1 Department of Internal Medicine III, Division of Nephrology and Dialysis 2 Departments of Pathophysiology 3 Surgery, General Division 4 Nuclear Medicine, University of Vienna, Vienna, Austria
Keywords: primary hyperparathyroidism; Paget's disease of bone; hypercalcaemia; high turnover bone disease; renal stone formation
Introduction
The underlying cause of hypercalcaemia can often be diagnosed simply by clinical and laboratory findings. In rare cases, however, the occurrence of two or more different diseases poses a significant diagnostic as well as therapeutic challenge.
We report one of these patients with hypercalcaemia, whose leading symptoms were recurrent kidney stones, and whose serum calcium could be normalized by treating only one cause of hypercalcaemia, rather than all diseases, likely to be involved in the electrolyte disorder.
Case report
Medical history
A 59-year-old male Caucasian patient was referred to our nephrology outpatient clinic for the evaluation of hypercalcaemia (2.88 mmol/l). His past medical history was remarkable for an ectopic left kidney and recurrent kidney stones (three times). The patient presented in excellent clinical condition and did not report any symptoms related to hypercalcaemia. High calcium intake or ingestion of vitamin D containing medication was negated.
Laboratory values
In addition to the serum calcium of 2.88 mmol/l, the laboratory work-up revealed an increased ionized calcium of 1.51 mmol/l, and an elevated alkaline phosphatase of 212 U/l (normal range 60170 U/l). Calcium excretion in the 24-h urine collection was increased (10.2 mmol/24 h). The serum creatinine was 1.31 mg/dl, BUN 15.7 mg/dl and creatinine clearance 87.6 ml/min. Serum chloride (107 mmol/l), serum protein (73.3 g/l) and albumin (47.9 g/l), plasma bicarbonate (27.1 mmol/l) and pH (7.4) were within the normal range. Electrophoresis revealed no signs of paraproteinaemia. Serum phosphate was low (0.65 mmol/l). Parathyroid hormone (PTH) levels obtained at three different visits (40.6 pg/ml, 40.4 pg/ml and 43.2 pg/ml, respectively) and the 25-hydroxyvitamin D level (79.9 mmol/l, normal range 3085 mmol/l) were within the normal range. In contrast, osteocalcin was elevated (43.2 ng/ml; normal range 731 ng/ml). The serum angiotensin converting enzyme level was within normal limits (11.5 U/l; normal range 8.321.4 U/l).
Imaging techniques
The chest X-ray was normal without any signs of a malignant disease, sarcoidosis or other granulomatous diseases. The sonography of the abdomen was unremarkable, except for the ectopic left kidney, renal calculi and cholecystolithiasis. The ultrasound of the thyroid and parathyroid glands was normal. A parathyroid scan (technetium (99mTc)-Sestamibi scan) revealed one enlarged gland on the right side (Figure 1). X-rays of the long bones, the skull and spine were unremarkable, but the X-ray of the pelvis showed characteristic features of Paget's disease in the left ileosacral joint region. A bone scan showed a hot spot at the ileosacral joint corresponding to the area seen in the standard X-ray (Figure 2
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Treatment
As one adenoma was detected by parathyroid scan and the serum PTH level was in the high normal range despite hypercalcaemia, the patient was referred to surgery for parathyroidectomy. One adenoma located on the right side between the thyroid gland and the oesophagus was removed. The postoperative course was without complications.
Follow up
One year after parathyroidectomy the patient had a normal serum calcium (2.35 mmol/l), ionized calcium (1.2 mmol/l), phosphate (0.85 mmol/l), chloride (108 mmol/l), serum creatinine (1.26 mg/dl), BUN (14.8 mg/dl), serum protein (74.3 g/l), albumin (49.2 g/l), plasma bicarbonate (25.5 mmol/l), pH (7.45), urinary calcium excretion (2.5 mmol/24 h) and creatinine clearance (92.7 ml/min). Indicators of high bone turnover had returned to normal values (alkaline phosphatase (126 U/l), osteocalcin (22.5 ng/ml)). The PTH level was 26.6 ng/ml. After the parathyroidectomy no sign of further renal stone formation was detectable.
Discussion
The recurrence of kidney stones in our patient led to a thorough work-up in pursuit of the underlying cause for this disorder, and to the diagnosis of hypercalcaemia. Elevated serum calcium is a common clinical finding which can be associated with a variety of diseases. A malignant neoplasm is the single most common cause of hypercalcaemia among hospitalized patients, when osteolytic metastasis or circulating osteolytic substances secreted by the neoplasm (i.e. PTH-related hormone) induce a rise in serum calcium [1,2]. Other common causes of hypercalcaemia include primary hyperparathyroidism, which is relatively common in women after menopause but less frequently seen in men, Paget's disease of bone, in which a positive family history occurs in 40%, and granulomatous diseases [35].
In the absence of malignant disease, two different diseases emerged as possible reasons for the elevated serum calcium in our patient. Strong evidence for the presence of Paget's disease came from the characteristic findings in the X-ray of the pelvis and was supported by the respective hot spots in the bone scan. In contrast to plain radiography, scintigraphy reflects the status of the disease activity [6].
Paget's disease, as a chronic disorder of the bone, is characterized by increased osteoclastic activity, resulting in focal resorption of existing bone, followed by deposition of woven and lamellar bone in a characteristic pattern [79]. Often, as in the case of our patient, the patients are asymptomatic despite abnormal radiographs and elevated serum alkaline phosphatase levels. In patients with Paget's disease, serum phosphate levels and PTH levels are mostly within the normal range. If they are immobilized, which was not the case in our patient, hypercalciuria and hypercalcaemia may occur. An elevation of serum PTH levels has been described in patients with active Paget's disease and this correlates with serum alkaline phosphatase, but does not correlate with serum calcium levels [10].
However, several laboratory findings in our patient led us to believe that a second disorder might be concurrently present. First the hypercalcaemia was accompanied by hypophosphataemia, which is unusual for Paget's disease. The normal PTH levels would have been compatible with Morbus Paget, but in the presence of hypercalcaemia the levels are inappropriately high [4,11]. In addition, the increased urinary calcium excretion and a mildly elevated serum alkaline phosphatase were in accordance with primary hyperparathyroidism. Furthermore, elevated osteocalcin, as detected in our patient, is a special marker of high turnover bone disease and seems to be more often associated with primary hyperparathyroidism than with Paget's disease [12]. Also, there was no positive family history for this disease. Therefore we started to search for evidence of hyperparathyroidism. While an ultrasound of the parathyroid glands did not show signs of adenomas, the scan revealed the presence of one enlarged parathyroid gland. There are some reports on patients with Paget's disease of bone in which signs of primary hyperparathyroidism occurred [1315]. The reason for overproduction of PTH still remains unclear. In some patients removal of the parathyroid adenoma did not significantly influence biochemical bone markers, indicating that in these subjects high bone turnover was predominantly due to Paget's disease and not to hyperparathyroidism.
Nevertheless, because of the combination of parathyroid adenoma, hypercalcaemia and renal stone formation, despite normal PTH levels, parathyroidectomy was performed in our patient.
On follow up at 1 year, serum calcium levels, urinary calcium excretion, alkaline phosphatase and PTH levels were within the normal range. There was neither new renal stone formation, nor clinical or laboratory signs of high turnover bone disease. Since alkaline phosphatase, which is a very reliable marker of increased osteoclastic activity, was within the normal range no therapy for Paget's disease of bone was necessary until now.
The scintigraphic appearance of Paget's disease consists of a well-defined dense uptake generally corresponding to the radiographic distribution of the lesion [16]. These findings are typical for Paget's disease. In contrast, similar to renal osteodystrophy, primary hyperparathyroidism presents with normal, or in 50% of cases with generalized increased uptake (super scan), on scintigraphic imaging [17]. In our patient there was no scintigraphic evidence for alterations associated with primary hyperparathyroidism. A change in the scintigraphic demonstration of disease activity was not likely to occur in our patient, who was not treated for clinical silent Paget's disease, thus a follow-up scintigraphy was not performed.
Teaching point
In rare cases hypercalcaemia may be caused by two underlying disease entities (i.e. hyperparathyroidism and Paget's disease of bone).
In such a clinical situation successful treatment of at least one underlying disease may result in a long-term normalization of the serum calcium level.
Notes
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Correspondence and offprint requests to: Sabine Schmaldienst MD, Department of Medicine III, Division of Nephrology and Dialysis, University of Vienna, Währinger Gürtel 1820, A-1090 Vienna, Austria. Email: sabine.schmaldienst{at}univie.ac.at
References