When anaemia signals more than iron deficiency

Internal Medicine · General Medicine

Anaemia is a common clinical finding characterised by a reduction in haemoglobin concentration below the established reference threshold for an individual's age, sex and physiological status. Although iron deficiency is a leading cause, anaemia may also indicate underlying nutritional deficiencies, chronic inflammatory disorders, renal dysfunction, haemolysis, bone marrow abnormalities or malignancies. Consequently, attributing every case of anaemia to inadequate iron intake may delay the identification of potentially serious underlying conditions. The morphological characteristics of red blood cells (RBCs), associated clinical manifestations and relevant laboratory parameters should be evaluated to establish the aetiology. Recognising when anaemia signals more than iron deficiency is therefore essential for timely diagnosis, appropriate treatment and prevention of complications.[1]Beyond iron deficiency: Important causes of anaemiaAnaemia may develop through three principal mechanisms: Reduced RBC production, increased RBC destruction (haemolysis) or blood loss. Several underlying conditions can contribute to these mechanisms.Vitamin B12 and folate deficiencies: Vitamin B12 and folate are essential for DNA synthesis and normal erythropoiesis. Deficiencies in either nutrient can impair RBC maturation, resulting in megaloblastic anaemia, which is typically characterised by macrocytosis (mean corpuscular volume [MCV] above 100 fL)Vitamin B12 deficiency may develop due to inadequate dietary intake, pernicious anaemia, malabsorption or gastrointestinal disorders. Neurological manifestations, including peripheral neuropathy, paraesthesia, impaired balance and cognitive disturbances, may accompany the haematological abnormalities. Folate deficiency may occur in individuals with poor dietary intake, chronic alcohol consumption, malabsorption or increased physiological requirements, including pregnancyAnaemia of chronic inflammation: Anaemia of inflammation, previously referred to as anaemia of chronic disease, is frequently associated with chronic infections, autoimmune disorders, malignancies and inflammatory conditions. Increased inflammatory signalling, particularly through interleukin-6, stimulates hepatic hepcidin production. Hepcidin restricts intestinal iron absorption and prevents iron release from macrophages, resulting in reduced iron availability for erythropoiesisThis condition is generally characterised by normocytic or mildly microcytic anaemia, reduced serum iron, low transferrin saturation and normal or elevated ferritin concentrations. Unlike absolute iron deficiency, iron stores may remain adequate but become functionally unavailableChronic kidney disease: The kidneys produce erythropoietin, a hormone essential for stimulating RBC production in the bone marrowIn CKD, reduced erythropoietin synthesis contributes to impaired erythropoiesis and predominantly normocytic, normochromic anaemia. Additional factors, including systemic inflammation, shortened RBC survival, iron deficiency and blood loss during dialysis, may further aggravate the conditionHaemolytic anaemia: Premature destruction of circulating RBCs may result in haemolytic anaemia. It may be inherited, as observed in conditions such as thalassaemia and sickle cell disease, or acquired through autoimmune mechanisms, infections, medications and mechanical RBC damageClinical manifestations may include jaundice, dark-coloured urine, splenomegaly and fatigue. Increased reticulocyte counts, elevated lactate dehydrogenase (LDH), increased unconjugated bilirubin and reduced haptoglobin are characteristic laboratory findingsThalassaemia and other haemoglobinopathies: Inherited haemoglobin disorders should be considered, particularly in regions where thalassaemia and haemoglobin variants are prevalent. Thalassaemia results from reduced or absent synthesis of alpha- or beta-globin chains, leading to ineffective erythropoiesis and varying degrees of haemolysis. Patients may present with persistent microcytic anaemia despite adequate iron storesSickle cell disease, caused by a structural abnormality in haemoglobin, may result in chronic haemolytic anaemia, vaso-occlusive episodes and progressive organ damage. Haemoglobin electrophoresis or high-performance liquid chromatography (HPLC) may be required to establish the diagnosisBone marrow disorders and malignancies: Disorders affecting bone marrow function can impair the production of RBCs and other blood cellsAplastic anaemia, myelodysplastic syndromes, leukaemia and multiple myeloma may present with anaemia, sometimes accompanied by leukopenia or thrombocytopenia. Unexplained persistent anaemia, particularly when associated with abnormalities in multiple blood cell lines, should prompt further haematological evaluationChronic blood loss and occult malignancy: Chronic blood loss is another important cause of anaemia, particularly in adults. Gastrointestinal bleeding associated with peptic ulcers, colorectal malignancies, inflammatory bowel disease and gastrointestinal polyps may result in progressive iron depletion. In women, heavy menstrual bleeding may contribute to persistent anaemiaUnexplained iron deficiency, particularly in adult men and postmenopausal women, warrants evaluation for gastrointestinal blood loss and potential malignancyDiagnostic approach: Identifying the underlying causeA systematic evaluation should be undertaken rather than relying exclusively on haemoglobin levels or empirical iron supplementation. The World Health Organization (WHO) guidelines define anaemia in non-pregnant adults aged 15-65 years as haemoglobin below 13 g/dL in men and 12 g/dL in women. Pregnancy-specific thresholds are also recommended.Initial investigations should include:InvestigationDiagnostic significanceComplete blood count (CBC)Evaluates haemoglobin, RBC indices and other blood cell lines.Peripheral blood smearIdentifies abnormal RBC morphology and features suggestive of haemolysis or marrow disorders.Reticulocyte countDifferentiates reduced RBC production from increased destruction or blood loss.Serum ferritin and transferrin saturationAssess iron stores and iron availability.Vitamin B12 and folate levelsIdentify nutritional deficiencies associated with macrocytic anaemia.Renal and liver function testsEvaluate systemic causes of impaired erythropoiesis.LDH, bilirubin and haptoglobinHelp identify haemolytic processes.Haemoglobin electrophoresis/HPLCDetects haemoglobinopathies and thalassaemia.Further investigations, including thyroid function tests, inflammatory markers, stool occult blood testing, autoimmune studies and bone marrow examination, may be indicated according to clinical findings.Management: Treating the cause, not just the haemoglobin levelManagement should be directed towards the underlying aetiology. Iron supplementation should be prescribed when iron deficiency is established, while vitamin B12 and folate deficiencies require appropriate replacement. Anaemia associated with CKD may require iron therapy and erythropoiesis-stimulating agents in selected patients. Haemolytic disorders, haemoglobinopathies and bone marrow diseases require condition-specific treatment and specialist involvement.Blood transfusion may be considered in patients with severe or symptomatic anaemia, depending on haemodynamic stability, clinical symptoms and the underlying condition. Persistent unexplained anaemia, rapidly declining haemoglobin, pancytopenia, suspected haemolysis or evidence of gastrointestinal bleeding warrants timely specialist referral.ConclusionAnaemia should be regarded as a clinical finding rather than an independent diagnosis. Although iron deficiency remains an important cause, nutritional deficiencies, chronic inflammation, renal dysfunction, haemoglobinopathies, haemolysis and bone marrow disorders may also contribute. A morphology-based diagnostic approach supported by targeted laboratory investigations can help identify the underlying pathology and prevent delays in treatment. For clinicians, recognising when anaemia signals more than iron deficiency is essential to ensuring accurate diagnosis, appropriate therapeutic intervention and improved long-term patient outcomes.[2]Reference(s):1. Moss AS, Pakbaz Z. Iron Deficiency-More Than Just Anemia: A Literature Review. J Community Hosp Intern Med Perspect. 2025;15(3):38-45. Published 2025 May 5. doi:10.55729/2000-9666.1481. https://pmc.ncbi.nlm.nih.gov/articles/PMC12313286/2. Ozbilen M, Kaya Y. Beyond anemia: a comprehensive analysis of iron deficiency symptoms in women and their correlation with biomarkers. BMC Womens Health. 2025;25(1):376. Published 2025 Jul 28. doi:10.1186/s12905-025-03906-w. https://pmc.ncbi.nlm.nih.gov/articles/PMC12302447/