Overview
Anaemia of chronic disease, also called anaemia of inflammation, is a common type of anaemia that develops in people with long-lasting illnesses such as rheumatoid arthritis, inflammatory bowel disease, chronic infections, cancer, heart failure and chronic kidney disease. It is the second most common type of anaemia worldwide after iron deficiency, and the most common in hospitalised and older people.
In this condition, the body has iron stored but cannot use it properly to make red blood cells, because inflammation locks iron away. The anaemia is usually mild to moderate and develops slowly. It often improves when the underlying condition is treated. Distinguishing it from iron deficiency is important, because the treatment is different.
When to get urgent help
Seek urgent help for chest pain, severe breathlessness, fainting, or signs of bleeding such as black stools or vomiting blood.
Causes and risk factors
- Autoimmune diseases: rheumatoid arthritis, lupus, vasculitis, inflammatory bowel disease
- Chronic infections: tuberculosis, HIV, osteomyelitis, endocarditis, chronic abscesses
- Cancer, especially lymphoma and solid tumours
- Chronic kidney disease, which also reduces erythropoietin
- Heart failure
- Chronic lung disease
- Older age, where low-grade inflammation is common
- Obesity
How it develops (pathophysiology)
Normal red blood cell production and iron handling
Red blood cells are made in the bone marrow in a process called erythropoiesis, which is driven by erythropoietin (EPO), a hormone released by the kidneys when oxygen levels fall. Each red cell is packed with haemoglobin, which needs iron to carry oxygen. Iron is absorbed from food in the duodenum and recycled from old red cells by macrophages in the spleen and liver. Iron leaves cells through a channel called ferroportin and is carried in the blood by transferrin.
Iron levels are controlled by hepcidin, a hormone made by the liver. When iron is plentiful, hepcidin rises, binds to ferroportin and causes it to be destroyed, trapping iron inside cells. When iron is needed, hepcidin falls, allowing iron to be absorbed and released.
What goes wrong
In chronic disease, inflammatory signals, especially interleukin-6 (IL-6), cause three main problems:
- Raised hepcidin: IL-6 stimulates the liver to produce more hepcidin. This blocks ferroportin, so iron is trapped in macrophages and gut cells and cannot reach the bone marrow. Blood iron falls even though stores are full. This is thought to be a defence mechanism, starving bacteria of iron, but it starves the marrow too.
- Reduced response to erythropoietin: inflammatory cytokines such as tumour necrosis factor and interferon gamma make marrow cells less responsive to EPO and reduce EPO production by the kidneys.
- Shorter red cell survival: activated macrophages remove red cells more quickly.
In chronic kidney disease, the kidneys also produce less EPO, adding to the anaemia.
Why the symptoms and test results happen
- Tiredness, weakness and breathlessness reflect reduced oxygen delivery.
- Low serum iron and low transferrin saturation reflect iron trapped in cells.
- Normal or high ferritin reflects full iron stores, and ferritin also rises with inflammation.
- Normal-sized or slightly small red cells result from limited iron for haemoglobin.
- Raised inflammatory markers such as CRP and ESR reflect the underlying disease.
How treatment acts on the mechanism
Treating the underlying disease lowers IL-6 and hepcidin, releasing iron. Intravenous iron can bypass the blocked gut absorption when true iron deficiency coexists. Erythropoiesis-stimulating agents (synthetic EPO) overcome reduced EPO and marrow response, especially in kidney disease and some cancers. Newer medicines (HIF prolyl hydroxylase inhibitors) increase natural EPO and lower hepcidin in kidney disease.
Types
- Anaemia of inflammation, in autoimmune disease, infection and cancer
- Anaemia of chronic kidney disease, with EPO deficiency
- Mixed anaemia, with coexisting iron deficiency
Signs and symptoms
Often mild, and symptoms may be overshadowed by the underlying illness:
- Tiredness and lack of energy
- Weakness
- Breathlessness on exertion
- Pale skin
- Dizziness
- Reduced exercise tolerance
- Palpitations
- Worsening angina or heart failure in people with heart disease
How it is diagnosed
- Full blood count: usually mild to moderate anaemia with normal or slightly small red cells
- Iron studies: low serum iron, low or normal transferrin, normal or high ferritin
- Inflammatory markers: CRP and ESR
- Soluble transferrin receptor and hepcidin tests in some centres, to distinguish from iron deficiency
- Kidney function tests
- Tests for the underlying condition
Possible complications
- Reduced quality of life and physical function
- Worsening heart failure or angina
- Need for blood transfusion in severe cases
- Poorer outcomes in cancer and kidney disease
Goals of treatment
Treatment aims to control the underlying disease, correct coexisting deficiencies, and improve symptoms when anaemia is significant.
Medicines
- Treatment of the underlying condition, such as disease-modifying drugs for arthritis or treatment of infection
- Intravenous iron when iron deficiency coexists or in kidney disease
- Erythropoiesis-stimulating agents in chronic kidney disease or chemotherapy-related anaemia
- HIF prolyl hydroxylase inhibitors (such as roxadustat or daprodustat) in some countries for kidney disease
- Correction of vitamin B12 or folate deficiency
Other treatments
- Blood transfusion for severe or symptomatic anaemia
- Nutrition support
Living with it and prevention
- Keep chronic conditions as well controlled as possible
- Attend regular blood tests
- Eat a balanced diet with iron-rich foods
Monitoring and follow-up
Haemoglobin and iron studies are monitored regularly, along with the underlying disease. People receiving EPO need regular checks to avoid haemoglobin rising too high.
Outlook
The anaemia usually improves when the underlying condition is controlled. It may persist in long-term conditions but is usually mild.
Special considerations
- Older adults: anaemia is common and may worsen frailty
- People with heart failure: correcting iron deficiency with IV iron can improve symptoms
- Cancer patients: anaemia may be due to disease, treatment or bleeding
