Case 25

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 22/04/2025

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CASE 25

Anna is a 27-year-old woman who has been in your practice for many years. She is a teacher, a mother of two young boys, and a nonsmoker and has had no significant ailments of which you are aware. She now presents with generalized fatigue for several months that is significantly impacting on her home life and work. Your immediate concern is that Anna is anemic, which can occur as a result of a poor diet. On questioning, however, Anna is emphatic that she eats a balanced diet and is not a vegetarian. Strict vegetarians can become anemic from a diet-related deficiency of vitamin B₁₂ (cobalamin).

Routine physical examination is unremarkable, and chest radiograph is normal. Her blood work shows thrombocytopenia, leukopenia, and anemia (see Appendix for reference values). A peripheral blood smear reveals macrocytic anemia (large red blood cells) and hypersegmented polymorphonuclear neutrophils (PMNs). (Hypersegmented neutrophils have five or more lobes, whereas normal ones have three or four.) Anna is not aware of anyone else in her immediate family who has ever had this sort of problem, although her only siblings are two brothers. What are your thoughts so far?

QUESTIONS FOR GROUP DISCUSSION

1. This patient has had general fatigue for several months and you are concerned that she might be anemic. What is the most common cause of anemia? How would you treat this? What would you recommend for patients who do not absorb iron well?

2. List some of the conditions that you should rule out as causes of anemia due to occult loss of blood.

3. Anna’s blood smear revealed macrocytic red blood cells and hypersegmented polymorphonuclear neutrophils. This is consistent with megaloblastic anemia. What is the most common cause of megaloblastic anemia?

4. Review the steps of vitamin B₁₂ intestinal absorption. Include in your discussion each of the following: parietal cells, intrinsic factor, vitamin B₁₂, and cubilin.

5. Anna’s serum level of vitamin B₁₂ is below normal. She is not a vegetarian so it is unlikely that this is a dietary deficiency. How would you test for impaired absorption of this vitamin? Explain the general principle underlying this test and the general procedure.

6. A positive Shilling test indicates only that the absorption of vitamin B₁₂ is abnormal. To determine the etiology of the disorder, what autoantibodies would you measure?

7. Discuss the factors that could cause impaired absorption of this vitamin.

8. Explain why measures of homocysteine and methylmalonic acid are not used regularly to test for vitamin B₁₂ deficiency.

9. Compare and contrast Imerslund-Grasbeck syndrome and pernicious anemia.

10. Explain how deficiencies in vitamin B₁₂ (or folate) can result in anemia.

RECOMMENDED APPROACH

Implications/Analysis of Family History

There is no strong evidence for a genetic component of Anna’s clinical presentation, although we are only provided with information regarding the immediate family.

Implications/Analysis of Clinical History

Anna is a nonsmoker, has had no significant ailments, but has been experiencing fatigue for several months, suggesting that she might be anemic. Otherwise, the clinical history is unremarkable.

Implications/Analysis of Laboratory Investigation

Anna’s blood work is consistent with megaloblastic anemia. Although there are a number of conditions that can lead to megaloblastic anemia, one of the most common is a deficiency in vitamin B₁₂ or folic acid. Because Anna is not a strict vegetarian, a diet-related deficiency of vitamin B₁₂ is unlikely. Many patients with a deficiency of vitamin B₁₂ have normal serum levels of folate because these levels fluctuate with diet. An appropriate next step would be to test for serum levels of vitamin B₁₂.

Additional Laboratory Tests

Anna’s serum vitamin B₁₂ levels were low. In the absence of dietary deficiency, impaired absorption of vitamin B₁₂ is the most common cause of low serum levels.

Intrinsic Factor and Vitamin B₁₂ Absorption

Impaired absorption is generally due to a deficiency of intrinsic factor, the molecule to which dietary vitamin B₁₂ must bind before it can be transported across the intestinal wall. Intrinsic factor is produced by gastric parietal cells and so any clinical condition that destroys these cells will lead to a deficiency in intrinsic factor (see Etiology). In some autoimmune disorders, normal levels of intrinsic factor are produced but it is unavailable for binding vitamin B₁₂ because anti–intrinsic factor autoantibodies compete with vitamin B₁₂ for the intrinsic factor. Therefore, this effectively reduces the amount of vitamin B₁₂ that can be transported.

The Shilling Test

Although in some clinical laboratories the Shilling test has been replaced by other tests (see Etiology), this test is still performed in some centers to determine whether orally administered vitamin B₁₂ is being transported across the intestinal membrane. In essence, this test determines whether sufficient intrinsic factor is available to transport vitamin B₁₂ across the intestine.

In this test, the patient is given an oral dose of radiolabeled vitamin B₁₂, which is then measured in urine that has been collected over the following 24 hours. To ensure that radiolabeled vitamin B₁₂ does not bind to sites in the body (causing a false low measure), unlabeled vitamin B₁₂ is injected intramuscularly. Anna’s Shilling test result was shown to be grossly abnormal.

To confirm that the low serum levels of vitamin B₁₂ are due to a deficiency of intrinsic factor, the test is repeated with the exception that intrinsic factor is given along with the oral administration of vitamin B₁₂. On the basis of this test, it was concluded that Anna did have a deficiency of intrinsic factor and was diagnosed as having pernicious anemia.

Testing for Autoantibodies

Although you begin treatment immediately (see Therapy section), you also continue to investigate the ultimate etiology of this disorder and request screening for serum autoantibodies to parietal cells and intrinsic factor. The results are made available to you 3 weeks later. Your patient is producing autoantibodies both to gastric parietal cell antigens and to intrinsic factor.

DIAGNOSIS

Megaloblastic anemia resulting from a deficiency of vitamin B₁₂ absorption is also referred to as pernicious anemia. Anna was diagnosed with pernicious anemia.

THERAPY

Accordingly, you elect to treat this problem with injectable vitamin B₁₂ (every 2 to 3 weeks), which resolves the problem within 3 months. Contrary to conventional medical practice, a number of studies with patients diagnosed with malabsorption of vitamin B₁₂ and megaloblastic anemia have concluded that oral administration of very high doses of vitamin B₁₂ is as effective as intramuscular injections of vitamin B₁₂. The rationale for this approach is that about 1% of vitamin B₁₂ is absorbed in the absence of intrinsic factor.

ETIOLOGY: PERNICIOUS ANEMIA

Deficiencies in vitamin B₁₂ and/or folic acid cause megaloblastic anemia, a general term for anemias characterized by enlargement of proliferating cells, particularly red blood cell precursors. Cell enlargement is the result of delayed mitosis despite continuing DNA synthesis and normal synthesis of cytoplasmic proteins and RNA. As a result, megaloblasts accumulate in the bone marrow so few red blood cells are released into the circulation, resulting in anemia. Contributing to the anemia is the fact that the enlarged red blood cells undergo increased hemolysis.

Genetic Component

There is no strong evidence of a genetic component to pernicious anemia, although there are scattered reports that individuals inheriting HLA-A2, HLA-A3, HLA-B7, or HLA-DR5 are predisposed to disease. Some genetic component may yet be identified in that concordance has been reported in sets of monozygotic twins. Since these studies were reported in the 1960s, the monozygotic twins may, in fact, have had a congenital intrinsic factor deficiency, which would manifest as malabsorption and vitamin B₁₂ deficiency.

Source and Absorption of Vitamin B₁₂

Our bodies do not synthesize either folate or vitamin B₁₂, and so both must be obtained from our diets. Commensal bacteria, however, can synthesize this vitamin B₁₂, and so we get this vitamin from this source as well. Vitamin B₁₂ is absorbed after complexation with intrinsic factor, a protein synthesized by gastric parietal cells. There are two immunologic reasons for a decrease in the availability of intrinsic factor: the first is the production of anti-intrinsic factor autoantibodies, and the other is the autoimmune destruction of parietal cells such that the amount of intrinsic factor secreted is severely decreased.

Vitamin B₁₂–Intrinsic Factor Receptor, Cubilin

Intestinal absorption of B₁₂ occurs only when vitamin B₁₂ and intrinsic factor form a complex that binds to the cognate receptor, cubilin, present on the intestine and kidney epithelium. This receptor is encoded on chromosome 10.

New Strategies in Laboratory Testing

Elevations in total homocysteine are considered a good indication of vitamin B₁₂ deficiency. In fact, increased levels of homocysteine can be detected before symptoms occur. One downside to using this measure as an indicator of vitamin B₁₂ deficiency is that other deficiencies and causes can also lead to an increase in homocysteine.

Elevations in methylmalonic acid are also good indicators of vitamin B₁₂ deficiency and are more specific than measures of homocysteine, but other causes for elevation in methylmalonic acid have also been reported. Furthermore, assays are expensive and not available in most laboratories.

Imerslund-Grasbeck Syndrome: a Megaloblastic Anemia

Defects in the intrinsic factor/vitamin B₁₂ receptor (cubilin) can also lead to a megaloblastic anemia that has been named Imerslund-Grasbeck syndrome. Defects in the synthesis of this receptor or mutations that affect binding of the intrinsic factor/vitamin B₁₂ complex lead to Imerslund-Grasbeck syndrome, which is also characterized by a deficiency of serum vitamin B₁₂ levels. In a recent report, the functional intrinsic factor/vitamin B₁₂ receptor was shown to be a complex, consisting of two subunits, cubilin and amnionless, referred to as “cubam.” Whether mutations in amnionless will also prevent absorption of vitamin B₁₂ is the focus of ongoing studies.

Folic Acid Deficiencies

Folic acid deficiencies occur primarily in individuals who have had inadequate diets, as may be the case in drug addicts and alcoholics. However, impaired absorption of folate may also occur.

Iron Deficiency Anemia

In contrast, iron deficiency anemia (generally diet related) is not uncommon (microcytic anemia) and is easily treated with iron replacement. In this type of anemia, you should make sure the patient is not losing blood in an occult manner (gastrointestinal tract tumor or chronic gastritis/ulcer; heavy menses). Occasionally, patients do not absorb iron well, and you may have to resort to more readily absorbed oral formulations, or even injectable iron.

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