You are on page 1of 14


00/0 The Journal of Clinical Endocrinology & Metabolism 89(4):1512–1525

Printed in U.S.A. Copyright © 2004 by The Endocrine Society
doi: 10.1210/jc.2002-021444


Procalcitonin and the Calcitonin Gene Family of
Peptides in Inflammation, Infection, and Sepsis: A
Journey from Calcitonin Back to Its Precursors

Downloaded from by guest on 15 January 2019

Veterans Affairs Medical Center and George Washington University (K.L.B., E.S.N., J.C.W., R.H.S.), Washington, D.C.
20422; and University Hospitals (B.M.), CH-4031 Basel, Switzerland

Calcitonin (CT) is a hormone that received its name be- Immature and mature CT
cause of its secretion in response to induced hypercalcemia It had been found that immunoreactive CT was present in
and its hypocalcemic effect (1). It was shown to originate multiple heterogeneous forms in MTC tissue as well as in the
from the thyroid gland (2). More specifically, the hormone serum of patients with this tumor (20 –24). Consequently, it
was revealed to be located within the thyroidal parafollicular became apparent that when this peptide was measured with
cells, interspersed within and about the follicular epithelium antisera recognizant to different epitopes the values varied
(3–5). Subsequently termed C cells, they occur primarily in according to the antiserum and the immunochemical heter-
the central region of each lobe of the human thyroid gland ogeneity (25). The phenomenon of heterogeneity was then
(6, 7). These cells, which have CT-containing secretion gran- further clarified by a series of studies which demonstrated
ules, are neuroendocrine. Embryologically, they originate that CT is biosynthesized as part of a larger prohormone,
from the neural crest and migrate to the ultimobranchial procalcitonin (ProCT) (Fig. 1) (21, 23, 25–27).
glands (8). In mammals, the ultimobranchial glands fuse The term “mature” hormone has been used to indicate a
with the thyroid gland. bioactive hormonal peptide that has been derived from a
It was the demonstration that medullary thyroid cancer larger precursor prohormone. This prohormone may be less
(MTC) was a malignancy of the C cells (5, 9) that eventually active, inactive, or characterized by an activity that differs
led to the isolation of human CT from this tumor and the entirely from the mature hormone. Not uncommonly, much
determination of its structure (10, 11). Simultaneously, the of the bioactivity of a mature hormone may be linked to an
amino acid sequence of porcine CT was determined (12). amidation that occurs at its carboxyl end. Within ProCT, CT
Later, the development of immunoassays of serum CT in is in a nonamidated, immature 33-amino acid form, termi-
humans led to the observation that the level of this hor- nating with a glycine (28). It then undergoes posttransla-
mone was increased in the serum of patients with MTC tional processing that results in production of several addi-
(13–15) and to the demonstration that these levels were tional free peptides as well as mature CT (29 –31).
further augmented after iv calcium and/or pentagastrin All species of mature CT contain 32 amino acids, with a
administration (13, 16, 17). These findings had a great disulfide bridge at the amino terminal end (between amino
impact on the clinical diagnosis, the evaluation of efficacy acid positions 1 and 7) and a proline at the carboxyterminal
of surgical extirpation, and the follow-up monitoring of end; hence, for the purpose of clarity in this manuscript, the
MTC. Although RET germline mutation testing has re- term CT(1–32) will be used specifically to refer to this pep-
placed CT for the purpose of determining the presence of tide. Among the various species of CT(1–32), the amino acid
carriers of this tumor associated with multiple endocrine sequence of the peptide tends to be well conserved within the
neoplasia type 2 (18, 19), the measurement of serum CT has amino acid ring structure at the amino terminus, but there are
become and has remained the classical clinical marker for differences elsewhere within the molecule (32–34). At the
MTC. carboxyl terminus of the CT(1–32), the proline is amidated
(35, 36). Importantly, both the ring structure and this ami-
Abbreviations: CCP-I, 21-Amino acid CT carboxyterminus peptide I; dated proline are essential for the full expression of the
CGRP, CT gene-related peptide; CT, calcitonin; CTpr, CT precursors; known bioactions of this hormone.
LPS, lipopolysaccharide; MTC, medullary thyroid cancer; NO, nitric The accurate quantification of the free CT(1–32) peptide
oxide; NProCT, 57-amino acid sequence at the amino terminus of ProCT; requires the selective detection of the amidated carboxyl
PNE, pulmonary neuroendocrine (cell); ProCT, procalcitonin; SCLC,
small cell cancer of the lung. terminal portion of the molecule, thus excluding the nonami-
JCEM is published monthly by The Endocrine Society (http://www.
dated 33-amino acid immature CT, which is found within, the foremost professional society serving the en- some of the larger molecular weight precursors. Such com-
docrine community. mercially available assays were not developed until the late

Becker et al. • Clincal Review J Clin Endocrinol Metab, April 2004, 89(4):1512–1525 1513

Downloaded from by guest on 15 January 2019

FIG. 1. Schematic representation of ProCT and the other CT precursors (CTpr) derived from this prohormone (i.e. NProCT, CT-CCP-I, and
CCP-I). The mean concentrations of these peptides in normal serum is indicated. Note that there is appreciably more free NProCT in the serum
than CT(1–32). In sepsis, the principal elevations involve the intact ProCT, free NProCT, and free conjoined CT-CCP-I peptide. Sequencing
reveals that in sepsis, the ProCT may lack the first two amino acids of the aminoterminus of the molecule, presumably due to enzymatic
hydrolytic aminoterminal truncation (110), and perhaps other cleavage forms are present as well (111). The comparative extent to which any
one of these peptides is increased varies among patients. Levels of the free CCP-I peptide also increase but to a lesser extent. In sepsis, serum
CT(1–32) concentrations are undetectable, normal, or only slightly to moderately elevated (data from Ref. 30).

1980s; they use a double-antibody method: one antibody ever, these mice exhibited an increased calcemic response
reacts selectively with the amidated region and the other and a greater bone resorption in response to exogenous PTH,
with a different portion of the molecule (most commonly the perhaps due to the absence of an otherwise inhibiting effect
midportion). Thus, these assays do not cross-react with im- of CT(1–32) on bone resorption. Surprisingly, these knockout
mature CT (37–39). In this regard, it is important to empha- mice manifested a markedly increased bone formation; also,
size that most CT studies in the literature relating to phys- in contrast to wild-type mice that lose bone mass after ovari-
iopharmacologic manipulations as well as such influences as ectomy, they maintained their bone mass. These findings
age, gender, pregnancy, and hormonal milieu were not doc- suggest that the CT/CGRP-I gene product may somehow
umented with these specific assays. regulate bone formation, either directly or indirectly. Further
studies of these interesting observations are needed to de-
Physiologic actions of CT termine whether this action is related to CT(1–32), CGRP-I,
Hundreds of studies of the possible role of CT(1–32) have or both acting conjointly, and also whether it is species spe-
been performed. The great bulk of in vitro and in vivo inves- cific. Additional studies should also determine whether the
tigations have involved laboratory animals, some with prior induced knockout results in a compensatory overexpression
parathyroidectomy and some without. Often the species of of the gene that gives rise to CGRP-II, which, as a result, may
CT(1–32) used in these experiments were other than human conceivably modulate or modify the resultant phenotype.
(e.g. salmon, porcine, eel), the amino acid sequences of which The classic and best-studied action of CT(1–32), which
differ. Furthermore, pharmacologic, not physiologic, doses appears to occur generally throughout the mammalian spe-
often were employed. As a result, many actions have been cies, is the action on the osteoclast (34, 47, 48). Acutely, this
incorrectly imputed to this peptide. Known or alleged bio- hormone alters the osteoclast sensitivity to ambient calcium
logic actions of CT(1–32) have been reviewed elsewhere (31, and induces quiescence of osteoclast motility and a retraction
33, 40, 41). of the pseudopods that is associated with a cessation of
Although seemingly relevant effects have been observed membrane ruffling. The peptide also inhibits the elaboration
in blood, bone, kidneys, and the respiratory, gastrointestinal, by the osteoclast of acid phosphatase, carbonic anhydrase II,
embryogenic, and central nervous systems (40, 42– 45), the focal adhesion kinase, and osteopontin. Possible anabolic
function of CT(1–32) in humans remains enigmatic (41). The effects of CT(1–32) on the osteoblast have been reported (49)
hormone is not confined to the thyroid gland, and it is im- but require further documentation. The overall impact of the
possible to extirpate all cells producing this peptide (see osteoclastic inhibition is to decrease bone resorption (50).
below). However, the recent development of a knockout Nevertheless, neither the diminution of serum CT(1–32) oc-
mouse in which the coding sequences for both CT(1–32) and curring subsequent to thyroidectomy nor the marked excess
CT gene-related peptide (CGRP)-I were deleted have pro- of serum levels of CT(1–32) that occurs in patients with MTC,
vided important information (46). In these animals, no birth appear to be associated with alterations in serum calcium or
defects or difficulty with procreation were noted, and serum noticeable decreases or increases of bone mass (51). Perhaps
levels of basal calcium-related values were normal. How- the major function of CT(1–32) is to combat acute hypercal-
1514 J Clin Endocrinol Metab, April 2004, 89(4):1512–1525 Becker et al. • Clincal Review

cemia in emergency situations and/or to conserve calcium ProCT and CT precursors

stores during growth, pregnancy, and lactation. CT(1–32) is biosynthesized from the polypeptide precur-
The osteoclast has a CT receptor, as do other cells else- sor, ProCT. This 116-amino acid prohormone is comprised of
where, e.g. monocytes, kidney, brain, pituitary, placenta, three constituent peptides: a 57-amino acid sequence at the
prostate, testis, lung, and liver (52–55). The CT(1–32) receptor amino terminus (NProCT); the centrally positioned imma-
has been cloned (56 –58). In the human, there is a polymor- ture CT that contains a terminal glycine; and a 21-amino acid
phism of this receptor (59), which may clinically influence CT carboxyterminus peptide I (CCP-I) (Fig. 1) (28). Subse-
bone density and quality (60), and these different isoforms quent enzymatic posttranslational processing yields several
may also have other functional implications. Stimulation of peptides (31, 73, 74); in addition to CT(1–32), the serum of
the CT(1–32) receptor induces increased cAMP and an in- normal persons contains intact ProCT, free NProCT, free
creased cytosolic free calcium concentration, accompanied CCP-I, and the free conjoined CT-CCP-I peptide. Interest-

Downloaded from by guest on 15 January 2019

by activation of the MAPK pathway (61). ingly, the normal molar concentration of circulating NProCT
is 2-fold higher than that of CT(1–32) (4.15 fmol/ml vs. 1.84
fmol/ml) (30). Because these peptides are relevant to and
Therapeutic effects of CT(1–32) precede the biosynthesis of CT(1–32), they have been given
Although the usage of CT(1–32) as a drug has greatly the collective appellation CT precursors (CTpr) (75, 76). The
diminished, it continues to have a therapeutic role, princi- extent to which CTpr may have physiologic functions is
pally in osteoporosis and Paget disease. The commercially under study (see below).
used drug is the amidated, synthetic salmon preparation; in
the United States, human CT(1–32) has become an orphan CTpr in MTC
drug. For osteoporosis, it is commonly agreed that bisphos-
phonate therapy is more effective than CT(1–32) and is An appreciable number of conditions are associated with
currently the preferable therapy (62). However, salmon increased serum levels of CTpr (Table 1). Although it has
been known for many years that normal thyroid gland, MTC
CT(1–32) has been well demonstrated to increase bone den-
tissue, and the serum of MTC patients contain large amounts
sity and decrease fracture rate, especially in the vertebrae
of ProCT as well as its component peptides (22, 77), the
(63– 65); adverse effects are minimal. For osteoporosis, the
potential clinical utility of CTpr as a serum marker for MTC
nasal or sc route can be used. Bisphosphonates also have
has very rarely received attention. In this respect, initially it
replaced CT(1–32) for the therapy of Paget disease (66, 67); was found that the carboxyterminal region of ProCT (cor-
nevertheless, sc salmon CT(1–32) still may be useful in the responding to CCP-I, also termed katacalcin) was secreted
occasional patient who cannot tolerate high doses of bisphos- into the medium of MTC cultures as well as into the serum
phonates (68). In the United States, the nasal CT(1–32) prep- of patients with this tumor in a calcium-dependent manner
aration is not approved for Paget disease. As an acute or (78). Subsequently an assay for CCP-I was evaluated as a
subacute therapy for hypercalcemia, the sc or im adminis- serum marker for MTC (79). It was later reported that the
tration of salmon CT(1–32) is not a reliable procedure; the NProCT cleavage product of ProCT also was a potential
treatment of choice is adequate hydration and iv bisphos- marker for this tumor (80). Recently, in a study of MTC
phonates (69). Various possible antinociceptive effects of patients (81), a sensitive and rapid (3-h) two-antibody sand-
CT(1–32) have been described (70). For example, in patients wich assay that quantifies both intact ProCT and CT-CCP-I
with painful osteolytic metastases, symptomatic therapy (82) was compared with an assay that is specific for CT(1–32).
may be beneficial (71); however, the limited evidence in the CTpr were found to be universally present in the serum of
literature does not support its use for this purpose (72). patients with MTC. They were increased whenever CT(1–32)

TABLE 1. Clinical conditions in which serum CTprs are increaseda

Sepsis with or without documentation of bacterial infection; sepsis-related conditions, such as pancreatitis, severe burns, polytrauma,
heatstroke, marked systemic bacterial infection as may occur in pneumonia or pyelonephritis; occasional patients with marked systemic
viremia or fungal infection; and severe malaria
Medullary thyroid cancer
Aspirational or inhalational pneumonitis
Adult respiratory disease syndrome (ARDS)
Pulmonary neuroendocrine hyperplasia as occurs in chronic obstructive pulmonary disease or smoking-related chronic bronchitis
Small cell cancer of the lung
Non-small cell lung cancer (probably due to admixture of malignant small cells, and/or to smoking-related pulmonary neuroendocrine cell
Carcinoid tumor
Other neuroendocrine tumors (pheochromocytoma, pancreatic islet cell tumor)
Other, seemingly non-neuroendocrine malignancies, such as breast cancer
In these listed conditions, using a sensitive assay (76), CTpr may be increased to enormous levels in the serum, e.g. ranging from 1,000
to 100,000 pg/ml in patients with sepsis, or, only minimally increased, e.g. 200 pg/ml in pulmonary neuroendocrine hyperplasia [normal, less
than 76 pg/ml (12 fmol/ml)]. In sepsis and septic-related conditions, CT(1–32) usually is normal or only minimally increased. In contrast, the
high serum CTpr that occurs in medullary thyroid cancer, small cell carcinoma of the lung, carcinoid, and some other neuroendocrine tumors
is nearly always accompanied by a marked increase of serum CT(1–32).
Becker et al. • Clincal Review J Clin Endocrinol Metab, April 2004, 89(4):1512–1525 1515

was increased and, on a pg/ml basis, exceeded CT(1–32) of macrophages, altered capillary function, transudation of
levels by about 10-fold. Also, both markers responded to serum into the tissues, and the release of various humoral
pentagastrin. Whether CTpr are more sensitive markers for substances (Table 2).
the presence of MTC or might be more useful prognostically There are a variety of distinct conditions that manifest
remains to be determined. systemic inflammation (e.g. severe burns, pneumonitis or
other marked local infections, bacteremia, endotoxemia,
CTpr in several other clinical disorders trauma, heat stroke, and pancreatitis). Typically any of these
Other neuroendocrine tumors, such as small cell cancer of conditions may lead to a clinical syndrome that has been
the lung (SCLC), carcinoid, pheochromocytoma, and pan- termed the systemic inflammatory response syndrome,
creatic islet tumors may exhibit increased serum CTpr. In which is defined by varying combinations of fever or hypo-
contrast to MTC, in these conditions, the serum CTpr/ thermia, tachypnea, tachycardia, and polymorphonucleocys-
tosis or leukopenia (94, 95). Associated with these manifes-

Downloaded from by guest on 15 January 2019

CT(1–32) ratio is further increased, probably because these
lesions lack sufficient posttranslational enzymatic capability tations, there is a variable local as well as systemic increase
(30, 83, 84). In the case of SCLC and carcinoid tumor, the of many cytokines and other hormonal messenger molecules
occurrence of increased serum CTpr is very frequent. Using [e.g. TNF␣, IL-1␤, IL-6, interferon-␥, arachidonic acid deriv-
atives, cortisol] (Table 2). Some of these substances, acting in
an immunoassay that is reactive to the midportion of CT [and
a hemocrine and/or paracrine manner, are protective to the
hence detects the presence of the ProCT and free CT-CCP-I
host; some may be harmful, and some may be either bene-
molecules as well as CT(1–32)], there was found to be an
ficial or damaging, depending on their concentrations, their
association between the levels obtained and the clinical
timing, or the ambient humoral milieu. Alternatively, the
course of the tumor (85). Similarly, levels usually decreased
increases of some of these substances may be epiphenomenal
concomitantly with radiotherapy and/or chemotherapy.
and exert no relevant bioeffects.
Also, decreased levels corresponded to clinical remissions.
The clinical term, sepsis, has been used to indicate a sys-
Interestingly, SCLC is thought to originate from the same
temic inflammatory response syndrome in which bacteria or
precursor cell as does the normal pulmonary neuroendocrine
microbial products have been shown or suspected to be the
(PNE) cell, a cell that contains large amounts immunoreac-
etiology. In some cases, infection cannot be documented
tive CT (42, 86, 87). However, lung cancers other than SCLC
because microbial culture does not reveal a pathogenic mi-
may contain and secrete immunoreactive CT. In such pa-
crobe. It is likely that in some of these culture-negative cases,
tients, these peptides may originate from the tumor, admixed
the sepsis is indeed due to microbes, but the methods of
SCLC cells, or adjacent noncancerous PNE cells that are
detecting them are not completely reliable and, therefore, the
known to become hyperplastic in response to chronic ciga-
pathogen may not be identified. Moreover, in other cases,
rette smoking (88, 89). Heterogeneity studies that have been
toxic byproducts of the pathogen may be responsible for the
performed in such cancer patients also reveal a large CTpr/
syndrome. For example, the translocation through the gut
CT(1–32) ratio (83).
wall of toxins [e.g. endotoxin (lipopolysaccharide, LPS)] from
Some noncancerous conditions that are associated with
bacteria normally inhabiting the gastrointestinal tract may be
increased levels of serum CTpr appear to be explicable, all or
the cause of the sepsis (96, 97).
in part, on the basis of hypersecretion or hyperplasia of the
In sepsis, the patient is not ill principally because of the
PNE cells [i.e. chronic bronchitis (e.g. smoking, occupational,
initial injury or infection but because of a humoral and/or
cystic fibrosis), chronic obstructive pulmonary disease, acute
cellular overreaction of the host. The unrestrained or unbal-
inhalational burn injury, acute chemical pneumonitis, and
anced cytokine and humoral response in this illness may
tuberculosis] (84, 90). Furthermore, the kidney plays an im-
progress sufficiently to cause multiple organ failure, char-
portant role in the metabolism of CT(1–32) (91), and renal
acterized by varying degrees of severe occurrences, such as
disease often is associated with increased serum immuno-
myocardial insufficiency, hypoperfusion, shock, coagulopa-
reactive CT levels, much of it consisting of CT-precursor
thy, respiratory failure, hypoxemia, renal failure, and coma.
peptides (24, 92, 93).
Sepsis is the 11th leading cause of death in the United States.
Lastly, as emphasized in the present review, extraordinary
Approximately half of the fatalities in intensive care units
increases of serum CTpr occur in patients with severe in-
result from this condition. The incidence of sepsis is increas-
flammation, systemic infection, and sepsis. Indeed, CTpr
ing (currently approximately 750,000 cases per year), and the
serum levels can be used as markers for the presence and
mortality remains unchanged (approximately 30%, with
severity of these conditions. Furthermore, in these condi-
rates up to 75% in septic shock) (98).
tions, high levels of CTpr appear to play a harmful role, and
their immunoneutralization offers the potential of effective
therapy. CTpr as markers of inflammation, systemic infection, and sepsis.
An initial publication in 1983 first called attention to in-
CTpr in inflammation, systemic infection, and sepsis creased serum levels of immunoreactive CT in patients with
the staphylococcal toxic shock syndrome, a severe form of
Pathophysiology. Inflammation, a highly complex phenome- sepsis (99). The assay used an antiserum that was not selec-
non that may be beneficial and/or detrimental to the host, is tive for the amidated carboxyl terminal portion of CT(1–32)
a reaction to a large variety of injuries. Inflammation can be and hence would also bind to the immature CT within the
local or systemic. It is characterized by vasodilation, attrac- ProCT and CT-CCP-I molecules. Gel filtration studies dem-
tion of polymorphonuclear cells and lymphocytes, activation onstrated that this immunoreactive CT was of large molec-
1516 J Clin Endocrinol Metab, April 2004, 89(4):1512–1525 Becker et al. • Clincal Review

TABLE 2. Schematic illustration of events and humoral factors following exposure to a variety of insults that trigger an inflammatory

Downloaded from by guest on 15 January 2019

Several of these factors have multiple and/or variable roles, and some may be either anti- or proinflammatory. In addition, many other
humoral factors have been identified. For further documentation and elaboration, see Refs. 183–186. ADM, adrenomedullin; AP-1, activator
protein-1; AVP, arginine vasopressin; CRP, C-reactive protein; HMG-1, high mobility group-1; IFN, interferon; IL-ra, IL receptor antagonist;
LTs, leukotrienes; MIF, monocyte migration inhibitory factor; MOF, multiple organ failure; NF-␬B, nuclear factor-␬ B; PAF, platelet activating
factor; PAMPS, pathogen-associated molecular patterns; PGs, prostaglandins; PTX, pertussis toxin; RANTES, regulation on activation normal
T-expressed and secreted; ROI, reactive oxygen intermediates; TBs, thromboxanes; TNFr, TNF receptor.

ular weight, now known to correspond to ProCT and CT- and the routine laboratory tests (e.g. an abnormal leukocyte
CCP-I. This paper provided the inspiration for multiple count, elevated serum C-reactive protein, or positive bacte-
subsequent studies of CTpr in inflammation, systemic infec- riologic studies) may be nonspecific or may not occur at all.
tion, and sepsis. Furthermore, the classical associated proinflammatory cyto-
The traditional clinical signs of severe infection (e.g. fever kines of severe inflammation, systemic infections, and sepsis
or hypothermia, tachycardia, tachypnea, or hypotension) (i.e. TNF␣, IL-1␤, or IL-6) commonly are increased in the
Becker et al. • Clincal Review J Clin Endocrinol Metab, April 2004, 89(4):1512–1525 1517

serum only transiently or intermittently. In contrast, serum present in the sera of sepsis patients, there appears to be
levels of CTpr are very frequently increased, sometimes at- universal agreement that both ProCT and multiple fragments
tain levels several thousand-fold normal, and these high of ProCT are present. Interestingly, in all these sepsis and
levels often persist for long periods of time. Moreover, the sepsis-like conditions, CT(1–32) remains undetectable or nor-
levels often correlate positively with the severity of the con- mal or slightly to moderately elevated (30, 100, 102) (see
dition and mortality. Indeed, after the first systematic study below).
of sepsis due to severe bacterial infection (100), many clinical There are four assays that have been created to measure
studies have documented the considerable utility of serum serum CTpr. Currently none of these assays are commer-
CTpr to identify and follow the course of this illness and cially available in the United States. The authors developed
sepsis-like conditions (Fig. 2) (100 –102). a single-antibody RIA for NProCT, which quantitates ProCT
Thus, serum CTpr have been shown to be extremely useful and the free NProCT peptide (as well as ProCGRP and
markers in sepsis, whether blood cultures are positive or NProCGRP) (76, 101). This sensitive assay [10 pg/ml (1.6

Downloaded from by guest on 15 January 2019

negative, and also in sepsis-like conditions such as severe fmol/ml)] detects CTpr in healthy nonsmoking persons [the
burns, pancreatitis, pneumonitis, inhalational injury, bacte- upper limit of normal is 76 pg/ml (12 fmol/ml)]. There are
rial meningitis, heat stroke, and severe mechanical trauma two two-site rapid assays. In Europe, a commercially avail-
after extensive surgery, and also in some infections of non- able assay (LUMItest PCT, B.R.A.H.M.S. Diagnostica GmbH,
bacterial causation (e.g. severe malaria or systemic fungal Henningsdorf/Berlin, Germany), shortly to be available in
infections) (100 –108). This phenomenon also occurs in pa- the United States, measures both ProCT and the conjoined
tients with a prior thyroidectomy (100, 109). CT-CCP-I by means of a luminometer (100). This assay,
Molecular sizing by gel filtration and HPLC studies in which has been used in many clinical studies, is inaccurate
sepsis and in the above septic-like conditions have demon- at levels less than 300 pg/ml (24 fmol/ml). This company
strated that serum components corresponding to ProCT, manufactures another more sensitive double-antibody kit,
NProCT, CT-CCP-I, and the CCP-I peptide are all elevated which can reliably detect levels as low as 20 pg/ml (1.6
to varying degrees (30) (Fig. 1). The individual components fmol/ml) (82). The sensitive assays, including a recently de-
were quantified with antisera specific for CT(1–32), NProCT, veloped tracer technology Kryptor assay (B.R.A.H.M.S.), the
CCP-I, and also a two-site assay that used antibodies specific latter of which is commercially available in Europe, are es-
to the CT and CCP-I regions of ProCT. Using capillary zone pecially useful for the detection of early forms of infection
electrophoresis spectrometry and Edman sequence analysis, and for follow-up determinations (112).
the serum ProCT in sepsis has been reported to lack the first
two amino acids of the molecule (Ala-Pro), consequent to an Ubiquity of expression of the calcitonin-I gene in response to sepsis.
aminoterminal truncation by the dipeptidyl peptidase IV Normally, immunoreactive CT is found predominantly in
enzyme (EC3.4.14.5) (110). In another study, immunoreactive some neuroendocrine cells such as the thyroid C cells and
ProCT and its cleavage products were extracted from pooled PNE cells, and CGRP is found predominantly in brain and
septic serum using octadecylsilyl columns and characterized neurologic tissues. However, immunoreactive CT is found in
by HPLC and Western blot analysis of electrophoresis-sizing many tissues throughout the body (113). Furthermore, low
gels. The peptides were identified using antisera specific for levels of CT gene mRNAs have been reported to occur in liver
CT, NProCT, and CCP-I (111). These investigators found (55) and also several other tissues (114). In septic hamsters,
ProCT and multiple fragments of ProCT that appeared to substantially increased levels of immunoreactive CT (appar-
differ in molecular size from those found in the serum of ently mostly ProCT as shown by gel filtration chromatography
patients with MTC. Thus, whereas there is some uncertainty and HPLC) were found in liver, lung, kidney, pancreas, brain,
as to the absolute identities of some of the fragments of ProCT heart, and small intestine (115). In this investigation, quantita-

FIG. 2. Receiver operating-curve analysis of se-

rum CTpr for the diagnosis of sepsis in an inten-
sive care unit, as compared with values for cir-
culating C-reactive protein, IL-6, lactate, and
pentraxin-3 (PTX-3). The sensitivity of CTpr for
the diagnosis of sepsis was 89%, specificity 94%,
negative predictive value 90%, and positive pre-
dictive value 94% (as assessed by the commer-
cially available LUMItest PCT). However, the
other non-CTpr markers were considerably less
sensitive and less specific and had relatively poor
negative or positive predictive values (modified
from Ref. 102).
1518 J Clin Endocrinol Metab, April 2004, 89(4):1512–1525 Becker et al. • Clincal Review

tive analysis of CT mRNA expression was determined by the nating from this superfamily of genes: one of the genes yields
CT/␤-actin ratio of the septic tissues in relation to the CT/␤- a very slightly different form of CGRP (CGRP-II), another
actin ratio of the respective control tissues (Taq-Man technol- gene gives rise to amylin, and another gives rise to ad-
ogy). Among the tissues studied, the relative increase of CT renomedullin. Furthermore, there is a gene that gives rise to
mRNA, compared with controls, was, in descending order, a CT receptor-stimulating peptide with some homology to
adrenal, spleen, spinal cord, brain, liver, pancreas, colon, lung, CGRP (31, 124, 125).
fat, testes, and stomach (115). This phenomenon of marked Similar to the case for CT-mRNA, in septic hamster tissues
increase of CT mRNA in extrathyroidal tissues also occurs in the but not in similar healthy control tissues, there also is a
septic human (116). Of course, when evaluating the impact of tissue-wide expression of CGRP mRNA (126). Here, as well,
each increase, consideration must be given to the total weight CGRP mRNAs are more specifically up-regulated than are
of each organ. Thus, for example, the demonstration of CT the mRNAs of classical cytokines (e.g. IL-6 and TNF␣). A
mRNA in fat of septic individuals assumes marked pathophys- similar phenomenon occurs for adrenomedullin. In contrast,

Downloaded from by guest on 15 January 2019

iological significance when one considers the great bulk of amylin mRNA has not been found to be up-regulated in
adipose tissue (116). nonneuroendocrine septic tissues. Thus, in sepsis several
The extraordinary tissue-wide expression and secretion members of the CALC gene superfamily escape from their
explains the enormous elevation of CTpr in the sera of septic normal tissue-selective expression pattern. In studies in sep-
patients. The substantial suppression of CALC-I gene ex- tic humans, serum levels of CGRP and adrenomedullin are
pression by nonneuroendocrine cells that occurs in normal increased in sepsis, although to levels considerably below
persons is altered in septic patients by a unique stimulus those found for CTpr.
arising from the infectious and/or cytokine insult that then
influences the transcriptional regulation of the gene. Indeed, ProCT as a toxic factor in severe inflammation, systemic
in sepsis the mRNA is more uniformly up-regulated than are infection, and sepsis
the mRNAs of the classical sepsis-related cytokines, TNF␣,
IL-1␤, and IL-6. In a broader sense, in sepsis the entire body Development of animal models of sepsis and correlation of serum
becomes a CTpr-producing endocrine gland. It is because CTpr with sepsis and mortality. In humans, the concentration
this novel form of secretion is intrinsic to the host response of serum CTpr often reflects the severity of sepsis and may
to sepsis, and is reminiscent of the expression of the classical be predictive of mortality. Accordingly, to study this phe-
cytokines in this condition, that CTpr are referred to as hor- nomenon more extensively, a model for sepsis was devel-
mokines (115). oped in hamsters and pigs (127–131).
The lack of a significant increase of CT(1–32) in sepsis
merits further investigation. In part, this is indicative of a Sepsis in the hamster
shift away from the normal, regulated, neuroendocrine path- Severe peritonitis was induced in hamsters by the ip im-
way (characterized by a progressive posttranslational pro- plantation of pellets containing measured quantities of Esch-
cessing, maturation, and secretion via secretory granules) to erichia coli, and serum CTpr was determined at intervals.
a constitutive pathway (characterized by a nonstoring, bulk- According to the dosage of bacteria, the 72-h mortality in-
flow secretion from nonneuroendocrine cells); this latter creased proportionately from zero to approximately 20, 70,
pathway is deficient in the enzymatic processing required to and 100%. Serum CTpr also demonstrated a dose-related
produce CT(1–32) (31, 117). Furthermore, once secreted, increase; at the highest dose of bacteria, serum CTpr levels
ProCT and NProCT are extremely resistant to enzymatic exceeded control values by nearly 200-fold. Thus, CTpr levels
degradation; in contrast, CT(1–32) is extremely labile. Thus, correlated both with the severity of bacterial insult and the
circulating CT(1–32) may not be increased in sepsis because mortality. Gel filtration and HPLC studies revealed that most
of its rapid degradation. Yet another factor may be the in- of the CTpr in these septic animals was in the form of ProCT
fluence of heat shock proteins. These stabilizers of cellular (127).
function are synthesized in response to heat, other stressful
stimuli, and sepsis. In this latter illness, they may serve a Relationship between serum CTpr and cytokines. Using this an-
protective role (118). Heat shock proteins also are found imal model of sepsis, the relationship of CTpr to the proximal
in the blood as well as intracellularly (119, 120). They bind proinflammatory mediators, IL-l␤ and TNF␣, was studied
to CT(1–32) (121), and perhaps this further augments the (128). Whereas serum CTpr remained extremely high
disposal of CT(1–32) or interferes with its immunologic throughout the 24 h of this study, the increases of these
detection. cytokines in the serum were less than 2-fold greater than the
baseline and, importantly, were transient in duration. In
Other members of the CT-gene family of peptides in sepsis: CGRP healthy hamsters, the iv administration of human ProCT
and adrenomedullin. There are five genes in the CT-gene fam- caused no evident adverse effects and no changes in serum
ily of peptides. The gene that was initially discovered gives IL-1␤ and TNF␣ levels. In septic animals, the ProCT injec-
rise to two alternative splice variants: CT mRNA, resulting tions, albeit markedly increasing mortality (see below), only
in ProCT and its components, and CGRP mRNA, giving rise modestly blunted IL-1␤ levels and did not affect TNF␣ val-
to CGRP-I (122, 123). In the healthy, noninfected state, there ues. Interestingly, however, when TNF␣ was injected into
is a preferential synthesis of either CT(1–32) mRNA or healthy animals, there was a 25-fold increase of CTpr levels,
CGRP-I mRNA according to the cellular phenotype. Addi- compared with noninjected controls. Thus, as is the case in
tionally, there are other structurally related peptides origi- the human, the magnitude and duration of the CTpr eleva-
Becker et al. • Clincal Review J Clin Endocrinol Metab, April 2004, 89(4):1512–1525 1519

tion demonstrated its utility as a marker of sepsis in the hour of the experiment (131). In contrast to the parameters
hamster. It also revealed that ProCT does not secondarily for control septic animals, all of which progressively wors-
enhance levels of IL-1␤ or TNF␣ in the systemic blood. In ened and ultimately died, most physiologic and biochemical
contrast, it showed that in healthy animals, TNF␣ can induce parameters of the treated animals improved or stabilized
a sepsis-like elevation of serum CTpr. after infusion of the ProCT-reactive IgG (Fig. 3). Although all
untreated animals had died during the experiment, most of
ProCT as a toxic factor. Based on these clinical and animal
the treated pigs survived until being killed (P ⫽ 0.010). Thus,
studies, it was hypothesized that ProCT per se may be a
in this model, the findings indicate that the immunoneutral-
toxic factor in sepsis and may adversely influence survival.
ization of ProCT was useful in a clinically relevant situation
The iv administration of human ProCT, which appeared
in which sepsis was fully established and far advanced.
not to be overtly injurious to normal hamsters, doubled the
mortality of septic animals (129). In contrast, administra-

Downloaded from by guest on 15 January 2019

tion of human CT(1–32) to septic hamsters was without
effect. Furthermore, a goat antiserum raised to this hor-
mone, and shown to be completely cross-reactive with
ProCT, was found to increase survival whether adminis-
tered prophylactically or therapeutically.

Sepsis in the pig

To investigate in detail the physiologic and metabolic con-
sequences of sepsis and evaluate how ProCT immunoneu-
tralization might affect these parameters, a larger animal
model of a rapidly fatal porcine polymicrobial peritonitis
was then developed (130, 131). The subsequent sepsis is
similar pathophysiologically to that encountered in human
disease but far more lethal.
Early immunoneutralization. After having determined the
structure of porcine ProCT, and, in rabbits, having produced
an antiserum that was specific to the NProCT portion of this
peptide, sepsis was induced in Yorkshire pigs by the ip
instillation of a suspension of cecal content (l g/kg) plus E.
coli (2 ⫻ 1011 cfu). Simultaneous to the induction of the
peritonitis, experimental pigs received an iv infusion of the
ProCT-reactive purified rabbit IgG, whereas control animals
received non-ProCT-reactive IgG. All animals had physio-
logic data (e.g. urine output, core temperature, arterial pres-
sure, heart rate, cardiac index, and stroke index), and met-
abolic data (e.g. blood urea nitrogen, serum creatinine,
arterial lactate, and pH) collected or recorded hourly until
death or being killed (15 h after ip instillation) (130).
Similarly to what occurs in humans, in this large animal
model of lethal peritonitis, serum CTpr levels were found to
be significantly elevated. Most of the untreated animals died
within 9 h, and none survived for the 15-h duration of the
experiment. However, immune IgG administration resulted
in a significant improvement or a beneficial trend in most of
the measured physiologic and metabolic derangements in-
duced by sepsis. Moreover, most of these treated animals FIG. 3. Top, Time course in septic pigs showing the changes in mean
survived until the time of being killed, in contrast to animals arterial pressure (MAP). Time point 0 h represents commencement of
treated with the non-ProCT-reactive IgG (P ⫽ 0.007). the fourth hour after induction of sepsis and is the time of infusion of
purified nonreactive rabbit antibody to the control group and purified
Immunoneutralization of moribund pigs. In this septic pig antiporcine ProCT rabbit IgG to the treated group. After time point
0, there is a sharp fall in MAP in the control group, but the MAP of
model, the physiologic and metabolic parameters of the un-
the treated group remains near normal levels. *, Statistically signif-
treated animals worsened rapidly, so that the animals were icant data points (P ⬍ 0.017; mean ⫾ SEM). Bottom, Time course
essentially moribund by 4 h after the induction of the peri- showing the changes in serum creatinine. The graph shows very
tonitis. This state is comparable with the syndrome of mul- similar creatinine concentrations before antibody infusion, which is
tiple organ failure that occurs in humans with preterminal followed by a sharp rise in the control group but with concentrations
that remain near normal for the treated group. Other physiologic or
sepsis. Accordingly, to determine whether these gravely ill metabolic parameters also showed benefits. *, Statistically significant
animals might be rescued, an evaluation of iv therapeutic data points (mean ⫾ SEM, P ⬍ 0.037), which were noted at 2, 4, and
immunoneutralization was undertaken during the fourth 6 h, after which all control animals died (from Ref. 131).
1520 J Clin Endocrinol Metab, April 2004, 89(4):1512–1525 Becker et al. • Clincal Review

Mechanism of toxicity of ProCT in sepsis: hypotheses and early cAMP response to relatively small amounts of CT(1–32)
unanswered questions has been shown to be blocked by other hormones [e.g. PTH
Currently the physiologic actions of ProCT are relatively (147), epinephrine (148)].
unexplored, and it is not known how this polypeptide or its A principal function of the monocyte is its migration to
components might worsen the septic process. Although sites of inflammation, a phenomenon that has been demon-
acute studies have not been done in the human, the experi- strated to be induced by the addition of CT(1–32); in contrast,
ence in noninfected patients with MTC indicates that chron- when patients receive therapeutic doses, this motion is di-
ically high levels of ProCT do not appear to cause any ob- minished, strongly suggesting down-regulation of CT(1–32)
vious ill effects. Nonetheless, although administration of receptors (149).
ProCT to healthy, noninfected hamsters had no apparent ill The immunologic relevance of the monocyte response to
effects, its administration to hamsters that were septic sig- CT(1–32) remains to be fully elucidated. In vivo immunologic
activities of this hormone have been demonstrated in several

Downloaded from by guest on 15 January 2019

nificantly increased mortality. This indicates that ProCT is
not an initial toxic factor but requires the prior presence of studies (150, 151), and salmon CT(1–32) has been reported to
a proinflammatory stimulus followed by an altered cytokine diminish the local inflammation after various forms of in-
milieu. jury in rats (152). In humans with rheumatoid arthritis, eel
CT(1–32) decreased production of IgG immunoglobulin
Initial studies of actions of CTpr. In addition to the osteoclast, and inhibited IL-1␤ (153). However, as mentioned above,
it is well known that receptors for CT(1–32) are present in CT(1–32) is not appreciably elevated in patients with severe
different cell types, and multiple experimental studies of this inflammation or sepsis, and because of the marked increase
peptide have been performed. However, in the past, the of serum ProCT and its component CTpr in such patients in
effects of the various CTpr have very rarely been evaluated. the serum, more interest is being focused on the effects of
Insofar as ProCT is concerned, one study revealed the pres- these latter peptides on the monocyte.
ence of receptors to this prohormone in newborn rat calvarial
cells (132). Also, the human NProCT peptide portion of CTpr and the monocyte
ProCT has been reported to be mitogenic to human osteo-
In vitro studies of isolated human monocytes have dem-
blastic cells (U-2 OS osteosarcoma) and to induce an increase
onstrated that not only CT(1–32) but also ProCT and the free
in intracellular cAMP (133), although a subsequent study
CCP-I peptide act as chemoattractants, inducing migration,
was not confirmatory (134). In a preliminary and uncon-
which is dosage dependent. This phenomenon is accompa-
firmed report, a large-molecular-weight species of immuno-
nied by an intracellular elevation of cAMP levels. Further-
reactive CT, corresponding to an undetermined portion of
more, paradoxically, these peptides may deactivate the mi-
the ProCT molecule, appeared to suppress prostaglandin-
gratory effects of other unrelated chemoattractants and/or
E2-stimulated osteoclastic bone resorption (135). It is because
modify monocyte surface signals (154, 155). Monocytes and
of the recent awareness of the phenomenon of greatly in-
neutrophils are stimulated by LPS and another proinflam-
creased serum levels of CTpr in severe inflammation and
matory product of bacteria, formyl methionyl leucyl phe-
sepsis that studies of the action of CTpr are now underway
nylalanine peptide, which induces these cells to produce an
by several groups.
important integrin, CD11b, a substance that is involved in
The monocyte. Although the cell that has been most associated chemotaxis. Both NProCT and CGRP decrease this cellular
with the action of CT is the osteoclast, it is well known that CD11b production (156). In an initial study (157), human
this cell is produced from a precursor monocyte/macro- ProCT was added to mononuclear cells of peripheral blood
phage cell line that also gives rise to the mature monocyte harvested from normal humans, and cytokine secretion was
(136 –139). Moreover, monocytes influence osteoclast activity measured in the ambient culture media. When compared
and also directly induce bone resorption (139 –141). Impor- with background cytokine synthesis by unstimulated cells,
tantly, the monocyte plays an essential role in phagocytosis, IL-1␤ secretion was augmented 4-fold, TNF␣ 2-fold, and that
T lymphocyte immune activity, and inflammation; thus, it is of IL-8 2-fold. These preliminary findings suggest that ProCT
greatly involved in the initiation and course of sepsis. The might stimulate cytokine secretion from monocytes in local
awareness that monocytes have CT receptors (142, 143) circulatory pools. As mentioned, TNF␣ is a known stimulus
has led to several experiments investigating the effects of to ProCT secretion, and in sepsis this cytokine might locally
CT(1–32) and CTpr on these cells. induce a yet further local production of this prohormone in
a positive-feedback manner. The clinical impact of all of these
CT(1–32) and the monocyte actions and complex interactions on the monocyte awaits
Insofar as CT(1–32) is concerned, after exposure of the
lymphocyte/monocyte/macrophage family to this peptide, CTpr and nitric oxide (NO). The production of the vasodilator,
cAMP increases (144). This cAMP response is inhibited after NO, is elevated in sepsis (158), and this agent has been
exposure of these cells to various mechanical or hormonal proposed as a mediator of the shock that may occur during
stimuli (145). Also, analogous to the finding of down-regu- the course of this illness (159). However, others have re-
lation of the osteoclast CT(1–32) receptor that occurs when ported that NO may have a beneficial role. When ProCT is
hypercalcemic patients receive CT(1–32) therapy (146), a sim- added to cultures of vascular smooth muscle cells of normal
ilar response to an excess of this hormone occurs in vitro rats that had previously been exposed to LPS, TNF␣, and
when the monocyte CT(1–32) receptor is studied (143). The interferon-␥, the prohormone amplified the expression of the
Becker et al. • Clincal Review J Clin Endocrinol Metab, April 2004, 89(4):1512–1525 1521

inducible NO synthase gene as well as NO production (160). teins), thus perhaps modulating the action of the CT gene
The potentially detrimental effects of such an occurrence in products according to ambient circumstances (176 –180).
the septic process requires further evaluation. Conceivably, the much higher serum levels of CTpr may
interfere with receptors or with receptor-activity-modifying
CTpr and hypocalcemia. Hypocalcemia, involving particularly
protein expression. Such an occurrence may block CGRP
but not exclusively the ionized component, is a frequent
and/or andrenomedullin activity and hence impede their
concomitant of critical illness and sepsis (161, 162). Studies
otherwise beneficial effects. Nevertheless, both CGRP and
in the septic rat indicate that this hypocalcemia is accompa-
adrenomedullin have vasodilatory actions, and whether
nied by an increase of intracellular calcium (163), and a
such effects may be beneficial (e.g. by increasing the blood
similar intracellular increase occurs in the septic human
supply to vital organs) or harmful (e.g. by inducing systemic
(164). Interestingly, it is known that calcium infusions may
hypotension) requires additional clarification.
be harmful to septic humans (165, 166), and when septic
Clearly, it is essential to further investigate the means by

Downloaded from by guest on 15 January 2019

hypocalcemic rats are administered calcium, the fatalities
which ProCT exerts its toxicity in sepsis. ProCT and its com-
increase markedly (167). In a large study of critically ill pa-
ponents may exert actions that differ according to their target
tients, dose-related correlations were noted among the se-
tissues as well as having actions that differ according to the
verity of illness, the degree of hypocalcemia, and the level of
ambient milieu of the host. Multiple in vitro and in vivo
serum CTpr (161). Also, in this condition, serum ionized
investigations will be required.
calcium is known to correlate inversely with levels of TNF␣
and IL-6 (162). The cause of the hypocalcemia is unknown.
CT(1–32) has been demonstrated to augment the intracellular Potential advantages of ProCT as a target for
calcium concentration in several different cell lines (61, 168 – immunoneutralization in the human
170). However, CT(1–32) is rarely appreciably elevated in
The administration of endotoxin results in a form of sys-
sepsis. A direct effect of other CTpr on intracellular calcium
temic inflammation that is associated with cellular activation
has not been demonstrated. In a study in hamsters, admin-
and the release of inflammatory mediators (Table 2); albeit
istration of human ProCT did not cause hypocalcemia; in-
being different from sepsis, it is an experimental model of the
deed, this prohormone was found to completely block the
mediators and the control mechanisms that are relevant to
hypocalcemia normally induced by injection of CT(1–32)
this devastating state. In humans, it was shown that endo-
(171). Thus, further studies are required to define any rela-
toxin caused a rise in serum CTpr that persisted for the 24 h
tionships between the CTpr peptides and serum calcium.
of the experiment, although the duration of this elevation
Influence of other peptides of the CT gene family. Lastly, as dis- was unknown (179). Therefore, an investigation was under-
cussed above, both CGRP and adrenomedullin are increased taken to evaluate the duration of the CTpr elevation (180).
in sepsis. These hormones have been reported to exert an- Serum CTpr were observed to increase by 3 h and attained
tiinflammatory effects (172–175), and these actions could po- peak values at 24 h. Subsequently values very slowly and
tentially be beneficial in severe infections or sepsis (e.g. an- progressively declined. Surprisingly, at 7 d, all volunteers
tibacterial, increased dilatation of coronary arteries, positive still exhibited levels that were above normal (Fig. 4). In two
cardiac inotropic and chronotropic effects). Furthermore, the of the subjects who were studied for a longer period, the
biologic effects of the members of the CT gene family of levels did not normalize until 10 –14 d. In contrast, when
peptides are exerted via the same family of receptors. The subjects were administered identical doses of endotoxin and
physiological profiles of these receptors are modified by cytokines were measured for 24 h, serum levels of the proin-
certain accessory proteins (receptor-activity-modifying pro- flammatory cytokine TNF␣ increased at 1 h, reached a peak

FIG. 4. Exposure of human volunteers to one injection of

endotoxin illustrates the differences in the release and
subsequent decrease of several humoral markers of crit-
ical illness: TNF␣, IL-1 receptor antagonist (IL-1ra),
IL-6, C-reactive protein (CRP), and CTpr (from Ref. 183).
1522 J Clin Endocrinol Metab, April 2004, 89(4):1512–1525 Becker et al. • Clincal Review

at 1.5 h, and had normalized by 24 h. Similar patterns of suggest that this prohormone may possibly be a useful target
secretion occurred for the IL-1 receptor antagonist (IL-1ra), for therapeutic immunoneutralization in the human.
IL-6, and granulocyte colony stimulating factor and also sev-
eral other cytokines, some of which were even more transient Acknowledgments
(181, 182). Thus, these short-lived acute phase cytokine ele-
vations contrast with the extremely prolonged elevation of Received September 16, 2002. Accepted December 24, 2003.
serum CTpr after a systemic inflammatory episode in healthy Address all correspondence and requests for reprints to: Dr. Kenneth
humans; this suggests that CTpr not only have advantages L. Becker, Director of Endocrinology, Veterans Affairs Medical Center,
as excellent markers of sepsis but also may offer a durable 50 Irving Street NW, Washington, D.C. 20422. E-mail:
target for therapeutic immunoneutralization, even several
days after the severe inflammatory illness has commenced. References
1. Copp DH, Davidson AG 1961 Evidence for a new parathyroid hormone

Downloaded from by guest on 15 January 2019

which lowers blood calcium. Proc Soc Biol Med 107:342–344
Conclusions 2. Hirsch PF, Gauthier GG, Munson PL 1963 Thyroid hypocalcemic principle
and recurrent laryngeal nerve injury as factors affecting the response to
CT(1–32) was the initial peptide of the CT gene-related parathyroidectomy in rats. Endocrinology 73:244 –251
3. Nonidez JF 1932 The origin of the ‘parafollicular’ cell, a second epithelial
family to have been isolated from MTC and normal thyroid component of the thyroid gland in the dog. Am J Anat 49:479
tissue, and experimental studies demonstrated its hypocal- 4. Foster GV, MacIntyre I, Pearse AGE 1964 Calcitonin production and the
cemic activity, secretory responsivity, and marked effects mitochondrion-rich cells of the dog thyroid. Nature 203:1029 –1031
5. Meyer JS, Abdel-Bari W 1968 Granules and thyrocalcitonin-like activity in
on the osteoclast. This peptide rapidly became the classic medullary carcinoma of the thyroid gland. N Engl J Med 278:523–529
marker for MTC. The relatively recent development of spe- 6. Wolfe HJ, Melvin KEW, Cervi-Skinner SJ, Al Saadi AA, Juliar JF, Jackson
cific assays for the CT(1–32) molecule has considerably im- CE, Tashjian Jr AH 1973 C-cell hyperplasia preceding medullary thyroid
carcinoma. N Engl J Med 289:437– 441
proved its use as an MTC marker as well as ensuring the 7. McMillan PJ, Hooker WM, Deftos LJ 1974 Distribution of calcitonin-
accuracy and reproducibility of physiopathologic investiga- containing cells in human thyroid. Am J Anat 140:73–79
8. LeDouarin N, LeLievre C 1970 Demonstration of neural origin of calcitonin
tions. Many clinical studies demonstrated the utility of the cells of ultimobranchial body of chick embryo. C R Acad Sci Hebd Seances
this peptide as a therapeutic agent for osteoporosis and Paget Acad Sci D 270:2857–2860
disease. Nevertheless, in contrast to the continuing role of the 9. Williams ED 1966 Histogenesis of medullary carcinoma of the thyroid. J Clin
Pathol 19:114 –118
assay of serum CT(1–32) in patients with MTC, the use of 10. Neher R, Riniker B, Rittel W, Zuber H 1968 Menschliches calcitonin III.
salmon CT(1–32) as a therapeutic agent for these conditions Struktur von calcitonin M und D. Helv Chim Acta 51:1900 –1905
has markedly diminished. 11. Byfield PG, Turner K, Galante L, Gudmundsson TV, MacIntyre I, Riniker
B, Nehe, R, Maier R, Kahnt FW 1969 The isolation of human calcitonin.
Soon after the discovery of CT(1–32), this hormone was Biochem J 111:13P–14P
determined to be synthesized as part of the considerably 12. Potts Jr JT, Niall HD, Keutmann HT, Brewer HB, Deftos LJ 1968 The amino
acid sequence of porcine thyrocalcitonin. Proc Natl Acad Sci USA 59:1321–
larger prohormone, ProCT. ProCT and its components 1328
(CTpr) were found to be secreted by MTC and cultured C 13. Tashjian Jr AH, Howland BG, Melvin KEW, Stratton Hill Jr C 1970 Im-
cells and were noted to be markedly elevated in the blood of munoassay of human calcitonin. N Engl J Med 283:890 – 895
14. Clark MB, Byfield PGH, Boyd GW, Foster GVA 1969 radioimmunoassay for
patients with this tumor. Sensitive immunoassays for CTpr human calcitonin M. Lancet 2:74 –77
in the serum have been developed, and all of these peptides 15. Deftos LJ, Bury AE, Habener JF, Singer FR, Potts Jr JT 1971 Immunoassay
were found to circulate at low levels in the serum of normal for human calcitonin II. Clinical studies. Metabolism 20:1129 –1137
16. Parthemore JG, Bronzert D, Roberts G, Deftos LJA 1974 Short calcium
persons. Clinically, serum CTpr measurement has shown infusion in the diagnosis of medullary thyroid carcinoma. J Clin Endocrinol
promise of being of utility as markers for patients with MTC Metab 39:108 –111
17. Hennessey JF, Wells Jr SA, Ontjes DA, Cooper CW 1974 A comparison of
and perhaps for SCLC. pentagastrin injection and calcium infusion as provocative agents for the
In severe inflammation, systemic infections, sepsis, and detection of medullary carcinoma of the thyroid. J Clin Endocrinol Metab
sepsis-like conditions, serum levels of CTpr are markedly 39:487– 495
18. Hoff AO, Cote GJ, Gagel RF 2000 Multiple endocrine neoplasias. Annu Rev
elevated. The levels of serum CTpr correlate positively with Physiol 62:377– 411
the severity of the illness and mortality, and their clinical 19. Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C,
utility as markers for these conditions has been facilitated by Conte-Devolx B, Falchetti A, Gheri RG, Libroia A, Lips CJ, Lombardi G,
Manelli M, Pacini F, Ponder BA, Raue F, Skogseid P, Tamburrano G,
the development of commercial assays for their measure- Takker RV, Thompson MW, Tamassehi P, Tonelli F, Wells Jr SA, Mara SJ
ment. In septic states, CTpr are produced throughout the 2001 Guidelines for diagnosis and therapy of MEN type I and type 2. J Clin
Endocrinol Metab 86:5658 –5671
body. Experimentally, ProCT is toxic to septic animals, as 20. Singer FR, Habener JF 1974 Multiple immunoreactive forms of calcitonin in
demonstrated by an increased mortality after its adminis- human plasma. Biochem Biophys Res Commun 61:660 – 666
tration and also by an amelioration of the metabolic and 21. Roos BA, Okano K, Deftos LJ 1974 Evidence for a pro-calcitonin. Biochem
Biophys Res Commun 60:134 –140
physiologic parameters of illness as well as an increased 22. Moukhtar MS, Jullienne A, Taboulet J, Calmettes C, Raulais D, Milhaud
survival after its immunoneutralization. The normal physi- G 1975 Heterogeneity of immunoreactive calcitonin in the plasma of patients
ologic actions of ProCT and its component CTpr, if any, are with bone marrow cancer. Pathol Biol 23:809 – 814
23. Deftos LJ, Roos BA, Bronzert D, Parthemore JG 1975 Immunochemical
unknown. Furthermore, the mechanism(s) by which this tox- heterogeneity of calcitonin in plasma. J Clin Endocrinol Metab 40:409 – 412
icity occurs also is unknown, and these are subjects that 24. Snider RH, Silva OL, Moore CF, Becker KL 1977 Immunochemical heter-
ogeneity of calcitonin in man: effect on radioimmunoassay. Clin Chim Acta
clearly merit further investigation. 76:1–14
The beneficial effects of immunoneutralization of ProCT in 25. Moya F, Nieto A, Candela LL 1975 Calcitonin biosynthesis: evidence for a
two different species, the efficacy of treatment at a time when precursor. Eur J Biochem 55:407– 413
26. Goltzman D, Tischler AS 1978 Characterization of the immunochemical
the animals are nearly moribund, and the persistence of forms of calcitonin released by a medullary thyroid carcinoma in tissue
hyperprocalcitonemia for extremely long periods of time culture. J Clin Invest 61:449 – 458
Becker et al. • Clincal Review J Clin Endocrinol Metab, April 2004, 89(4):1512–1525 1523

27. Goodman RH, Jacobs JW, Habener JF 1979 Cell-free translation of messenger 55. Bracq S, Machairas M, Clement B, Pidoux E, Andreoletti M, Moukhtar MS,
RNA coding for a precursor of human calcitonin. Biochem Biophys Res Jullienne A 1993 Calcitonin gene expression in normal human liver. FEBS
Commun 91:932–938 Lett 331:15–18
28. LeMoullec JM, Jullienne A, Chenais J, Lasmoles F, Guliana JM, Milhaud 56. Lin HY, Harris TL, Flannery MS, Aruffo A, Kaji EH, Gorn A, Kolakowski
G, Moukhtar MS 1984 The complete sequence of human preprocalcitonin. LFJ, Lodish HF, Goldring SR 1991 Expression cloning of an adenylate
FEBS Lett 167:93–97 cyclase-coupled calcitonin receptor. Science 254:1022–1024
29. Treilhou-Lahille F, Pidoux E, Day F, Milhaud G, Moukhtar MS 1986 Gran- 57. Gorn AH, Lin HY, Yamin M, Auron PE, Flannery MR, Tapp DR, Lodish HF,
ular and extra-granular forms of immunoreactive calcitonin in normal rat “C” Krane SM, Goldring SR 1992 Cloning, characterization and expression of
cells. Biol Cell 57:221–230 human calcitonin receptor from an ovarian carcinoma cell line. J Clin Invest
30. Snider RH, Nylén ES, Becker KL 1998 Procalcitonin and its component 90:1726 –1735
peptides in systemic inflammation: immunochemical characterization. J In- 58. Goldring SR, Gorn AH, Yamin M, Krane SM, Wang JT 1993 Characteriza-
vest Med 552–560 tion of the structural and functional properties of cloned calcitonin receptor
31. Becker KL, Müller B, Nylen ES, Cohen R, White JC, Snider RH 2002 cDNAs. Horm Metab Res 25:477– 480
Calcitonin gene family of peptides. Structure molecular biology, and effects. 59. Moore EE, Kuestner RE, Stroop SD, Grant FJ, Matthewes SL, Brady CL,
In: Bilezikian JP, Raisz LG, Rodan GA, eds. Principles of bone biology, 2nd Sexton PM, Findlay DM 1995 Functionally different isoforms of the human
ed. San Diego: Academic Press; 619 – 639 calcitonin receptor result from alternative splicing of the gene transcript. Mol

Downloaded from by guest on 15 January 2019

32. Deftos LJ 1979 Calcitonin. In: Gray CH, James VHT, eds. Hormones and Endocrinol 9:959 –968
blood. London: Academic Press, Inc.; 97–141 60. Braga V, Sangalli A, Malerba G, Mottes M, Mirandola S, Gatti D, Rossini
33. Sexton PM, Findlay DM, Martin TJ 1999 Calcitonin. Curr Med Chem 6:1067– M, Zamboni M, Adam S 2002 Relationship among VDR (BsmI and FokI),
1093 COLIA1, and CTR polymorphisms with bone mass, bone turnover markers,
34. Inzerillo AM, Zaidi M, Huang CL-H 2002 Calcitonin: the other hormone. and sex hormones in men. Calcif Tissue Int 70:457– 462
Thyroid 12:791–798 61. Chen Y, Shyu JF, Santhanagopal A, Inoue D, David JP, Dixon SJ, Horne WC,
35. Riniker B, Neher R, Maier R, Kahnt FW, Byfield PGH, Gudmundsson TV, Baron R 1998 The calcitonin receptor stimulates Shc tyrosine phosphorylation
Galante L, MacIntyre I 1968 Menschliches calcitonin. I. Isolierung and chara- and Erk1/2 activation. Involvement of Gi, protein kinase C, and calcium.
kterisierung. Helv Chim Acta 51:1938 J Biol Chem 273:19809 –19816
36. Riniker B, Brugger M, Kamber B, Rittel W, Sieber P, Neher R 1969 Structure 62. Downs Jr RW, Bell NH, Ettinger MP, Walsh BW, Favus MJ, Mako B, Wang
and synthesis of human calcitonin M. Biochem J 111:14P L, Smith ME, Gormley GJ, Melton ME 2000 Comparison of alendronate and
37. Motté P, Vauzelle P, Gardet P, Ghillani P, Caillou B, Parmentier C, Bohuon intranasal calcitonin for treatment of osteoporosis in postmenopausal
C, Bellet D 1988 Construction and clinical validation of a sensitive and women. J Clin Endocrinol Metab 85:1783–1788
specific assay for serum mature calcitonin using monoclonal anti-peptide 63. Overgaard K, Hansen MA, Jensen SB, Christiansen C 1992 Effects of salmon
antibodies. Clin Chim Acta 174:35–54 calcitonin given intranasally on bone mass and fracture rates in established
38. Guilloteau D, Perdrisot R, Calemettes C, Baulieu JL, Lecomte P, Kaphan G, osteoporosis: a dose response study. BMJ 305:556 –561
Milhaud G, Bernard JC, Jallet P, Bigorgne JC 1990 Diagnosis of medullary 64. Nieves JW, Komar L, Cosman F, Lindsay R 1998 Calcium potentiates the
carcinoma of the thyroid (MCT) by calcitonin assay using monoclonal anti- effect of estrogen and calcitonin on bone mass: review and analysis. Am J Clin
bodies: criteria for the pentagastrin stimulation test in hereditary MCT. J Clin Nutr 67:18 –24
Endocrinol Metab 71:1064 –1067 65. Marcus R, Wong M, Heath III H, Stock JL 2002 Antiresorptive treatment of
39. Seth R, Moote P, Kehely A, Wimalawansa S, Self CH, Bohuon KC, Bettet postmenopausal osteoporosis: comparison of study designs and outcomes in
D, MacIntyre I 1989 The development of a two-site enzyme immunometric large clinical trials with fracture as an endpoint. Endocr Rev 23:16 –37
assay (EIA) for calcitonin and its application in the measurement of the 66. Siris ES 1999 Goals of treatment for Paget’s disease of bone. J Bone Miner Res
hormone in normal subjects, MCT patients and postmenopausal women. 14(Suppl 2):49 –52
Horm Metab Res 21(Suppl):3–5 67. Drake WM, Kendler DL, Brown JP 2001 Consensus statement on the modern
40. Pondel M 2000 Calcitonin and calcitonin receptors: bone and beyond. Int J therapy of Paget’s disease of bone from a Western Osteoporosis Alliance
Exp Pathol 81:405– 422 symposium. Clin Ther 23:620 – 626
41. Hirsch PF, Lester GE, Talmage RV 2001 Calcitonin, an enigmatic hormone: 68. Avioli LV 1998 The role of calcitonin in the prevention of osteoporosis.
does it have a function? J Musculoskelet Neuron Interact 1:299 –305 Endocrinol Metab Clin North Am 27:411– 418
42. Ardaillou R, Vuagnat P, Milhaud G, Richet G 1967 Effects of thyrocalcitonin 69. Body JJ, Mancini L 2003 Treatment of tumor-induced hypercalcemia: a
on the renal excretion of phosphates, calcium and hydrogen ions in man. solved problem? Expert Rev Anticancer Ther 3:241–246
Nephron 4:298 –314 70. Mehta NM, Malootian A, Gilligan JP 2003 Calcitonin for osteoporosis and
43. Jonderko K, Bueno L 1997 Effect of peripherally and centrally administered bone pain. Curr Pharm Des 9:2659 –2676
calcitonin on gallbladder emptying in dogs. Gastroenterology 32:380 –388 71. Roth A, Kolaric K 1986 Analgesic activity of calcitonin in patients with
44. Becker KL 1993 The coming of age of a bronchial epithelial cell. Am Rev painful osteolytic metastases of breast cancer. Results of a controlled ran-
Respir Dis 148:1166 –1168 domized study. Oncology 43:283–287
45. Dubay D, Ephgrave KS, Cullen JJ, Broadhurst KA 2003 Intracerebroven- 72. Martinez MJ, Roque M, Alonso-Coello P, Catala E, Garcia JL, Ferrandiz M
tricular calcitonin prevents stress-induced gastric dysfunction. J Surg Res 2003 Calcitonin for metastatic bone pain.. Cochrane Database Syst Rev
119:188 –192 3:CD003223
46. Hoff AO, Catala-Lehnen P, Thomas PM, Priemel M, Rueger JM, Nasonkin 73. Mehta NM, Gilligan JP, Jones BN, Bertelsen AH, Roos BA, Birnbaum RS
I, Bradley A, Hughes MR, Ordonez N, Cote GJ, Amling M, Gagel RF 2002 1988 Purification of a peptidylglycine ␣-amidating enzyme from transplant-
Increased bone mass is an unexpected phenotype associated with deletion of able rat medullary thyroid carcinomas. Arch Biochem Biophys 261:44 –54
the calcitonin gene. J Clin Invest 110:1849 –1857 74. Kurabuchi S, Tanaka S 2002 Immunocytochemical localization of prohor-
47. Zaidi M, Alam ASMT, Shankar VS, Bax BE, Moonga BS, Bevis PJR, Pa- mone convertases PCI and PC2 in the mouse thyroid gland and respiratory
zianas M, Huang CLHA 1992 quantitative description of components of in tract. J Histochem Cytochem 50:903–909
vitro morphometric change in the rat osteoclast model: relationships with 75. Ghillani PP, Motte P, Troalen F, Jullienne A, Gardet P, Le Chevalier T,
cellular function. Eur Biophys J 21:349 –355 Rougier P, Schlumberger M, Bohuon C, Bellet D 1989 Identification and
48. Zaidi M, Shankar VS, Adebanjo OA, Lai FA, Pazianas M, Sunavala G, measurement of calcitonin precursors in patients with malignant diseases.
Speilman AI, Rifkin BR 1996 Regulation of extracellular calcium sensing in Cancer Res 49:6845– 6851
rat osteoclasts by femtomolar calcitonin concentrations. Am J Physiol 271: 76. Whang KT, Steinwald PM, White JC, Nylén ES, Snider RH, Simon GL 1998
F637–F644 Serum calcitonin precursors in sepsis and systemic infection. J Clin Endo-
49. Farley J, Dimai HP, Stilt-Coffing B, Farley P, Pham T, Mohan S 2000 crinol Metab 83:3296 –3301
Calcitonin increases the concentration of insulin-like growth factors in serum- 77. Conlon JM, Grimelius L, Thim L 1988 Structural characterization of a high-
free cultures of human osteoblast-like cells. Calcif Tissue Int 67:247–254 molecular-mass form of calcitonin [procalcitonin-(60 –116)-peptide] and its
50. Friedman J, Raisz LG 1965 Thyrocalcitonin: inhibitor of bone resorption in corresponding N-terminal flanking peptide [procalcitonin-(1–57)-peptide] in
tissue culture. Science 150:1465–1467 a human medullary thyroid carcinoma. Biochem J 256:245–250
51. Hurley DL, Tiegs RD, Wahner HW, Heath H 1987 Axial and appendicular 78. Roos BA, Huber MB, Birnbaum RS, Aron DC, Lindall AW, Lips K, Baylin
bone mineral density in patients with long-term deficiency or excess of SB 1983 Medullary thyroid carcinomas secrete a noncalcitonin peptide cor-
calcitonin. N Engl J Med 317:537–541 responding to the carboxyl-terminal region of preprocalcitonin. J Clin En-
52. Marx SJ, Woodard CJ, Aurbach GD 1972 Calcitonin receptors of kidney and docrinol Metab 56:802– 807
bone. Science 178:999 –1001 79. Ittner L, Dambacher MA, Born W, Ketelslegers M, Buysschaert M, Albert
53. Goltzman D, Mitchell J 1985 Interaction of calcitonin and calcitonin gene- PM, Lambert AE, Fischer JA 1985 Diagnostic evaluation of measurements of
related peptide at receptor sites in target tissues. Science 227:1343–1345 carboxyl-terminal flanking peptide (PDN-21) of the human calcitonin gene in
54. Nicholson GC, D’Santos CS, Evans T, Moseley JM, Kemp BE, Michelangeli human serum. J Clin Endocrinol Metab 61:1133–1137
VP, Martin TJ 1988 Human placental calcitonin receptors. Biochem J 250: 80. Born W, Beglinger C, Fischer JA 1991 Diagnostic relevance of the amino-
877– 882 terminal cleavage peptide of procalcitonin (PAS-57), calcitonin and calcitonin
1524 J Clin Endocrinol Metab, April 2004, 89(4):1512–1525 Becker et al. • Clincal Review

gene-related peptide in medullary thyroid carcinoma patients. Regul Pept 109. Nishikura T 1999 Procalcitonin (PCT) production in a thyroidectomized
32:311–319 patient. Intensive Care Med 25:1031
81. Bihan H, Becker KL, Snider RH, Nylen E, Vittaz L, Lauret C, Modigliani 110. Wrenger S, Kahne T, Bohuon C, Weglohner W, Ansorge S, Reinhold D 2000
E, Moretti JL, Cohen R 2003 Calcitonin precursor levels in human medullary Amino-terminal truncation of procalcitonin, a marker for systemic bacterial
thyroid carcinoma. Thyroid 13:819 – 822 infections, by dipeptidyl peptidase IV (DP IV). FEBS Lett 466:155–159
82. Morgenthaler NG, Struck J, Fischer-Schultz C, Bergmann A 2002 Sensitive 111. Ittner L, Born W, Rau B, Stembach G, Fischer JA 2002 Circulating procal-
immunoluminometric assay for the detection of procalcitonin. Clin Chem citonin and cleavage products in septicaemia compared with medullary thy-
48:788 –790 roid carcinoma. Eur J Endocrinol 147:727–731
83. Becker KL, Snider RH, Silva OL, Moore CF 1978 Calcitonin heterogeneity 112. Nylén ES, Müller B, Becker KL, Snider RH 2003 The future diagnostic role
in lung cancer and medullary thyroid cancer. Acta Endocrinol 89:89 –99 of procalcitonin levels: the need for improved sensitivity. Clin Infect Dis
84. Becker KL, Silva OL, Snider RH, Moore CF, Geelhoed GW, Mash D, 36:823– 824
O’Neill WJ, Fink RJ, Murphy TM, Klass EM, Rohatge PK 1984 The patho- 113. Becker KL, Snider RH, Moore CF, Monaghan KG, Silva OL 1979 Calcitonin
physiology of pulmonary calcitonin. In: Becker KL, Gazdar AF, eds. The in extrathyroidal tissues of man. Acta Endocrinol 92:746 –751
endocrine lung in health and disease. Philadelphia: WB Saunders Co.; 272–299 114. Russwurm S, Stonans L, Stonane E, Wiederhold M, Luber A, Zipfel PF,
85. Silva OL, Broder LE, Doppman JL, Snider RH, Moore CF, Cohen MH, Deigner H-P, Reinhart K 2001 Procalcitonin and CGRP-1 mRNA expression
Becker KL 1979 Calcitonin as a marker for bronchogenic cancer: a prospective in various human tissues. Shock 16:109 –112

Downloaded from by guest on 15 January 2019

study. Cancer 44:680 – 684 115. Müller B, White JC, Nylén ES, Snider RH, Becker KL, Habener JF 2001
86. Becker KL, Monaghan KG, Silva OL 1980 Immunocytochemical localization Ubiquitous expression of the calcitonin-1 gene in multiple tissues in response
of calcitonin in Kultschitzky cells of human lung. Arch Path Lab Metab to sepsis. J Clin Endocrinol Metab 86:396 – 404
104:196 –198 116. Linscheid P, Seboek D, Nylén ES, Langer I, Schlatter M, Keller U, Becker
87. Becker KL, Gazdar AF 1985 What can the biology of small cell cancer teach KL, Müller B 2003 In vitro and in vivo calcitonin-1 gene expression in pa-
us about the endocrine lung? Biochem Pharmacol 34:155–159 renchymal cells: a novel product of human adipose tissue. Endocrinology
88. Tabassian AR, Nylen ES, Linnoila RI, Cassidy MM, Becker KL 1989 Stim- 144:5578 –5584
ulation of hamster pulmonary neuroendocrine cells and associated peptides 117. Burgess TL, Kelly RB 1987 Constitutive and regulated secretion of proteins.
by repeated exposure to cigarette smoke. Am Rev Respir Dis 140:436 – 440 Annu Rev Cell Biol 3:243–293
89. Kelley MJ, Becker KL, Rushin JM, Venson D, Phelps R, Ihde DC, Bliss Jr 118. Bruemmer-Smith S, Stübber F, Schroeder S 2001 Protective functions of
DP, Melby K, Snider RH, Johnson BE 1994 Calcitonin elevation in small cell intracellular heat-shock protein (HSP) 70-expression in patients with severe
lung cancer without ectopic production. Am J Respir Crit Care Med 149: sepsis. Intensive Care Med 27:1835–1841
183–190 119. Dybdahl B, Wahba A, Lien E, Flo TH, Waage A, Qureshi N, Sellevold OF,
90. Becker KL, Nash D, Silva OL, Snider RH, Moore CF 1981 Increased serum Espevik T, Sundan A 2002 Inflammatory response after open heart surgery:
and urinary calcitonin in pulmonary disease. Chest 79:211–216 release of heat-shock protein 70 and signaling through toll-like receptor-4.
91. Simmons RE, Hjelle JT, Mahoney C, Deftos LJ, Lisker W, Kato P, Rabkin Circulation 105:685– 690
R 1988 Renal metabolism of calcitonin. Am J Physiol 254:F593–F600 120. Xu Q, Schett G, Perschinka H, Mayr M, Egger G, Oberhollenzer F, Willeit
92. Silva OL, Becker KL, Shalhoub RJ, Snider RH, Bivins LE, Moore CF 1977 J, Kiechl S, Wick G 2000 Serum soluble heat shock protein 60 is elevated in
Calcitonin levels in chronic renal disease. Nephron 19:12–18 subjects with atherosclerosis in a general population. Circulation 102:14 –20
93. Lee JC, Parthemore JG, Deftos LJ 1977 Immunochemical heterogeneity of 121. Dana RC, Welch WJ, Deftos LJ 1990 Heat shock proteins bind calcitonin.
Endocrinology 126:672– 674
calcitonin in renal failure. J Clin Endocrinol Metab 45:528 –533
122. Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM 1982 Alternative
94. Bone RC 1995 Sepsis, sepsis syndrome and the systemic inflammatory re-
RNA processing in calcitonin gene expression generates mRNAs encoding
sponse syndrome (SIRS). JAMA 273:155–156
different polypeptide products. Nature 298:240 –244
95. Levy M, Fink P, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal
123. Nelkin BD, Rosenfeld KI, de Bustros A, Leong SS, Roos BA, Baylin SB 1984
SM, Vincent J-L, Ramsay G 2003 For the international sepsis definitions
Structure and expression of a gene encoding human calcitonin and calcitonin
conference. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Def-
gene related peptide. Biochem Biophys Res Commun 123:648 – 655
initions Conference. Crit Care Med 31:1250 –1256
124. Wimalawansa SJ 1997 Amylin, calcitonin gene-related peptide, calcitonin,
96. Ryan CM, Yarmush ML, Burke JF, Tompkins RG 1992 Increased gut per-
and adrenomedullin: a peptide superfamily. Crit Rev Neurobiol 11:167–239
meability early after burns correlates with the extent of burn injury. Crit Care
125. Katafuchi T, Kikumoto K, Hamano K, Kangawa K, Matsuo H, Minamino
Med 20:1508 –1512
N 2003 Calcitonin receptor-stimulating peptide, a new member of the calci-
97. Ammori BJ, Becker KL, Kite P, Snider RH, Nylén ES, White JC, Barclay GR, tonin gene-related peptide family. Its isolation from porcine brain, structure,
Larvin M, McMahon MJ 2003 Calcitonin precursors: early markers of gut tissue distribution, and biological activity. J Biol Chem 278:12046 –12054
barrier dysfunction in patients with acute pancreatitis. Pancreas 27:239 –243 126. Suarez-Domenech VS, Nylén ES, White JC, Snider RH, Becker KL, Land-
98. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky mann R, Müller B 2001 Calcitonin gene-related peptide expression in sepsis:
MR 2001 Epidemiology of severe sepsis in the United States: incidence, postulation of microbial infection-specific response elements within the cal-
outcome, and associated costs of care. Crit Care Med 29:1303–1310 citonin I gene promotor. J Investig Med 49:514 –521
99. Chesney RW, McCarron DM, Haddad JG, Hawker CD, DiBella FP, Joan 127. Steinwald PM, Whang KT, Becker KL, Snider RH, Nylén ES, White JC 1999
Chesney P, David JP 1983 Pathogenic mechanism of the hypocalcemia of the Elevated calcitonin precursor levels are related to mortality in an animal
staphylococcal toxic-shock syndrome. J Lab Clin Med 101:576 –585 model of sepsis. Crit Care 3:11–16
100. Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud J, Bohuon C 1993 128. Whang KT, Vath SD, Becker KL, Snider RH, Nylén ES, Müller B, Li Q,
High serum procalcitonin concentrations in patients with sepsis and infection. Tamarkin L, White JC 2000 Procalcitonin and proinflammatory cytokine
Lancet 341:515–518 interactions in sepsis. Shock 14:73–78
101. Nylén ES, O’Neill W, Jordan MH, Snider Jr RH, Moore CF, Lewis M, Silva 129. Nylén ES, Whang KT, Steinwald PM, Snider RH, White JC, Becker KL 1998
OL, Becker KL 1992 Serum procalcitonin as an index of inhalation injury in Procalcitonin increases mortality and procalcitonin recognizing antiserum
burns. Horm Metab Res 24:439 – 442 improves mortality in an experimental model of sepsis. Crit Care Med 26:
102. Müller B, Becker KL, Schächinger H, Rickenbacher PR, Huber PR, Zim- 1001–1006
merli W, Ritz R 2000 Calcitonin precursors are reliable markers of sepsis in 130. Wagner KE, Vath SD, Snider RH, Nylén ES, Becker KL, Müller B, White
a medical intensive care unit. Crit Care Med 28:977–983 JC 2002 Early immunoneutralization of calcitonin in precursors markedly
103. Davis TME, Assicot M, Bohuon C, St. John A, Li GQ, Anh TK. 1994 Serum attenuates the adverse physiology response to sepsis in pigs. Crit Care Med
procalcitonin concentrations in acute malaria. Trans R Soc Trop Med Hyg 30:2313–2321
88:670 – 671 131. Martinez JM, Wagner KE, Snider RH, Nylén ES, Müller B, Sarani B, Becker
104. Nylén ES, Alarifi A, Snider RH, Becker KL, Alzeer A 1997 The effect of KL, White JC 2001 Late immunoneutralization of procalcitonin arrests in the
classical heat stroke on serum procalcitonin. Crit Care Med 25:1362–1365 progression of lethal porcine sepsis. Surg Infect (Larchmt) 2:193–203
105. Nylén ES, Snider RH, Thompson KA, Rohatge P, Becker KL 1996 Pneu- 132. Becker KL, Bivins LE, Radfar RH, Snider RH, Moore CF, Silva OL 1978
monitis-associated hyperprocalcitonemia. Am J Med Sci 312:12–18 Study of calcitonin heterogeneity using a radioreceptor assay. Horm Metab
106. Wanner GA, Keel M, Steckholzer U, Beier W, Stocker R, Ertel W 2000 Res 10:457– 458
Relationship between procalcitonin plasma levels and severity of injury, 133. Burns DM, Forstrom JM, Friday KE, Howard GA, Roos BA 1989 Procalci-
sepsis, organ failure, and mortality in injured patients. Crit Care Med 28: tonin’s amino-terminal cleavage peptide is a bone-cell mitogen. Proc Natl
950 –957 Acad Sci USA 86:9519 –9523
107. Rau B, Steinbach G, Gansauge F, Mayer JM, Crunert A, Beger HG 1997 The 134. Hassager C, Bonde SK, Anderson MA, Rink H, Spelsberg TC, Riggs BL 1991
potential role of procalcitonin and interleukin in the production of prediction Procalcitonin NH2-terminal cleavage peptide has no mitogenic effect on nor-
of necrosis in acute pancreatitis. Gut 41:832– 840 mal human osteoblast-like cells. J Bone Miner Res 6:489 – 493
108. Molter GP, Soltesz S, Kottke R, Wilhelm W, Biedler A, Silomon M 2003 135. Wright DR, Voelkel EF, Sides KM, Tice JE, Tashjian Jr AH 1977 Hetero-
Procalcitonin plasma concentrations and systemic inflammatory response geneous forms of human calcitonin: direct assessment of biologic activity.
following different types of surgery. Anaesthesist 52:210 –217 Clin Res 25:404A
Becker et al. • Clincal Review J Clin Endocrinol Metab, April 2004, 89(4):1512–1525 1525

136. Horton JE, Oppenheim JJ, Mergenhagen SE, Raisz LG 1974 Macrophage- tonin amplifies inducible nitric oxide synthase gene expression and nitric oxide
lymphocyte synergy in the production of osteoclast activating factor. J Im- production in vascular smooth muscle cells. Crit Care Med 30:2091–2095
munol 113:1278 –1287 161. Müller B, Becker KL, Kränzlin H, Schächinger PR, Huber PR, Nylén ES,
137. Quinn JM, Neale S, Fujikawa Y, McGee JO, Athanasou NA 1998 Human Snider RH, White JC, Schmidt-Gayk H, Zimmerli W, Ritz R 2000 Disor-
osteoclast formation from monocytes, peritoneal macrophages, and bone dered calcium homeostasis of sepsis: association with calcitonin precursors.
marrow cells. Calcif Tissue Int 62:527–531 Eur J Clin Investig 30:823– 831
138. Shui C, Riggs BL, Khosla S 2002 The immunosuppressant rapamycin, alone 162. Lind L, Carlstedt F, Rastad J, Stiernström H, Stridsberg M, Ljunggren Ö,
or with transforming growth factor-␤, enhances osteoclast differentiation of Wide L, Larsson A, Hellman P, Ljunghall S 2000 Hypocalcemia and para-
RAW 264:7 monocyte/macrophage cells in the presence of RAMP-ligand. thyroid hormone secretion in critically ill patients. Crit Care Med 28:93–99
Calcif Tissue Int 71:437– 446 163. Song S-K, Karl IE, Ackerman JJH, Hotchkiss IE 1993 Increased intracellular
139. Miyamoto N, Higuchi Y, Mori K, Ito M, Tsurudome M, Nishio M, Yamada Ca2⫹: a critical link in the pathophysiology of sepsis? Proc Natl Acad Sci USA
H, Sudo A, Kato K, Uchida A, Ito Y 2002 Human osteosarcoma-derived cell 90:3933–3937
lines produce soluble factor(s) that induce differentiation of blood monocytes 164. Zaloga GP, Washburn D, Ward Black K, Prielipp R 1993 Human sepsis
to osteoclast-like cells. Int Immunopharmacol 2:25–38 increases lymphocyte intracellular calcium. Crit Care Med 21:196 –202
140. Horton JE, Raisz LG, Simmons HA, Oppenheim JJ, Mergenhagen SE 1972 165. Carlon GC, Howland WS, Goldiner PL, Kahn RC, Bertoni G, Turnbull AD
Bone resorbing activity in supernatant fluid from cultured peripheral blood 1978 Adverse effects of calcium administration. Arch Surg 113:882– 885

Downloaded from by guest on 15 January 2019

leukocytes. Science 177:793–795 166. Carlon GC, Howland WS, Kahn RC, Schweizer O 1980 Calcium chloride
141. Dominguez JH, Mundy GR 1980 Monocytes mediate osteoclastic bone re- administration in normocalcemic critically ill patients. Crit Care Med 8:209 –212
sorption by prostaglandin production. Calcif Tissue Int 31:29 –34 167. Zaloga GP, Sayer A, Black KW, Prielipp R 1992 Low dose calcium admin-
142. Marx SJ, Aurbach GD, Gavin III JR, Buell DW 1974 Calcitonin receptors on istration increases mortality during septic peritonitis in rats. Circ Shock 37:
cultured human lymphocytes. J Biol Chem 249:6812– 6816 226 –229
143. Body JJ, Gilbert F, Nejai S, Fernandez G, Van Langendonck A 1990 Cal- 168. Teti A, Paniccia R, Goldring SR 1995 Calcitonin increases cytosolic free
citonin receptors on circulating normal human lymphocytes. J Clin Endocri- calcium concentration via capacitative calcium influx. J Biol Chem 270:16666 –
nol Metab 71:675– 681 166670
144. Perry 3rd HM, Kahn AJ, Chappel JC, Kohler G, Teitelbaum SL, Peck WA 169. Gesek FA, Friedman PA 1993 Calcitonin stimulates calcium transport in
1983 Calcitonin response in circulating human lymphocytes. Endocrinology distal convoluted tubules. Am J Physiol 244:F744 –F751
113:1568 –1573 170. Stroop SD, Moore EE 1995 Intracellular calcium increases mediated by a
145. Stock JL, Coderre JA 1982 Calcitonin and parathyroid hormone inhibit ac- recombinant human calcitonin receptor. J Bone Miner Res 10:524 –532
cumulation of cyclic AMP in stimulated human mononuclear cells. Biochem 171. Whang KT, Snider RS, White JC, Becker KL, Steinwald PM, Müller B,
Biophys Res Commun 109:935–942 Nylén ES 1998 Impact of precalcitonin peptides on calcium in experimental
146. Takahashi S, Goldring S, Katz M, Hilsenbeck S, Williams R, Roodman GD sepsis. Program of the 80th Annual Meeting of The Endocrine Society, New
1995 Down-regulation of calcitonin receptor mRNA expression by calcitonin Orleans, LA, 1998, p 241 (Abstract P1–594)
during human osteoclast-like cell differentiation. J Clin Invest 167–171 172. Ichinose M, Sawada M 1996 Enhancement of phagocytosis by calcitonin
gene-related peptide (CGRP) in cultured mouse peritoneal macrophages.
147. MacManus JP, Whitfield JF 1970 Inhibition by thyrocalcitonin of the mito-
Peptides 17:1405
genic actions of parathyroid hormone and cyclic adenosine-3⬘,5⬘-monophos-
173. Clementi G, Caruso A, Cutuli VM 1999 Antiinflammatory activity of ad-
phate on rat thymocytes. Endocrinology 86:934 –939
renomedullin in the acetic acid peritonitis in rats. Life Sci 65:PL203
148. Whitfield JF, MacManus JP, Franks OJ, Braceland BM, Gillan DJ 1972
174. Isumi Y, Kubo A, Katafuchi T, Kangawa K, Minamino N 1999 Ad-
Calcium mediated effects of calcitonin on cyclic AMP formation and lym-
renomedullin suppresses interleukin-1-␤-induced tumor necrosis factor-␣
phoblast proliferation in thymocyte populations exposed to prostaglandin E1.
production in Swiss 3T3 cells. FEBS Lett 463:110 –114
J Cell Physiol 80:315–328
175. Stangl K, Laule M, Richter C, Stangl V, Koch J, Göktas Ö, Baumann G,
149. Sacerdote P, Bianchi M, Panerai AE 1990 Human monocyte chemotactic
Oschietzig T 2001 Pulmonary adrenomedullin counteracts deterioration of
activity of calcitonin and somatostatin-related peptides: modulation by
coronary flow and myocardial performance evoked by pulmonary endothe-
chronic peptide treatment. J Clin Endocrinol Metab 70:141–148 lins in experimental acute respiratory distress syndrome. Crit Care Med
150. Adami S, Suppi R, Residori M, Braga V, Zamboni M, LoCascio V 1988 29:1027–1032
Intramuscular administration of salmon calcitonin impairs delayed cutane- 176. McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, Solari
ous hypersensitivity. Bone Miner 4:91–94 R, Lee MG, Foord SM 1998 RAMPs regulate the transport and ligand spec-
151. Mulder H, van Bolhuis H, Naafs MAB, Winckers PLM 1985 Influence of ificity of the calcitonin-receptor-like receptor. Nature 393:333–339
pharmacological doses of calcitonin on serum ␤2 microglobulin concentra- 177. Christopoulos A, Christopoulos G, Morfis M, Udawela M, Laburthe M,
tion. Calcif Tissue Int 37:367–371 Couvinyau A, Kuwasako K, Tilakorathe N, Sexton PM 2003 Novel receptor
152. Abdullahi SE, Arrigoni E, Martelli A, Bram E, Franco L, Velo GP 1977 Effects partners and function of receptor activity-modifying proteins. J Biol Chem
of calcitonin on different inflammatory models. Agents Actions 7:533–538 278:3293–3297
153. Aida S, Okawa-Takatsuji M, Aotsuka S, Shimoji K, Yokohari R 1994 Cal- 178. Born W, Fischer JA, Muff R 2002 Receptors for calcitonin gene-related pep-
citonin inhibits production of immunoglobulins, rheumatoid factor and tide, adrenomedullin and amylin: the contributions of novel receptor activity-
interleukin-1 by mononuclear cells from patients with rheumatoid arthritis. modifying proteins. Receptors Channels 8:201–209
Ann Rheum Dis 53:247–249 179. Dandona P, Nix D, Wilson M, Aljada A, Love J, Assicot M, Bohuon C 1994
154. Wiedermann FJ, Kaneider NC, Egger P, Tiefenthaler W, Wiedermann CJ, Procalcitonin increase after endotoxin injection in normal subjects. J Clin
Lindner KH, Schobersberger W 2002 Migration of human monocytes in Endocrinol Metab 79:1605–1608
response to procalcitonin. Crit Care Med 30:1112–1117 180. Preas HL, Nylén ES, Snider RH, Becker KL, White JC, Agosit JM, Suffredini
155. Kaneider NC, Egger P, Wiedermann FJ, Ritter M, Wöll E, Wiedermann CJ AF 2001 Effects of antiinflammatory agents on serum levels of calcitonin
2002 Involvement of cyclic adenosine monophosphate-dependent protein precursors during human experimental endotoxemia. J Infect Dis 184:373–376
kinase A and pertussin toxin-sensitive G proteins in the migratory response 181. Suffredini AF, Hochstein HD, McMahon FG 1999 Dose-related related
of human CD14⫹ mononuclear cells to katacalcin. J Bone Miner Res 17:1872– inflammatory effects of intravenous endotoxin in humans: evaluation of a
1882 new clinical lot of Escherichia coli 0:113 endotoxin. J Infect Dis 179:1278 –1282
156. Monneret G, Arpin M, Venet F, Maghni K, Debard AL, Pachot A, Lepape 182. Suffredini AF, O’Grady NP 1999 Pathophysiologic responses to endotoxin
A, Bienvenu J 2003 Calcitonin gene related peptide and N-procalcitonin in humans. In: Braude H, Opal SM, Vogel SN, Morrison DC, eds. Endotoxin
modulate CD11b up-regulation in lipopolysaccharide activated monocytes in health and disease. 1st ed. New York: Marcel Dekker; 817– 830
and neutrophils. Intensive Care Med 29:923–928 183. Nylén ES, Alarifi AA 2001 Humoral markers of severity and prognosis of
157. Müller B, Becker KL, Snider RH, Nylén ES, White JC, Struck J, Procalcitonin critical illness. Best Pract Res Clin Endocrinol Metab 15:553–573
induces the synthesis of inflammatory cytokines by human peripheral blood 184. Alarifi AA, Van Den Berghe GH, Snider RH, Becker KL, Müller B, Nylén
mononuclear cells. Proc Interscience Conference on Antimicrobial Agents ES 2001 Endocrine markers and mediators in critical illness. In: Becker KL,
and Chemotherapy (ICAAC), San Diego, CA, 1999 ed. Principles and practice of endocrinology and metabolism. Philadelphia:
158. Ochoa JB, Udekwu AO, Billiar TR, Curran RO, Cerra FB, Simmons RL, Lippincott, Williams and Wilkins; 2077–2087
Peitzman AB 1991 Nitrogen oxide levels in patients after trauma and during 185. Van Amersfoort ES, Van Berkel TJ, Kuiper J 2003 Receptors, mediators, and
sepsis. Ann Surg 214:612– 626 mechanisms involved in bacterial sepsis and septic shock. Clin Microbiol Rev
159. Kilbourne RG, Traber DL, Szabo C 1997 Nitric oxide and shock. Dis Mon 16:379 – 414
5:277–348 186. Riedemann NC, Guo RF, Ward PA 2003 The enigma of sepsis. J Clin Invest
160. Hoffman G, Czechowski M, Schloesser M, Schobersberger W 2002 Procalci- 112:460 – 467

JCEM is published monthly by The Endocrine Society (, the foremost professional society serving the
endocrine community.