ENDOCRINOLOGYBOARD REVIEW

THYROID DISORDERSHenri Godbold, MD

General- Thyroid produces two related hormones

thyroxine(T4) and triidothyronine (T3)- Function is through nuclear receptors playing a

role in cell differentiation- Maintains thermogensis, and metabolic

homeostasis- Disorders result from autoimmune processes that

either stimulate overproduction of hormones (thyrotoxicosis) or glandular destruction and hormone deficiency (hypothyroidism)

- Benign nodules and various forms of thyroid cancers

Anatomy- Located anterior to trachea consist two lobes- Weighs 12-20gm soft and highly vascular a

posterior region gland contain four parathyroid gland that produce parathyroid hormone

- Lateral borders of the gland is transversed by the recurrent laryngeal nerves

- Develops from the floor of the primitive pharynx third week of gestation migrates from the foramen cecum, at the base of tongue along the thyroglossal duct to neck

- Hormonal synthesis usually begin at about 11 weeks’ gestation

Thyroid Physiology- Thyroid releases (2) forms of hormones - Thyroxine (T4) and triiodothyroxine (T3) ratio

14:1 - T3 is 80% derived from peripheral tissue- T4 all within the thyroid gland- T3 is produced from T4 in liver, kidneys,

pituitary gland and CNS- T3 is the physiologically active in almost all

tissue binding to specific nuclear receptors regulating the transcription of thyroid hormone dependent genes

Drugs decreasing Peripheral conversion of T4 to T3

Propranolol Corticosteroids Propylthiouracil (PTU) Amiodarone

SYNTHESIS AND RELEASE

- TSH controls release under the influence TRH from the hypothalamus- TSH stimulate thyrocyte function resulting in iodide uptake actively on the basal surface of the thyroid follicle cell- Iodide undergoes oxidation to iodine which iodinates tyrosine residues catalyzed by peroxidase - Thyroglobulin coupling occurs to form mono-

and diiodotyrosine (MIT and DIT- Two DITs coupling = T4- One DIT and one MIT combine =T3- If iodine scarce, the production of T3 is increase - Activity is dictated by # iodines attached to tyrosine molecules and location

Secretion Degradation process with endocytosis of the follicular

colloid containing MIT, T3, T4, DIT attached to thyroglobulin undergoes fusion

with lyosome resulting in proteolysis release Deiodination occurs with the recycling iodide and

secretion of T3 and T4 Circulating thyroid hormones are more than 99%

protein bound, are thyroxine-binding globulin, albumin, and transthyretin.

80% of circulating T3 is derived from the conversion of T4 outside the thyroid

Serum half-life of T3 is much shorter than that T4 (1day vs 8days)

Storage- Iodine as iodinated tyrosine of thyroglobins 8000 micrograms total- T4 and T3 represent 600 micrograms

each- Enough hormone is stored in the

follicular colloid to last 2-3 months

Overveiw of Thyroid Fx Workup

N/APituitary hyperthyr’ismLow

TRH to confirmSubclinical hypothyr’ismNormal

N/APituitary hyperthyr’ismHigh

TRH to confirmSubclinical hypothy’ismNormal

RAIUThyrotoxicosisHighLOW

N/APrim hypothyr’ismLowHIGH

3rd Test

Clinical StatusFT4-I,

FT4

2nd Test

TSH

1st Test

Measurement RAIU

Thyroiditis, severe iodine excess, amiodarone induced thyrotoxicosis

Low

EuthyroidNormal

Hyperfunction (Graves’, multinodule goiter, toxic solitary nodule, hCG secreting tumor)

High

Specific disordersLevels

Drugs and condition that affect thyroid Function Tests

Lithium

Iodine

Propranolol

Glucorticoid

PTU

Amiodarone

Androgens

Gluccorticoid

Nephrotic syn

Estrogen

OCT,

pregnancy

Tamoxifen

Clofibarate

Narcotics

Hepatitis

Bililary cirrhosis

Blocks thyroidal release T4 and T3

Block peripheral conversion of T4 to T3

Decrease TBGIncrease

TBG

Thyroid PathologyA. Thyroid Gland

1. Multinodular goiter (nontoxic goiter) Presentation

i. Females > males ii. Frequently asymptornatic iii. Typically euthyroid iv. Goiter

v. Plummer's syndrome:development of hyperthyroidism (toxic multinodular Goiter)late in course

B. GROSS enlarged thyroid gland with multiple colloid nodules

C. MICROSCOPIC i. Nodules of varying sizes composed of colloid

follicles ii. Calcification, hemorrhage, cystic degeneration,

and fibrosis

D. LAB: normal T4, T3, and TSH

B Hyperthyroidism1. General features of hyperthyroidism I

a. Clinical featuresi. Tachycardia and palpitationsii. Nervousness and diaphoresisiii. Heat intoleranceiv. Weakness and tremorsv. Diarrhea vi. Weight loss despite a good appetite

b. Labs

i. Elevated free T4 ii. Primary hyperthyroidism: decreased TSH

Graves'diseasea. Definition: autoimmune diseases characterized

by production of IgG autoantibodies to the TSH receptor

b. Clinical features i. Females > males; age 20 40‑ ii. Hyperthyroidism iii. Diffuse goiter

iv. Ophthalmopathy: exophthalmus v. Dermopathy: pretibial myxcdema c. Micro: hyperplastic follicles with scalloped

colloid

Other causes of hyperthyroidisma. Toxic multinodular goiterb. Toxic adenoma: functioning adenoma

producing thyroid hormonec. Hashimoto’s and subacute thyroiditis (transient hyperthyroidism)

Juvenile Graves Disease Diffuse hyperplasia Most common cause of thyrotoxicosis in children and

adolescents Clinical manifestation - muscle weakness - behavior problems - anxiety - cardiomegaly - palpitations - tachycardia - appetite - widen pulse pressure - Tremor - Emotional liability - rapid DTR time - Excessive perspiration Opthalmopathy, dermopathy, pretibial myxedema rare in children

Test: TSH suppressed and serum T4 high Treatment:

a. Blunting toxic effects circulating T3/T4 b. Stop further increase in production

B-blockers prior to Sx intervention RAI rarely used in children and adolescences

potential risk leukemia, thyroid Ca, and genetic disorder.

Medical management: PTU and methimazolemechanism: Both inhibit the coupling of

iodotyrosines, oxidation and binding of iodide

PTU 5-10mg/kg PO div q8hr Methimazole 0.2 mg/kg PO daily Once gland cools off and decrease in size tapper drugs Give synthetic T4 once euthyroid adjust to

maintain a euthyroid status

Neonatal Thyrotoxicosis Due to TSH-receptor stimulating antibodies(TSH) Transmitted transplacentally in mother with inactive or active Graves or Hashimoto thyroiditis Presentation: newborn irritability, flushing, tachycardia,

HTN, thyromegaly High total T4, FT4, T3 postnatal blood, low TSH

Treatment: a. sedative and digitalis if neededb. Iodidec. Lugol (5% iodine and 10% K iodine) d. Methimazole

Hypothyroidisma. Clinical features

i. Fatigueii. Sensitivity to cold temperatures

iii. Decreased cardiac output iv. Myxedema:

- Facial and periorbital edema - Peripheral edema of the hands and

feet - Deep voice

- Macroglossiav. Constipationvi. Anovulatory cycles

b. Labi. Decrease Free T4ii. Primary hypothyroidism: elevated TSH

Iatrogenic hypothyroidism Most common cause of hypothyroids in US Secondary to thyroidectomy or RAI rx Rx: Levothyroxine 12.5-50mcg PO qd adjusting dose by 12.5-25mcg/d q4-8wks

Congential Hypothyroidism(cretinism)a. Etiology i. Endemic region: iodine deficiency during intrauterine and neonatal life ( worldwide) ii. Non endemic regions: thyroid dysgenesisb. Presentation i. Failure to thrive ii. Stunted bone growth and dwarfism -Commonly absent distal femoral epiphysis iii. Spasticity and motor incoordination iv. Mental retardation v. Goiter (endemic cretinism)‑ Endemic goiter a. Uncommon in the US b. Etiology: dietary deficiency of iodine

Clinical Manifestation congenital Hypothyroidism

Occurs in 1/4000 Worldwide Most infant are asymptomatic at birth because of

transplacental passage of T4 (usu 3rd day of life) Most common cause is thyroid dysgenesis Presentation: hypoglycemia, jaundice micropenis, midline facial anomalies, enlarge posterior fontanelle, macroglossiaRx: Initial dose: Sodium L-tyroxine 10-15 microgrms/kg/day( should not be mixed soy protien or iron) Then, 4 micrgms/kg/day

Thyroiditis1. Hashimoto's thyroiditis a. Definition: chronic autoimmune disease characterized by

immune destruction of the thyroid gland and hypothyroidismb. Most common noniatrogenic cause of hypothyroidism and Goiter

in children > 6yo and adults in US c. Clinical presentation

i. Females > males; age 40 65‑ii. Painless goiteriii. Hypothyroidiv. Initial inflammation may cause transient hyperthyroidism.

d. Gross: pale enlarge gland e. Micro:

i. Lymphocytic inflammation with germinal centers ii. Epithelial "Harthle cell" changes

f. May be associated with other autoimmune diseases (SLE, RA, SS [Sjogren's syndrome], etc.)

g. Complication: increased risk of non Hodgkin‘‑ lymphoma (NHL) B cell lymphoma‑

2. Subacute thyroiditis a. Synonyms: De Quervain's thyroiditis, granulomatous thyroiditis b. Clinical features i. Second most common form of thyroiditis

ii. Females > males; age 30 50‑ iii. Preceded by a viral illness iv. Tender, firm, enlarged thyroid gland v. May have transient hyperthyroidism

c. Micro: granulomatous thyroiditis d. Prognosis: typically the disease follows a self limited course‑ e. Symptoms: control with analgesics, prednisone very severe dx

Riedel's thyroiditisa. Definition: rare disease of unknown etiology characterized by

destruction of the thyroid gland by dense fibrosis and fibrosis of surrounding structures (trachea and esophagus)

b. Clinical features i. Females > males; middle age

ii. Irregular, hard thyroid that is adherent to adjacent structures

iii. May mimic carcinoma and present with stridor, dyspnea, or dysphagia

c. Micro i. Dense fibrous replacement of the thyroid gland

ii. Chronic inflammation d. Associated with retroperitoneal and mediastinal fibrosis

Thyroid NeoplasiaAdenomas a. Follicular adenomas are the most common

b. Clinical features i. Usually painless, solitary nodules In first 20 yrs life likely malignant than older person ii. "Cold nodule" on thyroid scans iii. May be functional and cause hyperthyroidism (toxic adenoma)

2. Papillary carcinoma a. Epidemiology

i. Account for 80% of malignant thyroid tumors

ii. Females > males; age 20 50 ‑ iii. Risk factor: radiation exposure

b. Micro i. The tumor typically exhibits a papillary pattern.

ii. Occasional psammoma bodiesiii. Characteristic nuclear features Clear "Orphan Annie eye" nuclei Nuclear grooves

Intranuclear cytoplasmic inclusionsc. Lymphatic spread to cervical nodes is common.d. Treatment

i. Resection is curative in most cases.ii. Radiotherapy with iodine 131 is effective for metastases.

e. Prognosis: excellent; 20 year survival = 90%‑

Follicular carcinomaa. Accounts for 15% of malignant thyroid tumorsb. Females > males; age 40 60‑c. Hematogenous metastasis to the bones or lungs is common.d. High mortality rate because most present with distant mets

Medullary carcinoma

a. Accounts for 5% of malignant thyroid tumors

b. Arises from C cells (parafollicular cells) and secretes calcitonin

c. Micro: nests of polygonal cells in an amyloid stroma

d. Minority (25%) are associated with MEN 2 and MEN 3 syndromes

Treatment: primarily surgical- Advance disease external RT and chemo

Anaplastic carcinoma

a. Presentation i. Females > males; age > 60 ii. Firm, enlarging, bulky mass

iii. Dyspnea and dysphagia iv. Tendency for early widespread

metastasis and invasion of the trachea and esophagus b. Micro: undifferentiated, anaplastic, and pleornorphic cells c. Prognosis: very aggressive and rapidly fatal

Diagnosis

Fine needle aspirate vs. excision - Hx RT to neck or head - rapidly growing nodule - satellite LN and/or distant mets - Hoarseness or dysphagiaRx: Well differentiated neoplasm should be excised - TSH suppression - RAI ablation

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Q1 An 18yo old boy presents with a 1 month history of slowly enlarging neck mass. You palpate a 2-cm mass in the superior lobe of the rt. thyroid with no lymphadenopathy.

Of the following, the BEST next step is to:D. Begin therapy with RAIE. Obtain anteroposterior and lateral CXRF. Perform needle bx of the neckG. Perform total thyroidectomyH. Prescribe oral cephalexin

Q2. 15yo female presents with an asymptomatic goiter. She has type 1 diabetes that was diagnosed at age 7 years

Of the following, study that is MOST likely to establish the diagnosis is

D. Measurement of antiperoxidase antibodiesE. Needle bx of thyroidF. Technetium thyroid scanG. Thyroid-binding globulin levelsH. US of the thyroid

Q3. 44yo male involved in a MVA unresponsive intubated in ICU with multiple orthropedic injuries. He is stabilized medically on day 2 undergoes open reduction and internal fixation of right femur and right humerus. After returning to the ICU, his TSH is 0.3mU/L and total T4 is normal. T3 is 0.6 micrograms/dl. What is the next appropriate step in the management of this patient?

B. Start levothyroxineC. RAIU scanD. Thyroid USE. Observe patientF. Initiate prednisone

Q4. Which of the following statements regarding hypothyroidism is true?

B. Hashimoto’s thyroiditis is the most common cause of hypothyroidism worldwide

C. The annual risk of developing overt clinical hypothyroidism from subclinical hypothyroidism in patients with positive thyroid peroxidase antibodies is 20%.

D. Hashimoto’s is characterized by marked infiltration of thyroid with activated T and B cells

E. Low TSH excludes the diagnosis of hypothyroidismF. Thyroid peroxidase antibodies are present in 50% of

patients with autoimmune hypothyroidism

References

American College of Physicians MKSAP 13 MedStudy Pediatric Board Review Harrison’s Principle of Internal Medicine