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due to renal failure or drugs such as lithium) or arise due to mechanisms independent of PTH (chronic
granulomatous disorders, hyperthyroidism, acromegaly, pheochromocytoma, and adrenal insufficiency) [88-90] .

Management
To improve patients’ outcome, a periodic monitoring of calcium serum levels and prompt correction of
potential hypercalcemia should be performed. To define an effective hypercalcemia, it is important to
avoid the presence of concomitant factors that can influence the share of bound and free calcium (e.g.,
hyperglobulinemia might increase total calcium levels without modifying ionized concentrations; acidemia
and reducing albumin-calcium affinity might increase the level of the ionized form, without altering total
[87]
calcium levels) . Diagnosis is often incidentally during routine laboratory investigations, as most patients
[88]
with mild hypercalcemia are asymptomatic . Chronic hypercalcemia, due to hyperparathyroidism, is often
asymptomatic; however, in some cases, this long-lasting electrolyte disorder might cause nephrolithiasis.
Instead, chronic hyperparathyroidism secondary to renal failure and dialysis might cause bone pain related
to bone remodeling process, fibrous degeneration, and formation of cysts and nodules of fibrosis.

Clinical presentation depends on grade and time of onset. Most common symptoms are general malaise,
thirst, lethargy, and constipation often associated with abdominal pain. Renal symptoms and signs such as
polyuria, polydipsia, nycturia, nephrolithiasis, and rarely renal failure and nephrocalcinosis should be also
considered.

Neuromuscular disorders, starting from muscles weakness, emotional instability, and confusion, until
development of delirium, psychosis, stupor, and coma, could be observed in acute or severe hypercalcemia
(serum calcium levels > 12 mg/dL). Furthermore, hypercalcemia might cause cardiac arrhythmias. The
most common electrocardiographic changes are absent or shortened ST segment, shortened QT interval,
widened QRS complex, enlarged T wave, and prolonged PR interval. Rarely, it might cause branch block
[88]
and arrhythmias until to cardiac arrest in the case of serum calcium levels over 15 mg/dL .
Renal function and immunoreactive parathyroid hormone analysis are recommended for a complete
diagnostic classification that allows making differential diagnosis and to consider potential serious
conditions (cardiac arrhythmias).

[95]
Electrocardiography should also be performed in order to avoid presence of cardiac alterations .
Generally, primary hyperparathyroidism is usually characterized by hypercalcemia (with high ionized free
serum calcium levels), hypophosphatemia, PTH being inappropriately high (e.g., no hypocalcemia), and
excessive bone turnover.

Differential diagnosis between primary and secondary hyperparathyroidism could be difficult in the case of
renal failure, although hyperphosphatemia is often linked to secondary hyperparathyroidism and normal
[96]
or low phosphorus levels are indicative of primary hyperparathyroidism .

Furthermore, in the presence of secondary hyperparathyroidism, radiographic examination should be
useful to detect bone cysts presence and bone reabsorption.

When hyperparathyroidism has been excluded, a serum calcium level above 12 mg/dL is suspicious
of malignancies, mostly when associated with hypophosphatemia, hypoalbuminemia, and lower or
undetectable PTH level. PTHrP is a peptide that shows homology with the N-terminal portion of PTH,
mimicking the action. It can be produced from breast, lung, and kidney cancer cells. When possible, the
[88]
individuation of PTHrP is useful for reach diagnosis of paraneoplastic hypercalcemia .