Inflammatory Anemia

Inflammatory Anemia – Anemia of chronic disease (ACD)

Inflammatory anemia, also known as anemia of chronic disease (ACD), is a disorder of iron homeostasis promoted by hepcidin-25 in response to an inflammatory condition.

Suspected Causes of Anemia of Chronic Disease

From Hoffman R et al: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

Shortened erythrocyte survival Block in reuse of iron by erythrocyte
Direct inhibition of erythropoiesis
Relative deficiency of erythropoietin

Synonyms

  • Inflammatory anemia
  • Anemia of chronic disease
  • ACD

Epidemiology & Demographics

Prevalence

  • •Second-most prevalent anemia after iron deficiency anemia:
    • 1.Around 11% of men and 10% of women ages 65 to 85 yr
    • 2.>20% of adults older than 85 yr

Pathophysiology

Iron is carried in the bloodstream shelled by a hollow protein called transferrin (<0.2% of total iron body content) or at the core of hemoglobin in RBCs (60% of total iron body content).

It is mainly stored (15% to 30% of total iron body content) inside the liver, spleen, and skeletal muscle as ferritin and in lysosomes as hemosiderin.

The rest of the iron body content is trapped in myoglobin in skeletal muscle and cytochromes in mitochondria. In clinical practice, ferritin is a surrogate for iron stores, and total iron binding capacity (TIBC) is a surrogate for transferrin and the carrying capacity of iron.

Cells involved in the response to inflammatory insults cause the release of cytokines, such as IL-6, which stimulates hepatic release of hepcidin.

Hepcidin is a circulating protein that blocks ferroportin, an iron channel responsible for the exit of iron from enterocytes (and thus gastrointestinal absorption) and macrophages (which accumulate iron from engulfed senescent blood cells).

IL-1 and TNF-alpha stimulate IFN-gamma release by marrow stromal cells, which in turn suppress the erythroid response to erythropoietin (EPO). In chronic kidney disease, ACD is a consequence of decreased production of EPO and decreased renal clearance of hepcidin.

The low availability of serum iron causes iron deficiency in the bone marrow compartment and decreased reticulocyte levels.

Clinical Presentation

  • •Besides fatigue, shortness of breath, and generalized weakness from the anemia itself, it is important to consider other complaints if the underlying diagnosis is unknown, such as weight loss (malignancy, chronic infections, connective tissue diseases), anorexia, nausea, paresthesias, pleuritic chest pain, weight gain (CKD), diarrhea, bloody stools, abdominal pain, oral ulcers (IBD), and fevers (HIV, chronic infections).
  • •Physical findings may include pallor, lymphadenopathy, stigmatas of connective tissue diseases (malar rash, sclerodactyly), palpable or visible masses, and localized findings for infection or malignancy.

Diagnosis

Isolated ACD:

  • •CBC with differential: Normocytic, normochromic, moderate (Hb rarely <8 g/dl) anemia
  • •Hypoproliferative anemia (low reticulocyte index; corrected reticulocyte count <2%)

Iron studies:

  • •Low iron concentration as in IDA (iron deficiency anemia)
  • •Normal/high ferritin (>35 mg/dl) in ACD as it is an acute phase reactant
  • Low/normal TIBC (as opposed to IDA) and low transferrin saturation (as in IDA)
  • •Normal soluble transferrin receptor (sTfR, high in IDA)

Combined ACD/IDA:

  • •If normal to high ferritin, sTfR/log ferritin ratio <1 defines isolated ACD, and ratio >2 defines combined IDA/ACD

Etiology

  • •Malignancy
  • •CKD (patients with CKD stage IV [GFR<30 ml/min] should be screened for ACD)
  • •CHF (ACD is the main cause of anemia in CHF patients)
  • •Chronic infections
  • •Anemia of critical illness (develops within days)
  • •Connective tissue diseases

Differential Diagnosis

  • •Liver injury (increases ferritin):
    • 1.Iron deficiency anemia:
      • a.Other causes of normocytic anemia or microcytic anemia

Laboratory Features in Microcytic Hypochromic Anemias

McPherson RA, Pincus MR: Henry’s clinical diagnosis and management by laboratory methods, ed 23, Philadelphia, 2017, Elsevier.

Serum IronSerum TIBC% SaturationMARROWSerum FerritinZPPHb A2Hb F
% SideroblastsIron Stores
Iron deficiency↓︎↑︎↓︎↓︎↓︎↓︎↑︎N-↓︎N
β-Thalassemia traitN (↑︎)NNNN-↑︎N-↑︎N↑︎N-↑︎
ACD↓︎N-↓︎↓︎↓︎N-↑︎N-↑︎↑︎NN
Sideroblastic anemia↑︎↓︎↑︎↑︎↑︎↑︎↑︎ (↓︎)NN-↑︎

ACD, Anemia of chronic disease; Hb, hemoglobin; N, normal; TIBC, total iron-binding capacity; ZPP, zinc protoporphyrins; ↓︎, decreased; ↑︎, increased.

      • Red blood cell loss or destruction:
        • (1)Acute blood loss
        • (2)Hypersplenism
        • (3)Hemolysis
      • c.Decreased red blood cell production:
        • (1)Primary causes:
          • (a)Bone marrow hypoplasia or aplasia
          • (b)Myeloproliferative disease
          • (c)Pure red blood cell aplasia
      • d.Secondary causes:
          • (1)Chronic renal failure
          • (2)Liver disease
          • (3)Endocrine deficiency states
          • (4)Sideroblastic anemia

Workup

CBC, reticulocyte count, peripheral smear, iron level, ferritin, TIBC. The below table summarizes characteristic findings in inflammatory anemia. 

Laboratory Characteristics of ACD, IDA, and IDA with Inflammation

Anemia of Chronic Disease (ACD)Iron Deficiency Anemia (IDA)IDA with Inflammation
Mean corpuscular volume (MCV)72-100 fL<85 fL<100 fL
Mean corpuscular hemoglobin concentration (MCHC)<36 g/dl<32 g/dl<32 g/dl
Serum ironDecreasedDecreasedDecreased
Serum total iron-binding capacity (TIBC)Typical below mid-normal rangeElevatedLess than upper limit of normal range
Transferrin saturation 2%-20%<15% (usually <10%)<15%
Serum ferritin>35 μg/L<35 μg/L>35 μg/L, <200μg/L
Serum soluble transferrin receptor concentration (sTfR)Normal (may be increased if serum ferritin >200 μg/L)IncreasedIncreased
TfR index (sTfR/log ferritin)<1>2>2
HepcidinHighLowNormal
Stainable iron in bone marrowPresentAbsentAbsent

∗ Serum iron/TIBC ∗ 100.

Treatment

Treat the underlying disorder/disease.

Acute General Treatment

  • •The treatment of inflammatory anemia is directed primarily at treatment of underlying conditions, which can improve symptoms and facilitate hemoglobin recovery.
  • •Blood transfusion is usually reserved for severe anemia (with Hb level <7 g/dl or <8 g/dl in patients with cardiac disease), especially if complicated with ongoing bleeding.

Chronic Treatment

  • •Erythropoiesis-stimulating agents (ESA) (epoetin alfa and darbepoetin alfa) are FDA approved for use in patients with anemia resulting from:
    • 1.Chronic kidney disease
    • 2.Chemotherapy
    • 3.Zidovudine therapy
  • •A 1998 study, the Normal Hematocrit Cardiac Trial (NHCT), showed a nonsignificant increase in the combined endpoint death and nonfatal MI in patients with goal hematocrit of 33% versus 27%. Subsequent studies (CHOIR, CREATE, and TREAT) showed that higher doses and higher hematocrit targets were associated with increased cardiovascular events
  • •ESA dose should be individualized for each patient, and the lowest sufficient dose to reduce blood transfusions should be used. A hemoglobin target of approximately 10 g% is widely acceptable. Iron deficiency should be ruled out before ESA is started. After starting ESA therapy, ASH/ASCO guidelines recommend periodic monitoring of iron status. When there is no or suboptimal response to oral therapy, parenteral iron therapy should be considered before concluding that a patient is nonresponsive to iron therapy
  • •The hepcidin–ferroportin axis is the target of development of novel agents of which the most promising are hypoxia-induced factor modulators. HIF is a transcription factor that promotes expression of erythropoietin. HIF is upregulated by inhibition of PHD. Small molecule inhibitors of prolyl hydroxylase domain dioxygenases (HIF-PHI [prolyl hydroxylase inhibitor]) stimulate the production of endogenous erythropoietin and improve iron metabolism. The clinical development of three oral agents targeting this axis–daprodustat, roxadustat, and vadadustat–has now completed randomized clinical development and led to approvals in Asia

Suggested Readings

  • Collister D., et al.: The effect of erythropoietin-stimulating agents on health-related quality of life in anemia of chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med 2016; 164 (7): pp. 472-478.
  • Ganz T.: Anemia of inflammation. N Engl J Med 2019; 381 (12): pp. 1148-1157.
  • Means R.T.: Hepcidin and iron regulation in health and disease. Am J Med Sci 2013; 345: pp. 57-60.
  • Rizzo J.D., et al.: ASCO/ASH clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. J Clin Oncol 2010; 28 (33): pp. 4936-5010.
  • Ruchala P., Nemeth E.: The pathophysiology and pharmacology of hepcidin. Trends Pharmacol Sci 2014; 35 (3): pp. 155-161.
  • Sugahara M.: Prolyl hydroxylase domain inhibitors as a novel therapeutic approach against anemia in chronic kidney disease. Kidney Int 2017; 92 (2): pp. 306-312.
  • Sun C.C., et al.: Targeting the hepcidin-ferroportin axis to develop new treatment strategies for anemia of chronic disease and anemia of inflammation. Am J Hematol 2012; 87 (4): pp. 392-400.
  • Wen T., et al.: Hypoxia-inducible factor prolyl hydroxylase inhibitors in patients with renal anemia: a meta-analysis of randomized trials. Nephron 2020; 144: pp. 572-582.
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