Erythropoiesis and Vitamins B12, Folate

Learning Objectives

• Discuss factors regulating erythropoiesis
• Discuss vitamin B12 and folic acid metabolism
• Describe biochemical functions, dietary sources, and recommended daily intake of vitamin B12 and folic acid
• Discuss clinical significance of vitamin B12 and folic acid deficiency

Erythropoiesis Regulation

• Tissue oxygenation is a primary regulator of red blood cell (RBC) production.
• Factors like low blood volume, low blood flow, low hemoglobin, anemia, and impaired oxygen absorption in pulmonary disease decrease tissue oxygenation.
• Erythropoietin (a glycoprotein), primarily from the kidneys (80-90%), and also from the liver and macrophages, stimulates pro-erythroblast production from hematopoietic stem cells, increasing RBC production.

Vitamin Classification

• Vitamins are categorized as water-soluble and fat-soluble.
• B-complex vitamins include thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid, biotin, vitamin B6 (pyridoxine, pyridoxal, pyridoxamine), vitamin B12, and folic acid.
• Fat-soluble vitamins include Vitamin A, D, E, and K.

Vitamin B12

• Role: Essential for RBC formation, cell metabolism, nerve function, and DNA production.
• Deficiency symptoms: Weak muscles, numbness, trouble walking, nausea, weight loss, irritability, fatigue, and increased heart rate.
• Function: Healthy red blood cell and marrow production, nervous system function, sperm production, strong immunity, improved mental energy and memory. Protects against toxins like cyanide (in cigarettes)
• Sources: Milk, eggs, liver, dairy products, fish, and shellfish.
• Prevention: Pernicious anemia, intestinal malabsorption
• Toxicity: Slight stomach upset

Forms of Vitamin B12

• Cyanocobalamin (commercial preparation)
• Hydroxycobalamin
• Adenosylcobalamin (major storage form in the liver)
• Methylcobalamin (mostly found in blood circulation)

Vitamin B12 Structure

• Consists of a nucleotide, a tetrapyrrole corrin ring, a cobalt ion, and an R-group.
• Different forms of vitamin B12 vary based on the R-group. (e.g., cyanide in cyanocobalamin, hydroxyl in hydroxycobalamin)
• Coenzyme forms of vitamin B12, such as adenosylcobalamin and methylcobalamin, have specific R groups (adenosyl and methyl).

Coenzyme Forms

• Adenosylcobalamin and methylcobalamin are coenzymes, essential for metabolic reactions.

Dietary Recommendations of Vitamin B12

• Recommended daily intake 2.4ugm/day for men and women.

Vitamin B12 in Metabolism

• Two crucial reactions require Vitamin B12 in the body
• Methylmalonyl CoA conversion through propionyl CoA and methylmalonyl CoA mutase.
• Causes methylmalonic aciduria: Methylmalonyl CoA is excreted in the urine, disrupting myelin fatty acid synthesis which causes nerve damage.
• Important for converting homocysteine to methionine, a process crucial for maintaining neurological function
• Tetrahydrofolate synthesis, which is also crucial for DNA synthesis and cell division.

Deficiency of Vitamin B12

• Deficiency leads to homocysteine accumulation, leading to neurological manifestations.
• Impedes the formation of purines and thymidine monophosphate, resulting in megaloblastic anemia (abnormal blood cell formation)

Folate

• The word folate is derived from the Latin word for "leaf," referring to its presence in leafy green vegetables and spinach.
• Folic acid comprises a pteridine ring, para-aminobenzoic acid (PABA), and glutamic acid residues.
• Stored mainly in the liver.

Biochemical Function of Folate

• The active coenzyme forms of folic acid are tetrahydrofolic acid (FH4), N5-methyltetrahydrofolic acid (N5-methyl-THF), and N10-formyltetrahydrofolate.
• Essential for various synthetic reactions involving one-carbon units.

Folate Requirements

• Folate requirements are adjusted for varying folate absorption efficiencies in dietary forms versus supplements.
• Adult needs: 400µg DFE
• Pregnant needs: 600 µg DFE
• Lactation needs: 500 µg DFE

Folate Absorption

• Readily absorbed in the jejunum.
• Transported by beta-globulins.
• Taken up by the liver, where coenzymes are produced.

Folate Tissue Distribution

• 50% of total body folate located in the liver.
• Rapid cell division tissues have high folate requirements.

Folate Functions and Mechanisms

• THF acts as a coenzyme in both mitochondria and cytoplasm for accepting one-carbon units generated from amino acid metabolism.
• Folate derivatives are key donors of one-carbon units for various synthetic reactions, including amino acid synthesis.
• Methyl groups accepted by THF bind to nitrogen positions 5 or 10 (or both).

Folate in Heme Synthesis

• Involved in converting methylmalonyl CoA to succinyl CoA.
• THF involved in other synthetic reactions.

Folic Acid Deficiency Causes

• Alcoholism
• Folic acid antagonists
• Oral contraceptives
• Low dietary intake (e.g., excessive goat milk)
• Infection with giardia
• Celiac Sprue
• Pregnancy and psoriasis
• Old age
• Dilantin (phenytoin)

Deficiency Symptoms

• Symptoms similar to vitamin B12 deficiency.
• Folate deficiency affects cellular processes by impairing DNA synthesis, specifically dTMP and purine synthesis.
• Megaloblastic anemia is the result.
• Pregnancy deficiency can cause neural tube defects.
• Deficiency during pregnancy.

Folate Deficiency Anemia Assessment

• Methylmalonic aciduria
• Serum folate level (normal is ~ 20ng/mL)
• Peripheral smear (macrocytic, hypochromic)
• Homocysteinuria

Vitamin B12 & Folate Deficiency Treatment

• Initiated with folic acid and vitamin B12 until the cause is determined.
• Therapy with Vitamin B12 is typically lifelong and can involve oral supplements or IM injections.