A 52-year-old female patient was referred to our clinic because of the recent discovery of hypercalcemia in a routine oncological control. Her oncologist, assuming that the diagnosis was most likely to be tumor-induced hypercalcemia, referred her to an endocrinologist, who undertook further tests to reveal the etiology of hypercalcemia. The physical examination revealed her to be eupneic, blood pressure of 120/80 mmHg with 84 beats per second. The patient had a history of left breast carcinoma. Our patient had undergone a left mastectomy one year previously (estrogen-receptor positive, progesterone-receptor positive, Her2 negative) and received letrozole without any complications until hospitalization. She remained well and achieved a complete response without an increase of carcinoembryonic antigen (CEA, (normal value <5 ng/mL)) or carbohydrate antigen 15-3 (CA 15-3, normal value: 0.5-29 IU/mL) since ten months.
Currently she is 1.62 m tall, weighting 62 kg, with a body mass index (BMI) of 23 kg/m2 and using letrozole only for the indication prescribed. She had started a course of letrozole ten months earlier. Her family history was unremarkable. As her hypercalcemia was mild and did not elicit any symptoms, she did not require immediate measures to correct this.
Investigations to determine the cause of the hypercalcemia were performed. Initial laboratory evaluation showed hypercalcemia at 11 mg/dL, iPTH as 15 pg/mL normal albumin 4.3 g/dL, and phosphorus level 3.5 mg/dL (Normal: 2.5-4.8) and creatinine 0.57 mg/dL. 24 h urinary calcium excretion was found to be 247 mg/day (normal: 100-300 mg/day). Further blood tests demonstrated that alkaline phosphatase level was 64 U/L (35-104) and 25-hydroxy vitamin D level was 22 ng/mL (normal: 20-30) within normal limits. A dual energy X-ray absorptiometry (DEXA) scan was performed, which revealed mild osteopenia at the left femoral neck (T score: -1.6). No previous bone mineral density (BMD) measurement had been taken prior to this.
On other days, our patient's serum calcium and iPTH level returned to within normal range without any medications. When we analyzed the sequence of laboratory tests, there were episodes of calcium and iPTH levels with fluctuating on repeat analyses over a period of ten months between 9.5-11 mg/dL (Figure 1, normal: 8.5-10.2 mg/dL) and 11-17 pg/mL (Figure 2, normal: 12-65), respectively.
A workup investigation to exclude other causes of hypercalcemia was done. She underwent an extensive evaluation including careful history, family history, physical examination, and lab work to exclude possible other causes of hypercalcemia. Parathyroid hormone related peptide was 0.28 pmol/L (normal: 0-1.3) and bone scan was normal, thus making malignancy-related hypercalcemia unlikely. Computed tomography of thorax, neck and abdomen, and PET-BT did not reveal any malignancy.
Although serum phosphorus was normal and iPTH was not increased, in order to rule out hyperparathyroidism, evaluation of the parathyroid glands was performed using ultrasound and MIBI scan, which were normal. Clinically, patients with FHH (familial hypocalciuric hypercalcemia) have relative hypocalciuria and inappropriately normal or elevated iPTH in the face of persistent mild hypercalcemia, none of which our patient had.
In addition to malignancy-related hypercalcemia, the differential diagnosis of hypercalcemia includes calcium supplements hypervitaminosis D, milk-alkali syndrome, granulomatous diseases, medications, inflammatory and rheumatic diseases, and other endocrine disorders.
25-hydroxy vitamin D level was not elevated ruling out hypervitaminosis D. Tuberculin test, computed tomography of thorax, and bone survey were normal, thus ruling out a granulomatous process (tuberculosis or sarcoidosis). Erythrocyte sedimentation rate and ANA level were normal, ruling out inflammatory and rheumatic diseases. Thyroid-stimulating hormone and free thyroid hormones should be checked to help rule out hyperthyroidism. Free T4, Free T3, and TSH were normal, ruling out hyperthyroidism, and there were no signs or symptoms suggestive of Cushing disease, adrenal insufficiency, acromegaly, or pheochromocytoma. Normal prolactin level and IGF-I in the age- and gender-matched normal range excluded the diagnosis of prolactinoma and acromegaly in our patient, respectively. Basal cortisol level was 19 mug/dL, and therefore we could rule out adrenal insufficiency. An overnight dexamethasone suppression test (DST) was done. After a 1-mg dose DST, the plasma cortisol level was 0.8 mug/dL. Hence, we could rule out Cushing syndrome. A 24-hour total urinary metanephrines and fractionated catecholamines were within normal range. She had no evidence of leukemia and lymphoma and a normal complete blood count. Serum electrophoresis was negative for monoclonal proteins. She indicated no symptoms of peptic ulcer, and there was neither exogenous vitamin D intake nor family history of endocrinopathy. She had no history of taking vitamin A, calcium supplements, and thiazide medication and no recent history of immobilization. Assessment of bone metabolism using markers of bone turnover could yield useful information and guide management decisions in our case. Urinary hydroxyproline level was significantly increased (35 mg/24 h/m2; normal: 22-55 years:8.5-23.5 mg/24 h/m2).
Because of sufficient vitamin D level, oral bisphosphonate was administered and letrozole was restarted at one-half dose (1.25 mg). She was discharged and we closely follow up patient's serum calcium, CEA, CA 15-3, and for distant metastasis.