Page 315 - Concise Pathology for Exam Preparation ( PDFDrive )

300 SECTION II Diseases of Organ Systems

• Neurological manifestations: Vitamin B 12 deficiency causes sensorimotor demyelin-
ating peripheral neuropathy (leading to paraesthesias and numbness) and cerebral
changes (leading to dementia, psychosis or personality changes). This can be accompa-
nied by involvement of pyramidal tracts (causing spastic paraparesis, cerebellar dys-
function and optic neuropathy). Vitamin B 12 is required for transmethylation reactions,
which are essential for myelin synthesis. B 12 deficiency therefore affects white matter of
dorsal/posterior and lateral columns of spinal cord leading to sensory ataxia and loss of
position and vibration sense. Involvement of multiple pathways is labelled as ‘subacute
combined degeneration of the spinal cord’.
• Splenomegaly and hepatomegaly: Mild and nontender
• Gastrointestinal symptoms: Weight loss and poorly localized abdominal pain
• Glossitis: Loss of papillae leading to a smooth beefy red tongue
• Skin and hair changes: Premature greying of hair and melanin pigmentation of skin
with sparing of mucosa
• Infertility: Reversible with correction of deficiency
Clinical Features of Folate Deficiency
Folate deficiency mainly manifests with megaloblastic anaemia and glossitis. Subacute
combined degeneration is not seen and peripheral neuropathy is rare.

Laboratory Diagnosis of Megaloblastic Anaemia
• General blood parameters
• RBC count and haemoglobin levels are decreased.
• MCV is increased (.100 fL) and MCH is decreased (less than 33 pg).
• Reticulocyte count is normal.
• Peripheral smear (Fig. 12.2A and B)
• Red cells show anisopoikilocytosis with the presence of macrocytes and macroovalo-
cytes (large oval RBCs).
• Also present are Howell–Jolly bodies (nuclear remnants left after the nucleus is
extruded) and Cabot rings (abnormal histone synthesis causes arginine-rich his-
tones to accumulate as rings in red cells).
• Neutrophil hypersegmentation is seen which is defined as greater than 5% neutro-
phils having more than five lobes or presence of at least one six lobed cell. This is
the first haematological abnormality to be seen in megaloblastic anaemia and is
thought to be due to decreased production and a compensatory prolonged lifespan
of circulating neutrophils (senile neutrophils).
• Bone marrow
• Shows megaloblastic hyperplasia. Nuclei of erythroblasts are large with fine and open
sieve-like chromatin. Haemoglobinization of the cytoplasm proceeds at a normal rate;
whereas, nuclear maturation lags behind that of the cytoplasm (compared with iron
deficiency anaemia in which the cytoplasmic maturation lags behind that of the
nucleus). This is called nuclear-cytoplasmic asynchrony.
• Giant metamyelocytes and stab forms are seen.
• Megakaryocytes may be large and abnormal.
• Biochemical tests
• Serum vitamin B 12 levels ,200 pg/mL indicate vitamin B 12 deficiency (normal
200–900 pg/mL) and serum folate levels ,6 ng/mL indicate folate deficiency (nor-
mal 6–12 ng/mL). There are two methods to measure serum B 12 —microbiological
and radioisotope assay. The latter is the preferred method (as it is rapid and simple
and not affected by presence of antibiotics). Serum B 12 assay should however be
interpreted with caution as it represents the total and not metabolically active B 12 ; is
a late biomarker of megaloblastic anaemia and lacks specificity and sensitivity.
• Holotranscobalamin (holo-TC) is considered active B12 and is the earliest biomarker
for B 12 deficiency.
• Elevated methylmalonic acid (MMA) level indicates depletion of B 12 stores.
• Isolated decreased levels of holo TC supports vitamin B 12 deficiency and a combi-
nation of decreased holoTc and increased MMA (reference range: 0.08–0.28) and
homocysteine indicate a metabolically manifest B 12 deficiency. Increased MMA levels

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