A 24-year old black man with hemoglobin SC was hospitalized in 2003 because of a 5-day history of fever, headache, and diffuse joint pains; a longer history of tiredness; and an unexplained 30-lb weight loss in the past year. He had been minimally symptomatic all his life, other than one presumed crisis with pneumonia at the age of 12 years. In 2002 and 2003, however, he required hospitalization and antibiotics elsewhere twice for presumed crises with pneumonia. He was taking no medications other than daily folic acid and denied drug or alcohol abuse.
Physical examination in 2003 was remarkable only for fever that remitted spontaneously and a soft, apical, holosytolic murmur. No neurological abnormalities were described but he admitted to depression and his behavior was uncooperative and erratic. Chest radiography showed a small pleural effusion. Laboratory findings included a hemoglobin of 8.5 g/dl, MCV 115 fl, reticulocytes 83,200/μl, and white cells 15,200/μl with 64% neutrophils (hemoglobin had been 9.8 g/dl, MCV 106 fl, and white cell count 9500/μl at a brief first visit to our clinic 6 weeks earlier; blood smear was not examined on either occasion). Serum lactate dehydrogenase was 432 U/l. Cultures of blood and urine were negative. Studies done because of his worsened macrocytosis and anemia showed a low serum cobalamin (111 pmol/l) and high red cell folate. Further testing uncovered very high plasma methylmalonic acid (1840 nmol/l), homocysteine (125.9 μmol/l), and gastrin levels (631 ng/l), and a positive serum antibody to intrinsic factor.
The patient’s striking metabolic changes confirmed that his low cobalamin level and progressive macrocytic anemia represented clinically relevant cobalamin deficiency. His positive intrinsic factor antibody, supported by a high gastrin level, established pernicious anemia (PA; defined as cobalamin malabsorption resulting from loss of gastric intrinsic factor) as its cause. This diagnosis should be considered whenever anemia worsens, MCV rises, or neurologic or mental status changes in a patient with sickle cell disease.
The patient received 100-μg cyanocobalamin injections on two consecutive days and was discharged without folic acid. He was lost to follow-up thereafter, but contact reestablished in 2008 elicited the following information. He had continued his monthly cobalamin injections and restarted folic acid after leaving our hospital. Despite hospitalization elsewhere for one more crisis in 2003 and again in 2004, he regained weight (weight loss is not uncommon in PA),1 was no longer depressed, and soon recovered his premorbid crisis-free existence. On his doctor’s advice in 2007, he changed from injections to weekly oral doses of 500 μg cobalamin (the popularity of oral cobalamin treatment has come with reduced precision about doses, schedules, and durations appropriate to the cause of deficiency).2 His mother was told she too was cobalamin-deficient and received monthly cobalamin injections. At his visit to us in 2008, his hemoglobin level was 12.3 g/dl and MCV was 79 fl (iron status was normal), which are typical for uncomplicated SC hemoglobinopathy.3 Neurological examination was normal; he was bright, cheerful, and alert. He was given a cobalamin injection and advised to increase his oral cobalamin doses to 1000 μg daily or restart monthly injections(the popularity of oral cobalamin treatment has increased imprecision among physicians and patients about appropriate doses, schedules, and durations). He was also advised to obtain referral from his physician for endoscopy, because of the risk of gastric cancer and carcinoid tumors associated with PA, and for annual thyroid function testing because thyroid antibody was detected (thyroid function was normal) and the risk of thyroid dysfunction is increased in PA.1,2
This is the fourth documented case of PA occurring with sickle cell disease4-6 (the third seen by one of us, and the second at our hospital in recent years), and it suggests that the two diseases coexist often enough to warrant serious clinical notice. A retrospective survey of cobalamin levels in sickle cell disease claimed another 4 cases of PA7 but did not provide criteria or details. Greater awareness may uncover more cases of PA among patients with sickle cell disorders in the future because PA affects young adults proportionately more frequently among blacks than whites (19 of 100 black patients with PA were <40 years old vs only 5 of 115 white patients; p<0.01).8 The frequency of PA in blacks, especially young women, approaches even that in elderly whites,8,9 and there is no reason to think blacks with sickle cell disease are exempt. However, frequencies of PA in blacks with and without sickle cell disease have not been compared prospectively, a task made more difficult nowadays because the Schilling test is no longer available.10
The diagnosis of PA has often been delayed in patients with sickle cell disease, whose anemia is itself often macrocytic or becomes actually megaloblastic after hydroxyurea therapy. Diagnostic delay increases the risk of neurological irreversibility,1 and it may be exacerbated by the nearly universal use of folic acid supplements in sickle cell disease which was predicated on the now increasingly untenable presumption that such patients were not at risk for cobalamin deficiency because PA was rare in blacks and predominated in old age which was infrequently attained in sickle cell disease despite improving life span.11 Two earlier patients with sickle cell disease and PA had neurological symptoms.4,6 Our patient 1 was depressed, erratic, and uncooperative when deficient but not afterwards, although that could reflect reaction to circumstances. Routine folate supplement use in sickle cell disease merits rethinking, as suggested previously.6,12 Indeed, no benefits were apparent in a clinical trial.13 In any event, folic acid fortification of the American diet14 has probably rendered supplementation superfluous. At the least, periodic screening of cobalamin levels in patients taking folic acid is prudent.
The patient’s history of several sickle cell crises in the 9 months preceding his hospitalization and the return to his lifelong, virtually crisis-free state after cobalamin treatment is also noteworthy. This and the even more striking flurry of crises accompanying cobalamin deficiency and subsidence after cobalamin therapy in another such patient6 suggest that worsening of crises should raise suspicions of superimposed PA.