HYPERCALCEMIA, HYPOCALCEMIA, PARATHYROID DISORDERS. Dr. Csaba Horváth. 1st Department of Internal Medicine Semmelweis University Budapest

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1 HYPERCALCEMIA, HYPOCALCEMIA, PARATHYROID DISORDERS Dr. Csaba Horváth 1st Department of Internal Medicine Semmelweis University Budapest

2 MAIN TOPICS IN CALCIUM AND BONE METABOLISM - Hypercalcemia, hypocalcemia - Hyperparathyroidism - Calcium oxalate kidney stone disease - Vitamin D deficiency - Metabolic bone disease (osteoporosis)

3 FRACTIONS OF SERUM CALCIUM Bound to proteins 47 % to albumine 37 % to globulines 10 % Ultrafiltrable 53 % ionized 47.5 % complex-bound 5.5 % bicarbonate % phosphate % citrate % TOTAL 100 % = 100 %

4 VALUES OF SERUM CALCIUM Normocalcemia: mmol/l Hypocalcemia: < 2.25 mmol/l Hypercalcemia: > 2.60 mmol/l

5 CLINICAL SYMPTOMS IN THE HYPERCALCEMIA SYNDROME I. Cardiovascular Gastrointestinal - hypertension - bradycardia, I. degree AV-block - extrasystole, ventricular tachycardia - loss of appetite - nausea, vomiting - constipation - suffering from thirst, polydipsia (secunder) - rarely: acute pancreatitis, ulcus duodeni

6 CLINICAL SYMPTOMS IN THE HYPERCALCEMIA SYNDROME II. Renal - polyuria - renal stone, nephrocalcinosis - decreased renal function Neuro-psychiatric - decreased ability to concentrate - anxiety, confusion - personality disturbances - depression - somnolence, coma General - exhaustion, muscle weakness - exsiccosis

7 CAUSES OF HYPERCALCEMIA - I. Frequent causes Primary or tertiary hyperparathyroidism Malignant diseases - PTHrP or ectopic PTH production: lung, kidney, ovarium, urinary bladder, head-neck region, oesophagus tumors - ectopic production of calcitriol (1,25(OH)2D3): lymphoms, Hodgkin s-disease - local stimulation of bone resorption by the tumor: myeloma multiplex, breast cancer - direct osteolysis by the tumor cells: bone metastases

8 CAUSES OF HYPERCALCEMIA - II. Occuring causes Granulomatous disorders: - sarcoidosis Drugs: - vitamin D and it s derivatives - diuretics effecting in the distal tubule (thiazides) - vitamin A - androgenes, oestrogenes, antioestrogenes - lithium - aminophylline Endocrine disorders - thyrotoxicosis Others - immobilisation - long-term parenteral feeding

9 CAUSES OF HYPERCALCEMIA - III. Rare causes Granulomatous disorders - tuberculosis, silicosis, histoplasmosis, candidiasis, coccidiomycosis, eosinophilic granuloma, lepra, Wegener-granuloma Endocrine disorders - adrenal hypofunction - hypercorticism - pheochromocytoma Others - familial hypocalciuric hypercalcemia - milk-alkali syndrome - hypophosphatasia

10 TREATMENT OF HYPERCALCEMIA I. General - calcium-free (low-calcium) diet - avoiding drugs known to increase serum calcium level Stimulating urinary calcium excretion - fluid and electrolyte substitution - salt-diuresis - diuretics effecting in the Henle-loop (furosemid) - hemodialysis

11 TREATMENT OF HYPERCALCEMIA II. Inhibition of bone resorption - mobilization - calcitonine - bisphosphonates (clodronate, pamidronate) - glucocorticoides - inhibitors of prostaglandine synthesis (indomethacine) - galliumnitrate - mithramycine only in the past! Treatment of the disease causing hypercalcemia - primary hyperparathyroidism: surgery, as soon as possible! - malignancy: chemotherapy, surgery, irradiation - other disorders: specific treatment

12 CLINICAL FORMS OF PRIMARY HYPERPARATHYROIDISM - I. Osseal form: osteopenia, osteoporosis, rarely M. Recklinghausen Clinical symptoms: bone pain, increased fragility Characteristic X-ray findings: - cysts in long bones - subperiosteal bone resorption: cortical resorption in the radial surface of metacarpals moth-hole erosions on distal phalanx - acro-osteolysis on the fingers - vertebral bodies: sclerosis at the cortex atrophy inside Bone densitometry: decreased mineral mass in all bones, the peripheral bones involved more and earlier

13

14 CLINICAL SYMPTOMS OF PRIMARY HYPERPARATHYROIDISM Due to hypercalcemia Malaise, hypertension Thirst polydipsia polyuria Loss of appetite, loss of weight Abdominal dyscomfort, rarely spastic pain, constipation Renal colic (in case of kidney stones) Neuropathy, neuritis, neurosis, myositis, depression Due to hyperparathyroidism Locomotor complains (bone pain, articular pain, sometimes pathologic fractures) No any symptoms this is the most frequent

15 BIOCHEMICAL FINDINGS IN PRIMARY HYPERPARATHYROIDISM Hypercalcemia, hypercalciuria Hypophosphatemia Elevated serum PTH level (norm pg/ml) Hyperchloremic acidosis Decreased tubular reabsorption of phosphate (TRP) Elevated alkaline phosphatase acitivity in serum Elevated serum level of osteocalcin, collagen crosslaps Increased calcium and PTH concentration in the same blood sample = diagnosis!

16 LOCALIZATION OF THE PARATHYROID ADENOMA Ultrasound of the neck and the thyroid Parathyroid scintigraphy (tallium + technecium) Neck and mediastinum CT (MR?)

17 INDICATIONS FOR SURGERY IN PRIMARY HYPERPARATHYROIDISM Renal complications stones (recurrent!), calcinosis Low bone mass Serum calcium more than 3.0 mmol/l Progression in the above mentioned problems

18 COMPLICATIONS AFTER PARATHYROID SURGERY Transient complications: - postoperative hypocalcemia (atrophy in the remained glands) - recalcification tetany (hungry bone syndrome) Long-term complications: - final hypoparathyroidism - hypothyroidism - huskiness (vocal cord injury)

19 PARATHORMONE-DEPENDENT CAUSES OF HYPOCALCEMIA Hypoparathyroidism = low PTH level - congenital: isolated parathyreoid hypoplasia DiGeorge syndroma (defects in chromosome 22) - postoperative or after neck irradiation - autoimmune: multiple endocrine deficiency HAM: Hypopar + Addison + Moniliasis - other destructions (iron, copper, granulomes, tumors) - defect in PTH producing gene - defected regulation of PTH secretion mutation of calcium-sensor hypomagnesiemia PTH-resistency = high PTH level - Mg deficiency - end-organ receptor defects

20 PARATHORMONE-INDEPENDENT CAUSES OF HYPOCALCEMIA I. Lack of vitamin D effect - deficient intake of vitamin D malnutrition, malabsorption, maldigestion - deficient vitamin D activation in the skin: avoiding sunshine in the liver: cirrhosis, drugs in the kidney: uremia - vitamin D resistency

21 PARATHORMONE-INDEPENDENT CAUSES OF HYPOCALCEMIA II. Drugs Other disorders - anticonvulsants - drugs decreasing the seca level (bisphosphonates, mithramycine, phosphates, galliumnitrate, calcitonin) - cytostatics (rubidomycin, cytosin arabinosid, asparaginase) - ketokonazol - pentamidine - acute pancreatitis - disruption of a large tumor mass - big volume of citrated blood - toxic shock syndrome - acute rhabdomyolysis - rarely: any of severe acute diseases

22 SYMPTOMS OF HYPOCALCEMIA Symptoms due to low calcium concentration - paresthesias (perioral, hands) - tonic spasm in muscles = tetany - laryngospasm - carpo-pedal spasm - generalized muscle spasm - neural irritability, convulsion - cardiac manifestations - longer QT time - heart blocks - congestive heart failure

23 TREATMENT OF HYPOCALCEMIA I. Emergency treatment for tetany - aim: elevation of low serum Ca to normal level - iv mg kalcium: ml Ca-chlorate ml Ca-gluconate - give it slowly! Long-term treatment for maintenance - aim: to stabilize a normal serum Ca level - vitamin D - D3: 1000 U daily, sometimes more - activated D: ug daily - dihydrotachysterol (Tachystin, AT-10): 2-4 mg daily (quick onset of effect, shorter half-life) - calcium - only if needed: mg daily - thiazides - not alone

24 MARKERS OF BONE TURNOVER I. Formation - osteocalcin (OC) - alkaline phosphatase (AP, boneap) - prokollagén-i C-terminal propeptide (PICP) II. Resorption - collagen crosslinks - crosslink-containing telopeptides in blood (NTX, CTX = crosslaps) - crosslinks in urine (DPYD) - urinary calcium? - urinary hydroxyproline? - tartarate-resistant acid phosphatase (TRAP)

25 OSTEOPOROSIS Osteoporosis is a generalized skeletal disease, characterized by progressive bone loss and deterioration of microarchitecture, followed by increased bone fragility.

26 PROGNOSIS OF HIP FRACTURE Mortality in first year after fracture (!): 20 % Overlivings: 21 % completely cured 26 % need life-long help 53 % living in nursing homes

27 CHANCE FOR OSTEOPOROSIS AND FOR LOW-TRAUMA FRACTURE Woman, 50 ys old - for osteoporosis 46 % - for low-trauma fracture % Man, 50 ys old - for osteoporosis? - for low-trauma fracture %

28 WHY FRACTURE DOES OCCUR? Power effect falling + Mechanical competence decreases - loss of bone mass - deterioration of microstructure - decrease in bone quality

29 METHODS TO MEASURE BONE MASS Radiologic methods - classic X-ray film - radiogrammetry Photon absorption measures: bone densitometry (ODM) - radiographic absorptiometry (RA) - single or dual photon absorptiometry (SPA, SXA, DEXA) - quantitativ computer tomography (QCT) Quantitatív ultrasonometry of bone (QUS): - broadband ultrasound attenuation (BUA) - decrease in speed of sound (SOS)

30 WHO-RECOMMENDED CUT-OFF LEVELS IN BONE DENSITOMETRY Based on values measured in healthy young adults Normal: T-score over -1.0 Osteopenia: T-score between -1.0 and -2.5 Osteoporosis: T-score below -2.5

31 SECONDARY OSTEOPOROSIS OP in diseases of other organs 1, liver D-deficiency 2, gastrointestinal malabsorption 3, inflammatory bone resorbing cytokines 4, renal insufficiency D-aktivation, PTH excess 5, haematologic malignancies bone resorbing disease/cytokines/cytostatics 6, immobilization

32 INTERVENTION THRESHOLD FOR OSTEOPOROSIS TREATMENT 10 YEARS ABSOLUT FRACTURE PROBABILITY

33 FRACTURE PROBABILITY WHO 2008 Risk factors Fracture probability High Medium Low Treatment BMD test Fr probab recalculation High Low Treatment

34 ESSENTIALS OF OSTEOPOROSIS HIGH BONE RESORPTION (absolut) LOW BONE FORMATION (relativ) +

35 or Plus OSTEOPOROSIS TREATMENT FOR FRACTURE PREVENTION INHIBITING BONE RESORPTION - bisphosphonates - calcitonin - estrogene STIMULATING BONE FORMATION - PTH-analoges - strontium ranelate - calcitonin BASIS THERAPY - calcium, Vitamin D

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