Vu Ngo, D.C., MSACN, CCSP, CPT

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Introduction

Pernicious anemia [PA] is a prevalent disease that leads to a macrocytic anemia where there is a deficiency of red blood cells caused by a deficiency in intrinsic factor which leads to a treatable deficiency of Vitamin B12 (also known as Cobalamin) [ 1, 2, 3, 4]. Both PA and having long-standing cobalamin deficiency have similar pathophysiological mechanisms towards macrocytic anemia, but PA is distinctly different in that it is an autoimmune disease caused by antibodies against the oxyntic mucosa leading to the loss of parietal cells which produce hydrochloric acid and intrinsic factor [ 1]. A long-standing cobalamin deficiency, or hypovitaminosis B12, can have multiple etiological factors in addition to PA and includes an insufficient intake or malabsorption, hypochlorhydria, or antibodies against intrinsic factor or parietal cells [ 2, 3, 5]. The prevalence of pernicious anemia is high in populations older than 60 years old, and seen more frequently in women compared to men, but there may likely be an underdiagnosis of PA in other age groups as it is difficult to accurately identify due to a long delay between the initial deficiency and the onset of clinical symptoms [ 6, 7]. Treatment of pernicious anemia is highly effective and consists of early diagnosis and intervention by addressing the underlying cause of Vitamin B12 deficiency and the restoration of normal levels of Vitamin B12 [ 7]. In this paper, PA will be differentiated from cobalamin deficiency, and their pathophysiological mechanisms will be explained using current scholarly research.

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Background

PA is also known as Biermer’s disease or Addisonian anemia, and if untreated can lead to macrocytic anemia with low numbers of large red blood cells [ 1, 2, 3, 4]. This macrocytic anemia happens after prolonged cobalamin deficiency and PA is a common cause of cobalamin deficiency [ 8]. PA accounts for 20%-50% of those with cobalamin deficiency and is a health concern due to its prevalence, which is higher in women and the elderly [ 9]. True prevalence is difficult to determine due to a long delay from the deficiency to the onset of clinical symptoms, but once identified through clinically and with diagnostic lab testing, the treatment by supplementing cobalamin is highly effective with a good prognosis [ 6]. Signs of symptoms onset insidiously over 10-20 years and presents as fatigue and lethargy, and potentially more severe symptoms of the heart, brain, nerves, and gastrointestinal tract [ 3, 8].

Being of Northern European and African descent compared to other ethnic groups, as well as being of advanced age are factors that increase the risk of PA, although PA can also affect younger populations [ 3]. The difference in ethnicity may due to differences in genetics, and being older increases risk primarily due to decreased stomach acid and intrinsic factor [ 3].  Other factors that increase the risk of PA include a family history of PA, having another autoimmune disease that involves an endocrine gland such as Addison's disease, Type 1 Diabetes, Graves' disease, or vitiligo [ 3]. In addition to those risk factors specific for PA, there are other factors that increase the risk of long-standing cobalamin deficiency whose end-stage is also a macrocytic anemia, but would not be correctly called PA as it is reserved for an autoimmune condition impairing the secretion of intrinsic factor due to an antibody attack of oxyntic mucosa of the stomach leading to atrophic gastritis [ 1]. The factors that increase the risk of cobalamin deficiency include a gastric surgery that may alter or remove all or part of the stomach or terminal ileum, having altered gastrointestinal tissue or microbiome such as Crohn's disease, intestinal infections, and or bacterial overgrowth, nutrient depletion due to pharmacological agents such as antibiotics and certain seizure medicines or alcohol abuse, antacids such as H2 blockers or proton pump inhibitors, or insufficient dietary intake such as in vegetarians [ 3, 6].

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Pathophysiology

In PA, there are antibodies which act on the oxyntic mucosa of the fundus of the stomach which causes a loss of parietal cells which normally produce hydrochloric acid and intrinsic factor. These key elements produced by parietal cells are vital to the absorption process of cobalamin, as acid is required to release cobalamin from food before binding to haptocorrin which protects cobalamin from the acidic environment of the stomach until it reaches the small intestine where it binds to intrinsic factor to be carried to the terminal ileum [ 7]. Once in the terminal ileum, this complex breaks down and cobalamin is bound to transcobalamin and transported to the liver by cells after a receptor-mediated endocytosis puts it into circulation [ 7]. Cobalamin is highly sensitive to degradation by acid, and additionally only about 20% of cobalamin is bound to transcobalamin for transport and utilization at the terminal ileum, meaning that even under normal conditions there is limited absorption of dietary cobalamin [ 7].

Cobalamin is important in a number of processes, and its name is derived from its cobalt containing structure, and its active form of methyl-cobalamin is used as coenzymes in critical cellular metabolic pathways. The interruption of this process affects the hematopoiesis of the erythrocytes, can cause abnormal RBC apoptosis, as well as affecting the metabolism of branch chain amino acids and odd chain fatty acids [ 5, 7]. Hematopoiesis of erythrocytes is the process of red blood cells [RBC] being formed in the bone marrow, and the deficiency of cobalamin leads to the development of abnormally large RBC’s which makes it difficult for these cells to leave the cancellous bone where bone marrow is located, as well as affecting DNA synthesis which leads to abnormal DNA synthesis or apoptosis, all leading to the decreased RBC’s [ 3, 7].

With the limited absorption of cobalamin even under normal conditions as described above, a dietary deficiency can reduce the total cobalamin available. Decreased gastric acidity, or hypochlorhydria, from taking antacids or from the normal aging stomach can also reduce the available cobalamin as the gastric acid is necessary for the release of cobalamin from food. There may also be or antibodies against intrinsic factor or parietal cells which can produce the same results of decreased availability and transport of cobalamin in the terminal ileum. Another potential cause of cobalamin deficiency is abnormal bacterial overgrowth in the small intestine, leading to the bacterial utilization of cobalamin within the small intestine and decreasing the amount of cobalamin available at the terminal ileum [ 2, 3, 4, 5].

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Treatment

To provide the best prognosis in the treatment of PA, an early diagnosis with thorough clinical evaluation and pertinent laboratory testing should be obtained in order to determine the specific etiological cause, and once the causes and risk factors are identified, a treatment plan can be determined in order to intervene and address the cobalamin deficiency as early as possible [ 7]. Having an autoimmune gastritis like PA increases the risk of gastric carcinoid tumors or adenocarcinomas, and provides strong grounds for the early identification and intervention [ 8]. Diagnostic testing in addition to clinical examination can include lab testing specific biomarkers to identify the potential causative source. Atrophic gastritis can be diagnosed following positive lab findings for antibodies against parietal cells or intrinsic factor, and low pepsinogen levels can be caused by loss of zymogenic cells found in chronic atrophic gastritis [ 6].

There is currently no cure for PA, but the disease is effectively managed with parenteral or oral supplementation of cobalamin. The current treatment of PA involves parenteral injection of cobalamin, and as long as there are no permanent changes to tissues such as cancer, the symptoms of PA can be gradually reduced and resolved without complications by increasing serum levels of cobalamin. By introducing cobalamin parenterally, the steps by which the body would normally take to absorb cobalamin as described would be avoided, and there would be a higher percentage of cobalamin put into hematologic circulation. The latest research in the treatment of PA is in determining the efficacy of taking oral supplementation of cobalamin instead of having intramuscular injection. The results provide good outcomes with elevated serum cobalamin levels with high dose oral cobalamin intake, but the research is still in its early phases and needs further testing [ 7]. For individuals with PA or other autoimmune disease or those with permanently altered tissue structure, it is likely necessary to take lifelong oral supplements or intramuscular injection [ 3, 10]. For those individuals without an autoimmune or permanently altered tissue affecting cobalamin absorption, immediate intervention to restore cobalamin levels via oral supplements or intramuscular injection can be followed by addressing the other causes of cobalamin deficiency such as increasing dietary intake, reducing or seeking alternatives to antacid medications, or restoring gastrointestinal microbiome.

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Conclusion

While the current research and understanding of PA is understood enough that it should not be a public health concern, it is still prevalent due to difficulties in early diagnosis and intervention. Laboratory evaluation combined with thorough clinical examination provides a reliable means of identification, but it is important that professionals maintain PA as part of their list of differential diagnoses. Although early diagnosis is a challenge, current treatment options using oral supplements or intramuscular injections are easily administered with a good prognosis [ 2, 7]. In addition to normalization of serum cobalamin levels, patients that receive intervention can see improved neurological symptoms such as paresthesia, ataxia, cognitive dysfunctions, and neuropathy [ 7]. Strategies for improving these clinical outcomes aims for improving the early detection and early intervention of cobalamin deficiency. While there is currently no cure for the autoimmune disease affecting the oxyntic mucosa, there is ongoing research in the treatment of autoimmune disease. While this research continues to develop, patients with PA can live normal healthy lives with oral or parenteral cobalamin.