Concomitant presentation of collagenous sprue and HFE

Journal of Crohn's and Colitis (2011) 5, 369–372
available at www.sciencedirect.com
SHORT REPORT
Concomitant presentation of collagenous sprue and
HFE hemochromatosis
a
b
The Cleveland Clinic, Department of Gastroenterology and Hepatology, United States
The Cleveland Clinic, Department of Pathology, United States
Received 6 February 2011; received in revised form 17 March 2011; accepted 17 March 2011
KEYWORDS
Collagenous sprue;
Collagenous colitis;
Hemochromatosis
Abstract
Collagenous sprue (CS) is a progressive malabsorptive disorder characterized by collagen
deposition beneath the basement membrane of small bowel epithelium in refractory celiac
sprue. 1 CS is a pathologically distinct entity from celiac disease, despite a similar clinical
presentation. The etiology of CS is unclear, although there are speculations that CS and celiac
disease may share similar pathogenetic pathways.,2 On the other hand, HFE hemochromatosis
(HH) is a distinct disease entity. Celiac disease and HH are common HLA-associated genetic
disorders in Northern European populations. There are a few case reports linking celiac disease
and HH. We present a patient diagnosed with concurrent CS and HH.
© 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
1. Case presentation
A 40-year-old man of Irish and German descent with a history of
acute myocardial infarction 2 months prior, presented with
watery, malodorous, large volume liquid stool 15 times daily
for 5 months, and a 60-pound weight loss. The patient was
Abbreviations: CS, Collagenous sprue; HH, HFE Hemochromatosis.
⁎ Corresponding author at: The Cleveland Clinic, 9500 Euclid
Avenue, Desk A30, Cleveland, OH 44195, United States. Tel.: +1 216
636 9561; fax: +1 216 444 6302.
E-mail addresses: parisik@ccf.org (K.R. Parisian),
plesect@ccf.org (T.P. Plesec), fairbak@ccf.org (K.D. Fairbanks),
tavilla@ccf.org (A.S. Tavill), shenb@ccf.org (B. Shen).
initially evaluated at a local hospital with a negative work-up
including stool microbiological studies, CT abdomen and
pelvis, colonoscopy, and EGD without biopsies. He had no
response to loperamide and a gluten-free diet for 2 weeks. He
presented to our hospital for further evaluation. Physical
examination revealed a cachectic man with a soft abdomen,
increased bowel sounds, no hepatosplenomegaly and without
tenderness to palpation. A review of systems was significant
for alopecia, nausea, vomiting, bloating, and chest discomfort. Medications included aspirin, prasugrel, omeprazole,
potassium chloride, carvedilol, and simvastatin.
The patient was admitted to the hospital, where he was
found to have hypokalemia, hypomagnesemia, hypocalcemia
and a serum albumin level of 1.8 g/dL. He underwent a CT
enterography that showed no signs of active small bowel
disease or malignancy. He then had EGD showing diffuse
1873-9946/$ - see front matter © 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.crohns.2011.03.009
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Keely R. Parisian a,⁎, Thomas P. Plesec b , Kyrsten D. Fairbanks a ,
Anthony S. Tavill a , Bo Shen a
370
scalloping, blunting of the duodenal villi, and sloughing of
mucosa with biopsy forceps (Fig. 1). Duodenal histology
shows abnormal villous architecture with markedly thickened and irregular subepithelial collagen table that incorporates capillaries and lamina propria cells. A trichrome
stained section highlights the abnormal collagen table in
blue (100×, Fig. 2). A flexible sigmoidoscopy revealed normal
appearing mucosa of the sigmoid colon and rectum;
however, histopathology demonstrated collagenous colitis
and proctitis (Fig. 3). The patient was started on oral
budesonide and total parenteral nutrition (TPN), with
improvement in diarrhea and nutritional status. He continued to have approximately 8 bowel movements daily and was
transitioned to oral prednisone after trials of ciprofloxacin
and tinidazole for possible concurrent small bowel bacterial
overgrowth. The patient was then cycled off TPN as he had
sufficient oral intake and clinical improvement in diarrhea
after a 15-day hospital stay. He was discharged to home on
oral prednisone with outpatient follow up.
Figure 2 Trichrome stain highlights the abnormal collagen
table in blue (100×).
Figure 3 Sigmoid biopsy, H&E shows thickened subepithelial
collagen table that also incorporates lamina propria cells and
capillaries. The lamina propria is expanded by mononuclear
inflammatory cells, and the surface epithelium is injured.
Occasional intraepithelial lymphocytes are also identified.
At admission, serum iron was 224 μg/dL, serum ferritin
was 2200 ng/mL, and AST and ALT were elevated N 3 times
the upper reference limit. Further work up demonstrated a
homozygous C282Y mutation in the HFE gene. A liver biopsy
showed mild to moderate hemosiderosis with preserved liver
architecture without significant hepatocellular necrosis,
cholestasis or steatosis (Fig. 4). The duodenal biopsy did
not reveal stainable iron. After 12 once-weekly phlebotomy
sessions, serum ferritin and liver enzymes returned to
normal. Subsequent EGD and flexible sigmoidoscopy with
duodenum, colon, and rectal biopsies showed normal villous
architecture and resolution of the abnormal subepithelial
collagen table (H&E, 100×, Fig. 5). At follow-up 9 months
later and off prednisone therapy, EGD and flexible sigmoidoscopy with biopsies remain normal. The patient was treated
Figure 4 Liver biopsy shows increased periportal hepatocellular-predominant iron deposition, characteristic of hereditary
hemochromatosis. The portal tracts are demarcated by the
arrows, and the iron granules stain blue in this Perl's iron stain.
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Figure 1 EGD showing diffuse scalloping, blunting of the
duodenal villi, and sloughing of mucosa with biopsy forceps.
K.R. Parisian et al.
Concomitant presentation of collagenous sprue and HFE hemochomatosis
Figure 5 Duodenal biopsy off prednisone showing normal
villous architecture and resolution of the abnormal subepithelial
collagen table (H&E, 100×).
2. Discussion of diagnosis
Diagnostic criteria of CS and HH have been well defined in the
literature. A combined evaluation with endoscopy, laboratory
tests, and histopathology yield a specific diagnosis. However,
the challenging part is the identification of etiology and
pathogenesis of CS and HH and their relationship. Both CS and
collagenous colitis have been linked to immune-mediated
disorders.3 There are reported associations between collagenous colitis and Crohn's disease, ulcerative colitis, lupus,
primary biliary cirrhosis, polymyalgia rheumatica, diabetes,
thyroid disease, celiac disease, pancreatitis, and pernicious
anemia.3 There was an increased prevalence of Crohn's
disease, diabetes mellitus, and Sjogren's syndrome in patients
with celiac disease.4 Collagenous sprue or collagenous colitis
has also been reported to be a part of autoimmune disorders.
Environmental factors may contribute to the onset of many
autoimmune disorders. Rubio-Tapia et al. 5 proposed that
autoimmune disease in association with environmental factors
(drugs, infection, and food antigens) may lead to gut
inflammation and CS. Vesoulis et al. 6 reported a case of
synchronous occurrence of collagenous colitis and Clostridium
difficile-associated pseudomembranous colitis. While dysbiosis3 and viruses such as rotavirus4 may contribute to the
pathogenesis of collagenous colitis and celiac disease, their
role in CS has not been studied.
The relation of celiac disease and hemochromatosis has
been shown in case reports. The diagnosis of HH after the
successful treatment of celiac disease has been described.
Butterworth et al. concluded that HFE gene mutations are
more common in patients with celiac disease and may offer a
survival advantage.7 In another study, Leyden et al. failed to
show an increased frequency of HFE mutations in patients with
celiac disease.8 Thus the association of celiac disease and HH
remains uncertain. Interestingly, collagenous sprue, a distinct
disease entity from celiac disease with different pathogenetic
pathways, diagnostic criteria, and prognosis, has not been
reported to concomitantly occur with hemochromotosis in the
literature.
Our patient did not have celiac disease but rather CS and
collagenous colitis. A relationship between CS and HH
remains speculative. There are several possibilities that
the two disease entities have causality relationship; or the
two share common etiopathogenetic pathways; or the
concurrent presentation of two conditions was coincidental.
Mechanistically, it is hard to imagine that CS with characteristic poor iron absorption would lead to the phenotypic
features of HH; rather CS might conceivably protect against
or obscure such features. Our patient restored a normal
serum ferritin with only 12 one-unit phlebotomies. This
constitutes about 3 g of storage iron, roughly three times the
normal for an adult male, that while indicative of phenotypic
expression of an iron overload condition is a relatively low
value in clinical HFE hemochromatosis. On the other hand,
iron overload in HH has been reported to be associated with
chronic inflammation. Gut mucosal injury is known to occur
in response to reactive oxygen species involved in the
inflammatory cascade. Iron-derived oxidant activity may
exacerbate inflammation of intestinal mucosa in inflammatory bowel disease and conceivably iron overload of
relatively modest amounts may contribute to intestinal
mucosal damage.9,10 A prospective study shows that iron
chelators significantly reduce reactive oxygen species in
patients with ulcerative colitis.10 The data support the
speculation that HH with iron overload may be associated
with intestinal mucosal injury and resultant CS. Resolution of
submucosal collagen bands and associated inflammation in
the small and large bowels after phlebotomy, with and
without steroid use in our patient, might further support the
hypothesis.
CS and HH may share similar pathogenetic pathways. HH
has been reported to be associated with ulcerative colitis
and primary sclerosing cholangitis.11,12 CS is a rare disease
entity, with unknown genetic association. In contrast, the
HLA-D locus has been shown to be associated with celiac
disease, which is in close proximity to the HFE locus on
chromosome 6, leading to speculation that there might be a
genetic linkage of the two diseases.13 It may be further
hypothesized that the genetic predisposition for either
disease lessens manifestations of the other and may serve
as a mutual protective mechanism.13 Injury to iron transporters in the apical membrane of enterocytes in celiac
disease can lead to iron deficiency, reducing iron overload in
HH.13 Our first patient with HH had relatively low iron stores
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with prednisone for 6 months. Treatment response while off
prednisone demonstrates that phlebotomy contributed to
disease remission.
A second case of an 84-year-old man with a history of
hypertension, hyperlipidemia, atrial tachycardia, hypothyroidism, prostate cancer status post radiation therapy, chronic
renal insufficiency, gout, and hemochromatosis maintained
with once monthly phlebotomy presented with watery
diarrhea and incontinence over the course of one month. In
2004, he underwent gene testing that was negative for C282Y
and H63D mutations of the HFE gene. A liver biopsy at that time
showed severe hepatocellular iron deposition suggestive of HH
and an iron index of 5, however there was no significant
fibrosis. He had no history of blood transfusion or iron infusion.
A flexible sigmoidoscopy at the time of diarrhea showed
collagenous colitis. The patient responded to treatment with
bismuth subsalicylate and continued monthly phlebotomy.
371
372
and did not have advanced liver disease, which may be due to
a protective effect from underlying CS.
3. Treatment and management
Acknowledgments
There are no sources of funding. KP conceived the study,
participated in the design of the study, collected data, and
drafted the manuscript. TP carried out the studies and data
analyses and helped to draft the manuscript. KF participated
in the design and coordination, carried out studies and data
analyses, and helped to draft the manuscript. AT participated in the study design and coordination, provided significant
advice, and helped to draft the manuscript. BS participated
in the study design and coordination, carried out the studies
and data analyses, and helped to draft the manuscript. All
authors read and approved the final manuscript.
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CS is often associated with poor prognosis and even mortality.14 Recent literature has shown treatment success with a
combination of corticosteroids and other immunosuppressants.5,14–16 There was reported clinical response of 80% in
patients with CS treated with immunosuppressive drugs
(mainly steroids) and gluten free diet for 6 or more months.5
However, complete histopathological response and resolution
is uncommon. Most reported cases of CS demonstrate a poor
response to gluten free diet alone.16 Other reported treatment
options included parenteral nutrition, low carbohydrate and
low fat diets, probiotics, fiber supplementation, and vitamin
supplementation.16 Schmidt et al. 17 present a case report of
clinical improvement with infliximab (5 mg/kg body weight)
after failure of high dose steroids in a patient with CS.17 For the
treatment of HH with iron overload, periodic phlebotomy to
maintain normal body iron stores is the standard of care.18
The main treatment regimen in our patient was oral
corticosteroids (prednisone and budesonide) along with
phlebotomy. After 6 months of therapy, we observed both
clinical and histopathological remission for CS as well as
normalized serum ferritin and ALT/AST level for HH. One
year later and after corticosteroid taper, histopathology of
the small bowel and colon remain normal with intermittent
phlebotomy. In the second case, our patient responded to
therapy with bismuth subsalicylate and monthly phlebotomy. In summary, it is plausible that iron overload caused
collagen deposition in the small bowel and resultant CS.
K.R. Parisian et al.