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Summary: Background: Sequential use of non‐invasive fibrosis tests (NITs) to identify patients with advanced hepatic fibrosis is recommended. However, it remains unclear how reliable clinicians are staging liver fibrosis using combinations of NITs. Aim: Our aim was to assess concordance between NIT‐based 'clinician fibrosis assessment (CFA)' and histology in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD) and compare this with established algorithmic approaches. Methods: Six experienced hepatologists independently staged 230 MASLD patients for advanced fibrosis (F0‐2 vs F3‐4) using FIB‐4, FIB‐4+ELF, FIB‐4+ vibration controlled transient elastography (VCTE; Fibroscan™) and FIB‐4+ELF+VTCE. Concordance between histology and CFA or algorithmic approaches were assessed. Results: A total of 230 patients were included (median age 54 [22–78] years; 55% female; median FIB‐4 1.21 [IQR: 0.78–1.91]; ELF 9.3 [IQR: 8.6–10.2]; VCTE 9.4 [IQR: 6.3–14.3]; 41% F0‐1, 22% F2, 21% F3 and 16% F4). Overall, area under the receiver operator curves for histologic F3‐4 for the raw tests were 0.84 for FIB‐4, 0.86 for ELF and 0.86 for VCTE. Concordance between the hepatologists was good (FIB4, κ = 0.64; FIB‐4+ELF, κ = 0.70; FIB‐4+VCTE, κ = 0.69; FIB‐4+ELF+VCTE, κ = 0.70). Concordance between individual CFA and histology was variable, which was reflected in variability in sensitivity (44%–84%) and specificity (76%–94%). Concordance with histology was better when clinicians used NIT combinations. Purely algorithmic approaches, particularly sequential use of FIB‐4 then VCTE, tended to perform better than the CFA. Conclusions: Adhering to the recommended algorithmic approaches using NITs to stage fibrosis tended to perform more accurately than less‐structured clinician NIT‐based assessments conducted by experienced hepatologists. [ABSTRACT FROM AUTHOR]

Summary: Background: The prevalence, prediction and impact of acute kidney injury (AKI) in alcohol‐related hepatitis (AH) is uncertain. Aims: We aimed to determine AKI incidence; association with mortality; evaluate serum biomarkers and the modifying effects of prednisolone and pentoxifylline in the largest AH cohort to date. Methods: Participants in the Steroids or Pentoxifylline for Alcoholic Hepatitis trial with day zero (D0) creatinine available were included. AKI was defined by modified International Club of Ascites criteria; incident AKI as day 7 (D7) AKI without D0‐AKI. Survival was compared by Kaplan–Meier; mortality associations by Cox regression; associations with AKI by binary logistic regression; biomarkers by AUROC analyses. Results: D0‐AKI was present in 198/1051 (19%) participants; incident AKI developed in a further 119/571 (21%) with available data. Participants with D0‐AKI had higher 90‐day mortality than those without (32% vs. 25%, p = 0.008), as did participants with incident AKI compared to those without D0‐AKI or incident AKI (47% vs. 25%, p < 0.001). Incident AKI was associated with D90 mortality adjusted for age and discriminant function (AHR 2.15, 1.56–2.97, p < 0.001); D0‐AKI was not. Prednisolone therapy reduced incident AKI (AOR 0.55, 0.36–0.85, p = 0.007) but not mortality. D0 bilirubin and IL‐8 combined, miR‐6826‐5p, and miR‐6811‐3p predicted incident AKI (AUROCs 0.726, 0.821, 0.770, p < 0.01). Conclusions: Incident AKI is associated with 90‐day mortality independent of liver function. Prednisolone therapy was associated with reduced incident AKI. IL‐8 and several miRNAs are potential biomarkers to predict AKI. Novel therapies to prevent incident AKI should be evaluated in AH to reduce mortality. [ABSTRACT FROM AUTHOR]

Hepatitis C virus infection (HCV) is prevalent in prisons. Therefore, effective prison HCV services are critical for HCV elimination programmes. We aimed to evaluate the efficacy of a regional HCV prison testing and treatment programme. Between July 2017 and June 2022, data were collected prospectively on HCV test offer and uptake rates, HCV Antibody (HCV‐Ab) and HCV‐RNA positivity, treatment starts and outcomes for new inmates incarcerated in three prisons. Rates of HCV‐Ab and RNA positivity at reception, incidence of new HCV infections and reinfection following treatment were determined. From a total of 39,652 receptions, 33,028 (83.3%) were offered HCV testing and 20,394 (61.7%) completed testing. Including all receptions, 24.5% of tests (n = 4995) were HCV‐Ab positive and 8.4% of tests (n = 1713) were HCV‐RNA positive. When considering the first test for each individual (median age 34 years; 88.1% male), 14.8% (n = 1869) and 7.2% (n = 905) were HCV‐Ab and HCV‐RNA positive, respectively. The incidence of new HCV‐Ab and RNA positivity was 5.1 and 3.3 per 100 person‐years, respectively. Of 1145 HCV viraemic individuals, 18 died within 6 months and 150 were rapidly transferred out of area, leaving 977 individuals with outcomes. Of these, 835 (85.5%) received antivirals and 47 spontaneously cleared the infection, leaving 95 (9.7%) untreated. 607 (72.7%) achieved SVR. 95 patients had reinfection post‐treatment (rate 10.1 cases per 100 person‐years). Testing for HCV has increased in our prisons and the majority with viraemia are initiated on antiviral treatment. Reassuringly, a significant fall in frequency of HCV‐RNA positivity at prison reception was observed suggesting progress towards HCV elimination. [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to McPherson et al papers. To view these articles, visit https://doi.org/10.1111/apt.18061 and https://doi.org/10.1111/apt.18176 [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to McPherson et al papers. To view these articles, visit https://doi.org/10.1111/apt.18061 and https://doi.org/10.1111/apt.18171. [ABSTRACT FROM AUTHOR]

Background: Alcohol use increases the risk of many conditions in addition to liver disease; patients with alcohol‐related liver disease (ALD) are therefore at risk from both extra‐hepatic and hepatic disease. Aims: This review synthesises information about non‐liver‐related mortality in persons with ALD. Methods: A systematic literature review was performed to identify studies describing non‐liver outcomes in ALD. Information about overall non‐liver mortality was extracted from included studies and sub‐categorised into major causes: cardiovascular disease (CVD), non‐liver cancer and infection. Single‐proportion meta‐analysis was done to calculate incidence rates (events/1000 patient‐years) and relative risks (RR) compared with control populations. Results: Thirty‐seven studies describing 50 302 individuals with 155 820 patient‐years of follow‐up were included. Diabetes, CVD and obesity were highly prevalent amongst included patients (5.4%, 10.4% and 20.8% respectively). Outcomes varied across the spectrum of ALD: in alcohol‐related fatty liver the rate of non‐liver mortality was 43.4/1000 patient‐years, whereas in alcoholic hepatitis the rate of non‐liver mortality was 22.5/1000 patient‐years. The risk of all studied outcomes was higher in ALD compared with control populations: The RR of death from CVD was 2.4 (1.6–3.8), from non‐hepatic cancer 2.2 (1.6–2.9) and from infection 8.2 (4.7–14.3). Conclusion: Persons with ALD are at high risk of death from non‐liver causes such as cardiovascular disease and non‐hepatic cancer. [ABSTRACT FROM AUTHOR]

Summary: Background: Emergency admissions in England for alcohol‐related liver disease (ArLD) have increased steadily for decades. Statistics based on administrative data typically focus on the ArLD‐specific code as the primary diagnosis and are therefore at risk of excluding ArLD admissions defined by other coding combinations. Aim: To deploy the Liverpool ArLD Algorithm (LAA), which accounts for alternative coding patterns (e.g., ArLD secondary diagnosis with alcohol/liver‐related primary diagnosis), to national and local datasets in the context of studying trends in ArLD admissions before and during the COVID‐19 pandemic. Methods: We applied the standard approach and LAA to Hospital Episode Statistics for England (2013–21). The algorithm was also deployed at 28 hospitals to discharge coding for emergency admissions during a common 7‐day period in 2019 and 2020, in which eligible patient records were reviewed manually to verify the diagnosis and extract data. Results: Nationally, LAA identified approximately 100% more monthly emergency admissions from 2013 to 2021 than the standard method. The annual number of ArLD‐specific admissions increased by 30.4%. Of 39,667 admissions in 2020/21, only 19,949 were identified with standard approach, an estimated admission cost of £70 million in under‐recorded cases. Within 28 local hospital datasets, 233 admissions were identified using the standard approach and a further 250 locally verified cases using the LAA (107% uplift). There was an 18% absolute increase in ArLD admissions in the seven‐day evaluation period in 2020 versus 2019. There were no differences in disease severity or mortality, or in the proportion of admissions with decompensation of cirrhosis or alcoholic hepatitis. Conclusions: The LAA can be applied successfully to local and national datasets. It consistently identifies approximately 100% more cases than the standard coding approach. The algorithm has revealed the true extent of ArLD admissions. The pandemic has compounded a long‐term rise in ArLD admissions and mortality. [ABSTRACT FROM AUTHOR]

Hepatitis C virus infection (HCV) is common, and injecting drug use is the major risk factor for acquisition. Understanding HCV reinfection following treatment is an important consideration for HCV elimination programmes. The aim of this work was to assess the frequency and patterns of HCV reinfection in our region to develop avoidance strategies. All individuals who completed anti‐HCV treatment with a known outcome in Tyne and Wear, England between January 2016 and May 2021 were included. This was a retrospective analysis of prospectively collected data. HCV reinfection was defined as positive HCV RNA after achieving sustained virological response 12 (SVR12). 788 of 840 patients (76% male; mean age 45.7 ± 11.9 years; 47% Genotype 1; 11% Cirrhosis; 20% started in prison) achieved SVR (94%). 443 patients (56%) had HCV RNA testing post‐SVR after a median 0.82 (range 0.1–5.2) years. 56 reinfections (7.1% of all SVRs and 12.6% of SVRs who had post‐SVR testing) were diagnosed. The median time to reinfection was 1.37 (range 0.1–4.0) years and the rate of reinfection was 10.5 /100 person years. 45 (80%) reinfections became chronic, 17 of whom were retreated and achieved SVR. 5 individuals developed a second reinfection. Younger age was the only factor independently associated with reinfection (HR 0.91 [0.88–0.94] p <.001). In conclusion, HCV reinfection is common and may slow our HCV elimination efforts. In order to address high reinfection rates, harm minimization approaches need improved, and we have implemented an 'HCV track and trace' pilot to try to reduce onwards HCV transmission. [ABSTRACT FROM AUTHOR]

Introduction: Healthcare provision has been severely affected by COVID‐19, with specific challenges in organ transplantation. Here, we describe the coordinated response to, and outcomes during the first wave, across all UK liver transplant (LT) centers. Methods: Several policy changes affecting the liver transplant processes were agreed upon. These included donor age restrictions and changes to offering. A "high‐urgency" (HU) category was established, prioritizing only those with UKELD > 60, HCC reaching transplant criteria, and others likely to die within 90 days. Outcomes were compared with the same period in 2018 and 2019. Results: The retrieval rate for deceased donor livers (71% vs. 54%; P <.0001) and conversion from offer to completed transplant (63% vs. 48%; P <.0001) was significantly higher. Pediatric LT activity was maintained; there was a significant reduction in adult (42%) and total (36%) LT. Almost all adult LT were super‐urgent (n = 15) or HU (n = 133). We successfully prioritized those with highest illness severity with no reduction in 90‐day patient (P =.89) or graft survival (P =.98). There was a small (5% compared with 3%; P =.0015) increase in deaths or removals from the waitlist, mainly amongst HU cohort. Conclusions: We successfully prioritized LT recipients in highest need, maintaining excellent outcomes, and waitlist mortality was only marginally increased. [ABSTRACT FROM AUTHOR]

Many safe and effective severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccinations dramatically reduce risks of coronavirus disease 2019 (COVID‐19) complications and deaths. We aimed to describe cases of SARS‐CoV‐2 infection among patients with chronic liver disease (CLD) and liver transplant (LT) recipients with at least one prior COVID‐19 vaccine dose. The SECURE‐Liver and COVID‐Hep international reporting registries were used to identify laboratory‐confirmed COVID‐19 in CLD and LT patients who received a COVID‐19 vaccination. Of the 342 cases of lab‐confirmed SARS‐CoV‐2 infections in the era after vaccine licensing, 40 patients (21 with CLD and 19 with LT) had at least one prior COVID‐19 vaccination, including 12 who were fully vaccinated (≥2 weeks after second dose). Of the 21 patients with CLD (90% with cirrhosis), 7 (33%) were hospitalized, 1 (5%) was admitted to the intensive care unit (ICU), and 0 died. In the LT cohort (n = 19), there were 6 hospitalizations (32%), including 3 (16%) resulting in mechanical ventilation and 2 (11%) resulting in death. All three cases of severe COVID‐19 occurred in patients who had a single vaccine dose within the last 1‐2 weeks. In contemporary patients with CLD, rates of symptomatic infection, hospitalization, ICU admission, invasive ventilation, and death were numerically higher in unvaccinated individuals. Conclusion: This case series demonstrates the potential for COVID‐19 infections among patients with CLD and LT recipients who had received the COVID‐19 vaccination. Vaccination against SARS‐CoV‐2 appears to result in favorable outcomes as attested by the absence of mechanical ventilation, ICU, or death among fully vaccinated patients. [ABSTRACT FROM AUTHOR]

Summary: Background: Liver biopsy may be of diagnostic and prognostic value but its role in alcoholic hepatitis (AH) has been controversial. Aim: To assess the utility of liver biopsy in the assessment of clinically severe AH Methods: The histological features of alcoholic steatohepatitis (ASH) were recorded and scored in patients enrolled in the Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial who underwent liver biopsy. These features were then assessed relative to outcome and established clinical prognostic scores. Results: The STOPAH trial recruited 1068 patients; biopsies were obtained in 182 (17%). One hundred and sixty‐one biopsies were adequate for histological assessment and 140 (87%) were diagnostic for ASH. Only three biopsies (2%) did not have histological features of alcohol‐related liver injury. In biopsies performed prior to randomisation, ASH was identified in 92.5% of patients meeting clinical trial definitions of severe AH. In biopsies with ASH, taken before or within 48 hours of randomisation, survival differences between Alcoholic Hepatitis Histological Score (AHHS) groups were not significant: comparison of mild / moderate (91%: 21 of 23 patients) with severe (78%: 29 of 37 patients) groups: P = 0.18. The AHHS was not superior to clinical scores of prognosis: area under the curve for 28‐day mortality was 0.728, compared with 0.799 for the Glasgow alcoholic hepatitis score and 0.728 for the MELD score. Conclusion: Liver histology taken before treatment rarely changes the diagnosis in patients meeting strict criteria for a clinical diagnosis of AH. The AHHS is similar to clinical scores in determining prognosis. Clinical trial registration EudraCT reference number: 2009‐013897‐42. ISRCTN reference number: 88782125. MREC number: 09/MRE09/59. UKCRIN ID: 9143. [ABSTRACT FROM AUTHOR]

Summary: Background: Treating severe alcoholic hepatitis involves the exposure of patients to corticosteroids for 7 days to assess "response". Aim: To assess the prognostic and therapeutic implications of baseline neutrophil‐to‐lymphocyte ratio (NLR) in patients with severe alcoholic hepatitis. Methods: Patients recruited to the STOPAH trial and an independent validation group were analysed retrospectively. Area under the receiver operating curve (AUC) analysis was performed. Kaplan‐Meier analysis was used to assess survival. Log‐rank test and odds ratio (OR) were used for comparative analysis. Results: Baseline NLR was available for 789 STOPAH patients. The AUC for NLR was modest for 90‐day outcome (0.660), but was associated with infection, acute kidney injury (AKI) and severity of alcoholic hepatitis. Ninety‐day survival was not affected by prednisolone treatment if NLR < 5 or > 8 but mortality was reduced with prednisolone treatment when the NLR was 5‐8 (21.0% cf. 34.5%; P = 0.012). Prednisolone treatment increased the chance of Lille response if the NLR was  ≥ 5 (56.5% cf. 41.1%: P = 0.01; OR 1.86) but increased the risk of day 7 infection (17.3% cf. 7.4%: P = 0.006; OR 2.60) and AKI (20.8% cf. 7.0%: P = 0.008; OR 3.46) if the NLR was > 8. Incorporation of NLR into a modified Glasgow alcoholic hepatitis score (mGAHS) improved the AUC to 0.783 and 0.739 for 28‐day and 90‐day outcome, respectively. Conclusion: The NLR is associated with AKI and infection in severe alcoholic hepatitis. The NLR identifies those most likely to benefit from corticosteroids at baseline (NLR 5‐8). The mGAHS has a good predictive value for 28‐ and 90‐day outcomes. Linked Content This article is linked to Abdallah and Singal paper. To view this article, visit https://doi.org/10.1111/apt.15399. [ABSTRACT FROM AUTHOR]

Post-transplant sinusoidal fibrosis (SF) and pericellular fibrosis (PCF) have not been extensively investigated in adults. Fifty-two post-transplant liver biopsies from 28 consented patients (12 men, mean age 49, range 33-67 years) were studied. Tissue morphology, including an arbitrary summative fibrosis score was assessed in detail. Collagen proportionate area (CPA) and alpha-smooth muscle actin (α-SMA) immunostain were evaluated by digital image analysis (DIA). Anti-keratin 7, anti-C4d and anti-sonic hedgehog (Shh) immunostains were scored semi-quantitatively. SF was observed in 36/52 (69.2%) biopsies and most of these (20/36, 55.6%) had centrilobular fibrosis (CLF). PCF was seen in 7/52 (13.5%) biopsies exclusively in cases with CLF. CPA was significantly correlated with time since liver transplantation (p = 0.043), summative fibrosis score and its main components but not with α-SMA. α-SMA-positive area significantly correlated with the Banff rejection score (p = 0.022) and centrilobular inflammatory changes were more severe in cases with CLF (p = 0.003). Hepatocyte ballooning of cholestatic type was associated with PCF (p = 0.016) and Shh expression (p < 0.001). Sinusoidal fibrosis is a frequent occurrence in post-transplant adult livers, with predilection toward centrilobular areas. Graft age and oxidative stress may contribute to SF development, while hepatocyte ballooning may be implicated in PCF development. Hepatic stellate cell (HSC) activation is likely affected by centrilobular inflammation. [ABSTRACT FROM AUTHOR]

Pseudoaneurysms after visceral transplantation represent a significant risk to patients. We report the successful treatment of three transplant (pancreas, liver and kidney) artery anastomotic pseudoaneurysms using physician-modified fenestrated endovascular stent grafts. In all cases, surgical repair was considered high risk and would have compromised the arterial supply to the graft. The endovascular approach in all cases obviated the need for surgical intervention and maintained graft arterial supply. [ABSTRACT FROM AUTHOR]

Objectives There is a mismatch between research questions considered important by patients, carers and healthcare professionals and the research performed in many fields of medicine. The non-alcohol-related liver and gallbladder disorders priority setting partnership was established to identify the top research priorities in the prevention, diagnostic and treatment of gallbladder disorders and liver disorders not covered by the James-Lind Alliance (JLA) alcohol-related liver disease priority setting partnership. Design The methods broadly followed the principles of the JLA guidebook. The one major deviation from the JLA methodology was the final step of identifying priorities: instead of prioritisation by group discussions at a consensus workshop involving stakeholders, the prioritisation was achieved by a modified Delphi consensus process. Results A total of 428 unique valid diagnostic or treatment research questions were identified. A literature review established that none of these questions were considered 'answered' that is, high-quality systematic reviews suggest that further research is not required on the topic. The Delphi panel achieved consensus (at least 80% Delphi panel members agreed) that a research question was a top research priority for six questions. Four additional research questions with highest proportion of Delphi panel members ranking the question as highly important were added to constitute the top 10 research priorities. Conclusions A priority setting process involving patients, carers and healthcare professionals has been used to identify the top 10priority areas for research related to liver and gallbladder disorders. Basic, translational, clinical and public health research are required to address these uncertainties. [ABSTRACT FROM AUTHOR]

Background The risk of alcohol-related liver cirrhosis increases with increasing alcohol consumption, but many people with very high intake escape from liver disease. We postulate that susceptibility to alcoholic cirrhosis has a complex genetic component and propose that this can be dissected through a large and sufficiently powered genomewide association study ( GWAS). Methods The Genom ALC Consortium comprises researchers from Australia, France, Germany, Switzerland, United Kingdom, and United States, with a joint aim of exploring the genetic and genomic basis of alcoholic cirrhosis. For this National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism funded study, we are recruiting high-risk drinkers who are either cases (with alcoholic cirrhosis) or controls (drinking comparable amounts over similar time, but free of significant liver disease). Extensive phenotypic data are obtained using semistructured interviews and patient records, and blood samples are collected. Results We have successfully recruited 859 participants including 538 matched case-control samples as of September 2014, using study-specific inclusion-exclusion criteria and data collection protocols. Of these, 580 are cases (442 men and 138 women) and 279 are controls (205 men and 74 women). Duration of excessive drinking was slightly greater in cases than controls and was significantly less in women than men. Cases had significantly lower lifetime alcohol intake than controls. Both cases and controls had a high prevalence of reported parental alcohol problems, but cases were significantly more likely to report that a father with alcohol problems had died from liver disease (odds ratio 2.53, 95% confidence interval 1.31 to 4.87, p = 0.0055). Conclusions Recruitment of participants for a GWAS of alcoholic cirrhosis has proved feasible across countries with multiple sites. Affected patients often consume less alcohol than unaffected ones, emphasizing the existence of individual vulnerability factors. Cases are more likely to report liver disease in a father with alcohol problems than controls, consistent with a potential genetic component to the risk of alcoholic cirrhosis. [ABSTRACT FROM AUTHOR]

Return to drinking after liver transplantation for alcoholic liver disease ( ALD) remains a source of unease with varying reported rates of return to drinking and impact this has on graft function. In 2005, the UK Transplant liver advisory group recommended an 'alcohol contract' in which ALD patients listed for transplantation confirmed in writing their commitment to abstinence. We aimed to measure the rates and consequences of return to drinking alcohol in a UK transplant programme and assess the effect of the 'alcohol contract'. Consecutive patients transplanted for ALD during 1996-2011 were included. Every patient listed after Feb 2007 signed up to the 'alcohol contract'. We compared rates and pattern of return to drinking and survival before and after the introduction of the contract. Overall, 52 (37%) patients returned to drinking alcohol; 37 (39%) before and 15 (34%) after the contract. There was no significant difference in the rate of return or pattern of drinking. Median survival was 176 months (145-207 95% CI). There was no significant difference in survival, mortality rates, or in the causes of death in either group. We report high rates of return to drinking alcohol in a UK liver transplant programme. Despite this, the impact on patient and graft survival is low. There is no evidence that an 'alcohol contract' has had any effect on alcohol consumption. [ABSTRACT FROM AUTHOR]

Background Alcoholic liver disease ( ALD) is a significant threat to public health and a leading cause of death. Despite this, the long-term clinical course and predictive factors of survival in histologically advanced ALD are not well described. Aims The aim of this study was to identify clinical and histological factors that predict long-term (15-year) survival in outpatients with histologically advanced non-decompensated ALD. Methods Patients ( n = 134) with biopsy-proven histologically advanced (stage III or IV) ALD were followed up for 15 years or until death or orthotopic liver transplantation. At baseline, clinical and laboratory data were collected. On biopsy, the degree of fibrosis as well as other histological features (fat type and severity, lymphocyte and neutrophil infiltration) were scored semiquantitatively. Results Most patients were male (72%) with a median age 51 (46-57). Overall, the 5-, 10- and 15-year survival was 63, 36 and 24% respectively. In multivariate analysis, persistent drinking ( P = 0.01), smoking ( P = 0.03), age ( P = 0.01) and serum albumin at baseline ( P = 0.001) were associated with significantly increased risk of death. Persistent drinking was associated with the highest risk. No histological features, including whether the stage of ALD was bridging fibrosis or cirrhosis, correlated with prognosis. Conclusion In outpatients with biopsy-proven histologically advanced non-decompensated ALD, clinical but not histological factors determine prognosis. Persistent alcohol intake is the strongest predictor and smoking habit, age and serum albumin are also independently prognostic. Abstinence from alcohol and smoking cessation should be the priorities in the long-term management of ALD. [ABSTRACT FROM AUTHOR]

Macrophage activation syndrome ( MAS) is a rare, potentially fatal condition, which most frequently complicates rheumatological conditions and is often associated with liver dysfunction. In this case report of a patient with MAS, acute liver failure developed despite conventional immunosuppressive therapy. Liver transplantation resulted in rapid recovery and the patient has remained well for six years. A recent diagnosis of Adult Onset Still's Disease ( AOSD) provides additional supporting evidence that the initial presentation was caused by MAS. While transplantation in the context of systemic disease remains controversial, this first reported case of successful adult liver transplantation for acute liver failure caused by MAS raises an interesting clinical dilemma. [ABSTRACT FROM AUTHOR]

Background: Alcoholic hepatitis is the most florid presentation of alcohol-related liver disease. In its severe form, defined by a Maddrey's discriminant function (DF) ⩾32, the 28-day mortality rate is approximately 35%. A number of potential treatments have been subjected to clinical trials, of which two, corticosteroids and pentoxifylline, may have therapeutic benefit. The role of corticosteroids is controversial as trial results have been inconsistent, whereas the role of pentoxifylline requires confirmation as only one previous placebo-controlled trial has been published. Methods/design: STOPAH is a multicentre, double-blind, factorial (2 × 2) trial in which patients are randomised to one of four groups: 1. Group A: placebo / placebo 2. Group B: placebo / prednisolone 3. Group C: pentoxifylline / placebo 4. Group D: pentoxifylline / prednisolone The trial aims to randomise 1,200 patients with severe alcoholic hepatitis, in order to provide sufficient power to determine whether either of the two interventions is effective. The primary endpoint of the study is mortality at 28 days, with secondary endpoints being mortality at 90 days and 1 year. Discussion: STOPAH aims to be a definitive study to resolve controversy around the existing treatments for alcoholic hepatitis. Eligibility criteria are based on clinical parameters rather than liver biopsy, which are aligned with standard clinical practice in most hospitals. The use of a factorial design will allow two treatments to be evaluated in parallel, with efficient use of patient numbers to achieve high statistical power. Trial registration: EudraCT reference number: 2009-013897-42 ISRCTN reference number: ISRCTN88782125 [ABSTRACT FROM AUTHOR]

Background: Patients with suspected alcoholic hepatitis and a Discriminant Function ⩾32 underwent liver biopsy to confirm the diagnosis. Of these (n = 58), 43 had histological features of alcoholic hepatitis and 15 (25%) did not. We aimed to determine the laboratory features that differentiated those patients with a histological diagnosis of alcoholic hepatitis from those without, and assess potential clinical utility. Methods: Laboratory investigations at presentation for each of the histologically confirmed cases of alcoholic hepatitis (n = 43) were compared to those without (n = 15) to determine whether there were differences between the two groups. Univariate analysis was by Mann Whitney U Test and Multivariate analysis was by a stepwise approach. Results: White cell count (16.2 ± 10.5 v 6.9 ± 3.5 (× 109/L); p = 0.0001) and platelet count (178 ± 81 v 98.4 ± 43 (× 109/L); p = 0.0005) were higher in the patients with histological features of alcoholic hepatitis than in those without. The area under the ROC curve for AH diagnosis was estimated to be 0.83 (0.73, 0.94) and 0.81 (0.69, 0.93) for white cell count and platelet count respectively. Conclusions: Clinicians cannot accurately differentiate patients with or without alcoholic hepatitis without liver biopsy. This is critically important when deciding on specific therapies such as corticosteroids or when interpreting data from future trials in which biopsy is not mandated. In situations where liver biopsy is unsuitable or unavailable the white cell and platelet counts can be used to determine the likelihood of histological alcoholic hepatitis and guide treatment. [ABSTRACT FROM AUTHOR]

We investigated whether ancestral liver damage leads to heritable reprogramming of hepatic wound healing in male rats. We found that a history of liver damage corresponds with transmission of an epigenetic suppressive adaptation of the fibrogenic component of wound healing to the male F1 and F2 generations. Underlying this adaptation was less generation of liver myofibroblasts, higher hepatic expression of the antifibrogenic factor peroxisome proliferator-activated receptor ? (PPAR-?) and lower expression of the profibrogenic factor transforming growth factor ?1 (TGF-?1) compared to rats without this adaptation. Remodeling of DNA methylation and histone acetylation underpinned these alterations in gene expression. Sperm from rats with liver fibrosis were enriched for the histone variant H2A.Z and trimethylation of histone H3 at Lys27 (H3K27me3) at PPAR-? chromatin. These modifications to the sperm chromatin were transmittable by adaptive serum transfer from fibrotic rats to naive rats and similar modifications were induced in mesenchymal stem cells exposed to conditioned media from cultured rat or human myofibroblasts. Thus, it is probable that a myofibroblast-secreted soluble factor stimulates heritable epigenetic signatures in sperm so that the resulting offspring better adapt to future fibrogenic hepatic insults. Adding possible relevance to humans, we found that people with mild liver fibrosis have hypomethylation of the PPARG promoter compared to others with severe fibrosis. [ABSTRACT FROM AUTHOR]

Marine sediments account for up to 66% of the loss of nitrogen load to coastal areas. Sedimentary denitrification is the main sink for fixed nitrogen in the global nitrogen budget, and thus it is important to understand the structure and composition of denitrifying communities. To understand the structure and composition of denitrifying communities, the diversity of nitrite reductase ( nirS) genes from sediments along the Gulf of Mexico was examined using a PCR-based cloning approach. Sediments were collected at three different depths (0–0.5, 4–5 and 19–21 cm). Geochemical analysis revealed decreasing nitrate and oxygen concentrations with increasing sediment depth. This trend coincided with the decrease in diversity of denitrifying bacteria. LIBSHUFF analysis indicated that the clone library in the shallowest sediment (depth, 0–0.5 cm) was significantly different from that in the deepest sediment (depth, 19–21 cm), and that the deeper sediments (depths of 4–5 and 19–21 cm) were significantly similar. Community structural shifts were evident between the shallowest (oxic zone) and deepest (anoxic zone) sediments. Community changes within the deepest sediments were more subtle, with the presence of different nirS clone sequences gradually becoming dominant or, alternatively, decreasing with depth. The changes in community structure at this depth are possibly driven by nutrient availability, with lower quality sources of carbon and energy leading to the disappearance of nirS sequences common in the top layer. The majority of recovered nirS sequences were phylogenetically divergent relative to known denitrifying bacteria in the database. [ABSTRACT FROM AUTHOR]

Pharmacotherapy is the cornerstone of management in ulcerative colitis. However, controversy remains over optimal medical strategies. Specifically, differences in the onset of action of various drug therapies are thought to influence the achievement and maintenance of remission of disease, yet this is poorly characterised. There is a wide range of recent data concerning aminosalicylates, with much debate as to the relative merits of the various formulations and delivery systems. Meta-analyses confirm the efficacy of aminosalicylates for the induction and maintenance of remission and suggest that the newer agents are comparable in efficacy to sulfasalazine. Among aminosalicylates, data from clinical trials reveal that the onset of action is earlier with balsalazide than mesalazine. Although the efficacy of the newer 5-aminosalicylate agents is no greater than that of sulfasalazine, they have better adverse effect profiles. Factors such as tolerability and adherence appear more important than onset of action in long-term maintenance. Corticosteroids have long been used in the treatment of ulcerative colitis, yet there is a paucity of data regarding this. They have a rapid onset of action but considerable systemic adverse effects. Therefore, corticosteroids are reserved for disease that fails to respond to other agents or for primary therapy in patients with severe disease, although there is no universal acceptance of a threshold at which to initiate corticosteroid treatment. Rectal preparations of both aminosalicylates and corticosteroids have been developed in an attempt to exert a more rapid and direct onset of action while minimising adverse systemic effects. In clinical trials, topical preparations of both aminosalicylates and corticosteroids are effective in inducing remission. However, patient acceptability and proximal extent of disease dictate selection of a topical agent more than concern with rate of onset. A wide range of immunomodulators have been investigated in patients with steroid-refractory ulcerative colitis. The thioguanine derivatives are the most widely used but have a limited evidence base to support this use with controlled trials providing equivocal results regarding efficacy in severe ulcerative colitis. In addition, the thioguanine derivatives have a protracted onset of action and a considerable serious adverse effect profile. Calcineurin inhibitors and methotrexate have a more rapid onset of action than the thiopurines but have even less data to support their widespread use. They are widely regarded as salvage therapy and further data are required. Regarding biological agents, infliximab revolutionised the treatment of Crohn’s disease, yet results in ulcerative colitis have been disappointing. Further trials are ongoing with great anticipation for more favourable data. The practical clinical implications of any differences between the agents depend on patient satisfaction with various therapies. Noncompliance is a major concern in maintenance therapy and is probably associated with relapse. Dose administration schedules and acceptability of therapy appear to be important factors in adherence. Overall, it is not clear that onset of action has a major influence on patient adherence and addressing issues of compliance may have more direct clinical impact. [ABSTRACT FROM AUTHOR]

The article offers information regarding cholestasis, a disease associated with the use of anabolic steroids. It mentions a case of a 32-year-old man diagnosed with cholestasis deemed to be caused by the patient's intake of methandrostenolone to enhance his body. It cites another case of a 16-year-old boy diagnosed with jaundice and cholestasis following methandrostenolone intake. Furthermore, studies regarding the use of anabolic steroids suggest that the said drug induces abnormal liver function and other adverse effects including cardiomyopathy, hypertension, and prostatic hypertrophy.

Background: Alcoholic hepatitis is the most florid presentation of alcohol-related liver disease. In its severe form, defined by a Maddrey's discriminant function (DF) ≥32, the 28-day mortality rate is approximately 35%. A number of potential treatments have been subjected to clinical trials, of which two, corticosteroids and pentoxifylline, may have therapeutic benefit. The role of corticosteroids is controversial as trial results have been inconsistent, whereas the role of pentoxifylline requires confirmation as only one previous placebo-controlled trial has been published.Methods/design: STOPAH is a multicentre, double-blind, factorial (2 × 2) trial in which patients are randomised to one of four groups:1. Group A: placebo / placebo2. Group B: placebo / prednisolone3. Group C: pentoxifylline / placebo4. Group D: pentoxifylline / prednisoloneThe trial aims to randomise 1,200 patients with severe alcoholic hepatitis, in order to provide sufficient power to determine whether either of the two interventions is effective. The primary endpoint of the study is mortality at 28 days, with secondary endpoints being mortality at 90 days and 1 year.Discussion: STOPAH aims to be a definitive study to resolve controversy around the existing treatments for alcoholic hepatitis. Eligibility criteria are based on clinical parameters rather than liver biopsy, which are aligned with standard clinical practice in most hospitals. The use of a factorial design will allow two treatments to be evaluated in parallel, with efficient use of patient numbers to achieve high statistical power.Trial Registration: EudraCT reference number: 2009-013897-42 ISRCTN reference number: ISRCTN88782125. [ABSTRACT FROM AUTHOR]

Background: Patients with suspected alcoholic hepatitis and a Discriminant Function ≥32 underwent liver biopsy to confirm the diagnosis. Of these (n = 58), 43 had histological features of alcoholic hepatitis and 15 (25%) did not.We aimed to determine the laboratory features that differentiated those patients with a histological diagnosis of alcoholic hepatitis from those without, and assess potential clinical utility.Methods: Laboratory investigations at presentation for each of the histologically confirmed cases of alcoholic hepatitis (n = 43) were compared to those without (n = 15) to determine whether there were differences between the two groups. Univariate analysis was by Mann Whitney U Test and Multivariate analysis was by a stepwise approach.Results: White cell count (16.2 ± 10.5 v 6.9 ± 3.5 (× 109/L); p = 0.0001) and platelet count (178 ± 81 v 98.4 ± 43 (× 109/L); p = 0.0005) were higher in the patients with histological features of alcoholic hepatitis than in those without. The area under the ROC curve for AH diagnosis was estimated to be 0.83 (0.73, 0.94) and 0.81 (0.69, 0.93) for white cell count and platelet count respectively.Conclusions: Clinicians cannot accurately differentiate patients with or without alcoholic hepatitis without liver biopsy. This is critically important when deciding on specific therapies such as corticosteroids or when interpreting data from future trials in which biopsy is not mandated. In situations where liver biopsy is unsuitable or unavailable the white cell and platelet counts can be used to determine the likelihood of histological alcoholic hepatitis and guide treatment. [ABSTRACT FROM AUTHOR]

A correction to an article regarding the multigenerational epigenetic adaptation related to hepatic wound healing response published in the September 2, 2012 issue of the periodical is presented.