New Anemia Linked to Crohn’s Disease but Not Ulcerative Colitis Risk

Patients with anemia of new onset had an increased risk of developing Crohn's disease (CD), but not ulcerative colitis, and men were more at risk, according to a population-based study by South Korean researchers. They suggested that anemia may be a promising surrogate marker for the early detection of CD.

The risk of developing CD was inversely proportional to anemia severity as indicated by hemoglobin level: when patients were stratified by hemoglobin levels, the risk of CD was 3.3 times higher in the lowest 10% group than in the highest 10% group.

A diagnosis of anemia within the past 2 years of the index year 2009 was associated with a more than 2.8-fold greater risk of developing CD compared with no anemia. "To the best of our knowledge, this is the first epidemiological study to demonstrate the association between anemia and the development of IBD [inflammatory bowel disease] in the general population," researchers including Jong Pil Im, MD, PhD, of Seoul National University College of Medicine, wrote in the online journal PLoS One.

They also observed a J-curve relationship between age and the risk of developing CD among anemic patients, similar to that observed for CD incidence based on age. "Therefore, anemia should promote further investigation for early detection of CD in [the] general population, especially in males," they concluded.

Anemia is a common manifestation of IBD, but it has been unclear whether it is actually causative for IBD. Up to two-thirds of patients with IBD have anemia as a result of disease-related iron malabsorption, chronic intestinal blood loss, and inflammation that impairs iron homeostasis. As with other chronic conditions, anemia in IBD is linked with increased hospitalization rates, longer hospital stays, and decreased quality of life.

Study Details

Im and colleagues drew on population-based information from South Korea's National Healthcare Insurance database for patients during 2009, during which time 9,962,064 individuals older than 20 participated in the national health screening program. Anemia was defined as a hemoglobin level less than 13 g/dL in men and less than 12 g/dL in women.

The investigators compared the rate of newly diagnosed IBD in anemic and non-anemic patients. During the mean follow-up period of 7.3 years, the incidences of CD and UC in anemic patients were 2.89 and 6.88 per 100,000 person-years, respectively, which translated to a significantly higher risk of CD in anemic patients than in non-anemic patients, for an adjusted hazard ratio (aHR) of 2.084 (95% CI 1.769-2.455).

Furthermore, CD risk in anemic men was significantly higher than in women (aHR 1.432 versus 1.240).

In contrast, no statistically significant difference in the risk of developing UC in anemic versus non-anemic patients emerged (aHR 0.972, 95% CI 0.880-1.073).

"This work indicates that anemia is related to the development of CD, and this risk was inversely proportional to the hemoglobin concentration," Im and colleagues wrote.

They referred to a 2017 study reporting that subclinical inflammation may affect iron status and hemoglobin concentrations but it remains unclear whether the predictive role of anemia in the detection of CD differs according to the etiology of anemia.

Gastroenterologist Reezwana Chowdhury, MD, of Johns Hopkins Medicine in Baltimore, told MedPage Today, "This is an interesting study, especially the finding about males because you can't link anemia in males to menstruation. I think the findings in general could also be applicable to the U.S. population, but they would not change my practice."

Chowdhury, who was not involved in the study, said it's not surprising that anemia was more common in CD because of the chronicity of the disease and its impact on absorption across the entire intestinal tract.

She noted that gastroenterologists often get referrals of patients with anemia and they are promptly investigated for IBD or malignancy.

Chowdhury also pointed out that the study could not specify the type of anemia: "Was it a microcytic anemia or an iron deficiency anemia or one due to chronic disease or folate deficiency?"

Im and colleagues recommended that anemia should be a marker prompting investigation for early detection of CD in the general population, especially in men.

They acknowledged several study limitations, including its retrospective database-reliant design, which, as Chowdhury mentioned, could not assess the etiology of anemia from the claims data. Nor could the impact of anemia on IBD extent and severity be evaluated. "A subsequent population-based study will be required to determine the effects of anemia and anemia type on the development of IBD," Im and colleagues said.

In addition, they were concerned about immortal time bias since hemoglobin levels vary with time, but serial results of hemoglobin levels within 2 years were not available and furthermore not all the subjects underwent the 2-year follow-up screening exams. Because the Cox proportional hazard models were established in the subpopulations who participated in the 2-year follow-up screening exams among the non-anemic individuals at baseline, time-dependent Cox proportional hazard models were not used for controlling immortal time bias.

Comment