Bruno Annibale

Meticulous Prevention of Hypoglycemia Normalizes the Glycemic Thresholds and Magnitude of Most of Neuroendocrine Responses to, Symptoms of, and Cognitive Function During Hypoglycemia in Intensively Treated Patients With Short-Term IDDM

To test the hypothesis that hypoglycemia unawareness is largely secondary to recurrent therapeutic hypoglycemia in IDDM, we assessed neuroendocrine and symptom responses and cognitive function in 8 patients with short-term IDDM (7 yr) and hypoglycemia unawareness. Patients were assessed during a stepped hypoglycemic clamp, before and after 2 wk and 3 mo of meticulous prevention of hypoglycemia, which resulted in a decreased frequency of hypoglycemia (0.49 ± 0.05 to 0.045 ± 0.03 episodes/patient-day) and an increase in HbA1c (5.8 ± 0.3 to 6.9 ± 0.2%) (P < 0.05). We also studied 12 nondiabetic volunteer subjects. At baseline, lower than normal symptom and neuroendocrine responses occurred at lower than normal plasma glucose, and cognitive function deteriorated only marginally during hypoglycemia. After 2 wk of hypoglycemia prevention, the magnitude of symptom and neuroendocrine responses (with the exception of glucagon and norepinephrine) nearly normalized, and cognitive function deteriorated at the same glycemic threshold and to the same extent as in nondiabetic volunteer subjects. At 3 mo, the glycemic thresholds of symptom and neuroendocrine responses normalized, and surprisingly, some of the responses of glucagon recovered. We concluded that hypoglycemia unawareness in IDDM is largely reversible and that intensive insulin therapy and a program of intensive education may substantially prevent hypoglycemia and at the same time maintain the glycemic targets of intensive insulin therapy, at least in patients with IDDM of short duration.

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

Long-term recovery from unawareness, deficient counterregulation and lack of cognitive dysfunction during hypoglycaemia, following institution of rational, intensive insulin therapy in IDDM.

SummaryHypoglycaemia unawareness, is a major risk factor for severe hypoglycaemia and a contraindication to the therapeutic goal of near-normoglycaemia in IDDM. We tested two hypotheses, first, that hypoglycaemia unawareness is reversible as long as hypoglycaemia is meticulously prevented by careful intensive insulin therapy in patients with short and long IDDM duration, and that such a result can be maintained long-term. Second, that intensive insulin therapy which strictly prevents hypoglycaemia, can maintain long-term near-normoglycaemia. We studied 21 IDDM patients with hypoglycaemia unawareness and frequent mild/severe hypoglycaemia episodes while on “conventional” insulin therapy, and 20 nondiabetic control subjects. Neuroendocrine and symptom responses, and deterioration in cognitive function were assessed in a stepped hypoglycaemia clamp before, and again after 2 weeks, 3 months and 1 year of either intensive insulin therapy which meticulously prevented hypoglycaemia (based on physiologic insulin replacement and continuous education, experimental group, EXP, n=16), or maintenance of the original “conventional” therapy (control group, CON, n=5). At entry to the study, all 21 IDDM-patients had subnormal neuroendocrine and symptom responses, and less deterioration of cognitive function during hypoglycaemia. After intensive insulin therapy in EXP, the frequency of hypoglycaemia decreased from 0.5±0.05 to 0.045±0.02 episodes/patient-day; HbA1C increased from 5.83±0.18 to 6.94±0.13% (range in non-diabetic subjects 3.8–5.5%) over a 1-year period; all counterregulatory hormone and symptom responses to hypoglycaemia improved between 2 weeks and 3 months, with the exception of glucagon which improved at 1 year; and cognitive function deteriorated further as early as 2 weeks (p<0.05). The improvement in responses was maintained at 1 year. The improvement in plasma adrenaline and symptom responses inversely correlated with IDDM duration. In contrast, in CON, neither frequency of hypoglycaemia, nor neuroendocrine responses to hypoglycaemia improved. Thus, meticulous prevention of hypoglycaemia by intensive insulin therapy reverses hypoglycaemia unawareness even in patients with long-term IDDM, and is compatible with long-term near-normoglycaemia. Because carefully conducted intensive insulin therapy reduces, not increases the frequency of moderate/severe hypoglycaemia, intensive insulin therapy should be extended to the majority of IDDM patients in whom it is desirable to prevent/delay the onset/progression of microvascular complications.

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.

Relative roles of insulin and hypoglycaemia on induction of neuroendocrine responses to, symptoms of, and deterioration of cognitive function in hypoglycaemia in male and female humans.

SummaryTo assess the relative roles of insulin and hypoglycaemia on induction of neuroendocrine responses, symptoms and deterioration of cognitive function (12 cognitive tests) during progressive decreases in plasma glucose, and to quantitate glycaemic thresholds, 22 normal, non-diabetic subjects (11 males, 11 females) were studied on four occasions: prolonged fast (n=8, saline euglycaemia study, SA-EU), stepped hypoglycaemia (plasma glucose plateaus of 4.3, 3.7, 3 and 2.3 mmol/l) or euglycaemia during insulin infusion at 1 and 2 mU·kg−1·min−1 (n=22, high-insulin hypoglycaemia and euglycaemia studies, HI-INS-HYPO and HI-INS-EU, respectively), and stepped hypoglycaemia during infusion of insulin at 0.35 mU· kg−1·min−1 (n=9, low-insulin hypoglycaemia study, LO-INS-HYPO). Insulin per se (SA-EU vs HI-INS-EU), suppressed plasma glucagon (∼20%) and pancreatic polypeptide (∼30%), whereas it increased plasma noradrenaline (∼R10%, p<0.05). Hypoglycaemia per se (HI-INS-HYPO vs HI-INS-EU) induced responses of counterregulatory hormones (CR-HORM), symptoms and deteriorated cognitive function. With the exception of suppression of endogenous insulin secretion, which had the lowest glycaemic threshold of 4.44±0.06 mmol/l, pancreatic polypeptide, glucagon, growth hormone, adrenaline and cortisol had similar glycaemic thresholds (∼3.8-3.6 mmol/l); noradrenaline (3.1±0.0 mmol/l), autonomic (3.05±0.06 mmol/l) and neuroglycopenic (3.05±0.05 mmol/l) symptoms had higher thresholds. All 12 tests of cognitive function deteriorated at a glycaemic threshold of 2.45±0.06 mmol/l, but 7 out of 12 tests were already abnormal at a glycaemic threshold of 2.89±0.06 mmol/l. Although all CR-HORM had a similar glycaemic threshold, the lag time of response (the time required for a given parameter to increase) of glucagon (15±1 min) and growth hormone (14±3 min) was shorter than adrenaline (19±3 min) and cortisol (39±4 min) (p<0.05). With the exception of glucagon (which was suppressed) and noradrenaline (which was stimulated), insulin per se (HI-INS-HYPO vs LO-INS-HYPO) did not affect the responses of CR-HORM, and did not influence the symptoms or the cognitve function during hypoglycaemia. Despite lower responses of glucagon, adrenaline and growth hormone (but not thresholds) in females than males, females were less insulin sensitive than males during stepped hypoglycaemia.

Concomitant alterations in intragastric pH and ascorbic acid concentration in patients with Helicobacter pylori gastritis and associated iron deficiency anaemia

Background: Seroepidemiological and clinical studies suggest that Helicobacter pylori may cause iron deficiency anaemia (IDA) in the absence of peptic lesions by undefined mechanisms, which still remain to be fully elucidated. Gastric acidity and ascorbic acid (AA) promote iron absorption. AA is lowered in the presence of H pylori infection. H pylori can cause atrophic body gastritis with achlorhydria, decreased iron absorption, and consequent IDA. Whether alterations in intragastric acidity and AA concentrations play a role in IDA developing in patients with H pylori gastritis remains to be determined. Aim: To evaluate gastric juice pH and gastric juice and plasma AA in patients with H pylori infection and unexplained IDA, compared with controls with IDA and a healthy stomach or with controls with H pylori infection and no IDA. Results: Patients with IDA and H pylori gastritis were characterised by concomitant increased intragastric pH (median value 7) and decreased intragastric AA (median value 4.4 μg/ml) compared with controls with a healthy stomach (median pH 2; median intragastric AA 17.5 μg/ml) and with H pylori positive controls without IDA (median pH 2.1; median intragastric AA 7.06 μg/ml). Intragastric AA was inversely related to pH (r=−0.40, p=0.0059) and corporal degree of gastritis (r=−0.53, p=0.0039). Plasma AA concentrations were lower in all infected groups than in healthy controls. Conclusions: Patients with unexplained IDA and H pylori gastritis present concomitant changes in intragastric pH and AA that may justify impaired alimentary iron absorption and consequent IDA.

ENETS consensus guidelines for the standards of care in neuroendocrine tumors: Somatostatin receptor imaging with IIIIn-pentetreotide

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors : Somatostatin Receptor Imaging with In-111-Pentetreotide

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.

Systematic review: distribution of advanced neoplasia according to polyp size at screening colonoscopy

Background  The impact of not referring sub‐centimetre polyps identified at CT colonography upon the efficacy of colorectal cancer screening remains uncertain.

A Prospective Study of Gastric Carcinoids and Enterochromaffin-Like Cell Changes in Multiple Endocrine Neoplasia Type 1 and Zollinger-Ellison Syndrome: Identification of Risk Factors

CONTEXT Multiple endocrine neoplasia type 1 (MEN1) patients frequently develop Zollinger-Ellison syndrome (ZES). These patients can develop proliferative changes of gastric enterochromaffin-like (ECL) cells and gastric carcinoids (ECL-cell tumors). ECL-cell changes have been extensively studied in sporadic ZES patients and can be precursor lesions of gastric carcinoids, but little is known about factors influencing their severity or development of carcinoids in MEN1/ZES patients. OBJECTIVES Our objective was to prospectively analyze ECL-cell changes and gastric carcinoids (ECL-cell tumors) in a large series of MEN1/ZES patients to detect risk factors and deduct clinical guidelines. SETTING AND PATIENTS Fifty-seven consecutive MEN1/ZES patients participated in this prospective study at two tertiary-care research centers. INTERVENTIONS AND OUTCOME MEASURES Assessment of MEN1, gastric hypersecretion, and gastroscopy with multiple biopsies was done according to a fixed protocol and tumor status. ECL-cell changes and alpha-human chorionic gonadotropin staining were assessed in each biopsy and correlated with clinical, laboratory, and MEN1 features. RESULTS ECL-cell proliferative changes were universally present, advanced changes in 53% and carcinoids in 23%. Gastric nodules are common and are frequently associated with carcinoids. Patients with high fasting serum gastrin levels, long disease duration, or a strong alpha-human chorionic gonadotropin staining in a biopsy are at higher risk for an advanced ECL-cell lesion and/or gastric carcinoid. CONCLUSIONS Gastric carcinoids and/or advanced ECL-cell changes are frequent in MEN1/ZES patients, and therefore, regular surveillance gastroscopy with multiple routine biopsies and biopsies of all mucosal lesions are essential. Clinical/laboratory data and biopsy results can be used to identify a subgroup of MEN1/ZES patients with a significantly increased risk for developing gastric carcinoids, allowing development of better surveillance strategies.