Chronic, nonbloody, large bowel type of diarrhea is defined as abnormal (>3–4 times
per day) passage of stool of reduced consistency lasting for >4 weeks.[1] Though there are regional variations to this definition, nearly about 3%–20% of
children and 4%–5% of the adult population experience chronic, nonbloody diarrhea
and seek medical advice.[2] Evaluation of these patients needs careful clinical workup to narrow down the exact
etiology from a long list of possible causes, such as functional bowel disease, lactose
malabsorption, inflammatory bowel diseases (IBDs), microscopic colitis, Whipple’s
disease, amebiasis, bile acid diarrhea, drug-induced diarrhea, pseudomembranous colitis,
postradiation diarrhea, endocrinopathy-associated diarrhea, neuroendocrine tumors,
granulomatous colitis, amyloidosis, melanosis coli, and fecal incontinence or fecal
urgency.[3] The British Society of Gastroenterology has recommended a set of first-line investigations
to rule out the common causes of chronic diarrhea such as celiac disease, IBD, diarrhea-predominant
irritable bowel syndrome, and large bowel tumors, along with a set of second-line
investigations in patients where first-line investigations fail to identify the causes
of persistent diarrhea and malabsorption.[1] Similar guidelines were also given by the American Gastroenterological Association
Clinical Practice and Practice Economics Committee.[4] In summary, patients with chronic diarrhea under 40 years without typical symptoms
of functional bowel disorder and/or having severe symptoms should undergo a detailed
evaluation.[1],[4]
In the present issue, Lee et al. published an article including 182 patients with chronic diarrhea, of whom 86 patients
met the inclusion criteria.[5] They obtained colonic biopsies from them even if the colonic mucosa appeared normal
macroscopically. On histological evaluation, the colon showed abnormalities in 51
(59.3%) of them and the rest had normal mucosa (35 [40.7%]). The abnormalities reported
by them included nonspecific inflammation in 29 patients, lymphocytic colitis in 12
patients, eosinophilic colitis and tuberculosis in 3 patients each, and IBD in 4 patients.
Furthermore, among 22 patients (25.5%) with diagnostic histology, 21 (95.4%) patients
had diagnostic histological changes from the biopsies obtained from the right colon,
whereas only 9 (40.9%) patients had diagnostic histological changes from the rectosigmoid
region. Of 12 patients with lymphocytic colitis, left colon biopsies fulfilled the
diagnostic criteria in only four patients, whereas right colon biopsies were diagnostic
in all the 12 patients.[5]
The present study addresses two issues: first, during the evaluation of patients with
chronic, nonbloody diarrhea, multifocal mucosal biopsies should be obtained both from
the colon and terminal ileum even if the mucosa appears macroscopically normal. Second,
should a sigmoidoscopic examination or a full-length colonoscopy along with retrograde
ileoscopy be performed in such patients?
Whether a 60-cm flexible sigmoidoscopy or a full-length colonoscopy will suffice in
these patients to identify the etiology of nonbloody diarrhea is still a matter of
debate. While the sigmoidoscopic examination is favorable in terms of cost, availability,
rapidity, and easy patient preparation, there are, however, chances of missing the
patchy pathological lesions and lesions limited to the proximal large bowel or the
terminal ileum. Khanna et al. compared the utility of sigmoidoscopy with biopsy versus full-length colonoscopy
with terminal ileal evaluation and biopsy in patients with chronic diarrhea. Histologically
confirmed diagnosis could be achieved in 31.5% of cases based on colonoscopic biopsies,
9.5% with ileoscopic biopsies, and in only 12.4% with recto-sigmoidoscopic biopsies
alone.[6] The changes of microscopic colitis, though are often diffuse, can also be detected
only in the proximal colon. Routine ileoscopy in addition to these does contribute
an additional diagnostic yield in 18% of non-HIV patients with chronic diarrhea.[7] More importantly, in a proportion of patients with chronic diarrhea, the terminal
ileum can show pathological lesions, even when the whole colon appears normal.[7],[8]
While endoscopic visualization can identify altered vascular patterns, mucosal ulcerations,
pseudomembranous colitis, polypoidal tumors, and melanosis coli, many diseases of
the colon such as microscopic colitis, amyloidosis, and granulomatous colitis may
have a macroscopically normal mucosa.[9] Hence, a diagnosis can be missed if one relies only on the endoscopic visualization
of the mucosa without adequate tissue sampling. Geboes et al. reported that diagnostic yield increased up to 50% when mucosal biopsies were taken
from suspected pathological changes under endoscopic visualization.[9] Overall, combined full-length colonoscopy and ileoscopy with biopsy can increase
the diagnostic yield up to 15%–20% in patients with chronic, nonbloody diarrhea.[1] Consideration of full-length colonoscopy if the flexible sigmoidoscopy findings
remain inconclusive is another standard method of approach in symptomatic patients
with persistent diarrhea. Overall, it seems that combined full-length colonoscopy
and retrograde terminal ileal evaluation is more appropriate than isolated short-length
sigmoidoscopic evaluation in patients presenting with chronic, nonbloody diarrhea.
Mucosal biopsies should always be taken from any suspicious area under endoscopic
visualization, and random four-quadrant biopsies should be taken from macroscopically
normal ileum, cecum, ascending colon, transverse colon, descending colon, and rectosigmoid
colon to increase diagnostic yield, as was demonstrated in the present article as
well as by Lee et al.[5] Biopsy fragments from all these areas should be sent to the pathologist in separately
labeled vials for better identification of the specific site of pathology.
As described in this issue by Karri et al.[10] and others such as Lee et al. and Kagueyama et al., a significant number of patients in their series were labeled as having nonspecific
colitis.[5],[11] Nonspecific colitis is not a diagnostic category, but it merely represents the nonspecific
nature of the inflammation present in the colonic biopsies. It is, therefore, essential
for the pathology colleagues to avoid the use of such terminologies while reporting
the histological features. In such cases, colonic mucosa with increased chronic inflammatory
cell infiltrate in lamina propria; maintained crypt architecture, without any feature
of neutrophilic activity; basal plasmacytosis; or granulomas are expected, and one
may describe and conclude with a comment on the nonspecific nature of these inflammatory
changes. Furthermore, an unqualified diagnosis of microscopic colitis is not recommended,
and a distinction between collagenous and lymphocytic colitis should be made. Often,
pathology reports use the term “consistent with” or “in keeping with” or “compatible
with,” which also may be overrelied upon and misinterpreted. In such cases, the degree
of certainty should be conveyed.
We would like to highlight a couple of additional points. First, the clinician and
the endoscopist should provide appropriate clinical and imaging details including
possible differential diagnosis, which help a pathologist in the interpretation of
pathological findings in light of clinical possibility. While in many cases, the pathological
diagnosis is self-evident and clinical details may not have any great bearing. More
commonly, the pathological characteristics are interpreted in light of clinical details.
Second, a multidisciplinary approach including discussion between clinicians, pathologists,
and radiologists or other appropriate specialists often helps in solving the diagnostic
mysteries. Hence, a combined effort of the gastroenterologists and pathologists can
improve the diagnostic yield in endoscopic mucosal biopsy.
