Anemia of Chronic Disease

Dairion Gatot, Soegiarto Gani, Savita Handayani

Divisi Hematologi Onkologi Medik
Departemen Penyakit Dalam
 Anemia of Chronic Disease (ACD)
= Anemia of Chronic Inflammation
Can be due to infection, inflammation,
malignancy, DM, heart disease, trauma.
Typically: normochromic normocytic
hypoproliferative.
 Pathogenesis
Reduction in RBC production in BM:

Iron trapping in macrophages unavailable usage of Fe

Increased apoptotic death of red cell precursor

Blunted response toward EPO

Decreased RBC survival

 ACD Features

low serum iron (unavailability of Fe)

high ferritin (acute phase protein)
blunted response to EPO
 Hepcidin
An acute phase reactant protein
Predominant negative regulator of Fe
absorption from the intestine, and also Fe
release from macrophage.
Release of hepcidin from the liver is
dependent upon level of IL-6.
 Acute event-related anemia
Variant of ACD in conditions: after surgery,
major trauma, myocardial infarction or sepsis.
= Anemia of critical illness
Features ACD
 Laboratory findings

Most patients have mild anemia

More severe anemia (Hb<8) 20%
Absolute reticulocyte count is frequently low
(<25,000/microL) decrease in RBC
production.
Elevation in cytokines (eg, IL-6) and acute phase
reactants (fibrinogen, erythrocyte sedimentation
rate, C-reactive protein)
 .Laboratory Findings

Serum iron (SI) and total iron binding capacity, (TIBC) are
both low and the percent saturation of transferrin is
usually normal / increase.
Serum ferritin is a poor index of iron stores in chronic
inflammatory diseases because ferritin is also an acute
phase reactant.
 .Laboratory Findings

Bone marrow:

macrophages normal or increased amounts

of Fe storage

erythroid precursors Fe staining / (-)

 Differential Diagnosis
As a normochromic hypoproliferative anemia that
does not affect other blood cell lines DD:
chronic renal failure and several endocrine
disorders (hyperthyroidism, hypothyroidism,
panhypopituitarism, and primary and secondary
hyperparathyroidism)
 .Differential Diagnosis

Prominent ACD (Hb<8 g/dL) with hypochromic and

microcytic DD: chronic Fe deficiency,
thalassemia variants, and the sideroblastic
variants of the MDS.
ACD vs IDA = truncated forms of transferrin
receptors (sTfR). IDAcellular membrane
transferrin receptor density increases sTfR
 Treatment
Correction of underlying disorder
Treat other complicating factors: blood loss,
Fe/B12/folate deficiency
 .Treatment..EPO
EPO levels <500 IU/mL frequently respond to
rHuEPO.
A meta-analysis of 22 trials involving the use of EPO
for the anemia associated with cancer therapy found
that EPO significantly decreased the percent of
patients transfused (relative risk 0.38).
Anemia in Malignancy
 Pathophysiology of
Malignancy-Induced Anaemia
AIS
Tumour cells

Activated
Erythrocytes Erythrophagocytosis, immune system
= shortened survival dyserythropoiesis

TNF Macrophages

Cytokines (TNF, IL-1a/b, IFN-g)

Reduced Impaired Suppressed

Anaemia erythropoietin iron BFU-E
production utilisation CFU-E

AIS, Anaemia-Inducing Substance; BFU-E, Burst-Forming Unit-Erythroid; CFU-E, Colony-

Forming Unit-Erythroid; TNF, Tumour Necrosis Factor; IL, Interleukin; IFN, Interferon
Nowrousian. Med Oncol 1998; 15 (Suppl 1): S1928
 In terms of anaemia induced by the tumour itself, several mechanisms may
be involved.1
In most cases, anaemia associated with cancer is hyporegenerative,
normocytic and normochromic. Serum iron and transferrin saturation levels
are low, despite a normal or elevated serum ferritin level.
Several studies suggest that activation of the immune or inflammatory
system and the release of cytokines such as Tumour Necrosis Factor (TNF),
Interleukin-1 (IL-1) and interferons are involved in cancer-related anaemia.
Shortened red blood cell (RBC) survival, possibly owing to the tumour
directly or the activated immune/inflammatory system, is one pathogenic
mechanism. However, the failure of erythropoiesis to compensate for this
shortened survival appears to be the most important contributory factor to
anaemia. This failure occurs through reduced production of erythropoietin,
impaired utilisation of iron and suppression of erythroid progenitor cells.

1. Nowrousian MR. Recombinant human erythropoietin in the treatment of cancer-related or chemotherapy-

induced anaemia in patients with solid tumours. Med Oncol 1998; 15 (Suppl 1): S19S28.
 Anaemia is a Predictive Factor for Poor
Prognosis in Patients with Cancer
Anaemia

Tumour hypoxia

Chemo- and Genetic Selection pressure Angio-

radio-resistance instability Apoptotic deficiency genesis

Accelerated progression
Increased rate of distant metastases

Poor prognosis
 Tumour- or therapy-associated anaemia can lead to a reduced oxygen-
carrying capacity of the blood, contributing to hypoxia within the tumour.1
Tumour hypoxia is a therapeutic problem, as it induces resistance to
sparsely ionising radiation and some types of chemotherapy (e.g.
cyclophosphamide, carboplatin).
Furthermore, hypoxia can increase genetic instability and selection
pressure, leading to genetic variants. These may favour the survival of
tumour cell variants, e.g. those with reduced capability for apoptosis, and
those with increased angiogenic potential. Accelerated tumour progression
and increased rate of distant metastases may follow.
The combination of increased therapeutic resistance and disease
progression naturally result in poor long-term patient prognosis.

1. Hckel M, Vaupel P. Biological consequences of tumor hypoxia. Semin Oncol 2001; 28 (Suppl 8): 3641.
 Assessing the cause

Blood loss anemia

Increased RBC destruction (hemolytic anemia)

Decreased red blood cell production

(hypoproliferative anemia)
 Malignancy related

Direct effects of the neoplasm

Products of the neoplasm
Effects of treatment directed against the
neoplasm
Anemia due to direct effects of
cancer
Bleeding
Impaired Iron absorption
Bone marrow replacement (myelophthisic)
leukoerythroblastic features
 Anemia due to product of cancer.

Cytokines (interferon (IFN)-, IFN-, IFN-, TNF-

, TGF-, IL-1 and IL-6) block in iron
utilization & inhibiting erythropoietin mRNA
synthesis anemia
Anemia due to cancer therapy
Radiotherapy
Chemotherapy