Pernicious anemia is the most common type of megaloblastic anemia. It is a chronic condition caused by a malabsorption of vitamin B12, necessary for the production of DNA and the normal development of red blood cells. Vitamin B12 and a glycoprotein called intrinsic factor (IF), combine to form the erythrocyte maturation factor, which is required for maturation of red cells in the marrow.
Although absolutely vital to life, vitamin B12 is required in only minute amounts. The complex chemical structure of vitamin B12 includes a cobalt atom, whose position is analogous to that of the iron atom in heme. It also has a nucleotide component but does not link up in chains like DNA; and, despite its heme-like component, it has nothing to do with oxygen transport.
A lack of B12 changes the blood in the same way as a deficiency of folate, affecting both erythrocyte and leukocyte precursors in the bone marrow. The platelet precursors are usually less affected. The number and size of all developing erythroid cells increase, and enormous leukocytes with large and unusual shaped nuclei are found. Hematopoietic alterations vary, depending on the degree of cobalamin (B12) deficiency and metabolic causes leading to the anemia.
Intrinsic factor is a substance normally secreted by the parietal cells of the stomach lining and is essential for vitamin B12 absorption. It cannot be supplemented but must be made within the body. For some, this production is reduced by abdominal surgery, aging or other factors.
Normally, vitamin B12, obtained from dietary sources, combines with IF in the stomach and is carried to the ileum, where it is absorbed and transported by a carrier protein to the tissues of the body. However, a decreased gastric production of hydrochloric acid and a deficiency of IF, means that no matter how much B12 is eaten, it cannot be absorbed by the digestive tract and anemia occurs. This is a very serious condition since atrophy of gastric parietal cells and achlorhydria (absence of hydrochloric acid in the gastric juices) can also indicate stomach cancer or pellagra, as well as pernicious anemia.
If B12 levels fall too far, the result is lagging energy, depression, indigestion, diarrhea, and ultimately, anemia. An ongoing deficiency may also lead to neurological damage, and gastric and intestinal abnormalities; and, if left untreated, pernicious anemia may lead to permanent neurologic disability and death.
In fact, the term “pernicious” means highly injurious or destructive, verifying that this condition was once a fatal condition. Although malabsorption is the main cause, other factors may also be involved, including poor dietary habits, gastrointestinal infection, Crohn’s disease, gastric surgery, and sometimes uninformed vegetarianism.
Pernicious anemia is most common in late adult life. It is rare in individuals younger than 30, except in the congenital type that usually occurs before the age of two. The condition is most often seen among persons of northern European ancestry, particularly Scandinavian, English, and Irish peoples.
In Great Britain and Scandinavia, women are more commonly affected than men; but, in the USA, both sexes appear to be equally affected. However, it does seem to be more common in New England and the Great Lakes regions, likely because of ethnic concentrations. However, it is rare in children, blacks, and Asians.
Although a genetic predisposition is probable, the late age of onset of certain precipitating environmental agents are thought to interact with the genetic defect. Evidence suggests that the congenital type of pernicious anemia is caused by an autosomal recessive trait. Because the risk of developing pernicious anemia is greatest in individuals whose family members have had the disorder, some inherited mechanism is assumed and siblings of affected persons are at the highest risk.
Typical onset occurs between the ages of 50 and 60, with incidences rising with increasing age. Familial incidence suggests a genetic predisposition. Significantly higher incidence occurs in patients with such immunologically related diseases as thyroiditis, myxedema, and Graves’ disease.
This seems to support a widely held theory that an inherited autoimmune response causes gastric mucosal atrophy and,therefore, a deficiency of hydrochloric acid and IF. This, in turn, impairs vitamin B12 absorption. The resulting impairment inhibits overall cell growth, particularly red blood cells, leading to insufficient and deformed red blood cells with poor oxygen-carrying capacities. It also impairs myelin formation, causing neurologic damage.
One theory as to why such a condition is more prone to develop in later years is that long years of poor eating habits have changed the digestive tract to such an extent that any number of malabsorptive disorders may appear, including autoimmune types, as well as deficiency anemias. But, scientists loathe the idea of exploring any area that might be diet-related.
Autoantibodies against parietal cells, IF, and thyroid tissues have been found in the serum of individuals with pernicious anemia. It is known that chronic gastritis destroys glandular structures and diminishes gastric secretion of IF, hydrochloric acid, and pepsin. Impaired vitamin B12 absorption does seem to parallel the progress of gastric atrophy.
Poor absorption of B12 may also be caused by such conditions as Crohn’s disease, an inflammatory condition of the intestines. Sometimes a parasite is involved, for example, the tapeworm Diphyllobothrium latum, common in Finland. The tapeworm absorbs almost all of the B12, leaving none for the human host. The worm is acquired in fish, and about 2% of the Finnish population carry it.
Although many references point to the fact that vegetarians are at a greater risk of pernicious anemia, meat eaters may be in more danger. Digesting meat can take up to five days to complete, which causes putrification because of the delay. During this time, more meat has been consumed; and harmful bacteria begin to proliferate, crowding out the “friendly” bacteria needed for the formation and absorption of nutrients, including B12. Even when enough B12 is consumed, this type of environment cannot provide for it to reach its intended destination.
Pernicious anemia develops slowly; and, by the time it is diagnosed, it is severe. Vague early symptoms are often ignored – including infections, mood swings, and gastrointestinal, cardiac, or kidney ailments, and attributed to other causes.
When hemoglobin has decreased significantly (7 to 8 g/dl), the individual experiences the classic symptoms of anemia: weakness, fatigue, paresthesias (abnormal sensations) of feet and fingers, sore tongue, loss of appetite, abdominal pain, weight loss, and diffuculty walking. Untreated pernicious anemia is usually fatal, mainly because of heart failure.
Death occurs after a course of remissions and exacerbations lasting from one to three years. However, since the advent of B12 replacement therapy in 1926, mortality has decreased significantly.
Typical systemic symptoms include the following:
GI (gastrointestinal): It is gastric mucosal atrophy and decreased hydrochloric acid production that disturbs digestion and leads to nausea, vomiting, anorexia, weight loss, flatulence, diarrhea, and constipation. Bleeding of the gums and tongue inflammation will hinder eating and intensify anorexia.
CNS (central nervous system): Demyelation caused by a B12 deficiency initially affects the peripheral nerves, but gradually extends to the spinal cord. Consequently, the neurologic effects may include neuritis, weakness in the extremities, peripheral numbness and paresthesias (an abnormal sensation like tingling or burning), disturbed sense of position, lack of coordination and muscle coordination (ataxia), impaired fine finger movement, positive Babinski’s and Romberg’s signs, light-headedness, altered vision (diplopia, blurred vision), altered taste and hearing (tinnitus), optic muscle atrophy, loss of bowel and bladder control, and impotence in males. In addition, effects on the nervous system also produce irritability, poor memory, headache, depression, and delirium. Although some of these symptoms are temporary, irreversible CNS changes may have occurred before treatment.
Cardiovascular: Increasingly fragile cell membranes induce widespread destruction of RBCs, resulting in low hemoglobin levels. The impaired oxygen-carrying capacity of the blood secondary to lowered hemoglobin leads to weakness, fatigue, and light-headedness. Compensatory increased cardiac output results in palpitations, wide pulse pressure, dyspnea, orthopnea, tachycardia, premature beats, and eventually, congestive heart failure.
Diagnosis is reached through patient history, typical ethnic heritage, results of blood analysis, bone marrow aspiration, gastric analysis, and/or a Schilling test. Laboratory screening must rule out such other anemias with similar symptoms as folic acid deficiency anemia. Diagnosis must also rule out vitamin B12 deficiency from other malabsorption causes, including gastrointestinal disorders, gastric surgery, radiation, or drug therapy.
Treatment should involve early intervention. Vitamin B12 replacement can reverse pernicious anemia, minimize complications, and possibly prevent permanent neurologic damage. Conventional treatment usually involves an initial dose of parenteral vitamin B12 which causes rapid RBC regeneration. Within a few weeks, hemoglobin should rise to normal and the patient’s condition should markedly improve. Since rapid cell regeneration increases the patient’s iron and folate requirements, supplemental iron and folic acid replacement is necessary to prevent iron deficiency anemia. Oral preparations are poorly absorbed, but sublingual preparations (under the tongue), which bypass the digestive system, are proving to be just as effective as the injections.
After the patient’s condition improves, vitamin B12 dosage can be decreased to maintenance levels and given monthly. Since these injections are likely to continue for life, patients should learn self-administration. If anemia causes extreme fatigue, bed rest is advocated until hemoglobin rises.
If hemoglobin is dangerously low, the patient may require blood transfusions if the patient shows signs of circulatory collapse, heart failure, or severe angina pectoris.
Most important though, is the replacement of vitamin B12 to prevent all these conditions from taking place. Since pernicious anemia cannot be cured, all therapies must continue for the rest of the individual’s life.
One good website provides scientific references for finding alternatives to the monthly B12 injections.