Biopsy: not the “gold standard”

Is a small bowel biopsy: not the “gold standard” for celiac disease?

I am frequently asked: “Can you diagnose celiac disease without a small bowel biopsy?” A similar common query is: “Is the small bowel biopsy the ‘gold standard’ for the diagnosis of coeliac disease”?

Biopsy: not the “gold standard”

The answer to these questions is complex and deals with semantics and the changing knowledge about the way gluten causes damage in the body.

Is there a ‘gold standard’?

The big question is: “Is there currently a gold standard for celiac disease?” The concept of a gold standard comes from the monetary system.  In the past, the standard economic unit of account was a fixed weight of gold  literally “the gold standard”. This was supposed to remove “currency uncertainty.” However, now all countries have abandoned their gold standards in favour of a more flexible system.

This ‘gold standard’ metaphor has been carried over to medicine which now has the connotation of an absolute benchmark for diagnosis. Current medical dogma goes: “You can only make the diagnosis of celiac disease if the small biopsy shows villous atrophy.” But, over the last few years, the notion of such a “gold standard” has been relentlessly undermined.

To understand the focus of diagnosis on the small bowel biopsy requires an understanding of the history of celiac disease.

Why was the small bowel biopsy so important?

Celiac disease was first described over a hundred years ago. At this time it was a clinical description for patients who were unwell, had diarrhoea, had a distended abdomen and who grew poorly. The cause was unknown. The pathology was undiscovered. But poor absorption of nutrients (malabsorption) was recognized as the problem.

It was not until Willem Dicke, a Dutch pediatrician demonstrated that the removal of wheat from the diet caused the symptoms of celiac disease in children to disappear and reported his findings in an in 1950.

What stimulated Dicke to link coeliac disease and wheat flour will probably never be fully explained but one story is that during the Second World War wheat products were in very short supply in the Netherlands and Dicke noticed that children with the condition who were being fed other foods in place of wheat were improving. After the war when wheat consumption recommenced, the children again deteriorated with the development of symptoms.

It is interesting to note that in these early years it was noted by several doctors that bread aggravated symptoms but none made the link to causation of celiac disease as Willem Dicke was to do in the late 1940s.

Thus in these early days, the tests for celiac disease were based on investigations looking for evidence of malabsorption (eg: fat in the stool, blood tests for vitamin levels, and the xylose absorption test).

The characteristic small bowel tissue damage was not discovered until 1954.  John Paulley, a physician from Ipswich, took small bowel biopsies from coeliac patients who were undergoing abdominal operations.  By this method he obtained fresh tissue and conclusively showed the loss of normal villi (the finger-like projections on the bowel surface) producing the typical flat mucosa.

Following this breakthrough, the hunt was on to investigate the bowel more thoroughly. A few years later, 1956, Margot Shiner developed a method to take small bowel biopsies (that is to take a small sample of the lining of the upper bowel, the jejunum). This was a quick and safe method and thereby opening the door to diagnose coeliac disease.

The gold standard was set

At this stage in coeliac history, it became established that the way to diagnose coeliac disease was to find abnormalities in the gut through small bowel biopsy. At his time in history, coeliac disease was defined as people who had gut disease and who had an abnormal biopsy. So the biopsy became the diagnostic test for coeliac disease. The “gold standard” was established. However, this was based on a teleological argument: coeliac disease was a flat biopsy – and a flat biopsy meant coeliac disease.

Nothing but trouble

Histology uncertainty: There are problems with the interpretation of the histology of the small bowel in relation to coeliac disease. Marsh first suggested criteria to grade the various degrees of histological damage in 1993. This was because the extent of the small intestinal changes can vary from normal mucosa with increase in intraepithelial lymphocytes (IEL) to a completely flat looking mucosa. Subsequently, a group of pathologists revised this and wrote a report to standardize the histological features of coeliac disease. This is called the modified Marsh classification (Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology. 1992; 102:330-54):

So the question is “Where do you draw the line for the characterization of small bowel damage in coeliac disease?”

Patchy histology makes sample unreliable

Coeliac disease is patchy. Villous atrophy, the hallmark of celiac disease, is patchy in the duodenum (Lee et al, 2005). This makes the biopsy of the small bowel a little unreliable. Random biopsy, even of normal-appearing mucosa is necessary for the diagnosis of celiac disease. Thus at least 4 to 6 biopsy pieces need to be taken and examined. However, biopsy of the descending duodenum is sufficient. Just going a little further down the bowel has been found to increase the variability of the histology. Lee and colleagues conclude, “although characteristic endoscopic features may be useful, their absence does not exclude celiac disease.”
This was similar to an earlier study (Bionomic M et al, 2004) demonstrating that children with coeliac disease may have patchy villous atrophy of the duodenum. The bulb mucosa may be the only duodenal area involved, both at diagnosis and after gluten challenge. Therefore, the authors recommend multiple endoscopic biopsies should always be performed – not only in the distal duodenum, but also in the bulb.

Electron microscope show damage in normal biopsies

Gluten sensitivity has been shown to be associated with ‘minimal’ mucosal changes which cannot be seen with conventional light microscopy (Sarbati et al, 2003). For their study, duodenal biopsies of seven subjects with positive anti-endomysial antibodies (EMA) and normal conventional histology underwent “ultrastructural” evaluation of the epithelial surface by using electron microscopy. In four patients, the electron microscope showed changes of the enterocyte brush border with a significant reduction of the height of microvilli. They were kept on gluten. After several months, three of them had a second biopsy that subsequently showed histological changes suggestive of coeliac disease. They said, “Such lesions, which primarily involve microvillous structure, may imply a reduction of intestinal absorptive surface already in the latent stage of the disease process.”

Experienced pathologists needed

As you can see, this area of small bowel histology is complex. Not surprisingly, it has been found that community histologists are less likely to pick up small bowel changes compared with histologist whose speciality is the gut.


Taking this all into consideration, you can see that there is no such thing as a gold standard for the diagnosis of coeliac disease. It may end up a blood test diagnosis. The distinction between celiac disease and gluten-sensitivity (the gluten syndrome) is blurred.

Ending of endoscopy

In the next few years, blood tests (particularly the DGP tests) will take over the endoscopy and  we will see the end of the endoscopy to diagnose celiac disease.


Bonamico M, Mariani P, Thanasi E, Ferri M, Nenna R, Tiberti C, Mora B, Mazzilli MC, Magliocca FM. Patchy villous atrophy of the duodenum in childhood celiac disease. J Pediatr Gastroenterol Nutr. 2004 Feb;38(2):204-7.
Lee SK, Green PH. Endoscopy in celiac disease. Curr Opin Gastroenterol. 2005;21:589-94.
Magliocca FM, Bonamico M, Petrozza V, Correr S, Montuori M, Triglione P, Carpino F. Arch Histol Cytol. Scanning electron microscopy of the small intestine during gluten-challenge in celiac disease. 1992;55 Suppl:125-30.
Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology. 1992; 102:330-54

Oberhuber G., Granditsch G., and Vogelsang H. 1999. The histopathology of coeliac disease: time for a standardized report scheme for pathologists. Eur J Gastroenterol Hepatol 11:1185-1194

Sbarbati A, Valletta E, Bertini M, Cipolli M, Morroni M, Pinelli L, Tat L.  Gluten sensitivity and normal histology: is the intestinal mucosa really normal? Dig Liver Dis. 2003;35:768-73.