Resolving the Riddle of Obscure Iron Deficiency Anemia.
Authors: Hershko Chaim , Patz Julian , Ronson Aharon 
Published: April 2020

Abstract
Conventional endoscopic and radiographic methods fail to identify a source of gastrointestinal blood loss in about one third of males and post-menopausal females and in most women of reproductive age with iron deficiency anemia (IDA). Such patients are often referred for hematologic evaluation. In recent years there is increasing awareness of non-bleeding conditions with abnormal iron absorption as possible causes of unexplained IDA. Both H pylori gastritis and autoimmune atrophic gastritis are associated with impaired gastric acidity interfering with iron absorption. In a prospective study performed in a community hematology clinic, 300 consecutive IDA patients were screened for non-bleeding GI conditions including celiac disease (antiendomysial antibodies), autoimmune atrophic gastritis (hypergastrinemia with strongly positive antiparietal cell antibodies) and H pylori gastritis (IgG antibodies confirmed by urease breath test). Their mean age was 39±18 y, and 251 of 300 (84%) were women. A likely cause of IDA was identified in 93% of patients. As expected in a population of females of reproductive age, only 10% had a source of gastrointestinal bleeding identified. There were 13 new cases of adult celiac disease (4%). A history suggestive of menorrhagia was present in 32%. Autoimmune atrophic gastritis was documented in 77 IDA patients (26%) of whom 39 had coexistent H pylori infection. H pylori infection was the only positive finding in 57 patients (19%). To exclude the compounding effect of menstrual blood loss in evaluating the role of H pylori in the pathogenesis of IDA, we have focused on the 29 male IDA patients with negative gastrointestinal workup, poor initial response to oral iron treatment, and a high prevalence of H pylori infection (25 of 29). Following H pylori eradication, all patients achieved normal hemoglobin levels with follow-up periods ranging from 4 to 69 months (38±15 months mean± 1SD). This was accompanied by a significant decrease in H pylori IgG antibodies and serum gastrin. Sixteen patients discontinued iron treatment, maintaining normal hemoglobin and ferritin and may be considered cured. Remarkably, 4 of the 16 achieved normal hemoglobin without ever having received oral iron after H pylori eradication. To define the relation between IDA-associated autoimmune gastritis, and pernicious anemia, we studied 160 patients with autoimmune gastritis including 83 subjects presenting with IDA, 48 presenting with normocytic indices, and 29 with macrocytic anemia. Stratification by age cohorts of autoimmune gastritis from &lt;20 to &gt;60 y showed coexistent H pylori infection in 87.5% at age &lt;20 y, 47% at 20–40 y, 37.5% at 41–60 y, but only 12.5% at age &gt; 60y. With increasing age cohorts, there was a regular and progressive increase in MCV from 68±9 to 95±16 fl, serum gastrin from 349±247 to 800±627 u/mL, and a decrease in cobalamin from 392±179 to 108±65 pg/mL. Conclusions: The favorable long-term clinical results of H pylori eradication offer strong evidence for a cause-and-effect relation between H pylori and IDA. A proportion of H pylori patients will develop autoimmune gastritis. Our findings in autoimmune gastritis imply a disease presenting as IDA many years before the establishment of clinical cobalamin deficiency. It is likely caused by an autoimmune process triggered by antigenic mimicry between H pylori epitopes and major autoantigens of the gastric mucosa. Recognition of H pylori and autoimmune gastritis as common causes of obscure iron deficiency anemia should have a strong impact on the efficacy of diagnostic workup and management of unexplained, or refractory iron deficiency anemia.