W2L4 - Macrocytic Anaemia Flashcards
Megaloblastic (Macrocytic) Anaemia
Occurs primarily a result of nuclear maturation defect
Asynchrony of cytoplasmic & nuclear maturation
- macrocytic, MCV usually > 110 fL (100-150 fL)
- typically normochromic
- RBC are often oval shaped (ovalocytes)
- anaemia mild to marked
Common causes include:
- folic acid (folate) deficiency
- vitamin B12 (cobalamin) deficiency
- abnormalities of B12, folate metabolism enzymes
Megaloblastic Anaemia - Blood Film
Typically all 3 cell lines affected 1. RBC - macrocytic, normochromic/ hypochromic - ovalocytes, teardrop (dacrocytes), - poikilocytes, basophilic stippling, HJ bodies 2. WBC - hyper-segmented neutrophils - neutropenia 3. Platelets - large-giant size - thrombocytopenia Macro-ovalocytes are characteristic of vitamin B12 or folate deficiency states
Haematopoiesis in Megaloblastic Anaemia
B12 & folate are required for normal DNA synthesis
Deficiency => aberrant DNA synthesis
Manifested as abnormal nuclear to cytoplasmic maturation
Megaloblastic anaemia describes enlarged (megaloblastic) erythroid precursors, many of which undergo apoptosis in the marrow resulting in ineffective erythropoiesis
Bone marrow assessment is not routinely required for diagnosis
Haematopoiesis in Megaloblastic Anaemia - Bone Marrow Findings
Hypercellular Increased erythroid precursors Decreased myeloid to erythroid ratio Megaloblasts (RBC) - delayed nuclear maturation - loose, open chromatin pattern - nuclear: cytoplasmic dysynchrony - mixture of Hb and RNA gives cytoplasm increased grey-blue colour Poor maturation of myelocyte & megakaryocytes - hypersegmentation & nuclear fragments
Clinical Syndromes - Folate Deficiency
Affects haematological, gastrointestinal systems
Anaemia onset ~ 2-3 months > deficiency
History poor nutrition, alcoholism, food faddism
Glossitis
Splenomegaly
Clinical Features - B12 Deficiency
Usually > 60 years of age Insidious onset Fatigue, weakness Gastrointestinal complaints Neurological disorders, altered mental states
Vitamin B12 Metabolism
Composed of 4 pyrrole units with a central cobalt atom = ‘Cobalamin’
Vitamin B12 is an essential cofactor for 2 processes:
- methylmalonic acid -> succinyl CoA (step in haeme synthesis)
- homocysteine -> methionine (with folate)
Deficiency leads to:
- lack of product
- build up of substrate
Daily requirement ~ 1 µg
Stores: Liver, kidney
Absorption of Vitamin B12
Vitamin released from food by peptic digestion
Free vitamin binds to ‘R binder’
Pancreatic proteases degrade R-binder => vitamin released
Vitamin binds to ‘intrinsic factor’ (secreted from gastric parietal cells)
Intrinsic factor-vitamin complex binds to receptors on mucosal cells in ileum
Crosses S.I. into plasma attached to transport proteins ‘transcobalamin I & II’
Taken to cells of liver, bone marrow
Pernicious Anaemia
A cause of vitamin B12 deficiency
An autoimmune disease with antibodies to intrinsic factor
- blocking antibody which blocks the receptor site on intrinsic factor for B12
- binding antibody which binds intrinsic factor at site for binding to ileum preventing absorption of intrinsic factorB12 complex
Anti-parietal cell antibody found in 90% of cases of pernicious anaemia
Folic Acid Metabolism
Absorption of dietary folate is mostly via the jejunum intestinal mucosal cells
Reduced to 5-methyl tetrahydrofolate & transported via blood
Stored in the liver (5 - 10 mg)
Tetrahydrofolate methyltetrahydrofolate
Central role in nucleic acid synthesis
- deficiency of leads to misincorporation of deoxyuridine triphosphate (dUTP) instead of deoxythymidine triphosphate (dTTP)
Also has role in conversion homocysteine -> methionine (with B12)
Secondary Folate/B12 Deficiency
Use of drugs may result in folate/B12 deficiency
Anticonvulsant therapy interferes with folate metabolism
Oral contraceptives
- decreased serum folate but adequate RBC folate
Prolonged nitrous oxide anaesthesia destroys methylcobalamin & causes acute megaloblastic change
Other Causes of Macrocytosis (Non-Megaloblastic Macrocytosis)
Artefactual Reticulocytosis Excess alcohol consumption Liver disease Hypothyroidism/hyperthyroidism Myelodysplastic syndromes Erythroleukaemia Aplastic anaemia Drugs interfering with DNA synthesis
Macrocytosis - Artefactual
Incorrect MCV due to misclassification of small aggregates of 2-3 RBCs as a single cell
Evident on RDW, cytograms
Macrocytosis - Reticulocytosis
Increased erythropoiesis => increased reticulocytes
Reticulocytes are macrocytic (compared to mature RBC)
Consequently, a significant reticulocyte component may increase MCV
Macrocytosis: Liver Disease
Anaemia is secondary to abnormalities in liver function
Most commonly
- non-megaloblastic, macrocytic anaemia; normochromic
- however, some situations may be microcytic
- target cells commonly observed (also acanthocytes)
- altered lipid composition of RBC membranes
Underlying pathophysiology
- complex, multifaceted
- ↓ bone marrow production, haemolysis, blood loss, ↓ folate
