Hepatic angiotensin-converting enzyme 2 expression in metabolic dysfunction-associated steatotic liver disease and in patients with fatal COVID-19

BACKGROUND Metabolic dysfunction-associated steatotic liver disease(MASLD),characterised by hepatic lipid accumulation,causes inflammation and oxidative stress accompanied by cell damage and fibrosis.Liver injury(LI)is also frequently reported in patients hospitalised with coronavirus disease 2019(COVID-19),while preexisting MASLD increases the risk of LI and the development of COVID-19-associated cholangiopathy.Mechanisms of injury at the cellular level remain unclear,but it may be significant that severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)which causes COVID-19,uses angiotensin-converting expression enzyme 2(ACE2),a key regulator of the‘anti-inflammatory’arm of the renin-angiotensin system,for viral attachment and host cell invasion.AIM To determine if hepatic ACE2 levels are altered during progression of MASLD and in patients who died with severe COVID-19.METHODS ACE2 protein levels and localisation,and histological fibrosis and lipid droplet accumulation as markers of MASLD were determined in formalin-fixed liver tissue sections across the MASLD pathological spectrum(isolated hepatocellular steatosis,metabolic dysfunction-associated steatohepatitis(MASH)+/-fibrosis,end-stage cirrhosis)and in post-mortem tissues from patients who had died with severe COVID-19,using ACE2 immunohistochemistry and haematoxylin and eosin and picrosirius red staining of total collagen and lipid droplet areas,followed by quantification using machine learning-based image pixel classifiers.RESULTS ACE2 staining is primarily intracellular and concentrated in the cytoplasm of centrilobular hepatocytes and apical membranes of bile duct cholangiocytes.Strikingly,ACE2 protein levels are elevated in non-fibrotic MASH compared to healthy controls but not in the progression to MASH with fibrosis and in cirrhosis.ACE2 protein levels and histological fibrosis are not associated,but ACE2 and liver lipid droplet content are significantly correlated across the MASLD spectrum.Hepatic ACE2 levels are also increased in COVID-19 patients,especially those showing evidence of LI,but are not correlated with the presence of SARS-CoV-2 virus in the liver.However,there is a clear association between the hepatic lipid droplet content and the presence of the virus,suggesting a possible functional link.CONCLUSION Hepatic ACE2 levels were elevated in nonfibrotic MASH and COVID-19 patients with LI,while lipid accumulation may promote intra-hepatic SARS-CoV-2 replication,accelerating MASLD progression and COVID-19-mediated liver damage.

Role of inflammation and infection in the pathogenesis of human acute liver failure: clinical implications for monitoring and therapy

Acute liver failure is a rare and devastating clinical condition. At present, emergency liver transplantation is the only life-saving therapy in advanced cases, yet the feasibility of transplantation is affected by the presence of systemic inflammation, infection and resultant multiorgan failure. The importance of immune dysregulation and acquisition of infection in the pathogenesis of acute liver failure and its associated complications is now recognised. In this review we discuss current thinking regarding the role of infection and inflammation in the pathogenesis of and outcome in human acute liver failure, the implications for the management of such patients and suggest directions for future research.

Human thrombin for the treatment of gastric and ectopic varices

AIM:To evaluate the efficacy of human thrombin in the treatment of bleeding gastric and ectopic varices.METHODS:Retrospective observational study in a Tertiary Referral Centre.Between January 1999-October 2005,we identified 37 patients who were endoscopically treated with human thrombin injection therapy for bleeding gastric and ectopic varices.Patient details including age,gender and aetiology of liver disease/segmental portal hypertension were documented.The thrombin was obtained from the Scottish National Blood Transfusion Service and prepared to give a solution of 250 IU/mL which was injected via a standard injection needle.All patient case notes were reviewed and the total dose of thrombin given along with the number of endoscopy sessions was recorded.Initial haemostasis rates,rebleeding rates and mortality were catalogued along with the incidence of any immediate complications which could be attributable to the thrombin therapy.The duration of follow up was also listed.The study was conducted according to the United Kingdom research ethics guidelines.RESULTS:Thirty-seven patients were included.33 patients(89%) had thrombin(250 U/mL) for gastric varices,2(5.4%) for duodenal varices,1 for rectal varices and 1 for gastric and rectal varices.(1) Gastric varices,an average of 15.2 mL of thrombin was used per patient.Re-bleeding occurred in 4 patients(10.8%),managed in 2 by a transjugular intrahepatic portosystemic shunt(TIPSS)(one unsuccessfully who died) and in other 2 by a distal splenorenal shunt;(2) Duodenal varices(or type 2 isolated gastric varices),an average of 12.5 mL was used per patient over 2-3 endoscopy sessions.Re-bleeding occurred in one patient,which was treated by TIPSS;and(3) Rectal varices,an average of 18.3 mL was used per patient over 3 endoscopy sessions.No re-bleeding occurred in this group.CONCLUSION:Human thrombin is a safe,easy to use and effective therapeutic option to control haemorrhage from gastric and ectopic varices.

Update of endoscopy in liver disease:More than just treating varices

The management of complications in liver disease is often complex and challenging.Endoscopy has undergone a period of rapid expansion with numerous novel and specialized endoscopic modalities that are of increasing value in the investigation and management of the patient with liver disease.In this review,relevant literature search and expert opinions have been used to provide a brief overview and update of the current endoscopic management of patients with liver disease and portal hypertension.The main areas covered are safety of endoscopy in patients with liver disease,the use of standard endoscopy for the treatment of varices and the role of new endoscopic modalities such as endoscopic ultrasound,esophageal capsule,argon plasma coagulation,spyglass and endomicroscopy in the investigation and treatment of liver-related gastrointestinal and biliary pathology.It is clear that the role of the endoscopy in liver disease is well beyond that of just treating varices.As the technology in endoscopy expands,so does the role of the endoscopist in liver disease.

Impaired gluconeogenesis in a porcine model of paracetamol induced acute liver failure

AIM:To investigate glucose homeostasis and in particular gluconeogenesis in a large animal model of acute liver failure(ALF).METHODS:Six pigs with paracetamol induced ALF under general anaesthesia were studied over 25 h.Plasma samples were withdrawn every five hours from a central vein.Three animals were used as controls and were maintained under anaesthesia only.Using 1 H NMR spectroscopy we identified most gluconeogenic amino acids along with lactate and pyruvate in the animal plasma samples.RESULTS:No significant changes were observed in the concentrations of the amino acids studied in the animals maintained under anaesthesia only.If we look at the ALF animals,we observed a statistically significant rise of lactate(P<0.003)and pyruvate(P<0.018) at the end of the experiments.We also observed statistically significant rises in the concentrations of alanine(P<0.002),glycine(P<0.005),threonine(P< 0.048),tyrosine(P<0.000),phenylalanine(P<0.000) and isoleucine(P<0.01).Valine levels decreased significantly(P<0.05).CONCLUSION:Our pig model of ALF is characterized by an altered gluconeogenetic capacity,an impaired tricarboxylic acid(TCA)cycle and a glycolytic state.