In patients with inflammatory bowel disease (IBD), anemia is a highly prevalent and serious complication.
disease (IBD) patients, anemia is a highly prevalent and serious complication. Anemia is associated with decreased quality of life and longer hospital stays in patients with IBD. Anemia has been generally regarded by clinicians as an unavoidable concomitant symptom of IBD and has not been treated specifically. In recent years, the risks associated with anemia in patients with IBD have begun to be taken seriously, and the correction of anemia has become a clear principle in the treatment of IBD. The key point in the treatment of IBD-related anemia is the mechanism of occurrence of IBD and chronic disease anemia. The former is mainly due to chronic intestinal bleeding caused by inflammatory changes and ulcers in the intestinal mucosa, while the latter is mainly due to the inhibition of erythropoiesis mediated by inflammatory mediators and impairment of its transport pathway during iron absorption; vitamin B12 and folic acid deficiency, drug effects and hemolysis account for a smaller proportion of the causes. The vast majority of patients with IBD-associated anemia respond significantly to iron therapy, but oral iron is effective only for a short period of time, and drug intolerance causes nearly 21% of patients to stop taking oral iron medications. Also, there are a number of limitations to the use of oral iron. In contrast, intravenous iron sucrose has been very effective since its application to this population. The combination of intravenous iron sucrose and erythropoietin
The combination of intravenous iron sucrose and erythropoietin (EPO) has been recommended as the most effective treatment option for IBD-related anemia. In a systematic review published in 2004, the prevalence of anemia in patients with IBD ranged from 6% to 74%. In a review of studies on the prevalence of anemia in patients with IBD, the mean prevalence of anemia was 17%; the prevalence of IBD-related anemia in outpatients was 16%; this value rose to 68% when only inpatients were included in the group study. It can be concluded that anemia may be the most common systemic complication of acute inflammatory bowel disease. 2. Incidence of iron deficiency in IBD patients: iron deficiency is more common than anemia in IBD patients, but further studies are needed to confirm this. In fact, iron deficiency is the main cause of anemia in patients with IBD, mainly due to impaired iron absorption due to dietary restrictions, inflammatory changes in the intestine, gastrointestinal bleeding and/or inadequate corrective measures for anemia, such as achieving normal hemoglobin levels does not mean that there is sufficient stored iron in the body. A recent systematic review analysis mentioned that the prevalence of iron deficiency ranged from 36% to 90%, with the variation being influenced mainly by the different definitions of iron deficiency and the types of subjects enrolled in each locality. This also confirms that iron deficiency is prevalent rather than exceptional in IBD, especially during the active phase of the disease. Although the active phase of inflammatory disease involves many complex mechanisms related to absorption, anemia in patients with IBD mainly results from iron deficiency due to chronic blood loss in the intestinal tract in an inflammatory state of the intestinal mucosa.IBD-related anemia is multifactorial, often a combination of iron deficiency and chronic disease anemia, with the former being the main factor. Some patients with Crohn’s disease can further contribute to the development or even worsening of anemia due to impaired absorption of vitamin B12 and/or folic acid due to inflammatory changes in the small intestine and/or extensive bowel resection, and these causes often interact. Some drugs commonly used in the treatment of IBD also have myelosuppressive effects, such as the anti-folate effect of sulfasalazine, which indirectly affects hematopoiesis; in addition, azathioprine or mercaptopurine have direct inhibitory effects on the bone marrow. In particular, azathioprine affects erythropoiesis by a variety of mechanisms, including folic acid (folacin) uptake and impaired erythrocyte maturation. The simple anemia seen in patients applying azathioprine or mercaptopurine may not be caused exclusively by these drugs, however, in some cases, a slight and asymptomatic decrease in hemoglobin has been found when patients are treated with mercaptopurine. Thus, the causes of IBD-associated anemia are relatively complex and often represent a combination of iron deficiency anemia and anemia of chronic disease. III. Parameters relevant to the diagnosis of iron deficiency in patients with IBD The traditional diagnosis of iron deficiency is based on a combination of several parameters as a reference, including hematological and iron metabolism-related indices. In simple iron deficiency, the body serum iron (serum
iron (SI), serum ferritin (SF), transferin
saturation (TS) decreased, while the concentration of iron transferrin (transferrin) increased. However, the diagnosis of iron deficiency in patients with IBD is more difficult, especially in the presence of both iron deficiency and chronic disease anemia. In one patient with IBD, many laboratory iron-related indicators are not reliable because inflammation itself can affect the stability of parameters related to iron metabolism. Transferrin levels, a sensitive indicator of iron deficiency, may not be elevated in a state of chronic inflammatory changes, and transferrin concentrations are also low in patients with hypoalbuminemia. Similarly, serum iron and total iron binding (total
iron binding
capacity (TIBC) levels in inflammatory states are also difficult to explain. Serum ferritin levels, which are most commonly used to assess stored iron levels in the inflammatory state and are the most powerful indicator of iron deficiency in the body, may be normal or even elevated even in the presence of severe iron deficiency. Therefore, although ferritin is currently considered the most effective parameter for assessing iron deficiency, it does not provide enough information to properly evaluate the level of iron stores in an inflammatory state such as IBD. In iron deficiency and chronic disease anemia, the soluble transferrin receptor (sT
transferrin receptor (sTfR) is a reliable test for significantly elevated levels of iron in iron deficiency and chronic disease anemia, but it is still not widely used. Therefore, diagnostic criteria for iron deficiency need to be adapted to changes in the inflammatory state. In the absence of biochemical markers associated with inflammatory states (e.g., CRP) and clinical signs and symptoms such as diarrhea and endoscopic findings, the diagnostic criteria for low serum ferritin levels should be less than 30
µg/L; however, in inflammatory states, the low standard for normal serum iron stores should be raised to 100
Some experts suggest that the possibility of the presence of hypoferritinemia should be considered if there is a decrease in serum iron along with a TS below 16%. The impact of anemia on the quality of life of patients with IBD is striking, as Gasche et al. mentioned that the clinical symptoms of anemia (fatigue, headache, dizziness, shortness of breath, or rapid heartbeat) were long thought to occur only when there was a sudden and significant decrease in hemoglobin, and that patients gradually adapted to a slow decrease in hemoglobin, i.e., the concept of asymptomatic anemia The concept of asymptomatic anemia. In fact, this “asymptomatic state” seems to reflect the fact that both patients and physicians may not be fully aware of the impairment of this state of the body, quality of life and cognitive function. Thus, the patient’s adaptation to chronic anemia is in fact an adaptation to a low quality of life. The recognition of these concepts has progressed considerably in patients with other diseases, especially in the treatment of hemodialysis patients, where intravenous iron supplementation has become a key measure. It is worth mentioning that the quality of life of patients with IBD may be similar to that of patients with malignancy with anemia, and that the chronic fatigue caused by anemia can plague these patients as much as abdominal pain and diarrhea, so that the correction of anemia in IBD improves the quality of life of the patient as much as the control of diarrhea symptoms in this patient. Treatment of anemia in IBD patients 1. Treatment of IBD disease itself: There is a relationship between IBD activity and the degree of anemia, and several factors are involved in the anemia process during the active phase of the disease, including the recently confirmed chronic disease anemia and impairment of iron absorption mechanisms during the active phase of the disease. Therefore, treatment of IBD-related anemia ultimately starts with its underlying primary cause, although sometimes this step is often neglected in actual clinical practice. Furthermore, the long-term outcome of anemia relief depends on the proper management of IBD itself, and the therapeutic measures taken by the clinician are aimed at stopping the recurrent anemia in the patient. 2.. Iron therapy: Once a patient with IBD is found to have a decreased hemoglobin level (less than 130 g/L in men and less than 120
g/L), iron supplements should be promptly administered. At the same time, the WHO definition of anemia is also applicable to patients with IBD. In fact, patients without anemia but with iron deficiency should also be treated aggressively and accordingly. In conclusion, anemia in patients with IBD should be aggressively diagnosed, analyzed and managed. In addition to the correction of hemoglobin levels, the main goal of our treatment is the improvement of the patient’s quality of life. Therefore, the aim of treatment with oral iron should be the complete correction of anemia and iron deficiency status, not only the improvement of hemoglobin levels. When the hemoglobin level increases from 110
g/L to 130 g/L, the quality of life is significantly improved. In addition, all patients require adequate iron supplementation to correct anemia and replenish body iron stores. Conventional practice requires up to 200 mg of micronutrient iron per day (even 400 mg in some textbooks) for the correction of iron deficiency anemia. This may be wrong, since the maximum daily oral iron absorption is 10-20 mg.
In fact, there are no relevant experimental studies to support the use of high doses of iron in the treatment of iron deficiency anemia in patients with IBD or non-IBD. From a physiological point of view, the iron absorption process is eventually saturated even at high efficiency. One tablet of divalent iron ion preparation alone (e.g. ferrous sulfate) provides more iron than the intestine can absorb in 1
d than the amount that can be absorbed by the intestine. However, the unabsorbed iron salts in the intestine are themselves toxic to the intestinal mucosa and may exacerbate the activity of IBD itself. Moreover, high doses of iron may cause diarrhea, which not only affects patients’ quality of life but also makes it difficult for clinicians to distinguish it from a relapse of IBD disease. At the same time, unabsorbed iron ions may inhibit intestinal iron absorption through feedback, reducing drug tolerance and treatment compliance, especially in younger patients who are treated with multiple oral medications. Therefore, if oral iron is used, it is recommended to apply small doses of 50-100
mg/d of basic requirement. The greatest advantage of oral iron application is its ease of use. However, oral iron supplementation has many limitations: (1) the absorption rate of oral iron is low, the unabsorbed iron ions themselves are toxic and pro-inflammatory, and they may increase the activity of IBD itself.
IBD itself may become more active. Previously, iron was often supplemented with ferrous sulphate, ferrous gluconate, or ferrous fumarate.
fumarate, all of the divalent iron complexes are released in the intestinal lumen or intestinal mucosa as a result of activated hydroxyl
These oxidized components act on the intestinal mucosa of the intestinal wall, causing a range of gastrointestinal symptoms such as nausea, bloating, diarrhea and upper abdominal pain. (2) IBD activity can significantly affect the absorption of oral iron, and Hepcidin, an acute time-phase response protein, plays a key role in this process. Inflammatory factor-mediated overexpression of this protein in the liver significantly affects duodenal absorption of iron; in some patients with Crohn’s disease, it is also affected by pre-existing intestinal resection, even when the diseased tissue itself involves the duodenum. (3) Oral iron is frequently not tolerated by patients. In a recent systematic review of the treatment of IBD-related anemia, oral iron was described, in which intolerance of oral iron (mainly due to nausea, abdominal pain, and diarrhea) was so prevalent that more than 21% of patients discontinued this therapeutic measure. Furthermore, patients with IBD often require several oral medications, and the many adverse effects of oral iron have led to a gradual decrease in patient compliance. Moreover, some patients with persistent chronic bleeding of the intestinal mucosa lose more iron than the intestinal iron is absorbed. The efficacy of intravenous iron supplementation in the treatment of iron deficiency anemia in non-IBD patients has been demonstrated in numerous studies. Although studies of intravenous iron supplementation in patients with IBD are very limited, the results have been surprising. 50-91% of patients were particularly effective in correcting iron deficiency with iron sucrose. The use of this intravenous iron has been reported in the literature to be as effective as 73% in the treatment of iron deficiency anemia. In summary, intravenous iron sucrose is significantly more effective than oral iron in terms of speed of onset and duration of action, while enhancing tolerability in patients with IBD. According to the generally recommended algorithm, the initial treatment response for iron deficiency anemia in patients with IBD is based on the level of hemoglobin. Patients with hemoglobin levels above 100 g/L or 105
g/L, oral iron therapy should be initiated, but at hemoglobin levels below this value, the anemia is generally considered severe and iron supplementation by the intravenous route should be actively chosen at this time. A hemoglobin level above 100 g/L or 105
g/L and are not tolerated by the oral route, the intravenous route can also be chosen for iron supplementation. In summary, indications for adequate iron supplementation by the intravenous route include: severe anemia (generally defined as hemoglobin below 100
g/L, although in some individuals 105 g/L is chosen as the cut-off point), moderate anemia requiring rapid correction, intolerance to oral iron, and failure of oral iron therapy. Although iron sucrose is the most commonly used intravenous preparation in IBD, and other new intravenous iron preparations are theoretically available as well, with a very low incidence of adverse effects, especially serious ones, data are lacking in this regard in patients with IBD. Low-molecular-weight dextrose iron is also widely used, with a new molecular structure and intravenous iron supplementation, and its pharmacokinetic characteristics and preliminary clinical trials confirm that it can be used in high doses in patients with IBD. However, there have been reports of allergic reactions to iron dextran. Ferrous gluconate may lead to temporary capillary permeability syndrome; ionized state iron can lead to acute endothelial cell injury with symptoms such as nausea, hypotension, palpitations, dyspnea and edema of the extremities. In contrast, iron sucrose is safer than iron dextran and is well tolerated even by patients who have shown adverse effects to iron dextran, and its single dose of up to 300
A single dose of up to 300 mg has not been reported negatively, and the recommended maximum dose is 600 mg per week. 3.
EPO therapy: EPO was initially used in patients with chronic renal failure and has been shown to be equally effective in other conditions with chronic disease anemia. Several studies have evaluated the efficacy of EPO in patients with IBD and the results are promising. However, EPO is significantly more expensive than intravenous iron, which should be used as a first-line treatment for severe anemia, and EPO should only be used if the patient’s serum EPO concentration is reduced or if the patient’s anemia does not improve despite adequate intravenous iron supplementation. Other possible factors contributing to anemia in patients with IBD should also be excluded or corrected prior to EPO application. Finally, EPO should be used after the disease activity itself has been controlled by treatment, including immunosuppressive therapy. It is important to emphasize that EPO is an adjunct to, and not an alternative to, IBD-related treatment. EPO should always be used in combination with intravenous iron supplementation, since functional iron deficiency, i.e., a deficiency of iron available for erythropoiesis, may occur during this period despite normal total body iron stores. In special patients with Crohn’s disease, folic acid and vitamin B12 levels should be monitored frequently and corrected promptly in case of their deficiency. So far, the implementation of all EPO clinical trials has been accompanied by iron supplementation [1]. The increase in erythropoiesis and iron requirements due to EPO during the course of treatment makes iron supplementation even more necessary. Conclusion
Anemia is a common complication in patients with IBD, especially during the treatment of Crohn’s disease. Iron deficiency, vitamin B12 and/or folic acid deficiency, malabsorption, malnutrition, inflammatory altered states, bowel resection, and drug effects may all contribute to anemia, making it a multifactorial and complex dilemma for clinicians. Patients with inflammatory bowel disease with anemia are sicker and have a poorer quality of life and need to be diagnosed and treated aggressively and accurately. Iron deficiency is overwhelmingly supplemented with intravenous preparations, and iron sucrose has been shown to be a highly effective and easily tolerated preparation for patients. When clinicians are faced with refractory anemia that has failed to respond to iron therapy and is recurrent, the option of applying EPO has been shown to have significant results. The long-term improvement of anemia in patients with IBD also depends on the effective treatment of inflammatory changes in the intestine itself.