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Idiopathic anemia (Addison's D, Biermer), is a disease characterized by gastric parietal cell atrophy. This defect causes decreased secretion of IF and other gastric juices. The lack of IF leads to defective vitamin B12 absorption and consequently megaloblastic anemia.

Pernicious anemia is more common in people after age 50. In blacks, the disease may start earlier, with a mean of 53 years. Pernicious anemia is rare in children, and if it occurs, it may be in the congenital form. Congenital pernicious anemia is characterized by the total absence of IF and normal secretion of other gastric juices.

Pathophysiology

The main cause of pernicious anemia is atrophic gastritis characterized by atrophy of the gastric mucosa with decrease of gastric secretions and IF.

The cause of gastric atrophy however is not clearly known. It is postulated that genetic, immunologic, and environmental factors all play a role. IF is essential for absorption of vitamin B12. In absence of IF, only a small amount of vitamin B12 is absorbed.

The congenital form of pernicious anemias is inherited as an autosomal recessive trait. The genetic contribution to the adult form of pernicious anemia is supported by: (1) the concordant presence of pernicious anemia in identical twin (2) the increased risk in relatives of patients with pernicious anemia, (3) the presence of achlohydria with or without malabsorption in relatives of patients with pernicious anemia may produce antibody to gastric parietal cells.

The cause for the genetic predisposition of pernicious anemia is not yet clear. The association of pernicious anemia and the human leukocyte antigen (HLA) is not conclusive. Association of HLA-B7 and pernicious anemia has been reported in whites.

Diagnosis Clinical Features

The common features are anemia (angina effort, CCF), paraesthesia, Glossitis, recurrent diarrhoea, anorexia, weight loss, abdominal pain, mental disturbance, and visual disturbance.

Blood Picture

Hb decreased (7-9 g/l up to 3g/dl, occasionally is normal. MCV increased MCH is variable and MCHC is normal or slight increase (33-38 pg)

Blood Smear: Macrocytic cells many of these are oval. A small number of nucleated red cells and cell containing Howell-Jolly bodies are seen. A moderate leukopenia is associated with hypersegmented neutrophils are always present. A few myelocytes may appear in the peripheral blood. A moderate thromocytopenia is usual with the platlet count 100000-150000/L

Figure 9.1: Peripheral blood of megaloblastic anemia patient, showing ovalo-macrocytosis of red blood cells and hypersegmented neutrophils (8 lobes) .

Biochemical Finding

The serum bilirubin is usually at the upper limit of normal but may be slightly increased.

Serum haptoglobin level is reduced. Serum ferritin and iron are elevated but fall within 48h of adequate treatment. Plasma lactate dehydrogenase is increased.The direct coombs test is positive in 10%. The serum folate is usually normal but it may be elevated or rarely reduced.

Serum vitamin B12 assay is reduced. The presence of intrinsic factor antibodies is strong evidence in favour of a diagnosis of pernicious anemia.

Parietal cell antibodies are positive.

Radioactive vitamin B12 absorption test (Schiling test).

Serum Gastric Level: A pentagastrin or histamin fast achlohydria is almost inavailable in pernicious anemia, and 80% of patients have an elevated serum gastrin. The test is not specfic for pernicious anemia. Reticulocytosis is response to vitamin B12 administration.

Treatment

It is critical that an accurate diagnosis be made before therapy is started because folate supplementation may mask underlying B12 deficiency by improving the anemia, but not the neuralgic disease, associated with vitamin B12 deficiency and thus allowing the neuropathy to progress.

Folate deficiency is usually treated with oral daily replacement (1mg/day). B12 deficiency associated with pernicious anemia requires lifelong treatment. All patients should start with intramuscularly injection therapy at 100 to 1000 μg/day, to be given every week for 1 month. Maintenance treatment may be administered intramuscularly, subcutaneously, orally, or intranasally. In general, there is a dramatic improvement in well being within a day of therapy with parental B12.

Reticulocytosis becomes apparent in 1 week, whereas anemia resolves in 2 months. Neurologic symptoms take longer to improve (6-12 months).

Unfortunately, in upto 10% of patients with neurologic complications, and depending on the severity and duration of disease, the damage may be irreversible.

Response to Therapy

The initial sign of a positive response to therapy is an increase in the reticulocyte count. The number of circulatory reticulocytes increases 2 to 3 days after therapy with a peak at about 7 days. The reticulocyte count may increase to 50 to 70% initially. The megaloblastic morphology of the bone marrow disappears within the first 24 to 48 hours after therapy. The hematocrit rises in about 5 to 7 days after therapy, reaching normal levels in 4 to 8 weeks. Giant metamyelocytes and hypersegmented neutrophils disappear within 2 weeks. The entire therapeutic response process may take only 3 to 6 weeks depending on the severity of the disease.

REVIEW QUESTIONS

1. The pathophysiology of megaloblastic anemia is:

a. Defective RNA synthesis and abnormal cytoplasm maturation b. Defective DNA synthesis and abnormal nuclear maturation c. Defective RNA synthesis and abnormal nuclear maturation d. Defective DNA synthesis and abnormal cytoplasm maturation

2. All of the following laboratory findings coincide with megaloblastic anemia except:

a. Increased serum bilirubin b. Increase serum iron c. Decrease muramidase d. Increased LDH-1

3. Megaloblastic anemia is associated with:

a. Ineffective erythrpoiesis and increased reticulocytes b. Ineffective erythropoiesis and decreased reticulocytes c. Ineffective erythropoiesis and decreased LDH

d. Ineffective erythropoiesis and decreased erythropoiesis 4. According to the morphological classification of anemia is a:

a. Macrocytic, hypochromic anemia b. Macrocytic hyperchromic

c. Macrcytic, normochromic d. Normocytic, normochromic

5. Which of the following is not seen on the peripheral smear of megaloblastic anemia?

a. Macro-ovalocytes

b. Hypersegmented neutrophils c. Hyposegmental neutrophils d. Howell-Jolly bodies

6. Which of the following are the characteristic findings of the bone marrow in a patient with megaloblastic anemia?

a. Hypercellular with low M:E ratio b. Hypercellular with high M:E ratio c. Hypocellular with high M:E ratio d. Hypocellular with low M:E ratio

7. The glycoprotein necessary for absorption of vitamin B12 is:

a. Albumin

b. Transcobalamin II c. Haptocorrin d. Intrinsic factor

8. All of the following are clinical manifestations of both B12 deficiency and folate deficiency except:

a. Anemia and jaundice

b. Weakness and shortness of breath c. Thrombocytopenia and bleeding d. Hemoglobinuria

9. Which of the following schilling test results corresponds to a diagnosis of pernicious anemia?

a. Part I abnormal, part II not corrected b. Part I abnormal, part II corrected c. Part I and part II are abnormal

d. Part I normal, part II corrected

10. Which of the following is not a cause of vitamin B 12 deficiencies?

a. Atrophic gastritis b. Total gastrectomy c. Blind loop syndrome d. Chronic gastritis

11. Hypergemented neutrophils, a classic (nonspecific) finding in megaloblastic anemia, generally have ---or more nuclear lobes.

a. 4

b. 6

c. 8

d. 10

12. Pernicious anemia is caused by a:

a. Dietary folate deficiency b. Dietary vitamin B12 deficiency

c. Reduced intrinsic factor secretion in the stomach.

d. Defective intrinsic factor molecule

13. The laboratory findings in megaloblastic anemia many include:

a. Decrease serum folate

b. Decrease erythrocyte, leukocyte and platelet . c. Decrease serum vitamin B12

d. All of the above

14. Megaloblastic changes in the peripheral blood include:

a. Giant neutrophils with nuclear hypersegment b. An MCV as high as 130 fl

c. Oval macrocytes with increased cetral pallor d. All of the above

15. Megaloblastic changes in the bone marrow include:

a. Giant leukocyte , especially metamyelocyte b. A hypercellular marrow with leukocyte

precursors predominantly

c. An increased ratio of erythroblasts to myeloblasts

d. All of the above

16. Megaloblastic anemias can be due to:

a. Tapeworm infection b. Gastric resection c. Nutritional deficiency d. All of the above

17. Megaloblastic anemia related to folic acid deficiency is associated with:

a. Abnormal absorption b. Increased utilization c. Nutritional insufficiency d. All of the above

18. The underlying gastritis that causes pernicious anemia is immunologically related to:

a. Autantibodies to intrinsic factor b. A serum inhibitor of intrinsic factor c. Autoanntibodies to parietal cells d. All of the above

19. The suspected blood values related to the blood film are:

a. MCV increased, MCH increased, and MCHC normal

b. MCV increased, MCH variable and MCHC normal c. MCV increased, MCH decreased, and MCHC normal d. MCV normal, MCH increased and MCHC normal

20. In a case of classic pernicious anemia, the patient has:

a. Leukopenia

b. Hypersegmented neutrophils

c. Anemia

d. All of the above