J Med Allied Sci 2017; 7(1):03-08 DOI: https://doi.org/10.5455/jmas.254690
Review
Critical review of hypercalcemia
Uchendu Ikenna Kingsley1,
Chidozie Elochukwu Agu2,
Tochi Faith Nwosu3
Affiliation(s):
1Division of Clinical
Chemistry, Department of Medical Laboratory Science, University of Nigeria,
Enugu Campus, Enugu State, Nigeria.
2Division
of Clinical Chemistry, Department of Medical Laboratory Science, University of Calabar, PMB 1115 Calabar, Cross
River State, Nigeria.
3Barnes
Hospital and Cardiac Diagnostic Laboratories Ltd. 34b, Yesufu
Abiodun Oniru Road, Dideolu Estates, Victoria Island Extension, Lagos State, Nigeria.
Corresponding
author: Dr. Chidozie Elochukwu Agu, Department of Medical Laboratory
Science, University of Calabar, PMB 1115 Calabar, Cross River State, Nigeria.
Phone: +2348030984682 Email:
chidozieagu@gmail.com
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.
Keywords: Serum
calcium, Primary hyperparathyroidism, Bisphosphonates, Gallium nitrate, Denosumab, Glucocorticoids
Running title: Hypercalcemia
Introduction
Hypercalcemia 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 subjects1. 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 toxicity3. It is
decreased in alkalosis and increased in acidosis4. 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. Hypercalcemia is
associated with many diseases with primary hyperparathyroidism and some
malignancies accounting for greater than 90% of cases6.
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 involvement7. 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 1.07% and 3.9%,
in the normal population8; and women were reported to be more
affected than men9. 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 proteins7. 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 × (4 – albumin)] g/dL10. However the retrospective study by Steele et al11 and the prospective study by Slomp et al12 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 sensitivity11. Ionized Ca
measurement could be of essence in few cases such as in patients with hyperalbuminemia, hypoalbuminemia,
Waldenström macroglobulinemia,
thrombocytosis, and myeloma7,10.
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, 25 – dihydroxy 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 hypercalcemia7(Fig 1).
Fig 1. Major
etiologies of hypercalcemia.
The abnormal rise in the levels of PTH, 1,25-[OH]2 D, or PTH-related proteins (PTHrP) in the blood
causes hypercalcemia. Granulomatous
diseases such as tuberculosis, fungal diseases or sarcoidosis
causes increase in 1, 25- dihydroxyvitamin D3
(vitamin D intoxication) which enhances intestinal absorption of Ca into the
blood. Hyperparathyroidism leads to increased level of circulating PTH which
increases renal Ca reabsorption and bone resorption, causing hypercalcaemia.
Furthermore, Thiazides (anti-diuretic drugs) can
enhance renal Ca reasorption into the extracellular
fluid7.
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 PTH-related proteins (PTHrP) in the blood6.
These and other diseases that results to hypercalcemia
are listed in table 1.
Table 1: Causes
of hypercalcemia (Adapted from
Endres, 20126) |
|
Parathyroid hormone |
Primary hyperparathyroidism - Sporadic, familial, MEN I
or IIA Tertiary hyperparathyroidism Coexisting malignancy and primary hyperparathyroidism Ectopic PTH in malignancy (very rare) |
Cancer |
Humoral
hypercalcaemia of malignancy - Parathyroid
hormone-related protein(PTHrP) Local osteolysis - Cytokines,
Chemokines, PTHrP |
Vitamin D |
Granulomatous
disease (1,25[OH]2 D) - Sarcoidosis, Tuberculosis,
berylliosis, Coccidioidomycosis Vitamin D supplements, vitamin D metabolites or analog - (1,25[OH]2D) |
Renal failure |
Chronic renal failure with treatment with calcium and
(1,25[OH]2D) or vitamin D analogs Rhabdomyolysis
and acute renal failure Renal transplant |
Other endocrine disorders |
Thyrotoxicosis Adrenal insufficiency Pheomochrocytoma |
Medications |
Thiazide
diuretics Lithium Milk-alkali syndrome (calcium and antacids) Vitamin A |
Other |
Immobilization Familial
hypocalcuric hypercalcemia |
1, 25(OH)2D
= 1,25-dihydroxyvitamin D; MEN = Multiple
endocrine neoplasia; PTH = Parathyroid hormone; PTHrP = Parathyroid hormone-related protein |
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 independent7
(Table 2).
Table 2: Differential
diagnosis of hypercalcemia (Adapted from Maier and Levine; 20137) |
|
Parathyroid-dependent
hypercalcemia |
Parathyroid-independent
hypercalcemia |
Primary hyperparathyroidism ·
Adenoma ·
Hyperplasia ·
Carcinoma (rare) Tetiary
hyperparathyroidism Familial
hypocalcuric hypercalcemia Lithium |
Malignancy Local
osteolitic osteolysis ·
Multiple bone metastasis ·
Diffuse marrow
infiltration Humoral
hypercalcemia of malignancy ·
Parathyroid
hormone-related protein ·
1, 25 Dihydroxyvitamin
D Granulomatous
disease Hyperthyroidism Adrenal insufficiency Medications ·
Thiazide ·
Vitamin D ·
Calcium ·
Vitamin A ·
Teriparatide Immobilization |
Hypercalcemia as a marker in hypercalcemia-related
diseases
Primary hyperparathyroidism
Primary
hyperparathyroidism (PHPT) is a disorder caused by hyperactive parathyroid
glands with consequent hypercalcemia15. The finding of reproducible hypercalcemia in routine biochemical tests is an indication
of PHPT, especially in individuals over 50 years old and in postmenopausal
women16. Over secretion of PTH from one or more parathyroid glands
causes hypercalcemia and constitutes the biochemical characteristic
of PHPT17. 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/l19.
These values of serum PTH correspond to 20 pg/mL for assays with reference range of 10−65 pg/mL18.
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
cancer19. 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 cancer20,21. They are related to
local effects of metastatic deposit in bone and/or to generalized bone loss
from tumour-produced systemically circulating bone resorbing
hormones or cytokines21,22. These comprise
parathyroid 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 myeloma19,21,22.
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 outcome23.
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 hypercalcaemia24. 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 precursors26. Recently, Bellon et al22 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 patients26,27.
Granulomatous disorders
Hypercalcemia due to extra renal
production of 1,25-[OH]2 D has been associated with granulomatous disorders including sarcoidosis
and tuberculosis28,29 and also seen in lymphoma, a non-granulomatous condition30. 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 al31 and Chaychi et
al32 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 reported33,34. 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 al35. 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, 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
treatment36. Zoledronic is among the
currently available agents for the treatment of malignancy-associated hypercalcemia. Osteonecrosis of the jaw is a major side
effect among others37.
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 cells38. Gallium also inhibits PTH secretion from
parathyroid cells in vitro39. Unlike bisphosphonates,
gallium appears to be effective in both PTHrP-mediated,
and non-PTHrP-mediated hypercalcaemia40.
The disadvantages of gallium include its potential for nephrotoxicity, and the need
for continuous infusion over five days41. 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]2D. Increased 1, 25-[OH]2D 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 cells28.
Denosumab
Denosumab is a human
monoclonal antibody that binds and neutralizes human RANKL7. It
prevents RANKL from activating RANK on osteoclasts thereby
reducing bone resorption22. 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 use7.
Current investigation and future research
Currently,
there is one ongoing clinical trial studying the use of denosumab
for refractory hypercalcemia, 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 myeloma42. Results from
these studies are likely to expand the role of bisphosphonates
(especially zoledronic acid) and denosumab
in the treatment of hypercalcemia-related disorders.
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 hypercalcemia-related 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.
Acknowledgments: None
Competing interest: The authors declare no competing interests.
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