Thyroid Overview

Objectives1. Recognize the clinical findings of

hypothyroidism.2. Understand how to diagnose hypothyroidism:

distinguish between Primary Hashimoto’s and Primary Subacute Hypothyroidism.

3. Understand the role of thyroid functional scans in the diagnosis of hypothyroidism.

4. Know the specific cellular activities that are overactive in Grave’s disease.

5. Understand how to diagnose Grave’s disease.

Thyroid Hormone Physiology Review• Thyroid gland releases T4 and T3• Thyroid follicular cells uptake iodine.• Iodine oxidized & incorporated into MIT & DIT• Coupling of iodotyrosine with thyroglobuline forms T3 & T4.• Poteolysis of the thyroglbuline molecule releases MIRT, DIT, T3, T4.• MIT and DIT are deiodinated and the liberated iodine is reused.• T4 & T3 (to a much lesser extent) released from thyroid.• TPO (thyroperoxidate) medicates thyroid hormone synthesis.

(mediates both: Oxidation of iodine; incorporation into tyrosyl resudues).• Thyroid hormones transported to carrier proteins. .04% of T4 is

free; .4% of T3 is free; the free form is the biologically active form able to bind to thyroid receptors.

• T3 has a much higher affinity for the thyroid receptor than T4.• The body regulates thyroid activity by converting T4 to T3 (by

deiodinases). • Free thyroid hormone is transported through cell membrane by a

carrier and binds to thyroid receptors (TR).• Thyroid function is regulated by the hypothalamic-pituitary-thyroid axis. • Synthesis of T4 and T3 regulated by TSH.• A negative feedback loop is present.

Thyroid physiology

Labs

• Serum Total T4 (Thyroxin) reflects thyroid hormone activity. Measures both free and bound T4 in healthy patients.

• Serum Total T3 (Triiodothyronine) measures both free and

bound T3. • (TBG) is the major thyroid hormone binding proteins.

– Other proteins with binding capacity: transthyretin (thyroxine-binding prealbumin) and albumin.

• TSH is the only test that can detect small changes of thyroid hormone excess or deficiency.

• Free Thyroid Hormone – (rarely ordered) Usually what is reported is an estimate of free T4

which is a calculated Free T4 Index (FT4 I)

Labs

╬ Serum TSH is the best SCREENING test for the diagnosis of hypothyroidism or hyperthyroidism in healthy ambulatory individuals.

• TSH is the initial test done to assess thyroid function and the only test needed if it is normal.

╬ Possible Test Question

Which of the following is the best screening test for the diagnosis of hypothyroidism or hyperthyroidism in healthy ambulatory individuals.

1. Radioiodine I-123 uptake

2. Free T3

3. Free T4 Index

4. TSH (Correct answer)

5. TSH and functional scan

Objective 1

1. Recognize the clinical findings of hypothroidism.

2. Understand how to diagnose hypothyroidism: distinguish between Primary Hashimoto’s and Primary Subacute Hypothyroidism.




Clinical Findings of Hypothyroidism (part 1)

• Skin:dry, rough, non-pitting edema in lower extremities (myxedema), coarse hair, hair loss (lateral aspects of eyebrows).

• Ocular: swelling of eyelids.• CV: Bradycardia, impared contraction with reduced cardiac output, cardiomegaly,

pericardial effusion, increased incidence of coronary atherosclerosis.• Pulmonary: Shortnes of breath and resp. failure with mexedema coma.

• ENT: Husky voice due to infiltration of vocal cords, enlarged tongue with associated garbled voice and sleep apnea.

• GI: Reduced appetite, (increased weight is due to water retention), constipation, atrophic gastritis (50%), B12 malabsorption (12%).

• CNS: severe brain damage in children born with hypothyroidism (cretinism) - the earlier the treatment the better the result. Reduced concentration, lethargy, coma, carpal tunnel. Slow relaxation phase of reflexes due to muscle dysfunction.

• Muscles: Stiff, ache, elevated CPK and SGOT.• Anemia: mild normochromic normocitic is most common. Microcitic due to iron

malabsorption; macrocitic due to B12 malabsorption.

Clinical Findings of Hypothyroidism(part 2)

• Renal: Glomerular filtration rate, renal plasma flow, tubular reabsorption are reduced (however - BUN and creatinine are normal); water excretion impaired.

• Myxedema Coma: (decompensated hypothyroidism) – end stage of severe long-standing hypothyroidism, – mental obtundation is profound. – an endocrine emergencies as the mortality is over 50%. – usually accompanied by a subnormal temperature, bradycardia, and hypotension are

present.

Hypothyroidism

• Epidemiology/pathophysiology;5 to 10% over 65

• Causes:*Defect within thyroid gland (Primary)

(accounts for ~98% of hypothyroidism)

*Deficiency of TSH (secondary)*Deficiency of THR (tertiary or hypthalamic)*Peripheral Tissue resistance to thyroid hormone

Primary Hypothyroidism

Labs

╬ In primary hypothyroidism (99% of hypothyroidism) TSH is elevated.

• TSH is one of the most sensitive tests in medicine.

Labs• Order T4 after TSH if:

– hypothalamic/pituitary disease is suspected• then a measure of free T4 (index or direct assay) is

needed together with TSH.

– significant alterations in binding proteins are expected,

• then a measure of free T4 (index or direct assay) is needed together with TSH.

– Clinical conditions associated with elevation in thyroid hormone binding proteins include active hepatitis, pregnancy, drugs (estrogen, raloxifene, tamoxifen, 5-fluorouracil, perphenazine, clofibrate, heroin and methadone), acute intermittent porphyria and hereditary TBG excess.

– Clinical conditions associated with reduction in thyroid hormone binding proteins include cirrhosis, nephrotic syndrome, protein losing enteropathies, malnutrition, severe illness, drugs (androgens, glucocorticoids), and hereditary TBG deficiency.


Types of primary hypothyroidism– Hashimoto’s thyroiditis– Subacute thyroiditis– Iatragenic– Drugs– Iodine deficiency– Dyshormonogenesis– Primary and Metastatic Tumor to the Thyroid (rare)

Objective 2

1. Recognize the clinical findings of hypothroidism.





Primary HypothyroidismTypes of primary hypothyroidism *Hashimoto’s thyroiditis:

• Most common cause of primary hypothyrodism.• Etiology: autoimmune destruction of the thyroid gland

╬ TSH is elevated.

╬ Anti-thyroglobuline and/or anti-TPO antibodies are present in most (90%) patients.

• Autoimmune thyroiditis may coexist with other autoimmune diseases: pernicious anemia, RA, DM, “Burnt out” Grave’s disease.

– Subacute thyroiditis– Iatragenic– Drugs– Iodine deficiency– Dyshormonogenesis– Primary and Metastatic Tumor to the Thyroid (rare)

╬ Lab summary - hypothyroidism


Types of primary hypothyroidism – Hashimoto’s thyroiditis:

*Subacute thyroiditis (hypothryroid phase):Aka: granulomatous, lymphocytic or postpartum thyroiditis . . . . . . . . . . – Iatragenic– Drugs– Iodine deficiency– Dyshormonogenesis

Subacute thyroiditis-hypothyroid phase

• Etiology: destruction of the thyroid gland *(often due to upper respiratory illness). *Destruction leads to release of thyroid hormone in circulation (rather than from an increase in synthesis of hormone).

• Symptoms: depends on phase• Radioiodine I-123 uptake: low• Outcome:

1. after thyrotoxic phase, 2. subacute thyroiditis may progress to transient (6 - 12 months)

hypothyroidism (90% are transient)3. return to euthyroidism

• Supportive treatment only; no inhibitors of thyroid hormone synthesis are needed.

╬ TSH is elevated; Anti-thyroglobuline and/or anti-TPO antibodies are not present.It is important not to erroneously diagnose these patients with Hashimoto's and commit them to life-long thyroid hormone replacement therapy.

Primary HypothyroidismTypes of primary hypothyroidism

– Hashimoto’s thyroiditis:– Subacute thyroiditis:

*Iatragenic:

Post ablative following radioactive iodine administration or after thyroidectomy.

*Drugs:

Lithium, amiodarone (~40% iodine), high intake of iodine such as in seaweed

or algae tablets from health food stores. *Iodine deficiency:

in some less developed countries - goiter is present.

*Dyshormonogenesis:Enzymatic defects in thyroid hormone biosynthesis lead to poor hormone

secretion and development of goiter. This is a rare cause of hypothyroidism, especially in the adult patient. Failure of the thyroid gland to descend during embryogenenesis may also cause congenital hypothyroidism.

*Primary and Metastatic Tumor to the Thyroid (rare)

Secondary Hypothyroidism

• Adults:– Almost always due to pituitiary disease.╬ TSH is low or normal.– TSH may not be a biologically active as

usual, but still detected in the TSH assay; TSH is called, “inappropriately normal.”

• Selective TSH deficiency:– Very rare genetic cause of newborn hypothyroidism– May be seen in adults due to autoimmunity against

thyrotrophs (cells that produce TSH).

Tertiary Hypothryroidism

• Due to hypothalamic disease:– sarcoidosis – tumors– radiation

Resistance to Thyroid Hormone

• Peripheral resistance to thyroid hormone is very rare.

• Beyond scope of this lecture.

Functional Thyroid Imaging

• Radioactive iodine (I-123), administered orally

• the radioisotope and a scan (image) of the thyroid obtained 4 or 24 hours later.

• I-123 is accumulated by thyroid follicular cell & incorporated into thyroglobulin (trapped and organified).

Imaging

Radionuclide Imaging of the Thyroid

• The radiotracer uptake is increased whenever thyroid under increased stimulus:

*Raised TSH

*Stimulating antibody of Grave’s disease

*When thyroid becomes autonomous (“hot” nodule or toxic multinodular goiter).

ImagingRadionuclide Imaging of the Thyroid

• The radiotracer uptake is decreased whenever the thyroid is under decreased stimulus:

decreased TSH in hypopituitarismexogenous thyroid hormone administrationwhen thyroid cells are damaged so that the uptake

mechanism is defective Hashimoto's thyroiditis:

autoimmune destruction of the thyroid gland; Anti-thyroglobuline and/or anti-TPO antibodies are

present in most (90%) patients

Subacute thyroiditis: Destruction leads to release of thyroid hormone in

circulation (rather than from an increase in synthesis of hormone).

When excess iodine "swamps" the radioactive tracer.

Objective 3

1. Recognize the clinical findings of hypothroidism.2. Understand how to diagnose hypothyroidism: distinguish

between Primary Hashimoto’s and Primary Subacute Hypothyroidism.




Imaging

╬ Thyroid functional scans they are not helpful in the diagnosis of hypothyroidism and should not be used for this indication.

Hashimoto's thyroiditis: autoimmune destruction of the thyroid gland; Anti-thyroglobuline and/or anti-TPO antibodies are present in most (90%) patients.

DECREASED UPTAKE

Subacute thyroiditis:

Destruction leads to release of thyroid hormone in circulation

(rather than from an increase in synthesis of hormone). DECREASED UPTAKE

• Thyroid functional scans are helpful in the differential diagnosis of hyperthyroidism and in determining the function of a thyroid nodule

Imaging

╬ Thyroid functional scans they are not helpful in the diagnosis of hypothyroidism and should not be used for this indication.

Hashimoto's thyroiditis: DECREASED UPTAKE

Subacute thyroiditis:

DECREASED UPTAKE

Other Thyroid Imaging

• CT and MRI: – structural imaging modalities and provide no functional

information. – NO role in the initial evaluation of thyroid dysfunction.

• Ultrasound:– modality of choice for evaluation of thyroid structure (e.g.

evaluation of thyroid nodules).

• CT or MRI:– may be used to:

• visualize a large substernal goiter

• evaluate tracheal compression.

. . . Hypothyroidism and pregnancy

Maternal hypothyroidism during pregnancy may lead to adverse fetal outcomes. – lower IQ as adolescents. – It is controversial whether all pregnant women should be

screened for hypothyroidism. – Women with known hypothyroidism prior to pregnancy

should have their dose of levothyroxine adjusted to maintain normal thyroid levels before conception and during pregnancy.

Objective 41. Recognize the clinical findings of hypothroidism.2. Understand how to diagnose hypothyroidism: distinguish





Hyperthyroidism: clinical findings

• Weight loss• Heat intolerance• Insomnia• Sweating• Anxiety• Hyperkinesis• Dyspena• Palpitations• Atrial fibrilation

• Irregular menses• Infertility• Increased frequency of

bowel movements• Myalgia

Hyperthyroidism - with low TSH

• Grave’s Disease• Toxic Multinodular Goiter• Hyperthyroid phase of thyroiditis• Toxic Adenoma• Iodine-induced• Metastatic thyroid carcinoma, rare.• Excess beta-HCG from a molar pregnancy or

choriocarcinoama• Ectopic/Exogenous, rare

Grave’s Disease

• 60-70% of all cases of hyperthyroidism.

• 3% of population affected.

• Female:Male ratio is 5:1 in 3rd or 4th decade.

Graves Disease Findings

• Weight loss• Heat intolerance• Insomnia• Sweating• Anxiety• Hyperkinesis• Dyspena• Palpitations• Atrial fibrilation

• Irregular menses• Infertility• Increased frequency of

bowel movements• Myalgia• Proximal Muscle weakenss

• Eye findings:*lid retraction*lid lag*stare

Grave’s Disease

• May be cyclic with exacerbations and remissions.

• Usually, ongoing destructive inflammation of thyroid gland.

• Eventually leads to “burn out” form of the disease and resulting hypothyroidism.

• Getting to hypothyroid state may take many years.

Grave’s Disease

• Familial predisposition• Overlap with automimmune Hashimoto’s

thyroiditis and the associated:– Pernicious anemia– Myasthenia gravis– Vitiligo– Addisons disease – Type 1 Diabetes Mellitus

Grave’s Disease*Cause: circulating antibodies against

various thyroid antigens. – The most important antibody:

• The TSH receptor antibody (TSH-R Ab) is directed against the TSH receptor on the thyroid follicular cell membrane.

• Other antibodies present:– Antibodies agains thyroid peroxidase (TPO)– Antibodies against thyroglobulin (TG

– TSH-R Ab most often act as TSH receptor agonists.• increasing the activity of adenylate cyclase

• increasing intracellular cyclic AMP levels

╬ result in cellular overactivity:

» increased iodine uptake » Increased thyroid hormone synthesis

» Increased thyroid release

Grave’s DiseaseCause: circulating antibodies against various

thyroid antigens. – The most important antibody:



*TSH-R Ab most often act as TSH receptor agonists.

• increasing the activity of adenylate cyclase• increasing intracellular cyclic AMP levels

╬ result in cellular overactivity:

» increased iodine uptake

» Increased thyroid hormone synthesis

» Increased thyroid release

Grave’s DiseaseCause: circulating antibodies against various

thyroid antigens. – The most important antibody:



– TSH-R Ab most often act as TSH receptor agonists.• increasing the activity of adenylate cyclase• increasing intracellular cyclic AMP levels

╬ result in cellular overactivity:1.increased iodine uptake 2.Increased thyroid hormone

synthesis

3.Increased thyroid release

Objective 51. Recognize the clinical findings of hypothroidism.2. Understand how to diagnose hypothyroidism: distinguish





Grave’s DiseaseLabsIncreased T4 and T3

sometimes only T3 is elevatedDecreased TSH╬ IF TSH depressed, T3 T4 increased, & patient has

Grave’s ophthalmopathy:*lid retraction, *stare, *lid lag,

Then - your evaluation is finished; your diagnosis is made.

IF: TSH LOW; T3 T4 HIGH; EYE SIGNS; THEN, YOU DO NOT ORDER A SCAN. IF: TSH LOW; T3 T4 HIGH; EYE SIGNS; THEN, YOU DO NOT ORDER A SCAN. IF: TSH LOW;T3 T4 HIGH; EYE SIGNS; THEN, YOU DO NOT ORDER A SCAN. IF:TSH LOW; T3 T4 HIGH; EYE SIGNS; THEN, YOU DO NOT ORDER A SCAN. IF: TSH LOW; T3 T4 HIGH; EYESIGNS; THEN, YOU DO NOT ORDER A SCAN. IF: TSH LOW; T3 T4 HIGH; EYE SIGNS; THEN, YOU DO NOT ORDER A SCAN. IF: TSH LOW; T3 T4 HIGH; EYE SIGNS; THEN, YOU DO NOT ORDER A SCAN. IF: TSH LOW; T3 T4 HIGH; EYE SIGNS; THEN, YOU DO NOT ORDER A SCAN. IF: TSH LOW; T3 T4 HIGH; EYE SIGNS; THEN, YOU DO NOT ORDER A SCAN. IF: TSH LOW; T3 T4 HIGH; EYE SIGNS; THEN, YOU DO NOT ORDER A SCAN. IF: TSH LOW; T3 T4 HIGH; EYE SIGNS; THEN, YOU DO NOT ORDER A SCAN. IF: TSH LOW; T3 T4 HIGH; EYE SIGNS; THEN, YOU DO NOT ORDER A SCAN. IF: TSH LOW; T3 T4 HIGH; EYE SIGNS; THEN, YOU DO NOT ORDER A SCAN. IF: TSH LOW; T3 T4 HIGH; EYE SIGNS; THEN, YOU DO NOT ORDER A SCAN. IF: TSH LOW; T3 T4 HIGH; EYE SIGNS; THEN, YOU DO NOT ORDER A SCAN. IF: TSH LOW; T3 T4 HIGH; EYE SIGNS; THEN, YOU DO NOT ORDER A SCAN.

. . . however . . . IF TSH depressed, T3 T4 increased, & no

ophthalmopathy:Then get a Radioactive (I-123) scan:

Graves I-123 scan results will be:elevated, diffuse, symmetric,

In Grave’s: I-123 uptake Thyroid autoantibodies may also be present:

anti-TPO (measured in clinical practice)

anti-TG TSH-R Ab (not readily available)

In Graves: Orbital CT or MRI retro-orbital inflammation.

Subacute Thyroiditis - hyperthyroid phase

• Etiology: destruction of the thyroid gland *(often due to upper respiratory illness). *Destruction leads to release of thyroid hormone in circulation (rather than from an increase in synthesis of hormone).

• Symptoms: same without Grave’s eye findings (in hyperthyroid phase.

• Radioiodine I-123 uptake: low• Outcome:

after thyrotoxic phase, subacute thyroiditis may progress to transient (6 - 12 months) hypothyroidism

• Supportive treatment only; no inhibitors of thyroid hormone synthesis are needed.

Graves: Subacute Thyroiditis hyperthyroid phase

TSH-R Ab most often act as TSH receptor agonists

result in cellular overactivity:Increased thyroid hormone synthesis.

Increased thyroid release

Etiology: destruction of the thyroid gland

Result in cellular underactivity leads to release of thyroid hormone in circulation (rather than from an increase in synthesis of hormone).

Radioiodine I-123 uptake: high

Radioiodine I-123 uptake: low

Eye signs: present Eye signs: not present

Compare: Graves vs Subacute Thyroiditis hyperthyroid phase______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

Toxic Multinodular Goiter (MNG)

• Frequency: 20-30% of hyperthyroid patients.• Pathophysiology: follicles - with some

degree of autonomy - become large enough to increase overall hormone production. (Large doses of iodide can precipitate thyrotoxicosis in patients with non-toxic multinodular goiters).

Toxic Multinodular Goiter (MNG)

• Labs: *TSH suppressed; *T4 and T3 (high, normal, slightly

elevated)• Radioiodine (I-123) scan:

*Areas of “hot” or “warm” *With areas of “cold” uptake (corresponding to multiple nodules).

Toxic Ademoma• 3-5% of thyrotoxicosis• Cause:

*a single hyperfunctioning follicular thyroid adenoma

• ~50% have an activating mutation in the TSH receptor causing overproduction of thyroid hormone in the monoclonal tumor

• Excess thyroid hormone is produced; • Reduces TSH; • Remainder of thyroid gland remains quiet• Radiodine I-123 scan:

*One “hot” nodule; *Remainder of gland is suppressed.

Iodine-induced Thyrotoxicosis

• Administering iodine may cause thyrotoxicosis in patients with:*iodine deficiency (endemic) goiter*Multinodular goiter (with areas of autonomy or an Autonomous nodule)

• Pathogenesis: ? Perhaps loss of normal adaptation of thyroid to iodine excess. (Usually mild and remits after stopping the iodine therapy).

Troma Ovarii

• Ectopic thyroid tissue– Dermoid tumors– Ovarian teratoma

• Radioiodide scan of neck: decreased uptake

• Radioiodid scan of pelvic area: shows increased uptake

• Tx: remove tumor.

TSH producing Pituitary Tumor

• Very rare

• TSH high; T4 T3 high

Other causes of thyrotoxicosis

• Metastatic Thyroid Carcinoma• Molar Hydatiform Pregnancy and

Choriocardinoma• Thyrotoxicosis Factitia: serrupticious ingestion of

thyroid hormone. Seen in psychiatric patients, medical professionals, or people wanting to lose weight.

• Decreased:– TSH – Radioiodid I-123 uptake – secretion of thyroglobulin

Nuclear Imaging for thyrotoxicosis summary

OBJECTIVES



3. Recognize the clinical findings of hypothroidism.4. Know the specific cellular activities that are

overactive in Grave’s disease.


╬ Possible Test Question

Which of the following is the best screening test for the diagnosis of hypothyroidism or hyperthyroidism in healthy ambulatory individuals.

1. Radioiodine I-123 uptake

2. Free T3

3. Free T4 Index

4. TSH (Correct answer)

5. TSH and functional scan

╬ In primary hypothyroidism (99% of hypothyroidism) TSH is elevated.╬ Serum TSH is the best SCREENING test for the diagnosis of

hypothyroidism or hyperthyroidism in healthy ambulatory individuals.╬ Thyroid functional scans they are not helpful in the diagnosis of

hypothyroidism and should not be used for this indication.Hashimoto’s thyroiditis:

╬ TSH is elevated.╬ Anti-thyroglobuline and/or anti-TPO antibodies are present in

most (90%) patients.Subacute thyroiditis - hypothyroid phase:

╬ TSH is elevated.╬ Anti-thyroglobuline and/or anti-TPO antibodies are NOT

present.Radioiodine I-123 uptake: low (may order in hyperthyroid phase)

╬ RECOGNIZE THE CLINICAL FINDINGS OF HYPOTHYROIDISM (TOO MANY TO LIST).

╬ Cellular overactivities of Grave’s disease: increased iodine uptake, Increased thyroid hormone synthesis, Increased thyroid release (as a result of the TSH receptor agonist, TSH-R Ab).

╬ IF TSH depressed, T3 T4 increased, Grave’s ophthalmopathy (lid retraction, stare, lid lag) are present, then - your evaluation is finished; your diagnosis is made. (You do not need a functional scan for the

diagnosis).

Thyroid Overview

Health & Medicine

Transcript of Thyroid Overview