Thyroid and Parathyroids

Thyroid

Composed of thyroid hormone secreting follicular cells (originates from foramen caecum endoderm at base of tongue) arranged in acini with central collections of colloid (containing thyroglobulin). Perifollicular/”C” cells produce calcitonin (promotes absorption of calcium by bones, inhibits osteoclasts), arise from parafollicular tissue (not foramen caecum, hence medullary carcinoma does not ocur in ectopic thyroid or TGDC). Thryoid produces, stores and releases thyroid hormones (thyroxine T4 and triiodothyronine T3). TSH (thyrotropin) is produced by the anterior pituitary gland regulated by hypothalamic thyrotropin-releasing hormone (TRH, suppressed by T4 and T3). TSH binds to follicular epithelium and stimulates thyroid growth and hormone synthesis. Follicular cells convert thyroglobulin into thyroxine (T4) and triiodothyronine (T3), which is bound to thyroxine-binding globulin and others, or free/unbound (tight controls, active form); in the periphery T4 is mostly converted to T3 which is 10x more potent. Dietry iodine is absorbed in stomach/upper SB, iodide trapped by follicular cells and organified/incorporated into thyroglobulin. 25% of ingested iodine is taken up by thyroid, 75% urinary excretion. Lingual thyroid has 30% risk of hypothyroidism.

Goiter (generalised thyroid enlargement) is associated with any level of hormone function, not well imaged with Tc-99 due to large amount of blood pool activity in the chest. Nontoxic goiter from iodine deficiency, dietary goitrogens, medications, thyroid enzyme deficiency. Usually soft and symmetric, may have cystic degenertaion, haemorrhage, colloid formation, nodularity.

Hypothyroidism – Common, subclinical in >4% of population, incresed with age. Cretinism is from early childhood/infancy hypothyroidism, with severe mental retardation, short stature, coarse facial features, protruding tongue, umbilical hernia. Myxoedema (Gull disease) is slowing of physical and mental activity with fatigue, overweight, reduced sympathetic activity (constipation, reduced sweating) reduced cardiac output with SOB, accumulation of GAGs and hyaluronic acid in tissues (non-pitting oedema, coarsened facial features, enlarged tongue, deep voice).

  • Primary hypothyroidism (most) – From intrisic abnormality. Congenital is from endemic iodine deficiency, inborn error of thyroid metabolism (dyshormonogenetic goiter eg Pendred syndrome associated with sensorineural deafness), thyroid agenesis/hypoplasia/ectopia. Aquired is from surgery, radiation or drugs; autoimmune (most common in iodine-sufficient areas) is from chronic thyroiditis/Hashimoto disease (goiter). High TSH.
  • Secondary/central hypothyroidism – From pituitary or hypothalamic abnormality. Usually deficiency of TSH, less commonly TRH. From tumour, postpartum pituitary ncrosis, trauma, radiation, infiltrative disease. Low TSH.

Thyrotoxicosis is elevated free T3 and T4. Hyperthyroidism is hyperfunction of the thyroid gland. Causes include Graves disease/diffuse toxic goiter, toxic multinodular goiter, hyperfunctional adenoma, subacute/painless thyroiditis (release of preformed hormones), iodine-induced hyperthyroidism, rare TSH secreting pituitary adenoma (secondary hyperthyroidism), struma ovarii (ovarian teratoma with ectopic thyroid tissue), factitious hyperthyroidism (from ingestion of thyroid hormone tablets). Increased basal metabolic rate with weight loss, increased appetite, heat intolerance, tachycardia, palpitations/arrythmias, cardiomegaly, overactive sympathetic nervous system (tremor, hyepractivity, anxiety, insomnia, proximal muscle weakness, gut hypermotility), goiter, osteoporosis, suppressed TSH (except pituitary adenoma), elevated T4. Thyroid storm from abrupt severe hyperthyroidism (esp Graves disease) causes acutely elevated catecholamines with fever, tachycardia, cardiac arrythmias. Apathetic hyperthyroidism in elderly due to blunting of features.

Ultrasound shows normal midline trachea, lateral CCA, IJV, posterior longus colli, anterior strap muscles. Small colloid cysts seen within gland.

Ectopic Thyroid

50% at base of tongue (lingual thyroid), 50% betweeen tongue and normal location. In 80% the lingual thyroid is the only functining thyroid tissue, detected with iodine nuclear medicine scan. Thyroid tissue is hyperdense (due to iodine) and enhances. Other ectopic sites include ovary (struma ovarii) and heart (struma cardia). Risk of papillary carcinoma is 3-5%.

Thyroglossal Duct Cyst (TGDC)

90% of congenital neck lesions. Secretory epithelium-lined tract (identical to posterior tongue) along thyroid migration tract (foramen caecum at tongue base, anterior to strap muscles, to thyroid isthmus), usually involuting by 8-10/40. Remnants result in fusiform cyst or sinus tract. Ectopic thyroid tissue may be microscopic. 75% are midline. 65% infrahyoid, 15% hyoid, 20% suprahyoid. Cyst embedded in strap muscles, may become infected. Uniformly thin capsular enhancement, occasional septations. May be high T1 from protein. May have internal echoes or be solid, but most have posterior acoustic enhancement. If it is hyperdense, usually previously infected. DDx necrotic anterior cervical node, thrombosed anterior jugular vein, abscess, obstructed laryngocoele, dermoid, teratoma. Tx Sistrunk procedure (removal of the duct, midline tongue base and mid hyoid cartilage) with MR prior for extent as will recur if incompletely resected. Rarely carcinoma in 1%, usually papillary.

Thyroiditis

Rapid, asymmetric enlargement ± nodularity. Thyroid storm on ultrasound colour Doppler.

Graves Disease

(Diffuse toxic goitre). Most common cause of hyperthyroidism. Peak 20-40yo, F:M 10:1, increased risk with FHx. Autoimmune thyroid antibodies esp TSH receptor causing hyperplasia and hyperfunction. Homogeneously enlarged (2-3x), nodule free thyroid. May be associated with ophthalmopathy and/or localised pretibial myxedema (dermopathy). Orbital preadipocyte fibroblasts express TSH receptor leading to thyroid eye disease with extraocular muscle and retro-orbital infiltration with inflammatory cells, oedema, adipocytes, causing proptosis and lid retration. Elevated T4 and T3, reduced TSH. Diffuse uptake of radioiodine. Treated with oral I-131, 1-3 doses calculated from RAIU and weight of gland, ~5-20 mCi. Euthyroid by 10-12/52, inevidible hypothyroidism at ~6-12/12. Risks: transient worsening of thyrotoxicosis from release of preformed hormone, subacute thyroiditis, temporary hypoparathyroidism, recurrent laryngeal nerve damage (rare), thyroid storm (very rare). Other treatments include beta blockers, subtotal thyroidectomy or antithyroid drugs (propylthiouracil, methimazole, carbimazole).

Acute Suppurative Thyroiditis

From strep, staph or pneumococcus. Fever, sore throat, asymmetric swelling, sepsis. Greater risk in immunocompromised. Associated with haemorrhage, necrosis, abscess, airway compromise, adjacent vascular thrombosis. Medical emergency as it may spread into mediastinum. Thyroid function usually normal. May leave focal scarring.

Subacute Thyroiditis

(de Quervain thyroiditis, granulomatous thyroiditis). Pain (most common cause of thyroid pain), hyperthyroidism following URTI, F:M 4:1, 40-50yo, self-limiting. ?Viral infection with most having URTI just before onset, peaks in summer. Initial uni/bi-lateral oedematous enlargement, then granulomatous with multinucleate giant cells, fibrosis. Inflammation causes release of all preformed thyroid hormones with return to euthyroid state after occasionally transient period of hypothyroidism. Very low RAIU (<5%) as iodine is uptake decreased/absent in the acute stage.

Hashimoto Thyroiditis

Most common cause of goiter and primary hypothyroidism in developed countries. 45-65yo (but may occur in children), F:M 10-20:1, increased risk with FHx. Autoimmune with antithyroid antibody (esp thyroglobulins, thyroid peroxidase), elevated antimicrosomal antibodies. Progressive apoptosis of thyrocytes, and replacement with lymphocytes and fibrosis. Metaplastic epithelial cells with abundant eosinophilic cytoplasm (Hurthle cells). Thyroid is painless, diffusely enlarged and rubbery. Early hyperthyroid (‘hashitoxicosis’) or euthyroid with subsequent final hypothyroidism. Inhomogeneous activity throughout gland in 50%, others multinodular goiter, solidary hot/cold nodule or normal scan. Increased risk of lymphoma. May be associated with type 1 diabetes, myasthenia gravis, Sjogren syndrome, pernicious anaemia, SLE, RA.

Variants of Hashimoto thyroiditis cause mild hyperthyroidism and/or mild goitre. Most have circulating anti-thyroid peroxidase antibodies. 1/3 evolve to overt hypothyroidism over time.

  • Subacute lymphocytic thyroiditis (painless thyroiditis) – Middle-aged, F>M.
  • Postpartum thyroiditis – Up to 5% of women in postpartum period. 80% are euthyroid by 1yr.

Riedel Thyroiditis

Rare inflammatory fibrosis of thyroid commonly extending into neck. May be associated other autoimmune diseases (multifocal fibrosclerosis) including retroperitoneal fibrosis, orbital pseudotumour, mediastinal fibrosis, sclerosing cholangitis. Thyroid is firm and woody. Hypothyroidism in 50%. Homogeneous hypoechoic, hypodense and hypointense, variable enhancement, absent radionuclide uptake in involved area. DDx radiation-induced thyroiditis.

Secondary Hyperthyroidism

Hydatiform moles or choriocarcinoma produces HCG, a subunit of which is similar to TSH.

Diffuse Nontoxic Goiter

(Simple/colloid goiter). Impaired synthesis of thyroid hormone, with compensatory rise in TSH, hypertrophy and hyperplasia of the gland to ensure a euthyroid state in most (but TSH at upper limits of normal). If the underlying disorder is severe, compensatory response may be inadequate, hence results in goiterous hypothyroidism. Diffuse/simple goiter is enlargement without nodularity. Enlarged follicles are filled with colloid.

  • Endemic goiter – Areas low in iodine where >10% of population is affected. Esp mountainous areas including Andes and Himalayas. Some foods are goiterogens, interferring with hormone synthesis worsening the disease, including cabbage, cauliflower, Brussel sprouts, turnips, cassava.
  • Sporadic goiter – F>M, peak puberty and young adults. From ingestion of goiterogens, hereditary enzyme defect (AR, dyshormonogenetic goitre) or unknown aetiology.

Multinodular Goitre

Over time, almost all long-standing simple goiters (sporadic or endemic) convert into multinodular goiters, with recurent episodes of hyperplasia and involution, massive thyroid enlargement. Variations among follicular cells give rise to clones of proliferating cells, which may be autonomous. The uneven follicular hyperplasia and colloid accumulation produces physical stress leading to rupture with haemorrhage, scarring (nodularity), calcifications. Enlargement may lead to an intrathoracic/plunging goiter behind the sternum, occasionally behind the trachea and oesophagus, local mass effect with compression of adjacent structures. Most are euthyroid or subclinical hyperthyroid, 10% have autonomous nodule(s) with toxic multinodular goier (Plummer syndrome). Adenomatous follicular hyperplasia, enlarged nodular, heterogeneous uptake or hot nodules (functioning adenomas, usually benign) on background of normal/cool parenchyma. May have a dominant nodule. Malignancy in 4%, consider if there is sudden change in size or symptoms, dominant cold nodules.

Thyroid Nodules

Incidence of palpable nodules 5%, on US 40%, on autopsy 50%; higher in endemic goiterous regions, F:M 4:1, increases with age. Thyroid cancer in only 0.1%. US high sensitivity but low specificity (also low on MR and CT). Benign nodules tend to >50% cystic (may have debris, wall irregularity with solid components), sharp well-defined margins, peripheral calcification, haemorrhagic degeneration, homogeneously hyperechoic, comet tail artifacts, multiple, hot, shrink with thyroxine, sudden onset, female, older patient. Nodules more likely to be malignant are solid, solitary, cold on iodine scan, >40-50mm, history of neck irradiation, hard on palpation, younger patients esp <20yo, male, FHx thyroid cancer; on MR incomplete low signal pseudocapsule or irregular thickness. Indeterminate nodules are hypoechoic/isoechoic, solid, amorphous dense calcification, hypoechoic halo, increased colour Doppler flow, multiple nodules on US. Those suspicious and >15mm should have an FNA.

Nodules are either:

  • Hyperfunctioning/hot – Usually hyperfunctioning adenomatous tissue, rarely malignant. Hot nodules should be evaluated with I-123 to exclude discordant nodule (increased Tc-99 uptake but decreased I-123), hence possible malignancy; able to trap Tc-99 but unable to organify iodine.
  • Hypofunctinoing/cold – 40% are hypofunctionig adenomatous tissue; 15% of solitary and 5% in multinodular glands are malignant
  • Indeterminate/warm – Usually normal activity overlying or surrounding a cold nodule, may be suppressing other thyroid tissue. If palpable and growing should have FNA.

Benign lesions:

  • Colloid nodule/cyst (adenomatous nodule/hyperplasia) – 50% of thyroid nodules. Not true neoplasms, from cycle of hyperplasia and involution of a thyroid lobule. Frequently multiple, but one may be dominant. Hyperdense, high T1, cold. May have necrosis, haemorrhage, cystic degeneration, calcification.
  • Adenoma – Most common benign thyroid neoplasm, 20% of nodules. Average 30mm, may be >100mm. Follicular (most common) or papillary adenoma. Hurthle cell adenomas are borderline benign/malignant, may be aggressive and should be treated as a malignancy. Most solitary, round/oval, well encapsulated. May be heterogeneous with necrosis, haemorrhage, oedema, infarction, fibrosis or calcification. Highly differentiated nodules may conentrate iodine, being hot/warm, often autonomously sereting (toxic adenomas) suppressing the remainder of the gland. More likely cold if there is necrosis or intralesional haemorrhage.
  • Haemorrhagic cyst – Haemorrhage into normal parenchyma, adenomatous nodule or follicular adenoma.

Thyroid Cancer

Incidence 0.1%, 1.5% of all cancers, F>M, early/middle age. Increased risk with radiotherapy, esp <20yo. Most are indolent with 90% survival at 20yrs. Malignant nodules are not reliably differentiated from benign on any imaging. Lymphadenopathy is presenting sign in 50%, with occult thyroid primary. Most (except medullary) arise from the follicular epithelium.

  • Papillary carcinoma (85%) – F:M 4:1, 25-50yo. Multicentric in 20%, often cystic, fibrosis, calcification. Branching papillae with fibrovascular stalks. Orphan Annie eyes (ground-glass) nuclei with empty appearing nuceli and calcified psammoma bodies (specific). Several variants including follicular, tall-cell, diffuse sclerosing, papillary microcarcinoma (usually incidental, ?precursors). Cold on thyroid scan. Lymphatic spread to regional nodes (esp retropharyngeal), less likely haematogenous spread to lungs and bone. Nodes are cystic, calcified, highly vascular/enhancing, bright T1 (contain colloid), small, haemorrhagic. Good prognosis with 10-yr survival >95%.
  • Follicular carcinoma (10%) – F:M 3:1, peak 40-60yo, increased risk with iodine deficiency. Single nodules. Subtypes inlude Hurthle cell (oncocytic variant) with eosinophilic cytoplasm. Lymphatic spread is uncommon. Haematogenous spread to lung and bone. Prognosis worse than papillary.
  • Anaplastic/undifferentiated carcinoma (<5%) – Older with peak 65yo, 1/4 have history of previous thyroid carcinoma. No effective treatment, 5yr survival <4%. Highly aggressive with rapid enlargement, local invasion, early distant metastases. Large pleomorphic giant cells and spindle cells. 80% have tracheal invasion. May take up thallium or gallium, doesn’t usually take up iodine.
  • Medullary carcinoma (5%) – Neuroendocrine tumour from parafollicular C cells. Associated with MEN 2 in 10%, occuring earlier, may be <10yo and early metastases. Raised serum calcitonin (useful for follow-up, not typically associated with hypocalcaemia), may also secrete serotonin, ACTH, vasoactive intestinal peptide (VIP), increased CEA. Sporadic tumours are solitary; familial may be bilateral and multicentric. Stippled calcification. Large tumours often have necrosis and haemorrahge. Does not concentrate I-131, metastases detected by thallium-201, Tc-99m dimercaptosuccinic acid (DMSA) and I-123/131-metaiodobenzylguanidine (MIBG). Worse prognosis than papillary or follicular.
  • Non-Hodgkin lymphoma – Solitary or multiple nodules or diffuse enlargement. Bilateral in 50%. Often invades into carotid sheath. Primary or systemic. F>M. Increased risk with Hashimoto thyroiditis. 50% hypothyroid. Hypoechoic/pseudocystic, hypodense.
  • Metastases to thyroid are rare, include breast, lung, kidney, melanoma.

Staging:

  • Primary tumour: May be subdivided into a (solitary) or b (multifocal). Any anaplastic carcinoma is T4.
    • Tx – Primary cannot be assessed.
    • T0 – Primary not seen.
    • T1 – </= 20mm in greatest dimension.
    • T2 – 20-40mm.
    • T3 – >40mm, minimal extrathyroid extension into sternothyroid or perithyroid soft tissues.
    • T4a – Beyond capsule into SC, larynx, trachea, oesophagus, recurrent laryngeal nerve. Tracheal invasion of there is high T2 in the wall, >180deg encasement, intraluminal mass or >25mm displacement from midline. Oesophageal invasion if thre is abnormal wall signal/enhancement, >270deg encasement, intraluminal mass.
    • T4b – Prevertebral fasia, encases carotid a or mediastinal vessels.
  • Nodes
    • N1a – Level VI
    • N1b – Bilateral, midline or contralateral cervical/mediastinal nodes.

Initial post-thyroidectomy I-131 whole body scan with 72hr RAIU, size, presence of contralateral lobe involvement and LN status for staging and treatment planning. Post-thyroidectomy I-131 ablation with tumours >1-1.5cm. Doses >33mCi require hospitilisation to protect public. Patient should be hypothyroid with high TSH to activate transport of iodine into the thyroid cell and iodine-rich foods (shellfish, bread, kelp) avoided.

Parathyroids

Normal glands are 5 x 3 x 1mm, not usually seen on imaging. Mostly composed of chief cells with secretory granules (containing parathyroid hormone PTH). Release is stimulated by low free serum calcium, with actions to increase renal tubular re-absorption, increase conversion of vitamin D at the kidneys, increase urinary phosphate excretion and augment GI absorption. 80% of abnormal parathyroid glands lie close to the thyroid. Ectopic locations include thymus, posterior mediastinum, retro-oesophagesal, carotid sheath, parapharyngeal, occasionally intrathyroid; best demonstrated with Tc-99m-MIBI, Tc-99m-Tfos (Tl-201 has poor target-to-background) sensitivity 90-95% increased with SPECT, CT 75%, MRI 75% and ultrasound sensitivity 60%.

Parathyroid cysts may have a nodule, 95% below thyroid gland, thin-walled. Rarely causes PTH seretion with HPT.

Hyperparathyroidism (HPT)

Hyperparathyroidism is the most common cause of clinically apparent hypercalcaemia. Hyperparathyroidism (hypercalaemia) is primary (most common cause of asymptomatic incidental hypercalcaemia), secondary, or tertiary. Imaging helpful with persisting hypercalaemia after resection to search for abberant/ectopic tissue, possible location of an adenoma.

Primary hyperparathyroidism is autonomous overproduction of PTH. Usually adults >50yo, F:M 4:1, most incidental hypercalcaemia. ‘Painful bones, renal stones, abdominal groans and psychic moans’. Increased osteoclastic and osteoblastic activity with net loss of bone, increased marrow fibrous tissue and haemorrhagic foci (osteitis fibrosa cystica), aggregates of osteoclasts form Brown tumours. Constipation, nausea, peptic ulcers, pancreatitis, gallstones, depression, lethargy, seizures, muscle weakness and fatigue. Increased risk of urinary tract calculi, nephrocalcinosis, metastatic calcification at other sites (stomach, lungs, myocardium, aortic/mitral valves, vessels). Serum PTH is inappropriately elevated. Surgery is curative in 95% of patients.

  • Parathyroid adenoma (85-95%) – Almost always solitary, may be multiple. Most are sporadic; familial may include MEN1, MEN2 or familial hypocalciuric hypercalcemia. Characteristically oval, 8-15mm, homogeneous, very bright T2, avid enhancement. 30% atypical high T1, intermediate T2 from cellular degeneration, haemorrhage, fibrosis, haemosiderin. DDx LN, thyroid nodule.
  • Parathyroid hyperplasia (5-10%) – May be sporadic of as part of MEN syndrome. Unable to be differentiated from multiple parathyroid adenomas on imaging. Usually affects all parathyroids, but frequently asymmetric.
  • Parathyroid carcinoma (1%) – Usually >20mm, heterogeneous, cystic degeneration. Diagnosis based on cytology is unreliable; invasion and metastases are the only reliable criteria. May invade adjacent muscles or vessels. 1/3 local recurrence. 1/3 distant metastases.

Secondary hyperparathyroidism is from chronic hypocalcaemia leading to compensatory diffuse or adenomatous parathryoid hyperplasia. Most from renal failure, causing reduced phosphate excretion (hyperphosphataemia), directly reducing serum calcium levels hence stimulating the parathyroid; reduced active vitamin D also reduces intestinal absorption, and reduces suppressive effect on parathyroid growth and PTH secretion. Other causes include dietary calcium deficiency, steatorrhea, vitamin D deficiency. Parathyroid hyperplasia may be assymetric. Similar bone (renal osteodystrophy) and metastatic calcification as primary HPT, but generally less severe. Vascular calcification may cause ischaemic damage to skin and other organs (calciphylaxis).

Tertiary hyperparathyroidism is autonomous and excessive activity from long-standing secondary hyperparathyroidism.

Hypercalcaemia of malignancy is generally in advanced cancers, from increased bone resorption in osteolytic metastases and solid cancers secreting PTH-related protein (PTHrP, paraneoplastic syndrome). PTHrP promotes osteoclastic differentiation. Epecially lung, breast, H&N, renal, haematologic esp multiple myeloma.

Hypoparathyroidism

Much less common than HPT. Tetany with neuromuscular irritability, mental changes, calcification of basal ganglia, parkinsonism, increased ICP, lens calcification and cataracts, cardiac conduction defects (prolonged QT), dental hypoplasia, failure of eruption, defective enamel and root formation, carious teeth. Causes include:

  • Surgery – Inadvertent removal of all parathyroid glands during thyroidectomy or thought to be LN, or removal of too large a proportion during HPT treatment.
  • Autoimmune – Childhood, associated with chromic mucocutaneous candidiasis and primary adrenal insufficiency.
  • AD hypoparathyroidism – Hyperfunctioning calcium receptors suppresses PTH.
  • Familial isolated hypoparathyroidims (FIH) – Rare.
  • Congenital abscence – Associated with thymic aplasia (DiGeorge syndrome), cardiovascular defects, 22q11 deletion syndrome.

Pseudohypoparathyroidism is from end-organ resistance to PTH (PTH is normal or elevated), may be associated with resistance to TSH and FSH/LH.