Journal of Pediatric Gastroenterology and Nutrition
42:117–120 Ó January 2006 Lippincott Williams & Wilkins, Philadelphia
Letters to the Editor
Re: Fecal Elastase: Pancreatic Status
Verification and Influence on Nutritional
Status in Children with Cystic Fibrosis.
Cohen, et al. J Pediatr Gastroenterol Nutr
2005;40:438–44
To the Editor: In the April issue of the journal, Cohen et al.
(1) aimed to assess fecal elastase-1 (FE) levels in young
children with cystic fibrosis (CF) and pancreatic insufficiency
(PI) and to explore the relationship between FE values and
growth, nutrition, pulmonary status, and fat absorption over
a 24 month period. The authors concluded that a substantial
number of children with CF have a misclassified pancreatic
status. Children with detectable FE concentrations had greater
fat absorption, improved growth, and nutritional status over
24 months when compared with those with undetectable FE
levels. The reported observation that residual pancreatic exo-
crine secretion as documented by detectable FE activity has
a beneficial effect for CF patients and has important clinical
significance.
With respect to fat absorption, growth, nutritional, and skel-
etal maturity status, Cohen et al. (1), as expected, documented
that the clinical course is more favorable in children with higher
FE levels. The authors attributed better clinical status to lower
fecal fat losses not to the difference in energy intake that was
no-significantly higher in patients with residual FE concen-
trations. Fecal fat losses as assessed by coefficient of fat ab-
sorption were higher in patients with undetectable FE.
Surprisingly, this finding was not confirmed by bomb calorim-
etry, which indicates there is no real difference between the two
groups. The authors underlined that enzyme replacement
therapy, although undoubtedly essential for those with severe
steatorrhea, may have potential clinical and psychosocial
adverse effects. These include the assumption that poor growth
and nutritional status is a result of inadequate treatment of PI
with the resultant possibility that other causes of nutritional
failure may then be missed. On the basis of these results, a very
important question has been raised regarding whether the
patients with residual pancreatic secretion should be treated
with pancreatic enzymes. This question will only be reliably
answered by further studies. These will need to focus on those
patients with residual pancreatic function but with mild steat-
orrhea or reduced levels of FE (,200 mg/g stool). Patients with
mild steatorrhea are currently treated on the basis of clinical
experience, whereas those with FE greater than 200 mg/g stool
are unlikely to benefit from pancreatic enzyme therapy.
Cohen et al. (1) also documented that 12% of preadolescent
children who were diagnosed with PI and prescribed pancreatic
enzymes were possibly misdiagnosed. A similar observation
was also recently documented in a larger American multicenter
study (2). The authors proved that a considerable percentage
of both PI and pancreatic sufficient (PS) CF patients was
117
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
misclassified. As in most of the centers participating in the
Borowitz multicenter U.S. study, pancreatic function tests are
seldom routinely performed in CF patients. The reliable
determination of pancreatic status should be obligatory in all
CF patients, and the FE test is a very useful predictor of
pancreatic exocrine function (3,4). The measurement of FE
concentration could serve as a screening test for maldigestion in
CF (5), and, in addition, the test could be used for the longi-
tudinal assessment of declining exocrine pancreatic function in
PS patients (6).
Beharry et al. (5) documented a high predictive value (99%)
for ruling out PI in CF patients using a cutoff level of 100 mg/g
of stool for FE measurement. In all but one Polish PI CF patient
ever tested, FE concentrations lower than 200 mg/g have been
found (7,8). The use by Cohen et al. (1) of stool trypsin
concentrations lower than 80 mg/g of feces (in place of 72 hour
fecal fat balance studies) to classify some patients as PI may
have partly contributed to the high percentage of patients with
detectable FE concentrations found in this group. On the other
hand, as documented by Cohen et al., some of those patients
with FE concentrations greater than 15 mg/g of feces, even
when receiving pancreatic enzyme supplementation during the
study, fulfill the criteria for PI.
Jaroslaw Walkowiak
Aleksandra Lisowska
I Chair of Pediatrics
Department of Gastroenterology and Metabolism
Poznan University of Medical Sciences
Poznan, Poland
REFERENCES
1. Cohen JR, Schall JI, Ittenbach RF, et al. Fecal elastase: pancreatic
status verification and influence on nutritional status in children with
cystic fibrosis. J Pediatr Gastroenterol Nutr 2005;40:438–44.
2. Borowitz D, Baker SS, Duffy L, et al. Use of fecal elastase-1 to
classify pancreatic status in patients with cystic fibrosis. J Pediatr
2004;144:322–6.
3. Walkowiak J. Assessment of maldigestion in cystic fibrosis. J Pediatr
2004;145:285–7.
4. Walkowiak J, Nousia-Arvanitakis S, Henker J, et al. The use of
indirect pancreatic function tests in children. J Pediatr Gastroenterol
Nutr 2005;40:107–14.
5. Beharry S, Ellis L, Corey M, et al. How useful is fecal pancreatic
elastase 1 as a marker of exocrine pancreatic disease? J Pediatr 2002;
141:84–90.
6. Walkowiak J, Nousia-Arvanitakis S, Agguridaki C, et al. Longitu-
dinal follow-up of exocrine pancreatic function in pancreatic
sufficient cystic fibrosis patients with the use of fecal elastase-1 test.
J Pediatr Gastroenterol Nutr 2003;36:474–8.
7. Walkowiak J. Fecal elastase-1 test: clinical value in the assessment of
exocrine pancreatic function in children. Eur J Pediatr 2000;159:
869–70.
8. Walkowiak J, Nousia-Arvanitakis S, Cade A, et al. Fecal elastase-1
cut-off levels in the assessment of exocrine pancreatic function.
J Cystic Fibrosis 2002;1:260–4.
118 LETTERS TO THE EDITOR
Authors’ Response to Letter
Authors’ reponse: We appreciate the review and comments
from Walkowiak and Lisowska regarding our article, ‘‘Fecal
Elastase: Pancreatic Status Verification and Influence on
Nutritional Status in Children with Cystic Fibrosis’’ (1). There
have been a number of important additions to the literature
regarding fecal elastase assessment and in the diagnosis of
pancreatic insufficiency since the publication of our work (2–5).
These new studies have added to the European and American
experience with fecal elastase assessment in clinical care.
We agree that the patients with cystic fibrosis and fecal
elastase levels in the more uncertain range, 15 to 200 ug/g of
stool, should receive a careful clinical evaluation, pancreatic
status diagnosis, and optimal long-term care plan. Gaining a
better understanding of the natural history of this group of
patients will require further study.
Virginia A. Stallings
Division of Gastroenterology and Nutrition
The Children’s Hospital of Philadelphia
Department of Pediatrics
University of Pennsylvania
School of Medicine
Philadelphia, PA
Joan I. Schall
Division of Gastroenterology and Nutrition
The Children’s Hospital of Philadelphia
Philadelphia, PA
REFERENCES
1. Cohen JR, Schall JI, Ittenbach RF, Zernel BS, Scanlin TF, Stallings
VA. Pancreatic status verification in children with cystic fibrosis:
fecal elastase status predicts prospective changes in nutrition status. J
Pediatr Gastroenterol Nutr 2005;40:438–44.
2. Schall JI, Ittenbach RF, Zemel BS, Scanlin TF, Stallings VA.
Pancreatic status verification in children with cystic fibrosis: fecal
elastase status predicts prospective changes in nutritional status.
J Pediatr Gastroenterol Nutr 2005;40:438–44.
3. Borowitz D, Baker SS, Duffy L, et al. Use of fecal elastase-1 to
classify pancreatic status in patients with cystic fibrosis. J Pediatr
2004;145:322–6.
4. Walkowiak J. Assessment of maldigestion in cystic fibrosis. J Pediatr
2004;145:285–7.
5. Walkowiak J, Nousia-Arvanitakis S, Henker J, Stern M, Sinaasappel
M, Dodge JA. Indirect pancreatic function tests in children. J Pediatr
Gastroenterol Nutr 2005;40:107–14.
Will Hyperbilirubinemic Neonates Ever
Benefit from Oral Zinc Salt?
To the Editor: Neonatal hyperbilirubin is attracting in-
creasing attention (1). In a recent issue of JPGN, Vitek et al. (2)
addressed the issue of the effect of zinc salt on serum bilirubin
levels in hyperbilirubinemic rats. They showed that adminis-
tration of oral zinc salts for two weeks decreased serum
bilirubin levels in hyperbilirubinemic rats, presumably by in-
hibiting the enterohepatic circulation of bilirubin. They
J Pediatr Gastroenterol Nutr, Vol. 42, No. 1, January 2006
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
conclude that administration of zinc salts might be useful in
the treatment of severe unconjugated hyperbilirubinemias also
in neonates. We feel this conclusion is not warranted, and risks
disappointing health giversÕ expectations. Indeed, oral therapy
with zinc salt for the treatment of neonatal jaundice is far from
being applicable in clinical practice for several reasons. Firstly,
the most dangerous effect of neonatal hyperbilirubinemia oc-
curs too early for the oral zinc to be efficacious (within the first
five or six days of life with a peak in the third day (3)). Ac-
cording to Vitek et al., the therapeutic effect occurs after two
weeks—at which point, the infant would have already left the
hospital. Secondly, the metabolism of zinc is in a very steady
balance with that of copper, and any uncontrolled oral sup-
plementation of zinc salts may alter the absorption of trace
elements by the newborn. Thirdly, the human neonatal gut may
not absorb zinc as efficiently as rat gut. A study of preterm
neonates showed that doubling the zinc intake does not in-
fluence serum zinc concentration (4). Consequently, the use of
zinc supplementation for the prevention of neonatal jaundice
remains, at best, speculative.
Finally, we recently showed that neonates with unconjugated
jaundice have altered intestinal permeability with a positive sig-
nificant correlation with serum bilirubin (5). This is secondary
to a decrease in mannitole absorption, which is suggestive of
impaired intestinal epithelial surface. In such cases of altered
intestinal absorptive condition, oral supplementation, of any
type, is unlikely to have a therapeutic effect.
None of the in vitro studies aimed at identifying alternative
therapeutic approaches for the prevention or treatment of neo-
natal hyperbilirubin, has been confirmed in clinical trials.
Currently guidelines treatment for neonatal jaundice (1,3)
make difficult.
In conclusion, we suggest caution be exercised as to
the efficacy of zinc salt supplementation for the treatment of
jaundice in the newborns. However, we feel that other
types of unconjugated jaundice (such as Gilbert syndrome
and Crigler Naijar syndrome) may be more responsive to
zinc supplementation, particularly in preventing gallstone
formation.
Flavia Indrio, MD
Maria Elisabetta Baldassarre, MD
Ruggiero Francavilla, MD, PhD
Department of Pediatrics, Neonatology Section
University of Bari
Bari, Italy
REFERENCES
1. Ip S, Chung M, Kulig J, et al. Subcommittee on Hyper-
bilirubinemia An Evidence-Based Review of Important Issues
Concerning Neonatal Hyperbilirubinemia. Pediatrics 2004;114:
e130–53.
2. Vitek L, Muchova L, Zelenka J, Zadinova M, Malina J. The effect of
zinc salt on serum bilirubin levels in hyperbilirubinemic rats. J Pediatr
Gastroenterol Nutr 2005;40:135–40.
3. Ip S, Lau J, Chung M, et al. Hyperbilirubinemia and Kernicterus:
50 Years Later. Pediatrics 2004;114:263–264.
4. Loui A, Raab A, Wagner M, et al. Nutrition of very low birth weigth
infants fed human milk with or without supplemental trace elements:
a randomized controlled trial. J Pediatr Gastroenterol Nutr 2004;39:
346–53.
 LETTERS TO THE EDITOR
5. Indrio F, Baldassarre ME, Francavilla R, et al. Intestinal permeability
in healthy term newborns with physiologic jaundice. Pediatr Res
2005 (PAS abstract) in press.
Author’s Response to Letter
Reply: I would like to thank Drs. Indrio, Baldassarre, and
Francavilla for their interest in our study. In particular, I am
glad to have further opportunity to discuss therapeutic potential
of inhibition of enterohepatic circulation (EHC) of bilirubin for
treatment of unconjugated hyperbilirubinemias. We agree that
our suggestions about therapeutic potential of zinc salts are
based on scarce data (two in vivo/in vitro studies (1,2) and one
human study (3)). On the other hand, it is not true that the
therapeutic effect of zinc salts can be achieved only after two
weeks. We, indeed, demonstrated that in Gunn rats the
hypobilirubinemic effect occurred after two weeks of oral zinc
salt administration, but earlier changes of serum bilirubin were
not measured. However, when we used more appropriate
animal model represented by hyperbilirubinemic Wistar rats
(in which, in contrast to Gunn rats, bilirubin disposition is
independent of bilirubin present within the intestinal lumen),
we were able to measure significant changes of both serum
bilirubin levels and biliary secretion of bilirubin after seven
days (1). Moreover, it is likely that decrease in serum bilirubin
in response to the inhibition of EHC of bilirubin starts much
earlier. Unfortunately, our study was not designed to uncover
these kinetic characteristics.
The second and third points raised by Indrio et al. are based
on misunderstanding of the mechanism by which oral zinc salts
decrease serum bilirubin levels. Therapeutic effect of zinc
salts occurs within the intestinal lumen when absorption of
zinc is not desirable. Experience from Wilson’s disease patients
treated with zinc sulphate does not suggest there should be
serious apprehensions about toxic effects of administered
zinc (4). Nevertheless, we proposed that use of water insol-
uble, i.e. nonabsorbable, zinc salts would be preferable to
treat unconjugated hyperbilirubinemias. This mechanism, i.e.
inhibition of EHC of bilirubin within the intestinal lumen,
suggests that neonates with altered intestinal absorption might
profit from oral zinc salts treatment as well.
We fully agree that these experimental approaches cannot
be adopted into current guidelines for treatment of neonatal
jaundice. Only further human studies will determine whether
hyperbilirubinemic newborn infants may benefit from oral zinc
salts treatment.
Libor Vı́tek, MD, PhD
4th Department of Internal Medicine and
Institute of Clinical Biochemistry
1st Medical Faculty
Charles University of Prague Prague
Czech Republic
REFERENCES
1. Vı́tek L, Muchová L, Zelenka J, Zadinová M, Malina J. The effect
of zinc salts on serum bilirubin levels in hyperbilirubinemic rats.
J Ped Gastroent Nutr 2005;40:135–40.
2. Mendez-Sanchez N, Roldan-Valadez E, Flores MA, Cardenas-
Vazquez R, Uribe M. Zinc salts precipitate unconjugated bilirubin
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
119
in vitro and inhibit enterohepatic cycling of bilirubin in hamsters.
Eur J Clin Invest 2001;31:773–80.
3. Méndez-Sánchez N, Martı́nez M, González V, Roldán-Valadez E,
Flores MA, Uribe M. Zn sulphate inhibits the enterohepatic cycling
of unconjugated bilirubin in subjects with Gilbert’s syndrome. Ann
Hepatol 2002;1:40–3.
4. Czlonkowska A, Gajda J, Rodo M. Effects of long-term treatment in
Wilson’s disease with D-penicillamine and zinc sulphate. J Neurol
1996;243:269–73.
Re: Chronic Abdominal Pain in Children:
Clinical Report. Di Lorenzo et al. J Pediatr
Gastroenterol Nutr 2005;40:245–8
To the Editor: I read with interest the succinct clinical report
by Di Lorenzo et al. regarding recurrent abdominal pain. A
small number of patients with chronic and at times vague his-
tory of abdominal pain may have significant surgical pathology;
however, it is quite difficult to identify those in need of further
investigations to rule out a surgical cause.
Recently, we have encountered two patients with history of
recurrent abdominal pain, failure to thrive, and constipation
who eventually were diagnosed to have intestinal malrotation
necessitating surgery. Also, Uba et al. (1) have presented their
experience of malrotation in older children. Their review con-
sisted of nine patients (between 1992 and 2002, 1 patient per
year), all of whom had recurrent abdominal pain, eight of nine
who had vomiting, five of nine who also suffered from con-
stipation, and four of nine who failed to thrive.
Thus, those patients with recurrent pain, vomiting, con-
stipation, and failure to thrive in the absence of a nonsurgical
pathology could be appropriate candidates for pediatric sur-
gical opinion. The aim of the letter is not to invite a raft of
surgical referrals but to help define criteria for investigations
of these chronic sufferers.
Aruna Abhyankar
Guy’s Hospital and University Hospital Lewisham
London, United Kingdom
REFERENCE
1. Uba AF, Chirdan LB, Edino ST. Intestinal malrotation: presentation
in the older children. Niger J Med 2005;14:23–6.
Could it be the Liver?
To the Editor: We read with interest the case report of
‘‘Variceal Hemorrhage 13 Years After Nephrectomy for Wilms
tumor’’ by Hasan et al. (1). We would agree that portal hyper-
tension might have been caused by splenic vein thrombosis,
although we note that this was not confirmed radiologically.
Have the authors considered the possibility of chemotherapy
induced chronic hepatotoxicity and fibrosis as a cause of portal
hypertension in this case?
There have been several reports of acute venoocclusive
disease during treatment of Wilms tumour (2) but not many
J Pediatr Gastroenterol Nutr, Vol. 42, No. 1, January 2006
120 LETTERS TO THE EDITOR
reports of chronic hepatotoxicity. We have reviewed our ex-
perience with chemotherapy induced chronic hepatotoxicity
in children presenting to our unit over a 12 year period (3). Of
10 children reviewed, 3 had been treated for Wilm’s tumor, 2 of
whom presented with variceal bleeding without venous
thrombosis.
Similarly, we and others (4,5) have recently reported on
chronic hepatotoxicity secondary to 6-Thioguanine treatment
for acute lymphoblastic leukemia. These children presented
several months or years after completion of chemotherapy with
splenomegaly and persistent thrombocytopenia but normal con-
ventional liver function tests (4). In 2 of 10 cases, the initial
presentation was with variceal bleeding, and 1 child had iso-
lated gastric varices. Liver biopsy in these children has shown
varying degrees of fibrosis and vascular changes consistent with
noncirrhotic portal hypertension (4).
Did the authors perform a liver biopsy to exclude this diag-
nosis or to clarify whether hepatic fibrosis was a factor in the
etiology? This is particularly important because if noncirrhotic
portal hypertension is present, splenectomy will not be curative,
and there will be a significant risk of variceal recurrence. We
would recommend that this child should have prolonged follow-up
with abdominal ultrasound and surveillance endoscopy.
J Pediatr Gastroenterol Nutr, Vol. 42, No. 1, January 2006
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
M. Ravikumara
D. A. Kelly
P. J. McKiernan
Liver Unit
Birmingham Children’s Hospital NHS Trust
Birmingham, United Kingdom
REFERENCES
1. Hasan RA, Inoue S, Bruch SW, et al. Variceal Hemorrhage 13 years
after nephrectomy for Wilm’s tumor. J Pediatr Gastroenterol Nutr
2005;40:600–2.
2. Bisogno G, de Kraker J, Weirich A, et al. Veno-occlusive disease of
the liver in children treated for Wilm’s tumor. Med Pediatr Oncol
1997;29:245–51.
3. Chada L, Beath S, Kelly D, et al. Chronic liver disease following che-
motherapy in children. J Pediatr Gastroenterol Nutr 2003;36:551.
4. Ravikumara M, Hill F, Wilson DC, et al. 6-Thioguanine related
hepatotoxicity in children with acute lymphoblastic leukaemia: A
dual center experience. J Pediatr Gastroenterol Nutr 2005;40:677.
5. Broxson EH, Dole M, Wong R, et al. Portal hypertension develops in
a subset of children with standard risk acute lymphoblastic leukemia
treated with oral 6-thioguanine during maintenance therapy. Pediatr
Blood Cancer 2005 Mar;44:226–31.