2016 ENDOCRINOLOGY

THYROID GLAND
HARRISON’S PRINCIPLES OF INTERNAL MEDICINE 19E

ANATOMY AND DEVELOPMENT THYROID HORMONE SYSNTHESIS, METABOLISM, AND

- Location: anterior to the trachea (between cricoid and
suprasternal notch)
- Two lobes connected by an isthmus
- Size: 12-20g
- Highly vascular and soft in consistency
Associated Structures:
- Parathyroid Glands
o Posterior to each pole of the thyroid
- Recurrent Laryngeal Nerves
o Traverses the lateral borders of the thyroid gland
- C cells
o Produces calcitonin (lowers s. calcium)
o Greatest density in the upper 1/3 and lower 2/3 of
the gland
o Involved in medullary thyroid cancer
Embryology:
- Synthesis of Thyroid hormones begins at 11th weeks’
gestation
- Transplacental passage of maternal thyroid hormones
occurs before fetal thyroid gland begins to function 
provides partial hormone support in fetus with congenital
hypothyroidism
REGULATION OF THYROID AXIS
Thyroid Stimulating Hormone (TSH)
- Regulates increased demand for thyroid hormone
- Serves as the most useful physiologic marker of thyroid
hormone function
- Set-point in the axis is established by TSH
- Peak secretion: 15min after exogenous administration of
TRH
- Released in a pulsatile manner and exhibits diurnal rhythm
o Highest level at night
- Agents that suppress TSH:
o Thyroid hormone levels
 Dominant regulator of TSH production
 Reduced levels increases basal TSH
production and enhance TRH-mediated
stimulation of TSH
o Dopamine
o Glucocorticoids
o somatostatin
Thyrotropin-releasing Hormone
- Major positive regulator of TSH synthesis and secretion
ACTION
Thyroid Hormone Synthesis
- Thyroid hormones are derived from Thyroglobulin (Tg)
Iodine Metabolism and Transport
- Iodine Uptake: critical 1st step in thyroid hormone synthesis
o Mediated by NIS (sodium iodide symporter
 Low iodide = increase NIS and stimulate
uptake
o Recommended daily intake of iodine:
 Adult: 150-250ug/d
 Children: 90-120ug/d
 Pregnant and lactating: 250ug/d
- Iodine Deficiency
o Increased thyroid blood flow and upregulates NIS
 more efficient iodine uptake
- Iodine Excess
o Transient inhibition of thyroid iodide organification
(Wolff-Chaikoff effect)
o Thyroid Hormone Production may be enhanced
or Hyperthyroidism may be induced in quiet
Graves or autonomous nodules (Jodbasedow
phenomenon)
Organification, Coupling, Storage, and Release
- Other Factors that Influence Hormone Synthesis and
Release:
o IGF-1 and Epidermal growth Factor
o TGF-b
o Endothelins
THYROID HORMONE TRANSPORT AND METABOLISM
Serum Binding Proteins: increase the pool of circulating hormone;
delay hormone clearance; modulate hormone delivery to selected
tissue sites
- Thyroxine-binding globulin (TBG)
o Low plasma conc but High affinity for thyroid
hormones (T4 > T3)
o Carries 80% of the bound hormones
- Transthyretin(TTR)/ Thyroxine-binding prealbumin (TBPA)
o Carries 10% T4 but little T3
- Albumin
o High plasma conc but Low affinity for thyroid
hormones (10% T4; 30% T3)
Thyroid Hormones
- Difference of T3 from T4
o Less tightly bound
o Greater fraction of unbound than unbound T4
o Less unbound in the circulation
o Produced in smaller amounts
o Cleared more rapidly than T4
- Action:
o Increases basal metabolic Rate
o Increases Oxygen Consumption
o Essential for normal growth
o Mental Development
o Increase sensitivity of CVS and CNS to
catecholamines
o Sexual Maturation
PHYSICAL EXAMINATIONS
- Search for signs of abnormal thyroid function
- Opthalmopathy and Dermopathy
- Examination of the neck
o Slightly flexed

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 o Thyroid size Thyroid Ultrasound
o Consistency - Valuable for diagnosis and evaluation of nodular thyroid
o Nodularity disease
o Tenderness
o Fixation - Patterns suggestive of Malignancy:
o +/- Bruit or thrill: increased vascularity o Hypoechoic solid nodules with infiltrative borders
- Pemberton Sign o Microcalcifications
o Venous distention over the neck and difficulty in - Benign:
breathing when arms are raised o Spongiform nodules
o Occurs in large retrosternal goiters DISEASES OF THE THYROID GLAND
- Lymphadenopathy (supraclavicular and cervical) 1. Congenital
LABORATORY EVALUATION a. Agenesis/ Aplasia
TSH Assays b. Hypoplasia
- Suppressed TSH c. Accessory/ Aberrant/ Lingual Thyroid Gland
o Hyperthyroidism/ thyrotoxicosis d. Thyroglossal Duct Cyst
o Pregnancy (1st trimester d/t hCG secretion) i. On PE: moves upward when tongue is
o After hyperthyroidism treatment extended
o Medications ii. Complication:
 Glucocorticoids 1. Inflammation
 Dopamine 2. Sinus Tracts
- Elevated TSH 2. Inflammatory
o Hypothyroidism – MC cause 3. Functional
o TSH-secreting pituitary tumor 4. Diffuse/ Multinodular Goiter
o Thyroid hormone resistance
o Assay artifact Hyperthyroidism Hypothyroidism
Thyroid Hormone Measurement (unbound/ free) Lesion Thyroid TSH Thyroid TSH
- Direct Metjods: Hormones Hormones
o Unbound thyroid hormone competition with Primary Increase Decrease Decrease Increase
radiolabeled T4 Secondary Increase Increase Decrease Decrease
o Physical separation of the unbound fraction by (central) or normal or normal
ultracentrifugation or equilibrium dialysis Subclinical Normal Decrease Normal Increase
Total Thyroid hormone levels
- Elevated when TBG is increased d/t estrogens: HYPOTHYROIDISM
o Pregnancy Common Causes:
o Oral contraceptives - Worldwide: Iodine Deficiency
o Hormonal Therapy - In iodine sufficient areas:
o Tamoxifen o Autoimmune (Hashimoto’s Thyroiditis)
o SERM o Iatrogenic
o Inflammatory liver disease
- Decreased when TBG binding is reduced
o Androgens
o Nephrotic Syndrome
Tests to determine Thyroid Dysfunction Etiology
- Autoimmune thyroid disease:
o Anti-TPO: Graves’ disease
o Anti-Tg:
o TSI in Graves’ disease
- Serum Tg
o Increased in all types of thyrotoxicosis except
thyrotoxicosis Factitia (caused by self-admin of
thyroid hormone)
o Main role: in follow-up of thyroid cancer patients
(should by undetectable after treatment)
Radioiodine Uptake
- Grave’s disease: enlarged gland and increased tracer
uptake that is homogenous
- Toxic Adenoma: focal areas of increased uptake
- Toxic MNG: gland is enlarged with distorted architecture
with multiple areas of relatively increased or decreased
tracer uptake
- Subacute, viral, and postpartum thyroiditis: very low uptake
with TSH suppression
Thyroid Scintigraphy/ Scan
- Performed if serum TSH level is subnormal to determine if
functioning thyroid nodules are present
- Functioning/ hot nodule  almost never malignant 
FNAB not indicated

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 o Measure thyroid function with free T4 (not TSH) in
the months following radioiodine treatment
Endemic Goiter and Cretinism
- Iodine deficiency

Treatment/ Management:
- Goal: normal TSH (lower half of normal)
- Levothyroxine 1.6ug/kg (100-150ug) taken at least 30min
before breakfast
- TSH should be measured 2 months after treatment or any
subsequent change in L-thyroxine dosage
- Once full replacement is achieved and TSH levels are
stable  annual TSH
- Because t4 has a long half-life (7days), patient who miss a
dose can be advised to take 2 doses of the skipped tablets
at once
- Causes of increase L-thyroxine requirements:
o Malabsorption
o Estrogen or SERM therapy
Congenital Hypothyroidism o Ingestion with a meal
- Due to thyroid gland dysgenesis in 80-85% o Drugs (cholestyramine, FeSO4, Calcium
- Twice as common in girls supplements, PPI,…..)
- Clinical Manifestations:
o Prolonged jaundice
o Enlarged tongue
o Delayed bone maturation
o Umbilical hernia
o Other congenital malformations (esp. cardiac)
Autoimmune Hypothyroidism
- Classification:
o Hashimoto’s/ Goitrous Thyroiditis
 Marked lymphocytic infiltration of the
thyroid with germinal center formation
 Atrophy of thyroid follicles with oxyphil
metaplasia, absence of colloid
 Mild-mod fibrosis
o Atrophic Thyroiditis: end stage of Hashimoto’s
 Extensive fibrosis
 Less lymphocytic infiltration Subclinical Hypothyroidism
 Absent thyroid follicles - Biochemical evidence of thyroid hormone deficiency in
- Risks: patients who have few or no apparent clinical features
o Genetic factors - Levothyroxine recommend in:
o Chronic Exposure to high-iodine diet o Wish to conceive or pregnant
o Mean Age: 60yo (overt disease increases with o TSH above 10mIU/L
age) o TSH below 10mIU/L for those with (+) TPO Ab or
- Clinical Manifestations: any evidence of heart disease
o Hashimoto’s  goiter MYXEDEMA COMA
o Atrophic Thyroiditis  SSx of Hyperthyroidism - Almost always occurs in elderly
o Skin: dry, decreased sweating, thin epidermis, Precipitants:
hyperkeratosis st. corneum - Factors that impair respiration (drugs, pneumonia, CHF, MI,
 Skin thickening without pitting GI bleeding, CVD)
(myxedema) - Sepsis
 Pallor (yellow tinge) d/t carotene - Exposure to cold
accumulation - Hypoventilation leading to Hypoxia and Hypercapnia
 Thinning of outer third of eyebrows Clinical Manifestations:
o Weight gain despite poor appetite (mainly d/t - Reduced LOC with seizures
fluid retention in myxedematous tissues) - Other features of hypothyroidism
o Decreased libido - Hypothermia
o Oligo- or amenorrhea Treatment:
o Reduced Fertility; increased miscarriage - Steroid/ Parenteral Hydrocortisone (before replacement
o Modestly increased Prl therapy)
o Reduced myocardial contractility and PR - Levothyroxine
- Laboratory Evaluation - Ventilatory Support
o If TSH is elevated  free T4 is needed to confirm - Hypertonic Saline or IV glucose
presence of clinical hypothyroidism
o Once confirmed  TPO antibodies or FNAB
Iatrogenic Hypothyroidism
- First 3-4 months after radioiodine treatment

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 HYPERTHYROIDISM - Sinus tachycardia: most common CVS manifestation
Thyrotoxicosis - Hypercalciuria
- State of thyroid hormone excess as a result of excessive - Thyroid usually diffusely enlarged 2-3x normal
thyroid hormone - Opthalmopathy
o Earliest manifestations: sensation of grittiness, eye
discomfort, and excess tearing
o Optic nerve compression: most serious
manifestation
Laboratory Evaluation
- Supressed TSH, free thyroid hormones elevated
- Measurement of TPO antibodies or TRAb

Graves’ Disease
- 60-80% of thyrotoxicosis
- High iodine intake is associated with an increased
prevalence of Graves’ disease
- Typically occurs between 20-50yo Treatment
- Etiology; - Antithyroid drugs – Thionamides
o Genetic o Inhibit function of TPO, reducing oxidation and
 Monozygotic 20-30% (dizygotic <5%) organification of iodide
o Smoking o Reduces thyroid Ab levels
 Minor risk factor for Graves’ but major o Propylthiouracil: inhibits deiodination of T4  T3
for development of opthalmopathy  Indications:
o High iodine intake  1st trimester of preg
o Postpartum period  Thyroid storm
o After HAART or alemtuzumab therapy  Minor A/E to methimazole
- Autoantibody: TSI  S/E:
o Can cross the placenta and cause neonatal  Hepatotoxicity
thyrotoxicosis  Fetal aplasia cutis
Clinical Manifestations: o Thyroid function tests and clinical manifestations
are reviewed 4-6 weeks after starting treatment
o Side Effects:
 Jaundice
 PTU  Hepatitis
 Methimazole  cholestasis
 Agranulocytosis
 Fever and sore throat
- Propranolol
o Helpful to control adrenergic Sx (esp in early
stages before antithyroid drugs take effect)
o Useful in thyrotoxic periodic paralysis
- Radioiodine
o Causes destruction of thyroid cells
o Used as initial treatment or for relapses after trial
- In elderly, features may be masked, only presents as of antithyroid drugs
fatigue and weight loss  apathetic thyrotoxicosis o Carbimazole or methimazole must be stopped 3-
(mistaken as depression) 5days before RAI admin
- Unexplained weight loss despite enhance appetite d/t o Contraindications:
increased metabolic rate  Pregnancy (but can conceive 6mos
- Fine tremor after tx)
- Hypereflexia  Breastfeeding
- Proximal myopathy without fasciculation
- Hypokalemic periodic paralysis

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 - Subtotal or near-total Thyroidectomy - Risk:
o Recommended in young individuals particularly o 30-50yo
when goiter is very large o Female
o Only in previously euthyroid - Patchy inflammatory infiltrate with disruption of the thyroid
o Give SSKI prior to surgery to decrease vascularity follicles and multinucleated giant cells
o Complications: - SSx:
 Bleeding o Painful enlarge thyroid with fever
 Laryngeal edema o Hyper/ Hypothyroid depending on the phase
 Hypoparathyroidism o Malaise and sx of URTI preceded thyroid-related
 Damage to RLN features
THYROTOXIC CRISIS/ THYROID STORM Phase TFT RAI Uptake
- Presents as a life-threatening exacerbation of Thyrotoxic/ Follicular Inc T3 and T4; Low or
hyperthyroidism destruction dec TSH undetectable
- SSx: T4:T3 ratio greater
o Fever than in Graves
o Delirium Hypothyroid Low t4 and Normal or mod
o Seizures High TSH increased
o Coma Recovery/ Euthyroid Normal Normal
o Vomiting - Tx:
o Diarrhea o Large dose of Aspirin or NSAIDs
o Jaundice o Glucocorticoids
Precipitating events: o Thyroid function monitored every 2-4 weeks using
- Acute illness TSH and free T4
- Surgery o Levothyroixine if hypothyroid phase is prolonged
- RAI treatment Chronic Thyroiditis
Management: - Cause:
- Large dose of PTU PO or NGT or per rectum o Hashimoto’s – MC
- 1hr after 1st PTU  stable iodide is given to block thyroid o Reidel’s Thyroiditis : Painless
hormone synthesis (Wolff-Chaikoff) APPROACH TO THYROID NODULES
- SSKI - More common in:
- Propranolol o iodine-deficient areas
- Glucocorticoids o women
- Oxygen o with Aging
THYROIDITIS Clinical Importance: need to exclude thyroid cancer
Causes:
- Benign
o Multinodular goiter (colloid adenoma)
o Hashimoto’s Thyroiditis
o Folicular Adenoma
o Hurthle Cell Adnoma
- Malignant
o Papillary Carcinoma
o Follicular Carcinoma
o Medullary Carcinoma
o Anaplastic Carcinoma
o Lymphoma
o Metastasis
History and PE
- Rapid growth: Most palpable nodules are >1cm in dm
- Childhood Head and neck irradiation & Total body
irradiation
- Family history
- PE: fixed hard mass, cervical LAD, Obstructive symptoms
Work-up
- TSH
o Normal: Most have normal TFT
o Low or subnormal
Acute Thyroiditis  Proceed to thyroid scan
- Suppurative infection of the thyroid  Cold  FNAB
- MC cause in children and young adults: Piriform sinus  Hot  Thyroid FT (least likely to
(remnant of 4th branchial pouch) be malignant)
- SSx: o High: Proceed with FNAB
o Thyroid pain - Thyroid USD
o Asymmetric thyroid goiter - FNAB
o Fever, dysphagia, and erythema over the thyroid o Benign (65%)
- Dx: o Malignant or suspicious  Sx is recommended
o Elevated ESR and WBC o Nondiagnostic
o Normal thyroid function o Indeterminate
o FNAB: infiltration of PMN
Subacute Thyroiditis
- De Quervain’s Thyroiditis/ granulomatous thyroiditis/ Viral
Thyroiditis

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 DIFFUSE NONTOXIC (SIMPLE) GOITER PAPILLARY THYROID CARCINOMA
- AKA: Simple Goiter/ Colloid Goiter - Most common type of thyroid cancer
- Diffuse enlargement in the absence of nodules and - Tends to be multifocal
hyperthyroidism - Invade locally within the thyroid gland
Etiology: - Propensity to spread via lymphatics but can mets
- Iodine deficiency (endemic goiter) – MC hematogenously (bone and lung)
- Women - Most are identified in early stages (stage I or II) and have
- Goitrogens (cassava) an excellent prognosis
SSx: Cytologic Features:
- Most are asymptomatic - Psammoma bodies
- Symmetrically enlarged, non-tender, generally soft gland - Orphan-Annie nuclei
without palpable nodules - Papillary Structures
- Pemberton’s Sign (in substernal goiter) FOLLICULAR CARCINOMA
Dx: - More common in iodine-deficient regions
- Respiratory flow measurement - Difficult to diagnose between benign and malignant
- CT/MRI - Tend to spread by hematogenous routes (Bone, lung, and
- Thyroid FT brain)
NONTOXIC MULTINODULAR GOITER - Mortality: <PTC
Etiology: Poor Prognostic Features:
- Women - Distant mets
- Iodine-deficient regions - Age >50
Histology: - Primary tumor >4cm
- Extensive fibrois - Hurthle Cell histology
- Hypercellular or cystic with colloid - Marked vascular invasion
SSx: ANAPLASTIC THYROID CANCER
- Asymptomatic and euthyroid - Poorly differentiated and aggressive cancer
- Sudden pain (usually caused by hemorrhage) - Most patients die within 6months of diagnosis
Dx: - RAI uptake: negligible
- Distorted architecture LYMPHOMA
- Normal TFT - Arise in the Background of Hashimoto’s thyroiditis
- Tracheal deviation - MC type: Diffuse large cell lymphoma
- CT/MRI - PE: rapidly expanding thyroid mass
- USD Treatment:
THYROID CANCERS - Highly sensitive to external radiation
- Surgical resection is avoided as initial therapy
MEDULLARY THYROID CARCINOMA
- More aggressive in MEN2B than 2A; familial more
aggressive than sporadic
- Marker: calcitonin
- Does not take up RAI
TREATMENT OF WELL DIFFERENTIATED THYROID
CANCER
Surgery (Bilateral, near total thyroidectomy)
- Allows accurate histologic diagnosis and staging
- Pre-op USD shoul be performed
TSH Suppression Therapy – Levothyroxine
Radioiodine Therapy
- Indications:
o Larger tumors
o Aggressive variants of PTC
o Tumor vascular invasion
o Presence of of large-volume LN mets
- Neck USD should be performed 6mos after thyroid ablation

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Follow up Whole Body Thyroid Scan and Tg Determination
- WBS is reserved for patients with known iodine-avid mets or
those with elevated s. Tg and negative imaging
Potential Therapies – Kinase Inhibitors

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