This article appeared in the Summer 2005 edition of Celiac.coms
Celiac.com 01/11/2006 - For many years, biopsy of the small bowel demonstrating villous atrophy
has been fundamental to the diagnosis of celiac disease. Older celiacs
will remember, fondly or otherwise, the Crosby suction biopsy device
which was swallowed attached to a long tube and made its way down to
the small bowel where, position confirmed by x-rays, it guillotined
a small portion of tissue. The procedure was tedious and technical failures
common—only identified when the device was hauled up after several
hours. Later it became clear that biopsies from the duodenum obtained
during endoscopy were just as good, and the biopsy process became a
five minute job with no need for X-rays. Nevertheless, many celiacs
are reluctant to undergo biopsy and its necessity is increasingly questioned,
particularly now that blood tests for celiac-related antibodies are
highly sensitive and specific. There are a number of reasons why, in
my own practice, biopsies continue to be helpful in celiacs diagnosed
- Biopsies are necessary when blood tests are negative. While endomysial
(EmA) and tissue transglutaminase (TTGA) antibodies are detectable
in most cases where villous atrophy is present, 5-10% of patients
lack these antibodies1.
In this situation, where the story is suggestive of celiac, perhaps
with a family history or strongly suggestive symptoms, biopsy is the
only way to make the diagnosis. Increasingly, physicians recognize
that many patients with gluten sensitivity do not have villous atrophy
(Grade III of the Marsh classification) of "classic" celiac
disease, but have milder abnormalities such as crypt hyperplasia (Marsh
II) or an excess of the inflammatory cells called lymphocytes (Marsh
I). Patients in these categories are less likely to have positive
- Biopsies are necessary where false positive blood tests may occur.
TTGA, particularly where levels are low, may be associated with diseases
other than celiac: ulcerative colitis, Crohns disease, arthritis
and liver diseases without any evidence of celiac disease have been
Newer TTGA tests have steadily improved in this regard but I still
would be reluctant to diagnose celiac on a TTGA test alone. "False
positive" EmA is a different issue which I will return to.
- Biopsies give a baseline for comparison. Suppose a patient starts
a gluten-free diet without biopsy—we dont know whether
she or he had Marsh I, II or III or even normal histology. A year
later, same patient develops new symptoms of diarrhea, weight loss,
whatever. Well get a duodenal biopsy as part of the workup,
but its going to be difficult to interpret without knowing
what things were like before going gluten-free. Specifically, a baseline
to look back at tells us whether the small bowel is better, worse
or no different, and helps us decide whether we need to focus on celiac
disease as the most likely cause of new problems or explore other
possibilities involving the rest of the gut. The biggest diagnostic
disaster of all, of course, is the gluten-free diet started without
any sort of baseline investigation including antibodies, raising the
specter of the infamous gluten challenge if a definitive diagnosis
- Biopsies provide a "gold standard" assessment of the
state of the bowel. There has been much excitement recently about
capsule endoscopy, a wireless device the size of a large pill (not
to be confused with the Crosby capsule!) which makes its own way down
the small bowel taking pictures as it goes. Characteristic abnormalities
can be seen in celiac disease, raising the possibility that this device
might be useful in diagnosis. If experience with conventional endoscopes
is any guide, however, these abnormalities are missing in a sizeable
minority of celiacs particularly with mild disease4
(Capsule endoscopy in its present state of development can not take
biopsies). Certainly the capsule allows assessment of the bowel beyond
the reach of conventional "anaconda-style" endoscopes,
but I am not convinced at present that it can replace biopsy.
- A follow-up biopsy gives an indicator of progress. I offer my patients
a repeat biopsy after two years gluten-free and perhaps surprisingly
most take up the offer and are keen to hear how things have improved.
Ive increased the biopsy interval from one to two years because
only 40% of people had complete recovery after 12 months gluten-free5.
EmA and TTGA disappearance is only a marker of how successful gluten
exclusion has been and is not a reliable indicator of bowel recovery.
Does persisting villous atrophy matter if the patient is doing well
on a gluten-free diet? Intuitively, one might like to keep a closer
eye on the patient with persistently flat biopsies, who could be at
greater risk of complications in the future6.
- The endoscopy not only allows examination and biopsy of the duodenum
but also a look at the esophagus and stomach. Sad fact of the ageing
process is that you start to collect diseases like trading cards,
and just because youre celiac doesnt mean you cant
have something else. Its important to have a good look for
bleeding lesions in the upper gut even if the blood work for a seventy
year old with anemia says celiac (and check out the colon too, but
thats a topic for another day).
On the other hand, we recognize that biopsies are not
always the final arbiter in diagnosis. While the jury is still out on
what a TTGA positive, biopsy negative result means with regard to gluten
sensitivity, there is plenty of evidence that a positive EmA generally
does mean that biopsy abnormalities will follow: My own follow-up of EmA
positive, biopsy negative patients indicates that they will develop abnormal
histology if not treated7.
So it makes sense to start EmA positive people on gluten-free without
waiting for significant bowel damage—and as already stated, even
a normal baseline biopsy will provide a reference for any problems that
might arise in the future.
Sometimes I meet a patient with bad gut symptoms but
completely normal blood work up and biopsies and when all else fails I
will run a trial of gluten-free. It often works, particularly if there
is a family history of celiac. But then again, if it doesnt, we
have a baseline normal biopsy to say there is no need to persevere.
I guess in the future diagnosis of gluten sensitivity
will rely on totting up various factors, none individually essential:
blood tests, biopsies, family history, genetic testing for the HLA celiac
genes. Some researchers are making a case for dropping the biopsy requirement
if the antibody blood work checks out in children8,
for whom (and for the parents) endoscopy and biopsy is a major issue.
In adults however it is quick, straightforward and safe and will remain
a key part of my celiac workup.
William Dickey is a gastroenterologist at Altnagelvin
Hospital, Londonderry, Northern Ireland, with over 400 celiac patients
attending his clinics. His interest in celiac disease goes back some fourteen
years and he has published extensively on the subject. He is an associate
member of Coeliac UKs Medical Advisory Council.
- Dickey W, McMillan SA, Hughes DF. Sensitivity of serum tissue transglutaminase
antibodies for endomysial antibody positive and negative coeliac disease.
Scand J Gastroenterol 2001; 36: 511-4.
- Wahab PJ, Crusius JBA, Meijer JWR, Mulder CJJ. Gluten challenge in
borderline gluten-sensitive enteropathy. Am J Gastroenterol 2001; 96:
- Di Tola M, Sabbatella L, Anania MC, Viscido A, Caprilli R, Pica R,
Paoluzi P, Picarelli A. Anti-tissue transglutaminase antibodies in inflammatory
bowel disease: new evidence. Clin Chem Lab Med. 2004;42(10):1092-7.
- Oxentenko AS, Grisolano SW, Murray JA, Burgart LJ, Dierkhising RA,
Alexander JA. The insensitivity of endoscopic markers in celiac disease.
Am J Gastroenterol. 2002 Apr;97(4):933-8.
- Dickey W, Hughes DF, McMillan SA. Disappearance of endomysial antibodies
in treated celiac disease does not indicate histological recovery. Am
J Gastroenterol 2000; 95: 712-4.
- Meijer JWR, Wahab PJ, Mulder CJJ. Histologic follow-up of people
with celiac disease on a gluten-free diet: slow and incomplete recovery.
Am J Clin Pathol 118(3):459-63, 2002 Sep.
- Dickey W, Hughes DF, McMillan SA. Patients with serum IgA endomysial
antibodies and intact duodenal villi: clinical characteristics and management
options. Scand J Gastroenterol 2005: in press
- Barker CC, Mitton C, Jevon G, Mock T.Can tissue transglutaminase
antibody titers replace small-bowel biopsy to diagnose celiac disease
in select pediatric populations? Pediatrics. 2005 May;115(5):1341-6