Original Paper

Neonatology 2010;97:299304
DOI: 10.1159/000255161

formerly Biology of the Neonate

Received: October 21, 2008

Accepted after revision: April 14, 2009
Published online: November 4, 2009

High Faecal Calprotectin Levels in

Healthy, Exclusively Breast-Fed Infants
Francesco Savino Emanuele Castagno Roberto Calabrese Serena Viola
Roberto Oggero Roberto Miniero
Department of Paediatrics, Regina Margherita Childrens Hospital, University of Turin, Turin, Italy

Key Words
Calprotectin, faecal Infants Breast-feeding

Abstract
Background: Faecal calprotectin has been proposed as a
sensitive marker for gastrointestinal inflammation in children and adults. High levels have been reported in healthy
newborns and during the first months of life; the effect of
the kind of feeding on the calprotectin concentration in
stools is controversial. Objective: To evaluate faecal calprotectin values in healthy, exclusively breast-fed (BF) or formula-fed (FF) infants. Methods: Stool samples were obtained
from 74 healthy infants (39 exclusively BF and 35 exclusively
FF) with a median age of 51 days (range 1390). Exclusion
criteria were acute infections and treatment with anti-inflammatory drugs. Stool samples were stored at 20 C until
they were analysed, and the faecal calprotectin concentration was detected using a commercial quantitative enzymelinked immunoassay (Calprest; Eurospital SpA, Trieste, Italy).
Results: The median faecal calprotectin concentration was
significantly higher in BF infants (555.00 g/g, range 122.5
2,000.0 g/g) than in FF ones (206.60 g/g, range 31.2797.6
g/g) (p ! 0.001). We observed a significantly higher median
stool frequency in BF infants than in FF ones (p ! 0.001), but
multiple regression analysis (independent variables: kind of
feeding and stool frequency; dependent variable: calprotec-

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tin) showed a significant coefficient for the kind of feeding,

but not for stool frequency (p = 0.937). Conclusions: Our
findings show that the kind of feeding influences the faecal
calprotectin concentration, with higher values in healthy exclusively BF infants than in FF ones. Our study does not allow
us to clearly identify the reason for our finding; this could be
due to hormones (such as ghrelin and leptin), cytokines and
other immunostimulating and growth factors (such as epidermal growth factor and granulocyte colony-stimulating
factor) in human milk, which contribute to the development
of the gastrointestinal immune system. Further investigations are needed to better clarify the mechanism underlying
the relationship between feeding and faecal calprotectin
levels in young infants.
Copyright 2009 S. Karger AG, Basel

Introduction

Calprotectin is a 36.5-kDa heterotrimeric calciumbinding protein belonging to the S-100 protein family. It
is found in cells, tissues and fluids, but it should be considered mainly a myelomonocytic and epithelial protein.
It accounts for about 5% of the total proteins and 60% of
the cytosolic proteins in neutrophil granulocytes [13].
Multiple biological functions of this molecule have been
shown in vitro and in vivo, though its exact biological
Dr. Francesco Savino
Dipartimento di Scienze Pediatriche e dellAdolescenza
Ospedale Infantile Regina Margherita, Piazza Polonia 94
IT10126 Turin (Italy)
Tel. +39 011 313 5257, Fax +39 011 313 5108, E-Mail francesco.savino @ unito.it

role is not known. Calprotectin has been shown to be involved in the modulation of inflammatory processes and
in the regulation of apoptosis, and it has a strong antimicrobial activity, demonstrated in many studies in vitro
[4]. Several observations have suggested that it may play
a central role in cellular life and in the modulation of the
immune system; in fact, it is involved in intracellular signal transduction and is of vital importance for neutrophil
defence, through its action in stimulating immunoglobulin production and regulating inflammatory reactions
and its chemotactic activity [3]. The capacity to bind calcium and zinc has been reported to be crucial for its biological activity [4]. Moreover, calcium makes calprotectin
remarkably resistant to heat and proteolysis and stable in
stools for 7 days at room temperature (20 C) [3]. These
features make faecal calprotectin a reliable, non-invasive
marker of gut inflammation and permeability, as it has
an excellent correlation with granulocyte migration
through the gut wall [5]. It is related to the severity of colonic inflammation in children with inflammatory bowel disease and has been proposed both for the differential
diagnosis of functional and organic intestinal disorders
and for the follow-up of inflammatory bowel disease
[68].
Many authors have observed high faecal calprotectin
concentrations in healthy newborns and infants in the
first year of life, whereafter it decreases progressively to
the levels seen in adults [911]. High values have also been
observed in meconium [12]. This could be due to the
greater permeability of the gut wall in the first period of
life; the significant reduction in calprotectin during the
first months of life could indicate maturation of the intestinal mucosa [11]. In addition, feeding and intestinal
colonization induce consistent intestinal mucosa modifications [13], with leucocyte migration through the gut
wall.
To our knowledge, there are only a few studies investigating the influence of the kind of feeding on faecal calprotectin values in the first period of life, with contradictory findings. On the one hand, Campeotto et al. [10] observed no significant difference in faecal calprotectin
concentrations between breast-fed (BF) and formula-fed
(FF) newborns aged 37 days, while previously Bunn et al.
[14] demonstrated lower levels in BF infants than in FF
ones. Recently, Dorosko et al. [15] found higher calprotectin levels in healthy, exclusively BF infants aged 06
months compared to mixed-fed infants, but they showed
no data regarding exclusively FF infants. The aim of our
study was to evaluate faecal calprotectin values in healthy,
exclusively BF and FF infants in the first 3 months of life.
300

Neonatology 2010;97:299304

Patients and Methods

This study was performed at the Department of Paediatrics of
the Regina Margherita Childrens Hospital (Turin, Italy). The parents of infants seen consecutively between September 2007 and
May 2008 for routine outpatient controls were informed about the
study by a paediatrician and were recruited to the study. Inclusion
criteria were: infant age 3 months or less; gestational age between
37 and 41 weeks; birth weight appropriate for gestational age
(2,5004,000 g), and exclusive breast-feeding or formula-feeding.
The exclusively BF infants had to have received only their mothers milk from birth until the time of recruitment. Formula-feeding was chosen by mothers who decided not to breast-feed or
when their own milk was unavailable at birth. FF infants received
a standard starting formula for healthy term infants according to
the recommendations of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [16] and the European
Commission [Commission Directive on Infant Formulae and
Follow-On Formulae (91/321/EC) O.J. L175/35, 1991]. Exclusion
criteria were: any intake of steroidal or non-steroidal anti-inflammatory drugs, antibiotics or any other drug during the 2 weeks
before recruitment; mixed breast-feeding and formula-feeding;
intake of any kind of formula other than standard starting formula, such as those with added probiotics, prebiotics, long-chain
polyunsaturated fatty acids, thickening agents and/or hydrolysed
proteins, and any sign or symptom of infection or gastrointestinal
disease (diarrhoea, vomiting, fever, failure to thrive). Infantile
colic (defined as excessive crying in an otherwise healthy, thriving infant with normal weight gain) was not considered among
the exclusion criteria, as no difference has been observed between
colicky infants and healthy ones with regard to faecal calprotectin
values [11].
Seventy-four healthy infants (38 males and 36 females) who
fulfilled the inclusion criteria were enrolled. All the infants were
aged 90 days or less (median age 51 days, range 1390 days), were
born at term with a median gestational age of 39 weeks (range
3741) and had a mean birth weight of 3,202.6 8 407.6 g. At enrollment, the infants were visited by a paediatrician and assigned
to 1 of 2 groups: exclusively BF infants (n = 39) and exclusively FF
infants (n = 35; fed with a standard starting formula). Information
obtained at enrollment included data regarding the pregnancy,
delivery mode, birth weight, frequency and quantity of feeding,
stool frequency, drug consumption by mothers or their infants,
and family history of atopy and gastrointestinal disorders. A detailed questionnaire was filled out, and its content was known
only to the paediatrician who collected the information. All the
parents of FF infants were clearly asked which formula their babies received; only subjects receiving a standard starting formula
according to the cited criteria were enrolled in the study. Written
informed consent was obtained from the parents to collect a stool
sample from their infants. About 15 g of faeces were collected at
recruitment from each subject directly from the nappy by the
same paediatrician who enrolled them. Each sample was stored at
room temperature in a numbered, screw-capped plastic container
until it was brought to the laboratory of our hospital, where it was
frozen at 20 C. Which sample numbers corresponded to which
infants was known only to the paediatrician who collected the
stools; that is, the laboratory test was performed in a blinded fashion. Time from sampling to freezing was within 2 days in the great
majority of cases; no sample was frozen later than the time pre-

Savino/Castagno/Calabrese/Viola/
Oggero/Miniero

Table 1. Characteristics of the study population

Age, days
Birth weight, g
Weight at enrollment, g
Gestational age, weeks
Males/females

BF infants (n = 39)

FF infants (n = 35)

p value

45.0 (13.090.0)
3,230.88390.8
4,554.981,093.4
39.0 (37.041.0)
19/20

50.0 (23.090.0)
3,171.18429.1
4,816.98940.3
39.0 (37.041.0)
19/16

0.341a
0.534b
0.275b
0.401a
0.650c

Values are medians (range) or means 8 SD, unless otherwise indicated.

a
Mann-Whitney U test. b Students t test. c Fishers test.

Results

According to the Shapiro-Wilk test, faecal calprotectin concentration and age had a non-parametric distribution in the study population. BF and FF infants showed
no difference with regard to median age (45.0 vs. 50.0
Faecal Calprotectin Levels and Breast
Feeding

2,000

Calprotectin (g/g)

scribed by the assay manufacturer and reported in the literature

[3, 17]. Before analysis, frozen stool samples were thawed at room
temperature, and 40120 mg of faeces were taken from each sample. An extraction buffer containing urea, citrate and distilled
water was added in a weight per volume ratio of 1:50. The samples
were mixed for 30 s and homogenized for 25 min. Then, 1 ml of
the homogenate was transferred to an Eppendorf tube and centrifuged for 20 min at room temperature. Finally, the supernatant
was collected and the calprotectin concentration was determined
immediately with a commercial enzyme-linked immunosorbent
assay (Calprest; Eurospital SpA, Trieste, Italy). Calprotectin levels
were expressed as micrograms per gram of faeces.
The study protocol was approved by the ethical committee of
our institution.
The sample size was calculated for a difference in faecal calprotectin values between groups of 100 g/g. With = 0.05, =
0.20 and an estimated standard deviation within groups of 140
g/g, 33 patients were needed in each group.
The distribution of all continuous variables was assessed by
the Shapiro-Wilk test and by graphical analysis. Students t test or
the Mann-Whitney U test was used for comparison between
groups. Associations between categorical variables were assessed
by Fishers exact test.
The relationship between continuous variables was assessed
by Pearsons correlation coefficient. A multiple regression model
was performed to evaluate the effect of the kind of feeding and
stool frequency on faecal calprotectin values. Calprotectin concentration and stool frequency were entered into the model as log
values. All the tests were two-tailed, and statistical significance
was set at p ! 0.05.
Statistical analysis was performed using the SPSS software
package for Windows (release 15.0, 2006, SPSS Inc., Chicago, Ill.,
USA). Power analysis was performed using NCSS/PASS [18].

1,500
1,000
500
0
BF

FF
Kind of feeding

Fig. 1. Faecal calprotectin values (g/g) in healthy BF and FF in-

fants (p ! 0.001). The box plot shows the median (bold line), the
first quartile (lower border of the box) and the third quartile (upper border of the box); the whiskers indicate 1.5 times the interquartile range above and below the 75th and 25th percentiles. The
circles indicate the outliers.

days; p = 0.341), mean birth weight (3,230.8 8 390.8 vs.

3,171.1 8 429.1 g; p = 0.534), mean weight at enrollment
(4,554.9 8 1,093.4 vs. 4,816.9 8 940.3 g; p = 0.275) or
median gestational age (both 39 weeks; p = 0.401). The 2
groups did not differ with regard to family history of atopy and gastrointestinal disorders. The characteristics of
the 2 groups are shown in table 1.
The median faecal calprotectin concentration was significantly higher in BF infants (555.00 g/g, range
122.502,000.00 g/g) than in FF ones (206.60 g/g,
range 31.20797.60) (p ! 0.001; fig. 1).
Two outliers were observed among exclusively BF infants. The first one (faecal calprotectin concentration
2,000.00 g/g) was a 58-day-old female born at term (gestational age 39 weeks; birth weight 4,000 g) with infantile
colic and no family history of atopy or gut disorders; no
Neonatology 2010;97:299304

301

significant signs or symptoms of gastrointestinal disease

or food allergy were observed at the time of faeces collection, nor under our observation during the next months,
and the infantile colic resolved by the third month of age;
there was no blood in the stool either on macroscopic or
laboratory examination. The second outlier (faecal calprotectin concentration 1,551.90 g/g) was a 59-day-old
female born at term (gestational age 39 weeks; birth
weight 3,070 g) with no significant signs or symptoms,
but moderate regurgitation, and no family history of atopy or gut disorders.
We observed a positive correlation between calprotectin (log values) and stool frequency (log values; times/
day) (r = 0.236, p = 0.043) and a significantly higher median stool frequency in BF infants than in FF ones (2.5,
range 0.85.8 vs. 1.4, range 0.54.1; p ! 0.001). We performed a multiple regression analysis using the kind of
feeding and stool frequency (log values) as independent
variables and calprotectin (log value) as the dependent
variable. The model showed a significant coefficient for
the kind of feeding, but not for stool frequency [kind of
feeding (FF): b = 0.721, SE(b) = 0.200, 95% confidence
interval = 1.119 to 0.323, p = 0.001; stool frequency:
b = 0.013, SE(b) = 0.162, 95% confidence interval = 0.311
to 0.337, p = 0.937; adjusted R 2 = 0.19].

Discussion

In our study, we observed higher faecal calprotectin

levels in healthy, term, exclusively BF infants than in FF
ones in the first 3 months of life. In a previous study, Dorosko et al. [15] observed higher faecal calprotectin concentrations in BF infants compared to mixed-fed ones
aged 06 months.
Though it is well known that the faecal calprotectin
concentration is higher in young infants than in healthy
adults and shows wide interindividual and age-dependent variation, interestingly, we found a higher median
concentration in our infants than that reported by other
authors [811]. However, it is difficult to directly compare
our findings to those from previous studies, as infants of
different ages were recruited. Campeotto et al. [10] investigated newborns (37 days old), Bunn et al. [14] talks
about infants observed generally in the pre-weaning period and, finally, Dorosko et al. [15] monitored a wider
range of ages, which could have affected and perhaps reduced the median calprotectin concentration in comparison to our data. Moreover, the factors influencing calprotectin values in stools are not yet fully understood.
302

Neonatology 2010;97:299304

Sampling the stool directly from the nappy could increase

calprotectin levels because water is absorbed into the diaper, but there was no difference in the time of collection
between the 2 groups in our study and the methodology
was not different from that reported in similar studies.
Lastly, and unfortunately, there is a lack of detailed information about the infants background and the composition of the formulas used in previous studies, so it is difficult to determine whether these factors could have influenced the discrepancy between our findings and the
results of other authors.
High calprotectin concentrations in stools reflect an
increase in granulocytes in the gut lumen; this could be
due to the greater intestinal permeability of newborns and
young infants [19, 20] and also to increased leucocyte migration through the gut mucosa, as part of the development of the gut-associated lymphoid tissue (GALT), which
is particular to this period of life. Many environmental
factors may be involved in this process and both the kind
of feeding and the intestinal colonization play a key role,
as shown by Helm et al. [21] in neonatal piglets.
Gut maturation during the first weeks of life includes
the development of a mucosal barrier against antigens
and bacterial colonization, so that the absorption and
transport of nutrients are allowed, while pathogens and
foreign proteins are kept away [13]. Further, soon after
birth, the gastrointestinal tract becomes rapidly colonized by micro-organisms associated with the delivery
environment, after which the kind of feeding strongly influences the growth of different bacterial species. Breastfeeding is a significant source of Bifidobacteria and Lactobacilli, while FF infants have a higher count of anaerobic bacteria, such as Clostridium and Bacteroides [22].
The microbiota stimulates the normal development of
GALT, the synthesis and secretion of IgA and a balanced
T helper cell response. In this way, it represents the major
external driving force in the maturation of the immune
system after birth. Moreover, human milk itself modulates the development of the immune system through the
cytokines, hormones and other immunostimulating and
growth modulators it contains (such as ghrelin, leptin,
insulin-like growth factors, epidermal growth factor, and
granulocyte colony-stimulating factor) [13, 21, 2326].
On the other hand, it is not known how formula-feeding
influences the maturation of GALT and systemic immunity after birth [21]. All these factors make breast-feeding
the major preventive means of enhancing health and reducing mortality in the first period of life [24].
The low calprotectin values observed in human milk
[11] do not contribute significantly to the high calprotecSavino/Castagno/Calabrese/Viola/
Oggero/Miniero

tin concentration in BF stools. On the other hand, higher

faecal calprotectin values in exclusively BF infants than
in FF ones could be consistent with the promotion by human milk of the growth of the intestinal mucosa, even
though breast milk has been shown to promote the reduction of intestinal permeability more than cow milkbased formulas [13]. Calprotectin is able to induce proinflammatory chemokines and adhesion molecules and
to modulate transendothelial migration of leukocytes by
interaction with different receptors [27]. Moreover, we
can hypothesize that it could provide a protective effect
on the gut mucosa through its bactericidal and fungicidal properties [4] and contribute to modulation of the intestinal microflora by breast-feeding.
We could speculate that the calprotectin concentration in young infants stools might reflect the stronger
weight of the mild physiological intestinal inflammation
observed in the GALT development on a balance with the
reduction of intestinal permeability. The latter could be
better expressed by the reduction of faecal calprotectin
concentration during the first months of life. Though Josefsson et al. [28] report the value of 2,000.00 g/g as a
cutoff for abdominal disease in a population of very low
birth weight infants, we cannot support this finding with
our results in young term infants.

As concerns stool frequency, we found a positive correlation with faecal calprotectin concentration; nevertheless, a multiple regression analysis showed that this factor
does not influence calprotectin values.
In conclusion, our results show that healthy infants
have higher faecal calprotectin values than healthy adults
and show wide interindividual variation. BF infants have
higher concentrations than FF ones in the first 3 months
of life, and this could represent the influence of the immunomodulating factors in human milk on the gut.
Our finding indicates the need for better assessment
of faecal calprotectin as a biological marker of intestinal
inflammation in the first months of life. We hope that
further studies might provide new evidence about the
mechanisms underlying the relationship between breastfeeding and faecal calprotectin values in young infants.

Acknowledgement
This study was supported by a research grant from the Ministero dellUniversit e della Ricerca Scientifica e Tecnologica and
the University of Turin (2005).

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