Disorders of Ca Metabolism Hypercalcaemia (BY Basil OM Saleh) OBJECTIVE: • Clinical characteristics •Biochemical investigations in Diagnosis & Differentiation.

Because of technical difficulties in Free Ca measurement, the reference range is stated for Serum total Ca. But it is preferred for good investigation to measure the adjusted Ca (Ca in association with albumin concentration) when the free Ca assay is not available. Normal Range for Total serum Ca= 8.1-10.30 mg/dl (2.10-2.60 mmol/l). Serum Phosphate normal range is = 2.5-5.0 mg/dl (0.8-1.40 mmol/l), and this range is for fasting because of meal effect and for adult (For Child 4-7 mg/dl). With regard to phosphate, the serum measurement includes the inorganic phosphate (the organic phosphates like G-6-P) are only intracellular.

Serum Alkaline phosphatase (ALP) enzyme Serum Alkaline phosphatase (ALP) enzyme. This protein enzyme measurement is important for investigation of Ca++ & PO4– disorders. ALP is found (origin) in the liver, bone, kidney, placenta, and intestine. Serum Reference Range is age dependent (for children & adolescent is 3 times higher than for adults). Moreover, in pregnant women and during third trimester is higher than for non pregnant women. Bone ALP isoenzyme is synthesized by osteoblastic cells and increased in blood when there is increase in these cells activities like; Paget’ s disease, rickets, osteomalacia, carcinoma of bone.

Disorders of Ca Metabolism: These include; Hypercalcaemia & Hypocalcaemia. HYPERCALCAEMIA is an excessive circulated blood Ca++ levels with less than 12 mg/dl referred to Mild Hypercalcaemia and more than 13 mg/dl severe Hypercalcaemia that needed for urgent treatment. Investigation of Hypercalcaemia usually need for evaluation of Kidney function (measurement of serum Urea & creatinine).

Hypercalcaemia is the result of Flux of Ca into the ECF compartment from the skeleton, intestine, or kidney is greater than the Efflux, e.g., excessive resorption of bone mineral occurs in malignancy, capacity of the kidney to excrete filtered Ca is exceeded, increased intestinal absorption by vitamin D intoxication, increased renal retention by drug as Thiazide diuretics, increased skeletal resorption by Immobilization, and parathyroid gland disorders.

The clinical features of Hypercalcaemia are 1 The clinical features of Hypercalcaemia are 1. Neurological symptoms; depression, confusion, inability to concentrate 2. Generalized muscle weakness 3. Anorexia, nausea, vomiting, constipation 4. Polyuria and polydipsia 5. Nephrocalcinosis and nephrolithiasis (Renal colic AND THE PROLONGED lead to Renal failure) 6. Characteristic ECG (shortened Q-T interval) with bradycardia 7. pancreatitis and peptic ulcer.

The major causes of Hypercalcaemia are: 1 The major causes of Hypercalcaemia are: 1. Primary and Tertiary Hyperparathyroidism . The primary type is due to single (80-85 %) or diffuse (all four lobes, 15 %) parathyroid adenoma , or rarely to parathyroid carcinoma (<1 %). There is autonomous PTH secretion which is inappropriate to blood Ca++ levels???. In Tertiary type, the patient suffers from a history of hypocalcaemia mainly due to chronic renal failure or vitamin D deficiency. These two latter pathological conditions lead to hypocalcaemia which stimulates the PTH secretion.

The secreted PTH cannot correct the low blood Ca++ levels because of the underlying cause; renal defect or D deficiency, and this referred to a Secondary Hyperparathyroidism (IN which pth blood levels is high with sustained hypocalcaemia). However, the prolonged and sustained Parathyroid gland stimulation by untreated hypocalcaemia will lead to hypertrophy of the gland and autonomous secretion of PTH. After correction of Kidney or D intake, the hypocalcaemia will be corrected by the autonomous secreted

PTH with consequent Hypercalcaemia of Tertiary Hyperparathyroidism PTH with consequent Hypercalcaemia of Tertiary Hyperparathyroidism. In both Primary hyperparathyroidism PHPT & Tertiary Hyperparathyroidism THPT The serum Ca++ increases and PO4– decreases 2. Malignancy: a. Bony tumor which may be primary in the bone (release of both Ca++ & PO4- - in the blood from damaged bone), b. metastasized Bone which may be associated with bone damage and release of both Ca++ & PO4- -,

OR MAY be characterized by presence of PTHrP and so increase of blood Ca++ & decrease of PO4- - c. Extra bony metastasized tumor such as carcinoma of the lung, head and neck, in the absence of bony metastasized. In this latter tumor, the characteristic factor is also PTHrP and consequent increase of blood Ca++ & decrease of PO4--, d. Multiple Myeloma. In all malignancy types the blood levels of PTH is ???.

3. Excessive D intake (overdoses); both blood Ca++ & PO4– are increased. 4. Drugs; mainly Lithium which used for psychiatric causes, and also Thiazide diuretics. 5. Sarcoidosis; 10 % of such patients may have Hypercalcaemia and often accompanied by hypercalciuria due to increased conversion of 25OHD3 to 1,25DOHD3.

6. Familial benign Hypercalcaemia hypocalciuric (FBHH): It is an autosomal dominant usually asymptomatic disease in which there is mutation in the receptor gene sensing Ca++ blood levels. It is important to differentiate it from PHPT BY low urine Ca++ and mild increase of serum Mg level. This disease not need for Parathyroidectomy as with PHPT disease 7. Milk-Alkali syndrome: Excessive milk intake (high Ca) in the presence of peptic ulcer and use of antacid such as bicarbonate (NaHCO3). 8. Endocrine disorders; like severe thyrotoxicosis.

Biochemical Investigations of Hypercalcaemia 1 Biochemical Investigations of Hypercalcaemia 1. Measure Free Ca, if technically difficult the adjusted Ca (Total Ca & albumin)= high Ca++ 2. Drug Therapy; Lithium, Thiazide diuretics ( serum Ca++ increased & PO4– may be Normal) 3. If high Ca++ is accompanied by high PO4--, measure a. OHD3,DOHD3, when it is high D3 it is D3 toxicity, if not, b. Bone tumor, S.ALP is usually high with elevated ESR (Erythrocyte Sedimentation Rate), and X-ray, CT, MRI scan characteristics of bony tumor. 4. If high Ca++ is accompanied by Low PO4– (Hypercalcaemia & hypophosphataemia), measure serum PTH,

a. High PTH indicates PHPT(90 %) b a. High PTH indicates PHPT(90 %) b. Marginal increase of PTH (upper reference range or borderline high, 10 %), also PHPT or may be FBHH (differentiate between them). C. PTH lower reference range or suppressed, measure the PTHrP which may indicate Malignancy.