Low fecal elastase in immunotherapy diarrhea may reflect dilution, not pancreatic insufficiency

Immune checkpoint inhibitors have reshaped the treatment landscape for many cancers, but their benefits often come with a troublesome companion: diarrhea. When patients on these drugs develop persistent loose stools, clinicians frequently order a fecal elastase test to check whether the pancreas is still producing enough digestive enzymes. A new retrospective study suggests that this common reflex may be misleading, because watery diarrhea itself can dilute the enzyme marker and mimic pancreatic failure.

The study, made available online on July 16, 2026, in the Journal of Pancreatology, was conducted by researchers at The University of Texas MD Anderson Cancer Center and the Cleveland Clinic. The team reviewed the records of 388 patients who had been treated with immune checkpoint inhibitors, developed diarrhea, and underwent fecal elastase testing between 2016 and 2024. Their goal was to determine whether low fecal elastase in this setting reflects genuine exocrine pancreatic insufficiency or is simply an artifact of watery stool.

Fecal elastase-1 is a digestive enzyme secreted by the pancreas that resists degradation in the gut, making it a convenient proxy for pancreatic exocrine function. Concentrations below roughly 200 micrograms per gram of stool are conventionally interpreted as evidence of insufficiency. The test works well in chronic pancreatic disease, but it has a well-known weakness: stool water content dilutes the measured concentration. In patients with profuse watery diarrhea from any cause, elastase levels can fall into the abnormal range even when the pancreas is perfectly healthy.

That weakness is exactly what the new analysis appears to expose. Among the 388 patients, fecal elastase was low in 168 patients, or 43.3 percent, and normal in 220 patients, or 56.7 percent. On the surface, a low result in more than four in ten patients might seem to point to widespread pancreatic dysfunction. But the clinical picture told a different story. Patients with low elastase had significantly higher fecal calprotectin levels, a marker of intestinal inflammation, measuring 356.0 micrograms per gram compared with 124.9 micrograms per gram in those with normal elastase.

Fecal calprotectin is a protein released by neutrophils infiltrating the intestinal lining, and elevated levels indicate active inflammation of the gut, such as the colitis that immune checkpoint inhibitors can trigger. The correlation between low elastase and high calprotectin fits the dilution hypothesis: the more watery and inflamed the bowel, the more the stool is diluted and the lower the measured elastase concentration falls, regardless of pancreatic output. If true pancreatic insufficiency were driving the low values, one would not expect them to track so closely with markers of intestinal inflammation.

Objective assessment of the bowel reinforced this interpretation. On colonoscopy and histopathology, the rates of active inflammation were similar between the low-elastase and normal-elastase groups. In other words, patients whose stool tested low for elastase did not show a distinct pattern of pancreatic disease; they showed the same immune-related intestinal inflammation as everyone else in the cohort. The elastase result appeared to be a downstream consequence of the diarrhea rather than an independent signal of pancreatic failure.

Outcomes provided the most decisive evidence. Diarrhea remission occurred in 74.4 percent of patients with low elastase and 69.1 percent of those with normal levels, a difference small enough to be clinically inconsequential. If low elastase truly identified a separate population with pancreatic enzyme deficiency requiring enzyme replacement, those patients would be expected to follow a different course. Instead, their diarrheal trajectories were essentially the same, suggesting that the low values carried little prognostic or therapeutic meaning.

The researchers also examined pancreatic status directly. Baseline pre-existing pancreatic abnormalities were rare in the cohort and unrelated to elastase levels, which argues against occult chronic pancreatitis as a hidden explanation for the low readings. New immune checkpoint inhibitor-related pancreatic injury, however, was observed more frequently among patients with low elastase. This finding is intriguing, because checkpoint inhibitors can cause immune-mediated pancreatitis, yet even in these cases the low elastase values did not translate into the outcomes expected of true exocrine insufficiency.

Taken together, the results support a reframing of how clinicians interpret fecal elastase in patients with immune checkpoint inhibitor-related diarrhea. In this population, a low value is more likely a dilutional artifact of watery stool than evidence of genuine pancreatic enzyme failure. The authors recommend that when pancreatic disease is genuinely suspected, clinicians should consider confirmatory fecal fat testing before initiating pancreatic enzyme replacement therapy. Fecal fat quantification directly measures malabsorption of dietary fat, the functional consequence of enzyme deficiency, and is therefore less vulnerable to the dilution effects that undermine elastase measurements in watery stool.

The practical implications extend beyond a single test. Immune checkpoint inhibitor-related diarrhea is usually managed as colitis, with corticosteroids or other immunosuppressive strategies for severe cases, and enzyme replacement would add cost and complexity without addressing the underlying inflammation. By showing that low elastase does not predict worse diarrhea outcomes and does not correspond to more inflammation on endoscopy, the study encourages a comprehensive diagnostic approach rather than reflexive enzyme therapy. For the growing population of patients receiving checkpoint inhibitors worldwide, the message is that an abnormal elastase result in the context of watery diarrhea deserves scrutiny, and fecal fat testing should confirm exocrine pancreatic insufficiency before treatment is started.

Subject of Research: Fecal elastase testing in diarrhea caused by immune checkpoint inhibitors

Article Title: Low fecal elastase in immunotherapy diarrhea may reflect dilution, not pancreatic insufficiency

Article References: Low fecal elastase in immunotherapy diarrhea may reflect dilution, not pancreatic insufficiency. Original publication (Bibliographic details unavailable.)

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Keywords: immune checkpoint inhibitors, fecal elastase, diarrhea, pancreatic insufficiency, fecal calprotectin, colitis, immunotherapy side effects, fecal fat testing, pancreatic enzyme replacement, Journal of Pancreatology, MD Anderson Cancer Center, gastroenterology