Increased Mortality Among Patients With vs Without Cirrhosis and Autoimmune Hepatitis

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The Effectiveness of Subjecting \u3ci\u3eBos indicus\u3c/i\u3e Crossbred Beef Carcasses to Higher Temperatures to Improve Tenderness

Many studies have evaluated changes that occur in muscle during the aging process and how they relate to meat tenderness. Other research has shown that subjecting carcasses to higher temperatures soon after slaughter speeds the aging process that ultimately results in improved tenderness. Several things may explain this effect. The higher temperature causes the pH (acidity) of the muscle to decrease faster. Also, the combination of lower pH and higher temperature could promote an earlier release of calcium into the muscle, which normally occurs in muscle tissue after slaughter. This increase in calcium concentration in turn activates the calpain enzyme system (a naturally occurring enzyme system that is found in muscle tissue). When calpain is activated by calcium, it has the potential to degrade certain muscle proteins that must be degraded for meat to be tender. A discussion of this is found in the previous article. Therefore, because meat from Bos indicus breed crosses often is less tender than meat from Bos taurus breeds, we studied whether tenderness could be altered by carcass high-temperature conditioning and, if so, what mechanisms are involved

Seroprevalence of Hepatitis E Virus in Autoimmune Hepatitis Patients in the Netherlands

In recent years chronic courses of hepatitis E virus (HEV) infection have been described in immunosuppressed individuals. This may implicate a potential role for HEV in the development of autoimmune diseases, including autoimmune hepatitis (AIH). Here we investigated the prevalence of HEV-antibodies in AIH patients in an endemic Central European country. HEV-specific immunoglobulin G (IgG) and HEV RNA were determined in 354 and 377 AIH patients, respectively. Clinical characteristics and disease outcome parameters were retrospectively collected. No HEV viraemic patients were identified in this cohort. A total of 106 AIH patients (29.9%) tested positive for anti-HEV IgG, and this figure was slightly higher compared to the prevalence in a reference cohort including 5,329 healthy Dutch blood donors (26.7%; P>0.05). This is the largest study on the association between HEV infection and AIH. Apparently silent HEV infection is present in a significant proportion of AIH patients, yet appears not to have significant clinical repercussions in this immune compromised group of patients. Nevertheless, since acute hepatitis E may present with histological and biochemical features of AIH, the possibility of a (concomitant) HEV infection should be considered in this category of patient

Phenotype based prediction of exome sequencing outcome using machine learning for neurodevelopmental disorders

Purpose: Although the introduction of exome sequencing (ES) has led to the diagnosis of a significant portion of patients with neurodevelopmental disorders (NDDs), the diagnostic yield in actual clinical practice has remained stable at approximately 30%. We hypothesized that improving the selection of patients to test on the basis of their phenotypic presentation will increase diagnostic yield and therefore reduce unnecessary genetic testing. Methods: We tested 4 machine learning methods and developed PredWES from these: a statistical model predicting the probability of a positive ES result solely on the basis of the phenotype of the patient. Results: We first trained the tool on 1663 patients with NDDs and subsequently showed that diagnostic ES on the top 10% of patients with the highest probability of a positive ES result would provide a diagnostic yield of 56%, leading to a notable 114% increase. Inspection of our model revealed that for patients with NDDs, comorbid abnormal (lower) muscle tone and microcephaly positively correlated with a conclusive ES diagnosis, whereas autism was negatively associated with a molecular diagnosis. Conclusion: In conclusion, PredWES allows prioritizing patients with NDDs eligible for diagnostic ES on the basis of their phenotypic presentation to increase the diagnostic yield, making a more efficient use of health care resources

Relapse is almost universal after withdrawal of immunosuppressive medication in patients with autoimmune hepatitis in remission

Background &amp; Aims: Current treatment strategies in autoimmune hepatitis (AIH) include long-term treatment with corticosteroids and/or azathioprine. Here we determined the risk of relapse after drug withdrawal in patients in long-term remission and factors associated with such a relapse.Methods: A total of 131 patients (out of a cohort including 844 patients) from 7 academic and 14 regional centres in the Netherlands were identified in whom treatment was tapered after at least 2 years of clinical and biochemical remission. Relapse was defined as alanine-aminotransferase levels (ALT) three times above the upper limit of normal and loss of remission as a rising ALT necessitating the reinstitution of drug treatment.Results: During follow-up, 61 (47%) patients relapsed and 56 (42%) had a loss of remission. In these 117 patients, 60 patients had fully discontinued medication whereas 57 patients were still on a withdrawal scheme. One year after drug withdrawal, 59% of the patients required retreatment, increasing to 73% and 81% after 2 and 3 years, respectively. Previous combination therapy of corticosteroids and azathioprine, a concomitant autoimmune disease and younger age at time of drug withdrawal were associated with an increased risk of relapse. Subsequent attempts for discontinuation after initial failure in 32 patients inevitably resulted in a new relapse.Conclusions: This retrospective analysis indicates that loss of remission or relapse occurs in virtually all patients with AIH in long-term remission when immunosuppressive therapy is discontinued. These findings indicate a reluctant attitude towards discontinuation of immunosuppressive treatment in AIH patients. (C) 2012 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.</p

Cytotoxic T Lymphocyte Antigen-4+49A/G polymorphism does not affect susceptibility to autoimmune hepatitis

<p>Background & AimsSingle nucleotide polymorphisms (SNP) in the Cytotoxic T lymphocyte antigen-4 gene (CTLA-4) have been associated with several autoimmune diseases including autoimmune Hepatitis (AIH). In this chronic idiopathic inflammatory liver disease, conflicting results have been reported on the association with a SNP at position +49 in the CTLA-4 gene in small patient cohorts. Here, we established the role of this SNP in a sufficiently large cohort of AIH patients.</p><p>MethodsThe study population consisted of 672 AIH patients derived from academic and regional hospitals in the Netherlands and was compared with 500 controls selected from the Genome of the Netherlands' project cohort. Genotype frequencies were assessed by PCR for patients and by whole genome sequencing for controls.</p><p>ResultsNo significant differences in allele frequencies were found between patients and controls (G Allele: 40% vs 39%, P=0.7). Similarly, no significant differences in genotype frequencies between patients and controls were found. Finally, there was no relation between disease activity and the G allele or AG and GG genotypes.</p><p>ConclusionThe Cytotoxic T Lymphocyte Antigen-4 +49 A/G polymorphism does not represent a major susceptibility risk allele for AIH in Caucasians and is not associated with disease severity at presentation.</p>

Increased Mortality Among Patients With vs Without Cirrhosis and Autoimmune Hepatitis

BACKGROUND & AIMS: There have been few reproducible studies of mortality in patients with autoimmune hepatitis (AIH) and its variants. We calculated mortality in a large national cohort of patients with AIH, with vs without cirrhosis, in the Netherlands. METHODS: We collected data from 449 patients with established AIH (77% female), from 6 academic and 10 non-academic hospitals in the Netherlands. We identified 29 patients with AIH and primary biliary cholangitis and 35 patients with AIH and primary sclerosing cholangitis (AIH-PSC). Mortality and liver transplantation data were assessed from August 1, 2006 through July 31, 2016. Standardized mortality ratios (SMR) were calculated using age-, sex-, and calendar year-matched mortality for the general Dutch population. RESULTS: During the 10-year follow-up period, 60 patients (13%) died (mean age, 71 years; range, 33-94 years). Twenty-six causes of death were liver related (43%), whereas the others could not be attributed to liver disease. Patients with AIH and cirrhosis had significantly higher mortality than the general population (SMR, 1.9; 95% CI, 1.2-3.4), whereas patients without cirrhosis did not (SMR, 1.2; 95% CI, 0.8-1.8). Patients with AIH-PSC had the largest increase in mortality, compared to the general population (SMR, 4.7; 95% CI, 1.5-14.6), of all groups analyzed. Mortality in patients with AIH and primary biliary cholangitis was not greater than the general population. Four or more relapses per decade or not achieving remission was associated with an increase in liver-related death or liver transplantation. Nine patients underwent liver transplantation; 2 died from non-liver related causes. Four of 9 patients on the waitlist for transplantation died before receiving a donated liver. CONCLUSION: In an analysis of data from a large national cohort of patients with AIH, we found increased mortality of patients with cirrhosis, but not of patients without cirrhosis, compared to the general Dutch population. Survival was significantly reduced in patients with AIH and features of concurrent PSC

Assessing the efficacy and safety of mycophenolate mofetil versus azathioprine in patients with autoimmune hepatitis (CAMARO trial): study protocol for a randomised controlled trial

BACKGROUND: Currently, the standard therapy for autoimmune hepatitis (AIH) consists of a combination of prednisolone and azathioprine. However, 15% of patients are intolerant to azathioprine which necessitates cessation of azathioprine or changes in therapy. In addition, not all patients achieve complete biochemical response (CR). Uncontrolled data indicate that mycophenolate mofetil (MMF) can induce CR in a majority of patients. Better understanding of first-line treatment and robust evidence from randomised clinical trials are needed. The aim of this study was to explore the potential benefits of MMF as compared to azathioprine, both combined with prednisolone, as induction therapy in a randomised controlled trial in patients with treatment-naive AIH. METHODS: CAMARO is a randomised (1:1), open-label, parallel-group, multicentre superiority trial. All patients with AIH are screened for eligibility. Seventy adult patients with AIH from fourteen centres in the Netherlands and Belgium will be randomised to receive MMF or azathioprine. Both treatment arms will start with prednisolone as induction therapy. The primary outcome is biochemical remission, defined as serum levels of alanine aminotransferase and immunoglobulin G below the upper limit of normal. Secondary outcomes include safety and tolerability of MMF and azathioprine, time to remission, changes in Model For End-Stage Liver Disease (MELD)-score, adverse events, and aspects of quality of life. The study period will last for 24 weeks. DISCUSSION: The CAMARO trial investigates whether treatment with MMF and prednisolone increases the proportion of patients in remission compared with azathioprine and prednisolone as the current standard treatment strategy. In addition, we reflect on the challenges of conducting a randomized trial in rare diseases. TRIAL REGISTRATION: EudraCT 2016-001038-91 . Prospectively registered on 18 April 2016