Biochemistry Selective Paper
Angel Lee
November 2, 1999
Anemia is a broad term for a group of diseases that are characterized by a decrease in hematocrit or hemglobin concentration among their many effects on the human body. This can be a result of decreased production or increased destruction of red blood cells. Defects of stem cell proliferation, cell differentiation, DNA Synthesis, hemoglobin synthesis, or any combination would cause, among their effects, the levels of red blood cell production to be lower. Associated enzyme deficiencies, abnormally shaped hemoglobin and immune system activities will also lead to excessive destruction of red blood cells.
The disease Pernicious Anemia (PA), also known as Megaloblastic Anemia, is one form with these associated systemic effects. This disease is a result of impaired absorption of Vitamin B12, or Cobalamin, due to a deficiency of Intrinsic Factor and Hydrochloric Acid in gastric secretions. Generally, the disease manifests in two forms, a rare congenital form and an adult onset acquired form.
The disease is more prevalent in people of Scandinavian, English and Irish ancestry. In these high-risk groups, 0.13 &emdash; 0.20% of the population has established the disease. It is less common in Caucasians of Italian or Greek decent and rare in Blacks and Asians. In addition, it seems to be more predominant in females. Age is a major factor in the acquired cases. The disease effects the 40 &emdash; 70 year old age group, with the average onset of 60.5 years. Since the body can store up to a three-year supply of Vitamin B12, clinical onset is gradual and delayed. Contributing factors to the disease include a vegetarian diet, thyroid disease, stomach surgery or disease, eating disorder, diabetes mellitus, family history and genetic factors.
Vitamin B12 is a corrinoid, which resembles the heme of hemoglobin, however uses cobalt instead of iron. It functions as a coenzyme for only two reactions in the human body, methionine synthase and L-methylmalonyl CoA mutase. Methionine synthase is involved in the synthesis of the amino acid methionine from homocysteine. Therefore methionine can not be regenerated and levels decrease. L-methylmalonyl CoA mutase is involved in the conversion of methylmalonyl coenzyme A to succinyl CoA. The end results of the Vitamin B12 deficiency includes slow and restricted DNA synthesis
Intrinsic Factor (IF), formerly known as Castle’s Intrinsic Factor, is an alkaline stable glycoprotein secreted by the stomach’s membrane lining. Intrinsic Factor has a two fold function, to protect the Vitamin B12 from destruction in the gastrointestinal tract and to bind to the receptor sites, facilitating vitamin B12 absorption in the intestinal mucosa. The cause of the deficiency is unknown; however, it seems to be a genetic deficiency or autoimmune disorder.
Congenital Pernicious Anemia is an autosomal recessive trait as indicated by early onset and frequency of effected siblings. The congenital form presents before age 2, with significantly decreased levels of Intrinsic Factor, but normal levels of gastric secretions. Congenital PA does not present with antibodies. In comparison, the acquired is an adult onset disease with decreased Intrinsic Factor and other gastric secretions. The total amount of gastric secretion is significantly lower in patients with Pernicious Anemia.
Although there is not a genetic link between congenital and adult onset, genetic factors play a role in adult onset, as demonstrated by multiple occurrences among families. While the absolute cause is unknown, there are two major hypothesis, that it is a defect in immunological tolerance to a particular antigen found in the stomach, thyroid gland, pancreas, and skin; and that it is a defect in a metabolic system common to these tissues. The disease has also been found in patients that have deletions in chromosome 18. These are associated with selective IgA deficiencies.
For unknown reasons, the body initiates humoral and cell mediated immunity on itself. The body begins to manufacture high levels of antibodies specific for parietal cells and intrinsic factor, see Figure 1. The parietal cell antibody uses the beta unit of the ATPase proton pump as the auto antigen. Intrinsic factor antibodies act by blocking the combination with B12 by combining with the intrinsic factor at various receptor cites. In addition, cell mediated immunity is evident by the decrease in suppressor T cell and increases in the ratio of helper to suppressor cells.
Clinically, this disease presents with the following signs and symptoms:
- Sore, smooth appearance of tongue, difficulty swallowing, bleeding gums
- Nausea, epigastric pain, loss of appetite, weight loss
- General Weakness, Shortness of breath, Jaundice
- Numbness and tingling in hands and feet, difficulties maintaining balance
- Headache, poor memory, depression, confusion, and dementia
- Macro-ovalcytes, hypersegmented, polymorphonuclear leukocytes
The disease results in a variety of symptoms, seeming unrelated. However, upon further examination the symptoms can be fully associated. The smooth tongue, and other gastrointestinal manifestations, are a result of the effect on cell multiplication and the ability to renew epithelium. As a result of the Vitamin B12 deficiency, the synthesis of DNA is impaired. However, the synthesis of RNA remains normal. DNA synthesis utilizes two enzymes that require N,5,N10-methylene tetrahydrofolate as a methyl donor, and are therefore effected by the Vitamin B12 deficiency. In addition, the deficiency delays the DNA replication phase, thus cell replication and division. The effect is more pronounced on the tissues of bone marrow and buccal and gastric mucosa, which explains symptoms such as Macro-ovalcytes and the smooth tongue surface.
Methionine functions in three major pathways, protein structure, methyl transfers as S-adenosyl methionine or SAM, and glucogenesis. Myelin is lost, due to the inability to regenerate, on the spinal cord and peripheral nerves. The lack of methionine is manifested by the numbness and tingling in the hands and feet, and other neurological effects. If treated before the death of the neuron, then the neurological effects are reversible.
Diagnostic procedures include blood tests, Schilling’s test, and analysis of bone marrow. Blood smears should show the presence of macro-ovalcytes. In the Schilling’s test, an unlabeled dose of Vitamin B12 is injected intramuscularly to saturate the binding sites. Then, an oral dose of radioactive Vitamin B12 is given without intrinsic factor, followed by a dose with intrinsic factor. Subsequently, the amount of radioactive Vitamin B12 present in the urine and plasma is measured. An improvement with the dose of Vitamin B12 with intrinsic factor is indicative of Pernicious Anemia. This test is conducted after the Vitamin B12 deficiency is corrected. A more specific test is an assay for anti-intrinisic factor antibodies.
Through treatment of this disease, the majority of the symptoms can be completely reversed. However, if treatment is delayed, neuron death will occur, and the neurological effects will be irreversible. Treatment of this disease includes Vitamin B12 therapy. An administration route that the body can absorb must be used to supply the therapy. Generally, the therapy is administered by parenteral injections on a daily to a monthly basis. The amount varies depending on the patient, but it must be high enough to correct the deficiency and build an ample storage, in addition to allowing for normal excretion. Careful attention must be paid to the effects of treatment, with a focus on confirming the diagnosis and discovering associated deficiencies. A folate deficiency often accompanies this disease. Patients must learn how to administer home injections of Vitamin B12 because this treatment is lifelong.
In conclusion, Pernicious Anemia is a common disease among the aging. This disease is a result of impaired absorption of Vitamin B12 due to a deficiency of Intrinsic Factor and/or gastric secretions. The cause of the deficiency is unknown; however, it seems to be a genetic deficiency or autoimmune disorder. The disease effects multiple systems of the human body, but if recognized and treated early, all effects are completely reversible. Although the treatment is continuous for the life of the patient, it is a relatively simple and convenient.
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