Vitamin B12
Deficiency causes
- Nutritional (strict vegans)
- M/c: Alcohol
- Gastric
- ↓ intrinsic factor:
- Autoimmune pernicious anemia,
- Gastrectomy
- Gastric bypass surgery
- Intestinal
- Crohn's disease
- Diphyllobothrium latum (Fish tapeworm)
- Stagnant loop syndrome
- SIBO
- Terminal ileum resection
- Malabsorption
- Measure Methylmalonic acid level in urine after fasting
NOTE:
- In Orotic aciduria, PS shows
- Hypochromic Megaloblastic anemia
- Seen in
- Type 2 hyperammonemia
- No anemia
- Allopurinol
Clinical Features:
- Pale, fatigued.
- Reversible dementia in old age.
- Pure vegetarian diet
- Hyperpigmentation of knuckles and phalanges.
- Subacute Combined Degeneration of Spinal Cord
- Dorsal column + UMN
Peripheral Smear Findings (Megaloblastic Anemia):
- Howell-Jolly bodies
- Cabot ring
- Fine Basophilic stippling
- Macroovalocytes (Macrocytes),
- Hypersegmented neutrophils
- ≥ 5% neutrophils with ≥ 5 lobes /
- ≥ 1 neutrophil with ≥ 6 lobes.
RBC Inclusions
Inclusion | Composition | Seen in |
Howell–Jolly bodies | • DNA remnants | • Post-splenectomy • Megaloblastic • Sickle cell disease (NOT THALASSEMIA) • Dyshematopoiesis • Hemolytic anemia |
Reticulocytes | • Residual RNA (bluish network) | • Hemolysis • Blood loss • Response to therapy |
Basophilic Stippling | • Ribosomal RNA | • Coarse → Lead poisoning • Fine → Thalassemia, Megaloblastic Anemia • Also seen in 5’ Pyrimidine nucleotidase |
Heinz bodies | • Hb denaturation • Stained by Crystal Violet stain • (Supravital stain) | • G6PD |
Pappenheimer Bodies | • Iron granules | • Sideroblastic anemia • Post-splenectomy |
Cabot Rings | • Arginine-rich • Mitotic spindle remnants • Figure of eight/loop | • Severe anemia • Megaloblastic anemia • Sideroblastic anemia |
Hemoglobin H inclusions | • β4 tetramers • (precipitated Hb H) | • α-thalassemia (Hb H disease) |
Siderotic Granules | • Iron • In Prussian blue stain | • Sideroblastic states |
Target cells | ㅤ | • Thalassemia • Iron deficiency anemia • Liver disease • Post-splenectomy • Hemoglobin C disease |
Dohle bodies | • ER remnant | • Bacterial sepsis |
Perinuclear hof | • Golgi apparatus | • Plasma cells |
Q. The micronutrient that is deficient following postileal resection is:
- Most micronutrients are absorbed in the upper small intestine.
- Requires intrinsic factor (IF) from parietal cells
- Vitamin B12 is absorbed specifically in the terminal ileum with bile salts
- B12 deficiency is a common consequence of postileal resection.
Two Coenzyme Forms of B12
Cause | Features |
Adenosyl B12 | • MMA aciduria • Neurological manifestation |
Methyl B12 | • Homocystinuria • Methyl Folate Trap • Macrocytic anemia |
Adenosyl B12:
- Coenzyme for Methyl malonyl CoA mutase.
- In B12 deficiency, this enzyme is inactive.
- Methyl Malonyl CoA accumulates, causing Methyl malonic aciduria.
- Urinary Methyl Malonic acid is used to diagnose B12 deficiency.
- Accumulated Methyl Malonyl CoA incorporates into fatty acids.
- This forms abnormal fatty acids, causing abnormal myelin and demyelination.
- Demyelination starts peripherally (tingling)
- Subacute combined degeneration of the spinal cord.
Methyl B12:
- Coenzyme for Methionine synthase/ Homocysteine methyl transferase
- Homocysteine → Methionine (Methionine Synthase)
- Methionine → SAM (Transmethylation)
- SAM used for synthesis of → Creatine, Choline, Epinephrine
- In B12 deficiency,
- Homocysteine ↑↑ → Homocystinuria
Folic Acid
Source
- Leafy green vegetables
- Gut microbiota
- Absorbed in jejunum
Folate trap
- Cause:
- Vitamin B₁₂ deficiency
- THFA is trapped as Methyl THFA
- ↑↑ N5-methyl THFA
- Functional folate deficiency → Megaloblastic anemia
Crucial for:
- Conversion of Uridine to Thymidine.
- Methylation reaction
- Formation of Purine ring atoms C2 and C8.
- Without THFA, DNA synthesis is impaired,
- preventing cell division.
- This leads to Macrocytic anaemia
Deficiency
- Megaloblastic anemia.
- Neurological manifestation is not seen
Biochemical Tests
- Serum homocysteine ↑
- thrombosis risk
- Normal Methylmalonyl CoA
- Histidine load test:
- FIGLU excretion in urine
- Serum AICAR
Important Information:
- Form used in treatment:
- N5-formyl THF (due to its high stability).
- Formulate as tab → formyl
- Main form in circulation:
- Methyl THF (most abundant in plasma).
- Main in circulation → Methyl
- Form used in 1C transfer reactions:
- Methylene THF (involved in DNA synthesis and amino acid metabolism).
- Serine (3C) + THF → Glycine (2C) + Methylene THF
- TransferEnce → methylEne
Treatment/Prophylaxis
- Pregnancy prophylaxis:
- 60 mg iron & 500 mcg folic acid daily
- Folate supplementation
- masks hematologic symptoms of B12 deficiency
- but not neurologic
Differences between B12 deficiency and Folate deficiency
Laboratory Test | B12 Deficiency | Folic Acid Deficiency |
Absorption Site | Terminal ileum (requires Intrinsic Factor) | Jejunum, Duodenum? |
Intrinsic Factor | Released by Parietal cells | ㅤ |
Pernicious Anemia | Due to ↳ ↓ Intrinsic Factor ↳ Parietal cell issues | ㅤ |
Cause | • Veganism | • Inadequate vegetable intake |
Serum B12 level | ↓↓↓ | Normal |
Serum folic acid level | Normal | ↓↓↓ |
Serum LDH, Bilirubin | ↑↑↑↑ | Normal |
Achlorhydria | ++ | ㅤ |
Methyl Malonic aciduria | +++ | ㅤ |
Specific Test | Schilling test • Determine cause of megaloblastic anemia • Positive ⇒ No absorption problem | Figlu test (Formiminoglutamic acid) • After Histidine Load Test |
Neurological signs | Present (SACD) | Absent |
Prevention of Neural Tube Defects:
- Folic Acid Supplementation:
- 400 µg/day in all women of childbearing age.
- 4000 µg/day in high-risk women.
- Started at least one month before conception.
- Decrease risk of neural tube defects by 70%.
Folic Acid in Pregnancy
- 400 mcg/day
- All females → prevention
- Diabetic
- On anti epileptic → before conception
- 1 mg/day
- Treat folic acid deficiency
- 4 mg/day
- Prev h/o NTD
- Antiepileptic → after conception
- 5 mg/day
- Thalassemia or thalassemia trait.
- Sickle cell anemia
- To prevent NTD:
- 400 mcg/day given to all pregnant females
- Start 1 month before conception
- Continue till 3 months after conception
- To prevent recurrence of NTD:
- 4 mg/day given to females with h/o baby with NTD
- Start 3 months before conception
- Or from day a female plans pregnancy
- Continue 3 months after conception
- To treat folic acid deficiency: 1 mg/day
- In diabetic patients who are pregnant: 400 mcg/day
- In patients on antiepileptic:
- Before conception: 400 mcg/day
- After conception: 4 mg/day
Negative Schilling Test
- Definition
- Low urinary excretion of radiolabelled Vitamin B12 after oral dose.
- Indicates abnormal absorption.
Stage-wise Interpretation
- Stage I
- Patient given
- oral radiolabelled Vitamin B12 +
- IM injection of unlabelled Vitamin B12
- Correction (normal excretion): > 10%: Dietary deficiency
- < 10%: Go to Stage II.
- Stage II (with IF)
- Correction (normal excretion): Pernicious anemia
- < 10%: Stage III.
- Stage III (with antibiotics)
- Correction: Bacterial overgrowth syndrome.
- < 10%: Stage IV.
- Stage IV (with pancreatic enzymes)
- Correction: Pancreatic insufficiency.
- < 10% : Ileal disease or ileal resection
Q. A vegetarian patient presents with anemia and hypersegmented neutrophil. The most probable cause is?
- Anemia with hypersegmented neutrophils in a vegetarian suggests Megaloblastic anemia.
- This is typically caused by B12 or folate deficiency.
Q. Which of the following vitamin deficiencies cause accumulation of Methyl THFA and functional folate deficiency?
- B12 deficiency.
- This is due to the inactivity of Methionine synthase, which requires Methyl B12.
Q. Which of the following enzyme activities can be estimated in RBCs to diagnose Vitamin B2 deficiency?
- Vitamin B2 is Riboflavin.
- To diagnose B2 deficiency, RBC Glutathione reductase activity is estimated
- Mnemonic: Ribbon and Glue
Q. Which of the following activities are low in Riboflavin deficiency?
- Glutathione reductase: Low in Riboflavin deficiency.
- Transketolase: Low in Thiamine deficiency.
- Glycogen phosphorylase: Low in B6 deficiency.
- Propionyl CoA carboxylase: Low in Biotin deficiency.
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