· Pernicious anemia (PA) is the most common cause of vitamin B12 deficiency. B12 deficiency actually has many causes however PA applies only to the condition associated with chronic atrophic gastritis.
· PA was first described by Addison in 1849 and associated with the stomach by Austin Flint in 1860. PA was later successfully treated with cooked liver and subsequent theories on the pathogenesis of PA involved the loss of an extrinsic factor from the liver and an intrinsic factor (IF) from the stomach.
· A recent population survey found that approximately 2% of persons over 60 years of age have undiagnosed PA. The disease was previously thought to occur only in those of Northern European extraction, however subsequent studies have noted PA to occur in Hispanic and African-American patients.
· Gross pathology – The stomach has
three regions: the fundus and the body, which contain acid secreting parietal
cells and pepsinogen secreting zymogen cells, and the antrum which contain
gastrin secreting G-cells. Chronic atrophic gastritis is recognized grossly
by the loss of gastric mucosal folds and thinning of the gastric mucosa.
There are two types based on whether the lesion affects the antrum.
|Type A (autoimmune) Chronic Gastritis||Type B (nonautoimmune) Chronic Gastritis|
|Affects fundus and body, spares antrum||Affects antrum as well as fundus and body|
|Associated with PA, antibodies vs. IF, parietal cells||No autoimmunity, H. pylori infection common|
|Hypergastrinemia 2° G-cell hyperplasia and low serum pepsinogen-I||Hypogastrinemia 2° G-cell destruction with antral gastritis|
|Achlorohydria, gastric carcinoids|
· Histopathology – Gastric biopsy specimens from patients with early PA demonstrate a mononuclear cellular infiltrate in the submucosa extending into the lamina propria between the gastric glands; the infiltrate consists of plasma cells containing autoantibodies to parietal cells and intrinsic factor. Extension of the cellular infiltrate into the mucosa is accompanied by degenerative changes in parietal and zymogenic cells. In the fully established lesion, there is marked reduction in the number of gastric glands and the parietal and zymogenic cells disappear and replaced with mucus containing cells which resemble intestinal cells (intestinal metaplasia).
· Natural History – The progression of Type A chronic atrophic gastritis to gastric atrophy and anemia is estimated to be 20-30 years. The presence of parietal cell antibodies is predictive of the presence of autoimmune gastritis, being found in 90% of patients with PA (50% of those with gastric atrophy without PA); anti-intrinsic factor antibodies are found in 60% of PA patients; N.B.: antiparietal cell antibodies are found in 10-15% of the general population whereas anti-IF antibodies are typically seen only in those with PA.
· Immunopathogenesis – The pathologic process of type A gastritis appears directed against the gastric parietal cell. The pathology is restricted to the parietal cell containing gastric fundus and body, parietal cells are lost, and autoantibodies against parietal cells and their product, IF, are present in the serum and gastric juice. It was recently determined that antigen for the anti-parietal antibodies is the gastric H+/K+-ATPase. Although these antibodies fix complement and lyse parietal cells in vitro, it is unlikely that they are pathogenic in vivo as the H+/K+-ATPase is not accessible to circulating antibodies. Murine studies suggest that the lesion of autoimmune gastritis is initiated by CD4 cells that recognize the b subunit of gastric H+/K+-ATPase. However the mechanism of activation of the CD4 cells is not known, nor is the pathway by which these cells produce chronic gastritis.
· Genetics – A genetic predisposition to PA is suggested by the clustering of the disease and of gastric antibodies in families and the autoimmune endocrinopathies. About 20% of relatives of patients with PA have PA themselves. However there is no evidence of an association of PA with certain HLA molecules.
· Associated diseases – PA may be associated with many other autoimmune endocrinopathies, including Hashimoto’s thyroiditis, IDDM, Addison’s disease, 1° gonadal failure, 1° hypoparathyroidism, Graves’ disease, vitiligo, myasthenia gravis, and the Eaton-Lambert syndrome.
Vitamin B12 absorption, malabsorption, and metabolism
· B12 is a complex molecule that cannot be synthesized in the human body and must be supplied in the diet (MDR=2.5m g) from meat and dairy foods primarily. During gastric digestion B12 is released from food and complexes with gastric R binder; in the duodenum the B12-R binder complex is digested and the B12 then binds to intrinsic factor (IF). The B12-IF complex then travels to the distal ileum where specific receptors bind and absorb the complex. In the mucosal cell the IF is degraded and the B12 associates with another transport protein, transcobalamin II (TC II) which is secreted into the circulation where it is rapidly taken up by the liver, bone marrow, and other cells.
· B12 malabsorption in PA is due to lack of IF due to loss of gastric parietal cell as well blocking antibodies present in the gastric that can bind and block the B12 binding site on IF.
· Normally 2mg of B12 is stored in the liver and 2mg elsewhere in the body, \ in view of the MDR it would take 3-6 years to become B12 deficient if absorption were to cease.
· B12 is metabolically active in 2 forms – methylcobalamin which is an essential cofactor in the conversion of homocysteine to methionine and adenosylcobalamin which is required for the conversion on methylmalonyl CoA to succinyl CoA. Therefore with B12 deficiency one would expect to see elevated serum levels of homocysteine and methylmalonic acid.
· Anemia with symptoms that include fatigue, weakness, light-headedness, vertigo, tinnitus, palpitations, angina, CHF symptoms, decreased exercise capacity with pallor, slight icterus, tachycardia, and systolic flow murmur on exam.
· GI complications of B12 deficiency include atrophic glossitis with a smooth beefy red tongue and megaloblastosis of the small bowel with diarrhea and malabsorption. In the stomach intestinal metaplasia is a risk factor for adenocarcinoma – population based studies demonstrated that the risk of gastric adenocarcinoma was increased three times and the risk of gastric carcinoid (felt to be due to the trophic effects of gastrin) was increased 13 times in patients with PA and one study recommended endoscopic surveillance of patients with PA.
· Neurologic complications include peripheral neuropathy, most frequently seen as numbness and paresthesias, lesions of the dorsal columns (with loss of vibration and position sense and ataxia) and lateral columns (with limb weakness, spasticity, and extensor plantar reflexes) of the spinal cord (subacute combined degeneration) and cerebrum (with changes ranging from mild personality defects and memory loss to frank psychosis (megaloblastic madness)). These lesions begin as demyelination and progress to axonal degeneration and eventually neuronal death; these complications may not be reversed by treatment.
· The finding of macrocytosis suggests the presence of a megaloblastic anemia; an MCV <95fL implies a less than 0.1% chance of B12 (or folate) deficiency; an MCV of 100-110fL is most likely due to EtOH, stem cell disorders, liver disease, or the use of antineoplastics; as the MCV rises so does the chance of B12 or folate deficiency (MCV>130fL is associated with B12 or folate deficiency in nearly 100%).
· The peripheral blood smear may also show hypersegmented neutrophils (about 91%sensitive, defined as the presence of at least PMN with 6 lobes, the presence of ³ 5% of 5-lobe PMNs, or an increased PMN lobe average (normally <3.4lobes/PMN), RBCs, in addition to macrocytosis, demonstrate anisocytosis and poikilocytosis, decreased reticulocyte count as well as possible leukopenia and thrombocytopenia.
· Megaloblastic anemias are characterized by ineffective erythropoiesis with enhanced intramedullary destruction of erythroblasts as evidenced an increase in indirect bilirubin and LD1.
· Once a megaloblastic anemia has been identified, one should then determine whether a specific vitamin deficiency is responsible by measuring serum cobalamin (Cbl) and folate levels. However there has been some recent controversy regarding Cbl levels, with some feeling that the true lower limit of normal for B12 should be 300pg/mL (and not 193 as at UNCH).
· There are several other tests for diagnosing Cbl deficiency and PA. These include serum methylmalonic acid (MMA) and homocysteine (Hcy) levels, both of which should be elevated in B12 deficiency whereas only Hcy should be increased in folate deficiency; a recent study found that elevations of both MMA and Hcy had a 98% sensitivity for B12 deficiency. Additional tests include serum transcobalamin II, which delivers B12 to cells and whose concentration falls before that of B12, the deoxyuridine suppression test (dUST) which measures thymidine incorporation into DNA by marrow cells and their response on addition of Cbl and folate (not widely used due to need for bone marrow biopsy), MMA 24 hour urinary excretion, IF and parietal cell antibodies, type A chronic atrophic gastritis on gastric biopsy, achlorohydria (very sensitive as PA is the only gastric lesion that results in total achlorohydria); One may also obtain serum gastrin and pepsinogen levels, which are increased and decreased respectively.
· Once B12 deficiency has been established, its pathogenesis can be established by means of a Schilling test. The classic test is conducted by first giving the patient 1000 m g of cold B12 intramuscularly then giving 1 m g of 57Co-cyanocobalamin orally; a 24 hour urine is then obtained with normal subjects excreting more than 8% of the oral dose; subsequent steps entail the administration of the labeled B12 with IF (which should normalize the urinary excretion in PA patients), pancreatic extract for patients with suspected pancreatic insufficiency, and following antibiotic administration for those with suspected bacterial overgrowth. In patients with suspected PA usually only steps one and two are performed.
· As the defect of PA is one of malabsorption parenteral (IM) therapy is recommended; one possible regimen is to give 100 m g every day for a week. The frequency may then be decreased but the goal should be to give 2000 m g over the first six weeks. The patient may then be placed on maintenance therapy indefinitely.
· Response to therapy is rapid. Marrow morphology begins to revert to normal within hours, reticulocytosis is noted at about 3-5 days. Hypokalemia and salt retention may occur early after initiating treatment. The patient’s symptoms usually begin to improve within days, however as noted above the neurologic manifestations may not ameliorate.
Classification of the Megaloblastic Anemias
References: 1) NEJM 1997; 337:1441-8. 2) Br. J. Haematol 1997; 97: 695-700. 3) Am. J. Med. 1994; 96: 239-46. 4) Acta Haematol 1989; 81: 186-91. 5) Harrison’s, 14th Ed. 6) Cecil’s, 19th Ed
- Refractory megaloblastic anemia
- Di Guglielmo’s syndrome
- Congenital dyserythropoietic syndrome