Hyperthyroidism

Hyperthyroidism Microchapters
Patient Information
Overview
Classification
Differentiating hyperthyroidism from other diseases
Pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Younes M.B.B.CH [2] 'For the WikiDoc patient information for this topic, click here

Overview

Thyroid hormones are responsible for regulating the basal metabolic rate of the body. Over secretion of thyroid hormones can lead to a wide variety of syndromes depending on the cause of the hyperthyroidism. Hyperthyroidism can be due to hyperactivity of the thyroid gland itself (primary hyperthyroidism) or due to abnormalities in the pituitary gland or the hypothalamus causing irregularities in the upper control of the gland. Hyperthyroidism can also be classified according to the results of iodine uptake study into high uptake, high or normal uptake, and low uptake. Hyperthyroidism must be differentiated from other diseases that cause insomnia, anxiety, and hypertension such as pheochromocytoma, generalized anxiety disorder, and essential hypertension. The pathophysiology and the compilation of symptoms and signs differ between the different diseases causing high thyroid activity.

Classification

Thyrotoxicosis is classified along three complementary axes: the mechanism of hormone excess (thyrotoxicosis with versus without hyperthyroidism), the biochemical severity (overt, subclinical, or thyroid storm), and the radioactive iodine uptake (RAIU) pattern. The axes are not interchangeable; applied together they establish etiology and determine whether antithyroid drug therapy is appropriate.

Thyrotoxicosis Versus Hyperthyroidism

• Thyrotoxicosis is the clinical syndrome produced by excess circulating thyroid hormone from any source.
• Hyperthyroidism is the subset of thyrotoxicosis in which the excess arises from increased thyroid hormone synthesis and secretion by the thyroid gland.
• The distinction is treatment-defining: thionamides act by inhibiting hormone synthesis and are therefore ineffective in destructive and exogenous thyrotoxicosis.

Mechanistic Classification

The American Thyroid Association describes four mechanisms of thyrotoxicosis: excessive stimulation by trophic factors, constitutive activation of hormone synthesis, passive release of preformed hormone from a damaged gland, and an extrathyroidal hormone source.

Mechanistic classification of thyrotoxicosis

Category	Mechanism	Representative causes	Typical RAIU
Thyrotoxicosis with hyperthyroidism	Excessive stimulation by trophic factors	Graves disease (TSH-receptor antibodies); gestational thyrotoxicosis and trophoblastic disease (hCG); TSH-producing pituitary adenoma	High or normal
Thyrotoxicosis with hyperthyroidism	Constitutive activation of thyroid hormone synthesis	Toxic adenoma and toxic multinodular goiter (somatic TSH-receptor mutations); familial nonautoimmune hyperthyroidism (germline TSH-receptor mutations)	High or normal
Thyrotoxicosis with hyperthyroidism	Iodine-driven increase in synthesis	Iodine-induced hyperthyroidism (Jod-Basedow); type 1 amiodarone-induced thyrotoxicosis	Low, despite genuine hyperfunction, because the expanded iodine pool dilutes tracer uptake
Thyrotoxicosis without hyperthyroidism — destructive	Passive release of preformed hormone from inflammatory destruction	Subacute thyroiditis (painful); painless thyroiditis; postpartum thyroiditis; radiation thyroiditis; immune checkpoint inhibitor-induced thyroiditis; type 2 amiodarone-induced thyrotoxicosis	Low or absent
Thyrotoxicosis without hyperthyroidism — exogenous or ectopic	Extrathyroidal hormone source	Factitious thyrotoxicosis; iatrogenic levothyroxine overreplacement; struma ovarii; metastatic differentiated thyroid carcinoma	Low or absent

Biochemical Classification

Thyrotoxicosis exists on a continuum of severity that is categorized biochemically.

Biochemical categories of thyrotoxicosis

Category	TSH	Free T4	T3	Comment
Overt hyperthyroidism	Suppressed, usually undetectable	Elevated	Elevated or normal	Elevated free T4 and/or T3 with suppressed TSH
Subclinical hyperthyroidism	Low or suppressed	Normal	Normal	Subclassified as grade 1 (TSH 0.1–0.4 mIU/L), which accounts for 65–75% of cases, and grade 2 (TSH <0.1 mIU/L)
T3 thyrotoxicosis	Suppressed	Normal	Elevated	May represent early or mild Graves disease, or autonomous nodular disease
Thyroid storm	Suppressed	Thyrotoxic range	Thyrotoxic range	A clinical diagnosis of systemic decompensation superimposed on biochemical thyrotoxicosis; hormone concentrations do not define the diagnosis

Subclinical hyperthyroidism should be confirmed with repeat thyroid function testing at 3 to 6 months before the diagnosis is established, to exclude transient TSH suppression. The distinction between endogenous subclinical hyperthyroidism (from autonomous thyroid disease) and exogenous subclinical hyperthyroidism (from levothyroxine overreplacement) is clinically important, as natural history and management differ.

Treatment of grade 1 subclinical hyperthyroidism (TSH 0.1–0.4 mIU/L) is not recommended in asymptomatic patients younger than 65 years without cardiovascular disease or osteoporosis, in whom observation with periodic reassessment is appropriate. Professional organizations generally recommend treatment in persons older than 65 years and in postmenopausal women, particularly when TSH is less than 0.1 mIU/L. Whether symptomatic younger patients, or those with cardiovascular risk factors, warrant intervention at a TSH of 0.1–0.4 mIU/L remains contested.

Assay characteristics, analytical interference, and biochemical patterns by etiology are addressed in Hyperthyroidism laboratory findings.

Classification by Radioactive Iodine Uptake

RAIU pattern is a principal tool for etiologic classification when the cause is not clinically apparent.

Etiologic classification by radioactive iodine uptake pattern

Uptake	Distribution	Representative causes	Note
Elevated	Diffuse	Graves disease	Extensive toxic multinodular goiter can produce a pseudo-diffuse pattern; TRAb negativity helps distinguish
Elevated	Focal, with suppressed surrounding parenchyma	Toxic adenoma
Elevated	Multifocal, alternating areas of increased and suppressed uptake	Toxic multinodular goiter
Low or absent	Not applicable	Thyroiditis of all types; factitious thyrotoxicosis; recent iodine excess (iodinated contrast, amiodarone, dietary); struma ovarii	Low uptake does not equate to thyroiditis
Low or absent despite increased synthesis	Not applicable	Type 1 amiodarone-induced thyrotoxicosis; iodine-induced hyperthyroidism (Jod-Basedow)	Tc-99m sestamibi scintigraphy can aid separation of type 1 from type 2 amiodarone-induced thyrotoxicosis

Etiology may be established by TRAb measurement, RAIU, or thyroid ultrasound with Doppler, depending on local availability and expertise; a thyroid scan is specifically recommended when nodularity is present or suspected. Comparative selection among these strategies is addressed in Differentiating hyperthyroidism from other diseases.

Classification Pitfalls

• Misclassifying destructive thyrotoxicosis as hyperthyroidism. Destructive thyrotoxicosis reflects passive release of preformed hormone rather than increased synthesis; assigning it to the wrong mechanistic category leads to thionamide exposure that cannot alter a self-limited process.
• Assuming that all suppressed TSH represents thyrotoxicosis. Nonthyroidal illness, pituitary or hypothalamic disease, and medications such as glucocorticoids and dopamine suppress TSH without thyrotoxicosis.
• Interpreting RAIU without an iodine exposure history. Recent iodinated contrast or amiodarone suppresses uptake even in genuine Graves disease or toxic nodular disease.
• Overlooking the total T3:T4 ratio. A total T3:T4 ratio (ng/μg) greater than 20 favors Graves disease or toxic nodular goiter, whereas a ratio less than 20 suggests destructive thyroiditis or factitious thyrotoxicosis from levothyroxine, in which the T4-predominant stored hormone pool is released.
• Underrecognizing subclinical hyperthyroidism in older adults. In patients older than 65 years, TSH less than 0.1 mIU/L is associated with significantly increased risk of atrial fibrillation, heart failure, fractures, and dementia.

Differentiating hyperthyroidism from other diseases

Hyperthyroidism must be differentiated from other diseases that cause anxiety, elevated blood pressure, and insomnia; such as essential hypertension, generalized anxiety disorder, and pheochromocytoma.

Disease	Prominent clinical features	Investigations
Hyperthyroidism	The main symptoms include: Palpitations Insomnia Anxiety Weight loss Heat intolerance Diarrhea Depending on the underlying diagnosis, the patient might have exophthalmos or goiter	The patient usually has elevated T3 and T4 TSH might be increased or decreased depending on the underlying cause Thyroid stimulating antibodies (TSI) might be increased in cases of Graves’ disease
Essential hypertension	Most patients with hypertension are asymptomatic at the time of diagnosis. Common symptoms are listed below: Headache Blurry vision Dyspnea Epistaxis Tinnitus Fatigue Drowsiness	The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7 express) recommends the following routine laboratory tests before initiation of therapy for hypertension: 12-Lead electrocardiogram (ECG) Urinalysis, including urinary albumin excretion or albumin/creatinine ratio Blood glucose Blood hematocrit Serum electrolytes, especially potassium Serum calcium Lipid profile: Total cholesterol, LDL, HDL, triglycerides Creatinine or estimated GFR
Generalized anxiety disorder	According to DSM V, the following criteria should be present to fit the diagnosis of generalized anxiety disorder: The presence of sense of apprehension or fear toward certain activities for most of the days for at least 6 months Difficulty to control the apprehension Associated restless, fatigue, irritability, difficulty concentration, muscle tension or sleep disturbance (only one of these manifestations) The anxiety or the physical manifestations must affect the social and the daily life of the patient Exclusion of another medical condition or the effect of another administered substance Exclusion of another mental disorder causing the symptoms	-
Menopause	The perimenopausal symptoms are caused by an overall drop, as well as dramatic but erratic fluctuations, in the levels of estrogens, progestin, and testosterone. Some of these symptoms such as formication etc may be associated with the hormone withdrawal process. Vasomotor instability in the form of hot flushes, including night sweats and sleep disturbances Urogenital atrophy causing itching, dryness, bleeding, watery discharge, urinary frequency, urinary urgency, and urinary incontinence Skeletal symptoms in the form of osteoporosis (gradually developing over time), artharlgia, myalgia, and back pain Psychological manifestations such as mood disturbance, irritability, fatigue, memory loss and depression Sexual disorders: Decreased libido, vaginal dryness, problems reaching orgasm and dyspareunia	B-HCG should always be done first to rule out pregnancy, especially in women under the age of 45 years. FSH can be measured but it can be falsely normal or low. TSH, T3, and T4 should be assessed to rule out thyroid abnormalities. Prolactin can be measured to rule out prolactinoma, as a cause of menopause.
Opioid withdrawal disorder	According to DSM V, the following criteria should be present to fit the diagnosis of opioid withdrawal: Cessation of (or reduction in) opioid use that has been heavy and prolonged (i.e., several weeks or longer) or administration of an opioid antagonist after a period of opioid use. Development of three or more of the following criteria minutes to days after cessation of drug use: Dysphoric mood, nausea or vomiting, muscle aches, Lacrimation or rhinorrhea, pupillary dilation, piloerection, or sweating, diarrhea, yawning, fever, and insomnia. The signs or symptoms mentioned above must cause impairment of the daily functioning of the patient. The signs or symptoms mentioned above must not be attributed to other medical or mental disorders.	Urine drug screen to rule out any other associated drug abuse Routine blood work such as electrolytes and hemoglobin to rule out any associated disease explaining the symptoms
Pheochromocytoma	The hallmark symptoms of a pheochromocytoma are those of sympathetic nervous system hyperactivity, symptoms usually subside in less than one hour and they may include: Palpitations, especially in epinephrine producing tumors Anxiety often resembling that of a panic attack Sweating Headaches occur in 90 % of patients. Paroxysmal attacks of hypertension, but some patients have normal blood pressure It may be asymptomatic and discovered by incidence screening especially MEN patients Please note that not all patients with pheochromocytoma experience all classical symptoms.	Diagnostic lab findings associated with pheochromocytoma include: Elevated plasma, urinary catecholamines, and metanephrines Elevated urinary vanillyl mandelic acid

Differentiating the causes of thyrotoxicosis

Cause of thyrotoxicosis	TSH receptor antibodies	Thyroid US	Color flow Doppler	Radioactive iodine uptake/Scan	Other features
Graves' disease	+	Hypoechoic pattern	↑	↑	Ophthalmopathy, dermopathy, acropachy
Toxic nodular goiter	-	Multiple nodules	-	Hot nodules at thyroid scan	-
Toxic adenoma	-	Single nodule	-	Hot nodule	-
Subacute thyroiditis	-	Heterogeneous hypoechoic areas	Reduced/absent flow	↓	Neck pain, fever, and elevated inflammatory index
Painless thyroiditis	-	Hypoechoic pattern	Reduced/absent flow	↓	-
Amiodarone induced thyroiditis-Type 1	-	Diffuse or nodular goiter	↓/Normal/↑	↓ but higher than in Type 2	High urinary iodine
Amiodarone induced thyroiditis-Type 2	-	Normal	Absent	↓/absent	High urinary iodine
Central hyperthyroidism	-	Diffuse or nodular goiter	Normal/↑	↑	Inappropriately normal or high TSH
Trophoblastic disease	-	Diffuse or nodular goiter	Normal/↑	↑	-
Factitious thyrotoxicosis	-	Variable	Reduced/absent flow	↓	↓ Serum thyroglobulin
Struma ovarii	-	Variable	Reduced/absent flow	↓	Abdominal RAIU

Prominent features in the different causes of hyperthyroidism

Disease		Findings
Thyroiditis	Direct chemical toxicity with inflammation	Amiodarone, sunitinib, pazopanib, axitinib, and other tyrosine kinase inhibitors may also be associated with a destructive thyroiditis.
	Radiation thyroiditis	Patients treated with radioiodine may develop thyroid pain and tenderness 5 to 10 days later, due to radiation-induced injury and necrosis of thyroid follicular cells and associated inflammation.
	Drugs that interfere with the immune system	Interferon-alfa is a well-known cause of thyroid abnormality. It mostly leads to the development of de novo antithyroid antibodies.
	Lithium	Patients treated with lithium are at a high risk of developing painless thyroiditis and Graves' disease.
	Palpation thyroiditis	Manipulation of the thyroid gland during thyroid biopsy or neck surgery and vigorous palpation during the physical examination may cause transient hyperthyroidism.
Exogenous and ectopic hyperthyroidism	Factitious ingestion of thyroid hormone	The diagnosis is based on the clinical features, laboratory findings, and 24-hour radioiodine uptake.
	Acute hyperthyroidism from a levothyroxine overdose	The diagnosis is based on the clinical features, laboratory findings, and 24-hour radioiodine uptake.
	Struma ovarii	Functioning thyroid tissue is present in an ovarian neoplasm.
	Functional thyroid cancer metastases	Large bony metastases from widely metastatic follicular thyroid cancer cause symptomatic hyperthyroidism.
Hashitoxicosis		It is an autoimmune thyroid disease that initially presents with hyperthyroidism and a high radioiodine uptake caused by TSH-receptor antibodies similar to Graves' disease. It is then followed by the development of hypothyroidism due to the infiltration of the thyroid gland with lymphocytes and the resultant autoimmune-mediated destruction of thyroid tissue, similar to chronic lymphocytic thyroiditis.
Toxic adenoma and toxic multinodular goiter		Toxic adenoma and toxic multinodular goiter are results of focal/diffuse hyperplasia of thyroid follicular cells independent of TSH regulation. Findings of single or multiple nodules are seen on physical examination or thyroid scan.
Iodine-induced hyperthyroidism		It is uncommon but can develop after an iodine load, such as administration of contrast agents used for angiography or computed tomography (CT), or iodine-rich drugs such as amiodarone.
Trophoblastic disease and germ cell tumors		Thyroid-stimulating hormone and HCG have a common alpha-subunit and a beta-subunit with considerable homology. As a result, HCG has weak thyroid-stimulating activity and high titer HCG may mimic hyperthyroidism.

Pathophysiology

Rgulation of thyroxin secretion - By CFCF; slightly modified by Geo-Science-International - This file was derived from Thyroid vector.svg:, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=47043638

• Thyroid hormones (T3 and T4) are regulating basal metabolic rate, influence oxygen consumption by tissues. They are crucial for normal development of the brain and growth of the body, especially in prepubertal period.
• Secretion of thyroid hormones follows upper control from the hypothalamus and the pituitary. Thyroid releasing hormone (TRH) acts on thyrotropes releasing cells in the pituitary causing them to release thyroid stimulating hormone (TSH).
• TSH acts on thyroid gland by binding to specific membrane receptors and activating an intracellular pathway involving cAMP that ends in the formation and secretion of thyroid hormones.
• Iodine is essential for the synthesis of thyroid hormones. The daily iodide need is about 100 mcg/day. Iodide is up taken through a special Na/I transporter found in the membrane of thyroid follicular cell. After the iodide uptake, it goes through a series of organic reactions ending in the formation of the two forms of thyroid hormones: T3 and T4. T3 and T4 remain stored in the thyroglobulin of the follicles and are released in response to further stimulation by TSH to the thyroid follicles.
• While T3 is 3 to 5 times more potent than T4, it represents only one-fourth of the total hormone secretion. T3 is thought to be the biologically active form of the of the two forms of the hormone. Most of the circulating T3 is due to peripheral conversion of T4 in the liver and peripheral tissues while only a small percentage is secreted directly from the thyroid gland itself.
• T3 and T4 act on nuclear receptors (DNA binding proteins) and cause the regulate the transcription of many proteins to regulate the metabolic rate of the body.
• The higher regulation of thyroxine secretion follows the negative feedback role, meaning that high levels of T3 and T4 will suppress TRH and TSH secretion and vice versa (Low levels of thyroxine will stimulate TRH and TSH secretion). This is useful in diagnosing the cause of hyperthyroidism (in secondary hyperthyroidism, where the pituitary or the hypothalamus are the sources of the disease, TSH will be high; while in primary hyperthyroidism where the gland is the source of the excess hormones, TSH will be low).
• Graves' disease which is the most common cause of hyperthyroidism lies in the secretion of thyroid stimulating antibodies (TSI) that work on thyroid follicular cells causing an excessive uncontrolled release of the thyroxine. TSI responsible for many other aspects of the disease such as ophthalmopathy and the skin manifestations. This is thought to be due to the epitopic similarity between antigens on the surface of these cells and the thyroid receptors.
• Toxic nodular goiter involves the growth of a various number of nodules (ranging from one to tens). These nodules either bleed and undergo degeneration and fibrosis followed by calcification or they might have autonomous activity producing excess thyroxin.
• The majority of circulating T3 and T4 are bound to plasma proteins and thus not active (T4 is mostly bound to thyroxine binding globulin and T3 is mostly bound to transthyretin). Conditions that impair the production of thyroid binding globulins (such as pregnancy, liver failure, and certain drug administration) cause a change in the total serum thyroxine but the free T3 and T4 remain normal and the patient remain (this carries only laboratory significance).