Anemia, Inflammatory

Andre Luiz De Souza M.D
Bharti Rathore, M.D.

Basic Information

Definition

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

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).

Iron is mainly stored (15%-30% of total iron body content) inside the liver, spleen, and skeletal muscle cytoplasm as ferritin (although released to the bloodstream), and in lysosomes as hemosiderin. The rest of the iron body content is trapped in myoglobin in skeletal muscle and cytochromes in mitochondrias. 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 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.

Synonyms

Inflammatory anemia
Anemia of chronic disease
ACD

ICD-10CM CODES

D63.8 Anemia in chronic diseases classified elsewhere

D63.0 Anemia in neoplastic disease

D64.8 Anemia, unspecified

Epidemiology & Demographics

Prevalence

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

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 (MCV 80-100 fL), normochromic (<36 g/dL), moderate (Hb rarely <8 g/dL) anemia

Hypoproliferative anemia (low reticulocyte index; reticulocyte count corrected to hematocrit <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 (Fig. 1)

FIG.1

Differential diagnosis of anemia with low serum iron.

ACD, Anemia of chronic disease; IDA, iron deficiency anemia; sTfR, soluble transferrin receptor.

Modified and updated from Young NS et al. [eds]: Clinical hematology, St Louis, 2006, Mosby.
•

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 <1 defines isolated ACD, and >2 defines combined IDA/ACD

Etiology

•

Malignancy
•

CKD (patients with CKD stage IV [GFR<30 ml/min] should be screened for ACD)
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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)

•

Iron deficiency anemia

•

Other causes of normocytic anemia or microcytic anemia (Table 1)

TABLE1 Laboratory Features in Microcytic Hypochromic AnemiasMcPherson RA, Pincus MR: Henry’s clinical diagnosis and management by laboratory methods, ed 23, Philadelphia, 2017, Elsevier.

	Serum Iron	Serum TIBC	% Saturation	MARROW		Serum Ferritin	ZPP	Hb A₂	Hb F
	Serum Iron	Serum TIBC	% Saturation	% Sideroblasts	Iron Stores	Serum Ferritin	ZPP	Hb A₂	Hb F
Iron deficiency	↓	↑	↓	↓	↓	↓	↑	N-↓	N
β-Thalassemia trait	N (↑)	N	N	N	N-↑	N-↑	N	↑	N-↑
ACD	↓	N-↓	↓	↓	N-↑	N-↑	↑	N	N
Sideroblastic anemia	↑	↓	↑	↑	↑	↑	↑ (↓)	N	N-↑
ACD, Anemia of chronic disease; 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
•
Decreased red blood cell production Primary causes
1. Bone marrow hypoplasia or aplasia
2. Myeloproliferative disease
3. Pure red blood cell aplasia
Secondary causes:
1. Chronic renal failure
2. Liver disease
3. Endocrine deficiency states
4. Sideroblastic anemia

Workup

•

CBC, reticulocyte count, peripheral smear (Fig. E2, A), iron level, ferritin, TIBC. Table 2 summarizes characteristic findings in inflammatory anemia. Characteristic bone marrow findings of increased iron stores in stromal histiocytes and impaired erythroid iron incorporation are shown in Fig. E3.

FIG.E2

Slightly hypochromic normocytic red cells in anemia of chronic disease associated with rheumatoid arthritis **(A)**. Bone marrow erythroid precursors are present in normal numbers **(B)**

From Jaffe ES et al: *Hematopathology,* Philadelphia, 2011, Saunders.

TABLE2 Laboratory Characteristics of ACD, IDA, and IDA With InflammationModified and updated from Young NS et al (eds): Clinical hematology, St Louis, 2006, Mosby.

	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 iron	Decreased	Decreased	Decreased
Serum total iron-binding capacity (TIBC)	Typical below mid-normal range	Elevated	Less 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)	Increased	Increased
TfR index (sTfR/log ferritin)	<1	>2	>2
Hepcidin	High	Low	Normal
Stainable iron in bone marrow	Present	Absent	Absent

FIG.E3

In anemia of chronic disease, iron stores are increased in stromal histiocytes (A and B). Erythroid iron incorporation

Treatment

Treat the underlying disorder/disease.

Acute General Rx

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 Rx

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Erythropoiesis-stimulating agents (ESA) (epoetin alfa and darbepoetin alfa) are FDA approved for use in patients with anemia resulting from:
1. 1.
  
  Chronic kidney disease
2. 2.
  
  Chemotherapy
3. 3.
  
  Zidovudine therapy

Although a 1998 study called 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) suggest that higher doses and higher hematocrit targets are 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 most promising agents on the hepcidin–ferroportin axis are hypoxia-induced factor modulators. Prolyl-hydroxylase domains (PHD) are proteins that compose the proteasome–ubiquitin complex responsible for the degradation of hypoxia-induced factor (HIF). HIF is a transcription factor that promotes expression of erythropoietin. HIF is upregulated by inhibition of PHD. A double-blind, randomized phase 2b trial has elucidated the efficacy of vadadustat, an oral hypoxia-inducible factor, in anemia of kidney disease. Patients were not in dialysis and were classified as CKD stages 3a to 5. At the end of 20 wk of treatment, 54% of the patients receiving vadadustat achieved a hemoglobin of 11 g/dl or an increase of 1.2 g/dl.

Ferri – Anemia, Inflammatory