Lecture 3 - Megaloblastic Anaemia Flashcards Preview

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Flashcards in Lecture 3 - Megaloblastic Anaemia Deck (35)
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Microcytic anemia

- iron deficiency
- thalassaemia
- sideoblastic anaemia


Normocytic anemi

- acute bleeding
- hemolysis
- Chronic disease
- Metabolic, including renal failure
- endocrine dysfunction
- stem cell disorders


Macrocytic anemia

- megaloblastic anaemia
- alcohol + liver disease
- hypothyroidism
- reticulocytosis
- drugs
- bone marrow disorders


Macrocytic anemia

- MCV > 100fl, hb low
- megaloblastic or non-megaloblastic types


Non-megaloblastic macrocytic anemia



Megaloblastic anaemia caused by impaired DNA synthesis

- deficiency of vit B12 or folate
- abnormalities of vit B12 or folate metabolism: transcobalamin deficiency or NO exposure, antifolate drugs
- other defects of DNA synthesis: congenital enzyme deficiency or drugs


Vitamin B12 : cobalamin

- water soluble vitamin
- only synthesized by bacteria
- only found in animal products
- not affected by cooking
- total body stores: 2-5mg (half in liver), sufficient for 3/4 years
- in plasma 20% bount to TCII - active form
- 80% bound to TCI and TCIII, TCI=R protein, produced by salivary glands


Functions of vit B12

- essential coenzyme for methionine synthase, which has a role in DNA synthesis
- essential coenzyme for MCM which catalyses the formation of succinyl coA from methylmalonic acid


Causes of Vit B12 deficiency

1)inadequate intake

2)digestion and absorption problems:
- inadequate release of B12 from food due to absent/reduced enzymes and/or acid
- inadequate production of functional IF: pernicious anaemia, gastrectomy
- terminal ileal disease: coeliac disease, ileal resection, Crohn's disease
- competition for intestinal B12: bacterial overgrowth or fish tapeworm

3) Transport abnormalities: deficiency in TCII



- water soluble vitamin (B9),
- found in most foods, highest in liver and yeast, also in green vegetables and nuts
- easily destroyed by cooking
- body stores (mostly in liver) = 5=10 mg, lasts only 3-4 months


Folic acid fortification

- since 2009, folic acid must be added to wheat flour for bread making in Australia
- not if organic, unpackaged or non-wheat based bread
- also added to other foods
- prevalence of folate deficiency has fallen by 77%


Folate absorption

- folate in food travels to upper small intestine
- at the jejunal microvilli: enzymatic deconjugation to form methyl-THF
- absorption via active carrier mediated transport and concentration dependent diffusion


Folate transport

- in plasma, methyl THF is bound to albumin (weak) or soluble folate receptor (strong)
- rapidly cleared from plasma by entering liver and other cells via membrane transport proteins
- inside the cell, folate is polyglutamated and unable to diffuse back to plasma


Folate function

- coenzyme in transfer of carbon molecules between compounds
- methyl THF used in methylation of homocysteine to form methionine
- THF acts as intermediate acceptor of 1 carbon units for synthesis of purines and pyrimidines


Causes of folate deficiency

- inadequate intake
- malabsorption: small bowel disease, alcohol abuse, phenytoin
- increased requirements: pregnancy and lactation, infancy, haemolytic anaemia, hyperthyroidism, malignancy
- defective utilisation: inhibition of DHFR
- hereditary: folate malabsorption, metabolic defects


Concequences of B12 and folate deficiency

1) B12 deficiency results in
- increased homocysteine levels
- reduced methionine levels
- reduced formation of THF - also caused by folate deficiency


Reduced THF causes

1)impaired DNA syntehsis, affecting all rapidly growing tissues
- bone marrow: megaloblastic anaemia
- epithelial surfaces: GIT symptoms
- developing foetus: neural tube defects


How does B12 deficiency result in neurological damage

- MMA accumulation destabilises myelin
- role for methionine deficiency

- only B12 deficiency, not folate, results in neurological damage in adults


Summary: B12 vs folate

- source: animal product vs all food
- water soluble: yes/yes
- site of absorption: ileum/ duodenum, jejunum
- mechanism of absorption: uptake of If-CBl complex/ deconjugation of polyglutamate
- metabolic function: coenzymes
- body stores: 3-4 years / 3-4 months
- dietary deficiemncy: rare
- Megaloblastic anaemia: Yes
- neurological disease: Yes/no


Clinical presentation of B12 and folate deficiency

- symptoms of anaemia
- lemon-yellow skin
- shiny/beefy red tongue
- malabsorption
- vaginal atrophy


Neurological manifestations of B12 deficiency

- progressive neurological disease due to demyelination
- peripheral sensory nerves
- posterior and lateral columns of spinal cord affecting proprioception/vibration and lateral corticospinal tracts mediating motor function
- optic nerve atrophy
- CNS disease with cognitive disturbances


Blood results of megaloblastic anaemia

- low hb
- MCV 110-130 fl
- oval macrocytes
- aniso/poikilocytosis
- hypersegmented neutrophils
- WCC and platelets mostly normal but may be low
- signs of ineffective erythropoiesis: raised bilirubin, LDH


Bone marrow findings

- usually hypercellular
- erythroblasts: nuclear irregulatiry, increased N:C ratio and delayed nuclear maturation relative to that of the cytoplasm. RBC are so dysfunctional that they auto-hemolyze - raised bilirubin + LDH
- giant metamyelocytes
- dysplastic megakaryocytes


Think vitamin B12/folate deficiency if

- pancytopenia of uncertain cause
- oval macrocytes and hypersegmented neutrophils on blood film
- neurological: unexplained dementia, weakness, ataxia, paraesthesia
- elderly, alcoholics, malnourished, vegans, people with bariatric surgery


Vitamin B12 or folate deficiency diagnosis

- clinical
- serum B12 level + serum or RBC folate levels (serum for short term, RBC for long term)
- metabolic intermediates: raised homocysteine and raised MMA


Traps when diagnosing vit B12 deficiency

- falsely low levels of vit B12: drugs, reduced TCI lebels in pregnancy and neutropenic state/aplastic anaemia, injerited transcobalamin I deficiency
- falsely normal/high levels of vit B12 in hepatitis or cirrhosis, chronic renal failure, hypothyroidism, myeloproliferative diseases, TCII deficiency


Active B12 level: holotranscobalamin

- now widely available as additional test if low or equivocal serum vit B12 result
- measures only B12 bound to TCII
- normal range > 35pmol/L


Traps when diagnosing folate deficiency

1)serum folate
- can be corrected by one good meel
- unstable so can't test on specimen older than 1-2 days
- high levels in heamolysed samples
- rises in Vit B12 deficiency

2) RBC folate
- low level doesnt distinguish between folate and B12 deficiency
- reticulocytes have high levels so high results in marked reticulocytosis
- transfusion invalidates results


Diagnosis of pernicious anaemia

- severe lack of IF due to autoimmune disease affecting gastric parietal cells
- peaks in 60s, more common in female
- associated with other organ specific autoimmune disorders (hypoparathyroidism, addison's disease, thyroid disease)
- investigations: serum B12 levels +/- metabolic intermediates plus IF antibodies, gastric parietal cell antibodies and endoscopy


Management of megaloblastic anaemia

- treat cause
- give replacement therapy: initially both: never folic acid alone
- rarely necessary to transfuse


Replacement therapy

- in folate deficiency: folic acid 5 mg daily orally, for 3-4 months
- in vit B12 deficiency: 1000 mcg IMI daily x 4 doses, then weekly x 4 doses then every 1-3 months
- continue for life for patients with pernicious anaemia or ileal resection


Response to therapy

- reticulocyte response within 2-3 days with a peak at 6-7 days
- Hb should rise by 10g/L per week
- bone marrow normoblastic in 48 hours
- if inadequate response - further investigation


Which one of the following does not cause folate deficiency
A) antiepileptic drugs
B) Veganism
C) gluten sensitivity
D) inflammatin
E) pregnancy



Which one of the following is most commonly characterised by macrocytosis

- anaemia due to poor nutrition


Which of the following biochemical abnormalities is seen in severe vit B12 deficiency
- raised red cell folate concentration
- reduction in TCII
- MMA in urine
- reduced homocysteine in plasma
- excess deoxynucleotide production

- MMA in urine