Microscopic colitis is diagnosed through a colonoscopy with tissue biopsies, even though the colon looks normal or nearly normal during the procedure. That’s actually the defining feature of this condition: the inflammation is invisible to the naked eye and only shows up under a microscope. Because of this, and because its main symptom (chronic watery diarrhea) overlaps with many other conditions, microscopic colitis is frequently overlooked or delayed in diagnosis.
Why a Colonoscopy Alone Isn’t Enough
During a standard colonoscopy, the doctor can see the inner lining of the colon in real time. With most inflammatory bowel conditions, the damage is visible: ulcers, redness, swelling. With microscopic colitis, the lining typically looks completely normal. Occasionally there may be subtle signs like mild redness, slight swelling, or faint scratch-like marks on the surface, but these are easy to miss and not present in every case. Cross-sectional imaging like CT scans also appears normal.
This is exactly why biopsies are essential. Without removing small tissue samples and examining them under a microscope, there’s no way to confirm the diagnosis. The disease gets its name from this requirement: “microscopic” refers to the fact that the evidence of inflammation is only visible at the cellular level.
Where and How Many Biopsies Are Needed
The inflammation in microscopic colitis isn’t spread evenly throughout the colon. It tends to be patchy and is generally most severe in the upper (proximal) portions of the colon, particularly the ascending colon. Rectal biopsies, on the other hand, have the highest rate of false negatives. One study found a 20% missed diagnosis rate when biopsies were only taken from the rectosigmoid area. A flexible sigmoidoscopy, which only reaches the lower colon, has significantly lower sensitivity than a full colonoscopy with sampling from multiple sites.
European guidelines strongly recommend a full colonoscopy with biopsies from both the right and left sides of the colon. The American Society of Gastrointestinal Endoscopy recommends at least eight biopsies, with two or more taken from each of four regions: the right colon, transverse colon, left colon, and sigmoid colon. A recent systematic review narrowed this further, finding that a minimum of six biopsies (three from the ascending colon and three from the descending colon) provided high diagnostic certainty. Either way, the key principle is the same: sample from multiple locations across the entire colon to avoid missing the patchy inflammation.
The Two Subtypes and What Pathologists Look For
Once the biopsy tissue reaches the pathology lab, it’s stained and examined under a microscope. The pathologist is looking for two main features that distinguish the two subtypes of microscopic colitis: lymphocytic colitis and collagenous colitis.
Lymphocytic Colitis
In lymphocytic colitis, the hallmark finding is an abnormally high number of immune cells (lymphocytes) within the surface lining of the colon. A normal colon has relatively few of these cells scattered among the lining cells. In lymphocytic colitis, there are more than 20 lymphocytes per 100 surface lining cells, along with increased inflammation in the tissue layer just beneath the surface.
Collagenous Colitis
Collagenous colitis shares the increased lymphocyte count (typically 10 to 20 per 100 surface cells) but adds a second distinctive feature: a thickened band of collagen protein beneath the surface lining. Normally this band is less than 3 micrometers thick. In collagenous colitis, it exceeds 10 micrometers. This thickened collagen layer is the defining characteristic and must be measured in properly oriented biopsy samples to be accurate.
Both subtypes cause the same primary symptom, chronic watery diarrhea without visible blood, and are treated similarly. The distinction matters mainly for the pathologist making the diagnosis.
Blood Tests and Stool Markers
There is no blood test or biomarker that can diagnose microscopic colitis on its own. This is one of the reasons the condition requires biopsy confirmation.
Fecal calprotectin, a stool test commonly used to detect inflammation in Crohn’s disease and ulcerative colitis, has limited usefulness here. In studies of microscopic colitis patients, median fecal calprotectin levels were around 30 micrograms per gram, which is well within the normal range (typically under 50). For comparison, active Crohn’s disease or ulcerative colitis often produces levels in the hundreds or thousands. So a normal calprotectin result does not rule out microscopic colitis, and the test’s role in diagnosing or monitoring the condition has not been established.
Your doctor may still order blood work and stool tests, but these serve to rule out other causes of chronic diarrhea rather than to confirm microscopic colitis directly.
Ruling Out Other Conditions
Because chronic watery diarrhea has many possible causes, the diagnostic process often involves excluding other conditions. Celiac disease is one important consideration. The European Gastroenterology Association recommends screening for celiac disease in patients with microscopic colitis, since the two conditions can overlap. This screening typically involves blood tests for specific antibodies, with a small intestine biopsy if those come back positive. That said, research hasn’t produced strong enough evidence to recommend routine endoscopic celiac screening in all microscopic colitis patients, particularly those who respond well to treatment.
Other conditions that produce similar symptoms, such as irritable bowel syndrome, infections, or other forms of inflammatory bowel disease, are generally distinguished through a combination of stool cultures, imaging, and the colonoscopy findings themselves.
Medications That May Affect Diagnosis
Several common medications are associated with triggering or worsening microscopic colitis. These include proton pump inhibitors (used for acid reflux), NSAIDs like ibuprofen, SSRIs (a class of antidepressants), statins, aspirin, and certain cancer immunotherapy drugs. If you’re taking any of these, your doctor will likely document them as part of the diagnostic workup. In some cases, you may be asked to stop these medications if possible, both as a diagnostic step and as a first-line treatment approach. If the diarrhea resolves after discontinuing a suspected medication, that can support the diagnosis and may even resolve the condition entirely.
What to Expect During the Process
The colonoscopy itself is the same procedure used for colon cancer screening. You’ll do a bowel preparation the day before, and the procedure is typically done under sedation. It usually takes 30 to 60 minutes. During the exam, the doctor will take small tissue samples from several points along the colon, which you won’t feel.
Those samples are sent to a pathology lab for processing and microscopic examination. Results typically come back within a few days to two weeks, depending on the lab. The wait can feel long, especially when you’ve been dealing with symptoms for weeks or months. But the biopsy report is what ultimately confirms the diagnosis and identifies which subtype you have, which then guides treatment decisions.