nature publishing group
Response to Zanella
et al.
Luca Elli, MD1 and Erika Poggiali, MD2
doi:10.1038/ajg.2015.201
To the Editor: We thank Zanella et al.,
“About TMPRSS6 rs855791 Polymor-
phism, Iron Metabolism and Celiac Dis-
ease” (1), for their interest in our article
entitled “Does TMPRSS6 RS855791 poly-
morphism contribute to iron deficiency
in treated celiac disease?” (2) and for their
proper comments.
In our study, we investigated patients
affected by celiac disease (CD) with iron
deficiency anemia (IDA) for the presence
of genetic polymorphisms associated with
iron malabsorption (the TMPRSS6 gene
encoding for matripatse-2).
TMPRSS6 polymorphisms have been
associated with variations in iron para-
meters and with increased risk for iron
deficiency (3). Interestingly, TMPRSS6
variants were associated with IDA in
a small series of autoimmune gastritis
patients with polyendocrine autoimmune
syndrome (4), suggesting an interplay
between genetic and acquired factors in
an autoimmune setting. We decided to
investigate the variant rs855791 because
it influences iron homeostasis and eryth-
ropoiesis, being related to significantly
lower levels of serum iron, transferrin
saturation, hemoglobin, and mean corpus-
cular volume in genome-wide association
studies of twins and in the general adult
population (5). We selected only celiac
patients who had been following a gluten-
free diet for at least one year in order to
evaluate the possible correlation between
the persistence of IDA and the rs855791
variant.
The role of hepcidin in inflammatory
anemia is well known in inflammatory
bowel disease as well (6). In our work all
IDA CD patients had undetectable lev-
els of hepcidin. This finding rules out an
inflammatory status in these patients and
confirms the presence of a “true” iron defi-
ciency.
© 2015 by the American College of Gastroenterology
We are aware about the small size of our
cohort and larger and prospective stud-
ies are necessary to clarify the role of the
variant rs855791 in the pathogenesis of
IDA in CD, although to our knowledge
the prevalence of the variant rs855791 in
CD has been reported for the first time
in our study. Moreover, larger studies are
required to optimize the management of
iron therapy in selected patients with per-
sistent IDA despite oral iron supplementa-
tion and a gluten-free diet.
In conclusion, we thank Zanella et al. for
their useful suggestion for further studies
on this issue.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
REFERENCES
Zanella I, Caimi L, Biasiotto G. About TM-
PRSS6 rs855791 polymorphism, iron
metabolism and celiac disease. Am J Gastro-
enterol 2015;110:1240 (this issue).
5. Elli L, Poggiali E, Tomba C et al. Does TM-
PRSS6 RS855791 polymorphism contribute to
iron deficiency in treated celiac disease? Am J
Gastroenterol 2015;110:200–2.
6. McLaren CE, McLachlan S, Garner CP et al.
Associations between single nucleotide
polymorphisms in iron-related genes and iron
status in multiethnic populations. PLoS One
2012;7:e38339.
7. Canavese C, Quaglia M, Izzo C et al. Very
high frequency of TMPRSS6 gene variations
in iron deficiency anaemia of patients with
polyendocrine autoimmune syndromes: more
than a casual association? Br J Haematol
2013;161:147–50.
8. Poggiali E, Andreozzi F, Nava I et al. The role
of TMPRSS6 polymorphisms in iron deficiency
anemia partially responsive to oral iron treat-
ment. Am J Hematol 2015;90:306–9.
9. Arnold J, Sangwaiya A, Bhatkal B et al.
Hepcidin and inflammatory bowel disease: dual
role in host defence and iron homoeostasis.
Eur J Gastroenterol Hepatol 2009;21:425–9.
1
Center for the Prevention and Diagnosis of Celiac
Disease, Gastroenterology and Endoscopy Unit,
Fondazione IRCCS Ca’ Granda Ospedale Maggiore
Policlinico, Department of Pathophysiology and
Transplant, Università degli Studi di Milano,
Milan, Italy; 2Internal Medicine Unit, Fondazione
IRCCS Ca’ Granda Ospedale Maggiore Policlinico,
Department of Clinical Sciences and Community
Health, Università degli Studi di Milano, Milan,
Italy. Correspondence: Luca Elli, MD, Center for
the Prevention and Diagnosis of Celiac Disease,
Gastroenterology and Endoscopy Unit, Fondazione
IRCCS Ca’ Granda Ospedale Maggiore Policlinico,
Department of Pathophysiology and Transplant,
Università degli Studi di Milano, Milan 20122,
Italy. E-mail: lucelli@yahoo.com
Letters to the Editor 1241
Levels of Fecal
Calprotectin and the
Severity of Postoperative
Patients With Crohn’s
Disease
Cong Dai, MD, PhD1, Min Jiang, MD, PhD1
and Ming-Jun Sun, MD, PhD1
doi:10.1038/ajg.2015.174
To the Editor: We read with great interest
the article by Boschetti et al. “Levels of Fecal
Calprotectin Are Associated with the Sever-
ity of Postoperative Endoscopic Recurrence
in Asymptomatic Patients with Crohn’s
Disease” (1) evaluating the relationships
between levels of Fecal calprotectin (fCal)
and the presence and severity of postop-
erative endoscopic recurrence in asymp-
tomatic Crohn’s disease (CD) patients. The
authors found that measurement of fCal
concentrations is a promising and use-
ful tool for monitoring asymptomatic CD
patients after ileocolonic resection. Because
their findings are important to both current
practice and future research, several ques-
tions deserve attention.
It would indeed be attractive for patients
and for economic reasons whether repeti-
tive determination of fCal could help in
decreasing the frequency of ileo-colo-
noscopies being performed for post-
operative activity monitoring. Will the
repetitive determination of fCal alter ther-
apeutic decisions and thereby finally lead
to a reduction of disease-inherent compli-
cations and further surgical procedures?
The inflamed area around the anastomosis
in patients with CD is limited, but will lead
to restenosis over time if not appropriately
treated. It will be of interest whether fCal
has sufficient sensitivity to detect these
lesions and whether they are ultimately
able to replace endoscopy in this case.
At the same time, the specificity of
fCal has been questioned in patients with
CD, and what should be set as the fCal
baseline value is an important issue. In
patients with CD, there will be some degree
of variability based on disease activity. The
The American Journal of GASTROENTEROLOGY
1242 Letters to the Editor
issue of intra-individual variability must be
considered within the context of the popu-
lation measured, and there is variability
of fCal concentrations within the patients
with CD.
In summary, the prospective multicenter
observational cohort results of Boschetti
et al. are encouraging for the use of fCal in
the postoperative surveillance of patients
with CD. And more randomized prospec-
tive trials are needed to evaluate whether
disease activity or the severity of endo-
scopic lesions monitoring by fCal alters the
clinical outcomes (complications, reopera-
tions, and quality of life) in long term.
CONFLICT OF INTEREST
C.D., M.J., and M.-J.S. wrote the paper.
C.D. and M.-J.S. had the original idea for the
paper. All authors reviewed and approved
the final draft of the paper.
REFERENCE
1. Boschetti G, Laidet M, Moussata D et al. Levels
of fecal calprotectin are associated with the sever-
ity of postoperative endoscopic recurrence in
asymptomatic patients with Crohn’s disease. Am J
Gastroenterol 2015;110:1242 (this issue).
1
Department of Gastroenterology, First Affiliated
Hospital, China Medical University, Shenyang,
Liaoning, China. Correspondence: Ming-Jun Sun,
MD, PhD, Department of Gastroenterology, First
Affiliated Hospital, China Medical University,
No. 92, Beier Road, Heping District, Shenyang,
Liaoning 110001, China.
E-mail: 273159833@qq.com
Response to Dai et al.
Gilles Boschetti, MD1, 2, Jocelyne Drai, MD3,
Bernard Flourié, MD, PhD1, 2 and
Stéphane Nancey, MD, PhD1, 2
doi:10.1038/ajg.2015.199
To the Editor: We thank Dai et al. (1) for
their interesting comments and we fully
agree with their comments regarding the
potential impact for current clinical prac-
tice and future research. Our findings
showing a close relationship between fecal
calprotectin and the endoscopic severity
after surgery and identifying the optimal
cutoff for fecal calprotectin as 100 μ g/g for
The American Journal of GASTROENTEROLOGY
distinguishing patients in remission or in
recurrence in the postoperative setting (2)
have been recently confirmed by Wright
et al. (3) in an independent and large cohort
of patients with Crohn’s disease who have
undergone a surgery. Indeed, they reported
the usefulness of fecal calprotectin serial
measurements after intestinal resection to
accurately identify patients in endoscopic
recurrence or in remission. In this cohort,
using a cutoff point for fecal calprotectin
of 100 μ g/g, they found an excellent nega-
tive predictive value (90%), confirming our
results that ileocolonoscopy could have
been avoided in a substantial proportion of
patients with low fecal calprotectin levels
(30–47%). Altogether, these findings chal-
lenge, at least for a subgroup of patients
with Crohn’s disease, the recommenda-
tions to perform systematically an ileoco-
lonoscopy within the year after surgery to
detect preclinical recurrence. Therefore,
monitoring fecal calprotectin could be
an important noninvasive tool to detect
patients at high risk of recurrence.
However, we agree that these two
studies raise many questions, including
the optimal frequency of measurements
of fecal calprotectin within the year after
surgery and whether repeated measure-
ments of this marker help the clinicians
for making decisions and affect the thera-
peutic management of the patients. Our
study was neither designed nor pow-
ered to answer these critical questions
that will require specific investigations.
In addition, cost-effectiveness studies
are warranted as well as specific analysis
investigating the accuracy of fecal cal-
protectin in specific patients with inflam-
mation exclusively located around the
anastomosis and classified as in moder-
ately recurrence (i2), according to the
Rutgeerts index. In our cohort, 14 out of
16 patients classified as Rutgeerts i2 had
fecal calprotectin levels of >100 μ g/g.
Moreover, various factors, including the
conditions of stool collection (systematic
use of a kit), the delay of transportation of
the sample to the laboratory, the assay used,
and the intake of aspirin or nonsteroidal
anti-inflammatory drugs, may potentially
interfere in the results of fecal calprotectin
and should be known by the gastroentero-
logist. Further prospective studies are
nature publishing group
needed to answer these important ques-
tions and to better define the impact of
monitoring fecal calprotectin on disease
outcomes in the postoperative setting.
CONFLICT OF INTEREST
Guarantor of the article: Stéphane Nancey,
MD, PhD.
Specific author contributions: G.B. and
S.N.: drafting of the manuscript; J.D. and
B.F.: critical revision of the manuscript.
Financial support: None.
Potential competing interests: None.
REFERENCES
Dai Cong, Jiang Min, Sun Ming-jun. Levels
of fecal calprotectin and the severity of post-
operative patients with Crohn’s disease. Am J
Gastroenterol 2015;110:1241–2 (this issue).
2. Boschetti G, Laidet M, Moussata D et al. Levels
of fecal calprotectin are associated with the
severity of postoperative endoscopic recurrence
in asymptomatic patients with Crohn’s disease.
Am J Gastroenterol 2015;110:865–72.
3. Wright EK, Kamm MA, De Cruz PP et al. Meas-
urement of fecal calprotectin improves monitoring
and detection of recurrence of Crohn’s disease after
surgery. Gastroenterology 2015;148:938–47.
1
Department of Gastroenterology, Hospices
Civils de Lyon, Hopital Lyon-Sud, Pierre-Bénite,
France; 2INSERM U1111, International Center for
Research in Infectiology, Lyon, France; 3Hospices
Civils de Lyon, Laboratory of Biochemistry, Hopital
Lyon-Sud, Pierre-Bénite, France. Correspondence:
Stéphane Nancey, MD, PhD, Department of
Gastroenterology, Hospices Civils de Lyon,
Hôpital Lyon-Sud, 165 chemin du Grand Revoyet,
Pierre-Bénite 69395, France.
E-mail: stephane.nancey@chu-lyon.fr
The Utility of C-Reactive
Protein, Erythrocyte
Sedimentation Rate,
Fecal Calprotectin and
Fecal Lactoferrin to
Exclude Inflammatory
Bowel Disease in Adults
With IBS
Cong Dai, PhD1, Min Jiang, PhD1 and
Ming-Jun Sun, PhD1
doi:10.1038/ajg.2015.194
VOLUME 110 | AUGUST 2015 www.amjgastro.com