The Second Diagnosis

This patient's hemoglobin level should have normalized within two months of starting treatment, but she continued to be slightly

anemic at three months. Many physicians would not consider a hemoglobin level of 11.3 gm/dL in a 70-year-old woman cause for concern. But she should have had a hemoglobin level higher than 12 gm/dL.

The key to the problem can be found in the CBC. A drop in the MCV was to be expected since treatment with vitamin B12 cured the megaloblastic anemia, but in this case, the MCV fell too far. While many physicians regard an abnormally low

MCV as any value below 80 µm3, the lower limit of normal is about 83 µm3. In this patient, the MCV fell all the way to 72 µm3, and her physician was faced with microcytic anemia. The three most important conditions in the differential diagnosis of microcytic anemia are iron deficiency, anemia of chronic disease, and the thalassemic syndromes. Diagnosing iron deficiency is important because it usually results from chronic blood loss. Its resolution takes precedence over its correction, especially when the anemia is mild. In this patient, stool examination was negative for occult blood, which argued against chronic blood loss from the usual site. Nevertheless, she was immediately given iron. The results of iron studies subsequently ruled out iron deficiency. The patient also received additional vitamin B12, and the serum B12 and folate levels were measured. Perhaps her physician was concerned that she might not have received enough B12 or that folate deficiency had developed, but in either case, the MCV would have been high, not low. Parenthetically, this patient's B12 level was more than twice the upper limit of normal because the blood sample was drawn immediately after she had received a B12 injection. There is no point in measuring the serum B12 level until several days after an injection.

Anemia of chronic disease is almost as common as iron deficiency anemia, and is similarly important as a clue to an underlying abnormality. Until proved otherwise, it indicates an inflammatory, infectious, or malignant process. It usually is not microcytic. In most cases, the MCV is in the low-normal range, although in about 15% of cases, it is slightly below normal. Since this patient's MCV of 72 µm3 is lower than the value customarily seen in anemia of chronic disease (even when it is microcytic), this diagnosis can be eliminated with 90% certainty. The subsequent return of a normal iron level and iron-binding capacity ruled out the diagnosis completely.

Obviously, this patient did not have homozygous beta-thalassemia, a severe illness that appears in early childhood and is usually fatal. However, beta-thalassemia minor and alpha-thalassemia-1 (trait), the heterozygous forms, cause mild anemia and are extremely common, especially among African Americans, Asians, and people of Mediterranean extraction. Beta-thalassemia minor can be diagnosed by detection of an elevated hemoglobin a2 level; the hemoglobin F level is usually somewhat elevated as well. In contrast, alpha-thalassemia minor, which this patient almost certainly has, is a diagnosis of exclusion. Once other causes of mild microcytic anemia have been excluded, it is usually not worth the expense to perform the molecular testing required to establish the diagnosis. The normal RDW seen in microcytic patients supports the likelihood of thalassemia; RDW is usually increased in iron deficiency.

Thalassemia minor also provides an explanation for the MCV level of 103 µm3 seen at the initial presentation. Since the patient had mild microcytosis all of her life, the MCV was probably always at about 72 µm3 (and the hemoglobin level probably always at about 11.3 gm/dL). The elevation to 103 µm3 occurred when B12 deficiency supervened. In a patient without thalassemia minor and an MCV of about 87 µm3, B12 deficiency would have pushed the MCV into the 120s.

Follow-up is important in pernicious anemia, since complications frequently develop. Many authors recommend that follow-up include endoscopy because of the increased risk of gastric cancer.

Some recommend regular endoscopies so that cancer can be detected at an early stage. Others defer the procedure until symptoms appear or stool guaiac results are positive; however, at that point, the cancer may be unresectable.

In this patient, endoscopy showed atrophic gastritis with antral sparing-the classic gastric lesion of pernicious anemia. The presence of a gastric carcinoid in the antral polyp was also significant. In the past decade, it has been established that gastric carcinoid is an even more common complication of pernicious anemia than gastric cancer. The development of a carcinoid may result in part from hypertrophy of the enterochromaffin cells. Most gastric carcinoids in patients with pernicious anemia have a benign course, but a small percentage metastasize and produce a fatal outcome.