CASE REPORTS

Copper Overload in 6-year-old Twins

Mark G. Bartlett and Nissa I. Erickson

6-year-old boy presented to the emergency department

with increasing fatigue and abdominal distention that had
worsened over several weeks. Numerous visits to immediate care
clinics had resulted in various diagnoses such as pharyngitis, otitis,
and viral syndrome. He was previously healthy, but was learning
disabled. He had been incorrectly labeled as autistic by a chiropractor, who recommended vitamins and a caffeinated energy drink
that was purported to improve concentration and academic performance.
On examination he was afebrile but appeared fatigued.
Positive findings included abdominal distention and hepatosplenomegaly. An abdominal ultrasound confirmed an enlarged liver and
spleen, and he underwent the following liver tests: alanine aminotransferase (ALT) 275 U/L, aspartate aminotransferase (AST)
707 U/L, g-glutamyl transferase 155 U/L, and total bilirubin
1.2 mg/dL. Albumin was low at 2.7 g/dL. He was transferred to
our center for further evaluation and management.
Additional laboratory reports included immunoglobulin G of
1600 mg/dL, anti-nuclear antibody positive, and anti-smooth
muscle antibody elevated at 45 U. His hemoglobin was low at
10 g/dL but he had no hemolysis. Ceruloplasmin was normal at
24 mg/dL, and urine copper was mildly elevated at 212 mg/d.
A penicillamine challenge test raised the 24-hour urine copper to
1600 mg/d. Liver biopsy demonstrated extensive fibrosis, and
special staining with rhodamine was positive for copper (Fig. 1,
which includes 4 stains: H and E, trichrome, reticulin, and
rhodamine). A careful history for copper exposure was taken and
found to be unremarkable, so his dry copper weight of 1400 mg/g of
liver tissue was considered diagnostic for Wilson disease (WD).
He was started on chelation therapy with trientene and zinc. Within
1 week he developed acute liver failure with bilirubin rising to
50 mg/dL and international normalized ratio rising to 6. He received
a liver transplant within 72 hours from listing and has done well
postoperatively.
The patients 3 siblings were screened for WD with ceruloplasmin and 24-hour urine copper. His fraternal twin brother had
mild elevation of ALT and AST, normal ceruloplasmin, and
elevated 24-hour urine copper, so he underwent liver biopsy. He
also had abundant copper staining and a dry copper weight of
3020 mg/g of liver tissue. His liver biopsy was negative for fibrosis
or inflammation (Fig. 2, which includes 4 stains: H and E,
trichrome, reticulin, and rhodamine). He has responded to chelation
with penicillamine and remained stable for 12 months.
Genetic testing was obtained on the index case with sequencing of the entire ATP7B gene. There were no mutations found in

Received January 19, 2011; accepted July 14, 2011.

From the Division of Pediatric Gastroenterology, University of Minnesota,
Minneapolis, MN.
Address correspondence and reprint requests to Mark G. Bartlett, MD,
Division of Pediatric Gastroenterology, University of Minnesota, 6th
Floor, East Building, 2450 Riverside Ave, Minneapolis, MN 55454
(e-mail: Bartl204@umn.edu).
The authors report no conflicts of interest.
Copyright # 2012 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0b013e3182311a24

JPGN

Volume 55, Number 6, December 2012

the region known to code for Wilson disease. A heterozygous

sequence change c.2002A>G (p.M668V) was found in a region
of the gene not known to code for a functional domain (1,2).
On further questioning, the mother acknowledged feeding
both of her boys 8 servings per day of AdvoCare Spark energy
drink over the preceding 8 months mixed with chocolate milk
along with 2 daily Flintstones brand multivitamins. The estimated
copper intake from these 3 sources was significantly above the
440 mg recommended daily dose for copper for children this
age (3).

FIGURE 1. Index case: H and E stain (A) shows some damage, but
fibrosis is seen best on the trichrome and reticulin stains (B,C). At the
far right abundant copper can be seen (D).

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Case Reports

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100

% of subjects

Toxic normal
population

Normal
Wilson
disease

Heterozygous
WD

Idiopathic
copper
toxicosis

Physiologic needs

B
Safe range of intake

FIGURE 3. Population risk of copper excess on the basis of distribution

curves of requirements (bell-shaped curves) and exposure (broken
lines represent various cumulative distributions of population
exposure from food and water). The open curve on the far left
indicates normal subjects under a safe range of copper exposure (A
and B), and the solid curve on the extreme right indicates normal
subjects under excessive exposure. Genetically distinct population
groups are depicted as solid curves (Wilson disease [WD], heterozygous WD, and idiopathic copper toxicosis). These groups may be toxic
at intakes that are below normal requirements (A), at
the recommended intake (B), or close to the upper level (C) for the
normal subjects. All of the subjects, including the normal population,
will be toxic at extremely high exposure (D) (8). Possibly the heterozygous sequence change in ATP7B rendered the index case more
vulnerable than the normal population. Reproduced with permission
of the American Society for Nutrition (8).

FIGURE 2. Twin brother has twice the copper load by dry weight but
no evidence of fibrosis as seen in his brother.

DISCUSSION AND CONCLUSIONS

After genetic testing failed to show a known Wilson mutation
and the dietary history was better elucidated, we consider these
cases to be an Indian childhood cirrhosislike injury from copper
overload (46). The heterozygous sequence change in the ATP7B
gene is not previously described as being associated with WD.
Perhaps it could be responsible for this childs increased vulnerability to copper overload.
The liver failure in the index case even at a lower copper
load (half that of his twin) could also be because of concurrent
injury from underlying liver disease (eg, autoimmune hepatitis),
or perhaps a second basic defect of copper metabolism that has yet
to be found in this patient (7). The graph Figure 3 helps demonstrate
the variation in how much copper humans can tolerate. Above a
certain level, Copper is toxic for all humans; however, some have a
lower threshold for developing liver damage when exposed to
copper. Others, such as those with WD, are vulnerable even at
the recommended daily allowance (RDA) for copper.

e146

The sources of copper in these 6-year-old twins diet in

addition to any obtained through meals were as follows: Spark
energy drink 200 mg/8 oz (1600 mg in the daily amount consumed),
chocolate milk 436 mg/8 oz (3488 mg in the daily amount consumed), and Flinstones vitamins 2000 mg/tablet (4000 mg/d in the
amount consumed). These boys were therefore each consuming a
total of 9088 mg/d of copper, approximately 21 times the RDA for
their age.
This case illustrates the risk of unchecked use of vitamin
supplements in children. Although the amount of copper in Flintstones vitamins (9) is advertised as 100% of RDA in a single tablet,
this is actually twice the adult RDA of 1000 mg and is >4 times the
RDA for a 6-year-old. The AdvoCare (10) Spark energy drink has
22% of the adult RDA for copper, but this is 45% of a 6-year-olds
RDA (11). The directions are to mix with the beverage of your
choice 1 to 3 times daily and to consult a health care professional
before using in children. This family was vulnerable because they
had no consistent medical caregiver, were suspicious of allopathic
medicine (ie, had foregone vaccinations and well-child examinations), and had trusted the counsel of a chiropracter who they
believed provided more natural therapies. Although the diagnosis of
autism was later proven to be incorrect in this case, the fear of this
diagnosis led the parents to resort to untested therapies recommended by a provider unschooled in their dangers.

REFERENCES
1. ATP7B deletion/duplication analysis. http://dnatesting.uchicago.edu.
Accessed April 21, 2011.
2. Cox D, Roberts E. Wilson diseasehepatolenticular degeneration.
http://www.genetests.org. Accessed April 21, 2011.
3. Panel on Micronutrients. Dietary Reference Intakes for Vitamin A,
Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron,
Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc.
Washington, DC: National Academy press; 2001.

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JPGN

Volume 55, Number 6, December 2012

4. Pandit A, Bhave S. Present interpretation of the role of copper in Indian

childhood cirrhosis. Am J Clin Nutr 1996;63:830S5S.
5. Lefkowitch JH, Honig CL, King ME, et al. Hepatic copper overload and
features of Indian childhood cirrhosis in an American sibship. N Engl J
Med 1982;307:2717.
6. Adamson M, Reiner B, Olson JL, et al. Indian childhood cirrhosis in an
American child. Gastroenterology 1992;103:17717.
7. Hahn SH, Brantley ML, Oliver C, et al. Metallothionein synthesis and
degradation in Indian childhood cirrhosis fibroblasts. Pediatr Res
1994;35:197204.
8. Uauy R, Maass A, Araya M. Estimating risk from copper excess in
human populations. Am J Clin Nutr 2008;88:867S71S.
9. Product website. http://flintstonesvitamins.com. Accessed October 26,
2012.
10. Product website. http://www.advocare.com/products. Accessed October
26, 2012.
11. USDA Nutrient Database for Standard Reference, release 17. http://
fnic.nal.usda.gov. Accessed October 26, 2012.

Lamotrigine-induced Vanishing Bile

Duct Syndrome in a Child


Harsh Bhayana, Sreekanth Appasani,

B.R. Thapa, yAshim Das, and Kartar Singh

amotrigine is an effective oral anticonvulsant agent used as an

adjunctive treatment for refractory epilepsy with few minor
adverse effects, including dizziness, double vision, headache,
coordination problems, blurred vision, nausea, and vomiting, but
the most life-threatening side effects include hypersensitivity reactions. These idiosyncratic reactions commonly manifest with
clinical symptoms ranging from mild rashes to Stevens-Johnson
syndrome and toxic epidermal necrolysis. Hepatitis and other
immune-mediated reactions are also known.
Liver involvement with this drug has been documented in the
form of acute hepatitis resulting even in fulminant hepatic failure
(1). Cholestatic pattern of liver injury has never been reported with
this drug. We encountered a 12-year-old male child who developed
progressive cholestatic jaundice after starting lamotrigine, and his
investigations including liver biopsy confirmed it to be rare case of
vanishing bile duct syndrome (VBDS). The rare occurrence of
VBDS in a child and its association with lamotrigine prompted us to
document the present case, which has never been reported in the
literature earlier.
A 12-year-old male child presented with focal seizures in
December 2008 for which he started taking carbamazepine. While
Received May 21, 2011; accepted September 4, 2011.
From the Division of Pediatric Gastroenterology, Hepatology and
Nutrition, Superspeciality of Gastroenterology, and the yDepartment
of Histopathology, Postgraduate Institute of Medical Education and
Research, Chandigarh, Punjab, India.
Address correspondence and reprint requests to Dr B.R. Thapa, Division of
Pediatric Gastroenterology, Hepatology and Nutrition, Postgraduate
Institute of Medical Education and Research, Sector 12, Chandigarh
160012, Punjab, India (e-mail: br.thapa.pgi@gmail.com; brthapa1@
yahoo.co.in).
The authors report no conflicts of interest.
Copyright # 2012 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0b013e31823c2500

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Case Reports
taking carbamazepine, the child developed maculopapular rash,
which subsided after stopping carbamazepine. He started taking
valproate, which did not control his seizures, and he started taking
lamotrigine in September 2009. After 2 weeks of starting lamotrigine, child started developing macular rash. Lamotrigine was
stopped after the onset of rash. This rash persisted for approximately
1 month and then healed with residual hyperpigmentation.
One month after starting lamotrigine, when rash started
subsiding, child developed conjugated hyperbilirubinemia (total
bilirubin of 14.8 mg/dL with conjugated fraction of 10.8 mg/dL)
with elevated transaminases (aspartate aminotransferase [AST]
322 IU/L, alanine transaminse [ALT] 234 IU/L). In view of
persistent hyperbilirubinemia, child was referred to pediatric
gastroenterology in January 2010. On examination, he had icterus,
multiple postinflammatory healed hyperpigmented macules, and
scratch marks with firm hepatomegaly. There was no splenomegaly
or ascites. Investigations revealed normal hemogram, AST 134 IU/L,
ALT 321 IU/L, alkaline phosphatase 123 IU/L, with normal
prothrombin index (100%) and low serum albumin (2.1 g/dL).
Workup for viral hepatitis A, B, C, and E, autoimmune, and Wilson
disease was negative. Ultrasonography abdomen showed mild
hepatomegaly with normal hepatic echotexture and normal biliary
apparatus. A possibility of drug-induced liver injury was considered
and a liver biopsy was done, which showed absence of interlobular
bile ducts in 6 of the 9 portal tracts examined (Fig. 1) suggestive of
drug-induced cholestasis. He started taking ursodeoxycholic acid
(30 mg  kg1  day1) and vitamin supplements. Child initially
showed clinical as well as biochemical improvement (in May
2010, AST and ALT were 42 and 41 IU/L and ALP was 350 IU/L,
GGT was 96 IU/L with bilirubin of 4.5 mg/dL).
In June 2010, child again showed signs of worsening in the
form of increasing jaundice and pruritus. Biochemical markers
revealed elevated AST 110 IU/L, ALT 59 IU/L, and bilirubin
7.8 mg/dL. In view of no clinical improvement, repeat liver biopsy
was done, which showed marked ductular proliferation with paucity
of interlobular bile ducts (absent in 7 of the 8 portal tracts examined
as evident on immunohistochemical stains for cytokeratin CK7/
CK19). There was also evidence of bridging fibrosis (Figs. 2 and 3).
In view of the above findings, a diagnosis of VBDS was considered.
Subsequently, child started taking 2 mg/kg prednisolone and later
azathioprine in a dose of 1.5 mg  kg1  day1, and continued till
November 2010. But there was no improvement. In view of
worsening liver functions including coagulogram and hard liver

FIGURE 1. Liver biopsy showing intrahepatocytic and canalicular

cholestasis.

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ratio. In these cases, there was minimal portal inflammation without

evidence of hepatic necrosis or cholestasis (3).
Cholestasis is a common result of drug toxicity, explaining
2% to 5% of hospitalizations for jaundice and up to 20% of cases of
jaundice in the geriatric population (8). In a minority of cases,
cholestasis persists for >6 months and is associated with an
increasing risk of progression to the rare occurrence of VBDS.
There are only anecdotal reports showing improvement with immunosuppressive therapy, but our index child did not show any
improvement with prednisolone and azathioprine during 6-month
time, so liver transplantation was contemplated.
Lamotrigine has been associated with a number of adverse
reactions, of which hypersensitivity reactions are the most
important. Drug-induced hepatitis has been reported with lamotrigine (9). To the best of our knowledge, it is the first report of
bile duct injury associated with lamotrigine requiring liver
transplantation.
FIGURE 2. Periodic acid-Schiff stain shows lack of normal interlobular
bile duct in the portal tract.

on clinical examination, he was counseled for liver transplantation

and is waiting for the same presently.

DISCUSSION
Ductopenia is a term used to describe a decrease in the
number of interlobular bile ducts in >50% of portal tracts in a
pathologic specimen that is adequate for interpretation (2,3). Loss
of a bile duct is recognized in an individual portal tract when no duct
is identified in proximity to the parallel hepatic arterial branch.
Ductopenia is an end result associated with multiple insults, ranging
from congenital and genetic diseases, developmental disease,
immunological diseases, infectious diseases, neoplastic disorders,
and drugs or toxins. In the present case, lamotrigine was the
offending agent. These disorders result in progressive loss of
intrahepatic bile ducts, which is coined as VBDS. VBDS is a rare
condition in the pediatric population and sparsely reported (4). It
has been described in adults as a final result to multiple causes of
liver injury. Among the various causes of VBDS, drugs have an
increasing importance (57). Deggot et al (3) reported 8 cases of
persistent drug-induced cholestatic syndrome, of which 4 showed
persistent ductopenia, up to 76 months after the onset of jaundice,
with severe reduction of the interlobular bile ducts/portal tracts

REFERENCES
1. Ouellet G, Tremblay L, Marleau D. Fulminant hepatitis induced by
lamotrigine. South Med J 2009;102:824.
2. Ludwig J, Wiessner RH, LaRusso NF. Idiopathic adulthood ductopenia: a
cause of chronic cholestatic liver disease and biliary cirrhosis. J Hepatol
1987;7:1939.
3. Deggot C, Feldmann G, Larrey D, et al. Drug-induced prolonged
cholestasis in adults: a histological semiquantitative study demonstrating
progressive ductopenia. Hepatology 1992;15:24451.
4. Karnsakul W, Arkachaisri T, Atisook K, et al. Vanishing bile duct syndrome
in a child with toxic epidermal necrolysis: an interplay of unbalanced
immune regulatory mechanisms. Ann Hepatol 2006;5:1169.
5. Desmet VJ. Vanishing bile duct syndrome in drug-induced liver disease.
J Hepatol 1997;26(suppl 1):315.
6. Manuvel JC, Bloomer JR, Snover DC. Progressive bile duct injury after
thiabendazole administration. Gastroenterology 1987;93:2459.
7. Turner IB, Ecstein RP, Riley JW, et al. Prolonged hepatic cholestasis after
fluoxacillin therapy. Med J Aust 1989;151:7015.
8. Guebel AP, Sempoux CL. Drug and toxin-induced bile disorders.
J Gastroenterol Hepatol 2000;15:12328.
9. Mecarelli O, Pulitano P, Mingoia M, et al. Acute hepatitis associated with
lamotrignine and managed with the molecular adsorbents recirculating
system (MARS). Epilepsia 2005;46:16879.

15-year-old Girl With Metaplastic

Atrophic Gastritis and
Enterochromaffin-like Cell Hyperplasia


Alexandra C. Russell, yJennifer O. Black, zDavid A.

Schwartz, yHernan Correa, and Michael J. Rosen

FIGURE 3. Cytokeratin immunostaining shows loss of normal interlobular bile duct and marked bile ductular proliferation.

e148

e report a rare case of autoimmune metaplastic atrophic

gastritis (AMAG) and associated enterochromaffin-like
(ECL) cell hyperplasia in a 15-year-old girl. The patient presented
with 8 months of epigastric abdominal pain unresponsive to proton
pump inhibitor (PPI). Her mother had a history of immunoglobulin
(Ig) A nephropathy and vitamin B12 deficiency. Physical examination was unremarkable. Complete blood count, metabolic panel,
lipase, C-reactive protein, and celiac serology were normal.
Esophagogastroduodenoscopy revealed numerous 2- to 4-mm
nodules in the body of the stomach (Fig. 1).
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Case Reports
negative secretin stimulation test, neutral gastric pH confirming
achlorhydria, negative evaluation for H pylori, gastric pathology,
and family history of pernicious anemia, the patient was diagnosed
with AMAG with associated ECL cell hyperplasia.

DISCUSSION

FIGURE 1. Endoscopic image of nodules in the body of the stomach.

The nodules are actually retained islands of normal gastric mucosa.

On pathology, the stomach demonstrated multifocal

chronic atrophic gastritis, focal intestinal metaplasia, and ECL cell
hyperplasia (Fig. 2A and B). CDX-2 staining confirmed the
foci of small intestinal epithelium (Fig. 2H). Synaptophysin is
a glycoprotein present in neuronal presynaptic vesicles and is a
useful marker of neuroendocrine cells. Synaptophysin staining
highlighted an increase in ECL cells within the glands (linear
hyperplasia) and florets of ECL cells in the lamina propria
(nodular hyperplasia), which were most prominent in the areas
of glandular atrophy (Fig. 2CE). Because ECL cell hyperplasia is caused by hypergastrinemia, gastrin staining was
performed, which showed proliferation of antral G cells
(Fig. 2F). Helicobacter pylori staining, serology, and biopsy urease
testing were negative.
Because ECL cell hyperplasia can be associated with
neuroendocrine tumors (NETs), a second esophagogastroduodenoscopy with endoscopic mucosal resection of several clusters
of nodules was performed to assess for invasion into the submucosa.
No invasion or malignancy was identified, and histopathologic
findings were similar to those seen on the earlier biopsies
(Fig. 2B and E).
ECL cell hyperplasia results from hypergastrinemia
associated with atrophic gastritis (either H pyloriassociated or
autoimmune), chronic PPI use, or Zollinger-Ellison syndrome from
a gastrin-secreting tumor with or without multiple endocrine neoplasia 1 (1). Further laboratory evaluation undertaken to determine
the cause in this patient is detailed in Table 1. A pancreatic protocol
computed tomography scan was negative for any mass. Given her
Received August 15, 2011; accepted November 18, 2011.
From the Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, the yDepartment of Pathology, and the
zDepartment of Medicine, Vanderbilt University School of Medicine,
Nashville, TN.
Address correspondence and reprint requests to Michael J. Rosen, MD,
MSCI, Department of Pediatrics, Division of Pediatric Gastroenterology,
Hepatology, and Nutrition, Vanderbilt University School of Medicine,
2215 Garland Ave, 1025 Medical Research Building IV, Nashville, TN
37232 (e-mail: michael.rosen@vanderbilt.edu).
M.J.R. is supported by the CDHNF/NASPGHAN/George Ferry Young
Investigator Award and a Vanderbilt Physician Scientist Development
Award.
The authors report no conflicts of interest.
Copyright # 2012 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0b013e318242da36

www.jpgn.org

Atrophic gastritis typically presents in the 6th to 7th

decade and, when found in children, is almost exclusively
associated with H pylori infection. Here we present a rare case
of AMAG in an adolescent female with no evidence of H pylori
infection. Additionally, to our knowledge, this is the first description of ECL cell hyperplasia associated with AMAG in a
pediatric patient.
AMAG is caused by progressive autoimmune destruction of
the oxyntic glands leading to achlorhydria and hypergastrinemia.
Due to gradual loss of intrinsic factor production, patients are
at high risk for vitamin B12 deficiency. Although this patient does
not yet have a low serum vitamin B12 level, it is interesting that her
mother is vitamin B12 deficient. Although the patients mother has
never undergone gastroscopy, her history of vitamin B12 deficiency
and autoimmune disease suggests a familial origin.
In the early stages of AMAG, the gastric body may have
nodules or pseudopolyps, which are actually retained islands of
normal gastric mucosa amidst focal areas of atrophy (Figs. 1 and
2B) (2). Although nodular gastropathy associated with H pylori
infection can have a similar appearance, it is typically antral
predominant. Nonetheless, the similar endoscopic appearance
underscores the importance of multiple biopsies in the body and
antrum in patients with gastric nodularity.
AMAG can be associated with circulating antibodies
against intrinsic factor and parietal cells; however, absence of
autoantibodies in this patient does not exclude a diagnosis of
AMAG. In fact, only 70% of patients with pernicious anemia
produce anti-intrinsic factor antibodies and even fewer, 55%,
produce anti-parietal cell antibodies. Furthermore, younger patients
are more likely to be autoantibody negative (3).
Atrophic gastritis in children almost exclusively occurs in
the setting of H pylori infection. The largest series of children
with AMAG was in association with autoimmune thyroid
disorders (4). In the present study of 129 children with autoimmune
thyroid disorders, 30% had anti-parietal cell antibodies. Hypergastrinemia was demonstrated in 45% and 12% of anti-parietal
cell antibodypositive and negative children, respectively.
Gastroscopy was performed in 18 antibody-positive patients, and
10 were found to have H pylorinegative atrophic gastritis, all of
whom had hypergastrinemia.
ECL cell hyperplasia occurs in 60% of adults with
AMAG (1). Chronically, increased circulating gastrin in response
to achlorhydria directly stimulates ECL cell proliferation.
This feedback response can lead to progression from linear to
micronodular ECL cell hyperplasia, and, in some instances,
gastric NETs. PPIs have been implicated as a cause of ECL cell
hyperplasia in adults and children. In one study, 60% of children
treated with PPI for gastroesophageal reflux disease for a
median 2.3 years showed minor degrees of ECL cell hyperplasia
(5). Of note, most had only an increase in the number of ECL cells,
and none progressed to a micronodular pattern of hyperplasia.
Although it is important to recognize that long-term PPI treatment
can cause histologic changes, these data suggest that this patients
micronodular ECL cell hyperplasia cannot be attributed to PPI
use alone.
AMAG has been associated with gastric adenocarcinoma
and NETs. The incidence of gastric adenocarcinoma in adults
with AMAG varies from similar to the general population to a

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FIGURE 2. Histopathology demonstrating metaplastic atrophic gastritis with enterochromaffin-like (ECL) cell hyperplasia. A, Hematoxylin and
eosin (H&E) stain of the stomach demonstrating chronic inflammation, gastric atrophy (), and florets of ECL cells in the lamina propria (arrows).
B, Subsequent deeper endoscopic mucosal resection demonstrates the stomach nodules are actually remaining normal gastric mucosa. C and D,
Synaptophysin stain demonstrating both linear (arrowheads) and nodular (arrows) patterns of ECL cell hyperplasia in the body of the
stomach. E, Synaptophysin stain of EMR tissue demonstrates the ECL cell hyperplasia is limited to the lamina propria without invasion into
the submucosa. F, Gastrin stain demonstrates proliferation of antral G cells. G, H&E stain of the stomach demonstrating focal intestinal metaplasia
(arrows). H, Cdx-2 staining highlights the metaplastic intestinal epithelium.

TABLE 1. Laboratory evaluation for atrophic gastritis and enterochromaffin-like hyperplasia

Test
Gastric urease
H pylori serology
Gastric pH
Secretin stimulation test
Serum gastrin baseline
5 min
15 min
30 min
Anti-parietal cell antibodies
Anti-intrinsic factor antibodies
Vitamin B12

e150

Result
Negative
Negative
6.62
272 pg/mL
270 pg/mL
187 pg/mL
101 pg/mL
Negative
Negative
365 pg/mL

Normal range
Negative
Negative
04
1125 pg/mL

Negative
Negative
180914

3-fold increase (6). There are only 2 reported cases of gastric

adenocarcinoma associated with AMAG in adolescents (7,8).
Gastric NETs occur in 4% to 7% of patients with AMAG (6).
Gastric NETs associated with AMAG are typically small, welldifferentiated, benign tumors (6). We are not aware of any reports
of gastric NETs associated with AMAG in children.
The long-term outcome of AMAG in children is unknown.
American Society for Gastrointestinal Endoscopy guidelines
recommend a single endoscopy in adults with pernicious anemia
to evaluate for NET and gastric cancer, but state there are insufficient data to support routine surveillance endoscopy in patients
with AMAG (6).
To our knowledge, this is first description of AMAG with
associated ECL cell hyperplasia in an adolescent patient. Pediatric
gastroenterologists and pathologists must be aware that AMAG can
begin at a young age, and evaluate them for associated lesions such
as ECL cell hyperplasia or NET and gastric cancer.
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REFERENCES
1. Delle Fave G, Marignani M, Moretti A, et al. Hypergastrinemia
and enterochromaffin-like cell hyperplasia. Yale J Biol Med 1998;71:
291301.
2. Ikeda T, Senoue I, Hara M, et al. Gastric pseudopolyposis: a new clinical
manifestation of type A gastritis. Am J Gastroenterol 1985;80:8290.
3. Carmel R. Reassessment of the relative prevalences of antibodies to gastric
parietal cell and to intrinsic factor in patients with pernicious anaemia:
influence of patient age and race. Clin Exp Immunol 1992;89:747.
4. Segni M, Borrelli O, Pucarelli I, et al. Early manifestations of gastric
autoimmunity in patients with juvenile autoimmune thyroid diseases.
J Clin Endocrinol Metab 2004;89:49448.
5. Hassall E, Owen D, Kerr W, et al. Gastric histology in children treated
with proton pump inhibitors long term, with emphasis on enterochromaffin cell-like hyperplasia. Aliment Pharmacol Ther 2011;33:82936.
6. Hirota WK, Zuckerman MJ, Adler DG, et al. ASGE guideline: the role of
endoscopy in the surveillance of premalignant conditions of the upper GI
tract. Gastrointest Endosc 2006;63:57080.
7. Aichbichler BW, Eherer AJ, Petritsch W, et al. Gastric adenocarcinoma
mimicking achalasia in a 15-year-old patient: a case report and review of
the literature. J Pediatr Gastroenterol Nutr 2001;32:1036.
8. Wolach B, Rothschild M, Pomeranz A, et al. Idiopathic non-obstructive
hypertrophic cardiomyopathy, vitamin B12 deficiency and gastric
adenocarcinoma: an unreported association in a teenager. Eur J Pediatr
1998;157:7158.

Endoscopic Treatment of Traumatic

Duodenal Perforation


Barbara Bizzarri, yOsvaldo Borrelli,

Francesca Vincenzi, Giorgio Nervi, zNicola de Angelis,

Carmen Madia, zRaffaele Dalla Valle, and

Gian Luigi deAngelis

uodenal injuries represent a small but formidable,

challenging group of pediatric trauma. Due to its protected
retroperitoneal location, injuries to the duodenum are relatively
uncommon in children, accounting for 3% to 5% of all of the blunt
abdominal injuries (1,2); however, due to their rarity and
delayed diagnosis, duodenal trauma remains an important source
of morbidity and mortality (3). Although over the last decades,
management of blunt duodenal trauma has shifted from operative
surgery to selective nonoperative surgery; the former is still considered the cornerstone for primary repair of low-grade duodenal
injury to reduce the length of hospitalization, intensive care unit
Received November 24, 2011; accepted December 9, 2011.
From the Gastroenterology and Endoscopy Service, University of Parma,
Parma Italy, the yDepartment of Gastroenterology, Great Ormond Street
Hospital, London, UK, and the zEmergency Surgery, University of
Parma, Parma, Italy.
Address correspondence and reprint requests to Prof Gian Luigi
de Angelis, MD, Gastroenterology and Endoscopy Service, University
of Parma, via Gramsci 14, 43100 Parma, Italy (e-mail: gianluigi.dean
gelis@unipr.it).
The authors report no conflicts of interest.
Copyright # 2012 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0b013e318245fd8f

www.jpgn.org

Case Reports
time, need for parenteral nutrition, and overall complication rates
(4,5). However, endoscopic treatment through the use of operative
accessories could provide an excellent alternative option to
close limited wall defects without the need for surgery.
Herein we describe the use of a clipping device present to close
a post-traumatic duodenal perforation.
A 15-year-old-boy was admitted to the pediatric emergency
department of our university hospital after a motorbike collision.
The child was extensively bruised around and below the umbilicus
and manifested at physical examination lower abdominal
tenderness with significant lower abdominal pain. He was hemodynamically stable. Extraluminal oral contrast, discontinuity and
localized thickness of ileal wall with adjacent free air, and free
intraperitoneal fluid were detected by contrast-enhanced computed
tomography scan. No injury to any other solid organs was observed.
He was referred to the surgeons and was operated within 3 hours
after the injury. Under general anesthesia and broad-spectrum
antibiotic coverage, laparotomic exploration of the gastrointestinal
(GI) tract confirmed the presence of ileal subserosal hemorrhages,
and subsequently a segmental resection was performed. Moreover,
a sigmoid perforation was also identified and primarily repaired.
Postoperatively, the child remained in the intensive care unit
overnight and a parenteral nutrition was started.
After 2 days, he started presenting a biliary leak (approximately 1200 mL/day) from surgical abdominal drainage. A second
computed tomography scan failed to show any abnormalities.
Therefore, an upper GI endoscopy, performed using a pediatric
videoendoscope (Olympus GIF160 [Olympus, Tokyo, Japan]
1 9.8 mm, biopsy channel 1 2.0 mm) during propofol sedation,
revealed a 3-cm perforation in the posterior wall of second portion
of duodenum. With the patient clinically worsening, octreotide was
started at full dose to suppress the pancreatic secretion. After 7 days,
without any clinical improvement, a second GI upper endoscopy
was performed, which confirmed the duodenal perforation
(Fig. 1A). The endoscope was inserted into the perforation for
approximately 1 cm, and the retroperitoneal cavity did not show any
signs of infection, pus collections, or necrotic area. By using a
standard operative endoscopic catheter, 3 fibrin glue injections
(Tissucol; Baxter Healthcare Corp, Deerfield, IL) were performed:
the first (10 mL) into the retroperitoneal cavity close to the external
duodenal wall, the second (5 mL) into the perforation, and the third
into a large lateral parietal recess. Finally, by using a disposable

FIGURE 1. A, A perforation in the posterior wall of the duodenum.

B, After the injection of fibrin glue and the placement of the clips, the
edges of the defect are approximated. C and D, Persistence of small
wall defect and 1 additional clip is placed to close the wall defect. E and
F, Endoscopy performed 1 month after the discharge showing the
closure of the perforation.

e151

Copyright 2012 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.

Case Reports

JPGN

Volume 55, Number 6, December 2012

DISCUSSION

instance, numerous reports describe the possibility of nonsurgical

treatment for perforation of the upper GI tract when no peritonitis is
present (8). To our knowledge, the use of a clipping device in
combination with fibrin glue injections for closure of a traumatic
duodenal perforation, as in our case, has not been previously
described. In our study, the clinical worsening of the patient after
the first surgery was a contraindication for re-surgery. On the
contrary, the lack of infection signs and easy endoscopic access
were favorable conditions for positioning endoclips and injecting
fibrin glue. Obviously, the major risk of this procedure was the
therapeutic failure. Our patient was receiving oral feeding after
4 days and was discharged after 7 days.
Although large patient series are required, based on our
experience of using endoclips and fibrin glue in the closure of
large duodenal perforation, this procedure should be explored as
an option in the management of critically ill patients with duodenal
blunt trauma; however, technical mastery of the deployment of
endoclips is crucial for successful closure of surgical gaps.

Duodenal injuries following blunt abdominal trauma are

usually related to motor vehicle accidents. Despite their rarity in
pediatric age, they are associated with high morbidity and mortality
(13). The pathophysiology of organ rupture is still a matter of
debate; however, the direct compression with tearing between
2 opposing surfaces such as the abdominal wall and spine
is considered the leading mechanism of intestinal injury (6).
Obviously, fixed areas of the bowel such as the duodenum are at
increased risk. A surgical approach still remains the mainstay of
management of duodenal trauma secondary to nonpenetrating
injury, and present recommendations advocate primary repair for
low-grade injury and more complex procedures, such as pyloric
exclusion and duodenal diversion, for severe injuries (35).
Endoscopic clips were first introduced in 1975 by Hayashi
et al (7) for treating GI bleeding; however, over the last years,
endoscopic clip placement has been successfully used for a wide
variety of indications including closure of GI fistula, anastomotic
leak, and iatrogenic perforation throughout the GI tract (8). For

1. Ivatury RR, Nassoura ZE, Simon RJ, et al. Complex duodenal injuries.
Surg Clin North Am 1996;76:797812.
2. Clendenon JN, Meyers RL, Nance ML, et al. Management of duodenal
injuries in children. J Pediatr Surg 2004;39:9648.
3. Degiannis E, Boffard K. Duodenal injuries. Br J Surg 2000;87:14739.
4. Besselink MGH, Berende NCAS, Preshaw RM, et al. Non-operative
treatment of duodenal perforation secondary to blunt abdominal trauma.
Int J Care Injured 2001;32:5135.
5. Ladd AP, West KW, Rouse TM, et al. Surgical management of duodenal
injuries in children. Surgery 2002;132:74852.
6. Williams RD, Sargent FT. The mechanism of intestinal injury in trauma.
J Trauma 1963;31:73548.
7. Hayashi I, Yonezawa TM, Kuwabara T, et al. The study on staunch clip for
the treatment by endoscopy. Gastoenterol Endoscopy 1975;17:92101.
8. Raju GS, Gajula L. Endoclips for GI endoscopy. Gastrointest Endosc
2004;59:26779.

endoclipping device (Boston Scientific Corp, Natick, MA), 4 clips

(Resolution Clip; Boston Scientific Corp) were deployed on the
margins of the perforation (Fig. 1B), without a complete closure of
the wall defect to drain a potential abscess.
After the endoscopic procedure, no biliary leak from the
abdominal drainage was observed. The child was treated with
broad-spectrum intravenous antibiotics and remained on parenteral
nutrition. An endoscopy performed 7 days later still showed the
presence of a small area of perforation without any sign of infection.
Therefore, another clip was deployed with the complete apposition
of the wound margins. Because the patient recovered well without
complaining of any abdominal symptoms, he was started on oral
feeding after 4 days and discharge home after 7 days. An upper
endoscopy was performed 1 month after discharge showing the
presence of 3 clips still present in the duodenal wall and the
complete wound healing.

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REFERENCES

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Copyright 2012 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.