Pernicious anemia is one cause of vitamin B12 deficiency, whereas malabsorption secondary to

inflammatory bowel disease is one cause of folate deficiency.

A megaloblastic anemia is characterized by oval macrocytes and hypersegmentedneutrophils in

the peripheral blood and by megaloblasts or large nucleated RBC precursors in the bone marrow. The
MCV in megaloblastic anemia can be markedly increased (up to 150 fL), but modest increases (100 to
115 fL) occur as well.

Nonmegaloblastic forms of macrocytic anemias are also characterized by large RBCs, but in
contrast to megaloblastic anemias, they are typically related to membrane changes owing to disruption
of the cholesterol-to-phospholipid ratio. These macrocytic cells are mostly round, and the marrow
nucleated do not display megaloblastic maturation changes. Macrocytic anemias are often seen in
patients with chronic liver disease, alcohol abuse, and bone marrow failure. It is rare for the MCV to be
greater than 115 fL in these nonmegaloblastic anemias.

Megaloblastic anemias are a group of disorders characterized by peripheral blood cytopenia due
to ineffective hematopoiesis in the bone marrow. The most common cause is folate or vitamin B12
deficiency or both. Vitamin B12 or folate deficiency may result due to poor nutrition, malabsorption,
and drugs (e.g., methotrexate and hydroxyurea). Pernicious anemia is an important cause of vitamin B12
deficiency and is due to autoimmune destruction of the parietal cells. The parietal cells normally secrete
intrinsic factor, which is required for the absorption of vitamin B12. Antiparietal cell antibody and anti-
intrinsic factor antibodies are found in patients with pernicious anemia.

In megaloblastic anemia, macrocytic red cells are observed in the peripheral blood, and these
are classically oval macrocytes. Hypersegmented polymorphonuclear leukocytes may be seen.
Megaloblastic anemia is a cause of pancytopenia.

The bone marrow shows erythroid hyperplasia with large erythroid precursors. This is known as
megaloblastoid change. The myeloid precursors may also be large. Giant myelocytes and giant
metamyelocytes may also be observed. Nuclear cytoplasmic dyssynchrony may also be seen. Overt
features of dysplasia are seen in megaloblastic anemia. As such, this condition remains a differential
diagnosis of myelodysplasia. Both conditions are associated with peripheral blood cytopenias, bone
marrow hyperplasia, and dysplasia.
Pernicious Anemia (Macrocytic Anemia)

Macrocytic anemia is characterized by an MCV greater than 100 fL with large RBCs (greater than 8 mm
in diameter).

Macrocytic anemias arise from conditions that result in megaloblastic or nonmegaloblastic red cell
development in the bone marrow.

Megaloblastic anemias are caused by conditions that impair synthesis of deoxyribonucleic acid (DNA),
such as vitamin B12 and folate deficiency or myelodysplasia.

Pathophysiology of the condition/disease:

 Vitamin B12 (cobalamin) deficiency results from the lack of gastric intrinsic factor as a direct
consequence of autoimmune gastritis.
 Autoimmune atrophic gastritis/vitamin B12 deficiency
 There are two types of autoantibodies identified in pernicious anemia: intrinsic factor antibodies
(IFA) and parietal cell antibodies (PCA)
 Anti-parietal cell antibodies (PCA) react with gastric parietal cells and the antibody is directed
against the parietal cell proton pump ATPase activity.
 Two major types of Intrinsic factor antibodies are found in patients with pernicious anemia.
Type 1 autoantibodies (blocking) operates against the cobalamin binding site, whereas type 2
(binding) directs its activity against the ileal mucosa receptor.
 B12 and intrinsic factor bind to receptors on the ileum, which allows for absorption of B12.
Vitamin B12, once absorbed, is a cofactor for the enzyme methionine synthase, which takes part
in the conversion of homocysteine to methionine.
 A deficiency in vitamin B12 results in impaired production of methylene-THF, a defect in
thymidylate synthesis, and ultimately a defect in DNA synthesis which causes megaloblastic
anemia.
 All dividing cells including the hematopoietic cells in the bone marrow are affected, leading to
pancytopenia. A decrease in all three blood cell types; WBC, RBC, Platelets.

Prognosis:

In patients with a deficiency in intrinsic factor, either due to pernicious anemia or gastric bypass surgery,
a parenteral dose of B12 is recommended, as oral B12 will not be fully absorbed due to the lack of
intrinsic factor. A dose of 1000 mcg of B12 via the intramuscular route is recommended once a month.
In newly diagnosed patients, 1000 mcg of B12 is given intramuscularly once a week for four weeks to
replenish stores before switching to once-monthly dosing. Studies have shown that at doses high
enough to fully saturate intestinal B12 receptors, oral B12 is also effective, despite a lack of intrinsic
factor.

A deficiency in either vitamin or folic acid results in impaired production of methylene- THF, a defect in
thymidylate synthesis, and ultimately a defect in DNA synthesis. This produces megaloblastic anemia
and epithelial cell abnormalities. All dividing cells including the hematopoietic cells in the bone marrow
are affected.

Patients with aplastic anemia present with pancytopenia and reticulocytopenia. The bone marrow
cellularity is markedly decreased. In the peripheral blood and bone marrow, the lymphocytes and
plasma cells are intact.
Diagnosis: Megaloblastic Anemia with Vitamin B12 deficiency

Clinical Findings:

The RBC histogram has an abnormal shape due to the presence of multiple RBC populations
with different size characteristics. The red cell size distribution is widened (as it is also indicated by high
RDWcv and the interpretative flag ‘anisocytosis’). The RBC count is well below the normal range. The
low HGB and HCT levels are in line with anemia.

Of note, the red cell parameters MCV, MCH and MCHC indicate larger than normal red cells (see the
interpretative flags ‘macrocytic RBC’ and ‘hypochromic’).

1. How do u explain the weight loss of the patient?

Decreased appetite (anorexia) and weight loss. As a result of digestive problems, such as nausea, people
with vitamin B-12 deficiency may lose their appetite. A decreased appetite can lead to weight loss in the
long term.

1. How is pernicious anemia related to autoimmune gastritis?

Pernicious anemia is the end stage or advance stage of the disease while autoimmune atrophic gastritis
is the mild chronic inflammation affecting the gastric body. Autoimmune gastritis is Immune mediated,
meaning autoantibodies attack and destroy the oxyntic glands resulting to progressive atrophy and
metaplasia of gastric body.

There is Atrophic and metaplastic changes restricted to oxyntic mucosa in the gastric body and fundus.
Hence, the term autoimmune atrophic gastritis

1. Why does vitamin b12 deficiency causes macrocytic anemia?

Vitamin B12 deficiency is a cause of macrocytosis. Because DNA synthesis requires cyanocobalamin
(vitamin B12) as a cofactor, a deficiency of the vitamin leads to decreased DNA synthesis in the
erythrocyte, thus resulting in macrocytosis.

1. What are all the tests for megaloblastic anemia diagnosis?

 1. What are the clinical features of patients suffering from pernicious anemia/megaloblastic
anemia with vitamin B12 deficiency?

Loss of appetite, tiredness, fatigue, tiredness, muscle weakness, loss of weight, paler skin

- Symptoms of Anemia

 Combination of skin pallor and jaundice -> yellow appearance to the skin
 Tongue may be sore, smooth and pale (atrophic glossitis)
 Tongue may be red and raw (acute glossitis)

- GI symptoms

 Episodic abdominal pain, constipation, and diarrhea

-Central nervous system

 Pins and needles of the distal extremities, numbness, tingling. Loss of position sensation

1. What treatment would you recommend for patients with megaloblastic anemia with vitamin B12
deficiency?
 Oral supplements
 Foods with high v12
 Intramuscular vb12

1. Why is Vitamin B12 important?

Vitamin B12 plays a critical role in the production of RBCs, DNA and nerves.

1. What are causes of megaloblastic anemia?

Vitamin B12 deficiency and Folic acid deficiency

1. What are the difference between Megaloblastic Anemia, Autoimmune Gastritis and Pernicious
anemia?

 Megaloblastic anemia - caused by conditions that impair synthesis of deoxyribonucleic acid

(DNA), such as vitamin B12 and folate deficiency or myelodysplasia
 Autoimmune Gastritis - (immune mediated) meaning autoantibodies attack and destroy the
oxyntic glands resulting to progressive atrophy and metaplasia of gastric body/ inhibinting
intrinsic factor production
 Pernicious anemia -the end stage or advance stage of the disease/severe form of vitamin B12
deficiency

 Megaloblastic Anemia
 HOW TO TREAT MEGALOBLASTIC ANEMIA?

BEST: - intramuscular injections of NONRADIOACTIVE vitamin B12

oral dose of RADIOACTIVE vitamin B12

other: eating more vitamin b12 rich food

Anisocytosis = abnormalities in size

Poikilocytoais = abnormalities in shape

1. Erythrocytes

Megaloblastic Anemia:

 Macrocytosis
 Elliptocytosis
 Tear drop cells
 Burr cells (crenation)
 Howell-Jolly bodies
 Basophilic stippling
 Cabot rings

2. Leukocytes

 (hypersegmented neutrophil) -> Megaloblstic anemia

 Normal neutrophil, fewer than five lobes <5

3. Pathophysiology of Megaloblastic Anemia with V12 deficiency

 Vitamin B12 deficiency causes defective DNA synthesis which results to megaloblastic anemia.
 Vitamin B12 deficiency is a cause of macrocytosis. Because DNA synthesis requires cyanocobalamin
(vitamin B12) as a cofactor, a deficiency of the vitamin leads to decreased DNA synthesis in the
erythrocyte, thus resulting in macrocytosis.

Defective LIPID METABOLISM -> due to LOW VITAMIN B12 -> results to -> demyelination ->
“paresthesias” (pins and needles) for clinical symptoms
 Defective DNA SYNTHESIS -> due to LOW VITAMIN B12 -> results to impaired production of methylene-

THF-> a defect in thymidylate synthesis -> results to MEGALOBLASTIC ANEMIA

 Folate coenzyme required for conversion of deoxyuracilmonophosphate (dUMP) to

deoxythiminetriphospate (dTTP) ->
 B12 -> FH4
 Homocystein increased in plasma with vitamin B12 deficiency
 MMA increased in urine -> Vitamin B12 deficiency
SUMMARY:

Antibodies:

 Blocking IF antibodies: antibodies that block the binding site of V12

 Binding IF antibodies: antibodies that binds to the ileal mucose receptor hereby blocking the
Vitamin B12
 two types of autoantibodies identified in pernicious anemia: intrinsic factor antibodies (IFA) and
parietal cell antibodies (PCA)