Pernicious Anemia

The clinical picture of pernicious anemia is indistinguishable from megaloblastic anemia of vitamin B12 deficiency resulting from any etiology.

Symptoms

The onset of symptoms is insidious. The predominant symptoms include the following.

• Features of anemia: Pallor, weakness, tachycardia and dyspnea are present in all the patients suffering from pernicious anemia.
• Jaundice: There is mild jaundice caused by the excessive breakdown of hemoglobin due to ineffective erythropoiesis in the bone marrow.
• Mucosal changes: Angular stomatitis may be present at angle of the mouth. Red, sore tongue (glossitis) may also be present.
• Polyneuropathy: There may be symmetric loss of sensations in the fingers and toes. Later on, there is difficulty in balance due to loss of sense of vibration and proprioception. In advanced stages, abnormalities of cerebral function also develop that cause progressive weakness and ataxia.

Signs

The signs indicative of pernicious anemia include the following.

• Signs of anemia are present upon the physical examination of the hands and eyes.
• Jaundice is seen in the skin and the sclera.
• Spleenomegaly may be present.
• There may be low grade fever due to infection or anemia itself.
• Signs of polyneuropathy are seen upon the examination of the nervous system.
• Purpurae may be present due to thrombocytopenia.

The following investigations are helpful in establishing the diagnosis of pernicious anemia.

• Blood picture: Blood tests demonstrate low hemoglobin levels. The mean corpuscular volume is usually raised to around 110 to 140 fl. However, it may be normal if there is coexisting thalassemia or iron deficiency. Peripheral blood film shows anisocytosis and poikilocytosis. Neutrophils are characteristically hypersegmented with multilobed nuclei. The reticulocyte count is also reduced.
• Bone marrow biopsy: The abnormalities seen in bone marrow include large cell size, giant metamyelocytes and marked erythroid hyperplasia [4].
• Serum vitamin B12: Serum vitamin B12 is usually below 100 pg/ml in symptomatic disease. The normal vitamin B12 level is 150 to 350 pg/ml.
• Serum lactate dehydrogenase (LDH) and unconjugated bilirubin: The levels of lactate dehydrogenase and unconjugated bilirubin in the serum is also raised [5] [6].
• Schilling test: This is also known as vitamin B12 absorption test. It is the traditional test to detect decreased oral absorption of vitamin B12 that is characteristic of pernicious anemia. Addition of intrinsic factor causes an increased absorption of vitamin B12 in the patients suffering from pernicious anemia [7] [8].
• Anti-intrinsic factor antibodies: Antibodies against intrinsic factor are present in around 50% of the cases.

Therapy for pernicious anemia

Parenteral vitamin B12 therapy: Pernicious anemia is treated by the parenteral administration of vitamin B12 [9]. The parenteral forms of vitamin B12 are cyanocobalamin and hydroxocobalamin. 1000 micrograms of vitamin B12 are injected daily for first week, weekly for first month and then monthly for life. Clinical improvement may occur in as less as 48 hours.

Supportive measures for anemia

Blood transfusion: If the levels of hemoglobin are very low (below 4 g/dl), blood should be transfused in the form of packed cells and furosemide should also be given.

Iron: Ferrous sulphate should be given after treatment with vitamin B12 is started. This is done because in some patients, rapid restoration of blood volume can deplete the iron stores of the body.

With early diagnosis and proper treatment, the prognosis of the patients suffering from pernicious anemia is excellent. However, if the treatment is delayed, anemia and later neurological complications may develop; the latter may be permanent.
There may be an association between pernicious anemia and gastric cancer but it has not yet been proved.

Pernicious anemia is caused by the deficiency of intrinsic factor that is produced by the gastric parietal cells. In adults, it usually results from gastrectomy or the autoimmune destruction of parietal cells. Congenital deficiency of intrinsic factor without gastric atrophy may also cause pernicious anemia but is very rare.

Pernicious anemia is the most common cause of vitamin B12 deficiency. It usually affects people in the late adulthood at the age of 45 to 60 years [1]. The incidence in northern Europe is 1 in 10,000 cases. It is estimated that 0.1% of the general population is affected worldwide. The female to male ratio is 1.6:1 in Europe but equal in the US. It is associated with other autoimmune diseases including thyroid diseases, Addison's disease and vitiligo.

For the proliferation of hematopoietic tissue, DNA is required in large amounts. Since vitamin B12 is necessary for the formation of DNA, its deficiency leads to reduced synthesis of DNA. As a result, there is a delay or arrest of the cell division in the bone marrow. The division of cells is sluggish but cytoplasmic development progresses normally. Large megaloblasts are formed which tend to be destroyed by the bone marrow causing ineffective erythropoiesis.

The absorption of vitamin B12 from the lower ileum is facilitated by gastric intrinsic factor which is released by the parietal cells of the gastric mucosa. Intrinsic factor binds with vitamin B12 and forms a complex that is taken up by the binding sites on the ileal cells. Vitamin B12 is transferred into the cells and absorbed into the blood bound with a carrier protein. In the absence of gastric intrinsic factor, vitamin B12 can not be absorbed and pernicious anemia ultimately develops when the stores of vitamin B12 in the liver are exhausted [2] [3].

Primary (congenital) pernicious anemia can not be detected. However, pernicious anemia resulting from secondary causes such as gastrectomy can be prevented by initiating parenteral vitamin B12 substitution soon after the surgery is completed [10].

Pernicious anemia is the megaloblastic anemia that results from vitamin B12 deficiency as a result of the failure of secretion of intrinsic factor from the gastric parietal cells. It accounts for 30-50% of all cases of megaloblastic anemia due to vitamin deficiency.

Pernicious anemia is caused because of the deficiency of vitamin B12 due to poor absorption from the intestine. Normal blood cells can not form in the absence of vitamin B12. Vitamin B12 is administered by injections for life in all the patients suffering from pernicious anemia. The outcome of this treatment is excellent.

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