elevated levels of T₃ and T₄

caused by Graves' disease, hyperfunctional multilobular goiter, or hyperfunctional adenoma

increases BMR

skin is soft, warm, flushed; heat intolerance; weight loss; increased sweating; increased cardiac output, tachycardia, palpitations, cardiomegaly, arrythmias; wide, staring gaze; GI hypermotility, malabsorption, diarrhea; osteoporosis

abrupt onset of severe hyperthyroidism

most common in underlying Graves' disease

probably a result of an acute elevation in catcholamine levels (infection, surgery, stress)

pts are febrile and present with tachycardia out of proportion to the fever

medical emergency!

hypothyroidism and sensorineural deafness

caused by mutations in the SLC26A4 gene

pendrin product is an anion transporter on the apical surface of thyrocytes and inner ear

hypothyroidism that develops in infancy or early childhood

impaired development of skeletal system and CNS

severe mental retardation, short stature, coarse facial features, protruding tongue, umbilical hernia

severity correlates to time of thyroid deficiency in utero

hypothyroidism developing in the older child or adult

Overall physical and mental slowing: fatigue, apathy, mental sluggishness, cold intolerant, overweight, cool, pale skin, reduced cardiac output (causes shortness of breath, less exercise capacity)

increase in total cholesterol and LDL

accumulation of glycosaminoglycans and hyaluronic acid in skin and subcutaneous tissue --> non-pitting edema, a broadening and coarsening of facial features, tongue enlargement, deepening of voice

T₄ is decreased; TSH is increased

autoimmune hypothyroidism caused by autoantibodies against thyroglobulin and thyroid peroxidase

CTLA4, PTPN22 genes associated

CD8+ cytotoxic T cell and cytokine (T_H1, interferon γ)-mediated cell death

diffusely enlarged thyroid; pale, yellow-tan, firm, nodular

extensive mononuclear inflammatory infiltrate and germinal centers

atrophic follicles lined by Hurthle cells (epithelial cells with abundant, eosinophilic, granular cytoplasm)

fibrous variant = severe thyroid follicular atrophy and dense "keloid-like" fibrosis, broad bands of acellular collagen encompassing residual thyroid tissue

increased risk of B-cell non-Hodgkin lymphoma

transient hyperthyroidism caused by disruption of thyroid follicles, with secondary release of thyroid hormones

eventually, hypothyroidism ensues

Subacute (granulomatous) thyroiditis

De Quervain thyroiditis

believed to be virally triggered, particular after URI

most common cause of thyroid pain

unilaterally or bilaterally enlarged thyroid; firm, with intact capsule; involved areas are firm, yellow-white; patchy

aggregates of lymphocytes, activated macrophages, and plasma cells about collapsed, damaged follicles

multinucleate giant cells enclose fragments of colloid (granulomatous thyroiditis)

painful w/ visible enlargement; iodine uptake decreased; high T₄ and T₃, low TSH

transient hyperthyroidism recovers in 6-8 wks

mild hyperthyroidism, painless goitrous thyroid enlargement

usually middle-aged women

variant of Hashimoto; circulating anti-thyroid peroxidase antibodies; often a family history of autoimmunity

thyroid appears grossly normal

lymphocytic infiltration with hyperplastic germinal centers within the thyroid parenchyma

patchy disruption and collapse of thyroid follicles

no fibrosis or Hurthle cells

variant of Hashimoto occuring postpartum

circulating antibodies to thyroid peroxidase or family history of autoimmunity

transient hyperthyroidism

usually euthyroid within a year

hyperthyroidism, opthalmopathy with resultant exopthalmos, dermopathy (pretibial myxedema)

polymorphisms in CTLA4, PTPN22, HLA-DR3

presence of thyroid-stimulating antibodies (IgG), thyroid growth-stimulating Igs, TSH binding inhibitor Igs

diffuse, symmetrical hypertrophy and hyperplasia

parenchyma is soft, meaty; crowded follicular epithelial cells may form small papillae

colloid is pale w/ scalloped margins; T cell predominant lymphoid infiltrate; germinal centers

sympathetic overactivity

inc. T₄ and T₃; dec. TSH; diffuse iodine uptake

caused by infiltration of mononuclear cells (T cells) inflammatory edema and swelling of extraocular muscles

accumulation of ECM glycosaminoglycans (hyaluronic acid, chondroitan sulfate)

increased adipocytes

thyroid enlargement w/o nodularity; impaired synthesis of thyroid hormone

iodine deficiency, goitrogens, sporadic

hyperplastic phase - diffuse, symmetrical gland enlargement; follicles lined with crowded columnar cells

colloid involution - if iodine is increased or TH demand increases, follicular epithleium involutes to form an enlarged, colloid-rich gland; brown, glassy, somewhat translucent; follicular epithelium is flattened, cuboidal; abundant colloid

symptoms related to mass effect

T₃ and T₄ normal; TSH elevated/upper range of normal

caused by recurrent episodes of hyperplasia and involution

polyclonal and monoclonal nodules coexist

multilobulated with unpredictable enlargement pattern

intrathoracic/plunging goiter = behind sternum, clavicles

irregular nodules w variable amts of brown gelatinous colloid

older lesions have areas of hemorrhage, fibrosis, calcification, cystic change

colloid-rich follicles lined by flattened, inactive epithelium and areas of follicular hyperplasia

symptoms due to mass effects

uneven iodine uptake

a multinodular goiter in which an autonomous nodule may develop and produce hyperthyroidism (toxic multinodular goiter)

not accompanied by infiltrative opthalmopathy or dermopathy

Thyroid adenomas 

(follicular adenomas)

solitary, well-demarcated, spherical, encapsulated lesion

RAS, PIK3CA, PAX8-PPARG fusion gene; GOF mutations in TSHR or GNAS for toxic lesions

gray-white to red-brown; well-defined, intact capsule 

may have areas of hemorrhage, fibrosis, calcification, cystic change

uniform-appearing cells that contain colloid

unilateral, painless mass; difficulty swallowing

Hurthle cell adenoma is a variant

nonfunctioning = cold nodules on radioscan

toxic = hot nodules

most common thyroid carcinoma (>85%)

activation of MAP kinase pathway due to rearrangement of RET/PTC or NTRK1 or GOF point mutation in BRAF

most common b/w 25 and 50; previous ionizing radiation

branching papillae with a fibrovascular stalk covered by cuboidal epithelial cells

ground-glass/Orphan Annie eye nuclei w/ intranuclear inclusions (pseudo-inclusions)

psammoma bodies (concentric calcifications)

foci of lympathic invasion

has the characteristic nuclei of papillary carcinoma but has an almost totally follicular architecture

lower frequency of RET/PTC rearrangements; higher frequency of RAS mutations; distinct mutation in BRAF, resulting in a lower degrees of BRAF kinase activation

more frequenctly encapsulated; lower incidence of lymph node metastases and extra-thyroidal extension

papillary carcinoma marked by tall columnar cells with intensely eosinophilic cytoplasm lining the papillary structures

older age occurrence; high frequencies of vascular invasion, extra-thyroidal extension, cervical and distant metastases; more aggressive

BRAF mutations in most cases (55-100%), often with RET/PTC translocation

papillary carcinoma occuring in younger individuals, including children

prominent papillary growth pattern, intermixed with solid areas containing nests of squamous metaplasia

extensive, diffuse fibrosis; often with prominent lymphocytic infiltrate

lymph node metastases are always present

no BRAF mutations; RET/PTC mutation in half of cases

thyroid cancer more frequent in areas of iodine deficiency

well-circumscribed or infiltrative single nodules

gray to tan to pink; may be translucent 

uniform cells forming small follicles containing colloid

NO psammoma bodies; NO orphan annie nuclei

may be minimally or widely invasive

slowly enlarging, painless nodule; cold on scintigrams

tx with total thyroidectomy

 follicular carcinoma that tends to have a greater proportion of solid or trabecular growth pattern, less evidence of follicular differentiation, and increased mitotic activity

infiltrates thyroid parenchyma and adjacent soft tissues

50% mortality rate within 10 yrs

undifferentiated tumors of the thyroid follicular epithelium

aggressive, close to 100% mortality rate

mean age of 65

highly anaplastic cells with large, pleomorphic giant cells, spindle cells and mixed spindle and giant cells

neoplastic cells express markers for cytokeratin

rapidly enlarging bulky neck mass

dyspnea, dysphagia, hoarseness, cough

neuroendocrine neoplasms derived from parafollicular C cells; secrete calcitonin

70% sporadic; rest as part of MEN 2A or 2B or FMTC

assoc. w/ point mutations in RET proto-oncogene

sporadic origin = solitary; familial = bilateral, multicentric

polygonal to spindle-shaped cells that may form nests, trabeculae, or follicles; acellular amyloid deposits in the adjacent stroma from altered calcitonin polypeptides

familial only = C cell hyperplasia

NO hypocalcemia

solitary, well-circumscribed, soft, tan to reddish brown 

glands outside the nodule are normal in size or shrunken due to inhibition by elevated serum calcium

composed of uniform, polygonal chief cells with small, centrally placed nuclei; sometimes, bizarre or pleomorphic (endocrine atypia)

always few nests of larger oxyphil cells

rim of compressed non-neoplastic tissue separated by a fibrous capsule

hypercalcemia; serum PTH is inappropriately elevated for the levels of serum Ca²⁺

hypophophatemia, increased urinary excretion of phosphate and calcium

cause of hyperparathyroidism; increased [PTH]

frequent asymmetry; classically, all four glands involved

chief cell hyperplasia in a diffuse to multinodular pattern

constituent cells may contain abundant water clear cells; called "water-clear cell hyperplasia"

islands of oxyphils are present; poorly developed, delicate fibrous strands envelop nodule; no stromal fat

enlargement of one parathyroid gland

gray-white, irregular mass

cell are usually uniform, resemble normal parathyroid cells

nodular or trabecular patterns with a dense fibrous capsule

must have invasion of surrounding tissues and metastasis

malignancy is the most common cause of symptomatic hypercalcemia: "painful bones, renal stones, abdominal groans, psychic moans"

most common cause of asymptomatic hypercalcemia

serum PTH levels are inappropriately elevated for the level of serum calcium

caused by adenoma, primary hyperplasia

any condition that causes chronic hypocalcemia

usually renal failure

parathyroid glands are hyperplastic, not necessarily symmetric

increased number of chief cells; more water clear cells

decreased fat cells; bone changes and metastatic calcification are common

condition is dominated by symptoms of chronic renal failure: renal osteodystrophy, calciphylaxis (vascular calcifications that damage other organs and skin)

usually respond to dietary vitamin D supplements and phosphate binders

autoimmune hypoparathyroidism caused by mutation in AIRE gene

chronic mucocutaneous candidiasis and primary adrenal insufficiency

typically presents in childhood with the onset of candidiasis

caused by gain of function mutations in the calcium-sensing receptor (CASR)

suppresses PTH, leading to hypocalcemia and hypercalciuria

autosomal dominant or recessive hypoparathyroidism

autosomal dominant = mutation in the gene encoding PTH precursor peptide

autosomal recessive caused by loss of function mutations in the transcription factor gene glial cells missing-2 (GCM2), essential for parathyroid development

usually related to hypocalcemia

tetany, Chvostek sign and Trousseau sign, mental status change (instability, anxiety, depression, psychosis, etc.), intracranial manifestations like calcifications of the basal ganglia, parkinsonian-type movement disorders and increased ICP, ocular disease with calcification of the lens and cataract formation, prolonged QT interval, dental abnormalities

Skeletal changes: increased osteoclasts, increased osteoblastic activity; resultant bone contains widely spaced, delicate trabeculae like those seen in osteoporosis; may lead to osteitis fibrosa cystica, w/ increased amts of fibrous tissue, hemmorhagic foci and cyst formation

Brown tumors: aggregates of osteoclasts, reactive giant cells, and hemorrhagic debris that may be mistaken for neoplasms

Nepholithiasis: due to PTH-induced hypercalcemia

Extra-parathyroid metastatic calcifications

hypoparathyroidism due due end-organ resistance to the actions of PTH

serum PTH is normal or elevated

can be multi-hormone end-organ resistance, including TSH and FSH/LH

genetic defects in G-protein-second-messenger pathways

presents as hypocalcemia, hyperphosphatemia, elevated PTH

LH/FSH resistance presents as hypergonodatropic hypogonadism in females