The small-bowel mucosa is where the immune attack of celiac disease leaves its mark, and the duodenal biopsy is where those changes are graded. The changes are not random destruction: they reflect increased turnover of the surface epithelium, and how far that turnover has progressed is what the pathologist reports.
Mucosal changes
Pathological studies of different patients with celiac disease reveal intestinal villous loss of varying intensity. The villi disappear first, giving a flat mucosal surface, and the crypts below them elongate to compensate, so the overall thickness of the mucosa falls only slightly: the shortening caused by the loss of villi is mostly balanced by the elongation of crypts. The epithelial cells change too, from the normal columnar cells to cuboidal cells, and the tight junctions between them are disrupted, which is the structural basis of the increased permeability of the intestinal barrier.
Alongside the architectural changes, immune cells move in. There is infiltration of the lamina propria by CD4+ T cells, and infiltration of the intra-epithelial region by CD8+ T cells. The intraepithelial lymphocytes (IELs) themselves shift in type: γδ-T-cell infiltration increases about 6-fold and is the hallmark of CD, whereas in the normal mucosa the IELs are mostly αβ T cells.
Why “villous atrophy” is a misnomer
Mitosis in the crypts increases significantly in these patients, and the crypt cells supply the cells that migrate superficially to form the villi. The term villous atrophy (a true wasting of tissue) is therefore a misnomer; it is better to say that in patients with CD there is premature shedding of cells into the lumen. The mucosa is losing cells faster than it can replace them at the villous tip, not simply shrinking.
The Marsh score
CD is proposed to be a sequential and step-wise disorder, with worsening of the pathological findings through the 5 Marsh grades, numbered 0 to 4, based on the Marsh score:
- Marsh 0: normal pre-infiltrative intestinal mucosa
- Marsh 1: first infiltration of IELs, then infiltration of immune cells into the lamina propria
- Marsh 2: crypt hyperplasia
- Marsh 3: villous atrophy, with the length of villi : depth of crypts reported as a quantitative measure of the stage
- Marsh 4: total atrophy
Differential diagnosis
These findings, which can be seen in the celiac disease biopsy, can also be seen in a wide variety of other enteropathies, so differential diagnosis is an important step after the pathological diagnosis of CD. The grade alone does not make the diagnosis; the clinical and serological context does.