Liver Ischemia Research Articles

The pathogenesis of ischemic hepatitis

Ischemic hepatitis is inflammation caused by necrosis of liver cells due to ischemia and hypoxia caused by low cardiac output or septic shock. It is often complicated by heart failure or severe septic shock. One of the pathogenesis of ischemic hepatitis is hepatocyte injury caused by ischemia and hypoxia, which results in damage-associated molecular patterns (DAMPs) release and binding to membrane receptors such as toll like receptors (TLRs) to cause inflammatory reactions.The other is when the ischemic liver is reperfused, hepatocyte mitochondrias will produce a large amount of ROS causing ischemia reperfusion injury. These two mechanisms and related molecular pathways are elaborated in this paper.

Rosuvastatin alleviated the liver ischemia reperfusion injury by activating the expression of peroxisome proliferator-activated receptor gamma (PPARγ).

Liver ischemia and reperfusion could cause serious damage to liver tissues. Abnormal liver function could induce serious damage and threaten human health. Evidence emerged to suggest that rosuvastatin could relieve cerebral ischemia-reperfusion injury and alleviate the disease related to vessels by activating the expression of PPARγ. However, whether rosuvastatin could relieve the liver ischemia reperfusion injury by enhancing the expression of PPARγ is unclear. For the strictness of experimental findings, we established both the rat models and the cell model of liver ischemia reperfusion injury by respectively treating rats and cells with rosuvastatin. PPARγ inhibitor was also used for the stimulation of these cells and rats. Reactive oxygen species (ROS) levels, apoptosis and related protein levels were determined with ROS staining, ROS staining and western blotting for the detection of injury induced by oxygen-glucose deprivation and re-oxygenation (OGD/R). Pretreatment of rosuvastatin promoted the expression of PPARγ in liver tissues and MIHA cells. It also inhibited the ischemia reperfusion and OGD/R induced production of ROS while promoted the release of SOD in liver tissues and MIHA cells. Furthermore, rosuvastatin also alleviated the ischemia reperfusion -induced apoptosis of liver tissues and OGD/R-induced MIHA cells apoptosis. However, application of PPARγ inhibitor abolished the restorative effects of rosuvastatin on the apoptosis and oxidative stress on liver tissues and MIHA cells. Rosuvastatin prevented the liver ischemia reperfusion injury of rats by activating PPARγ.

Proteins of allogeneic hepatocytes and pharmacological preparations for the correction of immunometabolic disorders in experimental liver pathology

Introduction: The relationship of numerous metabolic shifts, disorders of hepatocytes functional activity resulting from hypoxia and toxic liver damage with the function of the immune system has not been sufficiently studied so far, nor have the most effective methods of pharmacological correction been established.
 Materials and Methods: The studies were carried out on 603 mature male Wistar rats and 45 mice. Acute toxic liver damage (ATLD) was modeled by intramuscular introduction of carbon tetrachloride; acute liver ischemia (ALI) was caused by clamping the hepatoduodenal ligament for 20 minutes; chronic alcohol intoxication (CAI) was modeled by forced intragastric administration of 20% ethanol solution for 60 days. Isolation of xenogeneic (murine) and allogeneic (rat) hepatocytes from newborn mice and rats was carried out according to the method of Berry and Friend (1969); culture fluid of hepatocytes and its protein fractions were prepared according to our developed techniques. The obtained biological material was intraperitoneally introduced into the rats with ATLD, ALI, and CAI.
 Results and Discussion: In all the models of the liver damage, there developed morphological and biochemical signs of the liver damage, impaired congenital and adaptive immunity, oxidative stress, increased lipid peroxidation processes.
 Conclusion: The introduction of allogeneic hepatocytes, culture fluid obtained on their basis,and proteins isolated from it with MW less than 130 kDa to the recipients with toxic and ischemic liver damage more effectively corrects the pathologic changes in the liver in comparison with xenogeneic hepatocytes, their culture fluid and pharmacological preparations (combinations of Essentiale N and Hypoxenum or Heptral and Mexicor).

Use of Direct Oral Anticoagulants in Inherited Thrombophilia

Introduction: Factor V Leiden mutation and prothrombin G20210A mutation are the most common causes of an inherited thrombophilia and together account for 50 to 60 percent of diagnoses. Traditionally, patients have been treated with oral warfarin therapy or injectable low molecular weight heparin (LMWH), which requires frequent laboratory monitoring or self-injections. The difficulty with administration and monitoring of traditional therapy has made direct oral anticoagulants (DOACs) increasingly favored for treatment of VTE. However, the efficacy and bleeding complication of DOAC use in inherited thrombophilia has not been well studied.Methods: We designed a retrospective analysis of patients with Factor V Leiden mutation and prothrombin G20210A mutation at the University of Virginia who were treated with a DOAC (rivaroxaban, apixaban, edoxaban, or dabigatran) for treatment of VTE or atrial fibrillation from January 28th, 2011 to May 30th, 2017. Adult patients with presence of either homozygous or heterozygous mutation for either Factor V Leiden mutation or prothrombin mutation were included. All patients were required to be treated for at least 48 hours with a documented follow-up of adverse events. Medical charts were reviewed for age, gender, weight, presence of Factor V Leiden mutation and/or prothrombin G20210A mutation, DOAC dose, and frequency, bleeding events, and recurrent thrombotic events. Our primary outcomes were efficacy defined as development of a recurrent VTE and safety defined as occurrence of any bleeding event. Efficacy was compared to the post-hoc sub-group analysis that was conducted on the data from the RE-MEDY trial, in which VTE/VTE-related deaths were observed to be 1.5% with patients taking dabigatran compared to 2.3% with patients taking warfarin (p=0.2277) (Skelley, et al. J Throm Thrombolysis, 2017). Major and minor events were defined per International Society of Thrombosis and Hemostasis (ISTH) anticoagulation committee guidelines.Results: Fifty eight patients were eligible for analysis. The median age was 52.7 ± 16.7 years with 39 (67.2%) females. Baseline patient characteristics, type of thrombophilia, and indication for DOAC therapy are represented in Table 1. Median length of time on a DOAC was 24 months.Four patients developed a recurrent VTE however on further analysis, 3 patients were found to be non-compliant with DOAC therapy. Excluding the noncompliant patients, the rate of a recurrent VTE was 1.7% (Table 2).Nine (15.5%) patients suffered a bleeding event, of which 4 were major and 5 were minor (Table 2). Of the 4 major bleeding events, 3 were gastrointestinal (GI). One patient bled due to arterio-venous malformations, the second patient developed a bleed at the esophagectomy site, and the third patient had biliary drainage from ischemic liver disease post liver transplant. One patient suffered an intracranial hemorrhage; this patient was concurrently taking aspirin and clopidogrel while on therapeutic apixaban. The minor bleeding events included epistaxis (n=1), hemoptysis (n=1) and GI (n=3). Hemoptysis was discovered simultaneously with the diagnosis of lung cancer. Three of the patients with minor bleeding events were taking ASA, including one who was also taking dual antiplatelet therapy with clopidogrel.Conclusion: DOACs have been shown to have similar efficacy and safety compared to warfarin in many patient populations. However, there are limited studies evaluating use of DOACs in patients with inherited thrombophilia. Substantial evidence supporting widespread DOAC use in these patients is lacking. Our study confirmed the efficacy of DOACs in this patient population with a thrombosis event of only 1.7% which is favorable compared to the warfarin historical control rate of 2.3% (Skelley, et al. J Throm Thrombolysis, 2017). There was a higher than expected rate of bleeding complications, however many patients were on dual antiplatelet therapy or had other risk factors for bleeding. It would be imprudent to attribute these bleeding events solely to DOAC use. Though this is the only study of its kind, it is limited by small numbers and retrospective design. Further studies are needed to evaluate the use of DOACs compared to warfarin and LMWH. We plan to conduct further analysis utilizing a control group of inherited thrombophilia patients on warfarin compared to those on DOACs. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Details and Outcomes of Distal Pancreatectomy with Celiac Axis Resection Preserving the Left Gastric Arterial Flow.

To describe the technical details and efficacy of distal pancreatectomy with celiac axis resection (DP-CAR) and left gastric artery (LGA) flow preservation for pancreatic ductal adenocarcinoma (PDAC). This single-center, retrospective analysis investigated short- and long-term outcomes of DP-CAR performed on 55 patients with PDAC from 2011 to 2019. Our method included LGA reconstruction after total resection of the CA (rDP-CAR group; 24 patients) or LGA preservation if the tumor invasion was away from its root (pDP-CAR group; 31 patients), a CA-first approach to reduce blood loss during dissection, and conservative drain management with or without jejunal serosal patching at the pancreatic stump. Among the study patients, 23 had locally advanced PDAC and 22 had borderline resectable PDAC. Median operation duration was 443min (248-810), estimated blood loss was 600mL (150-2280), and incidence of transfusion was 2%. Ischemic complications occurred exclusively in the rDP-CAR group, including two patients with ischemic gastropathy (8%) and three patients with findings of liver ischemia on computed tomography (13%). One patient underwent relaparotomy for stomach perforations, and 19 patients (35%) had pancreatic fistula, including 8 patients who underwent conservative drain placement for more than 3 weeks without specific symptoms. There were no Clavien-Dindo grade 4 or higher postoperative complications. Preoperative therapy showed improved 3-year overall survival rates than without (54% vs. 37%, p=0.027). Using the standardized technique, DP-CAR was safely performed with no mortality and acceptable long-term survival.

Noninvasive Detection of Ischemic Vascular Damage in a Pig Model of Liver Donation After Circulatory Death.

Liver graft quality is evaluated by visual inspection prior to transplantation, a process highly dependent on the surgeon's experience. We present an objective, noninvasive, quantitative way of assessing liver quality in real time using Raman spectroscopy, a laser-based tool for analyzing biomolecular composition. A porcine model of donation after circulatory death (DCD) with normothermic regional perfusion (NRP) allowed assessment of liver quality premortem, during warm ischemia (WI) and post-NRP. Ten percent of circulating blood volume was removed in half of experiments to simulate blood recovery for DCD heart removal. Left median lobe biopsies were obtained before circulatory arrest, after 45minutes of WI, and after 2hours of NRP and analyzed using spontaneous Raman spectroscopy, stimulated Raman spectroscopy (SRS), and staining. Measurements were also taken in situ from the porcine liver using a handheld Raman spectrometer at these time points from left median and right lateral lobes. Raman microspectroscopy detected congestion during WI by measurement of the intrinsic Raman signal of hemoglobin in red blood cells (RBCs), eliminating the need for exogenous labels. Critically, this microvascular damage was not observed during WI when 10% of circulating blood was removed before cardiac arrest. Two hours of NRP effectively cleared RBCs from congested livers. Intact RBCs were visualized rapidly at high resolution using SRS. Optical properties of ischemic livers were significantly different from preischemic and post-NRP livers as measured using a handheld Raman spectrometer. Raman spectroscopy is an effective tool for detecting microvascular damage which could assist the decision to use marginal livers for transplantation. Reducing the volume of circulating blood before circulatory arrest in DCD may help reduce microvascular damage.

COVID-19 and the liver - Lessons learned.

Liver involvement, indicated by elevated liver function test results, is common in hospitalized patients with coronavirus disease 2019 (COVID‐19) and has been linked to disease severity and outcome. A dual pattern of elevated liver function tests can be observed especially in patients with severe or critical COVID‐19, characterized by an increase in aminotransferases early in the course of this disease, followed by an increase in cholestasis‐associated biochemistry markers at later stages. This dual pattern is associated with inflammatory response markers and poor outcome. Current notions on the mechanisms of liver injury in COVID‐19 include direct cytopathic effects of the virus on hepatocytes and cholangiocytes, ischemic and hypoxic liver damage, drug‐induced liver injury, activation of hepatic immune cells by excess cytokine production and exacerbation of pre‐existing liver disease. Patients with obesity‐related non‐alcoholic fatty liver disease and, in particular, patients with cirrhosis are at high risk of liver injury and a fatal outcome from COVID‐19. In contrast, individuals receiving stable immunosuppressive medication for autoimmune liver diseases or during long‐term follow‐up after liver transplantation do not have a higher case‐to‐infection ratio and have a fairly favourable outcome. The present review describes the epidemiology, characteristics and potential pathological mechanisms of COVID‐19‐related liver injury. Moreover, the influence of pre‐existing liver disease on the susceptibility and severity of liver injury in COVID‐19 are discussed.

Protective effect of Coriandrum sativum extract against inflammation and apoptosis in liver ischaemia/reperfusion injury.

The aim of this study was to investigate the anti-inflammatory and antioxidant effects of Coriandrum sativum extract on liver ischaemia reperfusion injury at light microscopic and biochemical levels. Sham, ischaemia/reperfusion injury (IRI), IRI + Coriandrum sativum extract and only Coriandrum sativum extract groups were formed. Sixty minutes of ischaemia and 60 minutes of reperfusion were performed. In the treatment group, 300 mg/kg/day Coriandrum sativum was given by gavage. Hepatic tissues were fixed in 4% paraformaldehyde. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) enzymes were measured. Nuclear factor-kappa beta (NF-κB), tumour necrosis factor-alpha (TNF-α) and caspase-3 immunohistochemistry staining was performed. Microscopic scoring was performed in terms of sinusoidal congestion, vacuolisation, and necrosis. Sinusoidal enlargement and diffuse congestion, Kupffer cell increase, neutrophil increase in necrotic areas, vacuolisation in hepatocytes, and bile duct proliferation in the portal triad were observed in ischaemia/reperfusion hepatic tissue. Very rare, necrotic areas were observed in the Coriandrum sativum treatment group, while congestion and vacuolisation and bile duct proliferation were decreased compared to the ischaemic group. The AST and ALT levels were increased in the IRI and IRI + Coriandrum sativum groups. When compared to the IRI group, the AST and ALT levels of the Coriandrum sativum were considerably decreased. The IRI and IRI + Coriandrum sativum groups had statistically significant differences in ALP compared to that of the Coriandrum sativum and Sham groups. There was no significant difference between the ALP levels of the IRI and IRI + Coriandrum sativum groups TNF-α, NF-κB and caspase-3 immune positive stained hepatocytes were numerous and widely observed in the injury group. There were positive TNF-α immunohistochemical staining Kupffer cells in the IRI group. In the group treated with Coriandrum sativum, Kupffer cells were not stained, while TNF-α, NF κB and caspase-3 expressing hepatocytes were found to be decreased compared to the IRI group. When the expression values of the TNF-α, NF-κB and caspase-3 groups were evaluated statistically, it was seen that there was a significant decrease in the group treated with Coriandrum sativum. It was found that Coriandrum sativum extract decreased proinflammatory cytokine TNF-α and apoptotic cell death and liver enzymes in liver ischaemia/reperfusion injury.

New method of hepatic artery reconstruction after its injury or resection.

e16221 Background: Restoration the hepatic arterial blood flow is required in traumatic or iatrogenic damage to the hepatic artery and its branches, as well as in the planned resection of the hepatic artery with subsequent reconstruction. Various ways have been proposed to solve this problem: ligation of the hepatic artery and its branches, which is associated with an extremely high mortality rate, reaching 70%, and the need for extensive liver resections; portal vein arteriolization; transposition of the splenic artery with its severe complications (heart attack, abscess) or hepatic artery replacement sometimes are not available and imply aggressive anticoagulant therapy, which is often challenging after extensive oncological interventions. Prosthetic vascular grafts are associated with a high risk of infection. We propose replacement of the common hepatic artery defect by transposition of the left gastric artery and end-to-end anastomosis between the proximal end of the left gastric artery and the distal end of the hepatic artery. Methods: The proposed method was applied in 7 cancer patients - 4 cases of iatrogenic damage to the common hepatic artery in lymph node dissection of the hepatoduodenal ligament and 3 resection of the common hepatic artery with tumor infiltration. The mean age of patients was 53 years. 2 patients had surgery for gastric cancer, 5 - pancreatic cancer. Results: The vascular reconstruction lasted for 17 minutes. No thrombotic complications of the reconstruction area or liver necrosis in the postoperative period were registered. The main advantages of this method were the absence of synthetic materials or deficit blood supply to neighboring organs, and no need for extensive mobilization of the great vessels in other areas (renal artery, abdominal aorta). Conclusions: The proposed method for reconstruction of the hepatic artery allows performing a simple and adequate restoration of the hepatic arterial blood flow, reduced time of the vascular stage of the surgery and reduced incidence of postoperative complications associated with the vascular stage - reduced time of liver ischemia and reduced risk of thrombosis in the reconstruction area.

Significant Liver Injury During Hospitalization for COVID-19 Is Not Associated With Liver Insufficiency or Death

Background & AimsCoronavirus-19 disease (COVID-19) is associated with hepatocellular liver injury of uncertain significance. We aimed to determine whether development of significant liver injury during hospitalization is related to concomitant medications or processes common in COVID-19 (eg, ischemia, hyperinflammatory, or hypercoagulable states), and whether it can result in liver failure and death.MethodsThere were 834 consecutive patients hospitalized with COVID-19 who were included. Clinical, medication, and laboratory data were obtained at admission and throughout hospitalization using an identified database. Significant liver injury was defined as an aspartate aminotransferase (AST) level 5 or more times the upper limit of normal; ischemia was defined as vasopressor use for a minimum of 2 consecutive days; hyperinflammatory state was defined as high-sensitivity C-reactive protein value of 100 mg/L or more, and hypercoagulability was defined as D-dimer 5 mg/L or more at any time during hospitalization.ResultsA total of 105 (12.6%) patients developed significant liver injury. Compared with patients without significant liver injury, ischemia (odds ratio [OR], 4.3; range, 2.5–7.4; P < .0001) and tocilizumab use (OR, 3.6; range, 1.9–7.0; P = .0001) were independent predictors of significant liver injury. Although AST correlated closely with alanine aminotransferase (R = 0.89) throughout hospitalization, AST did not correlate with the international normalized ratio (R = 0.10) or with bilirubin level (R = 0.09). Death during hospitalization occurred in 136 (16.3%) patients. Multivariate logistic regression showed that significant liver injury was not associated with death (OR, 1.4; range, 0.8–2.6; P = .2), while ischemic (OR, 2.4; range, 1.4–4.0; P = .001), hypercoagulable (OR, 1.7; range, 1.1–2.6; P = .02), and hyperinflammatory (OR, 1.9; range, 1.2–3.1; P = .02) disease states were significant predictors of death.ConclusionsLiver test abnormalities known to be associated with COVID-19 are secondary to other insults, mostly ischemia or drug-induced liver injury, and do not lead to liver insufficiency or death.

Mechanism and risk factors of nausea and vomiting after TACE: a retrospective analysis

PurposeThe mechanism of postoperative nausea and vomiting after TACE is not clear. This study retrospectively analyzed the patient data to explore the mechanism and risk factors of postoperative nausea and vomiting after TACE.Materials and methodsThe data of 221 patients who underwent TACE in the interventional department from January 2019 to December 2020 were collected. Including: gender, age, liver function before TACE, etiology of liver cirrhosis, BCLC stage of hepatocellular carcinoma, preoperative use of analgesic drugs, preoperative limosis, previous history of vomiting, history of kinetosis, smoking history, history of drinking, chemotherapeutic drugs used during TACE, Dosage of lipiodol, and occurrence of postoperative nausea and vomiting.ResultsThere were 116 cases of nausea after TACE, using binary logistic regression analysis, Sig: ALT0.003; ALP0.000; history of vomiting 0.043; kinetosis 0.006; history of alcohol consumption 0.011; preoperative limosis 0.006; dosage of lipiodol (5–10 mL) 0.029, dosage of lipiodol (> 10 mL) 0.001.There were 89 cases of vomiting after TACE, all accompanied by nausea, Sig: ALP0.000; BCLC stage (B) 0.007; kinetosis 0.034; chemotherapeutic drugs 0.015; dosage of lipiodol (5–10 ml) 0.015, dosage of lipiodol (> 10 ml) 0.000; patients used analgesics before TACE 0.034.ConclusionsCauses of post-TACE nausea and vomiting included operative trauma, aseptic inflammation caused by ischemia and hypoxia, chemotherapeutic drugs, ischemia of liver and bile duct, stress and pain during TACE, and patient factors. ALP, BCLC stage, kinetosis, chemotherapeutic drugs, dosage of lipiodol, and preoperative usage of analgesics were risk factors affecting nausea and vomiting after TACE.

Need for Screening Triglyceride Levels in Women on Oral Contraceptives

Introduction: Oral contraceptive pills (OCPs) are the most used form of reversible contraceptives by women. Major risks are cardiovascular but OCPs also cause secondary hypertriglyceridemia (HTG) through effects of estrogen, which decreases hepatic triglyceride lipase and lipoprotein lipase activity. This causes increased triglycerides, cholesterol and free fatty acids,1 which then in turn can lead to life-threatening acute pancreatitis. Case Description: A 23-year-old morbidly obese (BMI 38.2 mg/kg2) female presented with severe epigastric pain, nausea and vomiting. She had a history of mild intermittent asthma, recently diagnosed pre-diabetes and recently started on OCPs. Initial labs were consistent with diabetic ketoacidosis with glucose 528 mg/dL (65-115 mg/dL), anion gap 21 mEq/L (5-15 mEq), and beta-hydroxybutyrate 2.00 mmol/L (0.02-0.27 mmol/L); and acute pancreatitis with triglyceride 4,425 mg/dL (30-200 mg/dL) and lipase >600 U/L (8-78 UL), confirmed on imaging.She rapidly deteriorated, developing acute hypoxemic respiratory distress requiring intubation and distributive shock requiring three vasopressors. She progressed into multi-organ failure with acute respiratory distress syndrome, ischemic liver and acute renal failure despite insulin drip, colloidal fluid resuscitation, continuous veno-venous hemofiltration and high positive end-exploratory pressures. She developed rhabdomyolysis, followed by abdominal compartment syndrome requiring decompressive laparotomy that resulted in large volume blood loss and retroperitoneal necrosis needing multiple laparotomies. Ultimately, she became non-responsive off sedation, attributed to malignant cerebral edema that progressed to brain herniation.While HTG was likely the cause of her pancreatitis, she had normal triglyceride levels on prior routine lab work while not on OCPs. Discussion: Severe acute pancreatitis is a life-threatening complication of HTG which may be precipitated by use of OCPs. We believe that there is a need for more research in this field and even propose periodic monitoring of HTG in women taking OCPs given the severity of the consequences. While there are currently no guidelines for monitoring lipid levels in women on OCP, appropriate clinical awareness of physicians prescribing OCPs to patients may prevent fatal outcomes.

Simulation of portal/hepatic vein associated remnant liver ischemia/congestion by three-dimensional visualization technology based on preoperative CT scan.

BackgroundRemnant liver hypoperfusion is frequently observed after hepatectomy, and associated with a higher risk of postoperative complications and poorer survival. However, the development of remnant liver hypoperfusion was not fully understood.MethodsWe retrospectively analyzed patients who received hepatectomy and took contrast-enhanced computed tomography (CT) scans before, 1-week (POW1) and 4-week (POW4) after resection in our department from June 2017 to July 2019. We simulated and estimated the occurrence of portal-vein-related remnant liver ischemia (RLI) and hepatic-vein-related remnant liver congestion (RLC) after hepatectomy via three-dimensional visualization technology (3DVT) according to blood vessels ligated in the resection; then we analyzed association between the estimated RLI, RLC, and postoperative clinical outcomes.ResultsA total of 102 eligible patients were analyzed. Remnant liver hypoperfusion was observed in 47 (46%) patients in the POW1 CT scans and shrunk in the POW4 CT scans. RLC had better diagnostic significance than RLI in predicting remnant liver hypoperfusion [area under receiver operating characteristic (ROC) curve: 0.745 vs. 0.569, P=0.026]. Multivariate analysis showed that larger RLI [odds ratio (OR), 1.154; 95% confidence interval (CI), 1.075–1.240; P<0.001] was independent risk factor for post-hepatectomy liver failure (PHLF). Besides, larger RLC (OR, 1.114; 95% CI, 1.032–1.204; P=0.006) was independent risk factor for major postoperative complications.ConclusionsRemnant liver hypoperfusion can be predicted during the preoperative surgical plan by 3DVT. Portal vein related RLI was associated with PHLF, and hepatic vein related RLC was associated with major postoperative complications. Preservation of the hepatic vein and complete removal of the perfusion territory of ligated vessels are essential procedures to reduce RLI/RLC and the risk of PHLF or other surgical complications.

The role of oxygen intake and liver enzyme on the dynamics of damaged hepatocytes: Implications to ischaemic liver injury via a mathematical model.

Ischaemic Hepatitis (IH) or Hypoxic Hepatitis (HH) also known as centrilobular liver cell necrosis is an acute liver injury characterized by a rapid increase in serum aminotransferase. The liver injury typically results from different underlying medical conditions such as cardiac failure, respiratory failure and septic shock in which the liver becomes damaged due to deprivation of either blood or oxygen. IH is a potentially lethal condition that is often preventable if diagnosed timely. The role of mechanisms that cause IH is often not well understood, making it difficult to diagnose or accurately quantify the patterns of related biomarkers. In most patients, currently, the only way to determine a case of IH is to rule out all other possible conditions for liver injuries. A better understanding of the liver's response to IH is necessary to aid in its diagnosis, measurement, and improve outcomes. The goal of this study is to identify mechanisms that can alter associated biomarkers for reducing the density of damaged hepatocytes, and thus reduce the chances of IH. We develop a mathematical model capturing dynamics of hepatocytes in the liver through the rise and fall of associated liver enzymes aspartate transaminase (AST), alanine transaminase (ALT) and lactate dehydrogenase (LDH) related to the condition of IH. The model analysis provides a novel approach to predict the level of biomarkers given variations in the systemic oxygen in the body. Using IH patient data in the US, novel model parameters are described and then estimated for the first time to capture real-time dynamics of hepatocytes in the presence and absence of IH condition. The results may allow physicians to estimate the extent of liver damage in an IH patient based on their enzyme levels and receive faster treatment on a real-time basis.

Does pre-operative embolization of a replaced right hepatic artery before pancreaticoduodenectomy for pancreatic adenocarcinoma affect postoperative morbidity and R0 resection? A bi-centric French cohort study.

Sacrificing a replaced right hepatic artery (rRHA) from the superior mesenteric artery is occasionally necessary to obtain an R0 resection after pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PA). Preoperative embolization (PEA) of the rRHA has been proposed to avoid the onset of postoperative biliary and ischemic liver complications. Eighteen patients with cephalic PA with an rRHA underwent PEA of the rRHA from 2013 to 2019. The monitoring after embolization and PD was systematic and included a clinical-biological evaluation and a computed tomography scan. This study aimed to determine the feasibility of PEA of the rRHA, postoperative morbidity at 90 days, and quality of oncologic resection after PD. Feasibility of PEA was 100% without complications. A PD was performed in 16/18 patients. Mortality was 2/16 with one death after septic shock with hepatic ischemia without an arterial obstruction. Overall morbidity was 44% including one hepatic abscess after hepatic ischemia (6%). Two resections were R1 (<1mm) in contact with the origin of the rRHA (2/4 R1). PEA of the rRHA before PD was safe and reproducible. PEA of the rRHA followed by en bloc PD resection seems to limit the risk of bilio-hepatic ischemia and could facilitate oncologic resection.

Cytokine Storm of COVID-19 and Its Impact on Patients with and without Chronic Liver Disease.

The coronavirus pandemic has resulted in increased rates of hepatic decompensation, morbidity and mortality in patients suffering from existing liver disease, and deranged liver biochemistries in those without liver disease. In patients with cirrhosis with coronavirus disease 2019 (COVID-19), new onset organ failures manifesting as acute-on-chronic liver failure have also been reported. The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) also directly binds to enterocytes and cholangiocytes via the angiotensin converting enzyme receptor 2, although the lung remains the portal of entry. Superadded with the COVID-19 related bystander hepatitis, a systemic inflammatory response is noted due to unregulated macrophage activation syndrome and cytokine storm. However, the exact definition and diagnostic criteria of the ‘cytokine storm’ in COVID-19 are yet unclear. In addition, inflammatory markers like C-reactive protein, ferritin, D-dimer and procalcitonin are frequently elevated. This in turn leads to disease progression, activation of the coagulation cascade, vascular microthrombi and immune-mediated injury in different organ systems. Deranged liver chemistries are also noted due to the cytokine storm, and synergistic hypoxic or ischemic liver injury, drug-induced liver injury, and use of hepatotoxic antiviral agents all contribute to deranged liver chemistry. Control of an unregulated cytokine storm at an early stage may avert disease morbidity and mortality. Several immunomodulator drugs and repurposed immunosuppressive agents have been used in COVID-19 with varying degrees of success.

Melatonin attenuates hepatic ischemia-reperfusion injury in rats by inhibiting NF-κB signaling pathway

BackgroundThe sterile inflammatory response is one of the key mechanisms leading to hepatic ischemia-reperfusion injury. Melatonin has been shown to prevent organ injuries, but its roles in the inflammatory response after hepatic ischemia-reperfusion injury have not been fully explored, especially in late ischemia-reperfusion injury. The present study aimed to investigate the roles and possible mechanisms of melatonin in the inflammatory response after hepatic ischemia-reperfusion injury. MethodsSixty Sprague-Dawley rats were randomly divided into a sham group, ischemia-reperfusion injury group (I/R group), and melatonin-treated group (M + I/R group). The rats in the I/R group were subjected to 70% hepatic ischemia for 45 min, followed by 5 or 24 h of reperfusion. The rats in the M + I/R group were injected with melatonin (10 mg/kg, intravenous injection) 15 min prior to ischemia and immediately before reperfusion. Serum and samples of ischemic liver lobes were harvested for future analysis, and the 7-day survival rate was assessed after hepatic ischemia-reperfusion surgery. ResultsIn comparison with the I/R group, the M + I/R group showed markedly decreased expression levels of inflammatory cytokines (IL-6 and TNF-α) and numbers of apoptotic hepatocytes (P < 0.05). Immunoblotting showed that the expression levels of IL-6, p-NF-κBp65/t-NF-κBp65 and p-IκB-α/t-IκB-α in the M + I/R group were significantly lower than those in the I/R group, and immunofluorescence staining showed that the expression level of p-NF-κBp65 in the M + I/R group was lower than that in the I/R group (P < 0.05). The 7-day survival rates were 20% in the I/R group and 50% in the M + I/R group (P < 0.05). ConclusionsMelatonin downregulated the activity of the NF-κB signaling pathway in the early and late stages of hepatic ischemia-reperfusion injury, alleviated the inflammatory response, protected the liver from ischemia-reperfusion injury, and increased the survival rate.

Continuous-Flow Left Ventricular Assist Device Support for Patients with Hypertrophic Cardiomyopathy: A Single Centre Experience

<h3>Purpose</h3> There is controversy over the use of durable left ventricular assist devices (LVADs) in supporting patients with hypertrophic cardiomyopathy (HCM) and advanced heart failure. HCM patients have smaller left ventricular (LV) dimensions and are at higher risk of LVAD inflow cannula occlusion from ventricular decompression. Right ventricular (RV) failure is also a concern in these patients. This study describes a single-centre experience of LVAD implantation in patients with heart failure due to HCM. <h3>Methods</h3> Cases were reviewed from a prospective registry of all LVAD implants at the University Health Network (Toronto, Canada) between 2006 and 2020 to identify patients with HCM. We determined baseline characteristics, peri-operative course and outcomes, including requirement for RV support, ICU and hospital length of stay and eventual outcome from LVAD support. <h3>Results</h3> We identified 15 patients with LVAD implantation for HCM with a history of heart failure of 6 (interquartile range: 4-12) years and peak VO₂ of 9.6 (9.2-10.4) ml/kg/min. Median age was 57 (46-60) years, 1 (7%) patient was female (Table). During the index admission for LVAD implant, 5 (33%) patients required renal replacement therapy and 3 (20%) died due to ischemic bowel, tracheobronchitis and liver failure/sepsis, respectively. No patients required RV support. ICU stay was 8 (6-11) days and hospital stay 33 (16-65) days in those discharged from hospital. Overall, patients were supported for 5153 patient-days; 9 (60%) patients underwent heart transplant after LVAD support of 206 (110-458) days, 2 (13%) are currently supported and 1 died after 1671 days from presumed pump thrombosis. One patient required LVAD exchange for late pump thrombosis. <h3>Conclusion</h3> This single-centre experience demonstrated that LVAD support in patients with HCM is safe and effective as a bridge to transplant or destination therapy. Further work should explore patient characteristics favourable to LVAD therapy in HCM patients.

Alpinetin protects against hepatic ischemia/reperfusion injury in mice by inhibiting the NF-κB/MAPK signaling pathways

Liver damage induced by ischemia/reperfusion (I/R) remains a primary issue in liver transplantation and resection. Alpinetin, a novel plant flavonoid derived from Alpinia katsumadai Hayata, is widely used to treat various inflammatory diseases. However, the effects of alpinetin on hepatic I/R injury remain unclear. The present study investigated the protective effects of alpinetin pretreatment on hepatic I/R injury in mice. C57BL/6 mice were subjected to 1 h of partial hepatic ischemia followed by 6 h of reperfusion. Alpinetin (50 mg/kg) was given by intraperitoneal injection 1 h before liver ischemia. The blood and liver tissues were collected to assess biochemical indicators, hepatocyte damage, and levels of proteins related to signaling pathways. Furthermore, a hepatocytes hypoxia/reoxygenation (H/R) model was established for in vitro experiments. In vivo, we observed that alpinetin significantly attenuated the increases in alanine aminotransferase, aspartate transaminase, proinflammatory cytokines, hepatocyte damage, and apoptosis caused by hepatic I/R. Moreover, the hepatic I/R-induced nuclear factor kappa-B (NF-κB)/mitogen-activated protein kinase (MAPK) pathways were suppressed by alpinetin. In vitro, we also observed that alpinetin inhibited the inflammatory response, apoptosis, and activation of the NF-κB/MAPK pathways in hepatocytes after H/R treatment. Our data indicate that alpinetin ameliorated the inflammatory response and apoptosis induced by hepatic I/R injury in mice. The protective effects of alpinetin on hepatic I/R injury may be due to its ability to inhibit the NF-κB/MAPK signaling pathways. These results suggest that alpinetin is a promising potential therapeutic reagent for hepatic I/R injury.

Median Arcuate Ligament Syndrome: an Important Consideration in Pancreaticoduodenectomy.

Pancreaticoduodenectomy (PD) is a common surgery performed with curative intent for periampullary and pancreatic head neoplasms. In the presence of intrinsic celiac artery narrowing due to atherosclerosis or extrinsic compression due to median arcuate ligament syndrome (MALS), division of the gastroduodenal artery during PD can result in liver ischemia. This report describes a patient who had MALS which was treated by intraoperative median arcuate ligament release during PD, resulting in restoration of hepatic artery pulsations. Preventive, management strategies for MALS and the communicating vascular arcades between the celiac and superior mesenteric arterial systems are discussed in the context of PD.