Robbins Pathology Chapter 24 – Endocrine

Pathology Chapter 24 – Endocrine Thyroid P 1116 Diffuse goiter   

Endemic – iodine deficiency o Goitrogen consumption Sporadic o Female, goitrogens, hereditary enzymatic defects affecting thyroid hormone synthesis (AR), idiopathic Clinical course: mass effects, normal T3 and T4, high-normal to mildly elevated TSH

Multinodular goiter    

Sporadic and endemic Caused by recurrent episodes of hyperplasia and involution of long-standing single nodule goiters Arise because of variation in follicular cell response to trophic hormones Clinical course: mass effects, euthyroid or subclinical hyperthyroidism (decreased TSH), uneven iodine uptake o Plummer syndrome: toxic multinodular goiter may develop in long-standing goiter (producing hyperthyroidism) without infiltrative ophthalmopathy and dermopathy

Neoplasms – benign:malignant::10:1; Malignancy is more likely in: solitary nodules, younger patients, males, history of radiation, cold nodules; DX by fine-needle aspiration 

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Adenomas o Discrete, solitary masses derived from follicular epithelium, most are non-functional, do not give rise to carcinoma o Somatic mutations of TSH receptor signalling pathway found in toxic adenomas o Hallmark is intact, well-formed capsule (vs multinodular goiters vs follicular carcinomas); Hürthle cells o Clinical course: unilateral painless mass (can cause mass effects), non-functioning adenomas are “cold”, toxic adenomas are “hot”; surgically removed, have excellent prognosis and do not recur or metastasize Carcinomas o Papillary: 85%; derived from follicular epithelium; activation of MAPK pathway by RET or NTRK1 rearrangements or activating BRAF mutations; RET/PTC rearrangements more common in tumors with radiation history; BRAF mutations associated with metastatic disease and extra-thyroid extension; increased risk with radiation exposure; solitary or multifocal, psammoma bodies (calcifications) seen, papillary foci point to dx, ground-glass “Orphan Annie eye nuclei”; first manifestation may be enlarged lymph node, thyroid nodule moves with swallowing, mass effects suggests advanced disease; cold nodules; excellent prognosis (better in pts depression of serum calcium levels -> stimulation of PTH; CRF -> loss of renal substance -> decreased -1-hydroxylase -> decreased vitamin D activation -> decreases intestinal absorption of calcium; vitamin D has suppressive effects on parathyroid growth and PTH secretion; parathyroid glands are hyperplastic (more chief cells, less fat cells); renal osteodystrophy (bone lesions); metastatic calcification of heart, lungs, stomach, blood vessels (calcifylaxis); tx with vitamin D and phosphate binders Tertiary: parathyroid activity becomes autonomous and excessive with resultant hypercalcemia; tx is parathyroidectomy

Hypoparathyroidism 

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Causes: o Usually due to inadvertent damage to parathyroids during thyroid surgery o Autoimmune hypoparathyroidism: associated with chronic mucocutaneous candidiasis and primary adrenal insufficiency (autoimmune polyendocrine syndrome type 1 (APS1)) caused by mutations in AIRE gene o Autosomal dominant hypoparathyroidism: caused by gain-of-function mutation of calcium-sensing receptor (CASR) gene which cause suppression of PTH -> hypocalcemia and hypercalciuria o Familal isolated hypoparathyroidism: AD mutation in PTH precursor peptide gene which impairs processing of mature hormone; AR loss of function mutation in glial cells missing-2 (GCM-2) transcription factor gene, essential for parathyroid gland development o Congenital absence of parathyroid glands: 22q11 deletion syndrome (DiGeorge) Clinical manifestations: o Tetany (neuromuscular irritability), paresthesias, carpopedal spasm, laryngospasm, generalized seizures; Chvostek sign, Trousseau sign; Mental status changes; Intracranial manifestations; ocular calcifications; cardiovascular manifestations (prolonged QT interval); dental abnormalities (hypoplasia, etc)

Pseudohyperparathyroidism: end organ resistance to actions of PTH; PTH is normal or elevated, hypocalcemia, hyperphosphatemia  

Albright’s hereditary osteodystrophy: AD kidney unresponsiveness to PTH One form with multi-organ hormone resistance due to genetic defects in G protein second messenger signalling pathway; THS and FSH/LH resistance