Clinical Thyroidology / Original Paper

Eur Thyroid J 2013;2:49–56 Received: September 28, 2012

Accepted after revision: November 21, 2012
DOI: 10.1159/000346020
Published online: January 16, 2013

Stimulated Calcitonin Cut-Offs by

Different Tests
Laura Fugazzola
Department of Clinical Sciences and Community Health, University of Milan and Endocrine Unit, Fondazione IRCCS
Ca’ Granda, Milan, Italy

Key Words cause it is widely available, has a low cost and it is associated
Medullary thyroid cancer ⴢ Calcitonin ⴢ Calcium ⴢ with a low number and intensity of side effects. In the pres-
Pentagastrin ⴢ Cut-offs ent review the different methods to stimulate Ct and the
cut-offs for the identification of the hyperplastic/neoplastic
transformation of the C cells will be reported and discussed.
Abstract Copyright © 2013 European Thyroid Association
Published by S. Karger AG, Basel
Medullary thyroid cancer can be highly aggressive, especial-
ly if the diagnosis is done in advanced stages. Early diagnosis
is based on RET genetic testing, for familial forms, and on the Calcitonin, the Marker of Medullary Thyroid Cancer
routine measurement of calcitonin (Ct). Nevertheless, since
false-positive results can be obtained with the basal mea- Medullary thyroid cancer (MTC) can be a very aggres-
surement of Ct, a provocative test to evaluate stimulated Ct sive tumor. Significant differences in survival have been
is often needed. Pentagastrin which has been widely used to reported according to the stage of the tumor at the time
stimulate basal Ct, especially in European countries, is now of diagnosis, the survival being similar to that of healthy
hardly available. Thus, the stimulation with calcium (Ca), subjects in the case of a local disease and progressively
used in the 1970s–1980s and then abandoned for around 30 decreasing in case of local or distant metastases [1]. Thus,
years, has recently elicited more interest. In the past 3 years, an early diagnosis is mandatory for this malignancy. The
studies in patients and normal controls have demonstrated routine measurement of calcitonin (Ct) was initially indi-
that the stimulation with Ca (2.3–2.5 mg/kg of elemental Ca, cated in 1994 as the best method, together with the RET
corresponding to 25 mg/kg of Ca gluconate) is highly potent genetic testing for familial forms, to precociously identify
and accurate. Novel gender-related cut-offs have been pro- sporadic forms of MTC. In particular, among more than
posed for the Ca test, though the analysis of additional large
series is predicted to modify these preliminary data. Finally,
Ca seems to be the test of choice to stimulate Ct for the di- This article is partially based on a lecture delivered at the annual
agnosis and follow-up of medullary thyroid cancer, also be- meeting of the European Thyroid Association, 2012, Pisa, Italy.
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© 2013 European Thyroid Association Laura Fugazzola, MD

Published by S. Karger AG, Basel Department of Clinical Sciences and Community Health
E-Mail [email protected] 2235–0640/13/0021–0049$38.00/0 University of Milan and Endocrine Unit, Fondazione IRCCS Ca’ Granda
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www.karger.com/etj Via F. Sforza 35, IT–20122 Milan (Italy)

E-Mail laura.fugazzola @ unimi.it
1,300 patients with nodular thyroid disease, the routine (3) Risk of false-positive results. These are mostly due to
measurement of Ct allowed to identify 8 MTCs, only 2 of assay interferences, such as the presence of heterophil-
whom were diagnosed also by a suggestive cytology [2]. ic antibodies that can cause falsely elevated and rarely
After that study, many others, for a total of more than falsely reduced Ct levels. Nevertheless, these inter-
70,000 cases, reported the results obtained with the rou- ferences are usually abolished by the use of immuno-
tine measurement of Ct, with a mean prevalence of MTC metric chemiluminescent assays two-site, two-step
of 0.5%. Interestingly, around half of the MTCs found (ICMAs), highly specific for monomeric Ct.
were micro-MTCs, confirming the importance of the (4) Presence of secondary C-cell hyperplasia, which can
routine measurement of Ct in the early diagnosis of C-cell be related to: (a) thyroid diseases: autoimmunity (in
diseases [3]. The impact on survival was clearly demon- 20% of cases), benign or malignant nodules; (b) other
strated in a study including 44 patients (group 1) diag- diseases: severe renal insufficiency, hyperparathy-
nosed with MTC by the routine Ct measurement and 45 roidism, hypergastrinemia.
patients diagnosed by other methods (group 2). A statisti- (5) Increased basal Ct secretion during treatment with
cally significant difference in the rate of complete remis- drugs, such as omeprazole, ␤-blockers, glucocorti-
sion was found between the two groups of patients (59% coids secretagogues and cigarette smoking [9, 10].
in group 1 and in 2.7% in group 2, p ! 0.0001), highlight- (6) Production of Ct by neuroendocrine tumors. In this
ing that the routine Ct measurement should always be context, it should be underlined that neuroendocrine
considered in the diagnostic evaluation of thyroid nod- tumors usually produce less Ct per gram of tissue than
ules [4, 5]. Nevertheless, this practice remains controver- MTC and typically do not increase their Ct secretion
sial and is definitely accepted only for the screening of in response to the stimulation testing.
familial MTC. In particular, the European Consensus (7) Difficulties in the set-up of the cut-offs for both basal
recommended it, whereas the American Thyroid Asso- and stimulated Ct needed to identify the C-cell dis-
ciation guidelines do not recommend either for or against eases.
it [6, 7]. Moreover, the recent American-European-Italian (8) Unavailability in the USA, and now also in Europe, of
joined guidelines consider that the testing of Ct may be a pentagastrin (Pg) which has been considered for sev-
useful test in the initial evaluation of thyroid nodules, but eral years as the best test to stimulate Ct.
do not recommend its routine use [8].

The Cut-Offs for Pg Test

Routine Measurement of Calcitonin: Why Not?
The Pg test has largely been used for many years to
The major arguments against the routine measure- stimulate Ct. The procedure consists of the injection of
ment of Ct are reported below: 0.5 ␮g/kg over 5 s and in the basal, +1–2, +5 and +10–15
(1) Costs/benefits. The prevalence of MTC is low, around min sampling. Several patients have been tested and
0.5% of the population with thyroid nodules. For this many studies have been published with the aim to estab-
reason it has been argued that the routine testing of lish the most precise cut-offs to differentially diagnose
serum Ct in all patients with unselected thyroid nod- between normal, C-cell hyperplasia (CCH) and MTC
ules could not be cost-effective. Nevertheless, a very [11–15]. The results of these papers have been summa-
detailed study has recently demonstrated that this test rized in table 1. The indication for surgery is almost wide-
has a cost/benefit ratio similar to those of TSH neo- ly accepted for Ct-stimulated levels 1100 pg/ml, whereas
natal screening, and colonoscopy and mammogram the best treatment for cases with stimulated Ct 150 pg/
screening [1]. ml is still controversial. Interestingly, in a recent study we
(2) Uncertain evolution of micro-MTCs. Since around demonstrated that, in patients with multinodular goiter,
half of the tumors identified by routine Ct measure- Pg-stimulated Ct levels 150 pg/ml were always associated
ment are micro-MTCs, it has been argued that these with a diffuse/nodular CCH. Moreover, in all cases the C
tumors could have a highly reduced malignant poten- cells displayed a neoplastic phenotype, concerning mor-
tial and will never become larger and aggressive tu- phology, distribution and localization, indistinguishable
mors. Indeed the prevalence of MTCs in unselected from that found in familial MTC and thus considered as
autopsies is roughly comparable to the Ct screening a preneoplastic lesion. According to those findings, in pa-
studies in the thyroid nodule population [3]. tients with Pg-stimulated Ct levels 150 pg/ml a ‘prophy-
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50 Eur Thyroid J 2013;2:49–56 Fugazzola

DOI: 10.1159/000346020
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Table 1. Cut-offs for basal and Pg-stimulated Ct Ct secretion are gender-related [9]. In this context, it
has been demonstrated that gender-specific Ct thresh-
Interpretation Indication olds predict occult MTC more accurately among
Basal Ct patients with increased basal Ct levels than unisex
≤10–20 pg/ml normal – thresholds. In particular, the most discriminatory
10–50 pg/ml gray zone stimulation test threshold between CCH and MTC was found to be for
50–100 pg/ml risk of MTC stimulation test basal Ct of 15 pg/ml for women and 80 pg/ml for men,
Pg-stimulated Ct and for Pg-stimulated Ct of 80 pg/ml for women and
<30–50 pg/ml normal –
50–100 pg/ml CCH surgery 500 pg/ml for men [12].
>100 pg/ml risk of MTC surgery

The Calcium Test

The unavailability of Pg in the United States and re-

lactic’ surgical treatment should be considered [16]. Nev- cently also in most European countries recently raised
ertheless, it should be highlighted that the peak value of the need to standardize other methods to stimulate Ct.
stimulated Ct should be interpreted not only as an abso- The calcium (Ca) test was seldom used in the 1970s and
lute value, but also taking into account the basal level of 1980s, but has been abandoned in the last 30 years (ta-
Ct and, more importantly, the degree of Ct increase after ble 2). There are some basic reasons for the removal of the
stimulus. Indeed, MTC has been found to be associated Ca test from clinical practice: (1) different doses in differ-
with a minimum percent increment of 160% [2]. ent protocols: from 2 up to 15 mg/kg of elemental Ca
(Ca2+); (2) lack of a precise specification of the dose of
Ca2+ (to be obtained from the starting solution, i.e. from
Why It Is So Difficult to Establish a Definite Cut-Off Ca gluconate of Ca chloride); (3) different times of injec-
tion: from 1 min to 4 h; (4) use of protocols including the
There are some reasons to explain the difficulties in injection of Pg and Ca on consecutive days [19] or Ca to-
the definition of the cut-offs. gether with Pg [20], and (5) no data available on the cut-
(1) Different assays in different centers. Although inter- off levels to be used for the preoperative identification of
national guidelines recommend each center to estab- a CCH or a MTC.
lish its own cut-off values for basal and stimulated Ct Moreover, the Ca test was initially performed as a long
[6, 7], the existence of different ranges largely contrib- Ca infusion, with 3.75–5 mg/kg/h for a total duration of
utes to the difficulties in the identification of definite 3–4 h. This procedure had the disadvantage of the large
basal and stimulated Ct levels to differentiate between amount of Ca infused, usually around 1.5 g, which pro-
normal and C-cell diseases. duced a significant and prolonged elevation of plasma Ca,
(2) Lack of different children- and gender-related ranges. rendering it not acceptable for the screening of a large
Although Ct values in children are believed to be high- number of family members [21]. In addition, discordant
er than in adults, American Thyroid Association data were available about the potency of the test, though
(ATA) guidelines report that due to the limited data the majority of studies indicated that Pg had a better
available, caution should be used in interpreting Ct stimulator than Ca. In particular, Hennessy et al. [20] and
values in children !3 years of age [10]. In a large cohort Verdy et al. [22] in 1974 suggested that Pg had a more
of healthy subjects we found that the normal range of rapid and intense secretory response than a 2- or 4-hour
serum Ct levels was wider in children (!0.2–11.7 pg/ infusion of Ca2+. In 1980, Emmertsen et al. [23] stated
ml for female and !0.2–17 pg/ml for males) than in that Pg was a better stimulative procedure than the rapid
adults, without significant gender differences in the infusion of 2 mg/kg of Ca2+. In 1978, Wells et al. [24] dem-
children population [18]. In adults, Ct values should onstrated that the combination of Ca2+ and Pg was more
be interpreted in the setting of sex-specific reference effective than Ca2+ and Pg alone. In 1987, Gharib et al.
ranges, as suggested by ATA guidelines [10], though [25] found Ca2+ injection (2 mg/kg over 5 min) to be more
most centers to date have a unisex threshold for Ct lev- potent than Pg in healthy volunteers and weaker in a
els. Indeed, since men physiologically have twice as small group of thyroidectomized MTC patients. The data
many C cells as women [18], both basal and stimulated available to date on the Ca test protocols reported in the
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Stimulated Calcitonin Cut-Offs by Eur Thyroid J 2013;2:49–56 51

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Table 2. Ca test protocols in the literature

Reference (first author) Year of Number of subjects/patients Infused dose of the Infused dose Time of i.v. Saline
publication starting solution1 of elemental Ca1 infusion

Hennessy [20]2 1974 38 patients Ca gluconate: 161 mg/kg 15 mg/kg 4h 500 ml

Parthemore [31] 1974 4 patients Ca chloride: 550 mg 150 mg 5–10 min 50 ml
Sizemore [32] 1975 4 patients Ca gluceptate 15 mg/kg 4h 500 ml
Parthemore [21] 1978 11 normal controls Ca chloride: 11 mg/kg 3 mg/kg 10 min –
10 normal controls Ca gluconate: 22 mg/kg 2 mg/kg 1 min
Verdy [22] 1978 39 family members Ca gluconate: 81/mg/kg 7.5 mg/kg 2h 250 ml
Graze [33] 1978 107 familial members Ca gluconate: 161 mg/kg 15 mg/kg 4h –
Wells [24] 1978 21 normal subjects Ca gluconate: 22 mg/kg 2 mg/kg 1 min –
26 MTC patients Ca chloride: 11 mg/kg 3 mg/kg
Emmertsen [23] 1980 6 patients with persistent MTC Ca laevulatis 2 mg/kg 1 min –
McLean [34] 1984 31 healthy subjects Ca chloride: 11 mg/kg 3 mg/kg 5 ml/min 50 ml
13 patients with MTC
Gharib [25] 1987 92 normal controls Ca gluconate: 22 mg/kg 2 mg/kg 1 ml/min 50 ml
12 patients with MTC
Doyle [26]3 2009 50 healthy subjects Ca gluconate: 27 mg/kg 2.5 mg/kg 10 ml/min –
Kudo [35] 2011 20 patients with thyroid Ca gluconate: 20.2 mg/kg 1.9 mg/kg 1 min –
diseases other than MTC
Colombo [28] 2012 56 patients with persistent/cured MTC Ca gluconate: 25 mg/kg 2.3 mg/kg 10 ml/min –
60 MNG patients; 16 healthy subjects
Giovanella [36] 2012 96 healthy subjects Ca gluconate: 2.5 mg/kg 0.2 mg/kg 10 ml/min –
1 Both the dose of Ca gluconate or Ca chloride and the corresponding dose of elemental Ca have been reported (according to the Ca equivalents cal-

culator on the website http://www-users.med.cornell.edu/⬃spon/picu/calc/cacalc.htm).

2 The infusion of Ca was preceded or followed by the injection of Pg (0.5 ␮g/kg).
3 Note: The authors requested to change the following text reported in the Materials and Methods section of the original paper [J Clin Endocrinol

Metab 2009;94:2970–2974]: ‘... calcium gluconate (Calcium Braun 10%; Braun Melsungen AG, Melsungen, Germany) as an intravenous injection of 2.5 mg/
kg at 10 ml/min,’ to: ‘... calcium, 2.5 mg/kg, was given as a calcium gluconate solution (Calcium Braun 10%; Braun Melsungen AG, Melsungen, Germany)
containing approximately 9 mg/ml calcium, injected intravenously at 10 ml/min’ [erratum in J Clin Endocrinol Metab 2009;94:4629].

literature are shown in table 2. The dose of Ca gluconate around 15 and 5 pg/ml, respectively [27]. On the other
or Ca chloride has also been reported together with the hand, the levels of Ct after Ca2+ stimulation resulted in
corresponding dose of Ca2+, according to the Ca equiva- being higher, around 40 pg/ml for men and 20 pg/ml for
lents calculator on the website http://www-users.med. women. To extend the results obtained in healthy subjects
cornell.edu/⬃spon/picu/calc/cacalc.htm. As stated above, and to get more insight into the standardization of the
the test was abandoned for many years up until it was re- Ca2+ test, we recently published the results obtained in
evaluated in 2009 by Doyle et al. [26], who reported data controls, in patients with multinodular goiter and in pa-
in 50 healthy subjects. They decided to use a dose of 2.5 tients with both familial and sporadic MTC, either in
mg/kg of elemental Ca in accord with the dose of 2–3 mg/ persistence or in remission [28]. As far as normal controls
kg which was the most frequently used in the 1970s and are concerned, peak serum Ct levels after Ca infusion did
1980s (table 2). The authors concluded that the Ca test is not significantly differ between men and women (around
more potent and better tolerated than Pg. In particular, 20 and 15 pg/ml, respectively). In 4 of 16 controls, both
they found that the peak of Ct after Pg injection is around tests were carried out and similar responses between Pg
10 pg/ml for males and 4 pg/ml for females, consistent and Ca2+ were obtained in 3 patients whereas in 1 female
with previous results reporting Pg-stimulated values of only Ca2+ was able to stimulate a response of Ct (fig. 1),
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52 Eur Thyroid J 2013;2:49–56 Fugazzola

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 Pentagastrin 160 Pentagastrin test
Calcium Calcium test

(number of observations)
15 140
120

Side effects
12 100
80
Ct (pg/ml)

9 60
40
6 20
0
3

ng

te

th

in

ea

ia
in

es
pa
ra

us
pi

sh

th
tu

ar
am

Na
ric

es
w
ic

Fl
st
cr

r
of
0

Pa
Ga
al

to

g
in

lin
y
Basal +2 +5 +15

nc

e
do

Fe
ge
Sampling time (min)

Ab

Ur
Fig. 1. Basal and Pg/Ca-stimulated levels of Ct in 4 normal sub- Fig. 2. Side effects reported by patients during either Pg or Ca
jects who underwent both tests. Similar responses were obtained tests.
in 3 cases, whereas in 1 case only Ca was able to induce a rise in
Ct levels.

consistent with the finding of Doyle et al. [26] who re- Ca gluconate was administered intravenously at a dose
ported a higher potency of Ca2+ with respect to Pg. In of 25 mg/kg at 10 ml/min (this corresponds to 2.3 mg/
patients with MTC and nodular goiter, we found a nice kg or 0.12 mEq/kg of elemental Ca). In clinical practice
correlation between the two tests, without statistically it is recommended to use 10% Ca gluconate: each 10-ml
significant differences in the levels of Pg or Ca2+ serum vial contains 950 mg monohydrate of Ca gluconate (cor-
Ct in patients submitted to both tests. Nevertheless, se- responding to 88.3 mg or 4.41 mEq of elemental Ca).
rum Ct levels have been found to be higher after Ca2+ Thus, for a 50-kg subject the dose of Ca gluconate need-
than after Pg in several patients, indicating that studies ed is: 25 ! 50 = 1,250 mg. The following calculation will
in larger samples could reveal a higher potency of the Ca be: 950: 10 = 1,250:x (x = 13.15 ml of 10% Ca gluconate
test. ROC plot analyses were used to find the basal and solution). Serial measurement demonstrated that at
Ca2+-stimulated Ct thresholds able to differentiate be- 2 min after Ca infusion, ionized Ca levels increase by
tween normal, CCH, and MTC, for men and women. As 30–35% and then progressively decrease, whereas PTH
reported in table 3, all patients with basal Ct levels 110 levels decrease by 50–60% and continue to decrease. 30
pg/ml were submitted to the Ca2+ test and the levels of min after high Ca infusion, Ca levels were 5–10% high-
basal and stimulated Ct were compared with the histo- er than baseline and PTH levels were 65–70% lower than
logical findings. The results obtained showed that the baseline.
Ca2+-stimulated Ct thresholds able to distinguish normal Overall, the number, intensity and duration of side ef-
controls and CCH cases from patients with MTC were fects were significantly lower during the Ca test and all
184 pg/ml for females and 1,620 pg/ml for males [28]. patients declared that they preferred it. Nausea and ab-
Concerning the degree of Ct elevation after stimulus, dominal cramping were the most frequent discomforts
MTC was associated with ⌬ increases ranging from 5.6 during the Pg test and were poorly tolerated by patients.
to 64.8 for females to 5.9 – 92.3 for males (table 3). On the contrary, the feeling of warmth, which was the
most frequent and often the only side effect with Ca test,
was not considered unpleasant (fig. 2).
Calcium Test: Procedure and Side Effects Ca is known to increase cardiac contractility and it
could lead to hypertensive peaks. On the other hand, hy-
To date, the paper by our group is the only one to re- pertension can cause bradycardia. Thus, anamnestic data
port the cut-offs for Ca-stimulated Ct [28]. The Ca test related to cardiopathy or bradycardia or severe hyperten-
was performed according to the following procedure: sion should be obtained by patients. In selected cases, the
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Stimulated Calcitonin Cut-Offs by Eur Thyroid J 2013;2:49–56 53

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Table 3. Clinical and histological data of patients with basal Ct levels >10 pg/ml. Adapted from Colombo et al. [28]

Age/ Basal Ct Ca Ct peak ⌬ increases Histology Tumor diameter, TNM CCH

gender pg/ml pg/ml mm

40/F 15/19 184 9.7 UNG – –thy yes

60/F 59/29 331 5.6 MTC 7 pT1Nxthy no
37/F 40 353 8.8 MTC 10 pT1N1athy yes
44/F 16 522 32.6 UNG – – yes
56/F 44.5 1,483 33.3 MTC 6 pT1N0thy no
76/F 68/57 1,524 22.4 MTC 10 pT1Nx yes
73/F 121 1,801 14.9 MTC 21 pT1Nx yes
49/F 126/164 2,349 14.3 MTC 11 pT1N0 yes
53/F 592 38,362 64.8 MTC 19 pT1N0 yes
58/M 10 190 19 MNG – – yes
64/M 14/12 196 14 MNG – – yes
43/M 16/11 205 12.8 PTC 2 pT1Nx yes
54/M 16 263 16.4 MNG – – yes
70/M 17/21 368 17.5 MNG – – yes
50/M 94/87 562 5.9 MTC 7 T1aNx not done
71/M 23/23 806 35 PTC 10 pT1Nx yes
70/M 95/68 1,620 17 UNG – –thy yes
65/M 218/198 2,900 13.3 MTC 17 pT1Nx yes
56/M 73 5,846 80 MTC 13 pT1Nx yes
60/M 154/170 15,700 92.3 MTC 14 pT1Nx not done

MNG = Multinodular goiter; UNG = uninodular goiter; PTC = papillary thyroid cancer; thy = associated thyroiditis.

test can be done under cardiac monitoring. Nevertheless, Discussion

in our hands, neither electrocardiographic changes nor
heart rate variations have ever been observed. The test MTC is a potentially highly aggressive tumor and the
has also been performed without any side effects in hy- diagnostic/therapeutic tools available to date are limited
perparathyroid patients [28]. and not sufficiently sensitive or effective. Thus, an early
diagnosis is mandatory, which can be achieved by RET
genetic testing and routine Ct measurement. In particu-
Other Tests lar, Ct (basal and stimulated) allows early diagnosis ei-
ther pre- or post-surgery. The majority of studies have
Scanty data are available on other tests for Ct stimula- been performed using the stimulus with Pg and cut-offs
tion. In a small series of 6 patients and 8 controls, the for Pg-stimulated Ct are available. Unfortunately, Pg has
stimulus with whisky resulted in being less efficient than virtually become unavailable. For this reason, in the last
Pg and Ca [23]. Omeprazole has also been used to stimu- 2 years the Ca test, which was abandoned in the last 30
late Ct at a dosage of 20 mg twice daily for 3–4 days, with years, has been demonstrated to represent a good choice
blood sampling every morning [29, 30]. Although a steady to stimulate Ct. Some data are available on the stimula-
and significant increase in Ct levels was achieved, omepra- tion response in normal subjects and in patients with Ca
zole appeared to be less potent and sensitive than Pg. gluconate doses of 25 mg/kg, corresponding to 2.3 mg/
Thus, its use should be limited to cases where Pg or Ca 2+ kg of elemental Ca [26, 28]. In these studies, Ca has been
cannot be performed. found to be equivalent or superior to Pg in the stimula-
tion of Ct for the diagnosis and follow-up of MTC. More-
over, cut-off values to differentially diagnose among
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54 Eur Thyroid J 2013;2:49–56 Fugazzola

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CCH and MTC in either males or females have been re- ability of Ca and the easiness of execution of the test
cently reported by our group [28]. Nevertheless, to better could render the routine measurement of Ct more wide-
refine the cut-off values, more series tested with the same ly used.
Ca protocol are definitely needed. In conclusion, Ca is
widely available, has a low cost and it has been demon-
strated to have at least the same potency of Pg and should Disclosure Statement
thus be used for the diagnosis and follow-up of MTC.
The personal final auspice of the author is that the avail- The author has no conflicts of interest to disclose.

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