PARATHYROID GLAND AND ITS RELATED ILLNESSES PARATHYROID GLAND • • • • • • •

4 small glands located on the dorsal side of the thyroid gland Yellow brown Ovoid or lentiform shape Measure 3-10 mm x 2-6 mm x 1-4 mm Weigh 50 mg each Produces parathyroid hormone Responsible for monitoring plasma Ca2+ PARATHYROID GLAND

PARATHYROID HORMONE •

A peptide hormone that increases plasma Ca2+

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Released by chief cells Chief cells contain receptors for Ca2+ A decrease in plasma Ca2+ levels mediates the release of PTH Conversely, hypercalcemia inhibits PTH release

PARATHYROID HORMONE PTH causes increase in plasma Ca2+ by: • • •

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Mobilization of Ca2+ from bone Enhancing renal reabsorption Increasing intestinal absorption (indirect)

CALCIUM METABOLISM Bone: main effect- stimulates osteoclasts -> bone breaks down -> Ca released Intestines: increases uptake of Ca from intestine Kidney: stimulates reabsorption of Ca from the Ca in kidney tubules

CALCIUM METABOLISM

CAUSES OF HYPERPARATHYROIDISM •

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PARATHYROID-RELATED -Primary hyperparathyroidism -Lithium therapy -Familial hypocalciuric hypercalcemia MALIGNANCY-RELATED -Solid tumor with metastases (breast) -Solid tumor with humoral mediation of hypercalcemia (lung, kidney) -Hematologic malignancies (multiple myeloma, lymphoma, leukemia) VITAMIN D-RELATED -Vitamin D intoxication -↑ 1,25(OH)2D; sarcoidosis and other granulomatous diseases

-Idiopathic hypercalcemia of infancy •

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Associated with high bone turnover -Hyperthyroidism -Immobilization -Thiazides -Vitamin A intoxication Associated with renal failure -Severe secondary hyperparathyroidism -Aluminum intoxication -Milk-alkali PRIMARY HYPERPARATHYROIDISM

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Estimated incidence is 1 case per 1000 men and 2-3 cases per 1000 women – Incidence increases above age 40 – Most patients with sporadic primary hyperparathyroidism are postmenopausal women with an average age of 55 years >80% of cases are caused by a solitary parathyroid adenoma Approximately 10% are caused by double adenoma

CLINICAL FEATURES OF HYPERPARATHYROIDISM •

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Osteitis fibrosa cystica Nephrolithiasis Pathologic fractures Neuromuscular disease Life-threatening hypercalcemia Peptic Ulcer Disease

Non specific symptoms – Fatigue – Subjective muscle weakness – Depression – Increased thirst – Polyuria – Constipation – Musculoskeletal aches and pains OSTEITIS FIBROSA CYSTICA

ASOCIATED SYNDROMES WITH HYPERPARATHYROIDISM MEN I MEN IIA Familial Hypocalciuric Hypercalcemia Hyperparathyroidism-jaw tumor syndrome Fibro-osseous jaw tumors Renal cysts Solid renal tumors Familial isolated hyperparathyroidism MEN I – –

1 in 30,000 persons Features:  Hyperparathyroidism (95%) – Most common and earliest endocrine manifestation  Gastrinoma (45%)  Pituitary tumor (25%)  Facial angiofibroma (85%)  Collagenoma (70%) HYPERPARATHYROIDISM IN MEN I

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Early onset Multiple glands affected

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Post-op hypoparathyroidism more common (more extensive surgery) Successful subtotal parathyroidectomy followed by recurrent HPT in 10 years in 50% of cases MEN II

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Features: – MTC(95%) – Pheochromocytoma(50%) – HPT(20%) RET mutation (98%) 1 in 30,000-50,000 people Usually single adenoma but may have multi-gland hyperplasia FAMILIAL HYPOCALCIURIC HYPERCALCEMIA

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Benign condition Autosomal dominant inherited disorder Clinical features: – hypocalciuria (usually < 50 mg/24 h) – variable hypermagnesemia – normal or minimally elevated levels of PTH These patients do not normalize their hypercalcemia after subtotal parathyroid removal and should not be subjected to

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surgery Excellent prognosis Diagnosed with family history and urinary calcium clearance determination

SECONDARY HYPERPARATHYROIDISM •

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Decreased GFR leads to reduced inorganic phosphate excretion and consequent phosphate retention Retained phosphate has a direct stimulatory effect on PTH synthesis and on cellular mass of the parathyroid glands Retained phosphate also causes excessive production and secretion of PTH through lowering of ionized Ca2+ and by suppression of calcitriol production SECONDARY HYPERPARATHYROIDISM

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Reduced calcitriol production results both from decreased synthesis due to reduced kidney mass and from hyperphosphatemia – calcitriol is known to have a direct suppressive effect on PTH transcription and therefore reduced calcitriol in CKD causes elevated levels of PTH –

Reduced calcitriol leads to impaired Ca2+ absorption from the GI tract, thereby leading to hypocalcemia,

which then increases PTH secretion and production TERTIARY HYPERPARATHYROIDISM •

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Develops in patients with long-standing secondary hyperparathyroidism, which stimulates the growth of an autonomous adenoma A clue to the diagnosis of tertiary hyperparathyroidism is intractable hypercalcemia and/or an inability to control osteomalacia despite vitamin D therapy INVESTIGATIONS IN HYPERPARATHYROIDISM

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Primary HPT – Increased serum calcium – Phosphorus in low normal range – Urinary calcium elevated Secondary HPT (renal etiology) – Low or normal serum calcium – High phosphorus Tertiary HPT (renal etiology) – High calcium and phosphorus

INVESTIGATIONS IN HYPERPARATHYROIDISM • Intact PTH and chemistry panel – PTH – Calcium – Phosphate – Creatinine •

24-hour urine calcium excretion – Used to rule out familial hypocalciuric hypercalcemia – Values below 100mg/24 hours or a calcium creatinine clearance ratio of 99% of all cases) Inability to make an active form of parathyroid hormone (extremely rare) Inability of the kidneys & bones to respond to the parathyroid hormone being produced by normal parathyroids (extremely rare)

CAUSES OF HYPOPARATHYROIDISM •

Isolated – Autosomal dominant • PTH gene mutation • CASR activating mutation • GCM2 mutation (dominant negative) –

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Autosomal recessive • PTH gene mutation • GCM2 mutation X-linked

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Congenital multi-system syndromes – DiGeorge & Velocardiofacial (22q11) – Barakat/HDR – Kenny-Caffey and Sanjad-Sakati CAUSES OF HYPOPARATHYROIDISM

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Metabolic disease – Mitochondrial neuromyopathies – Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency – Heavy-metal storage disorders Autoimmune disease – Autoimmune polyendocrine syndrome type I (APS-1 or APECED) Parathyroid resistance syndromes – Pseudohypoparathyroidism – Blomstrand chondrodysplasia and related PTH receptor defects – Hypomagnesemia CLINICAL FEATURES OF HYPOPARATHYROIDISM Muscle Cramps (spasms)

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Dry Skin Cataracts Seizures Pain in face, legs, feet Abnormal teeth formation Weakened tooth enamel INVESTIGATIONS IN HYPOPARATHYROIDISM Calcium Phosphorous PTH Magnesium