PARATHYROID GLAND DISEASES

1. PARATHYROID GLAND DISEASES Primary hyperparathyroidism Hypoparathyroidism

3. Causes of hypercalcemia • Primary hyperparathyroidism: sporadic, associated with MEN 1 or MEN 2a, familial, after renal transplantation • Secondary, tertiary hyperparathyroidism • Malignancies: humoral hypercalcemia (caused by PTHrP, 1,25(OH)2D3, PTH), local osteolytic hypercalcemia • Sarcoidosis • Endocrinopathies: thyrotoxicosis, adrenal insufficiency, pheochromocytoma, acromegaly • Drug induced: vitamin A, D intoxication, thiazides, lithium,milk-alkali syndrome, estrogens, androgens, tamoxifen • Immobilization • Acute renal failure

5. P-HPTH • Common, usually asymptomatic disorder • 2-3fold commoner in females than in males • Incidence approx. 42 per 100,000 inhibitants/year • Single parathyroid adenoma – ca. 80%, parathyroid hyperplasia – ca. 15%, parathyroid carcinoma – 1-2%

6. Defense mechanism against hypercalcemia Hypercalcaemia supression of PTH secretion  bone resorption  renal production of 1,25(OH)2D3  calcium resorption from intestine  urinary calcium loss

8. „Stones” Renal stones Nephrocalcinosis Polyuria Polydipsia Uraemia „Bones” Osteitis fibrosa with: -subperiosteal resorption - osteoclastomas - bone cysts Radiologic „osteoporosis” Osteomalacia or rickets Arthrithis „Abdominal groans” Constipation Indigestion, nausea, vomiting Peptic ulcer Pancreatitis P-HPTH signs & symptoms „Psychic moans” Lethargy, fatigue Depression Memory loss Psychoses – paranoia Personality change, neuroses Confusion, stupor, coma Other Proximal muscle weakness Keratitis, conjunctivitis Hypertension Itching

9. Hyperparathyroid bone disease • Osteitis fibrosa cystica (< 10% of patients) • Pain , pathologic fractures •  AlP • Cystic lesions containing fibrous tissue („brown tumours”) or cyst fluid • Subperiosteal resorption of cortical bone, „salt-and-pepper” appearance of the skull • Secondary osteoporosis (loss of cortical bone)

12. Hyperparathyroid kidney disease • Kidney stones (< 15% of patients) • Nephrocalcinosis • Polidypsia, poliuria (loss of renal concentration ability) • Gradual loss of renal function

13. Other features of P-HPTH • Lethargy, fatigue, depression, difficulty in concentrating, personality changes • Frank psychosis • Muscle weakness • Hypertension • Dyspepsia, nausea, constipation • Chondrocalcinosis („pseudogout”), gouty arthritis

14. Laboratory findings in P-HPTH •  total Cas (may be intermittent),  Cau,  Ps,  Pu •  intactPTH (may be upper normal) • hyperchloremic acidosis •  GFR Cas 2.25-2.75 mmol/l, Cau < 4 mg/kg/24 h (<250 mg/24 h in women, < 300 mg/24 h in men) Ps 3.0-4.5 mg% (1.0-1.5 mmol/l), Pu 400-1400 mg/24 h

15. Treatment of P-HPTH • The adenoma may be located throughout the neck or upper mediastinum • „The only localization study needed in a patients with hyperparathyroidism is to locate an experienced parathyroid surgeon” • Surgical parathyroidectomy  cure rate over 95% (adenoma + excellent surgeon) • Localization studies are very useful in reoperative parathyroid surgery: neck ultrasound, 99mTc-sestamibi scanning, CT, MRI (rarely angiography, venous sampling)

16. Treatment of P-HPTH (II) • No definitive therapy for hyperparathyroidism • Estrogen replacement therapy in postmenopausal women • Management of hypercalcaemia: rehydrating with saline, furosemide, calcitonin s.c. (4-8 IU/kg every 12 hrs.), bisphosponates (etidronate disodium, pamidronate disodium), glucocorticoids p.o.(in multiple myeloma, sarcoidosis, intoxication with vitamin D or A).

17. 1990 NIH Consensus Development Conference Surgery should be recommended if: • serum Ca is markedly elevated (above 2.8-3.0 mmol/l) • if there has been a previous episode of life-threatening hypercalcemia • if creatinine clearance is reduced below 70% of normal • if a kidney stone is present • if urinary calcium is markedly elevated (> 400 mg/24 h) • if bone mass is substantially reduced (less than 2 SD below normal for age, sex, and race) • if the patient is young (under 50 years of age, particularly premenopausal women)

18. Causes of hypocalcemia • Hypoparathyroidism:surgical, idiopathic, neonatal, familial, postradiation, infiltrative • Resistance to PTH action: pseudohypoparathyroidism,renal insufficiency, medications that block osteoclastic bone resorption (calcitonin, bisphosphonates) • Failure to produce 1,25(OH)2D3: vitamin D deficiency, hereditary vitamin D-dependent rickets, type 1 (1-hydroxylase deficiency) • Resistance to produce 1,25(OH)2D3: hereditary vitamin D-dependent rickets, type 2 (defective VDR) • Acute complexation or deposition of calcium: acute hyperphosphatemia (crush injury, rapid tumour lysis, excessive enteral and parenteral phosphate administration), acute pancreatitis, citrated blood transfusion, hungry bones syndrome

19. Clinical features of hypocalcemia • Neuromuscular manifestations: overt tetany: carpopedal spasm, painful; laryngospasmus, blepharospasmus latent tetany: Chvostek’s sign, Trousseau’s sign focal or generalized seizures, papilledema, confusion, organic brain syndrome, mental retardation in children, calcification of basal ganglia (skull X-ray, CT) • Cardiac effects: prolongation of QT interval, congestive heart failure • Ophtalmologic effects: subcapsular cataract • Dermatologic effects: dry and flaky skin, brittle nails, impetigo herpetiformis, pustular psoriasis

22. Hypoparathyroidism • Surgical, autoimmune, idiopathic, familial •  Cas,  Ps, low or undetectable intact PTH level • Surgical – ensues 1-2 days postoperatively, transient in 50% of cases • Autoimmune – most commonly associated with Addison’s disease and mucocutaneous candidiasis (type I polyglandular autoimmune syndrome) • Idiopathic – an isolated form, age of onset 2-10 years, commoner in females • Familial – due to activating mutation of the parathyroid calcium receptor gene

23. Pseudohypoparathyroidism (PHP) • A heritable disorder of target-organ unresponsineness to PTH (Ellsworth-Howard test: lack of an increase in urinary cAMP after administration of exogenous PTH) • Hypocalcemia and hyperphosphatemia, but elevated PTH level and a markedly blunted response to PTH administration • 2 distinct forms: PHP 1A – characteristic somatic phenotype, i.e. Albright’s hereditary osteodystrophy (short stature, a round face, short neck, brachydactyly, subcutaneous ossifications) PHP 1B – no characteristic somatic phenotype

24. Treatment of hypocalcemia • Acute hypocalcemia: calcium chloride or gluconate i.v. (up to 400-1000 mg/24 h), oral calcium and vitamin D should be started (caution: digitalis treatment, stridor) • Chronic hypocalcemia: objective: normalisation of serum calcium and phospate 1.0-2.0 g of elemental calcium p.o. per day, vitamin D3, active metabolites: alfacalcidol (1[OH]D3), calcitriol (1,25[OH]2D3), low phosphate diet (no milk)