|Pernicious Anemia in a Young Adult|
Pernicious Anemia in a Young Adult
Bruce Landres, M.D.
A 22-year-old female presented for a well patient examination. Her only complaint was a prior diagnosis made by her dermatologist of alopecia areata and mild anemia. There was no history of vegan diet, neurologic compromise, ataxia, paresthesias, altered mental status, depression or glossitis. Laboratory studies from the dermatologist showed hemoglobin of 12.7 g/dL, hematocrit of 34.4%, WBC 8300, andplatelets of 294K. Indices showed MCV of 93.6, MCH of 34.6, and MCHC of 36.9. Morphology showed hypersegmented polymorphonuclear leukocytes. Repeat indices showed MCV of 92, MCH of 31.5, and MCHC of 34.4.
Due to the presence of hypersegmented polymorphonuclear leukocytes, a serum B12 level was drawn and found to be 117 pg/ml and 114 pg/ml on two separate occasions (normal 160-930 pg/ml). Additional tests showed normal serum folate, homocysteine, and methylmalonic acid. Antibodies to H. pylori, parietal cells, and intrinsic factor (IF) were negative. Urine was negative for protein. Stool for O&P showed scattered blastocystis hominis cysts only. A Schilling Test showed percentage excretion without IF at 12.3% and with IF at 19.8% (normal >20%). This was consistent with pernicious anemia.
An upper gastrointestinal endoscopy showed normal mucosa to visualization and normal biopsy without inflammation, atrophy, H. pylori, intestinal metaplasia or dysplasia or malignancy. An upper gastrointestinal and small bowel follow-through radiologic study also showed normal mucosa pattern in the small bowel. There was no history of diarrhea, malabsorption or weight loss.
The patient is of Northern European heritage, but cannot be more specific about ethnic origins. There was no consanguinity known within her family history. The patient was placed on vitamin B12 injections, 1000 mg/month with resolution of her anemia and hypersegmented polymorphonuclear leukocytes.
Pernicious anemia is considered to be a disease seen in older populations. Multiple epidemiologic studies have shown that the average age of onset of pernicious anemia is greater than 60 years, with an increasing frequency with advancing age.1-3 Pernicious anemia during childhood and early adulthood is seen in a small subset of individuals but the diagnosis is often overlooked because of the patient\'s age.
Pernicious anemia is a disease of vitamin B12 deficiency, affected through an individual\'s inability to properly absorb cobalamin. Symptoms of pernicious anemia may include weakness, pallor, failure to thrive, fatigue, weight loss, glossitis, and a variety of neurologic abnormalities including peripheral neuropathy, loss of position and vibratory sense with ataxia, urinary and fecal incontinence, dementia, and psychosis. Laboratory studies show megaloblastic anemia with hypersegmented polymorphonuclear leukocytes, low serum B12 level, and abnormal Schilling Test.
Although first reported in 1937, juvenile pernicious anemia (JPA) is rarely seen. The prevalence of pernicious anemia is approximately 0.13-0.20% in the general population.1,4-6A study from 1944 reported a total of 1532 patients with pernicious anemia of whom only 4 were younger than 20 years of age.1 This represents only 0.26% of all patients with pernicious anemia and a prevalence within the general population of 5.2 per 100,000 individuals. A Swedish study by Borch noted a prevalence of pernicious anemia at 0.15% of the population, of which only approximately 1% were less than 30 years old.3 Other studies have cited a higher incidence of JPA going as high as 0.02% of the population.7 In a 1965 study by McIntyre, he noted that \"only 25 definitely proved cases (of childhood pernicious anemia) have been reported in the medical literature.\" 8 In 1999, Rosenblatt reported that the number of cases had risen to at least 45 patients.9
Originally, it was felt that only two subtypes of JPA existed. The first subtype was an absolute deficiency of IF found in children less than 2 years of age. These individuals had normal gastric acid secretion and normal gastric mucosa and parietal cells. Antibodies to IF and parietal cells were consistently absent. It was believed that virtually no IF was secreted, hence the inability of the patient to absorb vitamin B12. These infants usually presented with severe anemia, pallor, nausea, vomiting, failure to thrive, and weakness. Because of their absolute inability to absorb vitamin B12, these children invariably presented within the first two years of their life after their prenatal stores of cobalamin have dissipated.1,8-12
While the second subtype of JPA have similar presentation as that of the adult form, these individuals consistently showed gastric atrophy and low B12 levels. There was also a high incidence of autoantibodies directed against IF and the parietal cells of the stomach. Patients were usually in the second decade
Over time it became increasingly clear that there were additional subtypes of JPA. In 1960, Imerslund described a child under 2 years of age with IF in his gastric secretions, a low serum B12 level, symptoms of pernicious anemia, and an associated protein-uria.9,11-13 No autoantibodies were found, and deficiency could not be corrected by the addition of exogenous IF. Two explanations were given. The maladaptive mechanism was found to be a receptor at the enterocytes of the ileum for the IF-cobalamin complexed molecule. This receptor was either absent or the IF was unable to release the bound B12 at the ileal junction, resulting in malabsorption of the IF-cobalamin complex. Analysis of the proteinuria showed it to be consistently ++ to +++ on dipstick, but the 24-hour collection of urinary protein was only in the range of 0.2 g. The significance of the proteinuria has yet to be characterized, and it did not resolve with exogenous B12 injections.
Another case of variant IF was described by Lampkin of a child with no prior symptoms who developed pernicious anemia in his thirteenth year.10 This child represented the second case of forme fruste pernicious anemia. Autoantibodies could not be identified in this patient. A Schilling Test was diagnostic of pernicious anemia, and the patient was found to have an abnormally low serum B12 level. Stools were negative for ova or parasites, and a normal upper gastrointestinal radiological study was noted. Lampkin reported that the patient\'s presentation varied from the expected forms of JPA; the age of onset was well beyond the length of time that any neonatal accumulation of B12 should last. Lampkin offered two hypotheses for the delay in onset of symptoms in these patients when compared to those with congenitally absent IF. He hypothesized that these individuals have the ability to secrete IF at birth, albeit in marginal amounts. Thus, over several years, they gradually depleted their neonatal stores of B12. Alternately, IF secretion may have halted for unknown reasons after 4-5 years, leading to the onset of pernicious anemia symptoms.
In 1972, a new category of JPA was discovered with the finding of a functionally abnormal IF.
Although immunologically identical to normal IF, this binding protein was unable to effectively facilitate the absorption of vitamin B12. It was postulated that this IF was either unable to bind to B12 in the stomach or to the ileal receptors or it was unable to release the B12 after attachment to the ileum. All of these patients had normal gastric mucosa both macroscopically and microscopically. Additionally there was no evidence of autoantibodies directed against IF or parietal cells.1
Katz described a 13-year-old child who had an IF with a markedly reduced affinity to the ileal receptor.11,14,15 The absorption of radioactively tagged B12 was found to be greatly reduced in this patient. However, this absorption returned to normal with the addition of exogenous IF. In contrast, when using the patient\'s gastric juices containing his native IF in another patient with prior gastrectomy, there was a failure to promote absorption of cobalamin. Additional studies, including chromatographic and immunologic analyses, also showed normal affinity of the native IF molecule to bind B12. Clearly this form of pernicious anemia was mediated by a different mechanism than previously described by Imerslund. In Imerslund\'s case, the problem was a lack of ileal receptors on the enterocytes of the bowel. In this case, the patient had a functionally abnormal IF.
By 1974, Katz was able to elucidate the nature of the aberrant IF.15 The patient inherited an autosomal recessive trait from his parents who were heterozygous for the IF gene. His parents, who were first cousins, produced equal amounts of a normal IF and a structurally abnormal IF. The patient\'s B12 absorption had been sub-optimal over the years, and laboratory studies showed a 60-fold decrease in affinity for ileal receptors than would be expected with normal IF. Despite having the abnormal IF, the reduced affinity simply delayed the onset of pernicious anemia into the patient\'s second decade of life.
In 1985 another mechanism of B12 malabsorption was elucidated by Yang.16 He described three siblings with a dysfunctional IF that was able to normally bind B12 in vitro but rapidly degraded in vivo in the presence of an acid environment. Although producing adequate amounts of IF, the IF was unable to effectively bind to B12 within the gastric milieu, or later to bind to the ileal receptors. These patients usually presented with severe symptoms within the first 2 years of life without associated autoantibodies. Both parents synthesized only half as much normal IF as would be seen in normal subjects which suggested an autosomal recessive trait. This presentation represented a third form of variant and dysfunctional IF.
A variety of IF mutations may hinder the process of cobalamin absorption. These mutations could decrease or prevent IF synthesis by gastric parietal cells. They may also cause decreased IF secretion into the gastric juice. Other mutations could result in IF molecules with decreased affinity for cobalmain or increased susceptibility to alteration by acid or protolytic enzyme. Some mutations may decrease the affinity for ileal IF-cobalamin receptors or interfere with the ileal phase of B12 absorption. Some patients previously believed to have an absolute deficiency of IF may actually possess an immunologically nonreactive IF. As such, the IF could not be properly assayed at the time the patient was evaluated.15,16
Pernicious anemia in teens and young adults is uncommon. It has a multitude of causes including autoimmunity, absolute IF deficiency, and dysfunctional IF. Regardless of the actual cause, failure to diagnose this condition can lead to profound and lifelong medical consequences for the patient. A serum vitamin B12 level should be obtained in the evaluation of anemia in teens and young adults.