Megaloblastic A

Question 1

Macrocytic anaemia is characterized by abnormally large red blood cells with an MCV of? The causes can be broadly categorized into____&____ based on the appearance of developing erythroblasts in the bone marrow.

Answer 1

mean corpuscular volume, MCV >98 fL).

megaloblastic and non-megaloblastic,

Question 2

Give me an overview of megaloblastic A

Answer 2

Megaloblastic Anaemias

Megaloblastic anaemias are a group of anaemias where erythroblasts in the bone marrow show a characteristic abnormality: the maturation of the nucleus is delayed relative to that of the cytoplasm. This condition is primarily caused by defective DNA synthesis, usually due to deficiencies in vitamin B12 or folate. Other less common causes include abnormalities in the metabolism of these vitamins (often drug-induced) or inherited defects in DNA synthesis.

Question 3

What’s the pathophysiology of Megaloblastic A

Answer 3

Pathophysiology

Defective DNA Synthesis: The core defect in megaloblastic anaemias is in DNA synthesis, leading to asynchronous maturation of the nucleus and cytoplasm.

Morphological Changes: In the bone marrow, erythropoietic cells show a persistently open, loosely organized chromatin in the nucleus, while the cytoplasm displays changes typical of a later stage of maturation.

Question 4

Vitamin B12 (Cobalamin)
Vitamin B12, also known as cobalamin, is synthesized by microorganisms. Animals acquire it through consumption of food of animal origin, internal production from intestinal bacteria (not in humans), or by eating bacterially contaminated foods. The vitamin is comprised of cobalamins, which have a cobalt atom at the center of a corrin ring, with different groups attached to the reactive center

Question 5

Sources of Vitamin B12
Animal Products: Liver, meat, fish, and dairy produce.
Non-Animal Sources: Vitamin B12 does not naturally occur in fruits, cereals, or vegetables, except in small amounts due to contamination by insect parts during harvesting or by microorganisms in a natural environment.

Question 6

Explain the absorption & Transportation of Vit. B12

Answer 6

Absorption of Vitamin B12

A normal diet contains a large excess of vitamin B12 compared to daily requirements. The process of B12 absorption involves several steps and key proteins:

Release from Food: B12 is released from its protein-bound form in food by the action of pepsin in the stomach.

Binding to Intrinsic Factor (IF): After release, B12 combines with intrinsic factor, a glycoprotein synthesized by gastric parietal cells.

Ileal Binding and Absorption: The IF–B12 complex binds to the specific receptor cubam in the ileum. This receptor is a complex of cubilin and amnionless proteins. Amnionless directs the endocytosis of the cubilin IF–B12 complex into the ileal cell, where B12 is absorbed and IF is destroyed.

Maximum Absorption: The maximum amount of B12 that can be absorbed from a single oral dose via the IF–cubam mechanism is about 1–2 μg.

In addition, some dietary B12 binds first to haptocorrin, a glycoprotein present in saliva and gastric juice. Release of B12 from haptocorrin for binding to IF depends on pancreatic proteases.

Transport of Vitamin B12: The Transcobalamins

Once absorbed from the ileal cell into the portal blood, B12 attaches to the plasma-binding protein transcobalamin (TC or transcobalamin II). This protein delivers B12 to the bone marrow and other tissues. The amount of B12 bound to TC in plasma is normally very low (<50 ng/L).

Transcobalamin Deficiency

Congenital TC Deficiency: This is caused by germline mutations in the TCN2 gene and results in megaloblastic anaemia because B12 fails to enter marrow and other cells from plasma. Serum B12 levels in TC deficiency are normal since most B12 in plasma is bound to haptocorrin.

Haptocorrin: Synthesized in saliva, gastric juice, milk, and by granulocytes and macrophages, haptocorrin-bound B12 in the blood does not transfer to marrow and is considered functionally inactive. Increased granulocyte production, as seen in myeloproliferative neoplasms and some liver diseases, can raise haptocorrin and B12 levels in serum significantly

Question 7

What happens in Transcobalamin Deficiency?

Answer 7

Congenital TC Deficiency: This is caused by germline mutations in the TCN2 gene and results in megaloblastic anaemia because B12 fails to enter marrow and other cells from plasma. Serum B12 levels in TC deficiency are normal since most B12 in plasma is bound to haptocorrin.

Question 8

What are the Biochemical Functions of Vitamin B12?

Answer 8

Vitamin B12 acts as a coenzyme in two critical biochemical reactions:

Methionine Synthase (as Methyl B12): B12 acts as a cofactor for methionine synthase, which methylates homocysteine to methionine using methyltetrahydrofolate (methylTHF) as the methyl donor.

Methylmalonyl CoA Mutase (as Deoxyadenosyl B12): B12 assists in the conversion of methylmalonyl coenzyme A (CoA) to succinyl CoA, an important intermediate in the citric acid cycle.

Question 9

Folic (pteroylglutamic) acid is the parent compound of the folate family

Question 10

How is folate & folic acid absorbed in the body?

Answer 10

Absorption:

Folates are absorbed and converted to methylTHF in the bloodstream.

Inside cells, methylTHF is demethylated to THF and then converted to folate polyglutamates by adding multiple glutamate residues.

Folic acid is a poor substrate for dihydrofolate reductase; higher doses (200-400 µg) enter the plasma unchanged, to be reduced in the liver or excreted in urine.

Question 11

What’s the biochemical function of folate

Answer 11

Biochemical Reactions:

Folates are involved in single-carbon unit transfers in amino acid interconversions, such as converting homocysteine to methionine and serine to glycine, and in synthesizing purine precursors of DNA.

Question 12

What’s the Biochemical Basis for Megaloblastic Anaemia?

Answer 12

DNA Synthesis

DNA Synthesis Process:

DNA is made up of building blocks called deoxyribonucleoside monophosphates (dNMPs).

These building blocks are derived from deoxyribonucleoside triphosphates (dNTPs).

Role of Folate (Vitamin B9):

Folate is essential for the synthesis of one of the DNA building blocks called thymidine monophosphate (dTMP).

dTMP is crucial for DNA replication because it is one of the four nucleotides that make up DNA.

5,10-Methylene THF Polyglutamate:

This is a form of folate that acts as a coenzyme (helper molecule) for the enzyme that produces dTMP.

Without sufficient 5,10-methylene THF polyglutamate, the body can’t produce enough dTMP.

Consequence of Folate Deficiency:

If there’s a shortage of 5,10-methylene THF polyglutamate, the production of dTMP is limited.

This limitation causes a deficiency of dTTP (the triphosphate form used in DNA synthesis).

As a result, the S phase of the cell cycle (where DNA is replicated) is prolonged because the cell cannot complete DNA synthesis efficiently.

This delay can cause cells to die through a process called apoptosis.

Role of Vitamin B12 (Cobalamin)

Conversion of MethylTHF to THF:

Vitamin B12 is needed to convert methylTHF (a form of folate found in the bloodstream) into THF.

This reaction also involves converting homocysteine to methionine, an essential amino acid.

Importance of THF:

THF (tetrahydrofolate) is the form of folate that can be converted into various polyglutamate forms inside the cell.

These polyglutamates are the active forms of folate used in DNA synthesis and other cellular processes.

Indirect Role of B12 in Folate Function:

Without enough B12, the conversion of methylTHF to THF is impaired.

This reduces the availability of THF and, consequently, the active folate polyglutamates, including 5,10-methylene THF polyglutamate.

As a result, dTMP synthesis is impaired, leading to the same problems seen with folate deficiency: delayed DNA replication and cell death.

Question 13

Summary
Folate Deficiency: Directly limits the production of dTMP, which is necessary for DNA synthesis, causing problems in cell division and leading to cell death.
B12 Deficiency: Indirectly causes the same problem by preventing the formation of active folate forms (polyglutamates) needed for dTMP production.
Both deficiencies disrupt DNA synthesis, leading to the characteristic large, immature red blood cells seen in megaloblastic anaemia.

Question 14

Other Causes:

Other congenital or acquired causes of megaloblastic anaemia, such as antimetabolite drug therapy, inhibit purine or pyrimidine synthesis at different steps, resulting in reduced supply of DNA precursors.

Question 15

Folate Cycle During dTMP Synthesis
Folate as a Coenzyme:

Folate, in its active form (tetrahydrofolate or THF), is essential for the synthesis of thymidine monophosphate (dTMP), a DNA building block.
During this process, folate is converted from THF to dihydrofolate (DHF).
Regeneration of Active Folate (THF):

For continued DNA synthesis, DHF needs to be converted back to THF.
This conversion is carried out by the enzyme dihydrofolate reductase (DHF reductase).
Inhibition of DHF Reductase:

Certain drugs inhibit DHF reductase, blocking the conversion of DHF to THF.
This inhibition prevents the regeneration of THF, halting the production of dTMP and, consequently, DNA synthesis

Question 16

What are the drugs that Inhibit DHF Reductase?

Answer 16

Methotrexate:

Use: Primarily used to treat cancers (e.g., acute lymphoblastic leukaemia) and inflammatory diseases (e.g., rheumatoid arthritis, psoriasis).

Mechanism: Inhibits DHF reductase, blocking folate regeneration and thus DNA synthesis, which is particularly effective in cells with high turnover.

Pyrimethamine:

Use: Used mainly as an antimalarial drug.

Mechanism: Inhibits DHF reductase, but is weaker than methotrexate.

Trimethoprim:

Use: Used as an antibiotic, often in combination with a sulphonamide (e.g., co-trimoxazole).

Mechanism: Inhibits bacterial DHF reductase effectively, but is much less effective against the human enzyme.

Question 17

What are the Causes of Megaloblastic Anemia

Answer 17

Causes of Megaloblastic Anemia

Vitamin B12 Deficiency
Vitamin B12 deficiency can arise from a variety of causes, including:

• Dietary Deficiency: Inadequate intake of vitamin B12, commonly seen in strict vegetarians or vegans.
• Malabsorption: Conditions such as pernicious anemia, Crohn’s disease, celiac disease, or gastric bypass surgery can impair the absorption of vitamin B12.
• Intrinsic Factor Deficiency: Lack of intrinsic factor, a protein necessary for vitamin B12 absorption, often due to autoimmune destruction of gastric parietal cells.
• Ileal Disease or Resection: The terminal ileum is crucial for B12 absorption, so any disease or surgical resection can lead to deficiency.
• Pancreatic Insufficiency: Pancreatic enzymes are necessary for the release of B12 from binding proteins in food.
• Drug Interference: Certain medications, such as metformin or proton pump inhibitors, can interfere with B12 absorption.

Folate Deficiency
Folate deficiency can be due to several factors:

• Dietary Deficiency: Inadequate intake of folate-rich foods such as leafy green vegetables, legumes, and fortified cereals.
• Increased Requirement: Conditions that increase cell turnover, such as pregnancy, hemolytic anemia, or malignancy, can increase folate demand.
• Malabsorption: Disorders affecting the upper small intestine, such as celiac disease or tropical sprue, can impair folate absorption.
• Alcoholism: Chronic alcohol consumption can interfere with folate metabolism and absorption.
• Drug Interference: Medications such as methotrexate, phenytoin, and trimethoprim can inhibit folate metabolism or absorption.

Combined Folate and B12 Deficiency
A deficiency in both vitamins can occur due to:

• Dietary Deficiency: Poor overall nutritional intake, often seen in cases of severe malnutrition or strict dietary restrictions.
• Malabsorption Syndromes: Conditions like celiac disease or tropical sprue that affect the absorption of both vitamins.
• Drug Interference: Use of medications that affect the metabolism of both folate and B12.

Abnormalities of Vitamin B12 or Folate Metabolism
These can be caused by:

• Genetic Conditions: Inherited disorders affecting the metabolism of B12 or folate, such as transcobalamin deficiency.
• Environmental Factors: Exposure to nitrous oxide, which inactivates vitamin B12.
• Medications: Drugs like methotrexate, phenytoin, or trimethoprim that interfere with folate metabolism.

Genetic mutations can disrupt DNA synthesis or the methionine cycle, leading to megaloblastic anemia. Examples include:

• Methionine Synthase Deficiency: A rare inherited disorder affecting the enzyme needed for homocysteine conversion to methionine.

These are rare genetic conditions that impair DNA or nucleotide synthesis, such as:

• Orotic Aciduria: A disorder that affects pyrimidine synthesis, leading to megaloblastic anemia.

These can result from certain medications that inhibit key enzymes in nucleotide synthesis, including:

• Hydroxyurea: Used in the treatment of certain cancers and sickle cell anemia.
• Purine Synthesis Antagonists: Such as 6-mercaptopurine, which is used in the treatment of leukemia.
• Pyrimidine Antagonists: Such as cytosine arabinoside (cytarabine), used in chemotherapy.

Question 18

What are the common Causes of Severe Vitamin B12 Deficiency

Answer 18

Common Causes in Developed Countries:

Pernicious Anemia: Also known as Addisonian anemia, it is an autoantibody-mediated condition where the immune system attacks the stomach’s parietal cells, leading to intrinsic factor deficiency. This is the most common cause of severe B12 deficiency.

Dietary Deficiency: Severe B12 deficiency can occur in strict vegans who do not take B12 supplements, as B12 is predominantly found in animal products.

Gastrectomy: Surgical removal of part or all of the stomach can lead to a lack of intrinsic factor production, impairing B12 absorption.

Small Intestinal Lesions: Conditions affecting the ileum, such as Crohn’s disease, can hinder B12 absorption.

Nitrous Oxide Exposure: Nitrous oxide can rapidly inactivate B12 in the body, leading to severe deficiency.

Question 19

What are the less causes of of severe Vit B12 def

Answer 19

Less Common Causes:

Poor-Quality Diets: While entero-hepatic circulation can protect individuals with low dietary intake from severe deficiency, they may still develop mild B12 deficiency.

Chronic Conditions: Conditions that impair the entero-hepatic circulation or small intestine function can contribute to severe B12 deficiency.

Question 20

What are the causes of mild Vit B12 def

Answer 20

Causes of Mild Vitamin B12 Deficiency

Most Frequent Cause Worldwide:

Inadequate Diet: The primary cause of mild B12 deficiency globally is insufficient dietary intake.

Other Causes:

Malabsorption Conditions:

Atrophic Gastritis: Particularly common in the elderly, this condition involves chronic inflammation of the stomach lining, reducing B12 absorption.

Chronic Pancreatitis: Inflammation of the pancreas can impair the release of pancreatic enzymes needed for B12 absorption.

Gluten-Induced Enteropathy (Celiac Disease): Damage to the small intestine impairs nutrient absorption, including B12.

HIV Infection: The virus can damage the intestinal lining, leading to malabsorption.

Zollinger-Ellison Syndrome: Excessive gastric acid production lowers the pH in the duodenum, inactivating pancreatic enzymes that release B12 from haptocorrin.

Question 21

What medications can cause b12 def

Answer 21

Medication Effects:

Proton Pump Inhibitors (PPIs): Long-term use can reduce stomach acid necessary for B12 absorption.

Metformin: Commonly used in diabetes management, it can interfere with B12 absorption over prolonged use.

Cholestyramine: This bile acid sequestrant can interfere with B12 absorption.

Question 22

Other Conditions:

Pregnancy: Serum B12 levels can fall during pregnancy but typically return to normal post-delivery.

Infant Deficiency: Prolonged B12 deficiency can lead to irreversible motor function impairment in infants

Question 23

What can you tell me about pernicious Anemia / Pathophysiology

Answer 23

Pernicious Anemia (PA)

Pathophysiology

Autoimmune Attack on Gastric Mucosa: Pernicious anemia results from the immune system attacking the stomach lining.

Gastric Mucosa Atrophy: This leads to the stomach wall becoming thin, infiltrated with plasma cells and lymphocytes.

Destruction of Parietal Cells: This destruction causes a lack of stomach acid (achlorhydria) and nearly absent secretion of intrinsic factor (IF), which is necessary for vitamin B12 absorption.

Intestinal Metaplasia: The gastric mucosa may undergo a transformation to resemble intestinal tissue.

Serum Gastrin Levels: These are typically elevated in PA.

Helicobacter Pylori Infection: This bacterial infection can initiate autoimmune gastritis, leading to PA in older individuals or presenting as iron deficiency in younger patients

Question 24

What’s the epidemiology involved in pernicious anemia

Answer 24

Epidemiology

Gender and Age: More common in females than males.

Associated Autoimmune Diseases: Frequently occurs alongside other autoimmune diseases, especially thyroid disorders.

Increased Cancer Risk: There is a higher incidence (2-3%) of stomach carcinoma in PA patients

Question 25

What are the antibodies involved in pernicious anemia

Answer 25

Antibodies

Parietal Cell Antibody: Found in 90% of PA patients, these antibodies target the gastric proton pump (H+/K+-ATPase). However, these are not specific to PA.

Intrinsic Factor (IF) Antibodies:

Binding Antibody: Present in 50-70% of PA patients, this antibody inhibits the binding of IF to vitamin B12.

Gastric Juice Antibodies: These block any remaining IF from binding to B12 within the stomach.

Specificity: IF antibodies are specific for PA, but their absence does not rule out the disease. The parietal cell antibody, while more common, is less specific as it appears in older adults without PA.

Question 26

List the possible causes of Folate Deficiency

Answer 26

Causes

Poor Dietary Intake: Inadequate consumption of foods rich in folate.

Increased Utilization: Conditions like pregnancy increase the body’s need for folate due to higher cell turnover and DNA synthesis.

Malabsorption: Diseases affecting the small intestine can reduce folate absorption.

Drug-Induced: Certain medications, such as anticonvulsants and barbiturates, can interfere with folate metabolism.

Question 27

What are the clinical signs of megaloblastic A

Answer 27

Clinical Features of Megaloblastic Anemia

Gradual Onset: Symptoms develop slowly and progressively.

Anemia Symptoms: These include fatigue, weakness, and pallor.

Mild Jaundice: Patients may appear lemon-yellow due to the increased breakdown of hemoglobin from ineffective erythropoiesis.

Glossitis: A beefy-red sore tongue.

Angular Cheilosis: Inflammation and sores at the corners of the mouth.

Malabsorption Symptoms: Weight loss and gastrointestinal discomfort.

Purpura: Purple spots on the skin due to thrombocytopenia (low platelet count).

Melanin Pigmentation: Increased skin pigmentation, though less common.

Asymptomatic Cases: Often diagnosed through routine blood tests revealing macrocytosis (enlarged red blood cells).

Question 28

What can you tell me about Vitamin B12 Neuropathy?

Answer 28

Features

Progressive Neuropathy: Affects peripheral sensory nerves and spinal cord columns.

Symmetry: Neuropathy typically affects both sides of the body equally, with a preference for the lower limbs.

Symptoms: Tingling in feet, difficulty walking, and loss of positional sense, leading to falls.

Severe Cases: Can include optic atrophy or severe psychiatric symptoms.

Neuropathy Without Anemia: Anemia might be mild or absent, but neurological symptoms still prompt investigation.

Biochemical Cause: Likely related to the accumulation of S-adenosyl homocysteine and reduced S-adenosyl methionine, leading to defective methylation of myelin and other substrates essential for nervous tissue health.

Question 29

Vit b12 def & folate def can lead to?

Answer 29

Vit. B12 neuropathy

NTD

Sterility

Impact: Severe B12 or folate deficiency can cause sterility in both males and females.

Epithelial Abnormalities

Symptoms: Folate and B12 deficiencies can cause macrocytosis, excess apoptosis, and morphological abnormalities in the epithelia of the cervix, buccal cavity, bladder, and other tissues.

Pigmentation

Melanin Pigmentation: Widespread but reversible melanin pigmentation may occur with B12 deficiency.

Bone Health

Osteoblastic Activity: B12 deficiency is linked to reduced osteoblastic activity, which may affect bone formation and health.

Cardiovascular Disease including:
Myocardial infarction
Peripheral vascular diseases
Stroke
Venous thrombosis

Question 30

Causes and Risks
Maternal Deficiency: Low levels of folate or vitamin B12 in the mother increase the risk of NTDs in the fetus, which include:

Answer 30

Anencephaly
Spina bifida
Encephalocoele

Prevention

Supplementation: Taking folic acid supplements at conception and during early pregnancy can reduce the incidence of NTDs by up to 75%.

Mechanism: The prevention mechanism may involve reducing homocysteine and S-adenosyl homocysteine buildup in the fetus, which otherwise might impair the methylation of proteins and lipids

Question 31

What are the laboratory findings of megaloblastic Anemia?

Answer 31

Macrocytic Anemia

MCV (Mean Corpuscular Volume):

Definition: MCV > 98 fL

Severe Cases: MCV can be as high as 120–140 fL

Characteristics: The red blood cells (RBCs) are larger than normal and often oval-shaped.

Extramedullary Hematopoiesis

Megaloblasts: In severe cases, immature and abnormal RBC precursors called megaloblasts may appear in the peripheral blood due to hematopoiesis occurring outside the bone marrow (e.g., in the liver or spleen).

Iron Deficiency Co-occurrence

*MCV Normalization: If iron deficiency coexists, the MCV may appear normal.”

Red Cell Distribution Width (RDW): RDW will be very wide.

Blood Film: Shows a dimorphic pattern with distinct populations of large and small cells.

Low Reticulocyte Count

Low: Indicates a reduced production of new RBCs.

Total White Cell and Platelet Counts

Reduction: Especially in severely anemic patients with pancytopenia (reduction in RBCs, white blood cells, and platelets).

Neutrophils

Hypersegmented Nuclei: Neutrophils often show hypersegmentation, with six or more lobes in their nuclei.

Serum Biochemical Markers

Unconjugated Bilirubin: Raised due to increased breakdown of RBC precursors in the bone marrow.
Lactate Dehydrogenase (LDH): Elevated as a result of cell breakdown in the marrow.

Giant and Abnormally Shaped Metamyelocytes:

Metamyelocytes are immature white blood cells that develop into mature neutrophils.

Erythroblasts: Large erythroblasts with an open, fine, lacy primitive chromatin pattern but normal cytoplasmic hemoglobinization

Hypercellular Marrow

Increased Cellularity:

The bone marrow has an abnormally high number of cells.

This is a response to the body’s attempt to compensate for anemia by producing more blood cells, even though these cells are often abnormal.

Question 32

Diagnosis of Vitamin B12 or Folate Deficiency

Serum B12 and Folate Assays:

Serum B12: Low in megaloblastic anemia or neuropathy caused by B12 deficiency.

Serum Folate: Tends to rise in B12 deficiency but falls in folate deficiency.

Red Blood Cell Folate: More accurate for assessing tissue folate status. Low in both B12 and folate deficiencies.

Methylmalonic Acid and Homocysteine Measurements:

Serum/Urine Methylmalonic Acid: Elevated in B12 deficiency.

Homocysteine: Elevated in both folate and B12 deficiencies. These tests, however, are not specific and may vary by age.

Tests for Causes of Vitamin B12 or Folate Deficiency

Gastric Function Tests: Assess for pernicious anemia and gastric atrophy.

Antibody Testing: Check for antibodies against gastric antigens.

Endoscopy: Recommended for all cases of pernicious anemia to confirm gastric atrophy and exclude stomach carcinoma.

Dietary History: Important for diagnosing folate deficiency. Conditions like gluten-induced enteropathy should also be considered.

Treatment

Vitamin Therapy:

Folic Acid: Avoid giving alone in B12 deficiency as it can mask hematological symptoms while allowing neuropathy to progress. Start both vitamins if urgently needed and test results are pending.

Vitamin B12: Initial treatment with injections, followed by maintenance with either parenteral or large oral doses. Oral therapy is suitable for mild B12 deficiency cases.

Dosage and Duration:

Folic Acid: Oral dose of 5 mg daily, typically continued for 4 months before reassessment.

Vitamin B12: Injections for initial treatment, with oral therapy for maintenance, especially in mild deficiency cases.

Special Considerations:

Elderly Patients: Manage heart failure with diuretics if present.

Blood Transfusion: Avoid if possible to prevent circulatory overload.

Question 33

Other Megaloblastic Anemias
Drug-Induced: Commonly caused by drugs that inhibit DNA synthesis, such as hydroxyurea, cytosine arabinoside, methotrexate, and pyrimethamine.
Myelodysplastic Syndromes: A frequent cause in the elderly.
Congenital Deficiencies: Rare, such as orotic aciduria affecting DNA synthesis.

Question 34

Nitrous Oxide (N2O) Exposure:

Acute: Causes rapid inactivation of body B12 and can induce megaloblastic changes and pancytopenia after several days.

Chronic: Long-term exposure (e.g., in dentists and anesthetists) can lead to neurological damage resembling B12 deficiency neuropathy.
Antifolate Drugs: Drugs inhibiting dihydrofolate reductase (e.g., methotrexate, pyrimethamine) may cause megaloblastic changes.

Question 35

List the Non-Megaloblastic Causes of Macrocytic Anaemia & how

Answer 35

Alcoholism:

Alcohol is the most frequent cause of a raised MCV in the absence of anemia.

Mechanism: Increased lipid deposition on the red cell membrane or alterations of erythroblast maturation time in the marrow.

Hemolytic Anemia:

Reticulocytes (immature red blood cells) are larger than mature red cells.

Hemolysis causes an increase in reticulocyte count, leading to macrocytosis.

Antimetabolite Drugs:

Example: Hydroxycarbamide (hydroxyurea) can cause macrocytosis and megaloblastic changes in the bone marrow.

Question 36

Differential Diagnosis of Macrocytic Anaemias

Clinical History and Physical Examination:

Important factors: Diet, drug and alcohol intake, family history, malabsorption symptoms, autoimmune diseases, and gastrointestinal history.

Symptoms: Jaundice, glossitis (inflamed tongue), and symmetrical neuropathy suggest megaloblastic anemia.

Laboratory Features:

Shape of Macrocytes:
Oval macrocytes indicate megaloblastic anemia.
Hypersegmented Neutrophils:
Neutrophils with more than five lobes.

Leucopenia and Thrombocytopenia:
Low white cell and platelet counts often seen in megaloblastic anemia.

Bone Marrow Examination:
Hypercellular marrow with large erythroblasts and abnormal metamyelocytes in megaloblastic anemia

Answer 36

Specific Tests:

Serum B12 and Folate Assay:

Essential to confirm or exclude B12 and folate deficiency.

Alcoholism Exclusion:

Assess for alcohol use, especially if the patient is not anemic.

Liver and Thyroid Function Tests:

Important to rule out liver disease and thyroid disorders as causes of macrocytosis.

Bone Marrow Examination:

Necessary to investigate for myelodysplasia, bone marrow aplasia, or multiple myeloma when B12 and folate deficiency are excluded.