VITAMIN B12 DEFICIENCY,CLINICAL MANIFESTATIONS,TREATMENT AND PREVENTION

1. VITAMIN B12 DEFICIENCY
DR G VENKATA RAMANA
MBBS DNB FAMILY MEDICINE

2. VITAMIN B12
• Water-soluble B vitamin
• Also called cobalamin (Cbl).
• Resistant to cooking and boiling
• Synthesized by gut flora
• Present in foods derived from animal products.
• Vitamin B12 deficiency is virtually never caused by
inadequate intake except in vegetarians who
scrupulously avoid milk and eggs
• Normal vitamin B12 requirements
• Adults – 2.4 mcg per day
• Pregnancy – 2.6 mcg per day
• Lactation – 2.8 mcg per day

5. Physiologic roles of vitamin B12
• DNA synthesis, RNA synthesis, DNA
methylation
• Vitamin B12 play a critical role in DNA and RNA
synthesis.
• B12 deficiency can therefore impair DNA
synthesis, which in turn can cause a cell to arrest
in the DNA synthesis (S) phase of the cell cycle,
make DNA replication errors, and/or undergo
apoptotic death
• Hematopoiesis
• Hematopoietic precursor cells are among the most
rapidly dividing cells in the body and hence are
one of the cell types most sensitive to abnormal
DNA synthesis.
•

6. • Two major effects of the deficiency on hematopoiesis
• Megaloblastic changes
• caused by slowing of the nuclear division cycle relative to the
cytoplasmic maturation cycle (ie, nuclear-cytoplasmic dyssynchrony).
• Ineffective erythropoiesis
• occurs when there is premature death (eg, phagocytosis or apoptosis) of
the developing erythropoietic precursor cells in the bone marrow .
• There may be hypercellularity of the bone marrow
• laboratory findings of hemolysis, including elevated serum iron, indirect
bilirubin, and lactate dehydrogenase (LDH), and low haptoglobin.
• The reticulocyte count is typically low.
• Neuronal function
• Vitamin B12 deficiency is known to adversely affect neuronal function, but
the exact mechanisms remain elusive.
• Reduced methylation of neuronal lipids and neuronal proteins, such as
myelin basic protein, have been hypothesized to play a role in some of the
neurologic deficits.
• Myelin basic protein makes up approximately one-third of myelin, and
demyelination in the setting of vitamin B12 deficiency may explain many of
the neurologic findings

8. VITAMIN B12 ABSORPTION

9. VITAMIN B12 ABSORPTION
Two mechanisms exist for cobalamin absorption.
One is passive, occurring equally through buccal, duodenal, and ileal mucosa;
it is rapid but extremely inefficient, with <1% of an oral dose being absorbed
by this process.
The normal physiologic mechanism is active; it occurs through the ileum and
is efficient for small (a few micrograms) oral doses of cobalamin, and it is
mediated by gastric intrinsic factor (IF).
1. Peptic digestion releases dietary vitamin B12, allowing it to bind a
salivary protein called haptocorrin.
2. On entering the duodenum, haptocorrin–B12 complexes are
processed by pancreatic proteases; this releases B12, which attaches
to intrinsic factor secreted from the parietal cells of the gastric fundic
mucosa.
3. The intrinsic factor–B12 complexes pass to the distal ileum and
attach to cubilin, a receptor for intrinsic factor, and are taken up into
enterocytes.
4. The absorbed vitamin B12 is transferred across the basolateral
membranes of enterocytes to plasma transcobalamin, which delivers
vitamin B12 to the liver and other cells of the body.

10. • It is stored in the liver, which normally contains reserves
sufficient to support bodily needs for 5 to 20 years.
• Because of these large liver stores, clinical presentations of
vitamin B12 deficiency typically follow years of unrecognized
malabsorption
• The metabolic defects responsible for the anemia of vitamin
B12 deficiency are intertwined with folate metabolism.
• Vitamin B12 is required for recycling tetrahydrofolate,which,
as described previously, is the form of folate that is needed for
DNA synthesis
• In keeping with this relationship, the anemia of vitamin B12
deficiency is reversed with the administration of folate.
• By contrast, folate administration does not prevent and may in
fact worsen certain neurologic symptoms that are specific to
vitamin B12 deficiency

11. Causes of vitamin B12 deficiency
Gastric abnormalities Pancreatitis
Autoantibodies to intrinsic factor or
gastric parietal cells (pernicious anemia)
Pancreatic insufficiency
Gastrectomy/bariatric surgery Diet
Gastritis Breastfed infant of a mother with
vitamin B12 deficiency
Autoimmune metaplastic atrophic gastritis Strict vegan diet
Small bowel disease Vegetarian diet in pregnancy
Malabsorption syndrome Agents that block or impair absorption
Ileal resection or bypass Neomycin
IBD (eg, Crohn disease) Biguanides (eg, metformin)
Celiac disease Proton pump inhibitors
Bacterial overgrowth H2 receptor antagonists
Blind loop Nitrous oxide (N2O) gas, used for
anesthesia or recreationally
Dibothriocephalus latus (fish tapeworm) Inherited transcobalamin II
deficiency

12. CLINICAL PRESENTATION
• Macrocytic anemia
• Symptoms of anemia-fatigue, irritability, cognitive
decline,chest pain, shortness of breath,palpitations,light-
headedness
• Gastrointestinal symptoms
• Glossitis (including pain, swelling, tenderness, and loss of
papillae and/or hyperpigmentation of the tongue)
• Neuropsychiatric changes
• Symmetric paresthesias or numbness and gait problems .
• The neuropathy is typically symmetric and affects the legs
more than arms.
• Subacute combined degeneration of the dorsal (posterior) and
lateral columns (white matter) of the spinal cord due to
demyelination.
• It is associated with progressive weakness, ataxia, and
paresthesias that may progress to spasticity and paraplegia.

13. Subacute combined degeneration
(A) T2W demonstrating hyperintensity (brightness)
in the posterior columns from mid-C2 level to mid-
C6 level (white arrows). (B) T1W demonstrating
iso-intensity of the posterior columns with the
anterior columns (white arrows)
MRI T2W axial view of the
cervical spinal cord
demonstrating symmetrical
hyperintensities in the
posterior columns (black
arrows).

14. • Depression or mood impairment
• Irritability, Insomnia
• Cognitive slowing
• Forgetfulness
• Dementia
• Psychosis
• Visual disturbances, which may be associated with optic atrophy
• Peripheral sensory deficits
• Weakness, which may progress to paraplegia and incontinence if severe
• Impaired position and vibration sense
• Lhermitte sign, a shock-like sensation that radiates to the feet during neck
flexion
• Ataxia or positive Romberg test
• Abnormal deep tendon reflexes
• Extrapyramidal signs (eg, dystonia, dysarthria, rigidity)
• Restless legs syndrome
• Nonspecific fatigue

15. • Infants and maternal vitamin B12 deficiency
• Present with pancytopenia and/or macrocytosis;
there may be associated developmental delay or
regression, feeding difficulties, hypotonia,
irritability, tremors, or convulsions
• Skin
• Skin hyperpigmentation and hypopigmentation
can occur hyperpigmentation on the hands and
feet
• Cancer
• Increased risk of gastric cancer in individuals with
pernicious anemia.

16. HYPERPIGMENTATION OF HANDS
RETICULATE PIGMENTAION TONGUE IN VITB12 DEFICIENCY

17. • Findings supporting the diagnosis of
vitamin B12 deficiency are
(1) Low serum vitamin B12 levels,
(2) Normal or elevated serum folate levels,
(3) Moderate to severe macrocytic anemia,
(4) Leukopenia with hypersegmented
granulocytes
(5) A dramatic reticulocytic response (within
2 to 3 days) to parenteral administration of
vitaminB12.

18. LABORATORY FINDINGS
• CBC and blood smear
• Anemia
• Macrocytic red blood cells (MCV >100 fL) or macro-ovalocytosis
• An MCV value >115 fL is more specific to vitamin B12 or folate
deficiency
• Mild leukopenia and/or thrombocytopenia
• Low reticulocyte count
• Hypersegmented neutrophils on the peripheral blood smear (ie, >5
percent of neutrophils with ≥5 lobes or ≥1 percent of neutrophils with
≥6 lobes)
• Increased lactate dehydrogenase
• Increased bilirubin
• Serum vitamin B12
• Above 300 pg/mL (above 221 pmol/L) – Normal; deficiency unlikely
• 200 to 300 pg/mL (148 to 221 pmol/L) – Borderline; deficiency is
possible and additional testing is useful.
• Below 200 pg/mL (below 148 pmol/L) – Low; consistent with
deficiency

19. PERIPHERAL SMEAR
Peripheral smear shows marked macro-
ovalocytosis in a patient with vitamin B12
deficiency. In this case, teardrop cells are
an advanced form of macro-ovalocytes.
Peripheral blood smear showing a
hypersegmented neutrophil (seven lobes)
and macroovalocytes, a pattern that can be
seen with vitamin B12 (cobalamin) or folate
deficiency.

20. • MMA and homocysteine
• Normal – No deficiency of vitamin B12 or folate.
• MMA and homocysteine elevated
• Deficiency of vitamin B12 (does not eliminate the
possibility of folate deficiency).
• MMA normal, homocysteine elevated
• No deficiency of vitamin B12.
• Consistent with deficiency of folate.
• Autoantibodies to intrinsic factor
• Antiparietal cell antibodies,autoantibodies to IF-
Pernicious anemia

21. Bone marrow in severe megaloblastic anemia
Marrow is hypercellular. The cells are larger than normoblasts, and an
increased number of cells with eccentric lobulated nuclei or nuclear
fragments may be present .Giant and abnormally shaped metamyelocytes and
enlarged hyperpolyploid megakaryocytes are characteristic

22. TREATMENT
• Vitamin B12 is not given intravenously
• Intravenous use will result in urinary excretion of most of the vitamin B12.
• Dosage:
• Intramuscular First week-1000 mcg IM daily
• F/B 1000mcg once per week for 4 weeks
• F/B 1000mcg once a month
• Oral –In patients with normal absorption 1000 mcg once per day
• In patients with impaired absorption –vitamin B12 2000 mcg daily
• Duration of therapy
• Lifelong replacement is necessary for individuals with a condition that is not
reversed (eg, gastric bypass surgery, autoantibodies to intrinsic factor
[pernicious anemia]).
• If the cause of the deficiency can be treated or eliminated (eg, excessively
restrictive diet, drug-induced deficiency, reversible cause of malabsorption),
supplementation can be discontinued after the deficiency is corrected.
• Annual monitoring for vitamin B12 deficiency is recommended for patients
receiving Metformin
• Prevention
• Individuals at risk for vitamin B12 deficiency (eg, vegan or strict vegetarian
diet, gastric or bariatric surgery) should receive oral vitamin B12
supplements