Role of iron deficiency anemia in inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a relapsing chronic inflammatory disorder of the small and large gut with rising incidence and prevalence worldwide. Iron deficiency anemia is one of the most common extraintestinal manifestations of IBD, which correlates with the disease activity and tendency to relapse even after successful management. Anemia affects various aspects of quality of life, such as physical, cognitive, emotional, and workability, as well as healthcare costs. The anemia in IBD can be due to iron deficiency (ID) or chronic disease. The relative frequency of ID in IBD is 60%, according to some studies, and only 14% receive treatment. The evaluation of ID is also tricky as ferritin, being an inflammatory marker, also rises in chronic inflammatory diseases like IBD. The review of anemia in IBD patients involves other investigations like transferrin saturation and exploration of other nutritional deficiencies to curb the marker asthenia with which these patients often present. It underscores the importance of timely investigation and treatment to prevent long-term sequelae. We can start oral iron therapy in certain circumstances. Still, as inflammation of the gut hampers iron absorption, an alternative route to bypass the inflamed gut is usually recommended to avoid the requirement for blood transfusions.

Key Words: Colitis; Iron deficiency; Anemia; Inflammation; Ferritin

Core Tip: Iron deficiency is related to many complications in patients with inflammatory bowel disease (IBD) and further increases the mortality and morbidity in this patient group. The effective management of iron deficiency (ID) is essential to improve these patients' lifestyles and health-related complications. ID correlates with the disease activity in IBD and the tendency to relapse even after successful ID therapy. Parenteral iron therapy, a promising avenue, is showing potential in improving the target hemoglobin level in IBD patients.

INTRODUCTION

Iron deficiency (ID) anemia is a prevalent issue in chronic inflammatory bowel disease (IBD).Three-quarters of patients with IBD suffer from ID anemia. The current definition of anemia to holds for patients with IBD[1]. The mechanism of ID in IBD is multifactorial, and diagnosing and managing ID in such patients is a challenging in such patients. IBD (ulcerative colitis, Crohn’s Disease, and inflammatory disease undiagnosed) is characterized by immune-mediated inflammation of the small and large gut that leads to ulceration and bleeding in the intestine[2-4]. IBDs usually involve the whole gut from the mouth to the rectum, Crohn's disease involves the beginning of the small gut up till the start of the large gut and ulcerative colitis from the large gut to the rectum. The prevalence of ID in IBD as per a systematic review is 24% and the prevalence is higher in Crohn’s disease as compared to ulcerative colitis[5]. The anemia in IBD is unique as it is due to both anemia of chronic disease and ID. The ongoing loss of blood from the inflamed gut mucosa and impaired absorption of iron and vitamin B12 from the inflamed mucosa and other micronutrient deficiency, immune-mediated marrow suppression, drug toxicity (methotrexate), and surgical resection of the duodenum can also lead to impaired absorption, hence leading to depletion of iron stores and therefore ID. Anemia of chronic disease develops due to chronic inflammation, leading to the release of inflammatory cytokines. This increases the production of liver hepcidin which blocks ferroportin-1 and prevents iron release from enterocytes, macrophages and hepatocytes and as a result, iron is sequestrated from erythropoiesis[6,7]. The risk of developing anemia relates to disease activity. The minimum number of investigations required to screen anemia is complete blood count, C-reactive protein, and serum ferritin, which will detect inflammatory flare and ID at an early stage. For patients in remission screening should be done every 6-12 mo, and for patients with active disease screening should be done every 3 mo. The annual vitamin B12 and folic acid screening should be done as and when required[8]. The diagnostic investigations for confirmation of ID are complete blood count, reticulocyte count, serum ferritin, and transferrin saturation, and if more extensive investigations are required vitamin B12, folic acid, and bone marrow examination should be done. The management of ID in IBD is complex, and intravenous iron shows more acceptance and a better rise in hemoglobin and the repletion of iron stores.

PATHOPHYSIOLOGY OF ID IN IBD

Iron is an essential component of hemoglobin in erythrocytes, myoglobin muscle, and enzymes and it accounts for 80% of total body iron. Iron is necessary for oxygen carrying, cellular respiration and cellular proliferation[9]. The daily iron loss is 1-2 mg/day, and this ongoing loss is exaggerated in IBD due to chronic inflammation. ID leads to chronic fatigue, adverse effects on the growing brain, and a negative impact on quality of life[10]. Hepcidin, a 25-amino acid polypeptide that is synthesized primarily in hepatocytes, reduces the iron absorption from the intestine by binding to the only known cellular iron exporter, ferroportin, causing it to be degraded. Therefore, hepcidin is now considered to be the most critical factor controlling iron absorption[11].

The ID in IBD can be absolute or functional. Absolute ID is due to impaired absorption through the inflamed mucosa and chronic blood loss because of dietary restrictions are due to disease, malabsorption, and the effect of drugs being used for the management of the disease[12]. Anemia of chronic disease is due to an increase in hepcidin level. As a polypeptide synthesized in the liver, and it is an acute phase reactant that regulates the plasma iron concentration at the systemic level. The increase in hepcidin is directly related to the release of proinflammatory cytokines like interleukin (IL)-6, IL-7, and tumor necrosis factor-alpha. Hepcidin induces cellular degradation of the ferroportin transporter. This transporter regulates the iron transfer from intracellular to extracellular medium[13]. Hepcidin reduces the absorption of ferrum due to inhibition of divalent metal transport[14]. Transferrin is the main iron carrier protein during inflammation and the inflammatory cytokine -antitrypsin blocks the receptor of transferrin in erythroid progenitor cells, thus inhibiting erythropoiesis.

CONCLUSION

The management of ID in IBD requires continuous monitoring both in terms of clinical signs and symptoms and biochemical investigations. Parenteral therapy should be instituted as soon as possible to avoid the deleterious effect of chronic anemia on quality of life. Parenteral treatment is more effective, faster, and better tolerated by patients with anemia.