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Thyroid Disorders – including

hypothyroidism, hyperthyroidism

and thyroid cancers.

Ernest Asamoah, MD FRCP

Thyroid Disease Spectrum

0 10 5

TSH, IU/mL

Mild Thyroid Failure TSH >4.0 IU/mL, Free T4 Normal

Overt Hypothyroidism TSH >4.0 IU/mL, Free T4 Low

Euthyroid TSH 0.4-4.0 IU/mL, Free T4 Normal

Thyrotoxicosis TSH <0.4 IU/mL, Free T3/T4 Normal or Elevated

Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.

Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.

Vanderpump MP, et al. Clin Endocrinol (Oxf). 1995;43:55-68.

Objectives

Discuss hypothyroidism (causes, presentation and

management)

Discuss hyperthyroidism (causes, presentation and

management)

Know the current state of diagnosing and managing thyroid

cancers (brief discussion).

Have all their questions answered.

Progression of Thyroid Disease

Ayala AR, et al. Endocrinologist. 1997;7:44-50.

Years

Normal Range

TSH

Overt Hypothyroidism

Mild Thyroid Failure Euthyroid

T3

T4

Prevalence of Elevated Serum TSH

by Decade of Age and Gender

0

24

6

810

12

1416

18

13-

19

20-

29

30-

39

40-

49

50-

59

60-

69

70-

79

>80

Age, y

• At <40 years of

age, prevalence is

relatively low and

similar between

males and

females

• At ≥40 years of

age, a higher

percentage of

female patients

have elevated

TSH levels

Males

Females

NHANES III Study (N=17 353)

Hollowell JG, et al. J Clin Endocrinol Metab. 2002;87:489-499.

Part

icip

ants

With

Ele

vate

d T

SH

, %

Clinical Manifestations of Hypothyroidism

• Fatigue

• Weight gain

• Dry skin and cold intolerance

• Yellowing or yellow hue of the skin

• Coarseness or loss of hair

• Hoarseness

• Goiter

• Delayed relaxation of deep

tendon reflexes

• Ataxia

Braverman LE, et al. Werner & Ingbar’s The Thyroid.

A Fundamental and Clinical Text. 8th ed. 2000.

• Constipation

• Memory and mental

impairment

• Decreased concentration

• Depression

• Irregular or heavy menses

and infertility

• Myalgias

• Hyperlipidemia

• Bradycardia and hypothermia

• Myxedema

Hypothyroidism and Depression

Have Many Common Features

Depression Hypothyroidism

• Sleep decrease

• Suicidal ideation

• Weight loss

• Appetite increase/

decrease

Nemeroff CB, J Clin Psychiatry. 1989;50(suppl):13-20.

• Bradycardia

• Cardiac and lipid

abnormalities

• Cold intolerance

• Delayed reflexes

• Goiter

• Hair and skin

changes

• Constipation

• Appetite decrease

• Decreased concentration

• Decreased libido

• Delusions

• Depressed mood

• Diminished interest

• Sleep increase

• Weight increase

• Fatigue

Screening for Thyroid Dysfunction

Recommendations for Asymptomatic Adults

Organization

American Thyroid Association

American Association of

Clinical Endocrinologists

American College of

Physicians

Screening Recommendation

Women and men >35 years of age should be screened every 5 years

Older patients, especially women, should be screened

Women >50 years of age with an incidental finding suggestive of symptomatic thyroid disease should be evaluated

Ladenson PW, et al. Arch Intern Med. 2000;160:1573-1575.

Cooper DS. N Engl J Med. 2001;345:260-265.

Ann Intern Med. 1998;129:141-143.

Thyroid-Stimulating

Hormone (TSH) Assays

• Key test for diagnosis of hypothyroidism and hyperthyroidism

• TSH assay sensitivity has improved with subsequent test generations – First generation: RIA Sensitivity: 1.0 IU/mL – Second generation: IRMA Sensitivity: 0.1 IU/mL – Third generation: ELISA Sensitivity: 0.03 IU/mL

Ladenson PW, et al. Arch Intern Med. 2000;160:1573-1575.


Zophel K, et al. Nuklearmedizin. 1999;38:150-155.

Additional Laboratory Tests for

Thyroid Function

Test Normal Levels When to Use

Serum total T4 5-11 µg/dL Bound and free T4; use

with TSH for diagnosis

Free T4 0.7-1.8 ng/dL Use with TSH to assess

degree of hypothyroidism

TPOAb, TgAb Negative In combination with TSH,

predictor of disease

progression

Endocr Pract. 2002;8:457-469.


Demers LM, Spencer CA, eds. The National Academy of Clinical Biochemistry Web site. Available at:

http://www.nacb.org/lmpg/thyroid_lmpg.stm. Accessed July 1, 2003.

Goals for Treating Thyroid Disease

• Hypothyroidism – Restore thyroid hormones to normal levels

– Levothyroxine sodium is the treatment of choice

• Hyperthyroidism – Restore a eumetabolic state

– 3 treatments available: antithyroid drugs, radioactive iodine (131I), and thyroid surgery

Singer PA, et al. JAMA. 1995;273:808-812.

Hypothyroidism Treatments

Treatment of Hypothyroidism Thyroid Hormone Replacement

• Treatment of choice: levothyroxine (synthetic

levothyroxine, LT4)

– Chemically stable

– T4 converted to T3 in periphery

• Other therapies (T3 or T3 and T4 mixtures)

– Thyroid USP, liothyronine, liotrix, thyroglobulin

– Some disadvantages, no advantages versus

levothyroxine


Endocr Pract. 2002;8:457-469.

Braverman LE, et al. Werner & Ingbar’s The Thyroid. A

Fundamental and Clinical Text. 8th ed. 2000.

Diagnosis Algorithm for Hypothyroidism

TSH

0.4 to 4.0 IU/mL

Patient

Euthyroid

TSH

<0.4 IU/mL

Patient Hyperthyroid?

Consult Hyperthyroidism

Diagnosis

Algorithms

TSH

>4.0 IU/mL

Go to Next

Step


Demers LM, Spencer CA, eds. The National Academy of Clinical

Biochemistry Web site. Available at:


Suspect

Hypothyroid? Test TSH

Primary Hypothyroidism

Diagnosis Algorithm

FT4 E

High

Consult

Endocrinologist

for Possible

TSH-Secreting

Pituitary Tumor or

Thyroid Hormone

Resistance

TSH >4.0 IU/mL Test FT4 E*

*Free T4 estimate

FT4 E

Low

Patient

Hypothyroid

Consult

Hypothyroidism

Management

Algorithm

FT4 E

Normal

Consult

Hypothyroidism

Management

Algorithm

Patient

Subclinical

Hypothyroid

Demers LM, Spencer CA, eds. The National Academy of Clinical Biochemistry Web site. Available at:


Ayala AR, et al. Cleve Clin J Med. 2002;69:313-320.

Ayala AR, et al. The Endocrinologist. 1997;7:44-50.

Endocr Pract. 2002;8:457-469.

Primary Hypothyroidism

Treatment Algorithm

TSH >4 IU/mL TSH <0.5 IU/mL

Initial Levothyroxine Dose

Increase

Levothyroxine

Dose by

12.5 to 25 g/d

Repeat TSH Test

6-8 Weeks

TSH 0.5- 2.0 IU/mL

Symptoms Resolved

Measure TSH at 6 Months,

Then Annually or

When Symptomatic

Continue Dose Decrease

Levothyroxine

Dose by

12.5 to 25 g/d


Demers LM, Spencer CA, eds. The National Academy of

Clinical Biochemistry Web site. Available at:

http://www.nacb.org/lmpg/thyroid_lmpg.stm. Accessed

July 1, 2003.

Therapy Initiation and Titration

• Therapy with levothyroxine sodium products requires individualized patient dosing – Careful titration: use a formulation with consistent doses – Clinical evaluation: symptoms resolve more slowly than

TSH response – Laboratory monitoring: need consistent, sensitive TSH

measurements

• Individualized patient dosing is influenced by – Age and weight – Cardiovascular health – Severity and duration of hypothyroidism – Concomitant disease states and treatment

Endocr Pract. 2002;8:457-469.


Therapy Monitoring

• Clinical and laboratory monitoring enable

– Evaluation of the clinical response

– Assessment of patient compliance

– Assessment of drug interactions, if applicable

– Adjustment of dosage, as needed

• Clinical and laboratory evaluations should be performed

– At 6- to 8-week intervals while titrating

– Annually once a euthyroid state is established

Singer PA, et al. JAMA. 1995;273:808-812. Demers LM, Spencer CA, eds.

Demers LM, Spencer CA, eds. The National Academy of Clinical

Biochemistry Web site. Available at:


Thyrotoxicosis and

Hyperthyroidism Treatments

Thyrotoxicosis and Hyperthyroidism

Definitions

• Thyrotoxicosis

–The clinical syndrome of hypermetabolism that results when the serum concentrations of free T4, T3, or both are increased

• Hyperthyroidism

–Sustained increases in thyroid hormone biosynthesis and secretion by the thyroid gland

• The 2 terms are not synonymous



Common Signs and Symptoms

of Thyrotoxicosis

Symptoms Signs Nervousness Hyperactivity

Fatigue Tachycardia

Weakness Systolic hypertension

Increased perspiration Warm, moist, or smooth skin

Heat intolerance Stare and eyelid retraction

Tremor Tremor

Hyperactivity Hyperreflexia

Palpitations Muscle weakness

Appetite/weight changes

Menstrual disturbances



Prevalence of Thyrotoxicosis

• In a cross-sectional study of urban and

rural adults, the prevalence of

thyrotoxicosis ranged from

– 1.9% to 2.7% in women

– 0.16% to 0.23% in men

Tunbridge WMG, et al. Clin Endocrinol. 1977;7:481-493.

Graves Disease

• Autoimmune disorder – Production of TSH receptor autoantibodies

– Stimulate thyroid hormone overproduction

• Characterized by the presence of B- and T-lymphocytes in thyroid tissue – TSH receptor activation

– Thyroglobulin and thyroid peroxidase antibodies

– Sodium/iodide cotransporter (NIS) activity enhanced (increased RAI)

– Autoantigens Abbott Laboratories Diagnostics Division Web site.

Available at: http://www.abbottdiagnostics.com/medical_

conditions/ thyroid/disorders/graves.htm. Accessed July 1, 2003.

Braverman LE, et al. Werner & Ingbar’s The Thyroid.

A Fundamental and Clinical Text. 8th ed. 2000.

Toxic Multinodular Goiter

• More common in places with lower iodine intake – Accounts for less than 5% of thyrotoxicosis cases

in iodine-sufficient areas

• Evolution from sporadic diffuse goiter to toxic multinodular goiter is gradual

• Thyrotropin receptor mutations and TSH mutations have been found in some patients with toxic multinodular goiters

• Surgery or 131I is recommended treatment



Treatment of Hyperthyroidism

• Antithyroid drugs

– Inhibit the synthesis of T4 and T3

• Surgical resection

– Remove hyperplastic and adenomatous tissues

– Restore normal thyroid function and, consequently, pituitary function

• Radioactive iodine therapy

– Iodine 131 taken up by functioning thyroid tissue can decrease thyroid hormone production



Summary

• Thyroid disease is a prevalent condition

• Effective screening requires biochemical confirmation to avoid misdiagnosis

• Levothyroxine therapy is recommended

– Effective in different types of thyroid disorders

– Provides benefit for many organ systems

– Reduces CAD risk factors

Update on Thyroid Cancer Management

Worrisome Clinical Features of Thyroid

Malignancy

History

– Age <20 or >60 – Family history of thyroid carcinoma – Rapid enlargement of nodule – Hoarseness, dysphagia, hemoptysis – exposure to ionizing radiation – History of Graves disease

Physical – Firm, hard, or fixed nodule – Enlarged cervical lymph nodes – Paralyzed vocal cords – MEN IIB, (marfanoid, mucosal neuromas)

Ionizing radiation and thyroid cancer

• No threshold dose

• cancers develop 20-30 years later

• 50% of patients develop thyroid abnormalities

• 15-30% will develop thyroid cancer

• earlier the exposure, higher risk of cancer.

Ionizing radiation and thyroid cancer

• Most (>90%) are papillary

• Tumor behavior is similar to sporadic

• I-131 therapy for graves disease does not pose increased risk at any dose

OTHERWISE

• Thyroid cancer “uncommon”

• In 2001, ACS estimates thyroid cancer 1.5 % of all new cancers

• SEER (NCI) estimates prevalence 0.1% of all Americans

• Death even more uncommon, 0.23% of all cancer deaths

Thyroid Cancer

• Papillary most common (> 80%)

• Local invasion

• Good prognosis (10 year survival >90%)

• Follicular (15%)

• Invasion into vessels, metastasis more

likely

• Good prognosis (10 year survival 65-

85%)

Thyroglobulin is a maker for these

cancers

Thyroid Cancer

• Medullary

• Associated with MEN syndromes

• Bilateral cervical lymphatic involvement

• Calcitonin is a tumor marker

• Fair prognosis

• Anaplastic

• Local invasion and distant metastasis

• Fast growing

• Poor prognosis

Latest ATA Guidelines - October 2009

Recommendation Ratings

• Recommendation A – Good Evidence for benefit

• Recommendation B – Fair Evidence for benefit

• Recommendation C – Expert Opinion in favor

• Recommendation D – Expert Opinion against

• Recommendation E – Fair Evidence Against

• Recommendation F – Good Evidence Against

• Recommendation I – Insufficient evidence for or against recommendation

Recommendation for Surgery – Positive FNA

• For patients with thyroid cancer >1 cm, the initial surgical procedure should be a near-total or total thyroidectomy unless there are contraindications to this surgery

• Thyroid lobectomy alone may be sufficient treatment for small (<1 cm), low risk, unifocal, intrathyroidal papillary carcinomas in the absence of prior head and neck irradiation or radiologically or clinically involved cervical nodal metastases.

• Recommendation rating: A

Lymph Node Dissection

• Therapeutic central-compartment (level VI) neck dissection for patients with clinically involved central or lateral neck lymph nodes should accompany total thyroidectomy to provide clearance of disease from the central neck.

• Recommendation rating: B

Staging

• Because of its utility in predicting disease mortality, and its requirement for cancer registries, AJCC=UICC staging is recommended for all patients with DTC. The use of postoperative clinico-pathologic staging systems is also recommended to improve prognostication and to plan follow-up for patients with DTC.


RAI Remnant Ablation

• Remnant ablation can be performed following thyroxine withdrawal or rhTSH stimulation (for low risk patients or those who cannot tolerate thyroid hormone withdrawal).

• Recommendation rating: A

RAI Ablation

RAI ablation is recommended for all patients with known distant metastases, gross extra-thyroidal extension of the tumor regardless of tumor size, or primary tumor size >4 cm even in the absence of other higher risk features.

RAI ablation is recommended for selected patients with 1–4cm thyroid cancers confined to the thyroid, who have documented lymph node metastases, or other higher risk features when the combination of age, tumor size, lymph node status, and individual histology predicts an intermediate to high risk of recurrence or death from thyroid cancer.

Recommendation rating: C (for selective use in higher risk patients)

RAI Ablation

• RAI ablation is not recommended for patients with unifocal cancer <1cm without other higher risk features.

• RAI ablation is not recommended for patients with multifocal cancer when all foci are <1cm in the absence other higher risk features.

Recommendation rating: E

RAI Ablation

• Patients undergoing RAI therapy or diagnostic testing can be prepared by LT4 withdrawal for at least 2–3 weeks or LT3 treatment for 2–4 weeks and LT3 withdrawal for 2 weeks with measurement of serum TSH to determine timing of testing or therapy (TSH >30 mU=L).

• Thyroxine therapy (with or without LT3 for 7–10 days) may be resumed on the second or third day after RAI administration.


RAI Dose

• The minimum activity (30–100 mCi) necessary to achieve successful remnant ablation should be utilized, particularly for low-risk patients. Recommendation rating: B

• If residual microscopic disease is suspected or documented, or if there is a more aggressive tumor histology (e.g., tall cell, insular, columnar cell carcinoma), then higher activity (100–200 mCi) may be appropriate. Recommendation rating: C

Effect of age and initial surgical approach on

mortality in thyroid cancer

Cancer Research 51: 1234-1241

-

Follow-up of patients after thyroidectomy and

ablation (adapted from NEJM 339:297-306)

Thyroid ablation and iodine-131 TBS

thyroxine therapy

3 months check TSH and thyroglobulin

6 months, T4 withdrawal, TBS

(2 mCi) and thyroglobulin Iodine-131 (100-

150 mCi) +

Yearly thyroglobulin

on T4

Iodine-131 TBS every

2-5 years

Iodine-131 Rx/TBS

(100 mCi)

TG < 1 ng/ml 1-10

ng/ml

> 10

ng/ml

Radioactive iodine ablation and death from

cancer

No ablation 8% mortality

Ablation 0% mortality

rhTSH (Thyrogen)

• Has replaced thyroid hormone withdrawal in routine follow up.

• Very few side effects

• Replicates a rise in TSH equal to or greater than withdrawal.

• Avoids thyroid hormone withdrawal symptoms

And in combination with stimulated TG > 2 ng/mL….

– Detects 100% of patients with metastatic disease identified by T4 withdrawal/TBS

– Detects 90% of patients with uptake in the thyroid bed identified by T4 withdrawal/TBS

Conclusions

• Most Thyroid cancers do well (low risk patients)

• All thyroid cancers DO NOT do well (especially very high risk patients)

• Latest Guidelines by ATA: THYROID Volume 19, Number 11, 2009

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