J Bone Miner Metab (2009) 27:635–642
DOI 10.1007/s00774-009-0119-x
REVIEW ARTICLE
A review of drug-induced hypocalcemia
George Liamis Æ Haralampos J. Milionis Æ
Moses Elisaf
Received: 15 April 2009 / Accepted: 27 July 2009 / Published online: 4 September 2009
Ó The Japanese Society for Bone and Mineral Research and Springer 2009
Abstract Hypocalcemia (defined as total serum calcium
lower than 8.5 mg/dl or as ionized serum calcium lower
than 4.7 mg/dl) is a relatively common metabolic abnor-
mality observed in hospitalized patients. Although it is
associated with certain pharmacological agents such as
bisphosphonates and cisplatin, hypocalcemia may occa-
sionally develop in the course of treatment with drugs used
in everyday clinical practice, including antiepileptics,
aminoglycosides, and proton pump inhibitors. Hypocalce-
mia associated with drug treatment can be easily missed as
a consequence of coexistence of multiple factors contrib-
uting to low serum calcium levels. Drug-related hypocal-
cemia is usually mild and asymptomatic but may be severe
as well. Effective clinical management can be handled
through awareness of this adverse effect induced by certain
pharmaceutical compounds on serum calcium concentra-
tions. Herein, we review pertinent clinical information on
the incidence of hypocalcemia associated with specific
drug treatment and discuss the underlying pathophysio-
logical mechanisms.
Keywords Adverse drug reaction
Hypocalcemia

Calcium homeostasis
Tetany
Introduction
Hypocalcemia is a relatively common electrolyte distur-
bance occurring in a broad spectrum of patients from
asymptomatic to critically ill. It is mainly encountered in
G. Liamis
H. J. Milionis (&)
M. Elisaf
Department of Internal Medicine, School of Medicine,
University of Ioannina, 451 10 Ioannina, Greece
e-mail: hmilioni@uoi.gr
hospitalized patients [1, 2]. Hypocalcemia is defined as a
serum level of total calcium lower than 8.5 mg/dl
(2.12 mmol/l). Serum calcium exists in three forms: (1)
free or ionized calcium, the physiologically active form
that accounts for 50% of total serum calcium; (2) calcium
complexed to anions, including bicarbonate, lactate,
phosphate, and citrate; and (3) as calcium bound to plasma
proteins, constituting the remaining approximately 40%.
Approximately 80% of the protein-bound calcium fraction
is associated with albumin [3, 4]. Therefore, a patient with
abnormally high serum albumin will have proportionally
elevated serum calcium whereas the reported serum cal-
cium in a patient with low serum albumin will be reported
as less than the true value. In hypoalbuminemic states, one
of the commonly used formulas to correct total calcium
levels is by adding 0.8 mg/dl (0.2 mmol/l) to measured
calcium values for every 10 g/l decrease in serum albumin
from normal value (assumed to be 40 g/l). Given that the
accuracy of this method is poor (particularly among criti-
cally ill and geriatric patients), the biologically important
ionized calcium concentration should be measured when
possible [normal range of ionized calcium is 4.65–
5.25 mg/dl (1.16–1.31 mmol/l)] [5, 6].
In clinical practice, drug treatment is commonly impli-
cated as a cause of electrolyte disturbances, and a careful
drug history is of major significance to the diagnostic
approach. Nevertheless, hypocalcemia may be masked by
other adverse drug reactions or disease states, and the
involvement of a specific agent in its pathogenesis may be
overlooked. Drug-related hypocalcemia, although usually
mild and asymptomatic, may be clinically severe. Unrec-
ognized or poorly treated hypocalcemic emergencies can
lead to significant morbidity or death. Consequently, a
thorough understanding of the underlying pathophysiology
of drug-induced hypocalcemia and the associated risk
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factors may be of great value for the prevention and
effective management of this disorder.
Herein, we review clinical information on the incidence
of hypocalcemia associated with specific drug treatment
and discuss the underlying pathophysiology.
Pathogenetic aspects of hypocalcemia
Calcium is the third most abundant ion in the body and
plays an important role regarding normal cell function,
neural transmission, membrane stability, bone structure,
blood coagulation, and intracellular signaling [3]. A
decrease in extracellular (ECF) calcium (Ca2?) triggers an
increase in parathyroid hormone (PTH) secretion via acti-
vation of the calcium sensor receptor on parathyroid
cells [7]. PTH, in turn, enhances tubular reabsorption of
calcium by the kidney, increases calcium resorption from
bone, and stimulates renal 1,25-dihydroxycholecalciferol
[1,25(OH)2D3] production [4, 7, 8]. On the other hand,
vitamin D stimulates intestinal absorption of calcium,
regulates PTH release by the chief cells, and mediates
PTH-stimulated bone reabsorption [8]. Collectively, these
homeostatic mechanisms serve to restore serum calcium
levels to normal. Hypocalcemia takes place when there is a
net efflux of calcium from the extracellular fluid in greater
quantities than can be replaced by the intestine or bone as a
result of any disruption of the aforementioned regulatory
mechanisms [4, 9].
Classification of drug-induced hypocalcemia
Several medications have been implicated as established
causes of hypocalcemia. However, because the origin of
hypocalcemia may be multifactorial in various clinical
settings, the diagnosis of drug-induced hypocalcemia can
easily be missed. In the following sections, we provide an
overview of the relevant clinical information on the inci-
dence and the pathophysiology of drug-induced hypocal-
cemia (Table 1).
Pseudohypocalcemia
The gadolinium-based contrast agents gadodiamide and
gadoversetamide may interfere with the colorimetric assays
for calcium, thus resulting in spurious hypocalcemia. In
fact, marked reductions in the measured calcium levels of
as much as 6 mg/dl (1.5 mmol/l) can be observed if levels
are determined shortly after magnetic resonance imaging.
It should be noticed that patients do not exhibit symptoms
or signs of hypocalcemia, and no treatment is needed. This
type of hypocalcemia is rapidly reversible as the
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J Bone Miner Metab (2009) 27:635–642
Table 1 Principal causes and the underlying mechanisms of drug-
induced hypocalcemia
Pseudohypocalcemia
Gadolinium-based contrast agents: gadodiamide and
gadoversetamide
Low parathyroid hormone levels (hypoparathyroidism)
Infiltration of the parathyroid gland (iron overload): long-term blood
transfusion therapy, inappropriate use of iron
Neck radiation
Drug-induced hypomagnesemia: cisplatin, diuretics,
aminoglycosides, amphotericin
Drug-induced hypermagnesemia: magnesium-containing antacids
and laxatives, magnesium sulfate tocolytic therapy
Cinacalcet
Alcohol
High parathyroid hormone levels (secondary hyperparathyroidism)
Calcium chelators: ethylenediaminetetraacetic acid (EDTA), citrate,
foscarnet, hydrofluoric acid
Drugs that cause vitamin D deficiency or resistance: phenytoin,
phenobarbital, carbamazepine, isoniazid, theophylline,
glutethimide, and rifampin
Inhibitors of bone resorption: bisphosphonates, plicamycin,
estrogens, calcitonin, colchicine overdose
Loop diuretics
Drug-related hypomagnesemia: parathyroid hormone (PTH)
resistance
Drug-induced hyperphosphatemia: phosphate-containing enemas,
drugs that cause tumor lysis syndrome (e.g., anticancer agents)
Proton pump inhibitors (PPIs) and H2-blockers: diminished calcium
absorption caused by reduced gastric acid production
Glucocorticoids
Others: strontium-89, deferasirox, electroconvulsive therapy,
bicarbonates, propylthiouracil, dobutamine, calcium channel
blockers
gadolinium is excreted in the urine. However, special
attention should be paid in patients with impaired renal
function who may retain the contrast agent for prolonged
periods. Falsely lower serum calcium levels are not
observed with other gadolinium-based agents such as
dimeglumine gadopentetate, gadoteridol, or gadoterate
meglumine [10, 11].
Hypocalcemia with low PTH
Infiltration and destruction of the parathyroid glands as a
consequence of iron overload [long-term blood transfusion
therapy, inappropriate use of ferrum (iron)] and neck
irradiation, respectively, can induce hypocalcemia with
low PTH [12]. However, hypocalcemia has been reported
in a dialysis patient treated with deferasirox (a new oral
iron chelator) for iron overload [13]. The underlying
mechanisms are not entirely clear. However, it is possible
J Bone Miner Metab (2009) 27:635–642
that chelation of iron by deferasirox from a patient’s bones
allows for increased bone uptake of calcium.
Both hypomagnesemia and acute severe hypermagne-
semia may be responsible for the development of func-
tional hypoparathyroidism. Magnesium depletion leads to
hypocalcemia largely because of impaired release of PTH
and skeletal resistance to the action of PTH. Acute mag-
nesium restoration rapidly corrects the PTH level, sug-
gesting that hypomagnesemia affects the release of PTH,
rather than its synthesis. It is worth mentioning that
hypomagnesemia-related hypocalcemia cannot be cor-
rected with calcium; the patients must be given
magnesium.
Cisplatin, aminoglycosides, and amphotericin are the
most common causes of drug-induced hypomagnesemia. In
fact, in a series of 35 adult patients with hypomagnesemic
hypokalemia and hypocalcemia, among the main causes of
that combination of electrolyte disturbances were cisplatin
(n = 11), long-term treatment with aminoglycosides
(n = 2), and amphotericin-B administration (n = 1) [14].
It should be noted that cisplatin causes hypocalcemia in a
dose-dependent manner. Indeed, hypocalcemia is a fre-
quent adverse effect of high-dose cisplatin chemotherapy
[15]. By contrast, low-dose cisplatin has been rarely
associated with severe hypocalcemia. However, the com-
bined therapy of low-dose cisplatin, 5-fluorouracil, and
interferon-alpha increases the incidence of severe hypo-
calcemia. In fact, 15 of 23 patients (65%) who received this
combination exhibited mild to severe hypocalcemia
(defined as serum calcium concentration below 1.9 mmol/
l) and hypomagnesemia despite calcium and magnesium
supplementation [16].
Hypermagnesemia can also cause hypocalcemia by both
suppressing PTH secretion and blunting its peripheral
actions. Moreover, the magnesium ions compete with cal-
cium for reabsorption in the loop of Henle; thus, renal loss
of calcium contributes to hypocalcemia [17]. Excess serum
magnesium is almost always the result of long-term use of
magnesium-containing drugs, such as antacids and laxa-
tives, in patients with renal insufficiency. Symptomatic
hypocalcemia is rare in these cases, most likely because of
the antagonistic neuromuscular effects of hypermagnese-
mia. Moreover, metabolic acidosis (resulting from
impaired renal function) increases the ionized calcium
concentration and plays a protective role. Similarly,
asymptomatic hypocalcemia is relatively frequent during
magnesium sulfate tocolytic therapy. Indeed, only six cases
of clinically important hypocalcemia have been reported
when magnesium is given for tocolysis [18, 19].
Alcohol overconsumption has been associated with
hypocalcemia. In a series of alcoholic patients (n = 127)
admitted to our department because of causes related to
alcohol abuse, the incidence of true hypocalcemia was
637
14.2% [20]. It is known that acute alcohol consumption
suppresses the secretion of PTH, leading to hypocalcemia.
In addition, respiratory alkalosis (inducing renal PTH
resistance) and hypomagnesemia frequently observed in
alcoholic subjects may also contribute to the development
of hypocalcemia.
Finally, cinacalcet (a calcimimetic drug used in patients
with renal failure to control secondary hyperparathyroid-
ism) has been linked to hypocalcemia via an acute inhi-
bition of PTH release. Transient and usually asymptomatic
hypocalcemia has been reported in approximately 5% of
cases treated with cinacalcet [21].
Hypocalcemia with high PTH
Calcium chelators
Agents such as citrate (used to inhibit coagulation in
banked blood or plasma) [22, 23], foscarnet [24], fluoride
[25, 26], and ethylenediaminetetraacetic acid (EDTA) [27]
chelate calcium in serum, thereby diminishing serum ion-
ized calcium levels but not total serum calcium concen-
trations. It is worth mentioning that symptomatic
hypocalcemia during transfusion of citrated blood or
plasma is rarely observed in healthy patients who rapidly
metabolize citrate in the liver and kidney [22]. However, a
clinically important decrement in serum ionized calcium
levels can occur if citrate metabolism is impaired by
hepatic or renal failure or if large quantities of citrate are
administered rapidly, for example, during plasma exchange
or massive blood transfusion [23]. Similarly, fluoride,
particularly hydrofluoric acid, chelates calcium avidly and
causes profound hypocalcemia. In addition, excess intake
of fluoride can cause hypocalcemia via the formation of
fluorapatite [25, 26].
Bisphosphonates
Bisphosphonates are a class of drugs used for the treatment
of hypercalcemia, skeletal metastases, Paget disease of
bone, and osteoporosis. Bisphosphonates reduce osteo-
clastic bone resorption; as such, they slow calcium
efflux from the skeleton. Mild hypocalcemia is com-
monly observed following bisphosphonate administration,
whereas symptomatic hypocalcemia is rare. In a series of
143 breast cancer patients with bone metastases, the IV
administration of pamidronate (45 mg) was associated with
a 17% incidence of hypocalcemia, all of which cases were
asymptomatic [28].
In a trial comparing zoledronic acid to risedronate for
the treatment of Paget’s disease, hypocalcemia was
observed in 8 of 177 patients (4.5%) who received
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zoledronic acid. Six of these patients were asymptomatic
and 2 patients had mild symptoms. Among breast cancer
patients treated in a phase III study of zoledronic acid,
hypocalcemia, although often mild, was observed in 39%,
compared with 7% in the placebo arm [29]. In the health
outcomes and reduced incidence with zoledronic acid once
yearly (HORIZON) pivotal fracture trial, only 3 of 1065
patients (0.3%) in the zoledronic acid group had adjudi-
cated hypocalcemia (0% in the placebo group). All patients
received supplemental vitamin D and calcium. This
approach might account for the low rate of hypocalcemia in
this study [30].
Overall, the risk and the degree of hypocalcemia are
mainly related to the potency of the bisphosphonate and the
presence of factors that amplify the hypocalcemic effect of
these drugs. Indeed, hypocalcemia is more likely to take
place when high doses of especially potent bisphospho-
nates, such as zoledronic acid, are used for patients with
underlying vitamin D deficiency, unrecognized hypopara-
thyroidism, hypomagnesemia, or renal insufficiency [31].
Moreover, the risk of bisphosphonate-induced hypocalce-
mia is higher in normocalcemic patients with osteoblastic
metastases, particularly those with breast or prostate cancer
[32, 33].
It should be noted that bisphosphonate treatment in
patients who have an occult vitamin D deficiency can result
in catastrophic hypocalcemia. In a case of a 52-year-old
woman, tetany and atrial fibrillation with increased ven-
tricular response followed 3 weeks after pamidronate
40 mg given intravenously. Serum total calcium was
4.8 mg/dl (normal range, 8.5–10.0 mg/dl) and the serum
25-hydroxyvitamin D level was 7 ng/ml (normal range,
9–55 ng/ml) [34].
Interestingly, a high prevalence of vitamin D deficiency
has been reported in otherwise healthy adults living in
Canada and the United States [35]. An even higher prev-
alence has been observed among hospitalized patients and
elderly people [36, 37]. In the elderly, it is attributed to
both age-associated reduction in cutaneous vitamin D
production and decreased dietary vitamin D intake. Indi-
viduals with limited sun exposure and malabsorptive gas-
trointestinal disease are also at risk. Furthermore, it should
be emphasized that cancer patients represent a high-risk
group of vitamin D insufficiency, because they are usually
older and tend to suffer from low sun exposure, poor oral
intake, decreased gastrointestinal absorption, and impaired
renal function.
Renal insufficiency increases the risk of bisphospho-
nate-related hypocalcemia. In fact, impaired renal function
leads to a decrease in the conversion of 25-hydroxyvitamin
D to its active form 1,25-dihydroxyvitamin D; an increase
of the serum bisphosphonate levels also results from
diminished renal excretion of these agents [38].
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Latent hypoparathyroidism should also be considered
before bisphosphonate therapy. Indeed, hypoparathyroid-
ism is reported in 2–13% of cases after total thyroidectomy
[39]. A history of cervical radiotherapy or cervical surgery
(parathyroid or thyroid) is important in patients scheduled
to receive a bisphosphonate.
Drugs that cause vitamin D deficiency or resistance
Hypocalcemia and osteomalacia have been described with
prolonged therapy with anticonvulsants such as phenytoin
or phenobarbital [40–44]. These drugs are inducers of
cytochrome P450 (CYP450), causing increased vitamin D
degradation. They also decrease calcium resorption in the
gut. However, the mechanisms of antiepileptic medication-
induced hypocalcemia remain controversial. In fact, studies
have shown that changes in calcium metabolism can been
seen in the absence of vitamin D insufficiency as well as in
epileptic patients receiving nonenzyme-inducing antiepi-
leptic drugs (e.g., valproate) [43].
Decreased circulating levels of calcidiol are also
observed in patients treated with drugs such carbamaze-
pine, isoniazid, theophylline, and rifampin as a result of
induction of CYP450 enzyme activity, which metabolizes
calcidiol to inactive vitamin D metabolites [40–42, 45, 46].
Furthermore, in one series, the combination therapy of
5-fluorouracil and leucovorin induced hypocalcemia in
65% of patients, possibly the result of a reduction in cal-
citriol production [47].
Chronic excessive intake of glutethimide has been
reported to cause hypocalcemia by affecting vitamin D
metabolism [48].
Loop diuretics
Loop diuretics constitute another cause of drug-induced
hypocalcemia by increasing the renal excretion of calcium.
The reabsorption of Ca2? in the loop of Henle is primarily
passive, being driven by the gradient created by NaCl
transport. As a result, the inhibition of reabsorption of
NaCl leads to a parallel reduction in the reabsorption of
Ca2?. Moreover, volume contraction and alkalosis result-
ing from the use of loop diuretics increases the concen-
tration of serum proteins and protein-bound calcium and
decreases free calcium levels [49, 50]. Finally, hypomag-
nesemia owing to loop diuretics can also contribute to the
development of hypocalcemia [51].
Estrogens
Estrogens can cause hypocalcemia by inhibiting osteo-
clastic bone resorption. The incidence of hypocalcemia has
been reported to be 20% in patients with prostate cancer
J Bone Miner Metab (2009) 27:635–642
receiving an estamustine-containing chemotherapy regi-
men [52]. It appears that vitamin D insufficiency predis-
poses patients to either severe or mild hypocalcemia when
this estrogenic agent is administered intravenously or
orally, respectively [53].
Drugs causing hyperphosphatemia
It is known that hyperphosphatemia causes hypocalcemia
by depositing calcium mainly in bone, but also in extra-
skeletal tissues. Moreover, the final step of the formation of
active vitamin D in the proximal convoluted tubule cells of
the kidney is inhibited by hyperphosphatemia.
Hyperphosphatemia in conjunction with hyperkalemia,
hyperuricemia, and hypocalcemia is observed in patients
with tumor lysis syndrome (TLS) [54]. Treatment-associ-
ated TLS most often occurs after the initiation of cytotoxic
therapy in patients with hematological malignancies such
as lymphoma, leukemia, and multiple myeloma.
Laxatives or enemas containing phosphate represent
examples of drug-induced hyperphosphatemia. In fact, in a
series of 100 consecutive clinic outpatients undergoing
colonoscopy with a sodium phosphate preparation, hyper-
phosphatemia and hypocalcemia were observed in 45 and
11% of subjects, respectively [55]. Moreover, in a study of
36 hospitalized patients, the use of sodium phosphate as a
preparation for colonoscopy was invariably associated with
hyperphosphatemia, while hypocalcemia occurred in more
than 50% of patients [56]. Interestingly, neither study
found adverse clinical events.
Symptomatic and sometimes even life-threatening
hyperphosphatemia and hypocalcemia have been reported
after the administration of sodium phosphate, mainly in
patients with impaired renal function, and have been
attributed to reduced renal excretion of phosphate [57].
Hypoparathyroidism, vitamin D insufficiency, gastroin-
testinal obstruction, and inflammatory intestinal disorders
have been recognized as important predisposing condi-
tions for the development of clinically significant hypo-
calcemia resulting from sodium phosphate [58, 59]. This
side effect has been rarely reported to be fatal [60].
Additionally, elderly people, for reasons of age-related
decline in renal function and intestinal mobility, represent
a group at increased risk. In fact, a fatal case of hypo-
calcaemia and hyperphosphatemia after treatment with a
sodium phosphate enema has been reported in an elderly
patient [61].
With regard to the therapeutic manipulation of patients
with hyperphosphatemia-related hypocalcemia, the
administration of calcium is controversial, taking into
consideration the risk of calcium phosphate precipitation in
vital organs. Hemodialysis aiming at the direct removal of
phosphate, and intravenous calcium, are indicated and may
639
be lifesaving in patients with symptomatic hypocalcemia,
especially in cases of impaired renal function [62].
Proton pump inhibitors and H2-receptor antagonists
It is well known that an acidic environment is required for
calcium absorption. In contrast, achlorydria slows fat
breakdown, which is necessary to complex calcium for gut
absorption. In fact, in such cases calcium absorption is
reduced by approximately 80%. Consequently, drugs such
as proton pump inhibitors (PPIs) and H2-blockers, by
reducing gastric acid production, may reduce calcium
absorption and provoke hypocalcemia [63].
Omeprazole (an inhibitor of gastric H?, K?-ATPase)
has been reported to induce hypocalcemia via an additional
mechanism. It is known that the major proton transport of
osteoclast is mediated by a vacuolar-type H?-ATPase,
which is different from the gastric H?, K?-ATPase; none-
theless, in vitro studies have demonstrated that omeprazole
inhibits bone resorption [64]. The effect of omeprazole on
bone resorption was evaluated in a study involving patients
who had a history of gastric ulcer. Urinary excretion of
hydroxyproline and calcium decreased after omeprazole
treatment whereas serum intact PTH, alkaline phosphatase,
osteocalcin, and tartrate-resistant acid phosphatase (TRAP)
increased. The discrepancy between serum TRAP and
urinary excretion of hydroxyproline and calcium in the
study group was thought to result from the suppression of
bone resorption by omeprazole, which probably interfered
with the acidification at resorption lacunae and resulted in
the inactivation of TRAP and other lysosomal enzymes
[65].
Hypocalcemia caused by hypomagnesemic hypopara-
thyroidism following proton pump inhibitor treatment also
been reported [66].
Glucocorticoids
Glucocorticoids have been used in the treatment of
hypercalcemia. In fact, they inhibit calcium absorption in
the intestine, stimulate tubular calcium excretion, and
reduce osteoclastic bone resorption, thus diminishing the
calcium serum concentration in hypercalcemic conditions.
In normocalcemic subjects, glucocorticoids may induce
negative calcium balance. However, overt hypocalcemia is
rare. It appears that patients with vitamin D deficiency [67]
and hypoparathyroidism [68] are more prone to develop
glucocorticoid-related hypocalcemia.
Miscellaneous
It has been reported that the administration of a bicarbon-
ate, causing rapid alkalization of plasma, may result in
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acute symptomatic hypocalcemia [69]. Several other agents
(e.g., strontium-89 [70], electroconvulsive therapy [71],
propylthiouracil [72], dobutamine [73], and calcium
channel blockers [74, 75]) have been rarely implicated as
causes of hypocalcemia.
Concluding remarks
Hypocalcemia may occasionally develop in the course of
treatment with drugs used in everyday clinical practice.
However, it is entirely clear that careful oversight of the use
of implicated agents is required, especially in patients at
high-risk for the development of hypocalcemia (e.g., vitamin
D insufficiency, hypomagnesemia, hypoparathyroidism).
Discontinuation of treatment with these agents and the
restoration of serum calcium and vitamin D levels are fully
warranted. Furthermore, it should be noted that hypomag-
nesemia-related hypocalcemia cannot be corrected with
calcium (magnesium deficiency should be replenished). Of
note, rapid intravenous administration of calcium in hy-
pocalemic states or in patients receiving digitalis may
provoke life-threatening cardiac arrhythmias [76] and thus
should be avoided. Calcium should be administered with
caution in the setting of hyperphosphatemia and only to
alleviate symptoms related to hypocalcemia. In cases of
symptomatic hypocalcemia caused by severe hyperphos-
phatemia, dialysis is frequently required.
All things considered, awareness of the undesirable
effects of certain pharmaceutical compounds on serum
calcium concentrations facilitates a rational clinical man-
agement of a potentially life-threatening disorder.
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