Simon D. Johnston

BACKGROUND: Hyperlipidemia and hypertension have been reported in liver allograft recipients and contribute to an increased risk of ischemic heart disease (IHD) after orthotopic liver transplantation (OLT). The aims of the study were (1) to determine the prevalence of risk factors for IHD in these patients and (2) to compare the observed incidence of cardiovascular events and related mortality in allograft recipients with a matched population. METHODS: One hundred ten consecutive adults (50 male) who attended for review after OLT (median follow-up 3.9 years; range 0.1-17.9) were assessed for cardiovascular risk factors using current blood pressure, diabetic status, and smoking history and measurements of total cholesterol, high-density lipoprotein cholesterol, and triglyceride concentrations. Cardiovascular events and cardiovascular mortality data were collected from the prospective database of all adult liver allograft recipients and compared to matched data from myocardial infarction registries and Office for National Statistics data, respectively. RESULTS: Raised serum cholesterol (>5.0 mmol/L) was found in 48 (44%) patients (18 male), and systolic hypertension (>140 mmHg) was found in 69 (63%) patients (27 male). The relative risk of ischemic cardiac events was 3.07 (95% [confidence interval] CI, 1.98-4.53) and the relative risk for cardiovascular deaths was 2.56 (95% CI, 1.52-4.05) in allograft recipients compared to an age-matched population without transplants. CONCLUSIONS: Liver allograft recipients have a greater risk of cardiovascular deaths and ischemic events than an age- and sex-matched population. The prevalence of raised cholesterol concentrations in patients after OLT is similar to those in previous reports. Moderate hypertension and hyperlipidemia may be more detrimental in patients after OLT compared to non-transplant patients without these risk factors.

BACKGROUND: Oesophageal adenocarcinoma is the sixth most common cause of cancer death worldwide and Barrett's oesophagus is the biggest risk factor. We aimed to evaluate the efficacy of high-dose esomeprazole proton-pump inhibitor (PPI) and aspirin for improving outcomes in patients with Barrett's oesophagus. METHODS: The Aspirin and Esomeprazole Chemoprevention in Barrett's metaplasia Trial had a 2 × 2 factorial design and was done at 84 centres in the UK and one in Canada. Patients with Barrett's oesophagus of 1 cm or more were randomised 1:1:1:1 using a computer-generated schedule held in a central trials unit to receive high-dose (40 mg twice-daily) or low-dose (20 mg once-daily) PPI, with or without aspirin (300 mg per day in the UK, 325 mg per day in Canada) for at least 8 years, in an unblinded manner. Reporting pathologists were masked to treatment allocation. The primary composite endpoint was time to all-cause mortality, oesophageal adenocarcinoma, or high-grade dysplasia, which was analysed with accelerated failure time modelling adjusted for minimisation factors (age, Barrett's oesophagus length, intestinal metaplasia) in all patients in the intention-to-treat population. This trial is registered with EudraCT, number 2004-003836-77. FINDINGS: Between March 10, 2005, and March 1, 2009, 2557 patients were recruited. 705 patients were assigned to low-dose PPI and no aspirin, 704 to high-dose PPI and no aspirin, 571 to low-dose PPI and aspirin, and 577 to high-dose PPI and aspirin. Median follow-up and treatment duration was 8·9 years (IQR 8·2-9·8), and we collected 20 095 follow-up years and 99·9% of planned data. 313 primary events occurred. High-dose PPI (139 events in 1270 patients) was superior to low-dose PPI (174 events in 1265 patients; time ratio [TR] 1·27, 95% CI 1·01-1·58, p=0·038). Aspirin (127 events in 1138 patients) was not significantly better than no aspirin (154 events in 1142 patients; TR 1·24, 0·98-1·57, p=0·068). If patients using non-steroidal anti-inflammatory drugs were censored at the time of first use, aspirin was significantly better than no aspirin (TR 1·29, 1·01-1·66, p=0·043; n=2236). Combining high-dose PPI with aspirin had the strongest effect compared with low-dose PPI without aspirin (TR 1·59, 1·14-2·23, p=0·0068). The numbers needed to treat were 34 for PPI and 43 for aspirin. Only 28 (1%) participants reported study-treatment-related serious adverse events. INTERPRETATION: High-dose PPI and aspirin chemoprevention therapy, especially in combination, significantly and safely improved outcomes in patients with Barrett's oesophagus. FUNDING: Cancer Research UK, AstraZeneca, Wellcome Trust, and Health Technology Assessment.

A spectrum of histological changes may be seen in coeliac disease. Interpretation of duodenal biopsies can be problematic due to inadequate specimens or difficulties in detecting the minimal histological lesion. If serology is negative but clinical suspicion is high, a duodenal biopsy should always be performed. A combination of histology, serology, morphometry and HLA typing may be helpful in equivocal cases. Small intestinal histology is the current gold-standard diagnostic test for coeliac disease. Serological tests, immunohistochemistry and HLA typing may also have a role in the diagnostic algorithm. IgA antigliadin antibodies have mainly been replaced by IgA antiendomysial antibodies and IgA antitissue transglutaminase antibodies. The high sensitivity and specificity of these new markers have been used to challenge the necessity of obtaining a duodenal biopsy to confirm the diagnosis. It is widely recognized that relying on duodenal biopsies may be problematic. In equivocal cases where the biopsy material cannot be relied on accurately, further diagnostic tests are necessary. Quantitative morphometry and immunohistochemistry may be of value in identifying intraepithelial lymphocytes and a specific subset bearing the gamma/delta receptor. HLA-DQ2 may have a role in excluding the diagnosis in equivocal cases, its main limitation being its high frequency in the normal population. Each diagnostic test, namely histology, serology or genetic typing has limitations. A combination of these diagnostic tests should be used to clarify the full breadth of the gluten sensitivity spectrum, in particular, in those cases where duodenal histology may be equivocal.

Susceptibility to coeliac disease is genetically determined by possession of specific HLA-DQ alleles, acting in concert with one or more non-HLA linked genes. The pattern of risk seen in sibs and twins in coeliac disease is most parsimonious with a multiplicative model for the interaction between the two classes of genes. Based on a sib recurrence risk for coeliac disease of 10% and a population prevalence of 0.0033, the sib relative risk is 30. To evaluate the contribution of the MHC region to the familial risk of coeliac disease, we have examined haplotype sharing probabilities across this region in 55 coeliac disease families. Based on these probabilities the sib relative risk of coeliac disease associated with the MHC region is 3.7. Combining these results with published data on allele sharing at HLA, the estimated sib relative risk associated with the MHC region is 3.3. Therefore, the MHC genes contribute no more than 40% of the sib familial risk of coeliac disease and the non-HLA linked gene (or genes) are likely to be the stronger determinant of coeliac disease susceptibility.

Coeliac disease (CD) is associated with a wide spectrum of clinical presentation and may be overlooked as a diagnosis. There is some evidence that untreated CD is associated with a doubling of mortality, largely due to an increase in the incidence of malignancy and small intestinal lymphoma, which is decreased by a strict gluten-free diet. We studied the clinical features of screening-detected coeliacs compared to age- and sex-matched controls as a 3-year follow-up to a population screening survey, and followed-up subjects who had had CD-associated serology 11 years previously to determine whether they have CD or an increased mortality rate compared to the general population. Samples of the general population (MONICA 1991 and 1983) were screened for CD-associated serology and followed-up after 3 and 11 years, respectively, and assessed by a clinical questionnaire, screening blood tests and jejunal biopsy. Mortality rates for 'all deaths' and 'cancer deaths' were compared in subjects with positive serology in 1983 with reference to the general population. Thirteen coeliacs were diagnosed by villous atrophy following screening, compared to two patients with clinically detected CD, giving a prevalence of 1:122. Clinical features or laboratory parameters were not indicative of CD compared to controls. Subjects with positive serology followed up after 11 years did not have an excess mortality for either cancer deaths or all causes of death. Screening-detected CD is rarely silent and may be associated with significant symptoms and morbidity. In this limited study with small numbers, there does not appear to be an increased mortality from screening-detected CD, although the follow-up may be too short to detect any difference.