• Infection.
• Inflammation - including connective tissue disorders.
• Neoplasia.

Anaemia is also commonly associated with chronic renal failure.

Pathogenesis

The anaemia of chronic disease is still poorly understood:

• One theory is that the anaemia results from a depressed response to erythropoietin.
• An alternative theory is that inflammation causes a change in iron recirculation, with iron being held back in the reticuloendothelial system rather than being released to the marrow - the 'reticuloendothelial block'.² In this case, inflammatory mediators possibly interfere with the normal maintenance of iron homoeostasis, mediated by iron regulatory proteins.
• Ferritin synthesis may also be upregulated by proinflammatory cytokines, diverting iron into the reticuloendothelial system.

The anaemia of chronic renal failure is thought to be slightly different:

• It probably results from a combination of erythropoietin deficiency and anaemia of chronic disease.³
• Interleukin-6 appears to be the central mediator of anaemia of chronic disease in a range of inflammatory diseases, including end-stage renal disease and rheumatoid arthritis.⁴ It induces the expression of hepcidin, which suppresses the expression of the iron transporter, ferroportin-1, so inhibiting the absorption of iron from the duodenum and the release of iron from the reticuloendothelial system.⁵
• A further contributory factor may be the functional iron deficiency resulting from erythropoietin replacement for patients undergoing haemodialysis.
• In this situation, despite adequate ferritin concentration, the erythropoietic drive outstrips the ability of the reticuloendothelial system to release storage iron quickly enough to satisfy the demands of the erythropoietin-stimulated bone marrow.

Presentation

Symptoms

• Tiredness
• Pallor
• Breathlessness on exercise

Signs

• Tachycardia

Investigations

Anaemia of chronic disease typically occurs despite adequate reticuloendothelial iron stores.

• Reduced serum iron, transferrin and total iron binding capacity.
• Exclusion of a mixed cause for anaemia - B12 and folate levels.
• Measuring serum ferritin is essential in investigating unexplained anaemia:
  • Serum ferritin concentration is directly related to reticuloendothelial iron stores, and normally 1 μg/L serum ferritin roughly corresponds to about 8 mg of storage iron.
  • Reduced serum ferritin provides unequivocal evidence of diminished iron stores and occurs in no other condition.
  • Normal or raised ferritin is typical.
  • In the presence of inflammation, ferritin concentrations may remain normal even when reticuloendothelial iron stores are absent.
• High erythrocyte sedimentation rate (ESR).
• Red cells often normochromic, normocytic, but may be hypochromic, microcytic (as frequently seen in rheumatoid arthritis and Crohn's disease).
• Bone marrow examination for iron is the definitive test for deficiency - very uncomfortable and expensive.
• Estimation of soluble transferrin receptor (if available):
  • This will differentiate microcytic anaemia of chronic disease from genuine iron deficiency when ferritin values are normal.⁶
  • Values of both soluble transferrin receptor and the soluble transferrin receptor-ferritin index are raised in iron deficiency anaemia, but are normal or only slightly raised in anaemia of chronic disease.
  • Soluble transferrin receptor concentrations have high sensitivity and specificity for identifying iron deficiency in anaemic patients with rheumatoid arthritis.⁷
  • They are comparable to bone marrow aspiration as a diagnostic test.⁸
  • They are, however, five times more expensive than ferritin measurement and should be reserved for patients in whom marrow iron assessment is being considered.

Management

Treatment of the underlying condition should cause Hb level to rise.
Apart from chronic renal failure, the anaemia is generally unresponsive to iron therapy.

Pharmacological treatment

• Transfusion of packed red blood cells should be reserved for patients who have severe, symptomatic anaemia. This is a palliative measure only and its use should be weighed against the associated risks with transfusion, e.g. volume overload, iron overload and transfusion reaction.
• Erythropoetin (EPO) with IV or oral iron if required in chronic renal failure. Response to treatment may be disappointing.¹
• Novel erythropoiesis-stimulating protein (NESP) - darbepoetin alfa - stimulates erythropoiesis by the same mechanism as recombinant human erythropoietin (rHuEPO) but it is biochemically distinct:
  • It has a 3-fold greater serum half-life and can maintain Hb levels as effectively as rHuEPO in anaemic patients with chronic renal failure, with less frequent dosing.⁹
• Also, consider erythropoiesis-stimulating agents in rheumatoid arthritis,¹⁰ heart failure¹¹ and cancer.¹²
• In temporal arteritis or polymyalgia rheumatica, hypochromic microcytic anaemia with dysproteinaemia can be treated with prednisolone and maintained on low-dose steroids.¹³

Prognosis

Usually this will depend on the underlying cause of the anaemia. However, the severity of the anaemia and the speed with which it developed can play a significant role. Similarly, the age of the patient and the existence of other comorbid conditions influence outcome.

Document references

1. Fitzsimons EJ, Brock JH; The anaemia of chronic disease. BMJ. 2001 Apr 7;322(7290):811-2.
2. Weiss G, Goodnough LT; Anemia of chronic disease. N Engl J Med. 2005 Mar 10;352(10):1011-23.
3. Nissenson AR, Strobos J; Iron deficiency in patients with renal failure. Kidney Int Suppl. 1999 Mar;69:S18-21. [abstract]
4. Raj DS; Role of Interleukin-6 in the Anemia of Chronic Disease. Semin Arthritis Rheum. 2008 Mar 11;. [abstract]
5. Means RT Jr; Hepcidin and anaemia. Blood Rev. 2004 Dec;18(4):219-25. [abstract]
6. Punnonen K, Irjala K, Rajamaki A; Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency. Blood. 1997 Feb 1;89(3):1052-7. [abstract]
7. Suominen P, Mottonen T, Rajamaki A, et al; Single values of serum transferrin receptor and transferrin receptor ferritin index can be used to detect true and functional iron deficiency in rheumatoid arthritis patients with anemia. Arthritis Rheum. 2000 May;43(5):1016-20. [abstract]
8. Fitzsimons EJ, Houston T, Munro R, Sturrock RD, Brock JD. Erythroblast iron metabolism and serum transferrin receptor in anaemic patients with rheumatoid arthritis. Blood 1998; 92: 325a.
9. Macdougall IC; Novel erythropoiesis-stimulating agents: a new era in anemia management. Clin J Am Soc Nephrol. 2008 Jan;3(1):200-7. Epub 2007 Dec 12. [abstract]
10. Peeters HR, Jongen-Lavrencic M, Bakker CH, et al; Recombinant human erythropoietin improves health-related quality of life in patients with rheumatoid arthritis and anaemia of chronic disease; utility measures correlate strongly with disease activity measures. Rheumatol Int. 1999;18(5-6):201-6. [abstract]
11. Ngo K, Kotecha D, Walters JA, et al; Erythropoiesis-stimulating agents for anaemia in chronic heart failure patients. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD007613. [abstract]
12. Scrijvers D, Roila F; Erythropoiesis-stimulating agents in cancer patients: ESMO recommendations for Ann Oncol. 2009 May;20 Suppl 4:159-61.
13. Hume R, Dagg JH, Goldberg A; Refractory anemia with dysproteinemia: long-term therapy with low-dose corticosteroids. Blood. 1973 Jan;41(1):27-35.

Internet and further reading

• Conrad ME; Anemia. eMedicine, Dec 2009
• Inoue S et al; Anemia, Chronic, eMedicine, Dec 2008

Acknowledgements