Thursday, September 4, 2008

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

This comes from the National Anemia Action Council:

Anemia of Chronic Disease as a Harmful Disease State or Beneficial Adaptation
NAAC Review Published: September 4, 2008
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.
View original published article at PubMed

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