Anemia of Chronic Disease as a Harmful Disease State or Beneficial Adaptation

It is commonly believed that anemia of chronic disease (ACD) is an adverse consequence of systemic illness and should be treated. In this analysis, Zarychanski and Houston propose that ACD is not an adverse consequence, but a beneficial adaptive response to an underlying disease state. They present three arguments in support of this hypothesis.

First, the observation that anemia is associated with a poor prognosis is not evidence of causation. Although several studies identify anemia as an independent predictor of poor prognosis, this association cannot be considered as causation. In fact, the opposite may be true; both the degree of anemia and the prognosis may simply reflect the severity of the underlying disease. Since routinely measured clinical variables do not reliably measure inflammatory and stress responses, it is difficult to adjust for these effects. Several studies in heart disease and cancer, not specifically designed to study ACD, showed that anemia was not an independent predictor of survival when the studies were adjusted for these variables and other clinical factors.

Second, anemia of chronic disease has the characteristic of an adaptive physiologic response. ACD appears to be a highly coordinated response to systemic disease. The occurrence of several independent processes contributing to hemoglobin reduction, suggests a process of evolutionary adaptation. Iron sequestration is the best studied, and its potential beneficial effects include inhibition of bacterial growth and attenuated production of reactive oxygen species. Also, decreased bone marrow production reduces nutrient utilization in times of stress. Moderate anemia and compensatory expansion of plasma volume reduces blood viscosity, which decreases left ventricular stroke and may improve microvascular perfusion. Lastly, decreased margination of platelets and decreased scavenging of nitric oxide may also reduce thrombosis.

Third, treatment of mild to moderate anemia appears to increase mortality. If ACD is a protective measure, efforts to override this mechanism by increasing hemoglobin should elicit adverse consequences. This is seen in several studies ? not specifically designed to study ACD ? that have evaluated red blood cell transfusions or the use of erythropoietin stimulating agents. Among critically ill patients, patients with acute coronary syndrome or myocardial infarction, several observational studies showed transfusions to be an independent risk factor for mortality. Two recent meta-analyses of renal failure patients and cancer patients showed that treatment with erythropoietin to achieve a "normal" hemoglobin was associated with higher mortality compared to regimens designed to achieve lower target hemoglobin levels.

Even if ACD is a beneficial adaptive response, this response may sometimes be excessive or insufficient, and therefore maladaptive and potentially harmful. Nevertheless, the authors believe there is sufficient evidence to advocate restraint regarding the treatment of mild to moderate ACD. The possible risks of treatment should be weighed carefully against the potential benefits before therapy to override ACD is considered.

Zarychanski R, Houston DS. Anemia of chronic disease: a harmful disorder or an adaptive, beneficial response? CMAJ. 2008 Aug 12;179(4):333-7.

NAAC Expert Commentary:
In their provocative article, Zarychanski and Houston address the old age question asked by many in the medical field for years; is anemia a disease state or an adaptation? The authors postulate that anemia of chronic disease (ACD) is an adaptive response to an underlying condition that confers benefit to the patient and treatment is essentially harmful. There are many other medical conditions when pathologic states are a result of adaptation. For example, cardiomagaly in congestive heart failure, carbon dioxide retention in obstructive pulmonary disease, etc.

According to the authors, anemia may represent a special case since it is usually associated with another underlying disease or is a signal of one. Although scores of many more publication not presented here relate anemia to poor prognosis, they all rely on association and not direct causation, as pointed out by the authors. The lack of causation data does not negate the fact that anemia may still be a marker of poor prognosis and survival. In their argument they mix data derived from acute anemia (blood loss) with data (mostly meta-analysis) from studies done in chronic conditions. Although many patients seem to tolerate mild to moderate anemia, it is yet to be concluded that their quality of life (including exercise tolerance) would not improve with treatment.

Treatment of mild to moderate anemia with blood transfusion is counter-productive as stated by the authors. It is short term, requires an invasive procedure and is also associated with short and long term negative outcomes. In contrast, the use of erythropoietin (EPO) has been shown to improve both the quality of life and performance of patients suffering from renal failure and cancer. In three randomized controlled studies performed in critically ill patients, EPO raised hemoglobin, reduced exposure to transfusions in two studies and had a positive survival outcome in the last of this series. Deep vein thrombosis (DVT) has been established as risk in these patients and DVT prophylaxis is now recommended, although already the standard of care.

Dosing and hemoglobin targets have surfaced as the suspected reasons for poor outcome in both renal failure and cancer patients with or without chemotherapy treatments. To suggest that 'treatment' is harmful may deprive many of a better quality of life while sparing the few who suffer untoward complications.

In summary, this study contends that anemia is beneficial and an adaptive response to illness, rather than a disease state. The authors conclude that while evidence does support their hypothesis, further clinical trials are necessary to illuminate the mechanisms of these interactions. We agree more studies are needed to validate these theories, and we also encourage further exploration of the argument for anemia as a disease state. However, evidence is lacking for the authors to regard treatment of mild to moderate ACD as harmful, and some evidence also shows that treatment may in fact be beneficial. In either case, thought and care should be taken prior to instituting therapy for ACD, something the authors endorsed and a notion which should be applied to any medical therapeutic intervention.

Comparing Iron Doses to Treat Anemia in Pregnancy

Anemia is a common complication during pregnancy, and is associated with preterm birth, low birth weight, and maternal morbidity and mortality. Since iron deficiency (ID) is the most common cause of anemia in pregnant women, iron tablets are usually prescribed as treatment. Most iron dosages are given as 80 mg tablets, which often cause adverse gastrointestinal side effects and impairment of mineral absorption. To minimize these adverse events, upper limits of 45 mg of iron are recommended. However, little is known about alternatives to high dose iron administration to treat anemia during pregnancy. Therefore, a recent study was undertaken to assess the efficacy and side effects of low- vs. high-dose iron administration to treat anemia during pregnancy.

In the study, 179 women at mid-pregnancy were allocated into groups receiving ferrous sulfate containing 20, 40, or 80 mg of elemental iron. The dose was taken daily for 8 weeks or until birth occurred. The study's primary outcomes were hemoglobin (Hb) level, incidence of anemia at the end of treatment, and adverse gastrointestinal effects. A clear dose-response of increasing Hb with iron dosage was shown, and fewer women receiving 80 mg presented with ID at the end of treatment compared with the lower dosages. Despite a higher mean Hb level and an improved iron status in the 80 mg group, there was no difference in the incidence of anemia among all three groups. Also, adverse gastrointestinal events such as nausea, abdominal discomfort, and constipation were significantly more frequent in the 80 mg group, furthering the issue of clinical benefit vs. patient comfort.

From these results, the authors conclude that lowering the dose of iron provides the same clinical benefits in terms of anemia treatment, but with less adverse events. However, study limitations warrant further investigation into the potential benefits of higher Hb doses. Although several trials have examined Hb cutoff points in relation to adverse pregnancy outcomes, this present study does not have the statistical power to determine if higher Hb levels have an effect on pregnancy outcomes. On the other hand, some studies have indicated a risk of hemoconcentration and other adverse effects in pregnant women treated with higher dosages of iron supplements. More research will be needed to determine the appropriate levels of iron supplements and Hb levels to achieve optimal pregnancy outcomes.

Zhou SJ, Gibson RA, Crowther CA, Makrides M. Should we lower the dose of iron when treating anaemia in pregnancy? A randomized dose-response trial. Eur J Clin Nutr. 2007 Oct 10.

NAAC Expert Commentary:
Iron deficiency anemia (IDA) reportedly affects 20-40% of pregnant women. Although IDA has been associated with multiple maternal and fetal morbidities, little evidence exists to confirm a direct cause and effect relationship. Because of these concerns and because of the approximately 5% incidence of postpartum hemorrhage and its consequent risks, including transfusion-most experts believe anemia in pregnancy should be treated. However, oral iron replacement is poorly tolerated by many patients and therefore, compliance with treatment regimens may be poor.

In the controlled trial, Zhou et al demonstrated that a single 20 mg daily-dose of elemental iron given as ferrous sulfate produced a similar correction of mild to moderate IDA with fewer gastrointestinal side effects than an 80 mg daily-dose. However, iron stores and Hb levels were higher in patients that received the higher iron dose.

The authors were correct to question the clinical equivalence of anemia correction in the three groups, given the expected differences in Hb levels and iron stores. For example, although anemia correction was similar in all groups, women with lower Hb levels and iron stores might suffer prolonged or greater postpartum anemia following blood loss at delivery. Women with lower Hb levels and lower iron stores might benefit from higher Hb and iron levels due to administering a higher iron dose. Similarly, women with lower Hb levels at delivery have a greater risk of requiring a blood transfusion, which might be preventable by establishing higher Hb levels. Although the general rule in medicine is to prescribe the lowest dose of medication that will accomplish the therapeutic goal, there may be benefit in using the higher doses.

Participants in all three arms of the study were highly compliant in taking their medication, despite side effects. It may be difficult to compare this level of compliance among volunteer subjects to the reality of patients prescribed a supplement that is difficult to tolerate. Despite receiving only a single 20 mg daily-dose of elemental iron, even patients in the low dose iron group suffered a 46% incidence of uncomfortable side effects. Had they not been enrolled in a study, many of these women might have discontinued their treatment. Real world compliance with oral iron regimens is low (60%), emphasizing the need for better tolerated preparations and/or dosing schedules. This study provides good information about efficacy and side effects of three dosing protocols for ferrous sulfate, but further research is needed to identify a more ideal protocol for iron replacement in IDA.

Effectiveness of IV Iron Treating Patients with Chemotherapy-Induced Anemia

Cancer patients often experience chemotherapy-induced anemia (CIA), a condition that is associated with fatigue and a reduced quality of life. However, CIA can be effectively managed with erythropoiesis-stimulating agents (ESAs) in 50-70% of patients. Research has shown that the concomitant use of iron with ESAs could hold further potential therapeutic benefits, although the use of intravenous (IV) iron administration has not been well explored in CIA patients. A recent study examined whether concomitant IV iron use improved hemoglobin (Hb) level responses in patients treated with darbepoetin alfa.

The 16-week study enrolled 398 CIA patients receiving darbepoetin alfa who were randomized to either an IV iron or a standard practice (oral iron or no iron) group. Patients received 500 g of darbepoetin alfa and either 200 mg of IV iron or standard practice at 3-week intervals. The primary end point was defined as the proportion of patients achieving a hematopoietic response (Hb 12 g/dL or a 2-g/dL increase in Hb levels during the 16-week period). Several secondary end points were also measured, including time to hematopoietic response and the proportion of patients requiring red blood cell (RBC) transfusions.

Of the original cohort, 67% of patients in the IV iron group and 76% in the standard practice group completed the study. The hematopoietic response rates of the IV iron group were significantly higher compared to the control group. In terms of secondary endpoints, the IV iron group also responded more rapidly, and required significantly less RBC transfusions than the control group. Also, the incidence of adverse events, such as nausea, abdominal pain, and more serious cardiovascular and thromboembolic events, were similar in both treatment groups, indicating a favorable benefit-to-risk ratio.

The results of this study point to a wide range of clinical benefits associated with concomitant IV iron administration with ESAs. In addition to a higher hematopoietic response, a reduction in the number of RBC transfusions in CIA patients means lower risks of infection and other immune-related reactions. This study was also the largest trial of its kind, and the authors contend it will provide new options for ESA and iron dosing schedules. Although the results may not be generalizable to all CIA patients, more work is needed to determine which subsets of these patients will benefit most from this clinical technique, concluded the authors.

Bastit L, Vandebroek A, Altintas S, Gaede B, Pintér T, Suto TS, Mossman TW, Smith KE, Vansteenkiste JF. Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin alpha administered every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. J Clin Oncol. 2008 Apr 1;26(10):1611-8.

NAAC Expert Commentary:
Patients with cancer often experience anemia of inflammation (anemia of chronic disease). Despite adequate iron stores, these patients are unable to mobilize iron for erythropoiesis. Presumably, this is the effect of increased concentrations in the circulation of hepcidin - an enzyme that destroys ferroportin, the protein responsible for iron transport. The administration of iron intravenously may then improve the erythropoietic response to ESAs in cancer patients.

This study by Bastit et al proves this hypothesis and confirms a previous smaller study by Auerbach et al¹. In Bastit, patients treated with 200 mg of IV gluconate or iron sucrose experienced a more rapid and complete response to darbepoetin alpha. Iron-treated patients required a lower number of blood transfusions.

These data are of interest, but not unexpected, and are unable to influence current practice. Given the current guidelines for ESA treatment in cancer, a rapid erythropoietic response may represent an unfavorable event. It is encouraging that anemia management with iron was not associated with increased incidence of deep vein thrombosis, an association that had been feared. While a larger sampling of patients may reveal more differences in complication rates, it is unlikely that those differences may be expected because of a rapid hemoglobin improvement.

In summary, the study confirms the effectiveness of IV iron in patients treated with ESAs and indicates that rapid increases in erythropoietin are not associated with an increased risk of complications. However, the results of this study are unlikely to change current practice until, at a minimum, the safe utilization of ESAs is demonstrated.

Reference
1. Auerbach M, Ballard H, Trout JR, McIlwain M, Ackerman A, Bahrain H, Balan S, Barker L, Rana J. Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open-label, randomized trial. J Clin Oncol. 2004 Apr 1;22(7):1301-7.