Jashore University of Science and Technology

Department of Nutrition & Food Technology

An assignment on Megaloblastic macrocytic anemia

Course Title: Advanced Nutrition 2

Course No: NFT-5201

Submitted To Submitted by

Dr Md. Shimul Isla Roll no: MS-210931

Associate Professor Course no: NFT-5201
Dept. of Nutrition & Food Dept. of Nutrition &
Technology Food Technology
Jashore University of Jashore University of
Science & Technology Science & Technology.
 Deficiency: Megaloblastic macrocytic anemia

1. Cobalamin
Cobalamin, commonly known as Vitamin B12, is a
complex molecule with a unique structure at its core. It
consists of a central cobalt ion surrounded by a corrin
ring, forming the cobalamin structure. The cobalt ion
is coordinated with a nitrogen atom from a
benzimidazole group and a dimethylbenzimidazole
group. Attached to the corrin ring are various side
chains, including a nucleotide loop. The complexity of
the cobalamin structure is essential for its biological
activity, particularly in enzymatic reactions related to
Figure: Vitamin B12
DNA synthesis and red blood cell formation.

1.1 Sources of cobalamin

Vitamin B12 is predominantly found in animal products, making it essential for individuals who
follow vegetarian or vegan diets to pay attention to their B12 intake. Common sources include:

Meat: Beef, pork, lamb, and poultry are rich sources of Vitamin B12.
Fish: Salmon, trout, tuna, and other seafood contain substantial amounts of B12.
Dairy products: Milk, cheese, and yogurt provide B12, particularly for lacto-vegetarians.
Eggs: B12 is present in the yolks of eggs.
Fortified foods: Some plant-based foods, such as breakfast cereals, plant-based milk (soy,
almond, etc.), and nutritional yeast, are fortified with Vitamin B12.
Supplements: Vitamin B12 supplements are available in various forms, including oral tablets
and sublingual (under the tongue) formulations. In severe cases of deficiency, healthcare
professionals and dietitian may recommend B12 injections.
 Figure: sources of cobalamin

1.2 Signs and symptoms of cobalamin deficiency

Cobalamin (Vitamin B12) deficiency can lead to a range of signs and symptoms, affecting
various systems in the body. Here is a list of common indicators:

Anemia: Megaloblastic anemia, characterized by enlarged and underdeveloped red blood cells,
leading to fatigue, weakness, and pallor.
Fatigue and weakness: Generalized fatigue and weakness due to the decreased production of
healthy red blood cells.
Neurological symptoms: Numbness or tingling in the hands and feet, difficulty maintaining
balance and coordination, memory problems and difficulty concentration.
Mood changes: Irritability and mood swings, depression and feelings of apathy.
Gastrointestinal issues: Digestive problems, such as diarrhea or constipation, loss of appetite
and weight loss.
Pallor: Pale or jaundiced skin due to reduced red blood cell production.
Shortness of breath: Difficulty breathing and shortness of breath, especially during physical
exertion.
Cognitive impairment: Impaired cognitive function and memory loss, particularly in severe and
prolonged cases.
Vision problem: Blurred or disturbed vision.
2. Megaloblastic Macrocytic anemia
Megaloblastic macrocytic anemia is a type of anemia characterized by abnormally large and
immature red blood cells, known as megaloblasts. This condition is primarily caused by impaired
DNA synthesis in the bone marrow, leading to the formation of larger-than-normal red blood
cells. The two main vitamin deficiencies associated with megaloblastic macrocytic anemia are
deficiencies in Vitamin B12 (cobalamin) and folate (Vitamin B9).

2.1 Causes of megaloblastic macrocytic anemia:

Vitamin B12 deficiency:

 Inadequate dietary intake of Vitamin B12, which is primarily found in animal products.
 Impaired absorption of Vitamin B12 due to conditions such as pernicious anemia,
atrophic gastritis, or gastrointestinal surgeries that affect the absorption of nutrients.

Folate Deficiency:

 Insufficient intake of dietary folate, found in green leafy vegetables, legumes, and
fortified cereals.
 Malabsorption of folate in the small intestine due to conditions like celiac disease.

2.2 Features of Megaloblastic anemia:

Macrocytosis: Enlarged red blood cells (macrocytes) are present in the bloodstream. These cells
are larger than normal red blood cells.
Megaloblasts: Immature and abnormally large cells, called megaloblasts, are observed in the
bone marrow.

Anemia: Reduced red blood cell count and hemoglobin levels, leading to symptoms such as
fatigue, weakness, and pallor.

Neurological symptoms (in vitamin B12 deficiency): Difficulty maintaining balance and
coordination, Tingling or numbness in the extremities (peripheral neuropathy), memory loss and
cognitive impairment.

Figure: comparison of Erythropoiesis

2.3 Diagnosis and treatment:

Blood test: Complete Blood Count (CBC) to assess red blood cell size and count, peripheral
blood smear to examine the morphology of red blood cells, serum Vitamin B12 and folate levels.

Bone marrow examination: To confirm the presence of megaloblasts in the bone marrow.

Treatment: Depending on the underlying cause, treatment may involve Vitamin B12 or folate
supplementation. In the case of Vitamin B12 deficiency, oral supplements or injections may be
administered. Folate deficiency is often treated with dietary changes and oral folate supplements.

2.4 Cobalamin absorption and mediatory factor:

Cobalamin, (known as vitamin B12), is an essential water-soluble vitamin crucial for various
physiological processes in the human body, including DNA synthesis, red blood cell formation,
and neurological function. The absorption of cobalamin is a complex process that primarily
occurs in the small intestine, specifically in the ileum. The mechanism of cobalamin absorption
involves several intricate steps:

Ingestion of cobalamin: Cobalamin is obtained through the consumption of animal products

such as meat, fish, dairy, and eggs. Plants do not produce vitamin B12, and therefore, individuals
following a vegan diet may need to supplement or consume fortified foods.

Release of cobalamin from food: In the stomach, gastric acid and pepsin play a crucial role in
releasing cobalamin from food sources. This process is essential for subsequent binding to
specific proteins.

Bindings to R-Binders: Once released, cobalamin binds to proteins called R-binders, which are
present in saliva and gastric juice. These proteins protect cobalamin from degradation by
stomach acids and facilitate its safe transport to the small intestine.
Pancreatic Enzymes and intrinsic factor (IF): In the small intestine, pancreatic enzymes
further break down the R-binders, releasing cobalamin. The free cobalamin then binds with
intrinsic factor (IF), a glycoprotein secreted by the gastric parietal cells. IF is crucial for the
absorption of cobalamin and serves as a protective carrier, preventing its degradation.

Formation of cobalamin intrinsic Factor complex: The cobalamin-IF complex moves along
the small intestine until it reaches the ileum, where the actual absorption takes place. In the
ileum, specific receptors known as cubilins on the surface of enterocytes (intestinal cells)
recognize and bind to the cobalamin-IF complex.

Endocytosis and Absorption: The enterocytes internalize the cobalamin-IF complex through
endocytosis, a cellular process. Once inside the enterocyte, cobalamin dissociates from IF and
binds to a transport protein called transcobalamin II (TCII). This complex is then released into
the bloodstream, allowing for systemic distribution of cobalamin to various tissues and organs.

Mediatory factors influencing cobalamin absorption include:

Sufficient stomach acid: Adequate production of stomach acid is necessary for the release of
cobalamin from food and the subsequent binding to R-binders.

Intact intrinsic Factor Production: The gastric parietal cells must produce sufficient intrinsic
factor to form the cobalamin-IF complex.

Pancreatic Function: Proper pancreatic enzyme activity is crucial for breaking down R-binders
and releasing cobalamin for further processing.

Intact ileum Function: The presence of a healthy ileum with functional cubilin receptors is
essential for the final absorption of cobalamin.

3. DNA synthesis (role of vitamin B12 and folate)

Vitamin B12 (cobalamin) and folate (vitamin B9) play essential roles in DNA synthesis, and
their functions are closely interconnected in various biochemical pathways. A mechanism is
described as follow:
Methyl malonyl-CoA to succinyl-CoA conversion: Vitamin B12 is a co-factor for the enzyme
methylmalonyl-CoA mutase. This enzyme is involved in the conversion of methylmalonyl-CoA
to succinyl-CoA. This conversion is critical for the proper functioning of the tricarboxylic acid
(TCA) cycle, which provides energy for the cell.

Homocysteine to Methionine conversion: Vitamin B12 is also necessary for the conversion of
homocysteine to methionine. This reaction is catalyzed by methionine synthase, and it involves
the transfer of a methyl group from 5-methyltetrahydrofolate to homocysteine. Methionine is an
essential amino acid, and this conversion is crucial for maintaining adequate levels of methionine
for protein synthesis.

One-Carbon Transfer Reaction: Folate acts as a coenzyme in one-carbon transfer reactions.

These reactions are fundamental for the synthesis of purines and pyrimidines, which are the
building blocks of DNA.

Thymidylate Synthesis: Folate is specifically involved in the conversion of deoxyuridine

monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), a critical step in the
synthesis of thymidine. Thymidine is essential for DNA replication, and its availability is crucial
for the normal growth and division of cells.

Purine synthesis: Folate is also involved in the synthesis of purines, which are components of
both DNA and RNA. Adequate folate levels are necessary for the production of purine
nucleotides like inosine monophosphate (IMP), which serves as a precursor for both adenine and
guanine nucleotides.

4. Pathogenesis of megaloblastic anemia

Megaloblastic anemia is a type of anemia characterized by the presence of large, abnormal red
blood cells (megaloblasts) in the bone marrow. It is primarily caused by deficiencies in vitamin
B12 (cobalamin) or folate (vitamin B9). The pathogenesis of megaloblastic anemia involves
several steps, and I'll outline them below:
Impaired DNA synthesis: Both vitamin B12 and folate are essential for the synthesis of DNA,
especially during the formation of red blood cells in the bone marrow. Vitamin B12 is necessary
for the conversion of homocysteine to methionine, a critical step in DNA synthesis. Folate is
involved in the synthesis of thymidine, a nucleotide required for DNA replication.

Megaloblastic changes in the Bone marrow: Due to the deficiency of vitamin B12 or folate,
DNA synthesis is impaired, leading to the formation of megaloblasts in the bone marrow.
Megaloblasts are larger than normal precursor cells and have delayed nuclear maturation
compared to cytoplasmic maturation.

Ineffective Erythropoiesis: The abnormal megaloblasts are fragile and often do not survive the
normal stresses of the bone marrow environment. This results in fewer and larger red blood cells
being released into the bloodstream.

Macrocytic anemia: The large and immature red blood cells (megaloblasts) lead to macrocytic
anemia, characterized by larger-than-normal red blood cells. Despite the larger size, these cells
have less hemoglobin per unit volume, leading to decreased oxygen-carrying capacity.

Hypersegmented Neutrophils: Both vitamin B12 and folate deficiencies can cause
hypersegmentation of neutrophils, where neutrophils have more than the usual number of lobes
in their nuclei. This is a characteristic feature seen in the peripheral blood smear of individuals
with megaloblastic anemia.

Neurological Complications (in vitamin B12 deficiency): Vitamin B12 is crucial for the
maintenance of the nervous system. Deficiency can lead to neurological complications such as
peripheral neuropathy, subacute combined degeneration of the spinal cord, and cognitive
impairment.

5. Recommendations:

The incidence of vitamin B12 deficiency in the elderly may be as high as 15%, and the vitamin
B12 content of multivitamin preparations is usually not sufficient for treatment. Oral vitamin
B12 in amounts of at least 6 to 9 μg and possibly up to 300 μg appears necessary to correct
deficiency in the elderly Treating pernicious anemia or deficiency secondary to malabsorption
often requires monthly intramuscular injection of the vitamin in amounts of 500 to 1,000 μg or
oral ingestion of pharmacologic amounts (2 mg) of the vitamin. Vitamin B12 nasal sprays also
are available. Nascobal ®, for example, provides the vitamin as cyanocobalamin (500 μg/spray)
in a nasal spray that is beneficial to people with malabsorptive disorders such as inflammatory
bowel disease or those with pernicious anemia.

Reference:
1. ler S, Lindenbaum J, Allen R. Vitamin B12 deficiency in the elderly: Current dilemmas.
Am J Clin Nutr 1997; 66:741–49.