This article is written by MSc, Dr. Mai Vien Phuong - Department of Examination & Internal Medicine - Vinmec Central Park International General Hospital.
Megaloblastic anemia due to vitamin B12 (or folate) deficiency leads to defective red blood cell production and DNA synthesis, thus producing large red blood cells. In chronic autoimmune atrophic gastritis, autoantibodies against intrinsic factors and/or parietal cells lead to pernicious anemia (PA).
1. Consequences of vitamin B12 deficiency in chronic atrophic gastritis
Chronic atrophic gastritis leads to malabsorption of vitamin B12 from food due to reduced intrinsic factor production, resulting in megaloblastic anemia (a type of macrocytic anemia) and bile enzyme neuropathy. Folate deficiency can lead to a similar clinical picture.
The terms 'megaloblastic anemia' and 'macroloblastic anemia' should not be used interchangeably, as not all causes of macrocytosis are due to vitamin B12 deficiency. Still, all causes of megaloblastic anemia are due to B12 (or folate) deficiency. In contrast, the mechanism of iron deficiency anemia (iron deficiency anemia) in atrophic gastritis is less clearly understood but may be due to hyposecretion or H. pylori-associated atrophic gastritis. It is, therefore, important to exclude H. pylori-associated atrophic gastritis in any patient with iron deficiency anemia of unknown cause, as this condition is treatable.
2. Chronic autoimmune atrophic gastritis may be associated with other autoimmune diseases
Chronic autoimmune atrophic gastritis may occur as part of a polyglandular autoimmune syndrome and may be associated with other autoimmune diseases such as type I diabetes, vitiligo, and thyroid disease; therefore, these associated conditions should be considered in the evaluation of chronic atrophic gastritis.
In addition, other vitamin and micronutrient deficiencies (including vitamin D, calcium, and vitamin C) are known to occur in patients with chronic atrophic gastritis. However, their frequency and mechanism of onset are poorly understood.
>> See also: Vitamin D, C and calcium deficiency in patients with chronic atrophic gastritis – Posted by Master, Doctor Mai Vien Phuong - Department of Medical Examination & Internal Medicine - Vinmec International General Hospital Central Park
3. Vitamin and micronutrient deficiency due to vitamin B12 deficiency
The absorption of vitamin B12 in food depends mainly on the intrinsic factor glycoprotein produced by the gastric parietal cells. The vitamin B12 intrinsic factor complex is finally absorbed in the terminal ileum. In chronic atrophic gastritis, the lack of intrinsic factor production due to the destruction of parietal cells reduces the ability to absorb vitamin B12.
Megaloblastic anemia due to vitamin B12 (or folate) deficiency leads to defective red blood cell production and DNA synthesis, thus producing large red blood cells. In chronic autoimmune atrophic gastritis, autoantibodies against intrinsic factors and/or parietal cells lead to pernicious anemia (PA).
Testing for both antibodies significantly increases their diagnostic yield for the diagnosis of chronic autoimmune atrophic gastritis and pernicious anemia, getting a sensitivity of 73% and a specificity of 100% for pernicious anemia. Immune destruction of parietal cells leads to decreased production of intrinsic factors, resulting in pernicious anemia, which is particularly common in Western countries and older people. Other conditions causing megaloblastic anemia due to vitamin B12 deficiency need to be distinguished from chronic autoimmune atrophic gastritis causing pernicious anemia with intrinsic factor deficiency.
4. Consequences of vitamin B12 deficiency
Vitamin B12 deficiency affects two enzymes required by humans, methionine synthase (cytoplasmic) and methylmalonyl-CoA mutase (mitochondrial), and increases homocysteine and methylmalonic acid (MMA) levels, respectively. In cases of borderline vitamin B12 deficiency, elevations in homocysteine and MMA may confirm the diagnosis, especially when other compatible clinical or biochemical findings are present.
Interpret homocysteine and MMA levels with caution in renal failure and pregnancy, where falsely high levels may occur. Elevated plasma homocysteine is now recognized as an independent risk factor for cardiovascular disease and appears to play an important role in the development of dementia, diabetes, and kidney disease. Homocysteine also elevates when we have folate deficiency.
5. Signs of vitamin B12 deficiency
The clinical sequelae of vitamin B12 deficiency vary, ranging from asymptomatic to varying degrees of hematological and neurological dysfunction, which may or may not be reversible with supplementation. The classic neurological manifestations of a patient with pernicious anemia are sensory loss with gait abnormalities, demyelinating peripheral sensorimotor polyneuropathies, and paresthesias.
Cognitive changes may also be seen, including amnesia, apathy, depression, and eventually more severe cognitive impairment. In the most severe forms of vitamin B12 deficiency, complete myelopathy with subacute myelodegeneration and blindness due to optic atrophy may occur. Hematological manifestations are numerous, including megaloblastic anemia (due to impaired DNA synthesis and erythropoiesis) with thrombocytopenia despite a hyperplastic bone marrow. There appears to be a lack of awareness of chronic atrophic gastritis and its clinical consequences among physicians, often resulting in significant delays in diagnosis, which can result in the diagnosis of underlying vitamin B12 deficiency being overlooked for months. A recent study from Italy looking at 291 patients with chronic atrophic gastritis found an overall average diagnostic delay of 14 months, particularly among gastroenterologists.
6. Can proton pump inhibitors (PPIs) and H2 receptor antagonists lead to vitamin B12 deficiency?
There is a need for increased education and awareness of this and treating physicians to maintain a high index of suspicion. Whether acid-suppressing medications such as proton pump inhibitors (PPIs) and H2 receptor antagonists can lead to clinically significant vitamin B12 deficiency remains a matter of debate. It is unclear whether the effects of these medications on serum vitamin B12 are associated with an increased risk of functional or biochemical deficiency (as indicated by elevated blood homocysteine and MMA levels) or clinical deficiency (including megaloblastic anemia and neurological disorders).
A recent expert review and best practice advisory statement from the American Gastroenterological Association recommends that long-term PPI users should not routinely increase their vitamin B12 intake above the recommended daily allowance, nor should vitamin B12 levels be routinely checked or monitored.
The route of vitamin B12 replacement in deficient patients has also become a matter of controversy. Most patients with clinical vitamin B12 deficiency have malabsorption and require high-dose intramuscular (IM) or oral replacement. Those with chronic autoimmune atrophic gastritis causing pernicious anemia will require lifelong supplementation.
A recent Cochrane review by Wang et al. found that oral and intramuscular vitamin B12 supplementation had similar effects in normalizing serum vitamin B12 concentrations. Still, the cost of oral treatment was lower. However, the quality of evidence was low due to a lack of high-quality comparative studies.
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References
Gluckman CR, Metz DC. Gastric neuroendocrine tumors (Carcinoids). Current Gastroenterology Reports (2019) 21: 13.
2. Sato Y. Clinical features and management of type 1 gastric carcinoids. Clin J Gastroenterol (2014) 7: 381386.
Lahner E, Carabotti M, Annibale B. Atrophic gastritis: Clinical presentation, diagnosis and outcome. EMJ Gastroenterol. 2017; 6[1]: 75-82.
Banks M, Graham D, Jansen M, et al. British Society of Gastroenterology guidelines for the diagnosis and management of patients at risk of gastric adenocarcinoma. Gut. 2019 Sep; 68(9): 1545-1575.
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