Pivoting from blood to stomach

The most common cause of vitamin B12 deficiency is pernicious anemia. What is the primary pathology in pernicious anemia, i.e., the most proximate cause?

a
Bone marrow failure
No, vitamin B12 deficiency may result in pancytopenia, but the bone marrow is typically hyperproliferative. Besides, there is a more proximate cause than a defect in the bone marrow.
b
Defect in DNA synthesis
Vitamin B12 deficiency does decrease DNA synthesis, which then results in megaloblastic changes in the bone marrow, but these changes represent collateral damage. The primary lesion is elsewhere.
c
Atrophic gastritis
Correct! The primary defect in pernicious anemia is immune-mediated loss of parietal cells in the stomach. The resulting reduction in vitamin B12 levels has both hematological and neurological downstream effects.
d
Hypothyroidism

The scheme below, which you saw in the previous section, highlights the pathway of vitamin B12 from stomach to blood.

Upon ingestion, Cbl is released from the food and bound to salivary haptocorrin (HC), which protects vitamin B12 from stomach acids as it is transported to the small intestine. In the upper small intestine, HC is degraded by intestinal enzymes thereby allowing Cbl to associate with gastric intrinsic factor (IF) produced by gastric parietal cells. In the ileum, vitamin B12-intrinsic factor complex then binds to specific receptor known as cubam on the ileal mucosa and is internalized; vitamin B12 is subsequently released into circulation. A second, inefficient pathway of passive diffusion occurs throughout the intestine and accounts for about 1% of total absorption. After absorption, Cbl is released to the portal blood and is bound to either transcobalamin (TC) or HC (previously referred to as transcobalamin I, transcobalamin III or R-binder). Free Cbl is excreted in the urine; hence, Cbl remains in plasma only if it is bound to TC or HC.

Before going any further, let’s consider a broader differential diagnosis for vitamin B12 deficiency:

  • Impaired gastrointestinal absorption of vitamin B12:
    • Atrophic gastritis (pernicious anemia)
    • Gastrectomy (deficiency in intrinsic factor, hypo- or achlorhydria)
    • Bariatric surgery (hypo- or achlorhydria)
    • Corpus-predominant Helicobacter pylori gastritis (hypo- or achlorhydria)
    • Long-term proton pump inhibitor therapy (hypo- or achlorhydria)
    • Intestinal causes of impaired absorption:
      • Blind loop syndrome
      • Ileal disease or resection
      • Fish tapeworm from eating uncooked fish
    • Pancreatic insufficiency (lack of vitamin B12 release from haptocorrin complex due to inadequate pancreatic enzyme activity)
  • Decreased intake of vitamin B12:
    • Malnutrition
    • Vegan diet (about 50% of vegans have B12 deficiency)
    • Vegetarian diet (about 7% have B12 deficiency)
  • Inherited causes of defective vitamin B12 absorption or metabolism

Which of the following would support the diagnosis of pernicious anemia?

a
Anti-parietal cells antibodies
b
Anti-intrinsic factor antibodies
c
Gastric biopsy showing atrophic gastritis

There are two antibodies associated with pernicious anemia, anti-intrinsic factor (IF) antibodies and anti-parietal cell antibodies:

ParameterAnti-IF antibodiesAnti-parietal cell antibodies
Antibody targetIntrinsic factorGastric enzyme H+/K+-ATPase on gastric parietal cells
Sensitivity40-60%80%-90%, especially during early stages of disease
Specificity98-99%About 80%

Only anti-intrinsic factor antibodies were ordered in this patient. They were positive:

The database, then, is consistent with a diagnosis of pernicious anemia, caused by atrophic gastritis, and leading to malabsorption of vitamin B12 and macrocytic anemia. Again, note that the primary lesion is in the stomach, not the bone marrow. The bone marrow (and neurological system) suffer collateral damage.

The sequence of events begins in the stomach and ends at the bone marrow. Atrophic gastritis is a gastrointestinal disorder whose clinical manifestations are hematological and (as we shall see shortly) neurological.