Increased ventilation due to increased oxygen consumption and CO2 production
- Respiratory muscle weakness and decreased lung volume
- Tracheal obstruction if goiter large
- Exacerbation of underlying asthma
Gastrointestinal - Increased gut motility (and associated hyperdefecation and malabsorption)
- Hyperphagia (some patients have sufficient appetite to gain weight)
- Anorexia may be present for older patients
Thymic enlargement - Hyperplasia only with Graves disease
Hematologic - RBC mass increased and plasma volume increased more
- Results in normochromic, normocytic anemia
- Excess of thyroid hormone can also be prothrombotic
Genitourinary - Urinary frequency
- Nocturia
Neuropsychiatric - Thyrotoxicosis may cause behavioural changes such as psychosis, agitation, depression
- Insomnia
- Cognitive impairments such as impaired concentration, confusion, etc.
History & Physical Exam
Symptoms are often nonspecific and can vary in severity and combination. While severe forms of hyperthyroidism will often have a dramatic constellation, milder forms may present with one or few symptoms.
Conditions that may suggest the possibility of underlying hyperthyroidism include:
- Osteoporosis
- Hypercalcemia
- Heart failure
- PACs
- Shortness of breath
- Deterioration of glycemia in diabetic patients
Physical examination may find any of the features of hyperthyroidism as listed above. A thyroid exam may reveal a goiter and/or nodules.
Risk factors
Diagnosis
Criteria
Diagnosis of hyperthyroidism is based on thyroid function tests. A serum TSH, free T4, and T3 should be ordered.
Overt hyperthyroidism:
- Low TSH
- Elevated T3 and/or free T4
T3-toxicosis: - Low TSH
- High T3
- Normal free T4
T4-toxicosis: - Low TSH
- High free T4
- Normal T3
Subclinical hyperthyroidism:
- Low TSH
- Normal free T4, T3, and free T3
TSH-mediated hyperthyroidism
- Normal or high TSH (due to TSH-secreting pituitary adenoma or resistance to feedback effect such as T3-receptor defect)
- High free T4 and T3
Note, in critically ill hyperthyroid patients, serum T4 and T3 may be normal or evne low due to a decrease in protein-binding of T4.
Work-up
The approach following diagnosis is to determine the etiology.
If the presentation is obvious for Graves disease:
- New onset thyroid eye disease
- Large non-nodular thyroid
- Moderate to severe hyperthyroidism
it can be presumed to be Graves disease and the workup is complete.
If presentation is not obvious but goiter is not nodular, further assessed using an third generation assay for thyrotropin receptor antibodies (TRAb), which is sensitive (97%) and specific (99%) for Graves disease causing overt hyperthyroidism (may not be as specific in mild cases).
In cases of a nodular goiter or if TRAb is negative, a radioiodine uptake (RAIU) test (scintigraphy) can be done. Note that pregnancy and breastfeeding are absolute contraindications.
- High or normal radioiodine uptake indicates de novo synthesis such as with Graves disease (diffuse update), TMNG (patchy uptake), toxic adenoma (focal uptake at location of nodule)
- Low or absent radioiodine uptake indicates inflammation/destruction of thyroid tissue (and thus hyperthyroidism due to release of preformed hormone) or extrathyroidal source of thyroid hormone
If TRAb is negative and RAIU is not preferred/contraindicated and quantitative Doppler ultrasound is available, an assessment of thyroidal artery blood flow may be sufficient.
- High flow suggests Graves disease
- Low flow suggests thyroiditis
- Normal flow can be inconclusive but Graves disease is more likely
The workup is also visualized as a diagnosis algorithm.
Differential
Euthyroid hyperthyroxinemia: abnormalities with serum thyroid hormone-bidning protein gives the appearance of high T4 and normal T3. TSH is normal in these patients.
A number of conditions can cause low serum TSH without hyperthyroidism (in addition to subclinical hyperthyroidism):
- Central hypothyroidism
- Nonthyroidal illness, especially those using high-dose glucocorticoids or dopamine
- Recovery from hyperthyroidism (can take several months to normalize)
- Physiologic lowering of TSH during pregnancy
- Altered set point of HPT axis in otherwise healthy older person
Red Flags / Complications
Untreated hyperthyroidism can result in extreme case of hyperthyroidism known as thyroid storm. This is a potentially fatal complication and manifests as with severe symptoms.
Chronic hyperthyroidism is also associated with:
- Increased risk of cardiovascular events and ischemic stroke
- Arrythmias
- Osteoporosis
- Hip fractures
- Overall mortality
Management
Treatment of hyperthyroidism consist of symptom management and definitive therapy. Management depends on the etiology of hyperthyroidism - discussed here are for the most common causes: Graves disease, TMNG, and toxic adenoma.
Symptom management
For palpitations, anxiety, tremors, and other common symptoms:
- Beta blockers
- Calcium channel blockers (2nd line)
Definitive therapy
The first choice therapy are anti-thyroid drugs (thioamides) which function as competitive inhibitors of thyroid peroxidase (oxidation of iodide ions) and thus blocks thyroid hormone synthesis. They also have immunosuppressive effects and can induce remission in Graves disease.
- Methimazole PO once daily
- Free T4 1-1.5x upper limit of normal: 5-10mg daily
- Free T4 1.5-2x upper limit of normal: 10-20mg daily
- Free T4 2-3x upper limit of normal: 30-40mg daily
- Propylthiouracil PO BID or TID (due to shorter duration of action)
Free T4 and/or total T3 should be assessed every 4-6 weeks. Side effects include agranulocytosis and aplastic anemia so baseline and follow-up CBC are recommended.
Drugs should be continued for 12-18 months and TRAb assessed for remission of Graves disease. For toxic nodular goiter, ATDs can be used initially but radioactive iodine or surgery are preferred for long-term management.
Radioactive iodine (RAI) are used for patients which can’t use ATDs but should be avoiding in pregnant or planned to be pregnant patients and patients with Graves orbitopathy. Dosing depends on etiology but is typically a single dose.
Surgery is indicated for:
- Planned to be pregnant women in next 6 months
- Presence of Graves orbitopathy
- Patients with significant adverse effect to other treatment
- Suspicion of thyroid malignancy
- Presence of large compressive goiters
- Presence of coexisting hyperparathyroidism that also needs surgery
and vary based on the etiology. This ranges from near-total or total thyroidectomy for Graves disease or TMNG to ipsilateral thyroid lobectomy or isthmusectomy for toxic adenoma.