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CONGENITAL ANOMALIES

Usually 4 glands -2-3 glands (10%) -5 glands (5.2%) -6 glands (0.2%). 35 mgm (4 x 3 x 1.5 mm) each, yellow-brown ovoid encapsulated noduleCombined (4 glands) weight = 117.6

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CONGENITAL ANOMALIES

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    8. CONGENITAL ANOMALIES Ectopias Upper glands Inside carotid sheath Behind esophagus Lower glands with thymus in the mediastinum or thymus in the neck Intrathyroid (0.2%), in pharynx, in vagus n., or ganglia Parathyroid cysts Developmental failures DiGeorge syndrome

    12. HYPOPARATHYROIDISM clinical Tetany: Chvostek, Trousseau, Erb signs hyperreflexia: neuromuscular irritability laryngeal spasm (stridor) epilepsy EKG findings: prolonged Q-T interval Clinical manifestations due to: decreased serum Ca (increase in serum PO4-3)

    14. HYPOPARATHYROIDISM pathogenesis Surgical ablation & irradiation injury Congenital absence (DiGeorge syndrome) Autoimmune polyglandular syndrome Defective regulation of PTH secretion (hypocalcemia & hypercalciuria: activating mutations of Ca sensing receptors) Defective regulation of PTH secretion (hypocalcemia & hypercalciuria: activating mutations of Ca sensing receptors) Abnormal PTH hormone (familial)

    17. autoimmune polyglandular syndrome type I: affects 3-5 year olds or adolescent Autoimmune polyendocrinopathy -candidiasis-ectodermal dystrophy (APECED) or Whitaker syndrome associated with candidiasis, hypoparathyroidism, and adrenal failure type II: most common, primarily in adults 3rd-4th decades Schmidt syndrome. Addison's disease in combination with thyroid autoimmune diseases and/or type 1 diabetes mellitus (Carpenter syndrome) Primary hypogonadism, myasthenia gravis, and celiac disease are also commonly observed type III: typically in middle-aged women & includes 2 of the following: thyroid deficiency, pernicious anemia, type 1A diabetes mellitus, vitiligo, and alopecia.

    21. PSEUDOHYPOPARATHYROIDISM rare hereditary disorder loss of end-organ response to parathormone clinically identical to hypoparathyroidism administration of parathormone of no help short stature round faces stubby fingers (knuckle-knuckle-dimple -dimple sign) parathyroid hyperplasia

    24. Pseudohypoparathyroidism (PHP) type 1a Albright’s hereditary osteodystrophy (short stature & 4th & 5th metacarpal defects) Inactivating mutations in the ? subunit of Gs Skeletal abnormalities and TSH resistance (hypothyroidism) Pseudohypoparathyroidism type 1b PTH resistance without Albright’s (no phenotypic defect) Defective methylation within GNAS1 Pseudo-pseudohypoparathyroidism Mutation in GNAS1 gene in Albright’s without resistance to other hormones Gs = Guanine nucleotide stimulatory binding protein 1 encoded by GNAS1 gene (a complex locus, located on chromosome 20q, that encodes multiple proteins) PSEUDOHYPOPARATHYROIDISM PTH resistance

    27. HYPERPARATHYROIDISM etiology 1° hyperparathyroidism 2° parathyroid hyperplasia Tertiary hyperparathyroidism Parathyroid carcinoma Inappropriate hyperparathyroidism

    28. 1° HYPERPARATHYROIDISM Primary Sporadic 55y/o, nl-hi serum Ca, 1 gland, ?PTH, 20xnl, surgical tx Multiple Endocrine Neoplasia 25y/o, nl-hi serum Ca, >1 gland, ?PTH, 5xnl, surgical tx Familial Hypocalciuric Hypercalcemia Birth, lo-nl serum Ca, >1 gland, N PTH, slightly ?size, no surgical tx Neonatal Severe 1° Hyperparathyroidism Birth, lo-nl serum Ca, >1 gland, ???PTH, very large, surgical tx

    30. Primary sporadic hyperparathyroidism Single adenoma (85% of the 1? hyperparathyroidism) Multiple gland hyperfunction Hyperplasia Adenomas

    36. ADENOMA Histopathology Encapsulated Very cellular Compressed nl parathyroid seen in 60% Combination of cells are common Mostly diffuse, but may be: Follicular Nested Pseudopapillary B & T lymphs may be present (autoimmune?)

    42. ADENOMA VARIANTS Oxyphil adenoma Lipoadenoma

    44. PARATHYROID HYPERPLASIA Primary Chief Cell Clear Cell Secondary Tertiary

    45. Chief Cell Hyperplasia Primary MEN types I & Ia (+pancreatic/pituitary adenomas, adrenal cortical & C cell hyperplasia) All glands involved (10 gms or more) Tan to reddish Superiors larger than inferiors Diffuse or nodular (more common in young) patterns Variants: 1 with nodular hyperplasia, others nl (pseudoadenomatous) All 4 may appear grossly normal (occult hyperplasia) Parathyromatosis: many microfoci of hyperplasia in neck Chronic parathyroiditis

    50. Clear Cell Hyperplasia No familial incidence or MEN association Weight of the 4 glands may exceed 100g Rare now for unknown reasons May grossly fuse or form pseudopods Cells may vary considerably in size with water clear cytoplasm (Golgi apparatus-derived vacuoles) & basal nuclei

    57. HYPERPARATHYROIDISM Clinical Manifestations hypercalcemia, hypophosphatemia, & elevated serum alkaline phosphatase diminished neuromotor activity demineralization of bone and teeth osteitis fibrosa cystica metastatic calcification renal stones brown tumor

    68. Secondary Hyperplasia Variable parathyroid sizes (up to 2 cm & 6 gm) Inverse relation between size and serum Ca No path distinction between 1º and 2º More common in 1º Nodularity, fibrous septation, acinar formation, & giant cells More common in 2º Oxyphil cells Nuclear pleomorphism more common in adenoma

    71. Carcinoma Typically hyperfunctioning (very high Ca) Rarely nonfunctional (aggressive feature) In old literature: 73% with skeletal disease 26% with renal disease May coexist with adenoma or hyperplasia Palpable fixed mass, hard, vocal cord paralysis, and post-op recurrence

    80. Prognosis Immunohistology & molecular genetics (microarray): CK14-, lower p27 index , PTH+, Ki-67+, cyclin D1 overexpression in >90%, DNA ploidy, Rb gene loss, HRPT2 gene mutation (hereditary hyperparathyroidism and jaw tumors syndrome)- (Rosai, 04) Overall survival: 85.5% in 5 years; 49.1% in 10 years Recurrence in 2 years after surgery is ominous

    82. Other Lesions Parathyroid cysts usually in inferior glands Amyloidosis Langerhans’ cell histiocytosis Hemangioma Metastatic carcinoma

    83. PARTHYROID DISORDERS laboratory evaluation Hypercalcemia common causes: parathyroid adenoma or hyperplasia elevated intact PTH paraneoplastic (lung CA) elevated PTHrP, low PTH Hypocalcemia: surgical ablation, DiGeorge renal disease: elevated c-terminal PTH

    90. Variations in iPTH Assays immunoradiometric (IRMA) and immunochemiluminometric (ICMA) Mid-region & C-terminal are elevated in renal insufficiency iPTH in renal failure has to be 2-3 times above normal to correlate with normal bone histology normal levels of iPTH in these patients are associated with adynamic bone disease

    91. Ca Control on PTH Secretion Hypercalcemia Diminishes iPTH (1-84) secretion Promotes intracellular iPTH degradation to 7-84 Hypocalcemia Promotes iPTH (1-84) secretion Diminishes intracellular iPTH degradation to 7-84

    92. 2° Hyperparathyroidism Mid-region & C-terminal are elevated in renal insufficiency iPTH in 1990’s (1st & 2nd generation) in renal failure, levels had to be >2-3X normal to correlate with normal bone histology normal levels of iPTH in these patients were associated with adynamic bone disease High-performance liquid chromatography detects 2 immunoreactive peaks, 1 peak co-migrates with PTH-[1-84]), and a second more-hydrophilic peak, eluting slightly ahead of PTH 7-8 A third-generation assay, uses a detection antibody that recognizes antigenic determinants at the extreme amino-terminal (1-4) end of the PTH molecule

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