Differentials
Iron deficiency anaemia
SIGNS / SYMPTOMS
Symptoms associated with severe iron deficiency and not seen in alpha-thalassaemia include pica (the craving for non-food items).
INVESTIGATIONS
With iron-deficiency anaemia, iron indices will show low serum iron, high transferrin, low transferrin saturation, and low ferritin, whereas iron studies are usually normal in alpha-thalassaemia. Iron deficiency will also present as a microcytic, hypochromic anaemia; however, it will typically present as an acquired rather than a congenital disorder.
Red blood cell count will be high in alpha-thalassaemia and tend to be low or normal in iron-deficiency anaemia.
If the diagnosis is in question, a short well-monitored trial of iron repletion will frequently confirm the diagnosis.
Beta-thalassaemia
SIGNS / SYMPTOMS
Beta-thalassaemia major often presents at a few months of age with progressive pallor and abdominal distension; perinatal history is most often uneventful.
INVESTIGATIONS
Beta-thalassaemia, with impaired beta-globin chain synthesis, will also present as a microcytic, hypochromic anaemia.
Hb electrophoresis/high-performance liquid chromatography (HPLC) will reveal an increased Hb A2 in most forms of beta-thalassaemia. Beta-globin gene sequencing will detect most but not all underlying molecular defects in beta-thalassaemia. Sequencing will not detect deletional beta-thalassaemias.
Variant haemoglobins (Hb E, Hb Lepore)
SIGNS / SYMPTOMS
Patients with variant haemoglobin disorders have clinical manifestations of variable severity. When inherited in combination with beta(0)-thalassaemia, patients can present as beta-thalassaemia major.
INVESTIGATIONS
Variant haemoglobins, either alone or in combination with other globin diseases, can present as a microcytic, hypochromic anaemia.
Many of these will be detected by Hb electrophoresis/HPLC; however, DNA-based globin gene testing may be required to confirm the diagnosis.
Anaemia of chronic disease
SIGNS / SYMPTOMS
Clinical history is crucial in differentiating anaemia of chronic disease from thalassaemia. History includes age of onset, family history, ethnicity of patient, prior haemoglobin and red cell indices, history of acute and chronic infections, autoimmune disorders, malignant disease, major trauma and surgery, and critical illness, with physical findings of the underlying disorder.
INVESTIGATIONS
Degree of anaemia is typically mild to moderate and normocytic. Anaemia of chronic disease can uncommonly present as a microcytic, hypochromic anaemia.
Iron studies may show low serum iron and transferrin saturation with normal or elevated ferritin.
WBC and differential and platelet count may be elevated due to associated infection or inflammation.
Lead poisoning
SIGNS / SYMPTOMS
Appropriate history of exposure to lead; irritability, aggressive behaviour, low appetite, difficulty sleeping, headaches, reduced sensations, loss of previous developmental skills, constipation; rarely, vomiting, muscle weakness, seizures, or coma.
INVESTIGATIONS
Lead poisoning interferes with delta-aminolevulinic acid dehydratase (ALAD) and thus with haem synthesis, and can lead to a microcytic anaemia.
Peripheral smear will show basophilic stippling in lead poisoning, and the reticulocyte count will be depressed, in contrast to an elevated reticulocyte count in alpha-thalassaemia. Diagnosis can be confirmed by serum lead levels.
Sideroblastic anaemias (SA)
SIGNS / SYMPTOMS
Sideroblastic anaemias are due to defective haem synthesis and can be congenital (i.e., X-linked) or acquired (lead, ethanol).
History appropriate to acquired SA, including nutritional imbalances and prolonged exposure to toxins and drugs.
History of myelodysplastic syndrome.
INVESTIGATIONS
Two populations of red cells may be seen on peripheral smear in SA. Diagnosis is confirmed by bone marrow aspiration and biopsy.
B12 deficiency anaemia
SIGNS / SYMPTOMS
Although anaemia due to B12 deficiency is classically easily distinguishable from thalassaemia by the high mean corpuscular volume (MCV) and peripheral smear findings, B12 deficiency can also present as a normocytic or a microcytic disorder, often in the presence of co-existing iron deficiency.[55]
B12 deficiency may also lead to neurological deficits: classically, a symmetrical neuropathy with ataxia associated with loss of position and vibration sense.[56] Other neurological findings include memory loss, irritability, and dementia.
INVESTIGATIONS
The peripheral smear classically reveals hyper-segmented neutrophils and macrocytosis. Serum B12 level is low, and serum homocysteine and methylmalonic acid levels are elevated.
Bone marrow examination, if performed, will reveal hypercellularity and megaloblastic changes. The anaemia will correct with vitamin B12 repletion.
Folate deficiency
SIGNS / SYMPTOMS
Anaemia due to folate deficiency will typically be macrocytic.
INVESTIGATIONS
The MCV will be high, and serum homocysteine (but not methylmalonic acid) will be elevated. Serum and red blood cell folate levels will be low.
Other haemolytic anaemias
SIGNS / SYMPTOMS
The patient who presents with anaemia must always receive a full diagnostic evaluation. The differential diagnosis includes other causes of haemolytic anaemia.
INVESTIGATIONS
Active haemolysis will lead to an elevated LDH, low haptoglobin, indirect bilirubinaemia, and an elevated reticulocyte count. The evaluation must include investigation for both intra-corpuscular (enzyme and membrane defects) and extra-corpuscular (autoimmune-mediated haemolytic anaemia, drug-induced haemolysis, or micro-angiopathic causes) aetiologies of haemolysis.
Haematological malignancies
SIGNS / SYMPTOMS
The differential diagnosis of anaemia also includes haematological malignancies. Clues to the presence of an underlying malignancy include systemic symptoms (fever, weight loss), lymphadenopathy, and abnormalities in other cell lines with associated symptoms (i.e., thrombocytopenia and bleeding).
INVESTIGATIONS
The white cell and platelet counts will frequently be abnormal. The peripheral smear may reveal evidence of the underlying disorder: for example, dysplasia in myelodysplastic syndrome and circulating blasts in acute myeloid or lymphoid leukaemia. An urgent bone marrow aspirate and biopsy are required to confirm the diagnosis.
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