The Hidden Face of Pernicious Anemia: Age-Related Progression of Autoimmune Gastritis from Iron Deficiency to Cobalamin Depletion.

Because gastric acid secretion is critical for food iron absorption, iron deficiency is a known complication of the achlorhydria associated with pernicious anemia at presentation or following cobalamin (Cbl) treatment. In a previous study employing high serum gastrin and strongly positive antiparietal cell antibodies as a screening method for autoimmune atrophic gastritis, we have found a very high (27%) prevalence of atrophic gastritis among young subjects with iron deficiency anemia (IDA). The objectives of the present study were to explore the degree of overlap between patients presenting with atrophic gastritis and microcytic (MVC<80 fl) IDA on one hand, and those presenting with Cbl deficiency and normocytic (MCV 80–100 fl) or macrocytic (MCV>100 fl) anemia typical of pernicious anemia. Of 160 patients diagnosed with autoimmune gastritis presenting with iron, Cbl, or combined deficiency over the years 2001–2005, 83 presented with microcytic IDA, 48 with normocytic and 29 with macrocytic indices. Serum Cbl was abnormal in 100% of macrocytic, 92% of normocytic and 46% of microcytic subjects. IDA patients were 21 y younger (41 ±15 vs 62±15 y), predominantly female (78 vs 41%) and with a higher proportion of active H pylori infection (42 vs 21%). However, there were also marked similarities between all subgroups including a high prevalence of thyroid disease (20%) and diabetes (8%) known for their association with the autoimmune polyendocrine syndrome, and the rate of anti-intrinsic factor positivity was the highest (42% vs 31%) among IDA patients. Stratification by age cohorts from <20 to >60 y showed a very regular correlation, with progressive increase in MCV from 68±9 to 119±8 fl, serum ferritin from 4±2 to 37±41 μg/L, hypergastrinemia from 349±247 to 800±627 u/mL (normal 61±17), and a progressive decrease of Cbl from 392±179 in the youngest, to 108±65 pg/mL in the oldest age cohort. The prevalence of H pylori infection was 87.5% at age <20 y, 47% at 20–40 y, 37.5 % at 41–60 y and 12.5% at age > 60y implying a spontaneous elimination of H pylori by achlorhydria of increasing severity and duration. H pylori eradication by triple therapy in 24 patients resulted in a decrease in serum gastrin from 476±391 to 218±220 u/mL (paired t-test=0.00086) within 19± 12 months and complete remission of pernicious anemia in 2 patients. These findings challenge the common notion that pernicious anemia is a disease of the elderly manifested in megaloblastic anemia, and imply a disease starting many years before the establishment of clinical Cbl deficiency through an autoimmune mechanism directed against gastric parietal cells, likely triggered by H pylori by means of antigenic mimicry. Because of the added strain of young age and fertility on iron requirements, IDA may precede Cbl deficiency by many years until the crucial loss of remaining intrinsic factor in a proportion of patients terminating in typical pernicious anemia.