A patient with evidence of two underlying diseases causing hypercalcaemia

(Section Editor: K. Kühn)

Sabine Schmaldienst1,, Elisabeth Dittrich1, Peter Pietschmann2, Bruno Niederle3, Alexander Becherer4 and Bruno Watschinger1

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 60–170 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 30–85 mmol/l) were within the normal range. In contrast, osteocalcin was elevated (43.2 ng/ml; normal range 7–31 ng/ml). The serum angiotensin converting enzyme level was within normal limits (11.5 U/l; normal range 8.3–21.4 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 1Go). 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 2Go).



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Fig. 1. Tomographic images (SPECT) of the neck 3 h after application of 700 MBq technetium (99mTc)-Sestamibi reveal a focal tracer retention dorsal of the right caudal thyroid pole. This finding is typical for an adenoma of the parathyroid gland.

 


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Fig. 2. Whole body scintigraphy 3 h after injection of 600 MBq technetium (99mTc)-3,3-diphosphono-1,2-propanedicarboxylic acid shows an increased uptake in the left sacroiliacal joint and iliac bone. This is a typical feature of Paget's disease of bone. The right kidney is visualized in the normal position while on the left side kidney uptake is lacking. The explanation for this phenomenon is a known pelvic kidney, which is hidden by the higher bone activity.

 

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

Supported by an educational grant from

Correspondence and offprint requests to: Sabine Schmaldienst MD, Department of Medicine III, Division of Nephrology and Dialysis, University of Vienna, Währinger Gürtel 18–20, A-1090 Vienna, Austria. Email: sabine.schmaldienst{at}univie.ac.at Back

References

  1. Montellon JL, Javort-Jimenez F, de Miguel F et al. Parathyroid hormone-related protein, parathyroid hormone and vitamin D in hypercalcemia of malignancy. Clin Chim Acta2000; 290: 189–197[ISI][Medline]
  2. Mundy GR, Ibbotson KJ, D'Souza SM. Tumor products and the hypercalcemia of malignancy. J Clin Invest1985; 76: 391[ISI][Medline]
  3. Heath H, Hodgson SF, Kennedy MA. Primary hyperparathyroidism: Incidence, morbidity and potential economic impact in a community. N Engl J Med1980; 302: 189[Abstract]
  4. Utiger RD. Treatment of primary hyperparathyroidism. New Engl J Med1999; 341: 1301–1302[Free Full Text]
  5. Siris ES. Seeking the elusive etiology of paget disease: a progress report. J Bone Mineral Res1996; 11: 1599–1601[ISI][Medline]
  6. Fogelman I, Carr D. A comparison of bone scanning and radiology in the assessment of patients with symptomatic Paget's disease. Eur J Nucl Med1980; 5: 417–421[ISI][Medline]
  7. Krane SM. Skeletal metabolism in Paget's disease of bone. Arthritis Rheum1980; 23: 1087–1094[ISI][Medline]
  8. Meunier PJ, Coindre JM, Edouard CM, Arlot ME. Bone histomorphometry in Paget's disease. Arthritis Rheum1980; 23: 1095–1103[ISI][Medline]
  9. Delmas PD, Meunier PJ. The management of Paget's disease of bone. New Engl J Med1997; 336: 558–566[Free Full Text]
  10. Siris ES, Clemens TP, McMahon D et al. Parathyroid function in Paget's disease of bone. J Bone Mineral Res1989; 4: 75–79[ISI][Medline]
  11. Hollenberg AN, Arnold A. Hypercalcemia with low-normal serum intact PTH: a novel presentation of primary hyperparathyroidism. Am J Med1991; 91: 547–548[ISI][Medline]
  12. Pietschmann P, Niederle B, Anvari A, Woloszczuk W. Serum osteocalcin levels in primary hyperparathyroidism. Klin Wochenschr1991; 69: 351–353[ISI][Medline]
  13. Wilczek H, Kanka J. Coincidence of Paget's disease of bone and primary hyperparathyroidism. Sb Lek1993; 94: 213–217[Medline]
  14. Hanisch E, Schwille PO, Gebhardt C, Scholz D, Pichl J. Coexistence of Paget's disease of the bone and primary hyperparathyroidism. Dtsch Med Wochenschr1993; 108: 1415–1416
  15. Gutteridge DH, Gruber HE, Kermode DG, Worth GK. Thirty cases of concurrent Paget's disease and primary hyperparathyroidism: sex distribution, histomorphometry, and prediction of the skeletal response to parathyroidectomy. Calcif Tissue Int1999; 65: 427–435[ISI][Medline]
  16. Harbert JC. The musculoskeletal system. In: Harbert JC, Eckelman WC, Neumann RD, eds. Nuclear Medicine. Diagnosis and Therapy. Thieme Medical Publishers Inc, New York, 1996; 801–810
  17. Fogelman I, Carr D. A comparison of bone scanning and radiology in the evaluation of patients with metabolic bone disease. Clin Radiol1980; 31: 321–326[ISI][Medline]