Pathophysiology of Thyroid Disorders
PHCL 415Hadeel Alkofide
April 2010
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Learning Objectives
• Understand the pathophysiology of hyperthyroidism & hypothyroidism
• Describe the signs & symptoms of hyperthyroidism & hypothyroidism
• Outline the changes seen in thyroid function tests (free and total triiodothyronine [T3] & thyroxine [T4], force-time integral [FTI] & thyroid-stimulating hormone [TSH]) & the radioactive iodine uptake (RAIU) scan in hyperthyroidism & hypothyroidism
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Outline
• Introduction
• Epidemiology
• Causes/Classification
• Pathophysiology
• Manifestations (signs & symptoms)
• Diagnosis
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Introduction
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Introduction
• Thyroid Physiology
• The difference between T3 & T4
• Common thyroid disorders
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Thyroid Physiology
• The thyroid gland synthesizes the hormones thyroxine (T4) & triiodothyronine (T3), iodine-containing amino acids that regulate the body's metabolic rate
• Adequate levels of thyroid hormone are necessary:
Infants for normal development of the CNS
Children for normal skeletal growth & maturation
Adults for normal function of multiple organ systems
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Thyroid Physiology
• Triiodothyronine (T3) & thyroxine (T4) are the two biologically active thyroid hormones produced by the thyroid gland in response to hormones released by the pituitary & hypothalamus
• The hypothalamic thyrotropin-releasing hormone (TRH) stimulates release of thyroid-stimulating hormone [TSH]) from the pituitary in response to low circulating levels of thyroid hormone
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Thyroid Physiology
• TSH promotes hormone synthesis & release by increasing thyroid activity
• When sufficient synthesis has occurred, high circulating thyroid hormone levels block further production by inhibiting TSH release
• As the serum concentrations of thyroid hormone decrease, the hypothalamic-pituitary centers again become responsive by releasing TRH & TSH
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Thyroid Physiology
• T3 is 4 times more potent than T4, but its serum concentration is lower
• T4 is the major circulating hormone secreted by the thyroid
• About 80% of the total daily T3 production results from the peripheral conversion of T4 to T3 through deiodination of T4
• Certain drugs & diseases can modify the conversion rate of T4 to T3 and decrease the serum T3 levels
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Thyroid Physiology
• T3 & T4 exist in the circulation in free (active) & protein-bound (inactive) forms
• About 99.97% of circulating T4 is bound, only 0.03% exists as the free form
• This affinity for plasma proteins accounts for T4's slow metabolic degradation & long half-life of 7 days
• In contrast, T3 is considerably less strongly bound to plasma proteins
• The lower protein-binding affinity of T3 accounts for its threefold greater potency & shorter half-life of 1.5 days
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Thyroid Physiology
Common Thyroid Disorders
• Hypothyroidism: clinical syndrome that results from a deficiency of thyroid hormone
• Hyperthyroidism: or thyrotoxicosis is the hypermetabolic syndrome that occurs when the production of thyroid hormone is excessive
• Goiter: Diffuse thyroid enlargement most commonly results from prolonged stimulation by TSH
• Thyroid nodules & neoplasms
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Epidemiology
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Epidemiology
• General
• Hypothyroidism
• Hyperthyroidism
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Epidemiology
• Thyroid disease is common, affecting approximately 5% to 15% of the general population
• Females are 3-4 times more likely than males to develop any type of thyroid disease
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Hypothyroidism
• The prevalence of hypothyroidism is 1.4% to 2% in females and 0.1% to 0.2% in males
• The incidence increases in persons older than 60 years to 6% of women & 2.5% of men
• Hypothyroidism can be caused by either primary (thyroid gland) or secondary (hypothalamic-pituitary) malfunction
• Primary hypothyroidism is more common than secondary causes
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Hyperthyroidism
• Hyperthyroidism affects about 2% of females & about 0.1% of males
• The prevalence of hyperthyroidism in older patients varies between 0.5% & 2.3%
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Causes
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Hypothyroidism
Etiologic Classification Pathogenetic Mechanism
CongenitalAplasia or hypoplasia of thyroid gland
Defects in hormone biosynthesis or action
Acquired
Hashimoto's thyroiditis Autoimmune destruction
Severe iodine deficiency Diminished hormone synthesis, release
Lymphocytic thyroiditis Diminished hormone synthesis, release
Thyroid ablation
Diminished hormone synthesis, release
Thyroid surgery131 I radiation treatment of hyperthyroidism
External beam radiation therapy of head & neck cancer
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Causes
Hypothyroidism
Etiologic Classification Pathogenetic Mechanism
Acquired
Drugs
Diminished hormone synthesis, release
Iodine, inorganic
Iodine, organic (amiodarone)
Thioamides (propylthiouracil,methimazole)
Potassium perchlorate
Thiocyanate
Lithium
Amiodarone
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Causes
Hypothyroidism
Etiologic Classification Pathogenetic Mechanism
Acquired
Hypopituitarism Deficient TSH secretion
Hypothalamic disease Deficient TRH secretion
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Causes
Hypothyroidism
• Hashimoto's thyroiditis, an autoimmune disorder, is the most common cause of primary hypothyroidism & appears to have a strong genetic
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Causes
Hyperthyroidism
Etiologic Classification Pathogenetic Mechanism
Thyroid hormone overproduction
Graves' diseaseThyroid-stimulating hormone receptor-stimulating antibody (TSH-R [stim] Ab)
Toxic multinodular goiter Autonomous hyperfunction
Follicular adenoma Autonomous hyperfunction
Pituitary adenoma TSH hypersecretion (rare)
Pituitary insensitivity Resistance to thyroid hormone (rare)
Hypothalamic disease Excess TRH production
Germ cell tumors: choriocarcinoma, hydatidiform mole
Human chorionic gonadotropin stimulation
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Causes
Hyperthyroidism
Etiologic Classification Pathogenetic Mechanism
Thyroid gland destruction
Lymphocytic thyroiditis Release of stored hormone
Granulomatous (subacute) thyroiditis Release of stored hormone
Hashimoto's thyroiditis Transient release of stored hormone
Drug effect
Thyrotoxicosis medicamentosa, thyrotoxicosis factitia
Ingestion of excessive exogenous thyroid hormone
Amiodarone Excess iodine &/or thyroiditis
Interferon alpha Thyroiditis
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Causes
Hyperthyroidism
• Graves' disease is the most common cause of hyperthyroidism
• Toxic autonomous nodular goiters, both multi- and uninodular, account for a large proportion of the remaining causes
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Causes
Pathophysiology
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Pathophysiology
• Hypothyroidism
Hashimoto's Thyroiditis
• Hypothyroidism
Graves' Disease
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Hypothyroidism
• Hypothyroidism is characterized by abnormally low serum T4 & T3 levels
• Free thyroxine levels are always depressed
• The serum TSH level is elevated in hypothyroidism (except in cases of pituitary or hypothalamic disease)
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Pathophysiology
Hashimoto's Thyroiditis
• In the early stages of Hashimoto's thyroiditis, the gland is diffusely enlarged, firm, rubbery, & nodular
• As the disease progresses, the gland becomes smaller
• In the late stages, the gland is atrophic & fibrotic, weighing as little as 10–20 g
• Microscopically, there is destruction of thyroid follicles & lymphocytic infiltration with lymphoid follicles
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Pathophysiology
Hashimoto's Thyroiditis
• Autoimmune disease
• The pathogenesis of Hashimoto's thyroiditis results from an impaired immune surveillance, causing dysfunction of normal “suppressor” T lymphocytes & excessive production of thyroid antibodies by plasma cells
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Pathophysiology
Hashimoto's Thyroiditis
• The destruction of thyroid cells by circulating thyroid antibodies produces an underlying defect or block in the intrathyroidal, organo-binding of iodide
• As a result, inactive hormones or insufficient amounts of active hormones are synthesized, & this eventually produces hypothyroidism
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Pathophysiology
Hashimoto's Thyroiditis
• The clinical presentation of Hashimoto's thyroiditis can be variable, depending on the time of diagnosis:
The typical presentation is hypothyroidism & goiter (thyroid gland enlargement)
Patients can present with hypothyroidism & no goiter
Euthyroidism & goiter
Rarely (<5%) with hyperthyroidism (Hashi-toxicosis)
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Pathophysiology
Hyperthyroidism
• Whatever the cause of hyperthyroidism, serum thyroid hormones are elevated
• Both the free thyroxine (FT4) & the free thyroxine index (FT4I) are elevated
• In 5–10% of patients, T4 secretion is normal while T3 levels are high (so-called T3 toxicosis)
• Total serum T4 & T3 levels are not always definitive because of variations in concentrations of thyroid hormone–binding proteins
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Pathophysiology
Graves' Disease
• Graves' disease is the most common cause of hyperthyroidism
• The thyroid gland is symmetrically enlarged
• The gland may double or triple in weight
• Microscopically, the follicular epithelial cells are columnar in appearance and increased in number & size
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Pathophysiology
Graves' Disease
• Graves' disease is an autoimmune disorder
• Characterized by one or more of the following features:
Hyperthyroidism
Diffuse goiter
Ophthalmopathy (exophthalmos)
Dermopathy (pretibial myxedema)
Acropachy (thickening of fingers or toes)
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Pathophysiology
Graves' Disease
• The production of excessive quantities of thyroid hormone is attributed to a circulating IgG or thyroid receptor antibody (TRAb), which has a TSH-like ability to stimulate hormone synthesis
• The peak incidence of Graves' disease occurs in the third or fourth decade of life, the duration of the disease is unknown, & its clinical course is characterized by remission & relapse
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Pathophysiology
Graves' Disease
• Patients with hyperthyroidism from Graves' disease may later develop hypothyroidism by one of several mechanisms
1. Thyroid ablation by surgery or 131 I radiation treatment
2. Autoimmune thyroiditis, leading to thyroid destruction
3. Development of antibodies that block TSH stimulation (TSH-R [block] Ab)
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Pathophysiology
Manifestations
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Clinical Manifestations
• Hypothyroidism
Symptoms
Signs
Long term complication (Myxedema Coma)
• Hyperthyroidism
Symptoms
Signs
Thyroid storm39
Manifestations
Hypothyroidism
Symptoms
Slow thinking
Lethargy, decreased vigor
Dry skin; thickened hair; hair loss; broken nails
Diminished food intake; weight gain
Constipation
Menorrhagia; diminished libido
Cold intolerance
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Manifestations
Hypothyroidism
Signs
Round puffy face; slow speech; hoarseness
Hypokinesia; generalized muscle weakness; delayed relaxation of deep tendon reflexes
Cold, dry, thick, scaling skin; dry, coarse, brittle hair; dry, longitudinally ridged nails
Periorbital edema
Ascites; pericardial effusion; ankle edema
Mental depression
Anemia
Decreased metabolic rate41
Manifestations
Hypothyroidism
Signs
Bradycardia (↓ HR)
Hypertension
Goiter (primary hypothyroidism)
Thickening of tongue
Thinning of outer eyebrows
Yellowing of skin
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Manifestations
Hypothyroidism
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Manifestations
Myxedema Coma
• The end stage of long-standing, uncorrected hypothyroidism
• The classic features are hypothermia, delayed DTRs, & may reach to coma
• Other predominant features include hypoxia, carbon dioxide retention, severe hypoglycemia, hyponatremia, & paranoid psychosis
Hypothyroidism
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Manifestations
Myxedema Coma
• Precipitating factors include cold weather or hypothermia, stress (e.g., surgery, infection, trauma), coexisting disease states such as MI, diabetes, hypoglycemia, or fluid & electrolyte abnormalities (especially hyponatremia), & medications such as sedatives, narcotic analgesics, antidepressants, & other respiratory depressants & diuretics
• Mortality rates of 60% to 70% despite treatment
Hyperthyroidism
Symptoms
Alertness, nervousness, irritability, tremors
Poor concentration
Muscular weakness, fatigability
Palpitations
Voracious appetite, weight loss
Hyperdefecation (increased frequency of bowel movements)
Heat intolerance
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Manifestations
Hyperthyroidism
Signs
Hyperkinesia, rapid speech
Proximal muscle (quadriceps) weakness, fine tremor
Fine, moist skin; fine, abundant hair; onycholysis
Lid lag, stare, chemosis, periorbital edema, proptosis
Accentuated first heart sound, tachycardia, atrial fibrillation (resistant to digitalis), widened pulse pressure, dyspnea
Increased metabolic rate
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Manifestations
Hyperthyroidism
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Manifestations
Thyroid Storm
• The clinical manifestations of thyroid storm include acute onset of high fever, hyperglycemia & involvement of the following organ systems:
Cardiovascular (tachycardia, pulmonary edema, hypertension, shock)
CNS (tremor, emotional lability, confusion, psychosis, apathy, stupor, coma)
GI (diarrhea, abdominal pain, nausea & vomiting, liver enlargement, jaundice, elevations of bilirubin & PT)
Hyperthyroidism
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Manifestations
Thyroid Storm
• Thyroid storm develops in about 2% to 8% of hyperthyroid patients
• The pathogenesis of thyroid storm is not well understood, but the condition can be described as an “exaggerated” or decompensated form of thyrotoxicosis
• Decompensated means failure of body systems to adequately resist the effects of thyrotoxicosis
Diagnosis
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Diagnosis
• Thyroid Function Tests
• How to diagnose Hypothyroidism & Hyperthyroidism?
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Diagnosis
Thyroid Function Tests
• The principal laboratory tests recommended in the initial evaluation of thyroid disorders are:
TSH
FT4
• Positive thyroid antibodies indicate an autoimmune thyroid etiology
• Other tests: total T3 (TT3), free T3 (FT3) or FT3 index (FT3I), RAIU & scan, TRAb, ultrasound, & FNA biopsy
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Diagnosis
Thyroid Function Tests
• Free & Total Serum Hormone Levels
• Tests of the Hypothalamic-Pituitary-Thyroid Axis
• Tests of Gland Function
• Tests of Autoimmunity
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Diagnosis
Free & Total Hormone Levels
Free Thyroxine, Free Thyroxine Index, Free Triiodothyronine, & Free Triiodothyronine Index
• The FT4 & FT3 are the most reliable tests for the evaluation of hormone concentrations
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Diagnosis
Free & Total Hormone Levels
Total Thyroxine & Total Triiodothyronine
• TT4 & TT3 measure both free & bound (total) serum T4 & T3
• Because the bound fraction is the major fraction measured, situations that change the hormone's affinity for TBG or the TBG level will influence the results
• E.g. falsely elevated levels of TT4 & TT3 are common in the euthyroid pregnant woman
• TT3 can be low in older patients & nonthyroidal illnesses because the peripheral conversion of T4 to T3 is decreased
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Diagnosis
Free & Total Hormone Levels
Total Thyroxine & Total Triiodothyronine
• Careful interpretation of these tests is necessary
• TT3 is particularly helpful in detecting early relapse of Graves' disease & in confirming the diagnosis of hyperthyroidism despite normal TT4 levels
• The TT3 is not a good indicator of hypothyroidism because TT3 can be normal
• Measurement of only the total hormone levels is less reliable than either the free hormone
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Diagnosis
Tests of Hypothalamic-Pituitary-Thyroid Axis
Thyroid Stimulating Hormone (TSH)
• The serum TSH or thyrotropin is the most sensitive test to evaluate thyroid function
• TSH, secreted by the pituitary, is elevated in early or subclinical hypothyroidism (when thyroid hormone levels appear normal) & when thyroid hormone replacement therapy is inadequate
• TSH can be abnormal even if the FT4 remains within the normal range because the TSH is specific for each person's physiological set point
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Diagnosis
Tests of Gland Function
Radioactive Iodine Uptake
• RAIU, a measure of iodine utilization by the gland, is an indirect measure of hormone synthesis
• It is elevated in hyperthyroidism & in early hypothyroidism
• A low or undetectable RAIU occurs in hypothyroidism, thyrotoxicosis factitia, & subacute thyroiditis
• RAIU is used to calculate the dose of RAI therapy for treatment of Graves' disease & to determine the activity of one or several nodules in a gland. The RAIU is not necessary to diagnose classic Graves' disease or hypothyroidism.
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Diagnosis
Tests of Gland Function
Radioactive Iodine Uptake
• The RAIU is not necessary to diagnose classic Graves' disease or hypothyroidism
• A tracer dose of 131I is administered, & the radioactivity of the gland is measured at 5 & 24 hours after ingestion
• It is necessary to measure both the 5- & 24-hour RAIU so that patient with rapid turnover of iodine will not be missed
• In some hyperthyroid patients, the 5-hour uptake is elevated, but the 24-hour uptake can fall to normal or subnormal levels
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Diagnosis
Tests of Gland Function
Imaging Study
Thyroid Scan
• A scan of the gland is performed simultaneously with the RAIU
• The scan provides information concerning gland size & shape, & identifies hypermetabolic (“hot”) & hypometabolic (“cold”) areas
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Diagnosis
Tests of Gland Function
Thyroid Ultrasound
• A thyroid ultrasound can provide information about gland size & number of clinically palpable or nonpalpable nodules or cysts in the thyroid gland
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Diagnosis
Tests of Autoimmunity
Thyroperoxidase & Antithyroglobulin Antibodies
• Thyroperoxidase (TPO) & antithyroglobulin (ATgA) antibodies to the thyroid gland indicate an autoimmune process
• About 60-70% of patients with Graves' disease & 95% of patients with Hashimoto's thyroiditis have +ve antibodies to both thyroid antigens
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Diagnosis
Tests of Autoimmunity
Thyroperoxidase & Antithyroglobulin Antibodies
• Positive antibodies alone do not indicate thyroid disease because 5-10% of asymptomatic patients, as well as patients with other nonthyroidal autoimmune disorders, have positive antibodies
• Clinically, the TPO is more specific than ATgA in assessing disease activity
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Diagnosis
Tests of Autoimmunity
Thyroid Receptor Antibodies
• TRAbs are IgG immunoglobulins that are present in virtually all patients with Graves' disease
• Like TSH, these immunoglobulins can stimulate the thyroid gland to produce thyroid hormones
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Diagnosis
Tests of Autoimmunity
Thyroid Receptor Antibodies
• High titers of TRAb are useful in:
Diagnosing otherwise asymptomatic Graves' disease (i.e., ophthalmopathy)
Predicting the risk of relapse of Graves' disease after discontinuing medication
Predicting the risk of neonatal hyperthyroidism in utero through transplacental passage of TRAb from the pregnant mother
• Otherwise, TRAb measurement is expensive & offers no additional information in patient with Graves' disease
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Diagnosis
Summary of commonly used tests in thyroid disorders
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Common Thyroid Function Test
Tests Measures Assay Interference Comments
Measurement of Circulating Hormone Levels
FT4
Direct measurement of free thyroxine
No interference by alterations in TBG
Most accurate determination of FT4
levels; might be higher than normal
in patients on thyroxine
replacement
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Diagnosis
Common Thyroid Function Test
Tests Measures Assay Interference Comments
Measurement of Circulating Hormone Levels
FT4ICalculated free thyroxine index
Euthyroid sick syndrome
Estimates direct FT4
measurement; compensates for
alterations in TBG
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Diagnosis
Common Thyroid Function Test
Tests Measures Assay Interference Comments
Measurement of Circulating Hormone Levels
TT4
Total free & bound T4
Alterations in TBG
Specific & sensitive test if no
alterations in TBG
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Diagnosis
Common Thyroid Function Test
Tests Measures Assay Interference Comments
Measurement of Circulating Hormone Levels
TT3
Total free & bound T3
Alterations in TBG levels; T4 to T3
Euthyroid sick syndrome
Useful in detecting early, relapsing, &
T3 toxicosis
Not useful in evaluation of
hypothyroidism
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Diagnosis
Common Thyroid Function Test
Tests Measures Assay Interference Comments
Measurement of Circulating Hormone Levels
FT3
Direct measurement of free T3
No interferenceby alterations in TBG
Most accurate determination of FT4
levels; might be lower than normal in patients on thyroxine
replacement
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Diagnosis
Common Thyroid Function Test
Tests Measures Assay Interference Comments
Measurement of Circulating Hormone Levels
FT3ICalculated free T3
indexEuthyroid sick
syndrome
Estimates direct FT3
measurement; compensates for
alterations in TBG
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Diagnosis
Common Thyroid Function Test
Tests Measures Assay Interference Comments
Tests of Thyroid Gland Function
RAIUGland's use of iodine
after trace dose of either 123I or 131I
False decrease with excess iodide
intake
False elevation with iodide deficiency
Useful in hyperthyroidism to determine RAI dose in Graves'; does not provide information regarding hormone
synthesis
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Diagnosis
Common Thyroid Function Test
Tests Measures Assay Interference Comments
Tests of Thyroid Gland Function
ScanGland size, shape, & tissue activity after
123I
154I scan blocked by antithyroid/ thyroid
medications
Useful in nodular disease to detect
“cold” or “hot” areas
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Diagnosis
Common Thyroid Function Test
Tests Measures Assay Interference Comments
Test of Hypothalamic-Pituitary-Thyroid Axis
TSH Pituitary TSH level
Dopamine, glucocorticoids,
metoclopramide, thyroid hormone,
amiodarone, metformin
Most sensitive index for hyperthyroidism, hypothyroidism, &
replacement therapy
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Diagnosis
Common Thyroid Function Test
Tests Measures Assay Interference Comments
Tests of Autoimmunity
ATgAAntibodies to thyroglobulin
Nonthyroidalautoimmune
disorders
Present in autoimmune thyroid
disease; undetectable during
remission
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Diagnosis
Common Thyroid Function Test
Tests Measures Assay Interference Comments
Tests of Autoimmunity
TPOThyroperoxidase
antibodies
Nonthyroidalautoimmune
disorders
More sensitive of the two antibodies; titers detectable even after
remission
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Diagnosis
Common Thyroid Function Test
Tests Measures Assay Interference Comments
Tests of Autoimmunity
TRAbThyroid receptor
stimulating antibody—
Confirms Graves' disease; detects risk of neonatal Graves'
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Diagnosis
How to diagnose hypothyroidism &
hyperthyroidism?
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How to Diagnose?
• First look at signs & symptoms
• Major differences between hypothyroidism & hyperthyroidism?
• Diagnostic test
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Diagnosis
Diagnostic Tests
Hypothyroidism Hyperthyroidism
↑ TSH ↓ TSH
↓ TT4 ↑ TT4
↓ TT3 ↑ TT3
↓ FT4 ↑ FT4
↓ FT4I ↑ FT4I
↓ FT3I ↑ FT3I
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Diagnosis
Diagnostic Tests
Hypothyroidism Hyperthyroidism
Positive antibodies (in Hashimoto's) ↑ Alkaline phosphatase
↑ Cholesterol ↓ Cholesterol
↑ AST ↑ AST
Decrease radioiodine uptake by thyroid gland
Increased radioiodine uptake by thyroid gland
↓ Na, Hyponatremia (from excess secretion of antidiuretic hormone)
↑ Calcium
↑ CPK
↓ Hct/Hgb
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Diagnosis
References
• Pharmacotherapy: A Pathophysiologic Approach, 7e
• Pathophysiology of Disease: An Introduction to Clinical Medicine, 6e
• Applied Therapeutics: The Clinical Use of Drugs, 9e
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Thank You
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