Anaemia of Chronic Disease

Introduction

Anaemia of chronic disease (ACD), increasingly termed anaemia of inflammation, is a mild-to-moderate anaemia that develops in the setting of chronic infection, inflammatory disease, autoimmune disease or malignancy. It is thought to be the commonest anaemia among hospital inpatients and the second commonest anaemia overall after iron deficiency.¹

Unlike iron deficiency anaemia, where the problem is a genuine lack of iron, ACD arises because the body actively withholds iron from erythropoiesis as part of the innate immune response - a defence mechanism against pathogens that also need iron, which becomes maladaptive when inflammation is prolonged.

Pathophysiology

The central mediator is hepcidin, a peptide hormone produced by the liver that is the master regulator of systemic iron availability.² Inflammatory cytokines - principally interleukin-6 (IL-6) - strongly upregulate hepcidin production.

Hepcidin binds ferroportin, the only known cellular iron exporter, on duodenal enterocytes and on macrophages that recycle iron from senescent red cells. Binding causes ferroportin to be internalised and degraded, which traps iron inside macrophages and blocks dietary iron absorption. Total body iron is therefore normal or even high, but it is locked away in storage and unavailable to the bone marrow - a state termed functional iron deficiency.

Three further mechanisms contribute:

• Blunted erythropoietin response - inflammatory cytokines reduce renal EPO production and blunt the bone marrow's response to it
• Direct suppression of erythropoiesis - TNF-alpha and IL-1 inhibit erythroid progenitor proliferation and differentiation
• Mildly shortened red cell survival - from increased activity of the reticuloendothelial system in chronic inflammatory states

Causes

Any chronic condition that sustains an inflammatory cytokine response can produce ACD:

• Chronic infection - tuberculosis, infective endocarditis, chronic osteomyelitis, HIV, chronic abscesses
• Chronic inflammatory/autoimmune disease - rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, vasculitis
• Malignancy - solid tumours and haematological malignancy, both from tumour-driven inflammation and, in some cases, direct marrow infiltration
• Chronic kidney disease - shares the inflammatory mechanism but is usually considered separately because erythropoietin deficiency is the dominant driver, making it specifically responsive to erythropoiesis-stimulating agents

Clinical features

ACD is usually mild to moderate (haemoglobin rarely falls below around 80-90 g/L from this mechanism alone) and develops gradually, so specific anaemic symptoms are often overshadowed by the symptoms of the underlying disease - fatigue, malaise and reduced exercise tolerance are common to both.

There are no examination findings specific to ACD itself; findings reflect the underlying chronic condition (e.g. synovitis in rheumatoid arthritis, lymphadenopathy in malignancy, a murmur in endocarditis).

Investigations

Full blood count

Typically normocytic, normochromic anaemia. With more prolonged or severe inflammation it can become mildly microcytic, overlapping with iron deficiency anaemia - which is precisely why iron studies must be interpreted carefully rather than by MCV alone.

Iron studies - the key differentiator

Serum iron is low in both conditions, which is why it cannot distinguish them on its own. The key is TIBC/transferrin: in iron deficiency the body upregulates transferrin to maximise capture of scarce iron, so TIBC rises; in ACD, inflammation suppresses transferrin synthesis, so TIBC stays low or normal.¹

Ferritin is an acute phase reactant and rises with inflammation independent of iron stores, so a normal or high ferritin in an unwell patient does not exclude coexisting true iron deficiency. Soluble transferrin receptor is not affected by inflammation and rises only with genuine iron-deficient erythropoiesis, making it useful for distinguishing ACD from IDA, and particularly for identifying combined ACD with true iron deficiency - a common and easily missed scenario, for example in a patient with rheumatoid arthritis who is also having GI blood loss from NSAID use.

Supporting investigations

• CRP and ESR - typically raised, supporting an inflammatory process
• Investigations directed at the suspected underlying cause - e.g. autoantibodies, blood cultures, imaging, or malignancy work-up as clinically indicated
• U&Es and eGFR if chronic kidney disease is a possibility

Differential diagnosis

• Iron deficiency anaemia - distinguished as above; remember the two can coexist
• Anaemia of CKD - similar mechanism but erythropoietin deficiency predominates; check renal function
• Myelodysplastic syndrome - consider in older patients with unexplained anaemia and other cytopenias or dysplastic blood film features, especially if not clearly explained by an inflammatory illness
• Haemolytic anaemia - normocytic but with a raised reticulocyte count, raised LDH and bilirubin, and low haptoglobin, unlike the low reticulocyte count typical of ACD
• Marrow infiltration by malignancy - can coexist with, or mimic, ACD in cancer patients

Management

The fundamental principle is that ACD is a manifestation of the underlying disease, not a separate condition to treat in isolation. The single most effective intervention is treating the chronic infection, inflammatory disease or malignancy driving it.

• Iron supplementation is not indicated for ACD alone, since iron stores are typically adequate or increased - giving iron will not correct anaemia caused by iron being trapped, and in the context of active infection, providing free iron can theoretically fuel bacterial growth. Iron is only given if true concurrent iron deficiency is confirmed (e.g. by a low ferritin or raised sTfR)
• Erythropoiesis-stimulating agents (ESAs) such as epoetin or darbepoetin are used selectively - well-established in CKD-associated anaemia and in chemotherapy-induced anaemia meeting specific NICE criteria - but are used cautiously given risks of thromboembolism, hypertension, and (in cancer patients) a possible effect on tumour progression, so use follows specific guidelines rather than being routine
• Blood transfusion is reserved for symptomatic or severe anaemia, as in any other setting
• Ensure any coexisting nutritional deficiency (iron, B12, folate) is identified and corrected, since these are common and additive in chronically unwell patients

Complications

ACD carries little independent morbidity beyond exacerbating fatigue and reducing quality of life, and, in severe cases, contributing to cardiovascular strain in patients with pre-existing heart disease. Its main clinical significance is as a marker of disease activity or severity in the underlying condition, and the risk of missing a treatable coexisting cause (particularly true iron deficiency from occult bleeding) if the anaemia is simply attributed to "chronic disease" without adequate work-up.

Red flags

Prognosis

The trajectory of ACD mirrors the underlying condition: haemoglobin typically improves as chronic infection is eradicated, inflammatory disease is controlled, or malignancy is treated.¹ Because it is a consequence rather than a primary haematological disease, ACD itself does not require long-term monitoring separate from the underlying condition - but persistence or worsening despite good disease control should always prompt a fresh diagnostic look rather than being accepted as expected.