Vitamin B12 deficiency in hypersecretors during long-term acid suppression with proton pump inhibitors.

BACKGROUND: Proton pump inhibitors (PPIs) may cause cyanocobalamin (vitamin B12) malabsorption, but measuring serum B12 alone may underestimate the prevalence. However, B12 deficiency elevates methylmalonic acid and homocysteine, both additional markers of B12 deficiency. AIM: To determine the true prevalence of B12 deficiency and whether acid suppression by PPI caused it. METHODS: Sixty-one acid hypersecretors (basal acid output >15 mmol/h), 46 with gastrinoma [Zollinger-Ellison (ZE) syndrome] and 15 without [acid hypersecretor without gastrinoma (pseudo-ZE)], were treated with lansoprazole to determine its long-term (up to 18 years) pharmacological and clinical efficacy and safety, particularly as regards malabsorption of B12. RESULTS: Of 61 patients, six (10%) had low serum B12. Additional tests uncovered B12 deficiency in 13 (31%) of 41 still-available patients, despite normal serum B12. B12 replacement reduced elevated homocysteine and methylmalonic acid, supporting the diagnosis. Also, measuring both basal and stimulated gastric secretion, we found that acid suppression was neither prolonged nor profound enough to explain the B12 deficiency. CONCLUSIONS: In long-term recipients of PPIs, B12 deficiency was more frequent (29%) than detected by measuring only serum B12, and there was not enough acid suppression to explain this deficiency.

Chromogranin A in patients with acid hypersecretion and/or hypergastrinaemia.

BACKGROUND: Chromogranin has been proposed as a marker for gastrin-dependent enterochromaffin-like cell proliferation. AIM: To examine this question in three populations: acid hypersecretors with gastrinoma (Zollinger-Ellison), or without gastrinoma (non-Zollinger-Ellison), and also in pernicious anaemia with achlorhydria-caused hypergastrinaemia. METHODS: We measured serum chromogranin, gastrin, gastric secretion and counted and quantified hyperplasia of enterochromaffin-like cells in gastric biopsies from 38 Zollinger-Ellison and 13 non-Zollinger-Ellison patients being treated with lansoprazole, for 5 years (median) and again 2.5 years later. We also studied 12 patients with pernicious anaemia, half with gastric enterochromaffin-like cell carcinoids. RESULTS: Serum chromogranin was elevated in patients with gastrinoma, even without any enterochromaffin-like cell proliferation, but not in non-Zollinger-Ellison acid hypersecretors with normal gastrin (P < 0.001). In the hypersecretors chromogranin correlated well with serum gastrin (r = 0.82), but not with enterochromaffin-like cell proliferation. Moreover, chromogranin was normal or near normal (<75 ng/mL) despite very high serum gastrin in five of six patients with pernicious anaemia and enterochromaffin-like cell carcinoids. CONCLUSIONS: Chromogranin is not a reliable marker for enterochromaffin-like cell activity or proliferation up to and including carcinoid; chromogranin originates in the gastrinoma and, like gastrin, is a marker for gastrinoma in acid hypersecretors.

Comparison of 13C- urea blood test to 13C-breath test and rapid urease test for the diagnosis of Helicobacter pylori infection / Comparación entre el test de urea marcada con 13C- en sangre, test de urea marcada con 13C- en aire espirado y el test rápido de ureasa para el diagnóstico de la infección por Helicobacter pylori

At present, the available methods to diagnose active H. pylori infection are endoscopy with biopsy for histology, culture, rapid urease tests, 13C or 14C urea breath test, urine antibody and the stool antigen test. The aims of this study were to simplify the 13C urea test by measuring 13C in blood rather than breath, and to evaluate the usefulness of the 13C urea blood test for the diagnosis of H. pylori infection. Patients who underwent upper endoscopy for standard clinical indications (e.g. dyspepsia, abdominal pain) were enrolled. A total of 161 patients (93F, 68M, mean age 47 +/- 14.2) were evaluated; 50 (31%) of them were H. pylori positive, and 111(69%) were H. pylori negative. H. pylori infection was diagnosed with a rapid urease test (CLO-test) and 13C urea breath test (UBT). Performance characteristics for the 13C urea blood test for diagnosis and evaluation of H. pylori eradication were calculated using UBT and CLO as gold standards. The fifty H. pylori-positive patients were treated with triple antibiotic therapy for two weeks. Four weeks after finishing antibiotic therapy patients were retested with a commercial UBT and urea blood test. The 13C blood test had sensitivities of 92 and 98% and specificities of 96 and 100% as compared with urea breath test and CLO, respectively. We conclude that the 13C urea blood test is highly sensitive and specific for the initial diagnosis and control of eradication of H. pylori infection.

Los métodos diagnósticos disponibles para la identificación de la infección activa por H. pylori son endoscopia con biopsia para histología, test rápido de ureasa y/o cultivo, test del aire espirado con urea marcada con 13C o 14C, anticuerpos anti- H. pylori en orina y test de antígeno en materia fecal. La finalidad del presente estudio fue simplificar el test de aire espirado con urea marcada con 13C, midiendo 13C en sangre en vez de en el aire espirado y evaluar su eficacia para el diagnostico de la infección por H. pylori. Pacientes a los que se les realizó esofagogastroduodenoscopía con indicaciones de dispepsia y/o dolor abdominal fueron incluidos en el estudio. 161 pacientes (93 del sexo femenino y 68 masculino, edad media 47±14.2) fueron evaluados; 50 (31%) de ellos fueron H. pylori positivos, y 111 (69%) fueron negativos. La infección por H. pylori fue diagnosticada con test rápido de ureasa y test del aire espirado on urea marcada con 13C. Usando estos tests como referencia, se evaluó la eficacia del test de sangre con urea marcada con 13C para el diagnóstico y evaluación de la erradicación del H. pylori. Los 50 pacientes positivos para la infección con H. pylori fueron tratados con triple plan de antibióticos por 2 semanas. Cuatro semanas luego de finalizado dicho tratamiento, los pacientes fueron nuevamente testeados con test de aire espirado con urea marcada con 13C y urea marcada con 13C en sangre. El test en sangre con urea marcada con 13C tuvo sensitividad de 92% y 98% y especificidad de 96% y 100% comparado con UBT y test de ureasa respectivamente. Concluimos que el test en sangre con urea marcada con 13C es altamente sensible y especifico para diagnostico inicial y control de la erradicación de la infección por H. pylori.

Comparison of 13C- urea blood test to 13C-breath test and rapid urease test for the diagnosis of Helicobacter pylori infection

At present, the available methods to diagnose active H. pylori infection are endoscopy with biopsy for histology, culture, rapid urease tests, 13C or 14C urea breath test, urine antibody and the stool antigen test. The aims of this study were to simplify the 13C urea test by measuring 13C in blood rather than breath, and to evaluate the usefulness of the 13C urea blood test for the diagnosis of H. pylori infection. Patients who underwent upper endoscopy for standard clinical indications (e.g. dyspepsia, abdominal pain) were enrolled. A total of 161 patients (93F, 68M, mean age 47 +/- 14.2) were evaluated; 50 (31%) of them were H. pylori positive, and 111(69%) were H. pylori negative. H. pylori infection was diagnosed with a rapid urease test (CLO-test) and 13C urea breath test (UBT). Performance characteristics for the 13C urea blood test for diagnosis and evaluation of H. pylori eradication were calculated using UBT and CLO as gold standards. The fifty H. pylori-positive patients were treated with triple antibiotic therapy for two weeks. Four weeks after finishing antibiotic therapy patients were retested with a commercial UBT and urea blood test. The 13C blood test had sensitivities of 92 and 98% and specificities of 96 and 100% as compared with urea breath test and CLO, respectively. We conclude that the 13C urea blood test is highly sensitive and specific for the initial diagnosis and control of eradication of H. pylori infection.(AU)

Los métodos diagnósticos disponibles para la identificación de la infección activa por H. pylori son endoscopia con biopsia para histología, test rápido de ureasa y/o cultivo, test del aire espirado con urea marcada con 13C o 14C, anticuerpos anti- H. pylori en orina y test de antígeno en materia fecal. La finalidad del presente estudio fue simplificar el test de aire espirado con urea marcada con 13C, midiendo 13C en sangre en vez de en el aire espirado y evaluar su eficacia para el diagnostico de la infección por H. pylori. Pacientes a los que se les realizó esofagogastroduodenoscopía con indicaciones de dispepsia y/o dolor abdominal fueron incluidos en el estudio. 161 pacientes (93 del sexo femenino y 68 masculino, edad media 47±14.2) fueron evaluados; 50 (31%) de ellos fueron H. pylori positivos, y 111 (69%) fueron negativos. La infección por H. pylori fue diagnosticada con test rápido de ureasa y test del aire espirado on urea marcada con 13C. Usando estos tests como referencia, se evaluó la eficacia del test de sangre con urea marcada con 13C para el diagnóstico y evaluación de la erradicación del H. pylori. Los 50 pacientes positivos para la infección con H. pylori fueron tratados con triple plan de antibióticos por 2 semanas. Cuatro semanas luego de finalizado dicho tratamiento, los pacientes fueron nuevamente testeados con test de aire espirado con urea marcada con 13C y urea marcada con 13C en sangre. El test en sangre con urea marcada con 13C tuvo sensitividad de 92% y 98% y especificidad de 96% y 100% comparado con UBT y test de ureasa respectivamente. Concluimos que el test en sangre con urea marcada con 13C es altamente sensible y especifico para diagnostico inicial y control de la erradicación de la infección por H. pylori.(AU)

Minor effects of Helicobacter pylori on gastric secretion and dose of lansoprazole during long-term treatment in ZE and non-ZE acid hypersecretors.

BACKGROUND: Helicobacter pylori infection may increase or decrease acid secretion and may augment proton pump inhibitor efficacy. Pepsin effects have not been reported. In Zollinger-Ellison syndrome (ZE) specifically, H. pylori has been reported to decrease acid. AIM: To examine H. pylori effects on secretion and dose of medication in hypersecretors (basal acid output > 15 mmol/h) undergoing long-term treatment with individually optimized lansoprazole doses. METHODS: Sixty-five patients (47 ZE and 18 non-ZE), treated for > 3 months to 10 years, were tested every 6 months with endoscopy, gastric analysis and serum gastrin. RESULTS: Forty-three per cent were H. pylori-positive. Acid, pepsin and gastrin were not different between H. pylori-positive and H. pylori-negative patients before or during long-term lansoprazole treatment. Initially, H. pylori-positive patients required less lansoprazole than H. pylori-negative patients (68 +/- 6 vs. 96 +/- 8 mg/day), but after 3 years the doses converged (83 vs. 86 mg/day). The disappearance of H. pylori in 15 patients caused no significant changes in acid, pepsin, gastrin or lansoprazole dose in the following 4 years. CONCLUSIONS: H. pylori had no significant initial or long-term physiological or potential clinical effects on acid or pepsin secretion or gastrin in these acid hypersecretors.

Long-term lansoprazole control of gastric acid and pepsin secretion in ZE and non-ZE hypersecretors: a prospective 10-year study.

BACKGROUND: The majority of patients with Zollinger-Ellison syndrome require lifelong treatment with proton pump inhibitors. AIMS: To determine the efficacy of lansoprazole control of acid and pepsin secretion over the long term in Zollinger-Ellison syndrome and non-Zollinger-Ellison syndrome hypersecretors. METHODS: Sixty-three hypersecretors (basal acid output > 15 mmol/h), 46 Zollinger-Ellison syndrome and 17 non-Zollinger-Ellison syndrome, with a total history of 15.4 and 19.2 years, respectively, were entered into a long-term prospective study using lansoprazole. Sixty-one were studied every 3 months for 1 year and then every 3-6 months up to 10 years during lansoprazole treatment with endoscopy, serum gastrin and gastric analysis, measuring both basal and stimulated pH and acid and pepsin secretion. Doses were individually optimized and adjusted to keep the basal acid output at < 5 mmol/h in intact patients and < 1 mmol/h in antrectomized Zollinger-Ellison syndrome patients. RESULTS: The dose of lansoprazole could not be predicted a priori from pre-treatment acid or pepsin output, serum gastrin, prior omeprazole dose or diagnosis or prior complications. The median dose was approximately 80 mg/day, with a wide range from 15 mg every other day to 360 mg/day, and generally stabilized by 12 months. However, as doses were adjusted over time for indications, almost half the patients required higher doses. With adjustments, the basal acid output was maintained in the target range in > 90% of intact patients and in 80% of antrectomized patients. Gastric juice pH increased from approximately 1.2 before therapy to > 3.4 during therapy. Serum gastrin in Zollinger-Ellison syndrome patients, after excluding five outliers, did not change over the course of therapy, but doubled in non-Zollinger-Ellison syndrome patients. There were no adverse events due to lansoprazole, and routine laboratory studies remained normal. CONCLUSIONS: The dose of lansoprazole for hypersecretors cannot be predicted, and thus needs to be optimized empirically on an individual basis. With continued periodic adjustments, almost half the patients required increased doses, while safe dose reduction was possible in only one-quarter. When individually optimized, lansoprazole proved to be safe and effective in the control of secretion for the treatment of both Zollinger-Ellison syndrome and non-Zollinger-Ellison syndrome hypersecretors for up to 10 years.

Questions regarding future research on aspirin and the gastrointestinal tract.

Despite great proven and potential benefits, aspirin also has adverse side effects on all parts of the gastrointestinal tract including ulceration, bleeding, perforation, and stenosis. Because of widespread and growing use, there is a need to understand and, if possible, prevent the adverse effects of aspirin while maintaining its benefits. This article is part of a report from a consensus meeting in 1999 on nonsteroidal anti-inflammatory drugs, and examines possible mechanisms of each of the risks of normal and low-dose aspirin use including areas of uncertainty. Based on these issues, we recommend studies that would further clarify the actions of aspirin. We also examine various strategies that might be used to prevent or mitigate adverse effects. Finally, we propose future research prospects in the search for a safer aspirin.

Helicobacter pylori effects on gastritis, gastrin and enterochromaffin-like cells in Zollinger-Ellison syndrome and non-Zollinger-Ellison syndrome acid hypersecretors treated long-term with lansoprazole.

BACKGROUND: Helicobacter pylori is said to cause atrophy of the gastric corpus and enterochromaffin-like cell proliferation in gastro-oesophageal reflux disease (GERD) patients treated long-term with a proton pump inhibitor. AIMS: To determine the effect of H. pylori infection on gastritis, enterochromaffin-like cell density and hyperplasia, mucosal atrophy and serum gastrin in patients with gastric hypersecretion (basal acid output gt; 15 mmol/h) with either hypergastrinemia (Zollinger-Ellison syndrome) or normal gastrin (non-Zollinger-Ellison syndrome) before and during long-term treatment with lansoprazole. METHODS: Lansoprazole was individually titrated to reduce basal acid output to < 5 mmol/h (< 1 mmol/h in post-surgical Zollinger-Ellison syndrome). Gastric corpus biopsies were obtained every 6 months before treatment and up to 8 years later. RESULTS: H. pylori was present in corpus biopsies in approximately 50%, causing active gastritis which resolved rapidly in 15 subjects after elimination of H. pylori. Patchy mild/moderate corpus atrophy was present at entry in two and at the end in four out of 60 patients, one being H. pylori-positive. Intestinal metaplasia (< 10%) was seen in six isolated biopsies (1% of total). H. pylori did not affect serum gastrin, enterochromaffin-like cell density or hyperplasia. Enterochromaffin-like cell density was twice as high in Zollinger-Ellison syndrome as in non-Zollinger-Ellison syndrome patients (241 vs. 126 cells/mm2, P < 0.001). Enterochromaffin-like cells remained normal in the non-Zollinger-Ellison syndrome hypersecretors regardless of H. pylori status. CONCLUSION: Corpus enterochromaffin-like cell increases were related to serum gastrin elevation, but neither H. pylori nor long-term treatment with lansoprazole alone or together had any effect on enterochromaffin-like cell density or hyperplasia. Corpus acute gastritis resulted from H. pylori infection, but did not result in mucosal atrophy despite long-term proton pump inhibitor treatment and promptly resolved with loss of H. pylori.

Study of outcome after targeted intervention for peptic ulcer resistant to acid suppression therapy.

OBJECTIVE: Different factors might affect outcome in ulcers resistant to antisecretory therapy. The aim of the study was to define the odds of resistant ulcers being associated with NSAID use, and/or Helicobacter pylori (H. pylori) infection, or neither. METHODS: A total of 80 patients with resistant peptic ulcers were prospectively followed after targeted intervention for a mean follow-up of 39.5+/-6.9 months. RESULTS: NSAID use was involved in 24 cases (14 with and 10 without concomitant H. pylori infection), H. pylori alone was involved in 44, and 12 patients had neither factor present. Of the NSAID group, resistant ulcers healed in patients who stopped taking NSAIDs. Those continuing to use NSAIDs (10 of 24; 41.6%) had either persistent ulceration or ulcer complications despite H. pylori eradication and omeprazole therapy. Of the H. pylori group, infection eradication induced ulcer remission in most patients, but those with persistent infection and a small subset of H. pylori eradicated patients (16.6%) had persistent/recurrent ulceration. Of the 12 refractory patients with neither NSAID use nor H. pylori infection, three had persistent ulceration but nine were controlled with antisecretory agents. Other factors (e.g., smoking or acid hypersecretion) were not associated with final outcome after targeted intervention of H. pylori infection and NSAID use. CONCLUSIONS: With current antiulcer therapies, NSAID use is the main, but not the exclusive, factor leading to intractability and complications in refractory ulcers. In a subset of resistant ulcers, neither the presence of H. pylori nor use of NSAIDs are involved. In this study, despite specific therapeutic intervention, 22.5% of patients with resistant ulcers had continuing ulcer problems.

Association of obesity with hiatal hernia and esophagitis.

OBJECTIVE: Although weight loss is commonly recommended for symptoms of gastroesophageal reflux, a relationship between excessive body weight and esophageal reflux has not been established. The aim of this study was to determine whether obesity is associated with the presence of a hiatal hernia (HH) and/or an endoscopic diagnosis of esophagitis. METHODS: Retrospective case control studies were done using 1389 patients who underwent gastric analysis and upper GI endoscopy between 1974 and 1995. After excluding patients with Zollinger-Ellison syndrome, 189 cases of esophagitis with 1024 controls were identified. In a separate analysis of the database, 151 cases of HH with 1053 controls were also identified. Patients were classified by body mass index (BMI) as: thin (BMI <20 kg/m2), normal (BMI 20-25), mildly obese (BMI 25-30), and obese (BMI >30). RESULTS: Excessive body weight was significantly associated with the presence of HH, the probability of HH increasing with each level of BMI (p < 0.01), as well as with esophagitis (OR 1.8; 95% CI 1.4-2.1). HH was independently associated with esophagitis (OR 4.2 95% CI 2.9-6.1); when controlled for the effect of HH, the association between BMI and esophagitis diminished but remained significant. In the population as a whole, for the presence of esophagitis multiple logistic regression indicates BMI and hiatal hernia were significant factors but gender and race did not appear to be. CONCLUSIONS: Excessive body weight is a significant independent risk factor for hiatal hernia and is significantly associated with esophagitis, largely through an increased incidence of hiatal hernia. Whites are more likely to have the combination of esophagitis and hiatal hernia than are blacks.

Minimizing the risk of NSAID-induced GI bleeding.

Although nonsteroidal anti-inflammatory drugs (NSAIDs) have definite indications and can offer relief for many conditions, many patients have severe gastrointestinal problems after taking them. Physicians should prescribe these drugs more selectively and advise patients to limit their use of over-the-counter NSAIDs. For patients at high risk who need an NSAID, a prophylactic drug or a cyclooxygenase 2-selective NSAID can decrease the risk.

Toxicity of NSAIDs in the stomach and duodenum.

NSAIDs are widely used for analgesic, anti-inflammatory and anti-thrombotic indications. Such use carries the risk of gastrointestinal complications (1% over 6 months) which NSAIDs may promote from both ulcerous and nonulcerous lesions. Symptoms are poor predictors of serious lesions and complications, which may occur without previous symptoms. NSAIDs also delay healing of peptic ulcers, even to the extent of intractability, and may cause recurrence after gastric surgery. Prophylactic therapy is indicated in high-risk patients (age > 60 years, previous ulcer history, high dose, concomitant use of corticosteroids or anticoagulants). Misoprostol, omeprazole and high-dose famotidine have been shown to reduce the occurrence of both gastric and duodenal ulcers in NSAID users. At present, the role of Helicobacter pylori in NSAID-induced gastroduodenal lesions is controversial and there is no agreement in considering the organism as a risk factor and indicating its eradication in NSAID users.

Prospective evaluation of ranitidine bismuth citrate-based triple therapy for the treatment of Helicobacter pylori infection.

BACKGROUND: There is a need for effective and inexpensive therapy for Helicobacter pylori with good patient compliance. AIM: To evaluate a simplified twice daily schedule for treating H. pylori. METHODS: Patients infected with H. pylori (positive by CLO- and 13C-urea breath tests [UBT]) and not previously treated with anti-H. pylori therapy were treated with ranitidine bismuth citrate (RBC) and two inexpensive antibiotics (metronidazole, tetracycline) twice daily for 14 days in an open-label study. Eradication was established by a negative UBT 4 weeks after ending therapy. RESULTS: Twenty men and 30 women (age 54+/-14 years, range 26-74) were included in the study. Five patients were prematurely withdrawn (side-effects 2, took additional antibiotics 2 and surgery 1) and one patient was lost to follow-up; therefore, 44 (88%) patients completed the H. pylori eradication protocol. Per protocol (PP) cure rate was 82% (36/44 patients, 95% CI: 68-95%), and intention-to-treat cure rate was 72% (36/50 patients, 95% CI: 58-82%). Five patients (10%) developed side-effects during therapy, most commonly nausea (3 patients). Four weeks after the end of treatment, 78% (PP) of patients were symptomatically improved. CONCLUSIONS: A 2-week course of twice-daily RBC-based triple therapy was well tolerated, eradicated H. pylori in 72% (ITT) and 82% (PP) of patients, respectively, and relieved symptoms in 78%.

Pepsin and the esophagus.

Esophagitis results from excessive exposure of the esophagus to gastric juice through an ineffective or dysfunctional lower esophageal sphincter mechanism. A possible role of pepsin in damaging the esophageal mucosa with consequent esophagitis may be examined directly by testing pepsin under various conditions in experimental models of esophagitis. Since gastric juice contains both acid and pepsin, all experiments examine separately effects of perfusion of the esophagus by acid without and with pepsin in various combinations. Acid perfusion alone at concentrations represented by pH 1.3 or above does not produce esophagitis. The addition of pepsin to acid between pH 1 and 3.5 causes considerable acute esophageal damage. Outside the proteolytic range, i.e., higher than pH 3.5, pepsin does not damage the esophagus. The damage caused by acidified pepsin may be made much worse by the further addition of aspirin or other NSAIDs, presumably by further breaking down mucosal barriers.

Intractable upper gastrointestinal ulceration due to aspirin in patients who have undergone surgery for peptic ulcer.

BACKGROUND & AIMS: Postsurgical ulcer recurrence is a challenging problem. The aim of this study was to define the role of aspirin in postsurgical ulcers. METHODS: We studied 30 patients with postsurgical ulcer and aspirin abuse. Preoperatively 13 had stenosis, 7 bleeding, and 7 perforation or penetration; 18 had undergone vagotomy and 11 gastrectomy. RESULTS: Of 30 patients, 15 admitted long-term aspirin use (1-4 g/day), whereas 15 denied use but had positive salicylate blood levels (15.1 +/- 2.25 mg/100 mL; >1 mmol/L). Gastrin or gastric secretion was normal in the 24 patients tested. On follow-up, 3 (10%) healed after surgery (all stopped taking aspirin), whereas 27 continued and had new ulcers; 12 (44%) developed stenosis, and 6 (23%) developed bleeding. A second operation was required in 16 patients who had continued aspirin abuse, which was surreptitious in 10 (63%). Thirteen of these 16 had recurrent ulceration (7 [43%] with stenosis and 1 with bleeding); 1 died and 2 stopped taking aspirin and healed. A third operation was required in 8 patients. All had continued aspirin abuse (75% surreptitiously), and all again had relapses (3 with stenosis); 1 underwent an unsuccessful fourth operation, and 3 died. CONCLUSIONS: With continued aspirin abuse, recurrent ulceration is the rule, and complications, especially stenosis, are common. Surreptitious aspirin abuse, if discovered, is a clear contraindication to elective ulcer surgery, because aspirin-abuse ulceration is incurable by gastric surgery.

Clinical aspects of ECL-cell abnormalities.

ECL cell hyperplasia results from hypergastrinemia, and in man this occurs due to achlorhydria in atrophic gastritis (pernicious anemia [PA]) and gastrinoma (Zollinger-Ellison syndrome [ZES]). Progression to neoplasia, i.e., ECL cell carcinoids (usually small, multicentric and non-functional), occurs in some five to 10 percent of patients with PA where they remain gastrin-dependent and reversible by normalization of serum gastrin by antrectomy. Even if untreated, the carcinoids are almost invariably benign and do not cause death. In ZES, ECL cell hyperplasia is progressive due to hypergastrinemia. However, carcinoids develop only in the MEN-I subtype but pose no additional threat of malignancy. A conservative approach is recommended for small multicentric carcinoids, and the tumors do not need removal. By contrast, single, large, non-gastrin-dependent carcinoids represent a different biological and clinical problem and are frequently malignant.