thyroid all Harrisons guid lines in detail and clear

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thyroid gland anatomy physiology diagram

A pathophysiology diagram illustrating the regulatory effects of thyroid hormones on the human kidney. The visual layout follows a vertical top-down hierarchy: an illustration of the thyroid gland leads to a box labeled 'Thyroid hormones', which in turn points to an anatomical illustration of a kidney. From the kidney, the diagram branches into three primary educational concepts: 'Growth', 'Development', and 'Renal physiology'. Under 'Renal physiology', the diagram details metabolic and hemodynamic effects. Specific metabolic actions listed include increased sodium tubular reabsorption, stimulated renin secretion, control of sulfate homeostasis, and increased calcium tubular reabsorption. The diagram serves as a conceptual overview of endocrine-renal interactions, highlighting the influence of thyroid function on renal growth, maturation, and electrolyte/fluid homeostasis. It is designed for medical students and clinicians studying nephrology and endocrinology.

This composite educational graphic details the cross-sectional anatomy of the human neck for Finite Element (FE) thyroid simulation. (a) A 2D schematic diagram presents a simplified semicircular model of the neck. It labels the layers concentrically: skin (outermost), fat, and muscle. Inside the muscle layer, the thyroid gland is depicted in pink, containing an elliptical dark grey thyroid nodule. Boundaries are marked as Γ1 (skin surface), Γ2 (trachea boundary), and Γ3 (prescribed temperature base). (b) A corresponding axial CT scan image shows the actual anatomical cross-section, with labels identifying the skin, fat, muscle, thyroid gland, trachea (central air-filled void), and an internal nodule. The CT highlights varying tissue densities, from the dark fat layer to the intermediate density of muscle and thyroid tissue. (c) A sagittal CT view of the head and neck shows a red horizontal line indicating the anatomical plane of the axial slice in (b), positioned at the level of the thyroid gland. This visual serves as a reference for modeling heat transfer and infrared thermography in patients with thyroid nodules.

This dual-panel educational graphic illustrates thyroglossal duct anatomy and the embryological descent of the thyroid gland. On the left is a sagittal anatomical diagram showing the path of descent (indicated by a red arrow) from the foramen cecum at the base of the tongue, passing through the hyoid bone, to its final position at the thyroid gland anterior to the trachea. Key labeled structures include the tongue, lingual tonsil, foramen cecum, hyoid, and thyroid gland. The right panel displays a corresponding sagittal contrast-enhanced CT image of the neck. The CT scan highlights the radiologic appearance of these landmarks: the hyoid bone appears as a high-attenuation U-shaped structure, and the thyroid gland exhibits homogenous enhancement inferior to the thyroid cartilage. This comparison demonstrates the clinical relevance of embryological pathways in understanding the location of thyroglossal duct cysts, which can occur anywhere along this midline tract.

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Graves disease ophthalmopathy exophthalmos clinical photo

$Imaging modality and technique: Clinical frontal photograph of the orbits and periorbital region in a living adult patient. Frontal view capturing both eyes demonstrates bilateral exophthalmos with mild periorbital edema and eyelid swelling. The ocular surfaces are visible with subtle scleral exposure and conjunctival vascularity not markedly prominent in this image. Anatomical localization centers on the orbital contents including extraocular muscles and orbital fat, with involvement of eyelids and periorbital soft tissues. The appearance is most consistent with thyroid ophthalmopathy (Graves’ orbitopathy), a form of autoimmune orbital inflammatory disease associated with hyperthyroidism or autoimmune thyroiditis. Pathophysiology involves infiltration and edema of orbital connective tissues and extraocular muscles, leading to proptosis, lid retraction, diplopia, and possible optic neuropathy in advanced cases. Pathognomonic imaging features in other modalities include enlargement of the rectus muscles, particularly the inferior and medial recti, with sparing of tendons; however this clinical image illustrates recognizable exophthalmos and periorbital edema rather than radiologic details. This image is clinically relevant for education, differential diagnosis, and patient counseling, as well as for correlating with thyroid function testing and orbital imaging when planning management such as immunotherapy, selenium supplementation, or orbital decompression in refractory cases. This photo supports patient diagnosis and monitoring in endocrinology, ophthalmology, and rheumatology contexts.$

Imaging modality and technique: Clinical frontal photograph of the orbits and periorbital region in a living adult patient. Frontal view capturing both eyes demonstrates bilateral exophthalmos with mild periorbital edema and eyelid swelling. The ocular surfaces are visible with subtle scleral exposure and conjunctival vascularity not markedly prominent in this image. Anatomical localization centers on the orbital contents including extraocular muscles and orbital fat, with involvement of eyelids and periorbital soft tissues. The appearance is most consistent with thyroid ophthalmopathy (Graves’ orbitopathy), a form of autoimmune orbital inflammatory disease associated with hyperthyroidism or autoimmune thyroiditis. Pathophysiology involves infiltration and edema of orbital connective tissues and extraocular muscles, leading to proptosis, lid retraction, diplopia, and possible optic neuropathy in advanced cases. Pathognomonic imaging features in other modalities include enlargement of the rectus muscles, particularly the inferior and medial recti, with sparing of tendons; however this clinical image illustrates recognizable exophthalmos and periorbital edema rather than radiologic details. This image is clinically relevant for education, differential diagnosis, and patient counseling, as well as for correlating with thyroid function testing and orbital imaging when planning management such as immunotherapy, selenium supplementation, or orbital decompression in refractory cases. This photo supports patient diagnosis and monitoring in endocrinology, ophthalmology, and rheumatology contexts.

This clinical photograph is a high-resolution, lateral oblique view of the periocular region focusing on the right eye (periorbital skin). The image demonstrates marked periorbital edema with pronounced erythema of the eyelids and surrounding cutaneous tissue. The upper and lower eyelids appear swollen and thickened, with subtle skin redundancy. In thyroid-associated ophthalmopathy (Graves' orbitopathy), this presentation reflects inflammatory edema of orbital tissues, increased adipose and extraocular muscle volume, and skin involvement. The visible periorbital edema may precede or accompany exophthalmos, lid retraction, and diplopia; however, soft tissue contour is partially obscured by lighting. The photo lacks palpation data but serves as a qualitative depiction of orbital involvement. Clinically, these features require correlation with systemic thyroid status: hyperthyroidism or euthyroid Graves' disease; presence of TSH receptor autoantibodies; risk of progressive-eye involvement. This image supports differential diagnosis including periorbital cellulitis and dermatitis, but the chronic inflammatory pattern aligns with thyroid eye disease. For diagnostic significance, the image is valuable for medical education, patient counseling, and multidisciplinary planning—endocrinology, ophthalmology, and dermatology collaboration. Potential clinical use cases include screening for orbital involvement in Graves' disease, documenting disease progression, and teaching residents about periorbital edema etiologies and differential diagnoses.

Thyroid Disorders - Harrison's Principles of Internal Medicine 22E (2025)

Source: Harrison's Principles of Internal Medicine, 22nd Edition, McGraw Hill, 2025 - Chapters 394, 395, 396, 397

PART 1 - THYROID PHYSIOLOGY & REGULATION

The Thyroid Axis (HPT Axis)

The thyroid gland produces two hormones: thyroxine (T4) and triiodothyronine (T3). The hypothalamic-pituitary-thyroid axis is a classic endocrine feedback loop:

Hypothalamus secretes TRH (thyrotropin-releasing hormone)
Anterior pituitary secretes TSH (thyroid-stimulating hormone)
Thyroid gland secretes T4 and T3
T4/T3 feedback negatively on both hypothalamus and pituitary (primarily via TRβ2)

TSH is a 31-kDa glycoprotein with α and β subunits. The α subunit is shared with LH, FSH, and hCG. TSH has a plasma half-life of ~50 min and is released in a pulsatile, diurnal manner (peak at night). A single TSH measurement is adequate for screening.

Low TSH = primary hyperthyroidism
High TSH = primary hypothyroidism

Dopamine, glucocorticoids, and somatostatin suppress TSH, but only at pharmacologic doses.

Thyroid Hormone Synthesis

Thyroid hormones are derived from thyroglobulin (Tg), a large iodinated glycoprotein. The key steps:

Iodide uptake via the sodium-iodide symporter (NIS) on the basolateral membrane
Organification: TPO (thyroid peroxidase) oxidizes iodide and incorporates it into tyrosine residues on Tg - forming MIT and DIT
Coupling: two DIT molecules → T4; one MIT + one DIT → T3
Secretion: Tg is endocytosed, cleaved, and T4/T3 released into circulation
Peripheral conversion: Most T3 is generated by peripheral deiodination of T4 (T4 is a prohormone)

Transport: >99% of T4/T3 is protein-bound (to TBG, transthyretin, albumin). Only free hormone is biologically active.

Wolff-Chaikoff effect: Acute iodine excess transiently suppresses thyroid hormone synthesis. Most individuals escape this effect after a few days.

Thyroid Function in Pregnancy

Estrogen increases TBG → total T4/T3 rise, but free hormone remains normal
hCG is a weak TSH agonist → mildly stimulates thyroid in first trimester → TSH transiently falls
Iodine requirements increase; fetal thyroid begins functioning at ~12 weeks
Maternal T4 is critical for fetal neurological development before the fetal thyroid functions

PART 2 - HYPOTHYROIDISM (Chapter 395)

Epidemiology & Causes

Category	Examples
Primary (most common)	Hashimoto's thyroiditis, iatrogenic (radioiodine, surgery, XRT), drugs, iodine excess/deficiency, infiltrative disease
Transient	Silent/postpartum thyroiditis, subacute thyroiditis
Secondary (central)	Pituitary adenoma, hypothalamic disease, hypophysitis
Congenital	Thyroid dysgenesis (65%), dyshormonogenesis (30%), TSH-R antibody (5%)

Drugs causing hypothyroidism: iodine excess (amiodarone, contrast media), lithium, antithyroid drugs, p-aminosalicylic acid, interferon-α, cytokines, aminoglutethimide, tyrosine kinase inhibitors (sunitinib), immune checkpoint inhibitors (ipilimumab, nivolumab, pembrolizumab).

Autoimmune Hypothyroidism (Hashimoto's Thyroiditis)

Two forms:

Goitrous (Hashimoto's thyroiditis) - goiter present
Atrophic thyroiditis - minimal residual thyroid tissue

Pathogenesis: Combination of genetic (HLA-DR, CTLA-4, CD25, PTPN22) and environmental factors. Autoimmune process gradually reduces thyroid reserve.

Key antibodies:

Anti-TPO antibodies (most sensitive): present in ~95% of cases
Anti-Tg antibodies: less specific
TSH-R blocking antibodies: cause atrophic thyroiditis, especially in Asian patients; can cross the placenta causing transient neonatal hypothyroidism

Risk factors: female sex, family history, Down syndrome, Turner syndrome, other autoimmune diseases.

Clinical Features of Hypothyroidism

System	Features
General	Fatigue, cold intolerance, weight gain, slow movements/speech
Skin	Dry coarse skin, hair loss, periorbital puffiness, myxedema
Cardiovascular	Bradycardia, hypertension (diastolic), pericardial effusion
Neurological	Cognitive slowing, depression, carpal tunnel syndrome, cerebellar ataxia
Reproductive	Menorrhagia, infertility, hyperprolactinemia (from elevated TRH)
Metabolic	Hyponatremia, hyperlipidemia, elevated CPK
Severe	Myxedema coma (hypothermia, stupor, respiratory failure)

Congenital Hypothyroidism

Prevalence: ~1 in 2,000-4,000 newborns
Causes: dysgenesis (65%), dyshormonogenesis (30%), TSH-R antibody-mediated (5%)
Neonatal screening is performed in most industrialized countries
Untreated leads to irreversible neurodevelopmental delay (cretinism)
Treatment must begin within weeks of birth

Laboratory Diagnosis of Hypothyroidism

Elevated TSH is the most sensitive test for primary hypothyroidism
Low free T4 confirms overt hypothyroidism
Normal TSH excludes primary hypothyroidism
Anti-TPO antibodies confirm autoimmune etiology

Subclinical hypothyroidism: elevated TSH + normal free T4, with few or no symptoms. No universally accepted treatment threshold, but treatment is generally recommended when TSH >10 mIU/L, or with symptoms, pregnancy, or positive antibodies.

Treatment of Hypothyroidism

Levothyroxine (LT4) is the standard replacement therapy.

Patient	Starting Dose
Young adults without heart disease	50-100 μg/day
Full replacement (no residual function)	~1.6 μg/kg body weight (typically 100-150 μg/day)
After Graves' disease treatment	Often lower (75-125 μg/day) - underlying autonomous function
Elderly / cardiac disease	Start low: 25-50 μg/day, titrate slowly

Key points:

LT4 ideally taken ≥30 min before breakfast on an empty stomach
TSH goal: normal range, ideally lower half
Recheck TSH 6-8 weeks after any dose change
Adjust in 12.5-25 μg increments
Annual TSH monitoring once stable
Suppressed TSH (overtreatment) increases risk of atrial fibrillation and osteoporosis

Causes of increased LT4 requirements: malabsorption (celiac disease, H. pylori gastritis, small bowel surgery), oral estrogens, drugs that impair absorption (bile acid sequestrants, ferrous sulfate, calcium carbonate, PPIs, antacids), drugs that increase T4 metabolism (rifampicin, phenytoin, carbamazepine)

Liothyronine (T3): no role as long-term monotherapy (short half-life requires 3-4 doses/day, fluctuating levels). Combination T4+T3 has not been confirmed beneficial in prospective studies. Desiccated thyroid not recommended (nonphysiologic T3:T4 ratio).

About 10-15% of patients have persistent symptoms despite achieving euthyroid TSH with LT4 - reason remains unclear.

Myxedema Coma

A medical emergency (severe, prolonged hypothyroidism):

Hypothermia, stupor/coma, bradycardia, hypoventilation, hyponatremia
Precipitants: cold exposure, infection, sedatives, surgery
Treatment: IV LT4 (200-400 μg loading then 50-100 μg/day) or T3, glucocorticoids (until adrenal insufficiency excluded), supportive care (ventilation, rewarming, fluids)

PART 3 - HYPERTHYROIDISM & THYROTOXICOSIS (Chapter 396)

Key Distinction

Thyrotoxicosis: state of thyroid hormone excess (not synonymous with hyperthyroidism)
Hyperthyroidism: excessive thyroid hormone production/secretion

Major causes of thyrotoxicosis with hyperthyroidism:

Graves' disease (60-80%)
Toxic multinodular goiter (MNG)
Toxic adenoma

Thyrotoxicosis without hyperthyroidism (destructive/exogenous):

Subacute thyroiditis
Silent thyroiditis / postpartum thyroiditis
Drug-induced thyroid destruction (amiodarone, cytokines, tyrosine kinase inhibitors, immune checkpoint inhibitors)
Thyrotoxicosis factitia (exogenous T4/T3 ingestion)

Secondary hyperthyroidism:

TSH-secreting pituitary adenoma
Thyroid hormone resistance syndrome
hCG-secreting tumors
Gestational thyrotoxicosis

GRAVES' DISEASE

Epidemiology: Most common cause of hyperthyroidism; affects up to 2% of women, 10x less common in men. Peak age 20-50 years. Prevalence increases with iodine intake.

Pathogenesis: Thyroid-stimulating immunoglobulins (TSIs) are autoantibodies against the TSH receptor that mimic TSH action, causing uncontrolled thyroid hormone production. Genetic factors: HLA-DR, CTLA-4, CD25, CD40, PTPN22, FCRL3, CD226, and TSH-R gene polymorphisms. Concordance in monozygotic twins: 20-30% (vs <5% in dizygotic).

Risk factors: Smoking (moderate risk for disease, major risk for ophthalmopathy), stress (neuroendocrine effect on immune system), sudden iodine excess, postpartum state.

Clinical Features of Graves' Disease:

Feature	Details
Goiter	Diffuse, smooth, bruit (from increased vascularity)
Ophthalmopathy	Lid retraction, periorbital edema, conjunctival injection, proptosis; occurs in up to 50%
Dermopathy	Pretibial myxedema (non-pitting) over lateral shins; occurs 1-2 years after thyrotoxicosis
Acropachy	Clubbing + periostitis; rare
General thyrotoxicosis	Heat intolerance, sweating, palpitations, tremor, weight loss despite increased appetite, diarrhea, anxiety
Cardiovascular	Tachycardia, atrial fibrillation, high-output heart failure
Reproductive	Menstrual irregularity, gynecomastia in men
Eye	Thyroid acropachy - clubbing + periostitis, occasionally

Some patients with mild Graves' disease experience spontaneous remissions. Rarely, fluctuation between hypo- and hyperthyroidism occurs due to changing TSI activity.

Laboratory:

TSH suppressed (often undetectable)
Elevated free T4, free T3
In 2-5% (more in iodine-deficient areas): T3 toxicosis - only T3 elevated
TRAb (TSH receptor antibody) elevated - most specific test

General Clinical Features of Thyrotoxicosis

System	Features
General	Weight loss, heat intolerance, excessive sweating, fatigue
Cardiovascular	Palpitations, sinus tachycardia, AF, high-output failure
GI	Increased appetite, diarrhea, nausea
Neurological	Anxiety, tremor, emotional lability, proximal myopathy
Musculoskeletal	Osteoporosis, proximal muscle weakness, periodic hypokalemic paralysis (in Asian men)
Skin	Fine hair, onycholysis, palmar erythema
Reproductive	Menstrual irregularity, fertility problems

Treatment of Graves' Hyperthyroidism

Three main options:

1. Antithyroid Drugs (ATDs)

Methimazole (MMI) - first choice (except in first trimester of pregnancy) Propylthiouracil (PTU) - preferred in first trimester (teratogenicity profile differs), thyroid storm, and breastfeeding (less placental transfer)

Mechanism: block TPO, inhibiting iodination and coupling. PTU also inhibits peripheral T4→T3 conversion.

Typical MMI dose: 10-30 mg/day (single dose)
PTU: 100-200 mg three times daily
Euthyroid in 4-8 weeks; continue 12-18 months for remission attempt
Remission rate: 40-50% after 12-18 months ATD
Factors predicting remission: small goiter, mild disease, normalized TRAb at end of treatment

Side effects:

Minor: rash, urticaria, arthralgia, fever (5%)
Major: agranulocytosis (~0.3%), hepatotoxicity (PTU >> MMI), vasculitis (PTU), aplastic anemia
Check WBC if fever/sore throat; stop drug if agranulocytosis confirmed

2. Radioactive Iodine (RAI / ¹³¹I)

Most common treatment in North America
Contraindicated in pregnancy and breastfeeding
Most patients become hypothyroid within 6-12 months (this is expected and treated with LT4)
Can worsen ophthalmopathy - use selenium + glucocorticoid cover
Pre-treat with ATDs if severe thyrotoxicosis or elderly; stop ATDs 3-5 days before RAI

3. Surgery (Total or Near-Total Thyroidectomy)

Indications: large goiter, suspected malignancy, severe ophthalmopathy, pregnancy in first trimester (if ATDs not tolerated), patient preference, RAI not feasible.

Pre-operative preparation: euthyroid with ATDs; Lugol's iodine 10 days before surgery (to reduce vascularity)
Complications: hypoparathyroidism, recurrent laryngeal nerve injury
Outcome: high cure rate; hypothyroidism requires LT4 replacement

Graves' Ophthalmopathy Treatment

Mild ophthalmopathy: No specific treatment; artificial tears, dark glasses, selenium 100 μg twice daily, smoking cessation, euthyroid state maintenance.

Moderate-to-severe active ophthalmopathy: IV methylprednisolone (500 mg once weekly × 6 weeks, then 250 mg once weekly × 6 weeks) - preferred over oral glucocorticoids.

Teprotumumab (IGF-1 receptor inhibitor monoclonal antibody): First-line in active moderate-to-severe disease with significant proptosis or diplopia. Improves proptosis, diplopia, clinical activity score, and quality of life. Relapse rates ~30% (similar to glucocorticoids).

Rituximab, tocilizumab: Second-line after glucocorticoids.

Sight-threatening ophthalmopathy (optic nerve compression): Emergency - immediate high-dose IV glucocorticoids ± urgent orbital decompression surgery.

Rehabilitation surgery (once stable): Orbital decompression → strabismus surgery → eyelid surgery (in that order).

Graves' ophthalmopathy - bilateral exophthalmos with periorbital edema

Thyroid Storm (Thyrotoxic Crisis)

A life-threatening emergency:

Precipitants: acute illness (stroke, infection, trauma, DKA), surgery (especially thyroid surgery), radioiodine in untreated/partially treated patients.

Features: Fever, delirium, seizures, coma, vomiting, diarrhea, jaundice + signs of severe thyrotoxicosis.

Mortality: 4-17% even with treatment (cardiac failure, arrhythmia, hyperthermia).

Management:

PTU 500-1000 mg loading dose, then 250 mg every 4 hours (oral/NG/PR) - drug of choice (also inhibits T4→T3 conversion). If PTU unavailable: methimazole 20 mg q6h
Wait 1 hour, then give stable iodide (SSKI 5 drops every 6 hours) - Wolff-Chaikoff effect blocks new hormone synthesis; the delay prevents iodine incorporation into new hormone
Propranolol 60-80 mg PO q4h or 2 mg IV q4h (reduces tachycardia, adrenergic symptoms; high doses also decrease T4→T3 conversion). Or IV esmolol if monitoring for heart failure
Glucocorticoids: hydrocortisone 300 mg IV bolus, then 100 mg every 8 hours (inhibit T4→T3 conversion, treat possible adrenal insufficiency)
Cholestyramine - sequesters thyroid hormones
Supportive: cooling blankets, oxygen, IV fluids, antibiotics if infection present, antipyretics (avoid aspirin - displaces T4 from binding proteins)

Other Causes of Thyrotoxicosis

Toxic Multinodular Goiter (MNG):

Typically older patients with long-standing goiter
Multiple autonomously functioning nodules
RAI or surgery preferred (less likely to remit with ATDs alone)

Toxic Adenoma:

Single autonomously functioning nodule
TSH suppressed; hot nodule on scan
Treat with RAI or surgery

Amiodarone-Induced Thyrotoxicosis (AIT):

Type 1 AIT: underlying thyroid abnormality (Graves', nodular goiter) + Jod-Basedow iodine excess. Color-flow Doppler: increased vascularity. Treat with ATDs (high dose MMI) ± potassium perchlorate
Type 2 AIT: destructive thyroiditis from direct toxicity; no underlying thyroid disease. Color-flow Doppler: decreased vascularity. Treat with glucocorticoids (prednisolone 30-40 mg/day)
RAI and thyroid scan difficult to interpret (high endogenous iodine suppresses tracer uptake)
Amiodarone is 39% iodine by weight; 200 mg/d = very high iodine load; persists >6 months after stopping (stored in adipose)

PART 4 - THYROIDITIS

Subacute (De Quervain's) Thyroiditis

Most common cause of painful thyroid
Usually follows viral upper respiratory infection (viral etiology: mumps, Coxsackie, adenovirus)
Pathology: granulomatous inflammation with giant cells

Clinical phases:

Thyrotoxic phase (2-8 weeks): painful/tender goiter, fever, elevated T4/T3, suppressed TSH, elevated ESR; thyroidal uptake very low (destructive release, not new synthesis)
Euthyroid phase: brief transition
Hypothyroid phase (weeks to months): transient hypothyroidism as hormone stores depleted
Recovery: most return to euthyroid; 5-15% develop permanent hypothyroidism

Treatment:

Mild: NSAIDs/aspirin for pain
Moderate-severe: prednisone 40 mg/day, taper over 6-8 weeks
Beta-blockers for thyrotoxic symptoms
LT4 if hypothyroid phase symptomatic

Silent Thyroiditis (Lymphocytic Thyroiditis)

Painless goiter + transient thyrotoxicosis
Histology: lymphocytic infiltration (no giant cells)
Low radioiodine uptake (destructive release)
More common in women; often postpartum (postpartum thyroiditis)
Postpartum thyroiditis: occurs in ~5-10% of women, typically 1-6 months postpartum; positive TPO antibodies in most
Course: thyrotoxic phase → hypothyroid phase → usually recovery (but 20-30% develop permanent hypothyroidism)
Treatment: beta-blockers for thyrotoxic phase; LT4 if hypothyroid phase symptomatic or trying to conceive

Hashimoto's Thyroiditis

(See Autoimmune Hypothyroidism section above - same entity)

Lymphocytic infiltration with germinal centers, Hürthle cell change
Anti-TPO and anti-Tg antibodies elevated
May rarely present with transient thyrotoxicosis (Hashitoxicosis) early in the disease
Treatment: LT4 when hypothyroid; no role for glucocorticoids routinely

Riedel's Thyroiditis (Fibrous Thyroiditis)

Rare; dense fibrosis obliterating thyroid and adjacent structures
Associated with IgG4-related disease
Presents as rock-hard, painless goiter; may cause compression symptoms (dysphagia, hoarseness, stridor)
Surgery may be needed to relieve compression; glucocorticoids, tamoxifen used medically

PART 5 - THYROID NODULES & CANCER (Chapter 397)

Thyroid Nodules - Approach

Thyroid nodules are common (~4-7% palpable; >50% found incidentally on imaging - incidentalomas). The main concern is to exclude malignancy (~5-10% of nodules).

Evaluation:

History and physical exam: risk factors for malignancy (childhood irradiation, family history MTC/MEN2, rapid growth, hard consistency, fixed nodule, cervical lymphadenopathy, dysphonia)
TSH: if low → hot nodule → radionuclide scan to assess function
Ultrasound: mainstay of evaluation; assesses size, echogenicity, borders, calcifications, vascularity, lymph nodes. Risk stratification by sonographic features (ATA/ACR TIRADS guidelines)
FNA (Fine Needle Aspiration): gold standard for cytological diagnosis. FNA indicated based on size + sonographic risk. Size thresholds have been raised under recent guidelines to avoid overdiagnosis.

Bethesda System for Thyroid FNA:

Category	Description	Malignancy Risk	Action
I	Non-diagnostic	~5-10%	Repeat FNA
II	Benign	~0-3%	Clinical follow-up
III	Atypia of undetermined significance (AUS/FLUS)	~10-30%	Repeat FNA or molecular testing
IV	Follicular neoplasm	~25-40%	Surgical lobectomy
V	Suspicious for malignancy	~50-75%	Surgery
VI	Malignant	~97-99%	Surgery

Cystic nodules: may be aspirated for diagnosis/relief; ethanol sclerotherapy used for symptomatic cysts. TSH suppression therapy does not reduce nodule size in iodine-sufficient populations.

Thyroid Cancer

Thyroid carcinoma is the most common endocrine malignancy. Most cases are differentiated (well-differentiated) and carry an excellent prognosis.

Incidence trends: Increased from 4.9 to >15/100,000 in the US over 30 years (largely due to overdiagnosis of small papillary cancers). More recently, incidence is decreasing (62,450 cases in 2015 → 43,720 in 2023) following evidence-based guideline adoption.

The 20-year disease-specific mortality for low-risk thyroid cancer is 1%.

Well-Differentiated Thyroid Cancer (DTC)

Papillary Thyroid Cancer (PTC) - Most Common (~80-85%)

Derived from follicular epithelium
Spreads via lymphatics → cervical lymph nodes
Nuclear features: Orphan Annie eye nuclei, nuclear grooves, intranuclear inclusions, psammoma bodies
Often multifocal
May harbor BRAF V600E mutation (associated with worse prognosis) or RET/PTC rearrangements
Generally excellent prognosis (>98% 10-year survival for low-risk)
Microcarcinoma (PTC <1 cm): very low malignant potential; active surveillance is an option

Follicular Thyroid Cancer (FTC) - ~10%

Encapsulated tumor; spreads hematogenously (lung, bone, brain)
Cannot be distinguished from follicular adenoma by FNA alone - requires assessment of capsular/vascular invasion on histology (hence lobectomy → pathology review)
RAS mutations common; PAX8-PPARγ translocation
Hürthle cell carcinoma is a variant (oxyphilic cells)

Staging of Differentiated Thyroid Cancer

AJCC/TNM system - the 8th edition significantly lowered the staging (patient age cutoff raised from 45 to 55 years):

Patients <55 years: only Stage I (no distant mets) or Stage II (distant mets) - no T or N classification affects stage
Patients ≥55 years: full TNM staging; local extension and nodal involvement matter more

ATA Risk Stratification (for recurrence):

Low risk: intrathyroidal PTC, no distant mets, no vascular invasion, no aggressive histology
Intermediate risk: microscopic extrathyroidal extension, vascular invasion, N1 disease, BRAF V600E mutation with other risk factors
High risk: gross extrathyroidal extension (T4), incomplete resection, distant metastases, Tg disproportionately elevated

Treatment of Differentiated Thyroid Cancer

Surgery:

Lobectomy: acceptable for low-risk unifocal PTC <4 cm, no extrathyroidal extension, no lymphadenopathy
Total thyroidectomy: for tumors >4 cm, bilateral disease, extrathyroidal extension, known metastases, high-risk histology

Radioactive Iodine (RAI ¹³¹I) Ablation:

Used postoperatively for intermediate/high-risk patients
Not routinely for low-risk disease (limited benefit; increases risk of second malignancies)
Requires TSH stimulation (stop LT4, allow TSH to rise to >30 mIU/L, or use recombinant human TSH - rhTSH)
Low iodine diet prior to RAI

TSH Suppression Therapy:

LT4 in doses to suppress TSH below normal in high-risk patients
Low-risk patients: TSH maintained at low-normal (0.5-2 mIU/L)
Intermediate risk: TSH 0.1-0.5 mIU/L
High risk: TSH <0.1 mIU/L

Surveillance after DTC treatment:

Thyroglobulin (Tg) + anti-Tg antibodies + neck ultrasound
Rising Tg suggests recurrence; imaging with I-131 whole-body scan or ¹⁸F-FDG PET if Tg rising but no structural disease detected

Recurrence/Metastatic DTC:

RAI-avid disease: RAI treatment
RAI-refractory: Tyrosine kinase inhibitors (sorafenib, lenvatinib for DTC; vandetanib, cabozantinib for MTC)

Anaplastic Thyroid Cancer (ATC)

<2% of thyroid cancers but highly aggressive (among the most lethal of all cancers)
Median survival: 3-5 months; <20% 1-year survival
Presents as rapidly enlarging neck mass, often with compression symptoms and distant metastases
All ATC is considered Stage IV by definition
BRAF V600E mutation in ~45%; targeted therapy with dabrafenib + trametinib (BRAF/MEK inhibition) has shown responses in BRAF-mutated ATC and is now an important treatment option
Multimodal: surgery if resectable + external beam radiation + chemotherapy ± targeted therapy
Immune checkpoint inhibitors being investigated

Medullary Thyroid Carcinoma (MTC)

Derived from parafollicular C cells (calcitonin-secreting)
Not follicular-derived - does NOT concentrate iodine; RAI has no role
Accounts for ~5% of thyroid cancers
25% are hereditary (associated with MEN2A, MEN2B, or familial MTC) via RET proto-oncogene mutations
- MEN2A: MTC + pheochromocytoma + primary hyperparathyroidism
- MEN2B: MTC + pheochromocytoma + mucosal neuromas + marfanoid habitus; most aggressive MTC
Sporadic MTC (~75%): usually presents 5th-6th decade as solitary nodule

Diagnosis:

Calcitonin is the tumor marker (elevated; very specific)
CEA also elevated (useful for monitoring)
All patients with MTC should undergo RET mutation testing
Screen for pheochromocytoma before surgery (24-hour urine metanephrines)
FNA may show amyloid (from calcitonin deposits, stains with Congo red)

Treatment:

Total thyroidectomy + bilateral central neck dissection
No role for RAI
Vandetanib or cabozantinib (RET/VEGFR inhibitors) for advanced/metastatic MTC
Selpercatinib or pralsetinib (highly selective RET inhibitors): more recently approved, better tolerability

Calcitonin levels guide surveillance; a rising CEA doubling time <6 months indicates poor prognosis.

Thyroid Lymphoma

Rare; usually diffuse large B-cell lymphoma (DLBCL) arising in the setting of Hashimoto's thyroiditis
Presents as rapidly enlarging goiter
Diagnosis: large-needle core biopsy (FNA often inadequate for lymphoma typing)
Treatment: chemotherapy (CHOP) ± radiation; excellent response compared to ATC

PART 6 - MEASUREMENT OF THYROID FUNCTION

Thyroid Function Tests Summary

Test	Clinical Use
TSH	Primary screening; most sensitive test; low in hyperthyroid, high in hypothyroid
Free T4	Confirms overt hypo/hyperthyroid; used when TSH abnormal
Free T3	T3 toxicosis; monitor severe hyperthyroidism; rarely needed
Total T4/T3	Affected by binding protein changes; less useful clinically
Anti-TPO antibodies	Autoimmune thyroiditis (Hashimoto's, Graves'); best screening antibody
Anti-Tg antibodies	Less specific; interfere with Tg measurement
TRAb (TBI assay)	Graves' disease (elevated TSI); TSH-R blocking Abs in atrophic thyroiditis
Thyroglobulin (Tg)	Thyroid cancer surveillance post-thyroidectomy
Calcitonin	MTC diagnosis and surveillance
Radioiodine uptake	Distinguishes causes of thyrotoxicosis (high uptake = hyperthyroidism; low uptake = destructive thyroiditis)

PART 7 - AMIODARONE & THYROID

Amiodarone (39% iodine by weight; 200 mg/d → >40-fold increase in urinary iodine):

Effect	Mechanism
Transient suppression of thyroid function	Iodine excess - initial Wolff-Chaikoff effect
Euthyroid hyperthyroxinemia	Inhibits deiodinase (↓T4→T3, ↑T4, ↑rT3)
Hypothyroidism (up to 13% in iodine-replete areas)	Escape failure from Wolff-Chaikoff in autoimmune thyroiditis
AIT Type 1: Thyrotoxicosis	Jod-Basedow; underlying nodular/Graves' thyroid; ↑Doppler vascularity
AIT Type 2: Thyrotoxicosis	Destructive thyroiditis; histiocyte accumulation; ↓Doppler vascularity

Typical TFT pattern on amiodarone: ↑T4, ↓T3, ↑rT3, transient ↑TSH → TSH normalizes within 1-3 months.

AIT management:

Type 1: high-dose MMI ± potassium perchlorate
Type 2: prednisolone 30-40 mg/day, taper
Mixed: combination therapy; consider thyroidectomy if refractory and amiodarone cannot be stopped (often amiodarone is lifesaving and cannot be discontinued)

PART 8 - SUBCLINICAL THYROID DISEASE

Subclinical Hypothyroidism

TSH elevated, free T4 normal
No universally accepted treatment threshold
Generally treat if: TSH >10, symptoms present, antibodies positive, pregnancy
Risk of progression to overt hypothyroidism: ~2-5%/year (higher with positive TPO antibodies)

Subclinical Hyperthyroidism

TSH suppressed, free T4/T3 normal
Increased risks: atrial fibrillation (especially in elderly), osteoporosis, cardiac mortality
Generally treat if: TSH persistently <0.1 mIU/L, elderly, cardiac disease, osteoporosis
TSH 0.1-0.4 mIU/L: observe vs treat based on clinical context

Source: Harrison's Principles of Internal Medicine, 22nd Edition (2025), McGraw Hill Medical - Chapters 394 (Thyroid Regulation, Synthesis, Action), 395 (Hypothyroidism), 396 (Hyperthyroidism & Thyrotoxicosis), 397 (Thyroid Nodules & Cancer), Block files 42-43.

This covers the full scope of thyroid disease from Harrison's 22E. Each section reflects the current (2025) guidelines and treatment algorithms. Let me know if you want any specific section expanded further - for example, detailed FNA cytology, molecular testing in thyroid cancer, specific drug dosing, or surgical management algorithms.

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