Anaemia of chronic disease and inflammation

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Inflammation changes the normal relationship between iron stores and erythropoiesis. Interleukin-driven hepcidin reduces ferroportin activity, so dietary iron enters plasma less efficiently and macrophages retain recycled iron. Serum iron and transferrin saturation fall, but ferritin may rise because stores remain present and ferritin itself responds to inflammation. Marrow therefore receives insufficient accessible iron despite apparently adequate storage. Cytokines also blunt erythropoietin production and erythroid responsiveness, while macrophage clearance modestly shortens red-cell survival.

The typical phenotype is a slowly developing normocytic, normochromic anaemia with low absolute reticulocytes. Mild microcytosis can occur, particularly with prolonged disease or superimposed true deficiency. Ferritin is interpreted with CRP, transferrin saturation, renal function, clinical bleeding risk and previous results. A clearly depleted ferritin supports absolute iron deficiency, but a preserved result during inflammation cannot rule it out. The film is often non-specific; marked anisopoikilocytosis, blasts, teardrops, fragmentation or other cytopenias should redirect the assessment.

The label is only useful when it leads to a complete plan. The active disorder should be treated, iron deficiency replaced when demonstrated, renal anaemia managed through UK Kidney Association and NICE pathways, and cancer-related supportive treatment coordinated with oncology. A haemoglobin that continues falling after the inflammatory disorder improves requires renewed evaluation. Transfusion is reserved for clinical need under NICE guidance, while erythropoiesis-stimulating treatment requires specialist benefit-risk assessment because response, blood pressure and thrombosis risk vary with context.

Key points

Anaemia of inflammation is usually an underproduction anaemia caused by hepcidin-mediated iron sequestration, reduced erythropoietin effect and shorter red-cell survival; it is commonly normocytic but can become mildly microcytic.
Make the diagnosis from a compatible active inflammatory, infective, malignant or renal disorder plus iron studies and reticulocytes. A raised CRP alone does not explain severe or progressive anaemia.
Ferritin may remain normal or high because it is an acute-phase reactant, while transferrin saturation is low. This pattern indicates restricted availability but does not exclude coexisting absolute iron deficiency.
Search for bleeding, B12 and folate deficiency, kidney disease, haemolysis, medicine toxicity and marrow pathology. Mixed causes are more common than a perfectly isolated inflammatory mechanism.
Treating the underlying infection, inflammatory disease or cancer is the central intervention; improvement may lag because red-cell production and lifespan recover gradually.
Do not give oral iron simply because serum iron is low. Establish whether absolute deficiency or a guideline-supported functional-iron indication exists and choose route through the relevant specialty pathway.
Erythropoiesis-stimulating agents belong to defined chronic kidney disease and selected oncology pathways, with specialist targets, iron assessment and thrombotic or blood-pressure monitoring.
Use red-cell transfusion for clinical oxygen-delivery need, not as routine long-term treatment of a stable laboratory value; reassess after each unit in adults without active bleeding.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Chronic inflammatory disease

Rheumatological disease, inflammatory bowel disease, chronic infection and other sustained inflammatory states alter iron handling and suppress red-cell production through cytokine signalling.

Cancer-related inflammation

Malignancy can produce inflammatory iron restriction, reduced marrow responsiveness, blood loss, nutritional deficiency and treatment toxicity, so several anaemia mechanisms commonly coexist.

Chronic kidney disease

Reduced erythropoietin production, inflammation, shortened red-cell survival, uraemia, blood sampling and dialysis-related iron losses combine as kidney function declines.

Acute severe illness

Major infection, trauma, surgery and critical illness can rapidly reduce available iron and erythropoiesis, although dilution, bleeding, haemolysis and phlebotomy also require assessment.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Hepcidin rises
Inflammatory cytokines increase hepatic hepcidin, which binds ferroportin and reduces iron export from intestinal cells and iron-recycling macrophages.
2
Iron becomes sequestered
Circulating transferrin-bound iron falls despite preserved or increased storage iron, leaving developing erythroblasts without enough accessible substrate for haemoglobin synthesis.
3
Erythropoiesis is suppressed
Cytokines blunt renal erythropoietin production and marrow response while illness, renal dysfunction and nutrient deficits further reduce reticulocyte output.
4
Red-cell survival shortens
Inflammation increases macrophage clearance and modestly shortens erythrocyte lifespan, adding a destructive contribution to the dominant underproduction pattern.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Compatible inflammatory phenotype

Chronic inflammatory, infective, malignant or renal disease with normocytic anaemia, low reticulocytes, low transferrin saturation and preserved ferritin supports restricted erythropoiesis.

Coexisting absolute deficiency

Low ferritin, heavy menstrual or gastrointestinal loss, malabsorption, high RDW or a prior iron response suggests truly depleted stores alongside inflammation.

Renal contribution

Declining kidney function, low marrow response and CKD complications raise deficient erythropoietin and functional iron restriction, requiring the renal anaemia pathway.

Discordant severe anaemiaRed flag

Rapid progression, profound symptoms, additional cytopenias, abnormal cells, haemolysis or bleeding is not explained safely by a stable chronic inflammatory label.

Physiological compromiseRed flag

Chest pain, syncope, resting breathlessness, heart failure, shock or active haemorrhage indicates threatened oxygen delivery and requires immediate support before mechanistic refinement.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
FBC, indices, film and reticulocytesFirst step
Why
Define severity, morphology, trajectory and adequacy of marrow output.
Interpretation and limitations
A normocytic or mildly microcytic low-reticulocyte pattern is compatible. Additional cytopenias, dysplasia, blasts, marked fragmentation or an unexpectedly brisk response suggests an alternative or mixed mechanism.
02
Ferritin, transferrin saturation and CRP
Why
Distinguish depleted stores from inflammation-modified iron restriction.
Interpretation and limitations
Low saturation with preserved or raised ferritin supports restricted availability, but inflammation elevates ferritin and can conceal absolute deficiency. Use disease-specific criteria where a renal or oncology pathway applies.
03
Renal, liver and thyroid profile
Why
Identify systemic underproduction and conditions that alter iron markers.
Interpretation and limitations
Reduced kidney function may supply an overlapping erythropoietin mechanism. Liver and thyroid disorders can change MCV and ferritin and should not be conflated automatically with inflammation.
04
B12, folate and haemolysis profile
Why
Exclude common nutritional and destructive alternatives or coexisting disease.
Interpretation and limitations
Interpret B12 through NICE NG239 where indeterminate. Reticulocytes, bilirubin, LDH, haptoglobin and film should be concordant before calling haemolysis.
05
Bleeding and malignancy assessment
Why
Find occult loss or disease progression hidden by an inflammatory diagnosis.
Interpretation and limitations
Use menstrual, gastrointestinal and urinary history plus NICE cancer and specialty pathways. True iron deficiency still requires source investigation even when an inflammatory disease is present.
06
Bone marrow assessment
Why
Investigate unexplained low production, multilineage change or abnormal morphology.
Interpretation and limitations
Discuss with haematology when counts progress, the film is abnormal, systemic disease does not explain severity or treatment of the presumed cause fails to improve erythropoiesis.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Absolute iron deficiency

Depleted ferritin, compatible blood loss or malabsorption and a treatment response favour truly empty stores, although absolute and inflammatory iron restriction can coexist.

Chronic kidney disease anaemia

Renal erythropoietin deficiency often overlaps with inflammation; kidney stage, iron availability and other reversible causes determine how much each mechanism contributes.

Marrow infiltration or myelodysplasia

Additional cytopenias, abnormal film morphology, splenomegaly, progressive counts or poor reticulocyte response out of proportion to inflammation supports specialist marrow assessment.

Haemolysis or occult bleeding

Raised reticulocytes and a concordant haemolysis profile, or iron depletion and bleeding evidence, indicate loss or destruction rather than uncomplicated inflammatory underproduction.

Endocrine or nutritional anaemia

B12, folate, thyroid and broader nutritional disorders can produce low marrow output and must be checked when the history, indices or treatment response is discordant.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Establish mechanismConfirm restricted production and mixed causesFirst stepAnaemia occurs alongside chronic inflammation, infection, malignancy or kidney disease without immediate physiological instability.

1Review the haemoglobin trajectory, symptoms, bleeding, medicines and active disease, then obtain FBC, film, absolute reticulocytes, ferritin, transferrin saturation, CRP, renal function, B12 and folate.
2PreferredThe preferred interpretation integrates stores and inflammation: identify absolute deficiency, functional restriction, renal erythropoietin limitation and any bleeding or marrow warning features rather than naming one cause prematurely.
3EscalationEscalate rapid decline, additional cytopenias, haemolysis, abnormal cells or an explanation disproportionate to the known illness for urgent haematology and source-directed assessment.

02Treat the driverControl inflammation and replace proven deficitsThe underlying disease and contributing deficiencies have been characterised.

1First lineFirst-line management addresses the active infection, inflammatory disorder, malignancy or renal disease with the relevant specialist team while avoiding unnecessary blood sampling and correcting nutrition.
2AlternativeReplace absolute iron, B12 or folate deficiency with the supported regimen; alternative intravenous iron is selected only for an established indication and product-specific monitoring.
3EscalationRecheck symptoms, reticulocytes and haemoglobin after the driver should have improved, and escalate non-response to reassess continued inflammation, loss, malabsorption, haemolysis and marrow disease.

03Specialist supportUse ESA or transfusion selectivelyAnaemia remains clinically important despite causal treatment, within a renal, oncology or acute oxygen-delivery pathway.

1For CKD, follow UK Kidney Association and NICE assessment of iron status, blood pressure, symptoms and reversible causes before specialist erythropoiesis-stimulating treatment.
2AlternativeFor selected cancer treatment settings, oncology weighs transfusion avoidance and symptom benefit against thrombosis and disease-specific concerns; an alternative is red-cell transfusion when clinically indicated.
3EscalationEscalate unstable oxygen-delivery symptoms to urgent transfusion assessment, using individualised NICE thresholds and post-unit reassessment rather than a chronic disease label as reassurance.

Key medicines and prescribing safety2 treatments · regimens, roles and cautions

Supports erythropoiesis in a defined CKD anaemia pathway after iron availability and other reversible causes have been addressed.

Darbepoetin alfa (specialist CKD example)

For adult CKD correction, start 0.45 micrograms/kg subcutaneously or intravenously once weekly; adults not on dialysis may instead start 0.75 micrograms/kg subcutaneously once every 2 weeks, with renal-protocol titration.

Specialist initiation is required. Correct uncontrolled hypertension before treatment and monitor haemoglobin rate of rise, blood pressure, thrombosis, vascular-access events and iron availability; reduce or withhold according to the SmPC rather than chasing a normal haemoglobin.

Corrects coexisting depleted stores or a documented specialty-specific functional iron indication; it does not treat inflammation itself.

Ferrous sulfate for coexisting absolute deficiency

Give one 200 mg tablet by mouth once daily; if gastrointestinal intolerance limits adherence, use one tablet every other day or a different standard oral preparation.

A low serum iron alone is insufficient. Expect gastrointestinal effects and dark stools, separate interacting medicines using current BNF advice, keep tablets away from children and investigate non-response, bleeding or malabsorption.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Reduced functional capacity

Lower oxygen carriage compounds fatigue, breathlessness and exercise limitation from the underlying inflammatory, malignant or renal disease.

Cardiovascular stress

Persistent anaemia increases cardiac workload and may worsen angina, heart failure or frailty in people with limited cardiovascular reserve.

Diagnostic delay

Attributing every low haemoglobin to chronic disease can conceal gastrointestinal bleeding, nutrient deficiency, haemolysis, cancer progression or marrow pathology.

Transfusion exposure

Repeated red-cell transfusion for chronic symptoms creates alloimmunisation, reactions and iron-loading risks without correcting inflammatory iron sequestration or impaired production.

Treatment-related harm

Inappropriate iron or erythropoiesis-stimulating therapy can cause adverse effects and may distract from controlling the disease that sustains anaemia.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Trend haemoglobin, absolute reticulocytes and symptoms alongside activity of the underlying inflammatory, malignant or renal disorder.
Repeat ferritin and transferrin saturation only at an interval meaningful for the treatment and specialty pathway, accounting for inflammation and recent intravenous iron.
Document whether bleeding, nutritional deficiency, renal contribution, haemolysis and marrow warning features have been assessed rather than carrying forward an unverified label.
During erythropoiesis-stimulating treatment, follow blood pressure, haemoglobin rate of rise, iron availability, vascular events and the product-specific adjustment protocol.
After red-cell transfusion, reassess symptoms, haemoglobin and further need; repeated exposure should trigger review of alternatives, alloimmunisation and iron burden.
Reopen the diagnosis when anaemia worsens despite improving inflammation or becomes disproportionate to the systemic disease.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Stored iron is not available iron

Inflammatory hepcidin can leave ferritin preserved while transferrin delivery to marrow is poor. The apparent contradiction is central to the disorder.

Serum iron is labile

Serum iron varies with timing, food and illness and is low in both true deficiency and inflammation. It cannot define the mechanism alone.

Several causes commonly coexist

A patient with cancer or inflammatory bowel disease may have inflammation, occult loss, renal dysfunction, treatment toxicity and nutritional deficiency simultaneously.

Reticulocytes test the physiology

A low absolute response supports impaired production; a brisk response should prompt bleeding, haemolysis or recovery rather than uncomplicated chronic-disease attribution.

Recovery can lag

Haemoglobin may improve after disease control more slowly than CRP because erythroid production and circulating red-cell mass need time to recover.

11Common pitfallsFrequent interpretation and management errors.

01
Diagnosing anaemia of inflammation from a raised CRP alone.
02
Using preserved ferritin to exclude coexisting absolute iron deficiency.
03
Giving iron repeatedly for low serum iron without proving an indication.
04
Missing bleeding, haemolysis or marrow disease in a patient with known inflammation.
05
Using an erythropoiesis-stimulating agent outside a specialist renal or oncology pathway.
06
Transfusing a stable value repeatedly without causal treatment and reassessment.
07
Failing to revisit the diagnosis when the underlying disease improves but anaemia progresses.