Acromegaly and non‐parathyroid hormone‐dependent hypercalcemia: a case report and literature review

Hypercalcemia in acromegalics is usually attributable to co-existing primary hyperparathyroidism, which is common in individuals with MEN-1 [7]. Additionally, GH has been shown to stimulate parathyroid hyperplasia in rats [8]; this mechanism may also contribute to the development of parathyroid hyperplasia in humans. However, the present patient’s hypercalcemia was not PTH-dependent. His PTH concentration was close to the lower limit of the normal range with no imaging abnormality in the parathyroid gland, and after the treatment of cabergoline combined with somatostatin, the serum levels of GH, PRL, calcium concentration, urinary calcium concentration, as well as bone turnover markers, were all normalized, with serum PTH increased but not above the normal range. Therefore, mild primary hyperparathyroidism (PHPT) seems unlikely.

Both primary hyperparathyroidism and malignancy are the common causes of hypercalcemia. When the tumors metastasize to the bone or even do not metastasize to the bone, patients with malignant tumors may develop hypercalcemia. Malignancies can produce and release PTH-related peptide (PTHrP) or similar factors, which can mimic the biochemical effects of PTH and cause hypercalcemia. Hypercalcemia caused by PTHrP may present in patients with endocrine neoplasms such as pheochromocytoma, neuroendocrine tumors, and carcinoid tumors, and it can also present in nonendocrine neoplasms [5]. In addition, hypercalcemia has also been reported association with hydrochlorathizide or lithium use which may reduce renal calcium clearance or increase the synthesis of PTH, and with Vitamin A or Vitamin D use which may affect bone absorption and the synthesis of 1,25 dihydroxyvitamin D, and with theophylline use which increases local cyclic AMP levels [5]. However, the present patient’s disease started at age of 37, with no family history and no special medication history. Since ultrasonography showed no abnormality in the parathyroid gland, and the patient’s chest and abdomen CT, cranial MRI, colonoscopy and gastrocopy, and his biochemical examination showed no signs of nodules or tumors. And we excluded MEN-1 and all potential causes of non-PTH-dependent hypercalcemia, such as sarcoidosis, active tuberculosis, and malignancy. The most likely explanation for our patient’s hypercalcemia is that GH inappropriately activated 1-α hydroxylase mediated by IGF-1, which stimulated production of 1,25-dihydroxyvitamin D [9], resulting in increased absorption of calcium in the gut and distal renal tubules [4]. Furthermore, the enhancement of bone turnover mediated by GH may have contributed to his hypercalcemia [6]. However, using radioisotopic calcium, Sigurdsson et al. demonstrated that the major cause of hypercalcemia and hypercalciuria in acromegalics is increased calcium absorption from the gut [10]. Moreover, the normalization of calcium and phosphorus metabolism after biochemical remission of acromegaly is consistent with the above explanation [1, 4, 11, 12].

Although development of non-PTH-dependent hypercalcemia in individuals with acromegaly is theoretically logical, it is rare in clinical practice, possibly because of the strong capacity to self-regulate serum calcium concentrations. Approximately 30–60 % of patients with acromegaly have mild hyperphosphatemia and hypercalciuria, which may contribute to urolithiasis [13, 14]. Although serum calcium concentrations tend to increase [15], they generally remain within the normal range [6]. The rare development of hypercalcemia in acromegaly is reportedly usually attributable to co-existent primary hyperparathyroidism. Constantin et al. prospectively studied calcium and bone turnover markers in 22 patients with acromegaly and compared the findings with those in 22 patients with nonfunctioning pituitary adenomas. Two of their patients with acromegaly (2/22) developed non-PTH dependent hypercalcemia; however, no details concerning these two patients were provided. Whether they were taking vitamin D and/or calcium supplements, or receiving physiologic doses of hydrocortisone was not reported, such treatment may lead to hypercalcemia, as occurred in other patients in that study [6]. Takamoto et al. reported calcium homeostasis in 12 patients with acromegaly treated with pituitary adenomectomy. Only one of these patients, a 47-year-old man, was found to have hypercalcemia with normal PTH and a high serum PRL (100 ng/mL); however, no details were provided [16]. We found only three reported cases of non-PTH-dependent hypercalcemia associated with acromegaly, all of which had pathologically confirmed adenomas that were positive for expression of GH and PRL by immunohistochemistry. Although we did not obtain a pathological diagnosis in the present patient, we diagnosed him as having a GH and PRL co-secreting pituitary macroadenoma based on the clinical manifestations and his response to treatment with a combination of cabergoline and somatostatin. In animals, PRL increases the activity of 1-α hydroxylase [17], and serum 1,25-dihydroxyvitamin D concentrations have been found to be increased in lactating rats [18]; however, the effect of PRL on calcium regulation in humans is still unclear. Serum concentrations of 1,25-dihydroxyvitamin D in patients with prolactinoma are controversial and require further clarification [1]. Meanwhile, no cases of hypercalcemia related to prolactinoma have been reported thus far, other than in individuals with MEN-1. Although the effect of PRL on calcium metabolism may be slight, its effects in combination with GH could overwhelm the capacity to self-regulate serum calcium, resulting in detectable hypercalcemia.

Our patient also had hypogonadism, which is common in individuals with prolactinoma or acromegaly as a consequence of the effects of excess PRL on the hypothalamic–pituitary–gonadal axis or the mass effect of the tumor [13]. GH potentially increases bone turnover, with bone formation and absorption coupled and bone absorption slightly dominant [19]; however, serum calcium concentrations generally remain within the normal range. The presence of hypogonadism may shift the balance toward bone absorption [20], which may disturb calcium homeostasis, contributing to hypercalcemia and eventually an increased risk of vertebral fractures, as documented by others [21].

In summary, the proposed mechanisms for the present patient’s hypercalcemia include: (1) increased calcium absorption in the intestinal tract and kidney, which may be attributable to the combination of 1,25-dihydroxyvitamin D overproduction and enhancement of bone turnover mediated by excess GH; (2) 1,25-dihydroxyvitamin D overproduction potentially mediated by excess PRL; and (3) excessive bone absorption exacerbated by hypogonadism.

The effects of GH and IGF-1 on bone are complex, including stimulation of osteoblast differentiation, inducing osteoprotegerin production, receptor activator of nuclear factor kappa-B ligand (RANK-L) synthesis and osteoclastogenesis, which may be partially mediated by 1,25-dihydroxyvitamin D [20, 21]. Acromegaly is usually associated with increased bone turnover, which is characterized by coupling of bone formation and resorption with bone absorption slightly dominant and serum calcium balanced. Markers of bone formation and resorption such as osteocalcin, B-ALP, n-terminal telopeptide, and CTX are generally increased [13]. In the present patient, B-ALP and CTX were increased, with CTX dominant, and they gradually normalized after remission of the patient’s acromegaly [6].

Bone mineral density (BMD), as measured by dual energy X-ray absorptiometry (DXA), has been variously reported to be normal, increased, or decreased by different researchers. No matter the BMD according to DXA, the prevalence of morphometric vertebral fractures in acromegalics is higher than in the general population (39–59 % vs. 14 %); this phenomenon persists even after biochemical control of acromegaly [19‐21]. BMD according to DXA reportedly does not correlate with fracture risk in patients with acromegaly, whereas the risk of fracture is associated with hypogonadism, long duration of acromegaly, active acromegaly, diabetes mellitus, and glucocorticoid over-replacement, all of which can potentially worsen bone quality [21]. There is controversial evidence that bone microarchitecture rather than bone quantity is impaired; thus, BMD may not be an ideal means of identifying bone damage in acromegalics. Therefore, other means of reflecting bone microarchitecture, such as trabecular bone score and high-resolution peripheral quantitative computed tomography, have been introduced [20, 21] and may be preferable in acromegaly patients.

In summary, mild hyperphosphatemia and hypercalciuria are common in individuals with acromegaly and deserve attention because they may contribute to osteoporosis and urolithiasis. However, overt hypercalcemia is rare in these patients and is not always attributable to coexistent parathyroid hyperplasia or adenoma. It is rarely non-PTH-dependent, may be exacerbated by excess PRL and hypogonadism, and can resolve with remission of acromegaly. Moreover, acromegalics have an increased prevalence of vertebral fractures and BMD may not be the ideal means of assessing bone damage in such patients. Further studies are needed to clarify the development of non-PTH-dependent hypercalcemia and bone damage in individuals with acromegaly.

This study had several limitations. First, we are unable to measure 1,25-dihydroxyvitamin D, and only measured serum 25 hydroxyvitamin D. This was low, which is consistent with past reports and may be partly attributable to excessive conversion of 25 hydroxyvitamin D to 1,25-dihydroxyvitamin D. Second, the present patient’s diagnosis was not pathologically confirmed because he refused surgery. Third, the results included were limited to full-text articles published in English; thus, other reports may exist.