Bruno Monarca

Reversal of Iron Deficiency Anemia after Helicobacter pylori Eradication in Patients with Asymptomatic Gastritis

Standard care for men and postmenopausal women with iron deficiency anemia is use of gastrointestinal evaluation to exclude gastrointestinal tract abnormality (1, 2). Nevertheless, even when the gastrointestinal tract is investigated thoroughly, a large proportion of patients (around 30%) remain without a diagnosis (2, 3). Recent epidemiologic studies have suggested an association between Helicobacter pylori infection and iron deficiency (4, 5). Infection with H. pylori is recognized as a major risk factor in peptic ulcer disease and gastric cancer, in which lesions are likely to bleed either overtly or in an occult manner, eventually leading to iron deficiency anemia. However, most people infected with H. pylori only have chronic gastritis that is not associated with gastrointestinal bleeding or with any other specific disease (6). It has been suggested that infection with H. pylori may lead to iron deficiency or iron deficiency anemia by impairing iron uptake or increasing iron demand (4). Reversal of iron deficiency anemia after successful eradication of H. pylori was recently observed in children (7, 8) and in a young adult (9). We performed a prospective open study to verify the effects of eradication of H. pylori infection on iron deficiency anemia in patients with H. pylori-associated gastritis. Methods Patients Patients were observed from September 1994 to December 1997. A total of 189 consecutive adult outpatients who were older than 20 years of age and had iron deficiency anemia (158 women and 31 men; median age, 47 years [range, 20 to 79 years]) were referred to our gastroenterology department from the hematology department. Iron-deficiency anemia was defined as a hemoglobin concentration less than 14 g/L for men and less than 12 g/L for women, a mean corpuscular volume less than 80 fL, and a serum ferritin level less than 30 g/L (3). Outpatients with an obvious cause of blood loss, such as a heavy menstrual period (cycles>6 days), epistaxis, active gastrointestinal hemorrhage, or evidence of fecal occult blood positivity, were excluded from the study. Other exclusion criteria were gastrointestinal or hematologic cancer at the time of observation, chronic renal failure, severe cardiopulmonary disease, reported or suspected pica, hemolysis, aplastic anemia or thalassemia, alcoholism or liver cirrhosis, and pregnancy. After this selection, patients who were taking nonsteroidal anti-inflammatory drugs; had had gastric surgery; or had atrophic body gastritis and celiac disease, as described elsewhere (3), were excluded from the study. An iron-poor diet as a cause of iron deficiency anemia was excluded by a hospital dietitian (3). A double-contrast barium enema or colonoscopy plus radiographic examination of the small bowel, or Meckel scintigraphy, were also carried out if indicated. Interventions Patients were treated for 2 weeks with omeprazole, 40 mg, in the morning; amoxicillin, 1g; and metronidazole, 250 mg three times daily after meals, for the first week. Patients were also instructed to discontinue any iron replacement therapy, including over-the-counter iron-containing medication. A clinical evaluation was performed 3 months after eradication therapy to check for clinical signs of anemia. Two follow-up visits at 6 and 12 months were planned. At each visit, a complete blood count was done and ferritin levels were measured. Baseline and 12-month transferrin saturation indexes were also calculated. The 6-month follow-up examination included endoscopy with biopsy to evaluate H. pylori eradication. Patients were considered cured of H. pylori infection if both rapid urease testing and histologic examination of the gastric antral and body biopsy samples were negative. Successful eradication therapy for iron deficiency anemia was defined as no need for iron replacement therapy, recovery from anemia, or both. All patients gave full informed consent to participate the study, which was approved by the local ethical committee. Measurements History of anemia, expressed as length of time from first laboratory diagnosis of iron deficiency anemia to referral to the gastroenterology department, was assessed. Serum ferritin levels were measured by using commercial kits (Ciba-Corning Diagnostic Corp., Milan, Italy) (3). Hemoglobin concentrations and mean corpuscular volume were determined by an automated Coulter counter (Technicon H1, Bayer Corp., Tarrytown, New York) (3). Serum transferrin levels were measured by using a commercial kit (Beckman Analytical, Milan, Italy) (10). Serum iron levels were measured and the transferrin saturation index (normal value, 16% to 45%) was calculated as described elsewhere (10). Patients underwent gastroscopy with gastric antral (n=3) or body (n=3) biopsy. One sample was tested by using a rapid urease test, and the others were examined by conventional histology (3, 9). Duodenal biopsy specimens were also obtained to exclude celiac disease. The pathologist was unaware of clinical and endoscopic data. Gastritis status was described according to the Updated Sydney System classification (8). Helicobacter pylori status was considered positive when the organism was detected on histologic examination, by rapid urease testing, or both. Statistical Analysis Data are expressed as the mean ( SE) or median (range) as appropriate and were analyzed by using the t-test for paired data. Subgroups (percentages of patients) were compared by using the McNemar test. A P value less than 0.05 was considered statistically significant. Role of the Funding Sources Our funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Of the 189 patients referred to our gastroenterology department, 30 (15.9%) had iron deficiency anemia: 4 men and 26 women (of whom 3 were postmenopausal) with a median age of 35.5 years (range, 20 to 65 years). In these patients, H. pylori-associated gastritis was the only pathologic finding. Gastroscopy did not reveal any sign of current or past mucosal erosion or ulcer disease. All patients had a suboptimal response to oral iron therapy; they needed continuous or intermittent oral iron treatment to prevent the decrease of hemoglobin levels. All patients denied having any specific gastrointestinal symptom or having used antisecretory drugs. Occasional, nonpersistent, mild dyspeptic symptoms were considered nonspecific. Anamnestic interview and evaluation of previous medical records documented moderate to severe iron deficiency anemia in all patients (hemoglobin level, 9.5 0.25 g/L; mean corpuscular volume, 69 1.15 fL; and serum ferritin level, 6.2 0.8 g/L) associated with clear clinical signs of anemia, such as fatigue, pallor, and decreased exercise capacity. Median history of anemia and of oral iron therapy in these patients was 4.8 years (range, 2 to 20 years). All patients underwent an eradication regimen. At the 3-month clinical evaluation, no patients reported anemia-related symptoms. Twenty-eight patients underwent endoscopy at 6 months to verify H. pylori eradication. Two female patients (27 and 36 years of age) declined further follow-up because they were in good general health. Helicobacter pylori infection was cured in 25 patients (89.3% [95% CI, 72% to 98%]); at this point, one female 31-year-old patient was excluded from further follow-up because she had developed heavy menstrual periods due to a uterine myoma that was not present at the initial diagnosis. Thus, 24 patients (3 men and 21 women; median age, 35.7 years [range, 20 to 65 years]) in whom H. pylori infection was cured and 3 patients (1 man 21 years of age and 2 women 22 and 37 years of age) in whom H. pylori infection was not cured were eligible for evaluation. Effects of Helicobacter pylori Eradication on Iron Deficiency Anemia At 6 months of follow-up, 18 of 24 (75%) patients recovered from anemia (P<0.001) and had a significant increase in the hemoglobin concentration, mean corpuscular volume, and ferritin level (Table). Table. Hematologic Data from 24 Patients with Iron Deficiency Anemia At 12 months of follow-up, 4 more patients (22 of 24 [91.7%]) showed recovery from anemia without resuming iron supplementation. The mean values of all measurements obtained were similar to those seen at the 6-month evaluation (Table). Even though ferritin levels returned to normal in only 4 patients at the 12-month follow-up visit, we observed a significant increase of more than 300% over baseline values (5.7 0.7 g/L compared with 24.1 5.0 g/L [P=0.0018]; mean increase, 18.4 g/L [CI, 8.08 to 29.44 g/L]). Mean transferrin saturation index also significantly increased from baseline (from 5.5% 0.8% to 18.7% 1.8% [P<0.001]; mean increase, 13.2 percentage points [CI, 8.92 to 17.46 percentage points]), even though values in 5 patients were still below the normal range. Eight patients were followed for 1 more year. Hemoglobin levels returned to normal in the two patients who were still anemic at the previous 12-month examination. In these patients, ferritin levels further increased from those measured at the 12-month follow-up (23.9 6.7 g/L and 30.5 7.4 g/L [P=0.047]; mean increase, 6.6 g/L [CI, 0.5 to 12.6 g/L]). In the three patients who were not cured, the hemoglobin level at 6 months of follow-up was stable in the male patient and was slightly decreased in the two female patients. These three patients experienced mild fatigue. However, in all patients, a clear decrease in ferritin levels was observed (data not shown). Helicobacter pylori Gastritis At diagnosis, 7 patients had mild antral atrophic gastritis, of whom 4 had associated chronic, body nonatrophic gastritis; 1 patient had only body nonatrophic gastritis; and 22 patients had chronic antral nonatrophic gastritis, 20 of whom had a similar pattern in the gastric body mucosa. Thus, considering the involvement of both gastric compartments, 24 of 30 (80%) patients with iron de

Gastrointestinal causes of refractory iron deficiency anemia in patients without gastrointestinal symptoms

BACKGROUND The standard evaluation of a patient with iron deficiency anemia includes a complete evaluation of the gastrointestinal tract to identify a source of bleeding. However, even after a careful examination, many patients remain without a diagnosis. Because iron deficiency anemia results from iron loss or defective absorption, we sought to determine the prevalence of potential gastrointestinal sources for iron deficiency anemia in patients without gastrointestinal symptoms. METHODS Over a 10-month period, 668 outpatients were referred to the University Hematology Department with iron deficiency anemia, defined by a hemoglobin concentration less than 14 g/dL (less than 12 g/dL in women), mean corpuscular volume less than 80 fL, and ferritin level less than 30 microg/L. After excluding patients with obvious causes of blood loss, inadequate diet, chronic diseases, or malignancies, there were 81 eligible patients, 10 of whom refused investigation. The remaining 71 patients (51 women, median age 59 years) underwent colonoscopy, as well as gastroscopy with gastric (antrum and body) and duodenal biopsies. RESULTS A likely cause of iron deficiency anemia was detected in 60 patients (85%). Diseases associated with bleeding were found in 26 patients (37%), including colon cancer (10 patients), gastric cancer (2), peptic ulcer (7), hiatal hernia with linear erosions (5), colonic vascular ectasia (3), colonic polyps (2), and Crohns disease (1). Causes not associated with bleeding were found in 36 patients (51%), including 19 with atrophic gastritis, 4 with celiac disease, and 13 with Helicobacter pylori gastritis. Six (8%) patients had coincident gastrointestinal findings, and 11 (15%) had no cause identified. Patients with an identified nonbleeding-associated cause were younger than those with a bleeding-associated cause (median, 56 vs 70 years; P = 0.001) and included 59% of women (n = 30) versus 30% of men (n = 6) (P = 0.04). Hemoglobin level was not related to the site and severity of disease. CONCLUSION Gastrointestinal diseases that do not usually cause bleeding are frequently associated with iron deficiency anemia in patients without gastrointestinal symptom or other potential causes of gastrointestinal bleeding.

Mitoxantrone, etoposide, and intermediate-dose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia.

Thirty-two patients with refractory acute myeloid leukemia (AML) received salvage therapy with a single course of mitoxantrone 6 mg/m2 intravenous (IV) bolus, etoposide 80 mg/m2 IV for a period of 1 hour, and cytarabine (Ara-C) 1 g/m2 IV for a period of 6 hours daily for 6 days (MEC). Eighteen patients were primarily resistant to conventional daunorubicin and Ara-C induction treatment; eight patients had relapsed within 6 months from initial remission; six patients had relapsed after a bone marrow transplantation (BMT) procedure. Overall, 21 patients (66%) achieved a complete remission (CR), two (6%) died of infection during induction, and nine (28%) had resistant disease. Age greater than 50 years was the only factor predictive for a significantly lower response rate (P = .03). The median remission duration was 16 weeks; the overall median survival was 36 weeks. Severe myelosuppression was observed in all patients resulting in fever or documented infections in 91% of patients. Nonhematologic toxicity was minimal. We conclude that the MEC regimen has significant antileukemic activity and acceptable toxicity in salvage AML. Its benefit in front-line AML therapy is being investigated.

High prevalence of atrophic body gastritis in patients with unexplained microcytic and macrocytic anemia: A prospective screening study

OBJECTIVE: Atrophic body gastritis (ABG) is characterized by atrophy of the gastric body mucosa, hypergastrinemia, and hypo/achlorhydria. Its association with pernicious anemia is well recognized. Gastric hypo/achlorhydria is known to affect iron absorption but ABG is rarely considered as a possible cause of iron deficiency (microcytic) anemia. The aims of this study were to validate a screening methodology for the detection of ABG in a consecutive series of patients with microcytic and macrocytic anemia and to investigate the clinical and gastric morphofunctional characteristics of the two hematological presentations of ABG. METHODS: A two-part prospective study was carried out. Part A aimed to validate the screening methodology to detect the presence of ABG in patients with macrocytic and microcytic anemia who have no specific GI symptoms, by measuring their gastrin levels and verified by performing gastroscopy with biopsy. Part B aimed to detect the presence of ABG in a larger sample of anemic patients by our validated method and, by pooling the data of ABG patients, to determine the clinical, gastric histological, and functional characteristics pertaining to the macrocytic and microcytic presentations of ABG. RESULTS: In part A, ABG was detected in 37.5% of patients with macrocytic and in 19.5% of those with microcytic anemia. Pooling the data of the ABG patients from part A and part B, microcytic ABG patients were on average 20 yr younger than those with macrocytic anemia. The majority of microcytic ABG patients were female, most of whom were premenopausal. H. pylori infection was widely represented in the microcytic ABG group (61.1%). They also had a lesser grade of body mucosal atrophy and lower hypergastrinemia levels, suggesting a less severe oxyntic damage of shorter duration. CONCLUSIONS: Macrocytic anemia is not the only hematological presentation of ABG. Physicians evaluating patients with unexplained iron deficiency anemia should consider ABG as a possible cause by determining fasting gastrin levels and performing gastroscopy with biopsies of the body mucosa.

Impact of a new dosing regimen of epoetin alfa on quality of life and anemia in patients with low-risk myelodysplastic syndrome

This study evaluated the impact of a new epoetin alfa dosing regimen on quality of life (QOL), transfusion requirements, and hemoglobin (Hb) levels in 133 patients with low-risk myelodysplastic syndrome (MDS) and Hb ≤10 g/dl. Epoetin alfa 40,000 IU was given subcutaneously twice weekly; after 4 weeks, the dose could be reduced to 40,000 IU weekly in patients achieving erythroid response. QOL was assessed using the functional assessment of cancer therapy-anemia (FACT-An) questionnaire. FACT-An scores increased on average by 7.5 after 4 weeks and by 8.8 after 8 weeks compared with baseline. FACT-An scores were positively associated with Hb values (r=0.53, P<0.01). The mean FACT-An score increase at week 8 was 10.2 in responders and 5.6 in nonresponders. The overall erythroid response rate at week 8 was 68%: 74% in transfusion-independent patients and 59% in transfusion-dependent patients. Of all responders at week 8, response was maintained in 86% at week 12, 71% at week 16, 65% at week 20, and 54% at week 24. Treatment was generally well tolerated. Our data provide new and encouraging results regarding the benefits of 40,000 IU biweekly induction doses followed by 40,000 IU weekly in improving QOL, correcting anemia, and reducing transfusion requirements in low-risk MDS patients.

Low absolute lymphocyte count is a poor prognostic factor in diffuse-large-B-cell-lymphoma

The prognostic value of absolute lymphocytic count (ALC), has been a recent matter of debate in non-Hodgkin-lymphoma (NHL). We assessed prospectively the value of ALC at diagnosis and also after the completion of immuno-chemotherapy in 101 diffuse-large-B-cell-lymphoma (DLBCL). Analysis of prognostic factors with respect to overall survival (OS), event free survival (EFS) and progression free survival (PFS) was done by two-tailed log-rank test. The ALC cut-off value was calculated as <0.84 × 109/L at diagnosis: this was a strong negative prognostic factor for OS (p = 0.0004), EFS (p < 0.00001) and PFS (p < 0.00001) and in multivariate analysis was independent from the revised-international-prognostic-index (R-IPI). ALC after chemo-immunotherapy was not of prognostic value. As R-IPI and ALC < 0.84 × 109/L, were the factors better discriminating poor prognosis, a new trichotomous score (ALC/R-IPI) was built up: (1) low risk: R-IPI = very good or good and ALC < 0.84 × 109/L; (2) intermediate risk: patients with at least one risk factor (R-IPI = poor or ALC < 0.84 × 109/L). (3) high risk: patients with both risk factors. This new prognostic score was highly significant in univariate analysis for OS (p = 0.0002), EFS (p < 0.00001) and PFS (p < 0.00001). In multivariate analysis ALC/R-IPI was the most predictive factor for OS (OR = 2.954; p = 0.002) and EFS (OR = 2.381; p < 0.00001) and the only predictive factor for PFS (OR = 4.018; p < 0.00001).Our data, show that ALC at diagnosis has a strong prognostic relevance and is independent from the R-IPI. The new score including both values proved the most powerful predictor at multivariate analysis.

Absolute lymphocyte count is a prognostic factor in diffuse large B-cell lymphoma

imab is associated with a reduction in IgG antibodies to ADAMTS13. British Journal of Haematology, 136, 451–461. Yarranton, H., Lawrie, A.S., MacKie, I.J., Pinkoski, L., Corash, L. & Machin, S.J. (2005) Coagulation factor levels in cryosupernatant prepared from plasma treated with amotosalen hydrochloride (S-59) and ultraviolet A light. Transfusion, 45, 1453–1458.

Sequential combination of systemic high-dose ara-C and asparaginase for the treatment of central nervous system leukemia and lymphoma.

Eight patients with overt central nervous system (CNS) leukemia and lymphoma were treated with sequential administration of systemic high-dose cytosine arabinoside (HiDAC) and asparaginase (ASP) with no direct CNS therapy. Complete clearing of the cerebrospinal fluid (CSF) was achieved in six (86%) of seven patients with meningeal disease, generally after the first course of therapy. Two patients presented with evidence of extensive intracerebral disease; both responded with a greater than 50% regression of the tumor infiltrates. Concomitant extraneurologic localizations responded equally well to HiDAC/ASP: responses were seen in four of five patients, including complete remission in three of four patients who presented with marrow involvement. Toxicity was generally moderate and limited to myelosuppression (eight of eight patients), tolerable nausea and vomiting (eight of eight patients), mild hepatotoxicity (two of eight patients), and oral mucositis (one of eight patients). These results indicate that HiDAC/ASP is a tolerable and highly effective treatment modality for CNS leukemia and lymphoma and suggest its potential role for sanctuary chemoprophylaxis.

HCV-positive status and hepatitis flares in patients with B-cell non-Hodgkin's lymphoma treated with rituximab-containing regimens.

BACKGROUND Rituximab has provided a revolutionary contribution to the treatment of B-cell non-Hodgkins lymphomas (NHL). A high prevalence of hepatitis C virus (HCV) infection has been described in B-cell NHL patients. Cases of liver dysfunction in HCV-positive patients have been reported with rituximab-containing regimens. AIM to evaluate the liver-related effects of rituximab-containing regimens on HCV-positive CD20-positive B-cell NHL patients. PATIENTS AND METHODS Retrospective analysis of 104 consecutive patients. HCV status was determined, and development of hepatitis flares analysed. RESULTS Nine patients (8.6%) were HCV-positive. No correlation was shown between viral load and alanine transaminase levels. Three of the 9 HCV-positive, and none of the 95 HCV-negative developed hepatitis flares (p<0.001). At the 12-month follow-up hepatitis flare patients were alive and in remission for their haematological disease and no hepatitis flares, liver-related death had developed. CONCLUSIONS HCV-positive status may represent a risk factor for the development of hepatic flares in B-cell NHL patients receiving rituximab-containing regimens. Despite the increase in liver function tests, there were no major clinical events.

Endoscopic evaluation of the upper gastrointestinal tract is worthwhile in premenopausal women with iron-deficiency anaemia irrespective of menstrual flow

Background: In premenopausal women, iron-deficiency anaemia is common and menstrual flow is often held responsible, but it is not clear whether these women should be submitted to gastrointestinal (GI) evaluation. We aim to prospectively investigate whether premenopausal women with iron-deficiency anaemia benefit from GI evaluation regardless of menstrual flow. Methods: The study population comprised 59 consecutive premenopausal women with iron-deficiency anaemia. Excluded were women with obvious or suspected causes of anaemia and those ≤21 years. Heavy menstrual loss was not considered an exclusion criterion. All subjects had: complete blood count, ferritin, non-invasive testing by faecal occult blood (FOB), 13C-urea breath test (13C-UBT), anti-tissue transglutaminase antibodies (tTG) and gastrin levels. Gastroscopy with antral (n = 3), corporal (n = 3) and duodenal (n = 2) biopsies was performed in women with positive 13C-UBT or tTG titre or hypergastrinaemia. Results: Heavy menstrual loss was present in 50.8%. Non-invasive tests were positive in 40/59 (67.8%): 30 had positive 13C-UBT, 12 had hypergastrinaemia, 7 had positive tTG and 3 had positive FOB. Women tested positive were similar to those tested negative as far as concerned age, haemoglobin and ferritin levels and heavy menstrual flow (55% versus 42.1%). All 40 women tested positive underwent gastroscopy with biopsies. Four (10%) had bleeding-associated lesions and 34 (85%) had non-bleeding-associated lesions. As regards upper GI findings, no differences were observed between women with normal and those with heavy menstrual flow. No lower GI tract lesions were detected in the three women with positive FOB. Conclusions: Our data suggest that premenopausal women with iron-deficiency anaemia benefit from endoscopic evaluation of the upper GI tract irrespective of menstrual flow.