Critical review of hypercalcemia

Uchendu Ikenna Kingsley, Chidozie Elochukwu Agu, Tochi Faith Nwosu Division of Clinical Chemistry, Department of Medical Laboratory Science, University of Nigeria, Enugu Campus, Enugu State, Nigeria. Division of Clinical Chemistry, Department of Medical Laboratory Science, University of Calabar, PMB 1115 Calabar, Cross River State, Nigeria. Barnes Hospital and Cardiac Diagnostic Laboratories Ltd. 34b, Yesufu Abiodun Oniru Road, Dideolu Estates, Victoria Island Extension, Lagos State, Nigeria. Article history: Abstract

Hypercalcemia is a clinical condition with an abnormally high serum calcium (Ca) level. Hypercalcemia is associated with many diseases with primary hyperparathyroidism and some malignancies accounting for greater than 90% of cases. Hypercalcemia may be clinically useful as a diagnostic or prognostic marker for these diseases. This paper covers the various etiologies attributing to hypercalcemia, pathogenesis and the differential diagnosis of hypercalcemia. Hypercalcemia is a useful diagnostic marker in hypercalcemia-related diseases such as primary hyperparathyroidism, malignancies and granulomatous disorders. Adequate managements or treatments are aimed to reduce serum Ca levels by preventing bone resorption, enhancing urinary Ca excretion, or preventing intestinal Ca absorption. The optimal choice is dependent on the cause and/or severity of hypercalcemia. Drug treatment or management of hypercalcemia include: Bisphosphonates, Gallium nitrate, Glucocorticoids and Denosumab.
ypercalcemia is a clinical condition with an abnormally high serum calcium (Ca) level. Total serum Ca ranges from 8.8-10.4 mg/dL (2.20-2.60 mmol/L) in apparently healthy subjects 1 . Total serum Ca comprises free ions (≈50%), protein-bound complexes (≈40%), and ionic complexes (≈10%) 2 . The free ionic Ca, the physiologic active form, is stringently regulated within a range of 4.4-5.4 mg/dL (1.10 -1.35 mmol/L) so as to avoid Ca toxicity 3 . It is decreased in alkalosis and increased in acidosis 4 . In patients with abnormality of extracellular fluid pH, each 0.1 reduction in pH elevates ionized calcium by approximately 0.2 mg/dl (0.05 mmol/L) 5 . Hyper-calcemia is associated with many diseases with primary hyperparathyroidism and some malignancies accounting for greater than 90% of cases 6 .
Hypercalcemia may be clinically useful as diagnostic or prognostic marker for these diseases. However, it is non-specific and this may undermine its usefulness as a first-line marker. Patients manifest symptoms with neuromuscular, gastrointestinal, renal, cardiovascular and skeletal involvement 7 .
Report showed that the prevalence of hypercalcemia in patients range from 0.17%-2.9% in some hospitals; while surprisingly a higher prevalence of hypercalcemia was reported to vary between H J Med Allied Sci 2017; 7(1) 1.07% and 3.9%, in the normal population 8 ; and women were reported to be more affected than men 9 . This therefore suggests that its prevalence may depend on the population studied in relation to the underlying disease. Relevant studies to date done on the subject have been considered for this review article. The studies considered for this article are available in various books on the subject and research articles printed or hosted over the internet by reputable online journals.

Interpretation of calcium
In serum, albumin and globulin are the main Ca binding proteins 7 . Because 1g/dL albumin approximately binds 0.8 mg/dl Ca, ionized Ca is estimated from measurements of total Ca and serum albumin; and the ionized Ca concentration adjusted using the formula: Corrected calcium = Measured Ca (mg/dL) + [0.8 × (4albumin)] g/dL 10 . However the retrospective study by Steele et al 11 and the prospective study by Slomp et al 12 show that albumin adjusted Ca is a relatively poor indicator of ionic Ca levels in patients that are critically ill. Patients who are hypocalcemic are often under-diagnosed and classified to be hypercalcemic. The use of ward-based analyzers can increase the test sensitivity 11 . Ionized Ca measurement could be of essence in few cases such as in patients with hyperalbuminemia, hypoalbuminemia, Waldenström macroglobulinemia, thrombocytosis, and myeloma 7,10 . In Waldenström macroglobulinemia and myeloma cases, hypercalcemia may be diagnosed but the ionized serum Ca is normal (pseudohypercalcemia) 10 .

Pathogenesis of hypercalcemia
Ionized Ca is tightly regulated by the actions of two principal hormones and their receptors: PTH (parathyroid hormone) and PTHR (the PTH receptor) 13 and 1, 25-[OH] 2 D (1, 25dihydroxy vitamin D3) and VDR (the vitamin D receptor) 14 . Disease(s) which chronically elevate levels of PTH and 1, 25-[OH] 2 D may result to increased: bone resorption, releasing Ca; intestinal absorption and renal reabsorption of Ca. The net effect is an increase in plasma Ca above the normal physiological levels leading to the clinical condition known as hypercalcemia 7 (Fig 1).

Causes of hypercalcemia
Hypercalcemia is one of the consequences of the pathophysiology of diseases which inappropriately increase the levels of PTH, 1, 25-[OH] 2 D, or PTHrelated proteins (PTHrP) in the blood 6 . These and other diseases that results to hypercalcemia are listed in table 1.

Differential diagnosis of hypercalcemia
Once hypercalcemia has been established and pseudo-hypercalcemia ruled out, it is very helpful to differentiate those etiologies of hypercalcemia that are PTH dependent as opposed to those that are PTH independent 7 ( Table 2).

Primary hyperparathyroidism
Primary hyperparathyroidism (PHPT) is a disorder caused by hyperactive parathyroid glands with consequent hypercalcemia 15 . The finding of reproducible hypercalcemia in routine biochemical tests is an indication of PHPT, especially in individuals over 50 years old and in postmenopausal women 16 . Over secretion of PTH from one or more parathyroid glands causes hypercalcemia and constitutes the biochemical characteristic of PHPT 17 . A cohort study based on the population of Tayside used the following biochemical criteria for diagnosing PHPT: albumin-corrected serum calcium > 10.22 mg/dL (8.4-10.22 mg/dL) at least on 2 occasions, with serum PTH > 13.5 ng/L (4.5-31.05 ng/L); or albumin-corrected serum calcium > 10.22 mg/dL on only one occasion with serum PTH > 31.05 ng/l 19 . These values of serum PTH correspond to 20 pg/mL for assays with reference range of 10−65 pg/mL 18 . Although not all patients selected by these criteria and who have serum PTH levels within the reference range have morphological confirmation, it seems reasonable to consider inappropriately normal serum PTH levels, in the presence of hypercalcemia, as indicative of the diagnosis of PHPT.

Malignancies
Hypercalcemia is common in patients with cancer 19 . Cancer-induced bone disease can result from the primary disease itself, either due to circulating bone resorbing substances or metastatic bone disease, such as commonly occurs with breast, lung and prostate cancer 20,21 . They are related to local effects of metastatic deposit in bone and/or to generalized bone loss from tumourproduced systemically circulating bone resorbing hormones or cytokines 21,22 . These comprise para-thyroid hormone-related protein (PTHrP), like in lung and breast cancer, or tumor stimulated secretion by the osteoblast of local bone resorbing factors such as receptor activator of nuclear factor kappa-B ligand (RANKL), interleukin (IL)-6 or IL-3, like in multiple myeloma 19,21,22 .
Hypercalcemia is a severe complication arising in >80% of acute Adult T-cell leukaemia (ATL) patients and serves as a major prognostic factor for acute ATL disease outcome 23 . Osteolytic bone lesion has been reported in acute ATL patients, along with elevated levels of RANKL, MIP-1α, PTHrP, and IL-6, and is believed to contribute to hypercalcaemia 24 . Wnt-5a, a protein in humans that is encoded by the WNT5A gene, has been shown to increase osteoclastogenesis by enhancing RANKL expression in osteoclast precursors 26 .
Recently, Bellon et al 22 demonstrate that ATL cells stimulate osteoclast differentiation and secreted Wnt5a is responsible for increases in RANKL. Therefore, one may reasonably assume that ATL patients may benefit from anti-Wnt5a therapy; as the therapy may also reduce osteolytic bone lesions and hypercalcaemia levels in ATL patients 26,27 .

Granulomatous disorders
Hypercalcemia due to extra renal production of 1,25-[OH] 2 D has been associated with granulomatous disorders including sarcoidosis and tuberculosis 28,29 and also seen in lymphoma, a nongranulomatous condition 30 . Co-presentation of a parathyroid adenoma and a granulomatous disorder has been reported. However, granulomatous inflammation within a parathyroid adenoma is very rare. Yoshida et al 31 and Chaychi et al 32 reported hypercalcemia due to co-existing parathyroid adenoma and sarcoidosis in a 75-year-old woman and 67-year-old man respectively. Few cases of granulomatous inflammation within the parathyroid adenoma had been reported 33,34 . In these latter cases, the parathyroid glands had been demonstrated to be infiltrated by granulomatous inflammation of tuberculosis within parathyroid adenomas. However, a 50-year-old Caucasian woman with PHPT who was detected to have non-caseating granulomas within her parathyroid adenoma was reported by Anaforoğlu et al 35 . One may reasonably say that non-caseating granulomas could co-exist and also be detected within parathyroid adenoma in the elderly patients; and women may be more affected than men.

Treatment of hypercalcemia
Effective treatments reduce serum Ca by inhibiting bone resorption, increasing urinary Ca excretion, J Med Allied Sci 2017; 7 (1) or decreasing intestinal Ca absorption. The optimal choice varies with the cause and severity of hypercalcemia. Among others are:

Bisphosphonates
Bisphosphonates are potent in the treatment of severe hypercalcemia resulting from excessive bone resorption of any cause including malignancy-related hypercalcemia; and are the preferred agent for the treatment 36 . Zoledronic is among the currently available agents for the treatment of malignancy-associated hypercalcemia. Osteonecrosis of the jaw is a major side effect among others 37 .

Gallium nitrate
Gallium inhibits osteoclastic bone resorption, in part via inhibition of an ATPase dependent proton pump on the osteoclast ruffled membrane, without being directly cytotoxic or acting as a metabolic toxin to bone cells 38 . Gallium also inhibits PTH secretion from parathyroid cells in vitro 39 . Unlike bisphosphonates, gallium appears to be effective in both PTHrP-mediated, and non-PTHrP-mediated hypercalcaemia 40 . The disadvantages of gallium include its potential for nephrotoxicity, and the need for continuous infusion over five days 41 . Thus, clinicians may prefer to use bisphosphonates rather than gallium nitrate for the treatment of hypercalcemia due to excessive bone resorption.

Glucocorticoids
Glucocorticoids are used to treat hypercalcemia due to excess availability of 1,25-[OH] 2 D. Increased 1, 25-[OH] 2 D production can occur in patients with chronic granulomatous diseases (e.g. sarcoidosis) and in occasional patients with lymphoma. Glucocorticoids (e.g. prednisone) will usually reduce serum calcium concentrations by decreasing 1,25-[OH] 2 D production by activated cells 28 .

Denosumab
Denosumab is a human monoclonal antibody that binds and neutralizes human RANKL 7 . It prevents RANKL from activating RANK on osteoclasts thereby reducing bone resorption 22 . Therefore, RANKL inhibition through denosumab is a therapeutic target for preventing and treating bone metastases. Osteonecrosis of the jaw and atypical fractures of the femoral shaft have been reported with long-term use 7 .

Current investigation and future research
Currently, there is one ongoing clinical trial studying the use of denosumab for refractory hyper-calcemia, and the results are pending. Also there are several ongoing trials with an enrolment of over 20,000 patients to evaluate the efficacy of bisphosphonates for prevention of metastases in breast, prostate, and lung cancers; and multiple myeloma 42 . Results from these studies are likely to expand the role of bisphosphonates (especially zoledronic acid) and denosumab in the treatment of hypercalcemia-related disorders.

Conclusion
Hypercalcemia continues to be a clinical condition frequently encountered in both the outpatient and the inpatient setting. However, it is a useful marker for the diagnosis and prognosis of hypercalcemiarelated diseases. Establishing a specific aetiology for hypercalcemia is still necessary to provide timely therapy beyond these general measures. Studies evaluating the effectiveness and adverse effects of a new potent inhibitor of osteoclast activity, denosumab, are underway.