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Mitochondria are key organelles involved in energy production as well as numerous metabolic processes. There is a growing interest in the role of mitochondrial dysfunction in the pathogenesis of common chronic diseases as well as in cancer development. This review will examine the role mitochondria play in the pathophysiology of common liver diseases, including alcohol-related liver disease, non-alcoholic fatty liver disease, chronic hepatitis B and hepatocellular carcinoma. Mitochondrial dysfunction is described widely in the literature in studies examining patient tissue and in disease models. Despite significant differences in pathophysiology between chronic liver diseases, common mitochondrial defects are described, including increased mitochondrial reactive oxygen species production and impaired oxidative phosphorylation. We review the current literature on mitochondrial-targeted therapies, which have the potential to open new therapeutic avenues in the management of patients with chronic liver disease.

In this randomized trial in patients hospitalized with alcoholic hepatitis, pentoxifylline did not improve survival. The 28-day survival advantage in patients treated with prednisolone did not reach significance and was not sustained at 90 days or 1 year. Alcoholic hepatitis is a distinct manifestation of alcoholic liver disease that is characterized by jaundice and liver failure. This condition develops in persons with a history of prolonged and heavy alcohol use. 1 The severity of alcoholic hepatitis is conventionally defined by Maddrey’s discriminant function, which is calculated as 4.6×(patient’s prothrombin time in seconds−control’s prothrombin time in seconds)+patient’s serum bilirubin level in milligrams per deciliter; a value of 32 or higher indicates severe alcoholic hepatitis that carries an adverse prognosis, with mortality of 20 to 30% within 1 month after presentation and 30 to 40% within 6 months after presentation. 2 A . . .

Up to 40% of patients with severe alcoholic hepatitis (AH) die within 6 months of presentation, making prompt diagnosis and appropriate treatment essential. We determined the associations between serum keratin-18 (K18) and histological features, prognosis, and differential response to prednisolone in patients with severe AH. Total (K18-M65) and caspase-cleaved K18 (K18-M30) were quantified in pretreatment sera from 824 patients enrolled in the Steroids or Pentoxifylline for Alcoholic Hepatitis trial (87 with suitable histological samples) and disease controls. K18 fragments were markedly elevated in severe AH and strongly predicted steatohepatitis (alcoholic steatohepatitis) on biopsy (area under receiver operating characteristics: 0.787 and 0.807). Application of published thresholds to predict alcoholic steatohepatitis would have rendered biopsy unnecessary in 84% of all AH cases. K18-M30 and M65 were associated with 90-day mortality, independent of age and Model for End-stage Liver Disease score in untreated patients. The association for K18-M65 was independent of both age and Model for End-stage Liver Disease in prednisolone-treated patients. Modelling of the effect of prednisolone on 90-day mortality as a function of pretreatment serum K18 levels indicated benefit in those with high serum levels of K18-M30. At low pretreatment serum K18 levels, prednisolone was potentially harmful. A threshold of K18-M30 5 kIU/L predicted therapeutic benefit from prednisolone above this level (odds ratio: 0.433, 95% confidence interval: 0.19-0.95, P = 0.0398), but not below (odds ratio: 1.271, 95% confidence interval: 0.88-1.84, P = 0.199). Restricting prednisolone usage to the former group would have reduced exposure by 87%. In a large cohort of patients with severe AH, serum K18 strongly correlated with histological severity, independently associated with 90-day mortality, and predicted response to prednisolone therapy. Quantification of serum K18 levels could assist in clinical decision-making.

Increased bacterial translocation (BT) across the gut barrier due to greater intestinal permeability (IP) is seen across a range of conditions, including alcohol-related liver disease (ArLD). The phenomenon of BT may contribute to both the pathogenesis and the development of complications in ArLD. There are a number of methods available to assess IP and in this review we look at their various advantages and limitations. The knowledge around BT and IP in ArLD is also reviewed, as well as the therapeutic strategies currently in use and in development.

Alcohol-related hepatitis (ARH) is an inflammatory liver disease caused by excessive alcohol intake over time. This represents a major health burden with a high mortality and poor prognosis. Reducing alcohol consumption is key to improving health outcomes and long-term mortality. Therefore, various measures have been implemented to aid in the reduction of alcohol consumption. On a population level, this includes minimum unit pricing to reduce alcohol purchases. On a patient level, evidence-based psychosocial and pharmacological therapies aid in achieving and maintaining alcohol abstinence, which will be explored through this case report. A 39-year-old male with a four-year history of alcohol excess was admitted to a regional hospital. He presented with acute onset jaundice and examination findings were consistent with signs of chronic liver disease including abdominal distension and confusion. Investigations supported a diagnosis of severe ARH in this alcohol-dependent patient. Upon discharge, the patient received regular online cognitive behavioral therapy (CBT) sessions to aid in his abstinence. Psychosocial therapy for alcohol abstinence can be categorized into brief and extended interventions. Brief interventions are short counseling sessions, which may be most effective in non-alcohol-dependent patients, whereas extended therapies including CBT, motivational enhancement therapy, and 12-step facilitation are longer regular therapies that may be more effective for alcohol-dependent patients. Some pharmacotherapies are contraindicated in ARH patients due to their hepatotoxicity and liver metabolism. However, acamprosate and baclofen are appropriate and effective treatments. Combining psychosocial and pharmacological therapy may be more beneficial than individual treatments to achieve and maintain abstinence.

Gastro-intestinal function plays a vital role in conditions ranging from inflammatory bowel disease and HIV through to sepsis and malnutrition. However, the techniques that are currently used to assess gut function are either highly invasive or unreliable. Here we present an alternative, non-invasive sensing modality for assessment of gut function based on fluorescence spectroscopy. In this approach, patients receive an oral dose of a fluorescent contrast agent and a fibre-optic probe is used to make fluorescence measurements through the skin. This provides a readout of the degree to which fluorescent dyes have permeated from the gut into the blood stream. We present preliminary results from our first measurements in human volunteers demonstrating the potential of the technique for non-invasive monitoring of multiple aspects of gastro-intestinal health.

Objectives The primary objective of MATIS is to determine the efficacy of ruxolitinib (RUX) or fostamatinib (FOS) compared to standard of care (SOC) with respect to reducing the proportion of hospitalised patients progressing from mild or moderate to severe COVID-19 pneumonia. Secondary objectives, at 14 and 28 days, are to: Determine the efficacy of RUX or FOS to reduce mortality Determine the efficacy of RUX or FOS to reduce the need for invasive ventilation or ECMO Determine the efficacy of RUX or FOS to reduce the need for non-invasive ventilation Determine the efficacy of RUX or FOS to reduce the proportion of participants suffering significant oxygen desaturation Determine the efficacy of RUX or FOS to reduce the need for renal replacement therapy Determine the efficacy of RUX and FOS to reduce the incidence of venous thromboembolism Determine the efficacy of RUX and FOS to reduce the severity of COVID-19 pneumonia [graded by a 9-point modified WHO Ordinal Scale* Determine the efficacy of RUX or FOS to reduce systemic inflammation Determine the efficacy of RUX or FOS to the incidence of renal impairment Determine the efficacy of RUX or FOS to reduce duration of hospital stay Evaluate the safety of RUX and FOS for treatment of COVID-19 pneumonia. Trial design A multi-arm, multi-stage (3-arm parallel-group, 2-stage) randomised controlled trial that allocates participants 1:1:1 and tests for superiority in experimental arms versus standard of care. Participants Patients will be recruited while inpatients during hospitalisation for COVID-19 in multiple centres throughout the UK including Imperial College Healthcare NHS Trust. INCLUSION: Patients age ≥ 18 years at screening Patients with mild or moderate COVID-19 pneumonia, defined as Grade 3 or 4 severity by the WHO COVID-19 Ordinal Scale Patients meeting criteria: Hospitalization AND SARS-CoV2 infection (clinically suspected or laboratory confirmed) AND Radiological change consistent with COVID-19 disease CRP ≥ 30mg/L at any time point Informed consent from patient or personal or professional representative Agreement to abstain from sexual intercourse or use contraception that is >99% effective for all participants of childbearing potential for 42 days after the last dose of study drug. For male participants, agreement to abstain from sperm donation for 42 days after the last dose of study drug. EXCLUSION: Requiring either invasive or non-invasive ventilation including CPAP or high flow nasal oxygen at any point after hospital admission but before baseline, not related to a pre-existing condition (e.g., obstructive sleep apnoea) Grade ≥ 5 severity on the modified WHO COVID-19 Ordinal Scale, i.e. SpO 2 < 90% on ≥ 60% inspired oxygen by facemask at baseline; non-invasive ventilation; or invasive mechanical ventilation In the opinion of the investigator, progression to death is inevitable within the next 24 hours, irrespective of the provision of therapy Known severe allergic reactions to the investigational agents Child-Pugh B or C grade hepatic dysfunction Use of drugs within the preceding 14 days that are known to interact with any study treatment (FOS or RUX), as listed in the Summary of Product Characteristics Pregnant or breastfeeding Any medical condition or concomitant medication that in the opinion of the investigator would compromise subjects’ safety or compliance with study procedures. Any medical condition which in the opinion of the principal investigator would compromise the scientific integrity of the study Non-English speakers will be able to join the study. If participants are unable to understand verbal or written information in English, then hospital translation services will be requested at the participating site for the participant where possible. Intervention and comparator RUXOLITINIB (RUX) (14 days): An oral selective and potent inhibitor of Janus Associated Kinases (JAK1 and JAK2) and cell proliferation (Verstovek, 2010). It is approved for the treatment of disease-related splenomegaly or constitutional symptoms in myelofibrosis, polycythaemia vera and graft-versus-host-disease. RUX will be administered orally 10mg bd Day 1-7 and 5mg bd Day 8-14. FOSTAMATINIB (FOS) (14 days): An oral spleen tyrosine kinase inhibitor approved for the treatment of thrombocytopenia in adult participants with chronic immune thrombocytopenia. FOS will be administered orally 150mg bd Day 1-7 and 100mg bd Day 8-14. Please see protocol for recommended dose modifications where required. COMPARATOR (Standard of Care, SOC): experimental arms will be compared to participants receiving standard of care. It is accepted that SOC may change during a rapidly evolving pandemic. Co-enrolment to other trials and rescue therapy, either pre- or post-randomisation, is permitted and will be accounted for in the statistical analysis. Main outcomes Pairwise comparison (RUX vs SOC and FOS vs SOC) of the proportion of participants diagnosed with severe COVID-19 pneumonia within 14 days. Severe COVID-19 pneumonia is defined by a score ≥ 5 on a modified WHO COVID-19 Ordinal Scale, comprising the following indicators of disease severity: Death OR Requirement for invasive ventilation OR Requirement for non-invasive ventilation including CPAP or high flow oxygen OR O 2 saturation < 90% on ≥60% inspired oxygen Randomisation Participants will be allocated to interventions using a central web-based randomisation service that generates random sequences using random permuted blocks (1:1:1), with stratification by age (<65 and ≥65 years) and site. Blinding (masking) No participants or caregivers are blinded to group assignment. Clinical outcomes will be compared blind to group assignment. Numbers to be randomised (sample size) For an early informal dose examination by the Data Monitoring Committee a minimum of 30 participants will be recruited. For Stage 1 of this multi-arm multi-stage study, 171 participants will be randomised, with 57 participants in each arm. If at least one experimental intervention shows promise, then Stage 2 will recruit a further 95 participants per arm. Sample size calculations are given in the protocol. Trial Status Recruitment is ongoing and started 2 nd October 2020. We anticipate completion of Stage 1 by July 2021 and Stage 2 by April 2022. The current protocol version 2.0 of 11 th February 2021 is appended. Trial registration EudraCT: 2020-001750-22 , 9 th July 2020 ClinicalTrials.gov: NCT04581954 , 9 th October 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1 ). In the interest of expediting dissemination of this material, familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Alcoholic hepatitis is characterised by severe hepatic inflammation and is associated with high mortality. Monocytes are pivotal mediators of innate immunity and are described as three subsets in peripheral blood: classical CD14+16–, intermediate CD14+16+, and non-classical CD14lo16+ monocytes. Prednisolone improves liver function at 28 days but is also associated with serious infections that could explain the lack of survival benefit from this drug at 90 days. We aimed to assess the effect of prednisolone therapy on monocyte phenotype and function in alcoholic hepatitis. Blood samples from 27 patients with alcoholic hepatitis, nine patients with alcohol-related liver cirrhosis, and 46 healthy controls were analysed by flow cytometry. Monocytes were identified from whole blood using monoclonal antibody to CD14 and CD16. Paired longitudinal samples were obtained from 20 of the patients with alcoholic hepatitis who were treated by random allocation in the STOPAH trial. After unmasking, these 20 patients were subdivided into those who had been treated with prednisolone and those who had been treated without prednisolone. Before therapy, there was a relative monocytosis in patients with alcoholic hepatitis compared with those with alcohol-related liver cirrhosis and controls (median 0·96 × 109/L [IQR 0·6–1·2] vs 0·70 [0·6–0·8] vs 0·5 [0·4–0·7], p=0·003). In particular, the frequency of intermediate monocytes was increased (0·10 × 109/L [·04–0·24] vs 0·11 [0·05–0·15] vs 0·02 [0·015–0·036], p<0·0001). Intermediate monocytes from patients with severe alcoholic hepatitis had increased expression of the activation marker HLA-DR compared with those from patients with alcohol-related liver cirrhosis (11 811 median fluorescence intensity [MFI] [7821–17 694] vs 5848 [3752–8410], p=0·005), produced more tumour necrosis factor (TNF) α (419 [319–1499] vs 263 [195–1527], p=0·03), and expressed higher levels of chemokine receptor CCR5 (516 [227–870] vs 177 [133–281], p=0·01). Importantly, treatment with 7 days of prednisolone led to a reduction in proportion of intermediate monocytes (15% [9–28] reduced to 12 [4–15] in prednisolone treated patients, p=0·05), a finding that was not seen in patients treated without prednisolone. Similarly, activation marker HLA-DR was reduced in patients treated with 7 days of prednisolone compared with patients treated without prednisolone (loss of 8376 MFI [17 247–3990] vs gain of 1836 [–9958 to 4534], p=0·06). Before therapy, intermediate monocytes in alcoholic hepatitis show an activated phenotype that generates more TNFα than classical monocytes. Subsequently, 7 days of prednisolone treatment reduces the number and activation of intermediate cells, which might explain the improved liver function seen with this therapy. Elevation of chemokine receptor CCR5 on the surface of these intermediate monocytes offers a selective target to prevent hepatic infiltration of inflammatory cells, potentially sparing patients the infectious complications of prednisolone. Wellcome Trust.

Alcoholic hepatitis is characterised by florid hepatic inflammation, liver failure, and death within 28 days in 35% of patients. We recently showed proliferative peripheral blood mononuclear cell (PBMC) responses to alcohol dehydrogenase (ADH) in patients with alcohol-related cirrhosis, associated with T-helper-type 1 (Th1) immunity and disease severity. We aimed to define whether ADH-specific cellular immunity is present in alcoholic hepatitis. PBMCs were collected from 15 patients with alcoholic hepatitis (modified Maddrey's discriminant function >32), nine with alcohol-related cirrhosis (long-term alcohol abstinence), and three healthy controls. 25 overlapping peptides, spanning the human ADH β1 subunit, were constructed. Proliferation to ADH peptides (1 × 105 cells per well, cultured with 10 mM peptides for 7 days) was assessed by 3H-thymidine incorporation. A stimulation index (SI) of 2·5 or more was regarded as positive. ELISA measured concentrations of interferon γ (IFNγ), interleukin (IL) 17, and IL4 from supernatant. PBMCs from seven of 15 patients with alcoholic hepatitis recognised one to three ADH peptides (SI ≤5·7). IFNγ (mean 390·9 pg/mL [SE 31·4]) was detected in 48% of wells, IL17 (20·1 [3 ·4]) in 15%, and IL4 (90·5 [9·3]) in 14%. PBMCs from six of the nine patients with alcohol-related cirrhosis recognised one to five peptides (SI ≤5·2). IFNγ (360·7 [58·9], p>0·05) was detected in 31% of wells, IL17 (57·7 [10·9], p=0·0006) in 19%, and IL4 (219·7 [11·2], p=0·0012) in 28%. PBMCs from two healthy controls recognised one to two peptides (SI ≤3·1); all cytokine levels were below baseline. Proliferative anti-ADH immune responses in alcoholic hepatitis focused on individual epitopic regions. Predominance of proinflammatory Th1 responses was more pronounced in alcoholic hepatitis than in alcoholic-related cirrhosis. This finding requires investigation of targeted therapies to inhibit Th1 immunity in alcoholic hepatitis. Wellcome Trust.

IntroductionAlcoholic hepatitis (AH) is the most severe alcohol-related liver disease. Acute kidney injury (AKI) is associated with increased mortality. AKI may be present at the time of presentation (baseline) or develop subsequently (incident). We used data from the STOPAH (STeroids Or Pentoxifyline for Alcoholic Hepatitis) trial to describe the prevalence of AKI, its association with mortality and risk factors for its development.MethodsThe primary endpoint in analysis was 90-day mortality. Patients from the STOPAH trial were classified as having a baseline or incident AKI (within 7 days of starting treatment; D7). AKI was defined as any of: i) creatinine ≥ 26.5 micromol/L above or ≥ 1.5x the lowest recorded creatinine; ii) creatinine ≥ 133 micromol/L; iii) renal replacement therapy. The effect of AKI on 90-day mortality was tested by Kaplan-Meier survival analysis. Factors associated with incident AKI were compared by Student’s t-test, Mann-Whitney U test or Chi-squared test as appropriate.ResultsBaseline creatinine was recorded in 1051 patients; 282 patients with a normal creatinine at baseline were alive at D7 but did not have a second creatinine recorded so were excluded from survival analysis. Baseline AKI was present in 198/1051 (19%) patients while 119/1051 (11%) developed an incident AKI. Baseline AKI was associated with increased D90 mortality compared to patients without baseline or incident AKI. Incident AKI was associated with the highest mortality (Figure 1). There was no difference in mortality between patients with a baseline AKI that resolved by D7 or persisted (Breslow Chi-square 0.227, p = 0.633). Patients with incident AKI had significantly higher bilirubin (mean 374 mmol/L vs 281, p < 0.001), INR (2.0 vs 1.8, p = 0.001), and neutrophil count (8.1 vs 7.1, p = 0.031) than those without baseline or incident AKI. Prednisolone treatment was associated with a reduced risk of incident AKI (odds ratio 0.53, 95% confidence interval 0.34 - 0.81, p = 0.003). Age, gender, baseline observations and hepatic encephalopathy were not associated with incident AKI.Abstract ATU-7 Figure 1Kaplan-Meier survival curves for patients with a baseline acute kidney injury (n = 198, 63 events), incident acute kidney injury (n = 119, 56 events) and normal baseline and day seven creatinine (n = 452, 115 events)*Beslow (Generalised Wilcoxon) p < 0.05; **p < 0.001ConclusionsIncident AKI at D7 confers a worse prognosis than either no or baseline AKI. This highlights the need for proactive monitoring and treatment of factors predisposing to AKI in patients with AH, particularly for patients with markers of severe disease.