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.     

Systematic review: standard- and double-dose proton pump inhibitors for the healing of severe erosive oesophagitis – a mixed treatment comparison of randomized controlled trials

Background  No randomized controlled trial (RCT) has compared all European-licensed standard- and double-dose PPIs for the healing of severe erosive oesophagitis.
Aim  To compare the effectiveness of licensed doses of PPIs for healing severe erosive oesophagitis (i.e. esomeprazole 40 mg, lansoprazole 30 mg, omeprazole 20 mg and 40 mg, pantoprazole 40 mg and rabeprazole 20 mg).
Methods  Systematic review of CENTRAL, EMBASE and MEDLINE for RCTs in patients with erosive oesophagitis (completed October 2008). Endoscopically verified healing rates at 4 and 8 weeks were extracted and re-calculated if not analysed by intention-to-treat. A mixed treatment comparison was used to combine direct treatment comparisons with indirect trial evidence while maintaining randomization. Odds ratios (OR) are reported compared to omeprazole 20 mg.
Results  A total of 3021 papers were identified in the literature search; 12 were of sufficient quality to be included in the analysis. Insufficient data were available to included rabeprazole. Esomeprazole 40 mg was found to provide significantly higher healing rates at 4 weeks [OR 1.84, 95% Credible Interval (95% CrI): 1.50 to 2.22] and 8 weeks (OR 1.91, 95% CrI: 1.13 to 2.88). No other PPI investigated had significantly higher healing rates than omeprazole 20 mg.
Conclusion  Esomeprazole 40 mg consistently demonstrates higher healing rates compared with licensed standard- and double-dose PPIs.     

Mercaptopurine treatment should be considered in azathioprine intolerant patients with inflammatory bowel disease

Background  Adverse drug reactions are a significant reason for therapeutic failure during thiopurine treatment of inflammatory bowel disease. Some smaller series in this patient population have shown that a switch to mercaptopurine may be successful in many cases of azathioprine intolerance.
Aim  To assess the long-term outcome of mercaptopurine treatment in a large patient population with azathioprine intolerance.
Methods  We identified 135 patients (74 women; median age 40 years) with Crohn's disease ( n  = 88) or ulcerative colitis ( n  = 47) and reviewed their medical records.
Results  A total of 70 patients (52%) tolerated mercaptopurine and were followed up for 736 (362–1080) days; 65 patients discontinued mercaptopurine due to adverse events after 25 (8–92) days. Mercaptopurine was tolerated in 71% (12/17) with hepatotoxicity and in 68% (13/19) with arthralgia/myalgia during azathioprine treatment. Previous abdominal surgery was more common in mercaptopurine intolerant patients [39/65 (60%) vs. 27/70 (39%); P  = 0.02] and thiopurine methyltransferase activity was higher in mercaptopurine tolerant patients than in mercaptopurine intolerant patients [13.2 (11.4–15.3) vs. 11.8 (9.6–14.2) U/mL red blood cells; P  = 0.04; n  = 81].
Conclusions  A trial of mercaptopurine should be considered in azathioprine intolerance, as half of the patients tolerate a switch to mercaptopurine. Patients with hepatotoxicity or arthralgia/myalgia during azathioprine treatment might benefit more often than those with other types of adverse events.     

Discontinuation of proton pump inhibitors in patients on long-term therapy: a double-blind, placebo-controlled trial

BACKGROUND: The proportion of proton pump inhibitor users on long-term therapy who can discontinue proton pump inhibitor (PPI) medication without developing symptoms is unknown. AIM: To determine the proportion of patients on long-term PPI therapy who are able to discontinue PPIs without developing symptoms. METHODS: Patients on long-term PPIs, without a history of peptic ulcer or esophagitis underwent upper endoscopy. Patients were randomized double-blindly to taper down or continue a constant dosage of omeprazole for three weeks. Thereafter, all patients discontinued PPIs. RESULTS: Of the 97 patients enrolled, had used PPIs for 48 months, 78% had GERD. A total of 27% did not use PPIs during the year after discontinuation, 31% of the patients randomized to tapering discontinued PPIs and 22% of those who did not could discontinue therapy (NS). Gastro-oesophageal reflux disease (GERD) patients were more prone to continue PPIs than non-GERD patients. Only 16 (21%) of GERD patients were off PPIs vs. 48% of patients without GERD (p < 0.05). Serum gastrin was higher at baseline in GERD patients who resumed PPIs versus non-resumers (p < 0.05). GERD and serum gastrin were independent predictors of PPI requirement. CONCLUSIONS: Discontinuation of PPI was successful in 27% of long-term PPI users. GERD patients had more difficulty discontinuing PPIs than non-GERD patients.     

Clinical course of laryngo-respiratory symptoms in gastro-oesophageal reflux disease during routine care - a 5-year follow-up

Background  Gastro-oesophageal reflux disease (GERD) can be associated with laryngo-respiratory symptoms (LRS) such as chronic cough, asthma or laryngeal symptoms.
Aim  To analyse the long-term clinical course of LRS in a large population with GERD and LRS.
Methods  ProGERD is a prospective multicentre cohort study of 6215 adult out-patients with GERD. At baseline, the prevalence of LRS was assessed. Initial standardized treatment was esomeprazole for up to 8 weeks. After 5 years of follow-up, patients were interviewed for LRS and a multivariate analysis was performed with resolved vs. persistent symptoms for chronic cough, asthma and laryngeal symptoms.
Results  In all, 2886 patients (46.4%) were available for analysis at baseline and at 5 years. The prevalence of chronic cough and laryngeal disorders had decreased while the prevalence of asthma had increased. Resolution of LRS was independent of clinical reflux characteristics or PPI medication.
Conclusions  In a large population with GERD, only few patients reported persistent LRS over 5 years. Resolution of LRS was independent of the stage of GERD and PPI treatment. Accordingly, data on the direction of causality between GERD and LRS are lacking and the strength of the association between the two must remain controversial.     

Long-term effect of tacrolimus therapy in patients with refractory ulcerative colitis

Background  Little is known about long-term outcome of tacrolimus therapy for ulcerative colitis.
Aim  To evaluate long-term efficacy and safety of tacrolimus in Japanese patients with refractory ulcerative colitis.
Methods  Twenty-seven patients with UC refractory to conventional therapy were administered tacrolimus with trough whole-blood levels of 10–15 ng/mL to induce remission and 5–10 ng/mL to maintain remission. Median treatment duration was 11 months (1–39 months) and median follow-up duration was 17 months (2–65 months). Evaluation of the clinical response was based on a modified Truelove–Witts severity index (MTWSI).
Results  Tacrolimus produced a clinical response in 21 patients (77.8%), and remission was achieved in 19 of these 21 (70.4%) within 30 days. Overall cumulative colectomy-free survival was estimated as 62.3% at 65 months. In 18 of 19 patients treated with corticosteroids at the initiation of tacrolimus therapy, corticosteroids were discontinued or tapered. Adverse events were tremor (25.9%), renal function impairment (18.5%), infectious disease (14.8%), hot flashes (11.1%), hyperkalaemia (7.4%), headache (7.4%), epigastralgia (7.4%) and nausea (3.7%). No mortality occurred.
Conclusion  Long-term administration of tacrolimus appears to be an effective and well-tolerated treatment for Japanese patients with refractory ulcerative colitis.     

Proton pump inhibitors reduce the long-term risk of recurrent upper gastrointestinal bleeding: an observational study

Background  Between 3% and 40% of patients surviving an episode of upper gastrointestinal bleeding (UGIB) experience a recurrence within 1 year.
Aim  To characterize further the recurrence rate of UGIB and to investigate the role of long-term acid suppressive therapy in its secondary prevention.
Methods  Recurrent cases of UGIB were identified among patients registered in The Health Improvement Network in the UK. A nested case–control analysis provided relative risk (RR) estimates of factors associated with recurrence.
Results  Of 1287 patients included, 67 (5.2%) were identified with a recurrent UGIB episode, corresponding to a recurrence rate of 17.5 per 1000 person-years during a mean follow-up of 3 years. The greatest risk of recurrence was in patients prescribed the oral anticoagulant warfarin (RR: 5.38; 95% confidence interval: 2.02–14.36). Use of a single proton pump inhibitor (PPIs) was associated with a reduced risk of recurrence (RR: 0.51; 95% confidence interval: 0.26–0.99), even in patients taking warfarin, while current use of H₂-receptor antagonists was not. After the first episode of UGIB, use of nonsteroidal anti-inflammatory drugs and aspirin was greatly reduced, preventing estimation of the risk associated with these drugs.
Conclusion  Long-term PPI therapy reduces the risk of UGIB recurrence.     

Symptoms in patients on long-term proton pump inhibitors: prevalence and predictors

Background  Symptom control in primary care patients on long-term proton pump inhibitor (PPI) treatment is poorly understood.
Aim  To explore associations between symptom control and demographics, lifestyle, PPI use, diagnosis and Helicobacter pylori status.
Methods  A cross-sectional survey ( n  = 726) using note reviews, questionnaires and carbon-13 urea breath testing. Determinants of symptom control [Leeds Dyspepsia Questionnaire (LDQ), Carlsson and Dent Reflux Questionnaire (CDRQ), health-related quality-of-life measures (EuroQoL: EQ-5D and EQ-VAS)] were explored using stepwise linear regression.
Results  Moderate or severe dyspepsia symptoms occurred in 61% of subjects (LDQ) and reflux symptoms in 59% (CDRQ). Age, gender, smoking and body mass index had little or no influence upon symptom control or PPI use. Average symptom scores and PPI use were lower in patients with non-ulcer dyspepsia and gastro-protection than gastro-oesophageal reflux disease (GERD) and uninvestigated dyspepsia. H. pylori infection was associated with lower reflux symptom scores only in patients with GERD and uninvestigated dyspepsia. EQ-5D was not able to discriminate between diagnostic groups, although the EQ-VAS performed well.
Conclusions  A majority of patients suffered ongoing moderate or severe symptoms. GERD and uninvestigated dyspepsia were associated with poorer long-term symptom control; H. pylori appeared to have a protective effect on reflux symptoms in these patients.     

Quantitative colonoscopic evaluation of relative efficiencies of an immunochemical faecal occult blood test and a sensitive guaiac test for detecting significant colorectal neoplasms

Background  The guaiac faecal occult blood test (G-FOBT), HemoccultSENSA, is sensitive for significant neoplasms [colorectal cancer (CRC), advanced adenomatous polyps (AAP)], but faulted by non-specificity for human haemoglobin (Hb). Quantified, Hb- specific, immunochemical faecal occult blood tests (I-FOBT) are now used.
Aims  To (i) compare I-FOBT and G-FOBT efficacy in identifying significant neoplasms and colonoscopy needs for positive tests and (ii) examine number of I-FOBTs needed and test threshold to use for equivalent or better sensitivity than G-FOBT and fewest colonoscopies for positive tests.
Methods  Three daily G-FOBTs and I-FOBTs were collected and analysed in 330 patients scheduled for colonoscopy.
Results  Colonoscopy found significant neoplasms in 32 patients, 6 CRC, 26 AAP. G-FOBT, sensitivity and specificity were 53.1% (17 neoplasms) and 59.4%, resulting in 8.1 colonoscopies/neoplasm. One I-FOBT having ≥50 ngHb/mL of buffer provided equivalent sensitivity but 94.0% specificity, resulting in 2.1 colonoscopies/neoplasm. By analysing the higher of two I-FOBTs at 50 ngHb/mL threshold, sensitivity increased to 68.8% (22 neoplasms, P  = 0.063), specificity fell to 91.9% ( P  < 0.001), but still required 2.1 colonoscopies/neoplasm.
Conclusions  In this population, quantified I-FOBT had significantly better specificity than G-FOBT for significant neoplasms, reducing the number of colonoscopies needed/neoplasm detected. Results depend on the number of I-FOBTs performed and the chosen development threshold.     

Incidence of benign upper respiratory tract infections, HSV and HPV cutaneous infections in inflammatory bowel disease patients treated with azathioprine

Background  There are few data on the incidence of benign infections (upper respiratory tract infections, herpes lesions and viral warts) during exposure to azathioprine.
Aims  To determine the incidence of benign infections in IBD out-patients receiving azathioprine (AZA+) and to look at the influence of leucocyte counts in the onset of these events.
Methods  A total of 230 patients were included in a prospective cohort and observed during 207 patient-years. Episodes of benign infections were collected and incidences of benign infections were compared between the AZA+ group and patients without AZA (AZA−).
Results  The incidence of upper respiratory tract infections in the cohort was 2.1 ± 2.2 per observation-year. There was no difference between the AZA+ ( n  = 169) and AZA− ( n  = 61) groups (2.2 ± 2.3 vs. 2.1 ± 2.1, P  = 0.77). The incidence of herpes flares was significantly increased in the AZA+ group compared to the AZA− group (1.0 ± 2.6 vs. 0.2 ± 0.8 per year, P  = 0.04). Similarly, there were significantly more patients with appearance or worsening viral warts in the AZA+ group (17.2% (AZA+) vs. 3.3% (AZA−), P  = 0.004).
Conclusion  This study suggests that the incidence of herpes flares and the appearance or worsening of viral warts are increased in IBD patients receiving AZA.     

Proton pump inhibitor therapy in gastro-oesophageal reflux disease decreases the oesophageal immune response but does not reduce the formation of DNA adducts

Background  Chronic oesophageal inflammation and related oxidative stress are important in the pathogenesis of erosive oesophagitis (EO) and its malignant progression.
Aim  To study the effect of proton pump inhibitors (PPIs) on oesophageal cellular immune response and oxidative damage in EO patients.
Methods  Forty gastro-oesophageal reflux disease (GERD) patients [non-erosive reflux disease (NERD): 15, EO: 25] were included, after 7 days off antisuppressive drugs. EO patients were randomized to 20-mg rabeprazole once daily for either 4 or 8 weeks with baseline and follow-up endoscopy with distal oesophageal biopsies. T lymphocytes, macrophages and mast cells were quantified by immunohistochemistry. DNA adducts were measured by analysis of 8-oxo-deoxyguanosine levels.
Results  Erosive oesophagitis patients had more T lymphocytes and CD8⁺ T lymphocytes in squamous epithelium than NERD patients ( P  = 0.001, P  = 0.002, respectively). Levels of DNA adducts between both groups were, however, not different ( P  = 0.99). Four- and eight-week rabeprazole treatment in EO patients resulted in a significant decrease in number of T lymphocytes and CD8⁺ T lymphocytes (all P  < 0.05). PPIs did not, however, affect levels of DNA adducts.
Conclusions  Short-term PPI therapy in EO patients reduces the oesophageal cellular immune response, but does not change oxidative damage. PPI therapy may therefore not be effective in reducing the risk of oesophageal cancer in GERD patients.     

Long-term therapy with adefovir dipivoxil in hepatitis B e antigen-negative patients developing resistance to lamivudine

Background  The efficacy of long-term adefovir dipivoxil monotherapy or combination of adefovir and lamivudine in hepatitis B e antigen (HBe-Ag)-negative lamivudine-resistant chronic hepatitis B (CHB) patients is still under investigation.
Aim  To assess the safety and efficacy of the long-term adefovir treatment alone or in combination with lamivudine in HBe-Ag-negative CHB patients who had developed breakthrough because of lamivudine-resistant mutants.
Methods  Fifty-nine patients received combination therapy, while 23 switched to adefovir alone after a 3-month course of combination therapy.
Results  The median follow-up after adefovir's onset was 31 (18–40) months. Baseline characteristics were similar between the two groups. At 12 and 24 months, 69% and 89% of patients receiving combination therapy and 73% and 82% of patients receiving adefovir monotherapy had serum HBV-DNA <10⁴ copies/mL ( P  > 0.5). Normalization of alanine aminotransferase levels occurred in 81% and 79% of patients receiving combination vs. 61% and 53% receiving adefovir monotherapy at 12 and 24 months, respectively ( P  > 0.50). Virological breakthroughs because of adefovir-resistant mutants occurred in five patients under adefovir monotherapy and in none receiving combination therapy ( P  = 0.001). No one developed decompensated liver disease or hepatocellular carcinoma during follow-up. Re-introduction of lamivudine in adefovir-resistant patients achieved reduction in HBV-DNA and biochemical remission, but re-emergence of lamivudine mutants was observed in one patient after 7.5 months.
Conclusion  In HBe-Ag-negative CHB patients with lamivudine resistance, adding adefovir to continuing lamivudine therapy maximizes anti-viral efficacy because of absence of viral resistance.     

Low body mass not vitamin D receptor polymorphisms predict osteoporosis in patients with inflammatory bowel disease

Background  Osteoporosis is a recognized complication of inflammatory bowel disease (IBD).
Aim  To investigate the role of environmental factors and vitamin D receptor (VDR) variants on the prevalence of osteoporosis.
Methods  DEXA scans and case note review were performed on 440 IBD patients from 1997 to 2006. All the IBD patients and 240 healthy controls were genotyped for VDR variants Taq -1 and Apa -1 using PCR-RFLP.
Results  Osteoporosis and osteopenia rates were 15% and 18% for IBD, 16% and 18% for Crohn's disease (CD) and 13% and 19% for ulcerative colitis, respectively. On univariate analysis of the CD patients, low body mass index (BMI, <18.5) and smoking status ( P  = 0.008 and 0.005 respectively) were associated with osteoporosis and osteopenia. Low BMI was also associated with osteoporosis on multivariate analysis in CD ( P  = 0.021, OR 5.83, CI 1.31–25.94). No difference was observed between Taq -1 and Apa -1 VDR polymorphisms in IBD, CD, ulcerative colitis and healthy controls. However, CD males were more likely to carry the variant Taq -1 polymorphism than healthy controls males ( P  = 0.0018, OR 1.94, CI 1.28–2.92) and female CD patients ( P  = 0.0061, OR 1.60, CI 1.17–2.44).
Conclusions  In this well-phenotyped cohort of IBD patients, a relatively low prevalence of osteoporosis was observed. Low BMI was the only independent risk factor identified to be associated with osteoporosis.     

Factors influencing long-term changes in mental health after interferon-alpha treatment of chronic hepatitis C

Background  Antiviral treatment with interferon-alpha (IFN-α) is associated with several acute psychiatric side effects. Little is known about long-term effects on mental health after treatment independent from viral response and the influence of pre-existing psychiatric risk-factors.
Aim  To evaluate long-term effects of antiviral treatment with interferon-alpha (IFN-α) on mental health in patients with psychiatric risk factors.
Method  We prospectively investigated long-term mental health changes in 81 hepatitis C virus-infected patients. Psychiatric outcome was measured with the Montgomery–Asberg Depression Scale (MADRS), Brief Psychiatric Rating Scale, the Global Social Functioning Scale and the Global Clinical Impression Scale 6 months after the end of antiviral treatment with IFN-α and ribavirin.
Results  Six months after antiviral therapy, 49% of the patients showed a worsening and 27.2% an improvement of depression scores. The most important predictor for a long-term improvement of depression scores was a pre-treatment MADRS score ≥5 (OR 14.21, 95% CI: 2.51–81.30). Patients with pre-existing psychiatric disorders (OR = 0.117, 95% CI: 0.024–0.558), methadone substitution (OR = 0.20, 95% CI: 0.045–0.887) or genotype 2/3 (OR = 0.341, 95% CI: 0.138–0.845) were significantly less likely to show a long-term worsening of depressive symptoms.
Conclusions  Pre-existing psychiatric risk factors increase the chance for a long-term improvement and reduce the risk for a long-term worsening of mental health after antiviral treatment of chronic hepatitis C with IFN-α.