Anemia of Chronic Disease (ACD)

dr. Andi Sulistyo Haribowo, SpPD

Program Studi Pendidikan Dokter Universitas Islam Malang 2012

Anemia of chronic disease (ACD)

- definition
ACD is a common type of anemia that occurs in patients with infectious, inflammatory, or neoplastic diseases. It does not include anemias caused by marrow replacement, blood loss, hemolysis, renal insufficiency, hepatic disease, or endocrinopathy, even when these disirders are chronic.
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Anemia of Chronic Disease (ACD) of normocytic Most common outpatient etiology

anemia Misnomer - can be seen in acute illness Another name - anemia of chronic inflammation Occurs in infection/inflammation/neoplasia and unknown other conditions Anemia can be first clue to disease Without known disease - pursue further evaluation

Anemia of chronic disease (ACD) epidemiology

The ACD is extremely common ACD is more common that any anemia syndrome other than blood loss with consequent iron deficiency ACD is the most common cause of anemia in hospitalized patients After patients with bleeding, hemolysis, or known hematologic malignancy were excluded, 52% of anemic patients met laboratory criteria for the anemia of chronic disorders ACD is observed in 27% of outpatients with rheumatoid arthritis and in 58% of new admissions to hospital rheumatology units
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Disorders Associated with the Anemia of Chronic Disease

Chronic infections - Pulmonary infections: abscesses, emphysema, tuberculosis, pneumonia - Subacute bacterial endocarditis - Pelvic inflammatory disease - Chronic urinary tract infections - Chronic fungal disease - HIVinfections - Osteomyelitis Chronic, noninfectious inflammations - Rheumatoid arthritis - LES (Systemic lupus erythematosus) - Sever trauma, thermal injury - Vasculitis

Disorders Associated with the Anemia of Chronic Disease

Malignant diseases - Cancer - Hodgkins disease and Non-Hodgkins Lymphomas - Leukemias - Multiple myeloma Miscellanous - Alcoholic liver disease - Thrombophlebitis - Ischemic heart disease Idiopathic ACD
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Pathogenesis: Inflammatory cytokines i.e. interleukin 1, tumor necrosis factor (TNF) mediate etiology Sequester iron in RE system Impair proliferation of erythroid progenitor cells Blunt erythropoietin response

Pathogenesis of ACD

ANEMIA OF CHRONIC DISEASE ACD is Cytokine Driven

Production of pro-inflammatory cytokines, like TNF and gamma interferon, damage erythroid progenitors Changes in iron homeostasis Decreased proliferation of erythroid progenitor cells Decreased production of Epo and shortened lifespan of RBCs

Pathophysiology

Changes in Hb with Remicade

Anemia of chronic disease (ACD) pathogenesis

Shortened red cell life span, moderately 20-30% (from 120 to 60-90 days) Relative bone marrow(erythropoiesis) failure - Cytokines released from inflammatory cells (TNF-, IL-1, IFN-) affects erythropoiesis by inhibiting the growth of erythroid progenitors - Serum erythropoietin levels in patiens with ACD are normal when compared to healthy subjects but much lower than levels in non-ACD anemic patients
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Anemia of chronic disease (ACD) pathogenesis

ABNORMAL IRON METABOLISM Activation of the reticuloendothelial system with increased iron retention and storage within it impaired release of iron from macrophages to circulating transferrin (impaired reutilization of iron) Reduced concentration of transferrin (decreased production, increase sequestration in the spleen and in the foci of inflammation, increase loss )

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Anemia of chronic disease (ACD) symptoms

Symptoms of the underlying disease ( malignancy or chronic inflammatory disease) Symptoms of the anemia

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Evaluation for occult chronic disease

ESR TSH LFTs BUN & creatinine If normal PE & lab tests
No further workup is likely to be helpful

Hematology: Usually mild anemia (Hct 30 34%) Normochromic/normocytic May be complicated by true iron deficiency anemia

Anemia of Chronic disease (ACD)

But would be microcytic or have elevated RDW

Anemia of Chronic disease

Patients have impaired release of Fe from RE cells
Increased Fe stores, not Fe deficiency

Results in
Ferritin level - normal Serum iron & transferrin saturation - low
True for both ACD & IDA

Transferrin level normal or decreased

IDA - increased

Low reticulocyte count

Diagnosis of ACD
Diagnosis: Measure transferrin receptor level if unclear
Raised in Fe deficiency Normal in anemia of chronic disease
Female 1.9 - 4.4 mg/L normal range Male 2.2 - 5 mg/L normal range

Anemia of chronic disease (ACD) -laboratory features

The anemia is usually mild or moderate ( Hb 7-11g/dl) - lower values are observed in 20-30% of patients The anemia is most often normochromic and normocytic (MCHC and MCV are normal) - MCV 70-80 fl in 5-40% of patients with ACD - MCHC 26-32 g/dl in 40-70% Erythrocyte sedimentation rate (ESR) - usually rapid Retikulocytes - most often normal or slightly decreased number, increased count is rarely

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Anemia of chronic disease (ACD) -laboratory features

Iron metabolism 1. Serum Iron - decreased (it is necessary for the diagnosis of ACD) 2. TIBC - reduced or low-normal (N) 3. Transferrin saturation(TS) - moderately decreased ( higher than in iron-deficiency anemia), usually > 10% 4. Serum Ferritin-increased or normal 5. Serum Transferrin Receptor (sTR)-Normal 6. Sideroblasts in the bone marrow-reduced (5-20%)
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Anemia of chronic disease (ACD) -differential diagnosis

Laboratory features sFe TS TIBC sFerritin sTR Iron deficiency without iron deficiency <10% <10g/L >10% , N >200g/L, N N ACD with iron deficiency <10% N, <30g/L, N
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Laboratory

AICD vs. Iron Deficiency

Soluble Transferrin Receptor: elevated in cases of iron deficiency Ferritin: elevated in anemia of chronic disease If all else fails, Bone Marrow Biopsy
In anemia of chronic disease: macrophages contain normal/ increased iron&erythroid precursors show decreased/absent amounts of iron

Adventages of ACD for patients(?!)

- Withdrawal of iron by increased storage of the metal within the reticuloendothelial system acts to limit the availability of iron to microorganisms or tumor cells and thereby inhibit their growth and proliferation - Decreased hemoglobin reduces the oxygen transport capacity of the blood and decreases the overall oxygen supply, which may primarily affect rapid proliferating (malignant) tissues and micro-organism - Retention and storage of iron in retucoendothelial system directly and indirectly via cytokines strongly affects cell mediated immune function
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Anemia of Chronic disease

Treatment: Anemia resolves if correct underlying disorder If cannot correct underlying disorder treatment of anemia is not usually indicated Supplements of Fe, vitamin B12 or folate are of no benefit

Anemia of chronic disease (ACD) therapy

1. Treatment of the underlying disorder 2. Iron supplementation (IS) - for patients with ACD with chronic infection or malignancy IS should be strictly avoided - IS benefit patients with ACD associated with auto-immune or rheumatic disorders. - when ACD is complicated by iron deficiency (about 27% patients)

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Anemia of Chronic disease

Treatment: Iron supplements of no benefit unless
Patient has ACD & absolute iron deficiency ferritin < 100 ng/ml If ferritin > 100 ng/ml supplements associated with adverse outcomes

Anemia of chronic disease (ACD) therapy

3. Transfusion demand (about 30% )patients who have low Hb and are symptomatic 4. Recombinant erythropoietin 10.000 units 3 times a week i.v. or s.c. 2-3tg, in the absence of response 20000j., If there is still no respose, the treatment should be discontinued. (in 40% of patients it reduces number of transfusions) 5. Sequential administration of erythropoietin and iron (48h later) 5. Iron chelation with deferoxamine - in some patients therapy was associated with a rise in hemoglobin level 6. In future anti-TNF-antibodies
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Treatment
Treat the underlying cause Treat the underlying cause And Treat the Underlying Cause!
Consider co-existent iron deficiency as well If underlying disease state requires it, consider EPO injection

Anemia of chronic renal failure

Mechanism:
mainly due to reduced production of erythropoietin by diseased kidneys also iron or folate deficiency, chronic inflammation, shortened red cell survival, IDA (multipathogenesis)

Treatment
erythropoietin thrice weekly dialysis

Anemia of endocrine failure

Uncommon cause of anemia, but correctable
hypothyroidism hypogonadism pan-hypopituitarism

Polycythaemia
Polycythaemia (erythrocytosis) is defined as an increase in the haemoglobin concentration above the upper limit of normal for the patient's age and sex.

Polycythemia
Increase in circulating red blood cells above normal. May be associated with a real increase or only apparent because of decrease in plasma volume.

Classification of polycythaemia
Relative vs Absolute Absolute erythrocytosis
Hct male > 60%, female > 55%

Polycythemia
The diagnosis of polycythemia is most commonly suspected in a patient with an abnormally high result on one or more of the following blood tests :
Hematocrit The hematocrit (HCT) is expressed as the percent of a blood sample occupied by intact RBCs. Polycythemia is suspected when the HCT is >45 or >50 percent in women and men, respectively.

Erythrocytosis (Polycythemia)
I. Relative or spurious erythrocytosis Relative polycythemia is an apparent rise of the erythrocyte level in the blood; however, the underlying cause is reduced blood plasma. Dehydration: water deprivation, vomiting Plasma loss: burns, enteropathy

II. Absolute erythrocytosis

Primary marrow diseases: PV,1ry erythrocytosis

Secondary : increased EPO production

Secondary polycythemia
Secondary polycythemia caused by a circulating factor stimulating erythropoiesis, usually erythropoietin (Epo). It is most often due to an Epo response to hypoxia, but can also result from an Epo-secreting tumor.

Causes
Autonomous (inappropriate) increase of Epo inappropriately high serum Epo Erythropoietin-producing neoplasms -Renal cell carcinoma -Hepatocellular carcinoma -Hemangioblastoma -Uterine fibroids Erythropoietin-producing renal lesions Following renal transplantation (some cases are independent of erythropoietin)

Causes
Appropriate increases in erythropoietin - appropriately high serum erythropoietin Hypoxemia secondary to: -Chronic pulmonary disease -Right-to-left cardiac shunts -Sleep apnea -Massive obesity (Pickwickian syndrome) -High altitude -Red cell defects -Some cases of congenital methemoglobinemia -Chronic carbon monoxide poisoning (including heavy smoking),cobalt.

Causes
Miscellaneous causes -Use of androgens or anabolic steroids -Blood doping in athletes -Self-injection of erythropoietin

I want my oxygen!

O2 O2

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Treatment
Mild & Hypoxic: Leave it alone Severe & Symptomatic: Phlebotomy TREAT UNDERLYING DISEASE!!

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 "That which does not kill you makes you stronger." Friedrich Nietzsche, German philosopher (1844-1900)

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THANK YOU!!
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