Vitamin B12 Deficiency

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Basics

  • Vitamin deficiency related to inadequate intake or absorption of cobalamin (vitamin B12)
  • Cobalamin is critical for central nervous system myelination, red blood cell production, and DNA synthesis.
  • Deficiency can cause megaloblastic anemia, bone marrow dysfunction, and diverse and potentially irreversible neuropsychiatric changes.
  • Neuropsychiatric disorders are due to demyelination of cervical, thoracic dorsal, and lateral spinal cords; demyelination of white matter; and demyelination of cranial and peripheral nerves.
  • Elevated MMA and homocysteine levels may be early markers of vitamin B12 deficiency (1).

Description

Normal vitamin B12 absorption

  • Vitamin B12 is a water-soluble vitamin present in animal-source foods and foods fortified with vitamin B12.
  • Dietary vitamin B12 (cobalamin) bound to food is cleaved by acids in stomach and bound to haptocorrin (commonly known as R-factor).
  • Duodenal proteases cleave vitamin B12 from haptocorrin.
  • In duodenum, vitamin B12 uptake depends on binding to intrinsic factor (IF) secreted by gastric parietal cells.
  • Vitamin B12IF complex is absorbed by terminal ileum into portal circulation.
  • Body’s vitamin B12 stored in liver = 50–90%
    • Vitamin B12 secreted into bile from liver recycled via enterohepatic circulation
    • Delay 5 to 10 years from onset of vitamin B12 deficiency to clinical symptoms due to hepatic stores and enterohepatic circulation
  • Typical Western diet: 5 to 30 mg/day; however, only 1 to 5 mg/day is effectively absorbed.
    • Recommend 2.4 mg/day for adults and 2.6 mg/day during pregnancy and 2.8 mg/day during lactation (most prenatal vitamins contain vitamin B12).

Epidemiology

Prevalence

  • Endemic area: Northern Europe, including Scandinavia; more common in those of African ancestry
  • Increasing recognition in breastfed-only infant populations with vitamin B12deficient mothers (2)
  • Prevalence 5–20% in developed countries
  • Prevalence in those <60 years old is 6%, and in those >60 years old, it is 20%.

Etiology and Pathophysiology

  • Decreased oral intake
    • Vegetarians and vegans: Vitamin B12 is found in animal source foods.
  • Decreased IF
    • Pernicious anemia (PA): can be associated with autoantibodies directed against gastric parietal cells and/or IF
    • Chronic atrophic gastritis: autoimmune attack on gastric parietal cells causing autoimmune gastritis and leading to decreased IF production
    • Gastrectomy: removal of entire or part of stomach
  • Decreased absorption
    • Crohn disease: Terminal ileal inflammation decreases body’s ability to absorb vitamin B12.
    • Chronic alcoholism: decreases body’s ability to absorb vitamin B12
    • Gluten hypersensitivity (celiac disease) intestinal villi atrophy and subsequent malabsorption
    • Ileal resection
    • Pancreatic insufficiency: Pancreatic proteases are required to cleave the vitamin B12haptocorrin bond to allow vitamin B12 to bind to IF.
    • Helicobacter pylori infection: impairs release of vitamin B12 from bound proteins
  • Medications:
    • Proton pump inhibitors (PPIs), H2 antagonists, and antacids decrease gastric acidity, inhibiting vitamin B12 release from dietary protein; metformin
    • Metformin usage can cause calcium-dependent membrane inhibition, interfering with vitamin B12IF absorption.
  • Hereditary (rare)
  • Causes:
    • Food-cobalamin malabsorption syndrome
      • As many as 60–70% of cases
      • Primary cause in elderly
      • Pathophysiology: inability to release cobalamin from food or binding protein, especially if in the setting of hypochlorhydria
      • Seen in atrophic gastritis, long-term ingestion of antacids and biguanides, possible relationship to H. pylori infection
    • PA
      • 15–30% of all cases; most frequent cause of severe disease. Neurologic disorders are common presenting complaints.
      • Common in elderly, as high as 20%, with mild atrophic gastritis, hypochlorhydria, and impaired release of dietary vitamin B12
      • Antigastric parietal cell antibodies: sensitivity >90%, specificity 50%; use for screening test.
    • Insufficient dietary intake: 2% of cases; vegans or long-standing vegetarians
    • Infants born to vitamin B12deficient mothers may develop it if breastfed exclusively.
    • Intestinal causes:
      • 1% of cases; prevalence depends on risk factors, such as surgical conditions.
      • Gastrectomy: due to decreased production of IF
      • Gastric bypass: appears 1 to 9 years after surgery, prevalence 12–33%
      • Ileal resection or disease
      • Fish tapeworm
      • Severe pancreatic insufficiency
    • Undetermined etiology

Genetics
Imerslund-Gräsbeck disease (juvenile megaloblastic anemia) caused by mutations in the amnionless (AMN) or cubilin (CUBN) genes with autosomal recessive pattern of inheritance; inadequate ileal uptake of vitamin B12-IF complex and vitamin B12 renal protein reabsorption

General Prevention

Eating a diet with foods that contain vitamin B12 such as meat, fish, poultry, and dairy

Commonly Associated Conditions

  • Gastric abnormalities: PA, gastritis, gastrectomy/bariatric surgery
  • Small bowel disease: malabsorption syndrome, ileal resection, IBD, celiac disease
  • Pancreatitis: pancreatic insufficiency
  • Diet: breastfed infant in vitamin B12deficient mother, strict vegan diet
  • Medications: neomycin, metformin, PPI, histamine 2 receptor antagonists, nitrous oxide (NO) abuse (3)

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Basics

  • Vitamin deficiency related to inadequate intake or absorption of cobalamin (vitamin B12)
  • Cobalamin is critical for central nervous system myelination, red blood cell production, and DNA synthesis.
  • Deficiency can cause megaloblastic anemia, bone marrow dysfunction, and diverse and potentially irreversible neuropsychiatric changes.
  • Neuropsychiatric disorders are due to demyelination of cervical, thoracic dorsal, and lateral spinal cords; demyelination of white matter; and demyelination of cranial and peripheral nerves.
  • Elevated MMA and homocysteine levels may be early markers of vitamin B12 deficiency (1).

Description

Normal vitamin B12 absorption

  • Vitamin B12 is a water-soluble vitamin present in animal-source foods and foods fortified with vitamin B12.
  • Dietary vitamin B12 (cobalamin) bound to food is cleaved by acids in stomach and bound to haptocorrin (commonly known as R-factor).
  • Duodenal proteases cleave vitamin B12 from haptocorrin.
  • In duodenum, vitamin B12 uptake depends on binding to intrinsic factor (IF) secreted by gastric parietal cells.
  • Vitamin B12IF complex is absorbed by terminal ileum into portal circulation.
  • Body’s vitamin B12 stored in liver = 50–90%
    • Vitamin B12 secreted into bile from liver recycled via enterohepatic circulation
    • Delay 5 to 10 years from onset of vitamin B12 deficiency to clinical symptoms due to hepatic stores and enterohepatic circulation
  • Typical Western diet: 5 to 30 mg/day; however, only 1 to 5 mg/day is effectively absorbed.
    • Recommend 2.4 mg/day for adults and 2.6 mg/day during pregnancy and 2.8 mg/day during lactation (most prenatal vitamins contain vitamin B12).

Epidemiology

Prevalence

  • Endemic area: Northern Europe, including Scandinavia; more common in those of African ancestry
  • Increasing recognition in breastfed-only infant populations with vitamin B12deficient mothers (2)
  • Prevalence 5–20% in developed countries
  • Prevalence in those <60 years old is 6%, and in those >60 years old, it is 20%.

Etiology and Pathophysiology

  • Decreased oral intake
    • Vegetarians and vegans: Vitamin B12 is found in animal source foods.
  • Decreased IF
    • Pernicious anemia (PA): can be associated with autoantibodies directed against gastric parietal cells and/or IF
    • Chronic atrophic gastritis: autoimmune attack on gastric parietal cells causing autoimmune gastritis and leading to decreased IF production
    • Gastrectomy: removal of entire or part of stomach
  • Decreased absorption
    • Crohn disease: Terminal ileal inflammation decreases body’s ability to absorb vitamin B12.
    • Chronic alcoholism: decreases body’s ability to absorb vitamin B12
    • Gluten hypersensitivity (celiac disease) intestinal villi atrophy and subsequent malabsorption
    • Ileal resection
    • Pancreatic insufficiency: Pancreatic proteases are required to cleave the vitamin B12haptocorrin bond to allow vitamin B12 to bind to IF.
    • Helicobacter pylori infection: impairs release of vitamin B12 from bound proteins
  • Medications:
    • Proton pump inhibitors (PPIs), H2 antagonists, and antacids decrease gastric acidity, inhibiting vitamin B12 release from dietary protein; metformin
    • Metformin usage can cause calcium-dependent membrane inhibition, interfering with vitamin B12IF absorption.
  • Hereditary (rare)
  • Causes:
    • Food-cobalamin malabsorption syndrome
      • As many as 60–70% of cases
      • Primary cause in elderly
      • Pathophysiology: inability to release cobalamin from food or binding protein, especially if in the setting of hypochlorhydria
      • Seen in atrophic gastritis, long-term ingestion of antacids and biguanides, possible relationship to H. pylori infection
    • PA
      • 15–30% of all cases; most frequent cause of severe disease. Neurologic disorders are common presenting complaints.
      • Common in elderly, as high as 20%, with mild atrophic gastritis, hypochlorhydria, and impaired release of dietary vitamin B12
      • Antigastric parietal cell antibodies: sensitivity >90%, specificity 50%; use for screening test.
    • Insufficient dietary intake: 2% of cases; vegans or long-standing vegetarians
    • Infants born to vitamin B12deficient mothers may develop it if breastfed exclusively.
    • Intestinal causes:
      • 1% of cases; prevalence depends on risk factors, such as surgical conditions.
      • Gastrectomy: due to decreased production of IF
      • Gastric bypass: appears 1 to 9 years after surgery, prevalence 12–33%
      • Ileal resection or disease
      • Fish tapeworm
      • Severe pancreatic insufficiency
    • Undetermined etiology

Genetics
Imerslund-Gräsbeck disease (juvenile megaloblastic anemia) caused by mutations in the amnionless (AMN) or cubilin (CUBN) genes with autosomal recessive pattern of inheritance; inadequate ileal uptake of vitamin B12-IF complex and vitamin B12 renal protein reabsorption

General Prevention

Eating a diet with foods that contain vitamin B12 such as meat, fish, poultry, and dairy

Commonly Associated Conditions

  • Gastric abnormalities: PA, gastritis, gastrectomy/bariatric surgery
  • Small bowel disease: malabsorption syndrome, ileal resection, IBD, celiac disease
  • Pancreatitis: pancreatic insufficiency
  • Diet: breastfed infant in vitamin B12deficient mother, strict vegan diet
  • Medications: neomycin, metformin, PPI, histamine 2 receptor antagonists, nitrous oxide (NO) abuse (3)

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