Anaemias related to vitamin deficiencies

• Iron Deficiency Anemia: Caused by insufficient iron intake, leading to reduced hemoglobin production.

• Vitamin B12 Deficiency Anemia: Occurs due to inadequate vitamin B12, often linked to dietary insufficiency or absorption issues, resulting in megaloblastic anemia.

• Folate Deficiency Anemia: Results from low folate levels, which are essential for DNA synthesis and red blood cell production, typically due to poor diet or malabsorption.

Anaemia

Definition: Reduced red blood cell (RBC) mass which decreases the oxygen-carrying capacity of the blood and can lead to cellular hypoxia.

Laboratory Findings (CBC): Anaemia is characterized by decreased RBC measurement, Hemoglobin (Hb), and Hematocrit (Ht). Abnormalities in these parameters can provide clues to the underlying causes of anaemia.

WHO Criteria for Anaemia:

• Adult males: Hb < 13 g/dL

• Adult females: Hb < 12 g/dL

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  Children: Varies by age and sex, generally lower than adults; specific thresholds for anaemia in children should be referenced.Important Note: Anaemia itself is not a disease, but a sign indicating other underlying diseases that may include chronic infections, inflammatory diseases, or malignancies. It often necessitates further investigation to determine the cause.

Symptoms of Anaemia:Symptoms can vary in severity and may include:

• Tiredness and fatigue

• Weakness and lethargy

• Pallor (pale skin and mucous membranes)

• Shortness of breath, particularly with exertion

• Increased heart rate (tachycardia)

• Dizziness or light-headedness, potentially leading to fainting

• Cold hands and feet

Erythropoiesis:The process of producing red blood cells is influenced by several key factors.

• Reticulocyte Production: Typically around 1% of total blood volume; reticulocytes have a lifespan of 1-2 days and are indicative of bone marrow activity. A high reticulocyte count often signifies a compensatory response to anaemia.

• Erythropoietin (EPO):

  • This hormone controls RBC production and is predominantly produced by the kidneys in response to decreased tissue oxygenation due to conditions like anaemia, high altitude, or pulmonary disease.

  • EPO stimulates the bone marrow to produce more red blood cells, thus increasing oxygen delivery to tissues.

  • Understanding the factors affecting EPO production is crucial for diagnosing and managing various types of anaemia.

• Requirements for Normal Erythropoiesis: Normal erythropoiesis requires:

  • Adequate renal EPO production

  • Functioning red bone marrow, which is crucial for the maturation of erythrocytes

  • Adequate substrates for hemoglobin synthesis. Iron, folate, and Vitamin B12 are critical for RBC maturation, and deficiencies in any of these can lead to specific forms of anaemia.

Classification of Anaemias:Anaemias can be classified based on Mean Corpuscular Volume (MCV) and aetiology.

• By MCV (Mean Corpuscular Volume):

  • Microcytic Anaemia (MCV < 80 fL):

    • Iron deficiency anaemia: the most common form globally, often due to dietary insufficiency or chronic blood loss.

    • Hemolytic anaemias (e.g., thalassemia): caused by genetic mutations affecting hemoglobin synthesis.

    • Anaemia of chronic disease (later stage): associated with chronic infections or malignancies.

  • Normocytic Anaemia (MCV 80-100 fL):

    • Acute blood loss: post-traumatic or post-surgical scenarios leading to decreased RBC counts.

    • Some hemolytic anaemias (e.g., sickle cell disease): characterized by shortened RBC lifespan.

    • Anaemia of chronic disease (early stage): typical in inflammatory states.

  • Macrocytic Anaemia (MCV > 100 fL):

    • Vitamin B12 or folate deficiency: leading to impaired DNA synthesis and resultant large RBCs (macrocytes).

    • Myelodysplastic syndromes: a group of disorders caused by poorly formed or dysfunctional blood cells.

    • Alcoholism: can alter RBC production and maturation due to nutritional deficiencies.

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  By Aetiology:Causes can be classified into two main categories:

1. Increased destruction or loss:

   • Hemolytic anaemias: conditions where RBCs are destroyed faster than they can be produced.

2. Decreased production:

   • Bone marrow failure or suppression due to a variety of conditions such as aplastic anaemia or malignancy.

Iron Deficiency Anaemia:

• Characteristics:

  • RBCs are small (microcytic) and pale (hypochromic) due to low hemoglobin content.

  • Causes may include chronic blood loss (menstrual or gastrointestinal), increased demand (as seen in pregnancy or infancy), decreased intake (particularly in populations with low meat consumption), and decreased absorption (e.g., coeliac disease).

Hemolytic Anaemias:

• Characteristics:

  • Premature destruction of RBCs leads to a shorter lifespan and observable physical changes.

  • Fragile RBCs rupture due to osmotic changes or inherited defects.

  • Faster destruction than production leads to severe anaemia.

• Examples:

  • Types include structural defects in RBCs (e.g., hereditary spherocytosis), enzyme defects (e.g., G6PD deficiency), and hemoglobinopathies (e.g., sickle cell anaemia).

• Evidence of Hemolysis:

  • Increased reticulocyte count due to bone marrow hyperplasia, as a response to anemia.

  • Symptoms can include jaundice (increased unconjugated bilirubin levels), elevated LDH, decreased haptoglobin, splenomegaly, and autoantibodies in autoimmune hemolytic anaemias.

Sickle Cell Anaemia (Hemoglobinopathy):

• Associated with a specific mutation of the β-chain of hemoglobin (HbS), leading to distortion of the RBC shape under low oxygen conditions.

• Characteristics:

  • Normocytic anaemia present with episodes of painful crises, increased risk of infections, and complications such as stroke or acute chest syndrome.

• Genetic counselling is often recommended for families affected by this condition.

Thalassemia:

• A group of inherited blood disorders characterized by a quantitative defect in globin chain synthesis.

• Can result in microcytic anaemia and requires regular monitoring and treatment.

Megaloblastic Anaemias:

• Characteristics:

  • Presence of large RBCs (macrocytes) in the bloodstream due to delayed maturation from vitamin B12 or folate deficiencies.

• Caused by impaired DNA synthesis leading to ineffective erythropoiesis, with often increased reticulocyte counts due to compensatory responses.

Folate (Vitamin B9):

• Sources and Requirements:

  • Found in leafy green vegetables, legumes, and nuts; the minimum daily requirement is 50 μg, increased during pregnancy.

• Folate Metabolism:

  • Important for DNA synthesis; it participates in purine synthesis and the conversion of dUMP to dTMP for DNA synthesis, affecting cellular division.

  • Dietary folate:

    • Transported into the cell by a specific carrier

    • Folate is converted into dihydrofolate (DHF) and then to the active form tetrahydrofolate (THF) by the enzyme di-hydro-folate reductase (DHFR)

    In the folate metabolic cycle:

    • THF is converted to 5,10 methylene THF, by SHMT

    • 5,10 methylene THF can be used:

    1. to synthesize purine

    2. in the thymidylate synthase reaction

    3. in the methionine cycle

    In the thymidylate synthase reaction:

    • Deoxyuridylate monophosphate (dUMP) is converted into deoxythymidylate monophosphate (dTMP)

    • dTMP is involved in DNA synthesis

    • Meanwhile 5,10 methylene THF is converted to DHF

    To go into the methionine cycle:

    • 5,10 methylene THF is converted into 5-methyl THF by the enzyme 5,10 methylene THF reductase (MTHFR)

    • 5-methyl THF can be recycled by the enzyme methionine synthase (MTR) to THF, with production of methionine

    • Methionine can produce s-adenosyl-methionine (SAM), s-adenosyl homocysteine (SAH) and homocysteine, by MTRR (methionine synthase reductase)

    • SAM is involved in DNA methylation

    Folate metabolism: summary

    Folate is essential for the synthesis of:

    1. purine

    2. dTMP → DNA synthesis

    3. methionine → DNA methylation

Clinical Relevance of Folate Deficiency:

• Can lead to macrocytic anaemia and is associated with inadequate dietary intake, small bowel disease (e.g., coeliac disease), or increased demand in pregnancy or malignancies.

• folic acid:- synthetic form of vitamin B9 found in supplements and fortified foods - cereals , rice pasta etc .

• Treatment:

  • Folic acid supplements are often used to correct deficiencies.

Vitamin B12 (Cobalamin):

• Sources and Absorption Pathway:

  • Primarily found in animal products; minimum daily requirement is 3 μg, stored mostly in the liver.

  • Requires intrinsic factor (IF) for absorption; deficiency often results from inadequate intake or lack of IF, as in pernicious anaemia or after surgical removal of the stomach.

• Deficiency Effects:

  • Leads to a block in the folate cycle causing impaired DNA synthesis, increased homocysteine levels leading to cardiovascular issues, and neurological damage due to decreased methionine production.

  • Cobalamin has two metabolically active forms:

    • Methylcobalamin

    • Adenosylcobalamin

    Cyanocobalamin (therapeutic supplement) is not active, has to be converted to hydroxycobalamin, and then to methylcobalamin or adenosylcobalamin

    Cobalamin is an essential cofactor for two enzymes:

    • In the cytoplasm: methionine synthase

      • requires methylcobalamin- cofactor

      • catalyses conversion of homocysteine to methionine

    • In the mitochondria: methylmalonyl-coenzyme A synthase

      • requires adenosylcobalamin- cofactor

      • catalyses conversion of methylmalonyl-CoA to succinyl-CoA

    Cobalamin deficiency:

    • Block of folate metabolic cycle → defect in DNA synthesis

    • Accumulation of homocysteine → risk factor for arterial thrombosis

    • Decreased production of methionine → decreased production of choline and choline-containing phospholipids with nervous system damage

    • Accumulation of methylmalonyl-CoA (and its precursor propionyl CoA) → synthesis of non-physiologic fatty acids containing an odd-number of carbon atoms, which are then incorporated into neuronal membranes

    Causes of vitamin B12 deficiency:

    • Decreased supply/absorption

    • Inadequate dietary intake (vegan diet)

    • Pernicious anaemia (atrophy of gastric mucosa, lack IF)

    • Surgery (e.g. gastrectomy, lack IF)

    • Terminal ileal disease (e.g. coeliac disease)

    Treatment: vit. B12 supplements (im shots if malabsorption or deficit IF)

Pernicious Anemia:

• Characterized by severe vitamin B12 deficiency leading to CNS symptoms including peripheral neuropathy, confusion, and potentially reversible dementia.

• Requires lifelong treatment with vitamin B12 supplementation, often through injections in cases of malabsorption or intrinsic factor deficiency.

Summary of Anaemia Types:

• Macrocytic Anaemia: Presence of large hemoglobin-rich erythrocytes typically due to vitamin B12 or folate deficiency.

• Microcytic Anaemia: Characterized by small hemoglobin-poor erythrocytes often linked to iron deficiency.

• Different forms of anaemia necessitate specific investigations and tailored treatment strategies based on their etiology and underlying conditions.

Vitamin B12 Absorption Process:

1. Release from Food: Vitamin B12 is released from food in the stomach through the action of gastric acid and digestive enzymes.

2. Binding to Proteins:

   • Intrinsic Factor (IF): After release, vitamin B12 binds to intrinsic factor, a protein secreted by the parietal cells of the stomach, which is essential for its absorption.

   • Protein R: In the stomach, vitamin B12 can also bind to another protein known as R-protein (or haptocorrin), which protects it until it reaches the duodenum.

3. Transit to the Small Intestine: The vitamin B12-R protein complex moves into the small intestine, where pancreatic enzymes degrade R-protein, releasing vitamin B12.

4. Rebinding to Intrinsic Factor: The freed vitamin B12 then binds to intrinsic factor, forming a complex that is stable and enables absorption.

5. Absorption in the Ileum: In the terminal ileum, specialized receptors on the enterocyte cell membrane recognize the vitamin B12-intrinsic factor complex, facilitating its uptake into the intestinal cells.

6. Transcobalamin II (TCII): Once inside the intestinal cells, vitamin B12 is released from intrinsic factor and binds to Transcobalamin II (TCII), a transport protein that carries vitamin B12 through the bloodstream to tissues and organs.

This series of steps is crucial for the efficient absorption of vitamin B12, and any disruption in this process can lead to deficiencies, highlighting the importance of both intrinsic factor and transcobalamin II in vitamin B12 metabolism.