The theory that H. pylori is an important factor in the pathogenesis of gastritis, gastroduodenal ulcer, gastric cancer, MALT lymphoma, Ménétrier's disease, and other extragastric disorders is increasingly being accepted. In recent years, refractory iron-deficiency anemia, without pathologic hemorrhaging and a lack of responsiveness to oral iron therapy alone, has attracted attention in relation to H. pylori, but it manifests varying pathological features among individuals, indicating a need for further studies to fully understand the pathogenicity of this disease. We achieved complete remission in one case of H. pylori-positive Ménétrier's disease, characterized by recurrent iron-deficiency anemia and a high susceptibility to infection, and in another chronic iron-deficiency anemia case with atrophic gastritis, both of which have a past history extending beyond 20 years, by administering a combination therapy of iron and bacterial eradication. Based on the clinical findings obtained in the therapeutic course of these two cases, we will herein consider the involvement of H. pylori in Ménétrier's disease and iron-deficiency anemia.

In April 1989, a 24-year-old, eyeglasses craftsman visited Yoshimura Medical Clinic, with the chief complaint of shortness of breath, probably due to iron-deficiency anemia. He had had a sallow complexion since childhood, and had received iron preparations and blood transfusions for this iron-deficiency anemia three times, at the ages of 13, 16, and 17. He had never noticed having edema. He thought of himself as having a weaker constitution than others, as he had had meningitis at age 8, and he frequently had to stay home, due to diarrhea and colds, while in elementary school. After his symptoms improved through treatment with iron preparations, he stopped returning to our clinic. Later in 1989, at the age of 24, he was admitted to a public hospital, due to the development of left renal tuberculosis accompanied by hematuria. In February 1990, the patient returned to our clinic. Based on the appearance of giant folds of the gastric body on fluoroscopic images of the upper GI tract, we diagnosed his condition as Ménétrier's disease.

Laboratory investigation revealed microcytic hypochromic anemia, a decrease in total serum protein to 6.2 g/dl, and moderate decreases in immunoglobulins IgA and IgG. Daily oral treatments with two capsules of ferrous fumarate (Fe⁺⁺100 mg/cap) were continued for 10 months, but the disease recurred repeatedly at 2-month intervals when he was given this oral iron preparation alone. Again, he stopped returning to the clinic.

On January 25, 1996, he returned to the clinic for a third time, after having noticed shortness of breath, dizziness, and palpitations for about 6 months. His height was 165 cm, weight 72 kg and blood pressure 140/80 mmHg, with a regular pulse at 115 beats/min. His complexion was pale white; palpebral conjunctivae appeared severely anemic, and moderate edema was noted in the face and lower extremities. Laboratory tests showed abnormalities related to microcytic hypochromic anemia, and decreases in total serum protein, albumin, and γ globulin, but there were no other abnormalities.

As shown in Table 1, oral ferrous fumarate and intravenous saccharated ferric oxide were administered for severe iron-deficiency anemia. On February 1, 1996, endoscopy of the upper digestive tract demonstrated predominant thickening of the gastric mucosa from the lesser to the greater curvature of the body, and the walls of the mucosal folds showed a gyrus-like contortion on indigo carmine spray. No abnormalities were observed in the duodenum. Based on these endoscopic findings, the patient was diagnosed as having giant fold gastritis (Ménétrier's disease). In hematological tests performed on February 22, after several weeks of continuous administration of iron preparations, the patient's iron-deficiency anemia and hypoproteinemia were found to be almost normalized. In a Giemsa-stained biopsy specimen, a large number of H. pylori organisms were observed in the superficial layer of the foveolar epithelium (Fig. 1). The patient exhibited several histological features consistent with Ménétrier's disease, such as foveolar hyperplasia and cystic dilation of glands, with moderate cell infiltration of neutrophils, eosinophils, and lymphocytes observable in the edematous stroma (Fig. 2). The patient's parents had positive serum titers for H. pylori antibody. Eradication therapy with omeprazole (20 mg once a day), clarithromycin (400 mg b.i.d.), and metronidazole (500 mg b.i.d.) was continued for two weeks, beginning on February 22. The intravenous iron therapy was discontinued after February 22, but the oral therapy was continued.

On a subsequent endoscopy performed on April 11, the hypertrophic changes of foveolar epithelium had disappeared; infammatory cell infiltration into the stroma had resolved (Fig. 3), and no H. pylori organisms were detected, even with Giemsa staining. No bleeding was observed under endoscopy before or after the eradication. With the normalization of the abnormal laboratory test results observed earlier on January 25, including the anemia and hypoproteinemia, we decided to discontinue the iron therapy in May 1996. A hematological examination performed in December 2000 revealed neither anemia nor hypoproteinemia, and an H. pylori antibody test and urea breath test were both negative. In December 2002, a fluoroscopic study of the stomach showed no giant folds. On double-contrast radiograms taken in the dorsal position before and after eradication, the long×short axis of the stomach had been reduced from 27×11 cm to 23.5×10 cm over a period of 6 years and 10 months (Fig. 4). A second urea breath test, taken in December 2002, yielded the same negative result. In the 13 years since the patient's first visit to our clinic in 1989, all fecal occult blood tests performed were negative. Based on these hematological, biochemical, and radiographical findings, our patient's H. pylori-positive Ménétrier's disease with severe iron-deficiency anemia was thought to have been completely cured.

In August 1999, a 34-year-old man, who ran a clothing store, visited the Hirai Primary Care Clinic, complaining of lower abdominal pain. He had suffered from anemia since age 11, and had received blood transfusion therapy at age 12. His anemia was unresponsive to oral iron therapies, according to notes at every health check-up. As shown in Table 2, the laboratory investigation performed at the first visit revealed an Hb value of 8.3 g/dl, and a ferritin level of 3.1 μg/dl, suggesting microcytic hypochromic anemia. The presence of lower abdominal pain, together with the history of anemia, prompted the physician, Dr. Hirai, to perform an endoscopic examination, using total colonoscopy, on August 20, 1999. No lesions were found, and the patient was therefore suspected of having irritable bowel syndrome. A gastric endoscopic examination, on August 26, demonstrated only atrophic gastritis from the antrum to the middle corpus, with no bleeding. Recalling the findings from Case 1, Dr. Hirai performed a rapid urease test, and discovered infection with H. pylori. Eradication therapy with rabeprazole sodium (20 mg once a day), clarithromycin (400 mg b.i.d.), and amoxicillin (1,500 mg b.i.d.) was administered for 7 days. Daily oral treatment with two tablets of sodium ferrous citrate was started on September 2. On November 16, six weeks after starting the iron therapy, the iron preparation was discontinued, due to marked improvement in his anemia, with an Hb value of 15.2 g/dl and a ferritin level of 21.1 μg/dl. A bacterial culture, rapid urease test, and microscopic study of biopsy specimens obtained by endoscopy on November 22, were all negative for H. pylori. Several histological findings observed before the eradication, namely edema, congestion, and inflammatory cell infiltration, mainly composed of neutrophils and plasmocytes in the stroma, were resolved after the eradication (Fig. 5). No bleeding was observed endoscopically, and fecal occult blood tests were all negative before and after eradication. In the 3 years since the eradication, this patient has been followed at the same clinic, with no evidence of recurrent iron-deficiency anemia.

Since Warren and Marshall first discovered Helicobacter pylori in 1983 (1), H. pyrori infection has been clearly demonstrated as being involved in gastric diseases (1–6) and in several other extragastric disorders. We successfully treated refractory iron-deficiency anemia that had persisted for more than 20 years without response to oral iron therapy alone, in two patients, through eradication of H. pylori, although these patients exhibited different pathological conditions: Ménétrier's disease and atrophic gastritis. We analyzed their clinical courses to clarify the mechanism of the onset of anemia in each of the patients.

More than 100 years have passed since Ménétrier first reported this disease and dubbed it Polyádenomes ennappe (7), yet the cause remains unknown. Lepore et al provided the most promising lead when they detected H. pylori in the gastric mucosa of a patient with Ménétrier's disease in 1988 (6). Following the first successful treatment of Ménétrier's disease with cephalexin by Salmeron et al (8), Bayerdörffer et al (9) and Stolte et al (10) also reported remission of Ménétrier's disease after H. pylori eradication. This mounting evidence suggests that H. pylori often plays an important role in the pathogenesis of Ménétrier's disease. In contrast to the previous reports, the main clinical symptoms of our Ménétrier's disease were anemia without gastrointestinal bleeding, and a high susceptibility to infections. In other H. pyroli-positive Ménétrier's disease cases (9, 11–15), authors have taken great interest in the hypoproteinemia caused by protein-losing gastroenteropathy, yet none have reported presence of anemia. Kawasaki et al reported a case of Ménétrier's disease presenting with severe iron-deficiency anemia, but the fecal occult blood test was strongly positive (16), suggesting an etiology distinct from that of our Case 1. In our case, both the severe anemia and hypoproteinemia were almost completely eliminated by oral and intravenous iron therapies for about 1 month prior to the start of eradication therapy.

Although there would be a possible iron leakage with protein from giant folds (12,17), we hypothesize, based on rapid response to intravenous iron therapy and consistent negative tests for fecal occult blood, that the eradication therapy cured our special type of Ménétrier's disease by blocking the pathologic cycles induced by H. pyroli infection: disruption of the iron absorption function due to inflammatory changes that occur in the mucosa of the upper digestive system (18–20). When iron becomes deficient, mucosal function alters, leading to protein leakage. When iron is intravenously supplied, the altered mucosal function is temporarily repaired, and the protein leakage is prevented, thereby improving the hypoproteinemia and anemia simultaneously. However, a persistent H. pylori infection inhibits iron absorption from the upper digestive tract, leading to a recurrence of mucosal damage once the iron induced intravenously is consumed. In turn, this leads to the recurrence of hypoproteinemia and anemia, as well as an iron-deficiency that induces a high susceptibility to infections (21), such as renal tuberculosis.

When Dufour et al performed H. pylori eradication therapy on a 7-year-old boy with iron-deficiency anemia unresponsive to oral iron therapy, successful remission was obtained (22). Since then, the improvement of iron-deficiency anemia with the eradication of H. pylori has been increasingly reported, in pediatric (19, 23), adolescent (24), young adult (25), and adult patients (26, 27). Here, because no origin of bleeding could be identified through endoscopy and fecal occult blood tests were always negative in Case 2, and as in the case reported by Dufour et al, the disturbance of iron absorption or acquisition by H. pylori seemed to be the cause of anemia in this patient.

In our Case 1, iron-deficiency anemia could be improved by intravenous iron therapy, but the disease recurred when the patient was treated solely by oral iron therapy. Case 2 had no response to oral iron therapy, and he was always told he had anemia at every health check-up. According to Choe et al (28), many H. pylori-associated iron-deficiency anemia patients do not respond to treatment with oral iron therapy alone. Although our two cases had different pathological conditions: Ménétrier's disease and atrophic gastritis, the reason for the lack of improvement of anemia with oral iron therapy alone in both patients was thought to be because iron absorption dysfunction may occur as a result of structural or functional changes in the mucosal tissue of the upper digestive tract (12, 17–20), or that some mechanism of iron acquisition by H. pylori from the human host appears (29–31).

Here, an incidental question arises: Why is it that iron-deficiency anemia fails to develop in all infected subjects? We found that the parents of our patient with Ménétrier's disease were positive for H. pylori, yet they had no anemia, hypoproteinemia, or gastric lesions. The pfr gene of H. pylori has been reported to have no association with the presence or absence of anemia (32). These findings indicate that host and/or environmental factors have a major role in the onset of iron-deficiency anemia and Ménétrier's disease. In keeping with the theory of Sipponen et al (33), we believe that the present two cases were infected with H. pylori during childhood and manifested different pathologic features stemming from different host or environmental factors. We recommend that H. pylori eradication be considered as a treatment of choice for H. pylori-positive Ménétrier's disease, and the heretofore unexplained chronic iron-deficiency anemia that is unresponsive to oral iron therapy alone.