Pernicious Anemia: Causes, Investigations and Treatment

Pernicious anemia is a type of megaloblastic anemia that occurs when a person’s body is unable to absorb vitamin B12 from their gastrointestinal tract. This results in vitamin B12 deficiency and produces morphologically abnormal (unusually large and immature) red blood cells known as megaloblasts.

It is also known as Biermer’s anemia, Addison’s anemia, or Addison-Biermer anemia.

History

The disease was first described by Thomas Addison in 1855. The term pernicious means deadly and was used in the earlier days when the cause of the disease and treatment were unknown and hence the disease was considered fatal.

Sources and Metabolism of Vitamin B12

Vitamin B12 is naturally found in animal products, including fish, meat, poultry, eggs, milk, and milk products. It is generally not present in plant foods. Humans are entirely dependent on dietary sources for vitamin B12 requirement.

Dietary B12 is protein-bound. When the protein-B12 complex reaches the stomach, the stomach secretes acids and enzymes that detach the B12 from the protein. Another protein, R-protein (also known as transcobalamin I) picks up the B12 and transports it through the stomach and into the small intestine.

The stomach cells also produce a protein called intrinsic factor (IF), which travels to the small intestine and attaches to B12.

The cells lining the ileum contain receptors for the B12-IF complex and thus B12 gets absorbed from the ileum. The B12-IF complex protects the B12 against bacterial and digestive enzyme degradation.

In addition to the IF mechanism, passive diffusion of B12 also occurs and accounts for 1-3% of B12 absorbed by the body.

After B12 is absorbed into the intestinal cells, it attaches to transcobalamin II (TC2) which then transports it to all body tissues through the blood and cerebrospinal fluid.

Once the B12-TC2 complex arrives at the cell where it is needed, B12 is released from TC2 in the form of hydroxocobalamin. It is then turned into methylcobalamin or adenosylcobalamin and used for their respective enzymes.

Causes and Etiopathogenesis

The fundamental defect in pernicious anemia is a failure of secretion of intrinsic factor (IF) by the parietal cells of the stomach. In the absence of intrinsic factor, the vitamin B12 of food is not absorbed, resulting in vitamin B12 deficiency even with a good diet.

Pernicious anemia is considered to be an auto-immune disease with a genetic predisposition. In about 10% of patients, more than 1 family member is affected. It is associated with human leukocyte antigen (HLA) types A2, A3, and B7 and type A blood group.

The immune system attacks the cells in the stomach that produce intrinsic factor (parietal cells). This results in permanent atrophy of the gastric mucous membrane and is most marked in the body of the stomach.  Besides decreased intrinsic factor secretion, secretion of hydrochloric acid and pepsin are also reduced.

Two types of antibodies are seen in these patients:

• Intrinsic factor antibodies (binding and blocking type)
  • They are found in most patients with pernicious anemia and are specific for this disease.
• Antiparietal cell antibodies
  • They occur in 90% of patients with pernicious anemia. Since they can also occur in thyroid disease and other autoimmune disorders, they are not specific for pernicious anemia.

Patients of pernicious anemia have a higher incidence of developing other autoimmune diseases, including thyroid disorders, type 1 diabetes mellitus, ulcerative colitis, etc. An association between pernicious anemia and Helicobacter pylori infections has been postulated but not proven till date.

Besides autoimmunity, lack of intrinsic factor can also occur in the following conditions:

• having all or part of the stomach (where intrinsic factor is made) removed
• a rare, inherited condition known as congenital pernicious anemia

Deficiency of vitamin B12 results in impairment of conversion of homocysteine to methionine with resulting decreased formation of tetrahydrofolate and methylenetetra-hydrofolate from methyltetra-hydrofolate. This results in an inability to methylate deoxyuridylate to thymidylate in the DNA synthesis pathway. The end result is a block in DNA synthesis in rapidly dividing cells causing impaired cell division since nuclear maturation is arrested. This results in unbalanced cell growth and immature cells called megaloblasts. Megaloblastic changes are most apparent in rapidly dividing cells such as blood cells and gastrointestinal cells.

Gastric atrophy (probably autoimmune)

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Reduced intrinsic factor secretion

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Failure of absorption of dietary vitamin B12

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Deficiency of vitamin B12

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Megaloblastic anemia

Epidemiology

It is a disorder of middle and older age groups. Females are affected a little more commonly than males. Congenital pernicious anemia is a rare condition usually manifesting in children younger than 2 years.

It is most prevalent among individuals of Celtic (English, Irish, Scottish) or Scandinavian origin. In these groups, 10-20 cases per 100,000 people occur per year.

However, the disease is known to occur in all races. Also, the incidence in other ethnic groups and races is probably higher than was previously recognized.

Signs and Symptoms

Anemia

Usual signs and symptoms are those common to anemia due to any cause. These include fatigue, general malaise, poor concentration, shortness of breath, paleness of the skin (pallor), lightheadedness and dizziness.

In very severe anemia, the body may compensate for the lack of oxygen-carrying capability of the blood by increasing cardiac output. The patient may then have symptoms such as palpitations, irregular heartbeat, angina, and heart failure.

Neurological Symptoms

The initial neurological symptom may be tingling or numbness in the hands or feet. Over a period of time, other symptoms develop like balance or gait problems, vision loss due to degeneration (atrophy) of the optic nerve and mental confusion or memory loss. Several psychiatric abnormalities including depression, insomnia, listlessness, and panic attacks may also occur.

In fa ew cases, neurological symptoms may occur before the characteristic findings of anemia

Glossitis

Some individuals may develop a sore and reddened tongue.

Gastrointestinal Abnormalities

These include diarrhea, nausea, and loss of appetite, abdominal pain.

Mild enlargement of the liver (hepatomegaly) and mild splenomegaly may occur.

Patients are also at a higher risk for stomach cancer.

Gynecological Abnormalities

Amenorrhea may occur and patients are usually infertile.

Investigations

Lab diagnosis involves the following sequential steps.

• Recognition of anemia and megaloblastosis
• Identification of the specific disease entity causing the vitamin deficiency

Complete Blood Count

Decreased hemoglobin levels and red blood cell (RBC) count.

Increased mean corpuscular volume (MCV >100 fl) and mean corpuscular hemoglobin (MCH)

Mean corpuscular hemoglobin concentration (MCHC, 32–36 g/dL) is normal.

Many cases present with pancytopenia, ie, reduced levels of all the three formed elements of blood. In such cases, besides anemia, total leucocyte count (TLC) and platelet count are also reduced.

Reticulocyte Count

It is decreased due to the destruction of fragile and abnormal megaloblastic erythroid precursors (intramedullary hemolysis) resulting in ineffective hematopoiesis.

ESR

It is usually elevated.

Peripheral Blood Film

RBCs show anisocytosis (increased variation in size) and poikilocytosis (variation in shape). An important feature is the presence of macrocytes (larger than normal in size). Abnormally shaped red cells including ovalocytes (oval-shaped RBCs) and macro-ovalocytes (large oval-shaped cells) are usually present.

Polychromatic RBCs, nucleated RBCs, and megaloblasts can also be seen. Presence of megaloblasts is the hallmark of megaloblastosis seen in pernicious anemia.

Some of the RBCs may show inclusions within their cytoplasm

• Howell-Jolly bodies (chromosomal remnants)
• Cabot rings (thin, threadlike, rings or “figure 8” shaped inclusions which are remnants of the mitotic spindle)

Neutrophils show nuclear hypersegmentation (more than 5 % of neutrophils have 5 lobes or at least one neutrophil is 6 lobed )

Bone Marrow Examination

Bone marrow is hypercellular with erythroid hyperplasia.

Erythroid precursors have megaloblastic features. They are larger than normoblastic cells. Also, nuclear maturation lags behind cytoplasmic maturation. These changes are most prominent in more mature RBC precursors.

The neutrophil precursors show giant forms. Megakaryocytes may be large and hyperlobulated.

Megaloblastic changes in bone marrow are reversed within 12 hours of treatment of pernicious anemia and bone marrow morphology returns to normal within 2-3 days. Therefore, bone marrow aspiration, if required, should be performed before the initiation of therapy.

Serum Levels of Vitamin B12

Levels are reduced.

Reference range: 200-900 pg/mL

Serum Lactic Acid Dehydrogenase (LDH) Level.

Levels are increased.

Serum Indirect Bilirubin

Levels are increased due to the increased breakdown of hemoglobin.

Intrinsic Factor (IF) and Parietal Cell Antibodies

IF antibodies, type 1 and type 2, occur in more than half of patients with pernicious anemia. They are specific for pernicious anemia and can be used to confirm the diagnosis.

Parietal cell antibody occurs in 90% of patients with pernicious anemia. Since they can also occur in thyroid disease and other autoimmune disorders, they are not specific for pernicious anemia.

Serum Gastrin

In chronic atrophic gastritis and pernicious anemia, level of serum gastrin is usually increased due to gastric achlorhydria.

Schilling Test

It was performed in the past to determine the ability of the body to absorb B12 by measuring the absorption of a small oral dose of radio-labeled B12. An advantage of this test was that it often included vitamin B₁₂ with intrinsic factor.  This test is rarely performed now-a-days.

Treatment

Vitamin B12 Therapy

It needs to be administered parenterally (intramuscular or deep subcutaneous) throughout the patient’s life. Adequate initial and maintenance doses are necessary to correct the anemia, to arrest and reverse nervous system lesions and to replenish the depleted tissue stores.

Blood Transfusion

This is indicated in very severe anemia.

Dietary Measures

Patients should be instructed to consume vitamin B12 rich foods.

Monitoring Response to Therapy

Clinical improvement begins immediately after the initiation of therapy.

Increased levels of LDH and indirect bilirubin should fall rapidly.

Reticulocyte count starts increasing within 3-5 days and peaks in 4-10 days. White cells and platelets return to normal range within few days but hypersegmented neutrophils may persist for 10-14 days.

Hemoglobin level usually rises by approximately 1 g/dL per week.

Serum potassium levels can fall during treatment and can be fatal. Therefore, potassium levels should be monitored during treatment and supplements may be given, if required.

Prognosis

In the majority of patients, the prognosis is excellent with adequate and life-long treatment.

These patients, however, are at a slightly increased risk of developing cancer of the stomach.

In patients with nervous system involvement, prognosis depends on the degree of involvement and its response to treatment.