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Chapter 37 Anemia of Chronic Diseases 495

Treatments of anemia in symptomatic patients will need to be is cost-effective in dialysis patients, even those with elevated ferritin
individualized, as there are risks with erythropoiesis-stimulating levels; however, the widespread applicability of this approach, and its
agents as well as iron therapy. The optimal hemoglobin level in long-term effects, are not known.
ACD patients is not known. Observations of anemia in non-ACD
subjects religiously opposed to transfusions have suggested a physi-
ologic cutoff for anemia of 5 g/dL, below which increased mortality is Newer Therapeutic Strategies That Target the
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seen. In severe anemia, blood transfusions may be warranted, albeit Hepcidin-Ferroportin Axis
with recognition of long-term iron overload and human leukocyte
antigen–sensitization risks. However, randomized controlled studies Treatments to directly address the pathophysiology of ACD via the
5
indicate that acutely ill patients do not benefit from transfusion hepcidin-ferroportin axis, i.e., to decrease hepcidin levels and increase
triggers >7 g/dL. EPO has improved hemoglobin levels in patients ferroportin activity, are in development, and include direct hepcidin
with ACD, with reduction in the necessity for transfusion support; antagonists, RNA interference and gene silencing of hepcidin expres-
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iron supplementation, IV if needed, can be considered in those sion with antisense oligonucleotides, and hepcidin-binding proteins
5
patients that are unresponsive to EPO supplementation. In anemic and spigelmers. Strategies targeting upstream regulators of hepcidin
5
AIDS patients, recombinant EPO treatment significantly decreased production include inhibitors of the BMP6-HJV-SMAD, IL-6, and
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transfusion requirements, especially with endogenous EPO levels of JAK-STAT pathways. Ferroportin agonists or stabilizers prevent
<500 IU/L; however, all of these patients also received zidovudine, hepcidin-ferroportin interaction and subsequent internalization
5
a potential bone marrow suppressant. Recombinant EPO raised and degradation of ferroportin. Isocitrate supplementation, which
the hemoglobin level in patients with a variety of nonhematologic bypasses aconitase in erythroid precursors, may emerge as an adjunct
malignancies (with or without chemotherapy), including squamous to hepcidin-directed therapies. Of note, the recently identified physi-
cell cancer, breast cancer, and colon cancer. However, despite the ologic repressor of hepcidin, erythroferrone, may play a role in the
benefits of decreasing transfusion requirements and improved quality diagnosis and management of ACD, because of its central role in
of life, EPO supplementation (both short- or long-acting forms) in suppression of hepcidin and in physiologic recovery from experimen-
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patients with cancer and kidney disease increases the risk of stroke tally induced anemia of inflammation. These promising approaches,
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and thromboembolic events. Studies have also indicated that criti- however, are still under investigation and await confirmation in the
cally ill patients and those with cancer undergoing chemotherapy may clinical setting.
have an increased rate of thrombosis and overall death when treated
with EPO, particularly if target hemoglobins are >10–11 g/dL.
Increasing the hematocrit to 42% in a large number of hemodialysis SUMMARY AND FUTURE DIRECTIONS
patients with cardiac disease led to an increased number of deaths,
and the number of cardiac events was increased in patients with Anemia is a common consequence of many chronic inflammatory,
chronic renal disease treated with EPO with a goal of complete infectious, and malignant conditions; these are characterized by
normalization of hemoglobin (12.0–15.0 g/dL) as opposed to partial disturbances in iron metabolism, but are often multifactorial. Inflam-
normalization (10.5–11.5 g/dL). Although pretreatment hemoglobin matory cytokines are thought to be the most important causative
levels have been demonstrated repeatedly to be a predictor of good factors in ACD. ACD is difficult to diagnose but can usually be
response to chemotherapy and radiation, studies have demonstrated strongly suspected based on clinical findings, elimination of other
that patients with breast cancer or head and neck cancer treated causes of anemia, low serum iron and transferrin levels, and elevated
with EPO have increased disease progression and worse survival ferritin level. Cytokines such as IFN and TNF have wide-ranging
than placebo-treated patients. Based on these and other studies, the effects, including both direct and indirect inhibition of erythropoiesis
U.S. Food and Drug Administration has warned that EPO should and of red cell survival. Direct inhibition of erythropoiesis is medi-
be given only in the lowest possible doses necessary to avoid blood ated by both a relative decrease in EPO as well as a decrease in iron
transfusions. More recently, consensus has arisen that, for patients available for hemoglobin synthesis. Many of the abnormalities of
with cancer, erythropoiesis-stimulating agents should be used only iron metabolism in ACD are caused by cytokine-induced increases
in those receiving chemotherapy for palliative, rather than cura- in hepcidin, and appreciation of the role of hepcidin in ACD may
tive, intent. EPO should be used sparingly, if at all, with active aid in the diagnosis and treatment. Anemia, iron deficiency, and
malignancy. hepcidin may have independent antimicrobial and antitumor roles,
In the appropriate nonmalignant setting of symptomatic ACD, and this needs further study. The treatment of patients with ACD
a starting dose of 20,000 units of EPO given subcutaneously each should be focused on correcting the underlying disease. Increasing
week can be initiated. If a hemoglobin response is seen, the dose can hemoglobin with exogenous EPO can be quite effective, but the
be decreased and the interval prolonged to titrate the hemoglobin to potential deleterious results of this strategy, in malignancy, infec-
an asymptomatic level. Follow-up and dose titration are essential to tion, and inflammation, must be considered. Development of new
minimize expense, injections, and potential deleterious effects from agents that might exclusively target erythropoiesis but not cancer
high hematocrit or exogenous EPO levels. The EPO response may and identification of risk factors for deleterious EPO effects are
take 4 to 8 weeks and should be monitored for objective symptomatic needed. Since hepcidin overproduction is a key pathogenic feature
improvement (e.g., exercise tolerance). About 35% to 40% of patients of ACD, strategies targeting hepcidin, ferroportin, and iron depletion
show primary resistance. Predictors of resistance to EPO include pathways (such as isocitrate) are being studied and could be used
iron or vitamin deficiency, recent need for transfusion therapy, and in situations where the primary condition is not reversible and the
higher endogenous EPO levels (>100–150 mU/ml) before initiation anemia is severe enough to warrant intervention.
of therapy. If, after 2 weeks of treatment, the serum EPO level is
>100 mU/mL and the hemoglobin concentration has not increased
by ≥0.5 g/dL, or if the serum ferritin level remains >400 ng/mL, a
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response is unlikely. In a multivariate analysis of 80 patients with REFERENCES
chronic anemia of cancer, only the absolute hemoglobin value and
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response to EPO. 2. Nairz M, Haschka D, Demetz E, et al: Iron at the interface of immunity
An important factor limiting response to EPO is functional iron and infection. Front Pharmacol 5:152, 2014.
deficiency. Correction of functional iron deficiency with intravenous 3. Nemeth E, Tuttle MS, Powelson J, et al: Hepcidin regulates cellular iron
(IV) iron supplementation can improve the effect of EPO and also efflux by binding to ferroportin and inducing its internalization. Science
decrease the required dosage. IV iron improves EPO responses and 306:2090–2093, 2004.