The risk of oesophageal adenocarcinoma in a prospectively recruited Barrett's oesophagus cohort.

BACKGROUND: Varying rates of oesophageal adenocarcinoma (OAC) complicating Barrett's oesophagus (BO) have been reported. Recent studies and meta-analyses suggest a lower incidence, questioning the value of endoscopic surveillance. AIM: We aimed to retrospectively examine the rate of OAC, risk factors and causes of death in a prospectively recruited BO cohort. METHODS: Data from patients with BO from a cohort from 1982-2007 were studied. Patients were subdivided into surveyed, failed to attend surveillance and unfit for surveillance. Standardised mortality ratios (SMR) were calculated for common causes of death. Cox proportional hazards models were used to determine which factors were associated with progression to OAC. RESULTS: In total, 671 BO patients (61% male) were studied; 37 (76% male) were diagnosed with OAC. OAC incidence was 0.47% per annum and stable across three decades (1982-1991 0.56%, 1992-2001 0.46%, 2002-2012 0.41% (p = 0.8)). All-cause mortality was increased for the whole cohort (SMR 163(95% CI 145-183)). Mortality from OAC appeared higher in patients who failed to attend surveillance (SMR 3216(95% CI 1543-5916)) compared with surveyed (SMR 1753(95% CI 933-2998)) and those unfit for surveillance due to co-morbidity (SMR 440(95% CI 143-1025)). Multivariable analysis identified low-grade dysplasia (HR 4.4(95% CI 1.56-12.43), p = 0.005) and length of BO (HR 1.2(95% (1.1-1.3)), p < 0.001)) as associated with OAC. CONCLUSIONS: Progression to OAC appeared stable over three decades at 0.47% per annum. Patients with BO had a modest increase in all-cause mortality and a large increase in OAC mortality, particularly if fit for surveillance. Low-grade dysplasia and the length of the BO segment were associated with developing OAC.

Local approaches to hereditary breast cancer.

The diagnostic and local treatment modalities of hereditary breast cancer (HBC) are evolving based on emerging evidence from new imaging, radiotherapy and surgical studies. The optimal selection of diagnostic and therapeutic strategies for the individual HBC patient remains an area of active research in this relatively new patient population. In this context, some rational pathways of intervention are currently available to both reduce cancer risk in mutation carriers without a cancer diagnosis, as well as to reduce the risk of recurrence or new cancers among the carriers already diagnosed with a malignancy. It is encouraging to notice to what degree certain interventions have successfully reduced both the risk of malignancy and the anxiety associated with this genetic diagnosis. This updated report aims at summarizing the most recent findings, while it identifies the areas of uncertainty that remain, and continue to present difficult challenges, particularly among younger HBC patients.

Outcome of surgical fundoplication for extra-oesophageal symptoms of reflux.

BACKGROUND: The role of surgery in the management of extra-oesophageal symptoms of gastro-oesophageal reflux (EOR) is unclear. In this retrospective study we studied patients who had surgical fundoplication for EOR symptoms from 1995 to 2005. We analysed outcome with respect to symptomatic improvement and patient satisfaction. METHODS: From our database of 240 patients who had surgical fundoplication for gastro-oesophageal reflux disease, 51 patients who had predominantly EOR symptoms were identified. All the patients had objective evidence of reflux and had been offered surgery because of failure of medical therapy and/or of development of complications. Patients were asked to score their symptoms before and after surgery using the Reflux Symptom Index, and to record their use of medicine before and after operation, their experience with surgery and their overall quality of life using a written questionnaire. RESULTS: Forty of the 51 patients were available for analysis. Common symptoms were cough and breathlessness (32/40), throat clearing/postnasal drip (31/40), sensation of lump in the throat (29/40), and voice problems (22/40). Of these forty patients, 34 (85%) had associated classical symptoms as well. Mean follow up at the time of questionnaire was 53.3 (6-120) months. The mean Reflux Symptom Index score improved from 22.80 (SD 10.80) to 11.83 (SD 9.91) (p < 0.0001, paired t-test). Six of the 39 responders (15.3%) said they would not have had the operation knowing what they know now and that problems related to the operation outweighed any benefits. These problems included gas bloating, inability to retch and dysphagia lasting up to one year after surgery. Twenty-five percent of the 40 patients described their overall quality of life as excellent, 32.5% as good, 32.5% as satisfactory and 10% as bad. CONCLUSION: Surgery can be an effective treatment in the majority of patients with extra-oesophageal symptoms of reflux.

A role for iron in Wnt signalling.

There is an emerging body of evidence implicating iron in carcinogenesis and in particular colorectal cancer, but whether this involves Wnt signalling, a major oncogenic signalling pathway has not been studied. We aimed to determine the effect of iron loading on Wnt signalling using mutant APC (Caco-2 and SW480) and wild-type APC (HEK-293 and human primary fibroblasts) containing cell lines. Elevating cellular iron levels in Caco-2 and SW480 cells caused increased Wnt signalling as indicated by increased TOPFLASH reporter activity, increased mRNA expression of two known targets, c-myc and Nkd1, and increased cellular proliferation. In contrast wild-type APC and beta-catenin-containing lines, HEK 293 and human primary fibroblasts were not responsive to iron loading. This was verified in SW480 cells that no longer induced iron-mediated Wnt signalling when transfected with wild-type APC. The cell line LS174T, wild type for APC but mutant for beta-catenin, was also responsive suggesting that the role of iron is to regulate beta-catenin. Furthermore, we show that E-cadherin status has no influence on iron-mediated Wnt signalling. We thus speculate that excess iron could exacerbate tumorigenesis in the background of APC loss, a common finding in cancers.

Hypertension and fatty liver: guilty by association?

Essential hypertension is associated with the metabolic syndrome, insulin resistance and the development of fatty liver. Fatty liver disease is a spectrum of liver diseases ranging from simple hepatic steatosis through steato-hepatitis to cirrhosis and hepatoma. The purpose of this review is to discuss the evidence for an association between essential hypertension and non-alcoholic fatty liver disease, and to consider the diagnosis and management of non-alcoholic fatty liver disease. We conclude that it is important to consider the diagnosis of fatty liver disease in hypertensive patients, to measure the liver function tests at diagnosis and not to ignore minor elevations of serum aminotransferases. Hypertensive patients with raised liver enzymes should be referred for further assessment, particularly if risk factors for progressive liver disease, such as obesity and diabetes, are present.

Continuous treatment of Barrett's oesophagus patients with proton pump inhibitors up to 13 years: observations on regression and cancer incidence.

BACKGROUND: There is little evidence that treatment of patients with Barrett's oesophagus with proton pump inhibitors over periods up to 6 years results in major regression of Barrett's oesophagus. AIM: To determine if longer periods of treatment with proton pump inhibitors lead to significant regression of Barrett's oesophagus, and to determine the incidence of oesophageal adenocarcinoma in the proton pump inhibitor-treated patients. METHODS: We analysed prospectively-collected data on Barrett's oesophagus patients treated with proton pump inhibitors for 1-13 years. RESULTS: 188 patients with Barrett's oesophagus and intestinal metaplasia, were treated for 1-13 years with a proton pump inhibitor (966 years of treatment; mean 5.1 years). No change in length was seen during treatment but 48% of patients developed squamous islands (25% after 1-3 years; 100% at 12-13 years). Squamous islands correlated with treatment duration and male sex but not with proton pump inhibitor dose or patient age. Six patients developed dysplasia and three males developed adenocarcinoma during treatment (cancer incidence 0.31%). CONCLUSIONS: Proton-pump inhibitor treatment over 1-13 years does not shorten the Barrett's oesophagus segment but squamous islands appear in many patients. The incidence of oesophageal adenocarcinoma was low in these proton pump inhibitor-treated patients compared with published series.

Coeliac disease in South Asians resident in Britain: comparison with white Caucasian coeliac patients.

BACKGROUND: The catchment population of our hospital is ethnically diverse and we have seen a number of patients of South Asian origin with coeliac disease. We have suspected that there are differences compared with white Caucasian coeliacs, especially with respect to iron-deficiency anaemia and vitamin D deficiency at presentation. AIMS: To compare the clinical and laboratory features of South Asian adult coeliac patients with adult white Caucasian coeliacs. METHODS: We reviewed the notes of patients attending the adult coeliac clinic over the past 10 years. All patients were older than 16 years at diagnosis. There were 40 South Asians and 90 white Caucasians. Symptoms, haematology, biochemistry, endomysial antibody status, HLA alleles and small bowel histology at presentation were compared between the two racial groups. RESULTS: There were significant differences between the racial groups. South Asians were younger at presentation than the Caucasian patients (mean age 27 years compared with 47 years respectively, P<0.0001); they were less likely to have 'irritable bowel syndrome' symptoms (P<0.01), but more likely to have features of vitamin D deficiency (P<0.03). Their haemoglobin (P<0.05), mean cell volume (P<0.0004), serum iron (P<0.01), transferrin saturation (P<0.05), serum 1,25-dihydroxyvitamin D3 (P<0.002), and levels were lower, while serum alkaline phosphatase levels were higher (P<0.04) than in white Caucasian coeliac patients. There were no differences with respect to serum folate, vitamin B12, serum calcium, alanine aminotransferase and small bowel histology. IgA class endomysial antibody positivity was similar in the two groups (88.5% for South Asians compared with 73.5% for white Caucasians). White Caucasian patients were significantly more likely to be DQ2-positive than the South Asian patients (97.2% compared with 83.3%, P=0.02). CONCLUSION: South Asians with coeliac disease are less likely to present with 'irritable bowel syndrome' symptoms, but more likely to have features of vitamin D deficiency and iron deficiency, and have a higher alkaline phosphatase than white Caucasians. The differences in HLA alleles seen in South Asians with coeliac disease compared with white Caucasian patients suggests that among the South Asians, non-HLA regions may play a stronger role in disease susceptibility and presentation.

Ethnic differences in cirrhosis of the liver in a British city: alcoholic cirrhosis in South Asian men.

AIMS AND METHODS: We studied the ethnic origin of cirrhotic patients retrospectively over the 14-year period 1987-2000 and compared the ethnic make-up of the cirrhotic patients with the ethnic make-up of the local catchment population. RESULTS AND CONCLUSIONS: Of 381 cirrhotics, 64.1% were white, 29.1% South Asian, 4.7% Afro-Caribbeans and 2.1% other races. These proportions were different from those of the local community in that South Asians were over-represented and Afro-Caribbeans were under-represented. Alcohol was the commonest cause of cirrhosis (60.9%) and South Asian non-Moslem males with alcoholic cirrhosis were over-represented and were younger at diagnosis than white alcoholic cirrhotics.

Triple therapy for Helicobacter pylori eradication: a comparison of pantoprazole once versus twice daily.

BACKGROUND: Proton pump inhibitor-based triple therapy is recommended as treatment for Helicobacter pylori eradication. The proton pump inhibitor may be given once or twice daily. However, little information is available on how these two treatment strategies compare. METHODS: H. pylori-positive patients (two positive test results) with endoscopy-proven healed duodenal ulcer or non-ulcer dyspesia were randomly allocated to 1 week of double-blind treatment with pantoprazole 40 mg once or twice daily, plus clarithromycin 250 mg and metronidazole 400 mg twice daily. Eradication was defined as a negative 13C-urea breath test (13C-UBT) and histology, 4-5 weeks post-treatment. The follow-up phase comprised 12 months off therapy, with 13C-UBT at 6 and 12 months. RESULTS: Two hundred and four patients received treatment: pantoprazole once daily (x1), n=104; twice daily (x2), n=100. Eradication rates were 84% in both the pantoprazole x1 and pantoprazole x2 groups by modified intention-to-treat analysis and 89% and 87%, respectively, by per protocol analysis. Metronidazole resistance was found in 44% of pre-treatment cultures of H. pylori. Eradication rates were similar in susceptible (72%) and resistant (75%) strains. During follow-up, recrudescence of infection occurred in 3/118 patients. CONCLUSION: When using pantoprazole plus clarithromycin and metronidazole, the proton pump inhibitor can be used once daily without loss of efficacy.

Ethnic differences in gastro-oesophageal reflux disease.

OBJECTIVES: To see whether the anecdotal statement that gastro-oesophageal reflux disease is less common in blacks than in white Caucasians is true. DESIGN: Study of the racial origin of adult patients who, at endoscopy, have oesophageal damage due to gastro-oesophageal reflux. SETTING: Gastroenterology unit of a teaching hospital in inner city Birmingham, UK. MAIN OUTCOME MEASURE: Ethnicity and endoscopic grade of oesophageal damage (reflux oesophagitis) were recorded in every patient in whom oesophageal damage due to gastro-oesophageal reflux was diagnosed. RESULTS: Over the eight-year period 1989-1996, 1101 patients with endoscopically diagnosed grades I-V reflux oesophagitis have been seen, of whom 893 (81.9%) were white, 156 (14%) were Indian and 52 (5%) were Afro-Caribbeans. There were fewer patients with reflux oesophagitis from the two non-white ethnic groups than would be expected from their prevalence in the catchment population, and severe reflux oesophagitis was less common than expected in the two non-white groups. In all groups, patients with grades III, IV and V reflux oesophagitis were older than patients with grades I and II disease. Whites tended to be older than Afro-Caribbeans or Indians. CONCLUSION: There were fewer non-whites with reflux oesophagitis than would be expected but the reasons for this are unclear. This study has been useful as a pilot but further studies are needed in ethnically mixed non-migrant populations both in hospital, primary care and the community to clarify racial differences in reflux oesophagitis.

Ethnic differences in gastro-oesophageal reflux disease

OBJECTIVES: To see whether the anecdotal statement that gastro-oesophageal reflux disease is less common in blacks than in white Caucasians is true. DESIGN: Study of the racial origin of adult patients who, at endoscopy, have oesophageal damage due to gastro-oesophageal reflux. SETTING: Gastroenterology unit of a teaching hospital in inner city in Birmingham, UK. MAIN OUTCOME MEASURE: Ethnicity and endoscopic grade of oesophageal damage (reflux oesophagitis) were recorded in every patient in whom oesophageal damage due to gastro-oesophageal reflux was diagnosed. RESULTS: Over the eight-year period 1989-1996, 1101 patients with endoscopically diagnosed grades I-V reflux oesophagitis have been seen, of whom 893 (81.9 percent) were white, 156 (14 percent) were Indian and 52 (5 percent) were Afro-Caribbeans. There were fewer patients with reflux oesophagitis from the two non-white ethnic groups than would be expected from their prevalence in the catchment population, and severe reflux oesophagitis was less common than expected in the two non-white groups. In all groups, patients with grades III, IV and V reflux oesophagitis were older than patients with grades I and II disease. Whites tended to be older than Afro-Caribbeans or Indians. CONCLUSION: There were fewer non-whites with reflux oesophagitis than would be expected but the reasons for this are unclear. This study has been useful as a pilot but further studies are needed in ethnically mixed non-migrant populations both in hospital, primary care and the community to clarify racial differences in reflux oesophagitis.(Au)

Measurement of small intestinal permeability markers, lactulose, and mannitol in serum: results in celiac disease.

To date, tests of small intestinal passive permeability have involved the ingestion of test molecules whose permeation is assessed indirectly by measuring their urinary recovery. Excretion ratios of marker molecules (eg, lactulose-to-mannitol excretion ratio, LMER) are useful clinically. Measurement of permeability markers in serum would improve the convenience of the tests. Our aim was to assess small intestinal permeability in celiac patients using serum lactulose and mannitol levels with calculation of lactulose to mannitol serum ratios (LMSR) and to compare the results with the standard methods using urinary recoveries. Twenty-four newly diagnosed celiacs and 10 control subjects were studied; 10 celiacs were restudied while established on a gluten-free diet. Test subjects and patients ingested 10 g lactulose and 2.5 g mannitol in 50 ml water. In 10 untreated celiacs and the controls, blood was taken from 0 to 120 min and all urine was collected for 6 hr. The remaining 14 untreated and the 10 treated celiacs had a single serum sample taken 60 min after ingestion of the test solution. At 1 hr after ingestion, the mean mannitol level in normals (0.156 mmol/liter) was significantly higher than in untreated celiacs (0.06 mmol/liter). The 1-hr mean serum lactulose level in normals (0.125 micromol/liter) was significantly lower than in untreated celiacs (0.56 micromol/liter). The median 1-hr LMSR in untreated celiacs was 0.42 compared with 0.039 in normals and 0.08 in treated celiacs. There was a significant correlation between LMSR and LMER. Permeability testing using serum measurements of lactulose and mannitol gave comparable results in celiac patients to the tests using urinary recovery of the permeability markers and may prove to be more convenient, especially in pediatric patients.

Reduced cadherin/catenin complex expression in celiac disease can be reproduced in vitro by cytokine stimulation.

Celiac disease is characterized by a chronic immune response to dietary gluten, in which T cell responses result in elevated mucosal levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, interferon (IFN)-gamma, and transforming growth factor (TGF)-beta, which induce profound mucosal remodeling associated with increased enterocyte proliferation, apoptosis, and migration. Reduced intestinal expression of the morphoregulatory cell adhesion molecule E-cadherin, which forms complexes with beta-catenin, can increase enterocyte proliferation and migration. However, its mechanism of action in gastrointestinal inflammatory conditions and any involvement in celiac disease is unknown. In this study, we describe changes in E-cadherin and beta-catenin expression in celiac disease tissue and determine the effect of cytokines on their expression in an in vitro model. We assessed E-cadherin and beta-catenin expression in intestinal biopsies from 24 patients with celiac disease, 12 patients with treated celiac disease, and 10 healthy patients by immunohistochemistry, Western blotting, and confocal microscopy. Using Caco-2 cells, we examined the effect of TNF-alpha, IL-1, IFN-gamma, and TGF-beta on E-cadherin expression. E-cadherin transcription was assessed in both intestinal biopsies and Caco-2 cells by in situ hybridization and RT-PCR, respectively. A marked reduction in protein expression of E-cadherin and beta-catenin that returns to normal levels after treatment was observed in celiac disease; this reduction was associated with reduced levels of E-cadherin mRNA. E-cadherin expression in Caco-2 cells was significantly reduced after TNF-alpha, IL-1, and IFN-gamma stimulation. The effect of TNF-alpha on E-cadherin expression was maximal after stimulation for 48 hours and also induced modest reductions in beta-catenin expression. The action of TNF-alpha on E-cadherin was reversible and was shown to act at the transcriptional level. These results demonstrate the novel findings that E-cadherin and beta-catenin expression are reversibly down-regulated in celiac disease and that such changes in epithelial cadherin/catenin complexes may be mediated by cytokines acting on cadherin transcription.

Lactase haplotype frequencies in Caucasians: association with the lactase persistence/non-persistence polymorphism.

A genetic polymorphism is responsible for determining that some humans express lactase at high levels throughout their lives and are thus lactose tolerant, while others lose lactase expression during childhood and are lactose intolerant. We have previously shown that this polymorphism is controlled by an element or elements which act in cis to the lactase gene. We have also reported that 7 polymorphisms in the lactase gene are highly associated and lead to only 3 common haplotypes (A, B and C) in individuals of European extraction. Here we report the frequencies of these polymorphisms in Caucasians from north and south Europe and also from the Indian sub-continent, and show that the alleles differ in frequency, the B and C haplotypes being much more common in southern Europe and India. Allelic association studies with lactase persistence and non-persistence phenotypes show suggestive evidence of association of lactase persistence with certain alleles. This association was rather more clear in the analysis of small families, where haplotypes could be determined. Furthermore haplotype and RNA transcript analysis of 11 unrelated lactase persistent individuals shows that the persistence (highly expressed) allele is almost always on the A haplotype background. Non-persistence is found on a variety of haplotypes including A. Thus it appears that lactase persistence arose more recently than the DNA marker polymorphisms used here to define the main Caucasian haplotypes, possibly as a single mutation on the A haplotype background. The high frequency of the A haplotype in northern Europeans is consistent with the high frequency of lactase persistence.

Continuous treatment with omeprazole 20 mg daily for up to 6 years in Barrett's oesophagus.

BACKGROUND: Because of the malignant potential of Barrett's oesophagus, an aim of treatment is to cause the columnar epithelium to regress. A logical approach is to decrease acid reflux which is an important aetiological factor in Barrett's oesophagus. Treatment with omeprazole 20-80 mg over 1-3 years has yielded conflicting but largely disappointing results. AIM: To determine if treatment of Barrett's oesophagus with omeprazole 20 mg daily for up to 6 years can cause regression of the Barrett's epithelium. PATIENTS AND METHODS: Forty-seven patients with Barrett's oesophagus were treated in an open prospective study. Nine patients were treated for 2 years, 12 for 3 years, 10 for 4 years, eight for 5 years and eight for 6 years. Patients were endoscoped at 1-2-year intervals and endoscoped at the end of the treatment period. RESULTS: No significant shortening of the length of the Barrett's segment was seen during any treatment period, although omeprazole controlled reflux symptoms and was well tolerated. Macroscopic squamous islands appeared in 55% of patients, mostly in the first 2-3 years although in five patients they appeared later in treatment. CONCLUSION: Treatment of Barrett's oesophagus with omeprazole 20 mg daily for periods of up to 6 years did not cause regression in the length of the Barrett's segment, but it did lead in over half of the patients to partial re-epithelialization in the form of squamous islands.

Incidence of duodenal ulcer healing after 1 week of proton pump inhibitor triple therapy for eradication of Helicobacter pylori. The Lansoprazole Helicobacter Study Group.

BACKGROUND: A number of clinical studies have assessed the efficacy of short-term twice-daily Helicobacter pylori eradication regimens but few have investigated the proportion of patients in whom duodenal ulcer disease was healed with these regimens. AIM: To compare the safety and efficacy of four 1-week H. pylori eradication regimens in the healing of H. pylori associated duodenal ulcer disease. METHODS: Following endoscopic confirmation of duodenal ulcer disease and a positive CLO test, patients underwent a 13C-urea breath test to confirm H. pylori status. Treatment with one of four regimens: LAC, LAM, LCM or OAM, where L is lansoprazole 30 mg b.d., A is amoxycillin 1 g b.d., M is metronidazole 400 mg b.d., C is clarithromycin 250 mg b.d., and O is omeprazole 20 mg b.d., was assigned randomly to those patients who were H. pylori positive, with 62 (LAC), 64 (LAM), 61 (LCM) and 75 (OAM) patients in each treatment group. Follow-up breath tests and endoscopies were performed at least 28 days after the end of treatment. RESULTS: Duodenal ulcer disease was healed 28 days after treatment in 53/62 (85.5%) patients who were treated with LAC, 52/64 (81.3%) of patients treated with LAM, 49/61 (80.3%) of patients treated with LCM and 60/75 (80.0%) of patients treated with OAM (intention-to-treat analysis, n = 262, assumed unhealed if no follow-up endoscopy was performed). All the treatments were of similar efficacy (P = 0.85, chi-squared test) with regard to the healing of duodenal ulcer disease. CONCLUSIONS: The four 1-week treatment regimens were equally effective in healing H. pylori associated duodenal ulcer disease.

Sucrosemia in untreated celiac disease: a potential screening test.

During studies to develop serum tests of small intestinal permeability, we detected an unidentified disaccharide in HPLC traces of sera from untreated celiacs. This present study aimed to identify the disaccharide and determine whether the presence of the disaccharide in the serum after an oral challenge had potential as a simple screening test for celiac disease. The disaccharide was identified as sucrose by incubation studies of sera with disaccharidases. Twenty untreated celiacs, 15 treated celiacs, and 20 normal or dyspeptic controls were studied for the presence of sucrose in their serum after an oral load (8 g). The results in celiacs were compared with the presence of serum IgA endomysial antibodies. The 10 normal controls were also given a larger sucrose challenge (50 g). Ten of the untreated celiacs and 10 controls had their brush border disaccharidase activities measured. Sucrose eluted in the same position as the unidentified disaccharide in the HPLC trace and the latter could be removed by incubation with sucrase. All untreated celiacs but none of the treated celiacs had sucrose in their serum after the 8-g oral challenge. None of the controls had sucrose in their serum after the 8-g or 50-g challenges. Three untreated celiacs were IgA endomysial antibody negative as were all the treated cases. Brush border sucrase activity was low in untreated celiac disease. The presence of sucrose in the serum after an oral load shows promise as a noninvasive test for celiac disease.

An analytical method for the quantitation of mannitol and disaccharides in serum: a potentially useful technique in measuring small intestinal permeability in vivo.

An electrochemical-HPLC method for the determination of mannitol and lactulose is presented which may facilitate routine testing of intestinal permeability by requiring only a single blood sample instead of a 6-hour urine collection. Chromatographic conditions are described which allow separation of the closely related sugars lactulose and the dietary disaccharides lactose and sucrose. Preliminary results in normal controls and patients with untreated coeliac disease are presented.