Partially responsive celiac disease resulting from small intestinal bacterial overgrowth and lactose intolerance

Abstract

Celiac disease is a common cause of chronic diarrhea and malabsorption syndrome all over the world. Though it was considered uncommon in India in past, it is being described frequently recently. Some patients with celiac disease do not improve despite gluten free diet (GFD). A study described 15 cases of celiac disease unresponsive to GFD in whom small intestinal bacterial overgrowth (SIBO) or lactose intolerance was the cause for unresponsiveness.
During a three-year period, 12 adult patients with celiac disease were seen in the Luminal Gastroenterology Clinic in a tertiary referral center in northern India. Two of these 12 patients (16.6%), who did not fully respond to GFD initially, are presented here. Unresponsiveness resulted from SIBO in one and lactose intolerance in the other. The former patient responded to antibiotics and the latter to lactose withdrawal in addition to standard GFD.
In patients with celiac disease partially responsive or unresponsive to GFD, SIBO and lactose intolerance should be suspected; appropriate investigations and treatment for these may result in complete recovery.

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BMC Gastroenterology
Open Access
Case report
Partially responsive celiac disease resulting from small intestinal
bacterial overgrowth and lactose intolerance
Uday C Ghoshal*
1
, Ujjala Ghoshal
2
, Asha Misra
1
and Gourdas Choudhuri
1
Address:
1
Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India and
2
Department
of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
Email: Uday C Ghoshal* - ghoshal@sgpgi.ac.in; Ujjala Ghoshal - ujjala@sgpgi.ac.in; Asha Misra - ghoshal@sgpgi.ac.in;
Gourdas Choudhuri - gc@sgpgi.ac.in
* Corresponding author
Abstract
Background: Celiac disease is a common cause of chronic diarrhea and malabsorption syndrome
all over the world. Though it was considered uncommon in India in past, it is being described
frequently recently. Some patients with celiac disease do not improve despite gluten free diet
(GFD). A study described 15 cases of celiac disease unresponsive to GFD in whom small intestinal
bacterial overgrowth (SIBO) or lactose intolerance was the cause for unresponsiveness.
Case presentation: During a three-year period, 12 adult patients with celiac disease were seen
in the Luminal Gastroenterology Clinic in a tertiary referral center in northern India. Two of these
12 patients (16.6%), who did not fully respond to GFD initially, are presented here.
Unresponsiveness resulted from SIBO in one and lactose intolerance in the other. The former
patient responded to antibiotics and the latter to lactose withdrawal in addition to standard GFD.
Conclusion: In patients with celiac disease partially responsive or unresponsive to GFD, SIBO and
lactose intolerance should be suspected; appropriate investigations and treatment for these may
result in complete recovery.
Background
Celiac disease is a common cause of chronic diarrhea and
malabsorption syndrome (MAS) all over the world.
Though it was considered uncommon in India in past, it
is being described frequently recently [1,2]. Some patients
with celiac disease do not improve despite gluten free diet
(GFD). Tursi et al described 15 cases of celiac disease unre-
sponsive to GFD in whom small intestinal bacterial over-
growth (SIBO) or lactose intolerance was the cause of
unresponsiveness [3]. We describe two adult patients with
celiac disease only partially responsive to GFD; unrespon-
siveness resulted from SIBO in one and lactose intoler-
ance in the other.
Case presentation
During a 3-y period from July 2000 to July 2003, 12 adult
patients with celiac disease diagnosed using standard cri-
teria [2] were seen in the Luminal Gastroenterology Clinic
of the Department of Gastroenterology in a tertiary refer-
ral center in northern India. All except two (16.6%) of
them responded clinically to GFD. The data of the two
patients, who were initially unresponsive to standard GFD
is presented below.
Case 1
A 35-y-old female presented with chronic large volume
diarrhea for more than 3-y. She passed 20 liquid (includ-
ing nocturnal), frothy, pale, greasy, unusually offensive
Published: 22 May 2004
BMC Gastroenterology 2004, 4:10
Received: 24 December 2003
Accepted: 22 May 2004
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stools. She never passed blood with these stools. She lost
11 kg weight in 3 y. She had temporary reduction in
diarrhea and gain in weight while on anti-tubercular drug
therapy given 3 mo after onset of this disease. She was
emaciated (body mass index 13.7 kg/m
2
), pale, had angu-
lar stomatitis and clubbed fingers. Investigations revealed:
Hb 98 g/L (normal 120–150), total leukocyte count 5.9 ×
10
9
/L (normal 4.0 – 11.0 × 10
9
) with normal differential
counts, serum albumin 30 g/L (normal 40–60), serum
iron 9.7 µmol/L (normal 11–29); serum bilirubin and
transaminases were within normal limits. ELISA test for
human immunodeficiency virus was negative. Sudan III
stained spot-stool specimen showed 15 fat droplets/high
power field (normal ≤10); urinary excretion over 5 h after
ingestion of 5 g D-xylose was 0.29 g (normal ≥1 g). Esoph-
agogastroduodenoscopy revealed flattened duodenal
folds and biopsy revealed subtotal villous atrophy, crypt
hyperplasia and increased intra-epithelial lymphocytes
(Marsh's stage IIIB) [4]. Jejunal aspirate culture by a
method described by us previously [5,6] revealed growth
of Klebsiella pneumoniae and Pseudomonas aeruginosa (col-
ony counts >10
5
CFU/ml). Glucose hydrogen breath test
(GHBT) by a standard method [5] revealed fasting value
of 36 ppm and highest value of 200 ppm 60 minutes after
100 g glucose. This was interpreted as a positive test for
SIBO as per standard criteria [5]. Lactulose hydrogen
Course of a patient with celiac diseaseFigure 1
Course of a patient with celiac disease. Her response to gluten free diet (GFD) was inadequate despite a good compliance.
This might have resulted from small intestinal bacterial overgrowth (SIBO) as addition of antibiotics with disappearance of
SIBO (as evidenced by a negative glucose hydrogen breath test, GHBT) resulted in resolution of symptoms. EMA: anti-endomy-
sial antibody.
GHBT -veTetracycline
added
Tetracycline Tetracycline
stopped
EMA +ve
GFD started
GHBT +ve
>10
5
bacteria
in jejunal fluid
0
10
20
Dec 7
2000
Jan 18
2001
April 12
2001
July 26
2001
Jan 17
2002
August 30
2002
March 13
2003
Stool/d BMI (Kg/m2) Hb (g/dL)
D-xylose 1.5 g/5 g/5 h

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breath test by a standard technique [5] revealed two peaks;
the first peak was at 110 min after 15 ml lactulose (24
ppm above basal, basal value 17 ppm); this could be
related to SIBO. The time to second peak was 200 min
(which corresponds to oro-cecal transit time, OCTT) after
lactulose ingestion (21 ppm above basal). Therefore,
OCTT was prolonged (median value in healthy subjects in
India 65 min, range 40–110) [5]. The subsequent treat-
ment and course is depicted in Fig. 1. Though she
responded to treatment with tetracycline 500 mg t.i.d over
2 months, diarrhea recurred with reduction in body
weight 3 months after stopping the drug. At this time,
result of anti-endomysial antibody test using indirect
immunofluorescence assay (Binding Site, UK) was availa-
ble and was positive. She was started on GFD. Despite
good compliance to it, there was inadequate symptomatic
response (Fig. 1), even though D-xylose test result was
normal one y after presentation [urinary excretion over 5
h after ingestion of 5 g D-xylose 1.5 g (normal ≥1 g)]. In
view of finding SIBO at presentation and transient
response to antibiotics, tetracycline was re-started. She
improved symptomatically with gain in weight and nor-
malization of hemoglobin. GHBT repeated at this stage
failed to show persistence of SIBO.
Case 2
A 44-y-old female presented with large volume diarrhea
for 14 y. She passed 6–7 large volume, watery, explosive
stools everyday (including nocturnal). She gave history of
reduction of diarrhea on fasting and increase on taking
milk. She lost 9 kg weight in last 1 y. Antibiotic therapy
resulted in some reduction in stool frequency. Physical
examination revealed pallor and emaciation (BMI 16 kg/
m
2
). There was no clubbing, lymphadenopathy or orga-
nomegaly. Investigations revealed: Hb 97 g/L (normal
120–150), total leukocyte 7.7 × 10
3
/L (normal 4.0 – 11.0
× 10
9
) with normal differential counts, serum bilirubin
10.3 µmol/L (normal 2–18), alanine aminotransferase
and alkaline phosphatase 29 U/L (normal 0–40) and 88
U/L (normal <150), respectively. Serum total protein and
albumin were 57 and 27 (normal 60–84 and 35–55) g/L,
respectively; creatinine and fasting blood glucose were 53
µmol/L (normal 50–110) and 3.8 mmol/L (normal 3.9–
6.1). ELISA test for human immunodeficiency virus was
negative. Stool microscopic examination did not show
ova, cyst or parasite; fat in spot stool specimen stained
with Sudan III stain was 16 droplets/HPF (normal ≤10
droplets/HPF); urinary excretion over 5 h after ingestion
of 5 g D-xylose was 0.18 g (normal ≥1 g). Serum immu-
noglobulins were within normal limits. Esophagogas-
troduodenoscopy was normal and duodenal biopsy
revealed mild villous atrophy and broadening, crypt vil-
lous ratio 1:2 (normal 1: 3 to 5), lymphomononuclear
infiltrate in lamina propria and increased intra-epithelial
lymphocytes (Marsh's stage IIIA) [4]. Antiendomysial
antibody using indirect immunofluorescence assay (Bind-
ing Site, UK) was positive. Gluten free diet was started.
The subsequent course is shown in Fig. 2. Though she
responded to GFD to which she was fully compliant,
loose stool continued with a frequency of 4 to 5/d even 8
months after GFD. Anti-endomysial antibody repeated at
this stage was found negative. D-xylose test repeated at
this stage showed normal result [urinary excretion over 5
h after ingestion of 5 g D-xylose 1.1 g (normal ≥1 g)]. A
duodenal biopsy repeated 18 mo after GFD revealed
maintained villous architecture, mild lymphomononu-
clear infiltrate in lamina propria and mildly increased
intra-epithelial lymphocytes (Marsh's stage I). In view of
nearly normal villous morphology and function as was
evidenced by normal D-xylose test and negative anti-
endomysial antibody an osmotic cause like lactose intol-
erance was suspected. Lactose tolerance test and lactose
hydrogen breath test were done with 50 g oral lactose.
Fasting blood glucose and breath hydrogen were 4.6
mmol/L and 10 ppm, respectively; 1 h post lactose values
were 5.2 mmol/L and 36 ppm respectively. She had symp-
toms in the form of loose stools during 3-h observation
period. Based on these, a diagnosis of lactose intolerance
was made and lactose-free diet was started; diarrhea
resolved during follow-up (Fig. 2).
Discussion and conclusion
Diagnosis of celiac disease in both the patients was estab-
lished on standard criteria [2]. We have earlier shown that
half of patients with MAS resulting from various causes
including celiac disease may have SIBO [6]. In patients
with tropical sprue it resulted from small intestinal stasis
as evidenced by prolonged OCTT [5]. Similar mechanisms
may operate in patients with MAS due to other causes; the
patient with celiac disease with SIBO in this report had
prolonged OCTT. Prolonged OCTT has been reported by
other workers in patients with celiac disease, which nor-
malized after GFD [7]. Unabsorbed foods within the
intestinal lumen may also promote growth of bacteria in
small intestinal lumen. We believe that SIBO in patients
with MAS due to another cause may have following clini-
cal significances, (1) a response to antibiotics may lead to
a fallacious diagnosis of tropical sprue as response to anti-
biotics has been considered to be an important criterion
for diagnosis of this disease [8]; (2) it may be a cause for
inadequate response or refractory state despite GFD as
occurred in our first patient and as has been reported by
Tursi et al [3]. Lactose intolerance could be another cause
for such inadequate response to GFD. Lactase deficiency
causing intolerance to lactose is known to be either pri-
mary or secondary; though in our patient, whether it was
primary or secondary is a matter of conjecture, the latter is
more likely as degenerated intestinal epithelial cells in
patients with celiac disease are often found to have sparse
endoplasmic reticulum, reflecting low level of digestive

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enzymes including lactase [9]; primary lactase deficiency
is somewhat uncommon too [10]. However, a definite
diagnosis of lactose intolerance is important as a firm
diagnosis helps the clinician as well as the patient to com-
pletely withdraw lactose containing foods, compliance to
which may not be so easy for a patient with celiac disease
already on significant dietary restriction without a definite
diagnosis, particularly if the patient is vegetarian. The sec-
ond patient continued to have diarrhea despite improve-
ment in D-xylose test and duodenal biopsy, which led us
to suspect a predominantly osmotic factor as the cause of
diarrhea. Therefore, we investigated for lactose intoler-
ance contributing to osmotic diarrhea. Normal result of
D-xylose test was helpful as it suggested normalization of
intestinal mucosa; D-xylose test has a high sensitivity to
detect abnormal mucosa causing MAS [11]. In fact, serial
tests of intestinal permeability, which are based on a prin-
ciple similar to D-xylose test, have been used successfully
to non-invasively predict normalization of intestinal
mucosa before undertaking invasive tests like endoscopic
duodenal biopsy [12].
Small intestinal bacterial overgrowth in patients with
celiac disease may lead to persistent diarrhea due to
Course of the other patient with celiac diseaseFigure 2
Course of the other patient with celiac disease. Her response to gluten free diet (GFD) was inadequate despite a good compli-
ance as she continued to pass 4–5 liquid stools/day. She was found to have lactose intolerance (LI). Inadequate response to
GFD might have been due to LI as withdrawal of lactose from diet resulted in complete resolution of symptoms. Other abbre-
viations used: Bx: biopsy; PVA: partial villous atrophy; EMA: anti-endomysial antibody; LHBT: lactose hydrogen breath test; LT:
lactose tolerance test.
D-xylose 0.2g/5 g/5 h
Duodenal Bx: PVA
0
10
20
May 15 2002 August 20 2002 Jan 1 2003 March 6 2003
Stool/d BMI (Kg/m2) Hb (g/dL)
D-xylose 1.1 g/5/g/5 h
Duodenal Bx: nearly
normal
LHBT, LTT +ve for LI
Lactose withdrawn
EMA +ve
GFD started

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disturbances in luminal digestion and alteration of
mucosal function, albeit minor [13]. Bacteria in small
intestine in patients with SIBO causes deconjugation of
bile acids, which causes watery diarrhea due to stimula-
tion of colonic secretion and steatorrhea due to depletion
of bile acid pool [13]. Lactose intolerance results in per-
sistence of diarrhea mainly due to osmotic effect of unab-
sorbed lactose and flatulence due to production of gas
from fermentation of unabsorbed lactose.
Refractory celiac sprue is defined as an initial (primary) or
subsequent (secondary) failure of a strict GFD to restore
normal intestinal structure and function and may result
from several mechanisms [14]. It is important to keep all
these causes of refractory celiac sprue in mind and to
investigate and treat for all these factors [14]. Though
SIBO and secondary lactose intolerance are expected and
known to be common in celiac disease, until recently
[3,15], only a few reports have been published on this
issue [16,17]. Though normalization of duodenal histol-
ogy may take long time up to one to two years, clinical
response such as reduction in diarrhea and weight gain
occurs within weeks [14]. Failure of normalization of
duodenal histology has been proposed as a criterion for
diagnosis of refractory sprue [14]. Persistent symptoms
despite normalization of duodenal histology may suggest
causes other than refractory sprue such as SIBO and lac-
tose intolerance.
In conclusion, we believe that if diarrhea persists in a
patient with celiac disease despite improvement in duode-
nal biopsy and D-xylose absorption, lactose intolerance
and SIBO should be suspected; appropriate investigations
and treatment for these may result in complete recovery.
List of abbreviations
GFD: gluten free diet
SIBO: small intestinal bacterial overgrowth
MAS: malabsorption syndrome
Hb: hemoglobin
ELISA: enzyme linked immunosorbant assay
CFU: colony forming units
GHBT: glucose 'hydrogen breath test
PPM: parts per million
OCTT: orocecal transit time
BMI: body mass index
HPF: high power field
UK: United Kingdom
LI: lactose intolerance
Bx: biopsy
PVA: partial villous atrophy
EMA: endomysial antibody
LHBT: lactose hydrogen breath test
LT: lactose tolerance test
Declaration of competing interests
None declared.
Authors' contribution
Uday C Ghoshal was the clinician involved in the man-
agement of these patients, conceived the idea and drafted
the manuscript. Ujjala Ghoshal standardized and per-
formed microbiological works for the diagnosis of small
intestinal bacterial overgrowth syndrome. Asha Misra per-
formed the hydrogen breath tests. Gourdas Choudhuri
supervised the works. All the authors read and approved
the manuscript.
Acknowledgement
We thank the patients who are presented in this report for giving us writ-
ten consent for publishing their data.
References
1. Mahindra S, Yaccha SK, Srivastava A, Krishnani N, Aggarwal R,
Ghoshal UC, Prasad KK, Naik SR: Celiac disease in Asian Indian
children: Anthropometric and histological study. J Pop Health
Nutr 2001, 19:204-8.
2. Poddar U, Thapa BR, Nain CK, Prasad A, Singh K: Celiac disease in
India: Are they true cases of celiac disease? J Pediatr Gastroen-
terol Nutr 2002, 35:508-512.
3. Tursi A, Brandimarte G, Giorgetti GM: High prevalence of small
intestinal bacterial overgrowth in celiac patients with per-
sistence of gastrointestinal symptoms after gluten
withdrawal. Am J Gastroenterol 2003, 98:839-43.
4. Marsh MN: Gluten, major histocompatibility complex and
small intestine: A molecular and immunological approach to
the spectrum of gluten sensitivity (celiac sprue). Gastroenterol-
ogy 1992, 102:330-54.
5. Ghoshal UC, Ghoshal U, Ayyagari A, Ranjan P, Krishnani N, Misra A,
Aggarwal R, Naik S, Naik SR: Tropical sprue is associated with
contamination of small bowel with aerobic bacteria and
reversible prolongation of orocecal transit time. J Gastroenterol
Hepatol 2003, 18:540-7.
6. Ghoshal U, Ghoshal UC, Ranjan P, Ayyagari A: Spectrum and anti-
biotic sensitivity of bacteria contaminating upper gut in
patients with malabsorption syndrome in the tropics. BMC
Gastroenterology 2003, 3:9 [http://www.biomedcentral.com/1471-
230X/3/9].
7. Chiarioni G, Bassotti G, Germani U, Battaglia E, Brentegani MT,
Morelli A, et al.: Gluten-free diet normalizes mouth-to-cecum
transit of a caloric meal in adult patients with celiac disease.
Dig Dis Sci 1997, 42:2100-5.

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BMC Gastroenterology 2004, 4 http://www.biomedcentral.com/1471-230X/4/10
Page 6 of 6
(page number not for citation purposes)
8. Lim ML: A perspective on tropical sprue. Curr Gastroenterol Rep
2001, 3:322-7.
9. Farrell RJ, Kelly CP: Celiac sprue and refractory sprue. In: Gas-
trointestinal and Liver Disease. Pathophysiology, Diagnosis, Management
Edited by: Feldman M, Friedman LS, Sleisenger MH. Philadelphia: WB
Saunders; 2002:1817-41.
10. Heitlinger LA, Lebenthal E: Disorders of carbohydrate digestion
and absorption. Pediatr Clin North Am 1988, 35:239-55.
11. Bala L, Gowda GAN, Ghoshal UC, Misra A, Bhandari M, Khetrapal
CL:
1
H spectroscopic method for diagnosis of malabsoprtion
syndrome: A pilot study. NMR Biomedicine 2004, 17:69-75.
12. Johnston SD, Smye M, Watson RGP: Intestinal permeability test
in celiac disease. Clin Lab 2001, 47:143-50.
13. Isaacs PET, Kim YS: The contaminated small bowel syndrome.
Am J Med 1979, 67:1049-56.
14. Ryan BM, Kelleher D: Refractory celiac disease. Gastroenterology
2000, 119:243-51.
15. Abdulkarim AS, Burgart LJ, See J, Murray JA: Etiology of nonre-
sponsive celiac disease: Reults of a systemic approach. Am J
Gastroenterol 2002, 97:2016-21.
16. Fine K, Meyer R, Lee E: The prevalence and cause of chronic
diarrhea in patients with celiac sprue treated with a gluten
free diet. Gastroenterology 1997, 112:1830-8.
17. Roufail W, Ruffin J: Effect of antibiotic therapy on gluten sensi-
tive enteropathy. Am J Dig Dis 1966, 11:587-93.
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