Publications by authors named "Rajiv Jalan"

386 Publications

Plasma ammonia levels predict hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis.

J Hepatol 2022 Jul 21. Epub 2022 Jul 21.

Institute of Liver Studies, Dept of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King´s College London, London, United Kingdom.

Background And Aims: Hyperammonaemia is central in the pathogenesis of hepatic encephalopathy, but also has pleiotropic deleterious effects on several organ systems, impacting on immune function, sarcopenia, energy metabolism and portal hypertension. This study was performed to test the hypothesis that severity of hyperammonaemia is a risk factor for liver-related complications in clinically stable outpatients with cirrhosis.

Methods: We collected data from 754 clinically stable outpatients with cirrhosis from 3 independent liver units. Baseline ammonia levels were corrected to the upper limit of normal (AMM-ULN) for the reference laboratory. The primary endpoint was hospitalisation with liver-related complications (a composite endpoint of bacterial infection, variceal bleeding, overt hepatic encephalopathy, or new onset or worsening of ascites). Multivariable competing risk frailty analysis and fast unified random forest were performed to predict complications and mortality. External validation was carried out using prospective data from 130 cirrhotic patients in an independent tertiary liver centre.

Results: Overall, 260 (35%) patients were hospitalised with liver-related complications. On multivariable analysis, AMM-ULN was an independent predictor of both liver-related complications (HR=2.13; 95%CI=1.89-2.40; p<0.001) and mortality (HR=1.45; 95%CI=1.20-1.76; p<0.001). AUROC of AMM-ULN was 77.9% for 1-year complications, higher than traditional severity scores. Statistical differences in survival were found between high and low levels of AMM-ULN both for complications and mortality (p<0.001) using 1.4 as the optimal cut-off from the training set. AMM-ULN remained a key variable for the prediction of complications within the random forests model in the derivation cohort and upon external validation.

Conclusion: Ammonia is an independent predictor of hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis and performs better than traditional prognostic scores in predicting complications.

Lay Summary: We conducted a prospective cohort study evaluating the association of blood ammonia levels with the risk of adverse outcomes in 754 patients with stable cirrhosis across 3 independent liver units. We found that ammonia is a key determinant that helps to predict which patients will be hospitalised, develop liver-related complications and die; this was confirmed in an independent cohort of patients.
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http://dx.doi.org/10.1016/j.jhep.2022.07.014DOI Listing
July 2022

Impact of COVID-19 on the liver and on the care of patients with chronic liver disease, hepatobiliary cancer, and liver transplantation: an updated EASL position paper.

J Hepatol 2022 Jul 19. Epub 2022 Jul 19.

Centre for Individualised Infection Medicine (CiiM), a joint venture between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH). Hannover, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2022.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9296253PMC
July 2022

Abnormal brain oxygen homeostasis in an animal model of liver disease.

JHEP Rep 2022 Aug 24;4(8):100509. Epub 2022 May 24.

Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, UK.

Background & Aims: Increased plasma ammonia concentration and consequent disruption of brain energy metabolism could underpin the pathogenesis of hepatic encephalopathy (HE). Brain energy homeostasis relies on effective maintenance of brain oxygenation, and dysregulation impairs neuronal function leading to cognitive impairment. We hypothesised that HE is associated with reduced brain oxygenation and we explored the potential role of ammonia as an underlying pathophysiological factor.

Methods: In a rat model of chronic liver disease with minimal HE (mHE; bile duct ligation [BDL]), brain tissue oxygen measurement, and proton magnetic resonance spectroscopy were used to investigate how hyperammonaemia impacts oxygenation and metabolic substrate availability in the central nervous system. Ornithine phenylacetate (OP, OCR-002; Ocera Therapeutics, CA, USA) was used as an experimental treatment to reduce plasma ammonia concentration.

Results: In BDL animals, glucose, lactate, and tissue oxygen concentration in the cerebral cortex were significantly lower than those in sham-operated controls. OP treatment corrected the hyperammonaemia and restored brain tissue oxygen. Although BDL animals were hypotensive, cortical tissue oxygen concentration was significantly improved by treatments that increased arterial blood pressure. Cerebrovascular reactivity to exogenously applied CO was found to be normal in BDL animals.

Conclusions: These data suggest that hyperammonaemia significantly decreases cortical oxygenation, potentially compromising brain energy metabolism. These findings have potential clinical implications for the treatment of patients with mHE.

Lay Summary: Brain dysfunction is a serious complication of cirrhosis and affects approximately 30% of these patients; however, its treatment continues to be an unmet clinical need. This study shows that oxygen concentration in the brain of an animal model of cirrhosis is markedly reduced. Low arterial blood pressure and increased ammonia (a neurotoxin that accumulates in patients with liver failure) are shown to be the main underlying causes. Experimental correction of these abnormalities restored oxygen concentration in the brain, suggesting potential therapeutic avenues to explore.
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http://dx.doi.org/10.1016/j.jhepr.2022.100509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9293761PMC
August 2022

Hyperammonaemia induces mitochondrial dysfunction and neuronal cell death.

JHEP Rep 2022 Aug 23;4(8):100510. Epub 2022 May 23.

Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK.

Background & Aims: In cirrhosis, astrocytic swelling is believed to be the principal mechanism of ammonia neurotoxicity leading to hepatic encephalopathy (HE). The role of neuronal dysfunction in HE is not clear. We aimed to explore the impact of hyperammonaemia on mitochondrial function in primary co-cultures of neurons and astrocytes and in acute brain slices of cirrhotic rats using live cell imaging.

Methods: To primary cocultures of astrocytes and neurons, low concentrations (1 and 5 μM) of NHCl were applied. In rats with bile duct ligation (BDL)-induced cirrhosis, a model known to induce hyperammonaemia and minimal HE, acute brain slices were studied. One group of BDL rats was treated twice daily with the ammonia scavenger ornithine phenylacetate (OP; 0.3 g/kg). Fluorescence measurements of changes in mitochondrial membrane potential (Δψm), cytosolic and mitochondrial reactive oxygen species (ROS) production, lipid peroxidation (LP) rates, and cell viability were performed using confocal microscopy.

Results: Neuronal cultures treated with NHCl exhibited mitochondrial dysfunction, ROS overproduction, and reduced cell viability (27.8 ± 2.3% and 41.5 ± 3.7%, respectively) compared with untreated cultures (15.7 ± 1.0%, both <0.0001). BDL led to increased cerebral LP ( = 0.0003) and cytosolic ROS generation ( <0.0001), which was restored by OP (both <0.0001). Mitochondrial function was severely compromised in BDL, resulting in hyperpolarisation of Δψm with consequent overconsumption of adenosine triphosphate and augmentation of mitochondrial ROS production. Administration of OP restored Δψm. In BDL animals, neuronal loss was observed in hippocampal areas, which was partially prevented by OP.

Conclusions: Our results elucidate that low-grade hyperammonaemia in cirrhosis can severely impact on brain mitochondrial function. Profound neuronal injury was observed in hyperammonaemic conditions, which was partially reversible by OP. This points towards a novel mechanism of HE development.

Lay Summary: The impact of hyperammonaemia, a common finding in patients with liver cirrhosis, on brain mitochondrial function was investigated in this study. The results show that ammonia in concentrations commonly seen in patients induces severe mitochondrial dysfunction, overproduction of damaging oxygen molecules, and profound injury and death of neurons in rat brain cells. These findings point towards a novel mechanism of ammonia-induced brain injury in liver failure and potential novel therapeutic targets.
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http://dx.doi.org/10.1016/j.jhepr.2022.100510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9278080PMC
August 2022

Combination of G-CSF and a TLR4 inhibitor reduce inflammation and promote regeneration in a mouse model of ACLF.

J Hepatol 2022 Jul 14. Epub 2022 Jul 14.

Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom; European foundation of the study of chronic liver failure, Barcelona, Spain. Electronic address:

Background & Aims: Acute-on-chronic liver failure (ACLF) is characterised by high short-term mortality, systemic inflammation, and failure of hepatic regeneration. Its treatment is an unmet medical need. This study was conducted to explore whether combining TAK-242, a Toll-like receptor-4 (TLR4) antagonist, with Granulocyte-Colony Stimulating Factor (G-CSF) targets inflammation whilst enhancing liver regeneration.

Methods: Two mouse models of ACLF were investigated. Chronic liver injury was induced by carbon tetrachloride followed by either lipopolysaccharide (LPS) or galactosamine (GalN) as extrahepatic or hepatic insults, respectively. G-CSF and/or TLR4-antagonist, TAK-242, were administered daily. The treatment duration was 24h and 5d in the LPS model and 48h in the GalN model, respectively.

Results: In a LPS-induced ACLF mouse model treatment with G-CSF was associated with a significant mortality of 66% after 48 hours compared with 0% without G-CSF. Addition of TAK-242 to G-CSF abrogated mortality (0%) and significantly reduced liver cell death, macrophage infiltration and inflammation. In the GalN model, both G-CSF and TAK-242, when used individually, reduced liver injury but their combination was significantly more effective. G-CSF treatment, with or without TAK-242, was associated with activation of the pro-regenerative and anti-apoptotic STAT3 pathway. LPS-driven ACLF was characterized by p21 over-expression suggesting hepatic senescence and inhibition of hepatocyte regeneration. While TAK-242 treatment mitigated the effect on senescence, G-CSF, when co-administered with TAK-242, resulted in a significant increase of markers of hepatocyte regeneration.

Conclusion: TLR4 inhibition with TAK-242 rescued G-CSF-driven cell death, inflammation, enhanced tissue repair, and significantly induced regeneration thus suggesting that the combination of G-CSF and TAK-242 is a novel approach for the treatment of ACLF.

Lay Summary: The combinatorial therapy of Granulocyte-Colony Stimulating Factor and TAK-242, a Toll-like Receptor-4 inhibitor, achieves the dual aim of reducing hepatic inflammation and inducing liver regeneration for the treatment of acute-on-chronic liver failure.
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http://dx.doi.org/10.1016/j.jhep.2022.07.006DOI Listing
July 2022

SARS-CoV-2 infection and liver involvement.

Hepatol Int 2022 Aug 29;16(4):755-774. Epub 2022 Jun 29.

The Roger Williams Institute of Hepatology, Foundation for Liver Research, London, UK.

The COVID-19 pandemic is the largest public health challenge in living memory. Patients with underlying liver disease have been disproportionately affected, experiencing high morbidity and mortality. In addition, elevated liver enzymes appear to be a risk factor for disease progression, even in the absence of underlying liver disease. Nevertheless, the mechanism of liver injury in SARS-CoV-2 infection remains largely unknown. This review aims to provide an overview of the mechanisms by which SARS-CoV-2 induces liver injury, and the impact of COVID-19 on cirrhosis, alcohol-related liver disease, autoimmune liver disease, non-alcoholic fatty liver disease, hepatitis B and C virus infection, liver-transplant recipients and patients with hepatocellular carcinoma. Finally, emerging data on vaccination in liver diseases is discussed, to help inform public health policy.
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http://dx.doi.org/10.1007/s12072-022-10364-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9243815PMC
August 2022

Hepatic encephalopathy.

Nat Rev Dis Primers 2022 06 23;8(1):43. Epub 2022 Jun 23.

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.

Hepatic encephalopathy (HE) is a prognostically relevant neuropsychiatric syndrome that occurs in the course of acute or chronic liver disease. Besides ascites and variceal bleeding, it is the most serious complication of decompensated liver cirrhosis. Ammonia and inflammation are major triggers for the appearance of HE, which in patients with liver cirrhosis involves pathophysiologically low-grade cerebral oedema with oxidative/nitrosative stress, inflammation and disturbances of oscillatory networks in the brain. Severity classification and diagnostic approaches regarding mild forms of HE are still a matter of debate. Current medical treatment predominantly involves lactulose and rifaximin following rigorous treatment of so-called known HE precipitating factors. New treatments based on an improved pathophysiological understanding are emerging.
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http://dx.doi.org/10.1038/s41572-022-00366-6DOI Listing
June 2022

PRO: Patients With Acute-on-Chronic Liver Failure Should Receive Priority on the Liver Transplant Waiting List.

Clin Liver Dis (Hoboken) 2022 May 20;19(5):203-206. Epub 2022 May 20.

Liver Failure Group Institute for Liver Disease Health University College London London United Kingdom.

Content available: Audio Recording.
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http://dx.doi.org/10.1002/cld.1194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9135148PMC
May 2022

Fatty Hepatocytes Induce Skeletal Muscle Atrophy In Vitro: A New 3D Platform to Study the Protective Effect of Albumin in Non-Alcoholic Fatty Liver.

Biomedicines 2022 Apr 21;10(5). Epub 2022 Apr 21.

Biosensors for Bioengineering Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Baldiri I Reixac 10-12, 08028 Barcelona, Spain.

The liver neutralizes endogenous and exogenous toxins and metabolites, being metabolically interconnected with many organs. Numerous clinical and experimental studies show a strong association between Non-alcoholic fatty liver disease (NAFLD) and loss of skeletal muscle mass known as sarcopenia. Liver transplantation solves the hepatic-related insufficiencies, but it is unable to revert sarcopenia. Knowing the mechanism(s) by which different organs communicate with each other is crucial to improve the drug development that still relies on the two-dimensional models. However, those models fail to mimic the pathological features of the disease. Here, both liver and skeletal muscle cells were encapsulated in gelatin methacryloyl and carboxymethylcellulose to recreate the disease's phenotype in vitro. The 3D hepatocytes were challenged with non-esterified fatty acids (NEFAs) inducing features of Non-alcoholic fatty liver (NAFL) such as lipid accumulation, metabolic activity impairment and apoptosis. The 3D skeletal muscle tissues incubated with supernatant from fatty hepatocytes displayed loss of maturation and atrophy. This study demonstrates the connection between the liver and the skeletal muscle in NAFL, narrowing down the players for potential treatments. The tool herein presented was employed as a customizable 3D in vitro platform to assess the protective effect of albumin on both hepatocytes and myotubes.
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http://dx.doi.org/10.3390/biomedicines10050958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9139027PMC
April 2022

Location and allocation: Inequity of access to liver transplantation for patients with severe acute-on-chronic liver failure in Europe.

Liver Transpl 2022 09 16;28(9):1429-1440. Epub 2022 Jun 16.

Translational Hepatology, Department of Internal Medicine, Goethe University, Frankfurt, Germany.

There is growing evidence that liver transplantation (LT) is the most effective treatment for acute-on-chronic liver failure grade-3 (ACLF-3). This study examines whether and how this evidence translates into practice by analyzing the variability in intensive care unit (ICU) admissions, listing strategies, and LT activity for patients with ACLF-3 across transplantation centers in Europe. Consecutive patients who were admitted to the ICU with ACLF-3, whether or not they were listed and/or transplanted with ACLF-3, between 2018 and 2019 were included across 20 transplantation centers. A total of 351 patients with ACLF-3 were included: 33 had been listed prior to developing ACLF-3 and 318 had not been listed at the time of admission to the ICU. There was no correlation between the number of unlisted patients with ACLF-3 admitted to the ICU and the number listed or transplanted while in ACLF-3 across centers. By contrast, there was a correlation between the number of patients listed and the number transplanted while in ACLF-3. About 21% of patients who were listed while in ACLF-3 died on the waiting list or were delisted. The percentage of LT for patients with ACLF-3 varied from 0% to 29% for those transplanted with decompensated cirrhosis across centers (average = 8%), with an I index of 68% (95% confidence interval, 49%-80%), showing substantial heterogeneity among centers. The 1-year survival for all patients with ACLF-3 was significantly higher in centers that listed and transplanted more patients with ACLF-3 (>10 patients) than in centers that listed and transplanted fewer: 36% versus 20%, respectively (p = 0.012). Patients with ACLF-3 face inequity of access to LT across Europe. Waitlisting strategies for patients with ACLF-3 influence their access to LT and, ultimately, their survival.
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http://dx.doi.org/10.1002/lt.26499DOI Listing
September 2022

Letter: de novo infection in hepatic encephalopathy-The culprit or the victim? Authors' reply.

Aliment Pharmacol Ther 2022 05;55(9):1231-1232

Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK.

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http://dx.doi.org/10.1111/apt.16906DOI Listing
May 2022

Body fat composition determines outcomes before and after liver transplantation in patients with cirrhosis.

Hepatol Commun 2022 Aug 14;6(8):2198-2209. Epub 2022 Apr 14.

Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany.

Cachexia occurs in late stages of liver cirrhosis, and a low-fat mass is potentially associated with poor outcome. This study compared different computed tomography (CT)-derived fat parameters with respect to its prognostic impact on the development of complications and death before and after liver transplantation. Between 2001 and 2014, 612 patients with liver cirrhosis without hepatocellular carcinoma listed for liver transplantation met the inclusion criteria, including abdominal CT scan (±200 days to listing). A total of 109 patients without cirrhosis served as controls. The subcutaneous fat index (SCFI), the paraspinal muscle fat index, and the visceral fat index were assessed at L3/L4 level and normalized to the height (cm /m ). Data were collected and analyzed retrospectively. Low SCFI was associated with a higher rate of ascites and increased C-reactive protein levels (p < 0.001). In addition, multivariate Cox regression analysis adjusting for sex, age, body mass index (BMI), and Model for End-Stage Liver Disease showed that decreasing SCFI was also associated with an increased risk of cirrhosis-related complications (p = 0.003) and death on the transplant wait list (p = 0.013). Increased paraspinal and visceral fat were not only positively correlated with creatinine levels (p < 0.001), BMI, and metabolic comorbidities (all p < 0.001) before transplantation, but also predictive for 1-year mortality after transplantation. Conclusion: The distribution of body fat is a major determinant for complications and outcome in cirrhosis before and after liver transplantation.
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http://dx.doi.org/10.1002/hep4.1946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9315113PMC
August 2022

Heretical thoughts into hepatic encephalopathy.

J Hepatol 2022 Aug 28;77(2):539-548. Epub 2022 Mar 28.

Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada. Electronic address:

Clinical progress in the development of new diagnostic modalities and therapeutic strategies for the management of patients with hepatic encephalopathy has lagged behind the vast knowledge that has been generated from basic studies. In this article, we critically assess matters that should be revisited, such as definition, classification, diagnosis and grading of hepatic encephalopathy, which are difficult to apply reproducibly using the current criteria. Many lines of investigation have confirmed that hepatic encephalopathy is irreversible in many patients and suggest the need for further studies focussing on mechanisms of neuronal injury and death, to guide future drug development for these patients. The clinical evidence behind using lactulose for all severities of hepatic encephalopathy, which is currently considered the standard of care, is poor and placebo-controlled trials for hepatic encephalopathy should be considered ethically sound. This expert opinion identifies current challenges in hepatic encephalopathy and highlights areas which require further debate and investigation in order to help advance the field both scientifically and clinically.
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http://dx.doi.org/10.1016/j.jhep.2022.03.014DOI Listing
August 2022

Letter to the editor: The role of acute-on-chronic liver failure in predicting recovery in severe alcoholic hepatitis.

Hepatology 2022 Sep 14;76(3):E59-E60. Epub 2022 Apr 14.

Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK.

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http://dx.doi.org/10.1002/hep.32495DOI Listing
September 2022

High-risk liver transplant recipients with grade 3 acute on chronic liver failure should receive the good quality graft.

Liver Int 2022 07 12;42(7):1629-1637. Epub 2022 Apr 12.

Liver Failure Group, Institute for Liver and Digestive Health, UCL Medical School, London, UK.

Background & Aim: We aimed to develop a risk score for LT recipients and donor selection among patients with ACLF-3.

Methods And Results: A total of 7166 adult LT recipients (mean age 53 years, 63% males, 56% Caucasians, 42% obese, median MELD score 36.5) using deceased donor grafts in the UNOS database (01/2002-06/2018) who were in ACLF-3 at LT as per EASL-CLIF criteria were analysed. Cox regression model on the derivation dataset (N = 3583) showed recipient age, non-alcohol aetiology, pulmonary failure, brain failure and cardiovascular failure to be associated with 1-year patient survival. Observed and expected post-transplant 1-year survival showed excellent correlation (R = .920). Risk score from cox model on derivation dataset stratified 3583 recipients in validation cohort using cut-off scores 7.55 and 11.57 to low (N = 1211), medium (N = 1168) and high risk (N = 1199), with 1-year patient survival of 89%, 82% and 80% respectively. Based on poor versus good quality graft (donor risk index cut-off at 1.50), 1-year patient survival for low, medium and high-risk categories were 90 versus 89% (p = .490), 83 versus 82% (p = .390) and 83 versus 78% (p = .038) respectively. Among recipients with a high-risk score, donor factors of age ≥60 years, grafts obtained from national sharing and macro-steatosis >15% were associated with 1-year patient survival below 66%.

Conclusion: Among ACLF-3 liver transplant recipients, those with high risk at the time of transplant receiving better quality graft will improve post-transplant outcomes. Prospective studies using additional characteristics are needed to derive an accurate risk score model in predicting post-transplant outcomes among recipients with ACLF-3.
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http://dx.doi.org/10.1111/liv.15263DOI Listing
July 2022

Consensus care recommendations for alfapump in cirrhotic patients with refractory or recurrent ascites.

BMC Gastroenterol 2022 Mar 8;22(1):111. Epub 2022 Mar 8.

University Clinic for Visceral Surgery and Medicine, University Hospital Inselspital Bern and University of Bern, Freiburgstrasse 18, 3010, Bern, Switzerland.

Background: The alfapump is an implantable class III medical device that pumps ascitic fluid from the peritoneal space to the urinary bladder from where it is excreted. The pump reduces or abrogates the need for repeated paracentesis in patients with recurrent or refractory ascites.

Aims: To improve outcomes for alfapump implantation and pre- and post-implant patient management in both clinical trial and real-world settings by development of consensus recommendations.

Methods: The alfapump working group consisting of hepatologists and surgeons with extensive experience in implantation of the alfapump and patient management met on two occasions: (1) to determine the key areas where recommendations should be made; and (2) to discuss the experiences of the working group within those areas and formulate draft statements. Developed statements were submitted to the group and consensus sought on relevance and wording through a collaborative iterative approach in order to consolidate the recommendations into consensus statements. Only recommendations agreed upon unanimously were included.

Results: Twenty-three consensus recommendations were developed in the areas of pre-implantation procedure, (three statements), surgical implant procedure (11 statements), immediate post-implant care (three statements) and long-term management (six statements).

Conclusions: The consensus statements are a valuable reference resource for physicians managing patients with the alfapump and for those considering management strategies for patients with refractory ascites.
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http://dx.doi.org/10.1186/s12876-022-02173-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905806PMC
March 2022

Editorial: infections and hepatic encephalopathy-does the chicken or the egg come first? A novel perspective at the horizon. Authors' reply.

Aliment Pharmacol Ther 2022 03;55(6):746-747

Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK.

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http://dx.doi.org/10.1111/apt.16829DOI Listing
March 2022

Liver injury in non-alcoholic fatty liver disease is associated with urea cycle enzyme dysregulation.

Sci Rep 2022 03 1;12(1):3418. Epub 2022 Mar 1.

SeLiver Group, Instituto de Biomedicina de Sevilla/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Avda. Manuel Siurot s/n, 41013, Sevilla, Spain.

The main aim was to evaluate changes in urea cycle enzymes in NAFLD patients and in two preclinical animal models mimicking this entity. Seventeen liver specimens from NAFLD patients were included for immunohistochemistry and gene expression analyses. Three-hundred-and-eighty-two biopsy-proven NAFLD patients were genotyped for rs1047891, a functional variant located in carbamoyl phosphate synthetase-1 (CPS1) gene. Two preclinical models were employed to analyse CPS1 by immunohistochemistry, a choline deficient high-fat diet model (CDA-HFD) and a high fat diet LDLr knockout model (LDLr -/-). A significant downregulation in mRNA was observed in CPS1 and ornithine transcarbamylase (OTC1) in simple steatosis and NASH-fibrosis patients versus controls. Further, age, obesity (BMI > 30 kg/m), diabetes mellitus and ALT were found to be risk factors whereas A-allele from CPS1 was a protective factor from liver fibrosis. CPS1 hepatic expression was diminished in parallel with the increase of fibrosis, and its levels reverted up to normality after changing diet in CDA-HFD mice. In conclusion, liver fibrosis and steatosis were associated with a reduction in both gene and protein expression patterns of mitochondrial urea cycle enzymes. A-allele from a variant on CPS1 may protect from fibrosis development. CPS1 expression is restored in a preclinical model when the main trigger of the liver damage disappears.
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http://dx.doi.org/10.1038/s41598-022-06614-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8888708PMC
March 2022

Overt hepatic encephalopathy is an independent risk factor for de novo infection in cirrhotic patients with acute decompensation.

Aliment Pharmacol Ther 2022 03 1;55(6):722-732. Epub 2022 Feb 1.

Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK.

Background: The occurrence of overt hepatic encephalopathy (OHE) is associated with increased mortality. HE is commonly precipitated by infection, but whether HE predisposes to new infection is unclear. This study aimed to test if OHE predisposes to de novo infection during hospitalisation and its association with short-term mortality.

Aims And Methods: Seven hundred and fifty-nine consecutive patients were identified at two institutions from prospectively maintained clinical databases of cirrhotic patients admitted with acute decompensation (AD). Infection and HE data were collected on the day of admission, and the occurrence of de novo infections was assessed for 28 days after admission. EASL-CLIF organ failure criteria were used to determine the presence of organ failures. Multivariable analysis using the logistic regression model was used to assess predictors of 28-day mortality and de novo infection.

Results: Patients were divided into four groups; no baseline OHE or infection (n = 352); OHE with no baseline Infection (n = 221); no OHE but baseline infection (n = 100) and OHE with baseline infection (n = 86). On multivariate analyses, OHE (OR, 1.532 [95% CI, 1.061-2.300, P = 0.024]), and admission to ITU (OR, 2.303 [95% CI, 1.508-3.517, P < 0.001]) were independent risk factors for de novo infection. 28-day mortality was 25.3%, 60.2%, 55.0% and 72.1% in the 4-groups respectively. Age, INR and creatinine were independently predictive of mortality. The presence of overt HE, infection, coagulation, kidney, circulatory, respiratory and liver failures were significantly associated with higher mortality.

Conclusion: OHE is an independent risk factor for de novo infection in cirrhotic patients with AD.
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http://dx.doi.org/10.1111/apt.16790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303427PMC
March 2022

Severe alcoholic hepatitis as precipitant for organ failure and ACLF.

Z Gastroenterol 2022 Jan 18;60(1):67-76. Epub 2022 Jan 18.

Hôpital Beaujon, Clichy, France.

Alcoholic hepatitis is the acute deterioration of alcoholic liver disease with rapid onset or worsening of jaundice, which in severe cases, may transition to acute-on-chronic liver failure with extremely high short-term mortality, increasing with the number and severity of hepatic and extra-hepatic organ dysfunction. Diagnosis and treatment are insufficient and challenging, especially due to the complex, multi-factorial and as yet not fully understood pathogenesis. While current management is limited to steroids and best supportive care, debate is ongoing concerning liver transplantation for selected patients, and several novel approaches are under way with mixed results. These drawbacks in disease management together with increasing prevalence in Germany, and generally in Western countries, constitute an unmet need for the healthcare systems. This review tries to summarize the current status of these aspects and provides an overview for pathogenesis, management and potential future treatments.
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http://dx.doi.org/10.1055/a-1713-3796DOI Listing
January 2022

Reply to: "Sarcopenia should be evaluated in patients with acute-on-chronic liver failure and candidates to liver transplantation".

J Hepatol 2022 04 28;76(4):986. Epub 2021 Dec 28.

European Foundation for the Study of Chronic Liver Failure (EF Clif), 08021 Barcelona, Spain; Liver Failure Group, Institute for Liver and Digestive Health, UCL Medical School, London, UK.

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http://dx.doi.org/10.1016/j.jhep.2021.12.018DOI Listing
April 2022

Presence of multilobular necrosis on liver biopsy identifies corticosteroid responsiveness in acute indeterminate hepatitis.

Liver Int 2022 04 5;42(4):853-863. Epub 2022 Jan 5.

Liver failure Group, Institute for Liver and Digestive Health, Division of Medicine, University College London Medical School, Royal Free Hospital, London, UK.

Background And Aims: Treatment of patients with severe indeterminate hepatitis (IAH) is an unmet need. Corticosteroids are often used in the management of these patients but criteria for the selection of patients for this intervention are arbitrary. The aims of this study were to analyse the clinical and pathological features of patients with IAH to define predictors of corticosteroid responsiveness.

Methods: This study included consecutive patients with acute indeterminate hepatitis admitted to a single hospital and underwent a liver biopsy. The clinical manifestation and histopathological features of steroid and non-steroid groups were compared and their relationship with corticosteroids response was evaluated.

Results: Forty-eight patients were included, 24 (50%) recovered and the other half underwent liver transplantation or died within 3-months. Of the 48 cases, 24 received corticosteroids (initial dose of 45 ± 12 mg prednisolone). Corticosteroids were initiated 2.7 ± 3.8 days after admission. Liver biopsy was performed 2-days (median, IQR 1-3) after admission. Fifteen (62.5%) patients receiving corticosteroids survived without transplantation compared with 9 (37.5%) that did not receive steroids (P = .149). In those with multilobular necrosis, 50% reduction in the death/transplantation rate was observed after steroid treatment (P = .018). In patients without multilobular necrosis and with or without perivenulitis, corticosteroids did not impact the outcome. Response to corticosteroids was independent of the MELD score.

Conclusions: The presence of multilobular necrosis on liver biopsy helps identify a subgroup of IAH cases who may benefit from the administration of corticosteroids.
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http://dx.doi.org/10.1111/liv.15144DOI Listing
April 2022

The role of RIPK1 mediated cell death in acute on chronic liver failure.

Cell Death Dis 2021 12 17;13(1). Epub 2021 Dec 17.

Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK.

Acute-on-chronic liver failure (ACLF) is characterized predominantly by non-apoptotic forms of hepatocyte cell death. Necroptosis is a form of programmed lytic cell death in which receptor interacting protein kinase (RIPK) 1, RIPK3 and phosphorylated mixed lineage kinase domain-like (pMLKL) are key components. This study was performed to determine the role of RIPK1 mediated cell death in ACLF. RIPK3 plasma levels and hepatic expression of RIPK1, RIPK3, and pMLKL were measured in healthy volunteers, stable patients with cirrhosis, and in hospitalized cirrhotic patients with acutely decompensated cirrhosis, with and without ACLF (AD). The role of necroptosis in ACLF was studied in two animal models of ACLF using inhibitors of RIPK1, necrostatin-1 (NEC-1) and SML2100 (RIPA56). Plasma RIPK3 levels predicted the risk of 28- and 90-day mortality (AUROC, 0.653 (95%CI 0.530-0.776), 0.696 (95%CI 0.593-0.799)] and also the progression of patients from no ACLF to ACLF [0.744 (95%CI 0.593-0.895)] and the results were validated in a 2 patient cohort. This pattern was replicated in a rodent model of ACLF that was induced by administration of lipopolysaccharide (LPS) to bile-duct ligated rats and carbon tetrachloride-induced fibrosis mice administered galactosamine (CCL/GalN). Suppression of caspase-8 activity in ACLF rodent model was observed suggesting a switch from caspase-dependent cell death to necroptosis. NEC-1 treatment prior to administration of LPS significantly reduced the severity of ACLF manifested by reduced liver, kidney, and brain injury mirrored by reduced hepatic and renal cell death. Similar hepato-protective effects were observed with RIPA56 in a murine model of ACLF induced by CCL/GalN. These data demonstrate for the first time the importance of RIPK1 mediated cell death in human and rodent ACLF. Inhibition of RIPK1 is a potential novel therapeutic approach to prevent progression of susceptible patients from no ACLF to ACLF.
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http://dx.doi.org/10.1038/s41419-021-04442-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8683430PMC
December 2021

Early transplantation maximizes survival in severe acute-on-chronic liver failure: Results of a Markov decision process model.

JHEP Rep 2021 Dec 23;3(6):100367. Epub 2021 Sep 23.

Karsh Division of Gastroenterology and Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Background & Aims: Uncertainties exist surrounding the timing of liver transplantation (LT) among patients with acute-on-chronic liver failure grade 3 (ACLF-3), regarding whether to accept a marginal quality donor organ to allow for earlier LT or wait for either an optimal organ offer or improvement in the number of organ failures, in order to increase post-LT survival.

Methods: We created a Markov decision process model to determine the optimal timing of LT among patients with ACLF-3 within 7 days of listing, to maximize overall 1-year survival probability.

Results: We analyzed 6 groups of candidates with ACLF-3: patients age ≤60 or >60 years, patients with 3 organ failures alone or 4-6 organ failures, and hepatic or extrahepatic ACLF-3. Among all groups, LT yielded significantly greater overall survival probability . remaining on the waiting list for even 1 additional day ( <0.001), regardless of organ quality. Creation of 2-way sensitivity analyses, with variation in the probability of receiving an optimal organ and expected post-transplant mortality, indicated that overall survival is maximized by earlier LT, particularly among candidates >60 years old or with 4-6 organ failures. The probability of improvement from ACLF-3 to ACLF-2 does not influence these recommendations, as the likelihood of organ recovery was less than 10%.

Conclusion: During the first week after listing for patients with ACLF-3, earlier LT in general is favored over waiting for an optimal quality donor organ or for recovery of organ failures, with the understanding that the analysis is limited to consideration of only these 3 variables.

Lay Summary: In the setting of grade 3 acute-on-chronic liver failure (ACLF-3), questions remain regarding the timing of transplantation in terms of whether to proceed with liver transplantation with a marginal donor organ or to wait for an optimal liver, and whether to transplant a patient with ACLF-3 or wait until improvement to ACLF-2. In this study, we used a Markov decision process model to demonstrate that earlier transplantation of patients listed with ACLF-3 maximizes overall survival, as opposed to waiting for an optimal donor organ or for improvement in the number of organ failures.
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http://dx.doi.org/10.1016/j.jhepr.2021.100367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8603202PMC
December 2021

Biomarkers of extracellular matrix formation are associated with acute-on-chronic liver failure.

JHEP Rep 2021 Dec 27;3(6):100355. Epub 2021 Aug 27.

Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK.

Background & Aims: Acute-on-chronic liver failure (ACLF) is characterised by organ failure(s), high short-term mortality, and, pathophysiologically, deranged inflammatory responses. The extracellular matrix (ECM) is critically involved in regulating the inflammatory response. This study aimed to determine alterations in biomarkers of ECM turnover in ACLF and their association with inflammation, organ failures, and mortality.

Methods: We studied 283 patients with cirrhosis admitted for acute decompensation (AD) with or without ACLF, 64 patients with stable cirrhosis, and 30 healthy controls. A validation cohort (25 ACLF, 9 healthy controls) was included. Plasma PRO-C3, PRO-C4, PRO-C5, PRO-C6, and PRO-C8 ( collagen type III-VI and VIII ) and C4M and C6M ( collagen type IV and VI ) were measured. Immunohistochemistry of PRO-C6 was performed on liver biopsies (AD [n = 7], ACLF [n = 5]). A competing-risk regression analysis was performed to explore the prognostic value of biomarkers of ECM turnover with 28- and 90-day mortality.

Results: PRO-C3 and PRO-C6 were increased in ACLF compared to AD ( = 0.089 and <0.001, respectively), whereas collagen degradation markers C4M and C6M were similar. Both PRO-C3 and PRO-C6 were strongly associated with liver function and inflammatory markers. Only PRO-C6 was associated with extrahepatic organ failures and 28- and 90-day mortality (hazard ratio [HR; on log-scale] 6.168, 95% CI 2.366-16.080, <0.001, and 3.495, 95% CI 1.509-8.093,  = 0.003, respectively). These findings were consistent in the validation cohort. High PRO-C6 expression was observed in liver biopsies of patients with ACLF.

Conclusions: This study shows, for the first time, evidence of severe net interstitial collagen deposition in ACLF and makes the novel observation of the association between PRO-C6 and (extrahepatic) organ failures and mortality. Further studies are needed to define the pathogenic significance of these observations.

Lay Summary: This study describes a disrupted turnover of collagen type III and VI in Acute-on-chronic liver failure (ACLF). Plasma biomarkers of these collagens (PRO-C3 and PRO-C6) are associated with the severity of liver dysfunction and inflammation. PRO-C6, also known as the hormone endotrophin, has also been found to be associated with multi-organ failure and prognosis in acute decompensation and ACLF.
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http://dx.doi.org/10.1016/j.jhepr.2021.100355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581571PMC
December 2021

Cirrhosis-associated immune dysfunction.

Nat Rev Gastroenterol Hepatol 2022 02 26;19(2):112-134. Epub 2021 Oct 26.

Departamento de Medicina y Especialidades Médicas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.

The term cirrhosis-associated immune dysfunction (CAID) comprises the distinctive spectrum of immune alterations associated with the course of end-stage liver disease. Systemic inflammation and immune deficiency are the key components of CAID. Their severity is highly dynamic and progressive, paralleling cirrhosis stage. CAID involves two different immune phenotypes: the low-grade systemic inflammatory phenotype and the high-grade systemic inflammatory phenotype. The low-grade systemic inflammatory phenotype can be found in patients with compensated disease or clinical decompensation with no organ failure. In this phenotype, there is an exaggerated immune activation but the effector response is not markedly compromised. The high-grade systemic inflammatory phenotype is present in patients with acute-on-chronic liver failure, a clinical situation characterized by decompensation, organ failure and high short-term mortality. Along with high-grade inflammation, this CAID phenotype includes intense immune paralysis that critically increases the risk of infections and worsens prognosis. The intensity of CAID has important consequences on cirrhosis progression and correlates with the severity of liver insufficiency, bacterial translocation and organ failure. Therapies targeting the modulation of the dysfunctional immune response are currently being evaluated in preclinical and clinical studies.
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http://dx.doi.org/10.1038/s41575-021-00520-7DOI Listing
February 2022

Rapid detection for infected ascites in cirrhosis using metagenome next-generation sequencing: A case series.

Liver Int 2022 01 22;42(1):173-179. Epub 2021 Nov 22.

Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Empirical antibiotic therapy in patients with spontaneous bacterial peritonitis (SBP) is common as pathogen(s) are identified in only 5%-20% patients using conventional culture-based techniques. Metagenome next-generation sequencing (mNGS) test is a promising approach for the diagnosis of infectious disease. The clinical application of mNGS for infected ascites in cirrhotic patients is rarely reported. Here, we describe three cases to preliminarily explore the potential role of mNGS for microbiological diagnosis of ascites infection in an exploratory manner. The clinical performance of ascites mNGS in cirrhotic patients remains to be further evaluated.
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http://dx.doi.org/10.1111/liv.15083DOI Listing
January 2022

Waitlist Priority for Patients with Acute-on-Chronic Liver Failure: Not Just Horseplay.

Liver Transpl 2022 04 11;28(4):539-543. Epub 2021 Nov 11.

Liver Failure Group, Institute for Liver and Digestive Health, UCL Medical School, London, UK.

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http://dx.doi.org/10.1002/lt.26330DOI Listing
April 2022

Potential novel approaches to prevent the risk of infection in patients with variceal bleeding.

J Hepatol 2022 03 1;76(3):751-752. Epub 2021 Oct 1.

Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2021.09.027DOI Listing
March 2022
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