Severe Liver Injury Research Articles

Outcomes of High-Grade Immune Checkpoint Inhibitor Hepatitis in Hospitalized and Nonhospitalized Patients

Guidelines recommend hospitalization for severe immune checkpoint inhibitor (ICI) hepatitis. We compared patient outcomes in the inpatient versus outpatient settings. We conducted a multicenter, retrospective cohort study of 294 ICI-treated patients who developed grade 3-4 ICI hepatitis. The primary outcome was time to alanine aminotransferase (ALT) normalization (≤40); secondary outcomes included time to ALT ≤100 U/L and time to death. To account for confounding by indication, inverse probability of treatment weighting was applied to perform Cox regression. A sensitivity analysis was performed excluding patients with grade 4 hepatitis. One hundred and sixty-six patients (56.5%) were hospitalized for a median of 6 (interquartile range, 3-11) days. On inverse probability of treatment weighting Cox regression, hospitalization was not associated with time to ALT normalization (hazard ratio [HR], 1.11; 95% confidence interval [CI], 0.86-1.43; P= .436) or time to ALT ≤100 U/L (HR, 1.11; 95% CI, 0.86-1.43; P=.420). In the sensitivity analysis limited to patients with grade 3 hepatitis, hospitalization was also not associated with time to ALT normalization (HR, 1.11; 95% CI, 0.83-1.50; P= .474) or time to ALT ≤100 U/L (HR, 1.19; 95% CI, 0.90-1.58; P= .225). In a subgroup analysis of 152 patients with melanoma, hospitalization was not associated with reduced risk of all-cause death (HR, 0.93; 95% CI, 0.53-1.64; P= .798). Notably, despite their Common Terminology Criteria for Adverse Events classification of high-grade hepatitis, 94% of patients had "mild" liver injury based on International Drug-Induced Liver Injury Criteria. Hospitalization of patients with high-grade ICI hepatitis was not associated with faster hepatitis resolution and did not affect mortality. Routine hospitalization may not be necessary in all patients with high-grade ICI hepatitis and Common Terminology Criteria for Adverse Events criteria may overestimate severity of liver injury.

Ameliorative effect and mechanism of ursodeoxycholic acid on hydrogen peroxide-induced hepatocyte injury

To assess the ameliorative effect of ursodeoxycholic acid (UDCA) on hydrogen peroxide (H2O2)-induced hepatocyte injury. In our in vivo experiments, we modelled hyperlipidemia in ApoE−/− mice subjected to a 3-month high-fat diet and found that HE staining of the liver showed severe liver injury and excessive H2O2 was detected in the serum. We modelled oxidative stress injury in L02 cells by H2O2 in vitro and analyzed the levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) and related genes. UDCA significantly improved the level of oxidative stress in H2O2-injured L02 cells (P < 0.05). In addition, UDCA improved the transcription levels of inflammation and oxidative stress-related genes (P < 0.05), showing anti-inflammatory and anti-oxidative stress effects. UDCA has a protective effect on H2O2-damaged L02 cells, which lays a theoretical foundation for its application development.

Albiflorin Alleviates Severe Acute Pancreatitis-Associated Liver Injury by Inactivating P38MAPK/NF-κB Signaling Pathway.

Albiflorin (Alb) is a monoterpenoid component that is commonly found in Paeonia lactiflora Pall. or Paeonia veitchii Lynch. It is known for its impressive anti-oxidant and anti-inflammatory properties. However, the effect of Alb on severe acute pancreatitis (SAP)-associated liver injury has not been fully understood. To investigate this, we conducted a study using a rat model of SAP induced by administering two intraperitoneal injections of 20% L-arginine (3.3g/kg) over a period of 2h. Subsequently, the SAP-induced rats were randomly assigned into different groups with the treatment of gradient doses of Alb (5, 10, and 20mg/kg), with the normal saline as the sham group. The pathological changes in rat livers were evaluated through hematoxylin-eosin staining. Furthermore, the levels of amylase (AMY), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were determined using specific enzyme-linked immunosorbent assay kits. Moreover, the serum levels of inflammatory factors, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β, were quantified. Finally, immunohistochemical and Western blot analyses were conducted to determine phosphorylation levels of nuclear factor kappa B (NF-κB) p65 and mitogen-associated protein kianse (MAPK) p38 in the liver tissues. TNF-α stimulated liver cells were used as a cell model to further confirm the involvement of NF-κB and p38 in the effect of Alb. Our study revealed that Alb effectively mitigated the hepatic pathological damage in a dose-dependent manner and reduced the levels of indicators associated with hepatic malfunction (AMY, AST, and ALT) in rats with SAP-induced liver injury. Additionally, Alb demonstrated its ability to suppress inflammation and oxidative stress markers in the liver tissues. Alb exerted dose-dependent inhibitory effects by modulating the P38MAPK/NF-κB signaling pathway. Overall, our findings strongly support the hepatoprotective effect of Alb in rats with SAP-induced liver injury, suggesting that Alb protects against SAP-induced liver injury through the suppression of inflammation and oxidative stress via the P38MAPK/NF-κB signaling pathway.

A Comparative Analysis of Liver Injury Markers in Post-COVID Syndrome among Elderly Patients: A Prospective Study.

In the wake of the global COVID-19 pandemic, understanding its prolonged impact on vulnerable populations has become a critical area of investigation. This study aimed to elucidate the distinctive post-acute sequelae of SARS-CoV-2 infection (PASC) and liver injury in Romania's elderly population, hypothesizing unique demographic, clinical, and healthcare factors influencing the manifestation. A longitudinal design was employed, enrolling COVID-19 patients from the Victor Babes Hospital for Infectious Diseases and Pulmonology in Timisoara, Romania. Participants were stratified into three groups based on age and Long COVID status. The study focused on a variety of demographic, clinical, and biological parameters, including liver function tests, to assess the trajectory and severity of liver injury over six months post discharge. Involving 238 participants, the study revealed a significant increase in the duration of hospitalization for those over 65 (15.8 ± 8.2 days) compared to younger groups (p < 0.001). Notably, elderly Long COVID patients exhibited a marked elevation in liver enzymes post discharge, with median ΔALT and ΔAST of 24.1 U/L and 30.2 U/L, respectively, suggesting ongoing liver injury (p < 0.001). Significant metabolic disruptions were observed, with the ΔFasting glucose showing a substantial median decrease of 21.1 mmol/L in the elderly group (p < 0.001). A pronounced reduction in ΔGGT (16.7 U/L) and ΔLDH (48.7 U/L) was noted, indicating a recovery in liver function and reduced tissue damage (p < 0.001). Coagulation profiles and liver fibrosis risk scores, particularly ΔFIB-4 and ΔAPRI, also significantly improved post discharge, indicating a reduced risk of ongoing liver complications. This study confirms the hypothesis of more severe PASC and liver injury among the elderly Romanian population. Significant improvements post discharge suggest a degree of recovery, yet the persistent alterations in liver enzymes, glucose metabolism, and fibrosis risk scores call for continued monitoring and tailored management strategies.

Clinicopathologic Features of Adult-onset Still's Disease Complicated by Severe Liver Injury.

Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder. Severe liver injury has rarely been reported, although liver enzyme elevation is a common complication of AOSD. We herein report four cases of relapsed AOSD with severe liver disorder by tapering or terminating corticosteroids. Liver specimens revealed robust infiltration of inflammatory cells throughout the lobule, especially cluster of differentiation (CD) 8-positive cells. Relapsed AOSD was refractory to corticosteroid reintroduction and required immunosuppressants. Severe liver injury with AOSD is pathologically characterized by extensive lobular infiltration of CD8-positive cells, and we should consider additive immunosuppressive agents on corticosteroids for treatment.

Congenital neonatal hemochromatosis with recurrent neonatal deaths - a diagnostic nightmare: A case report

Background: Neonatal hemochromatosis (NH) is a rare disorder and the most common cause of acuteliver failure in neonates. NH is characterized by severe hepatic injury and iron overload with highperinatal mortality and morbidity. There is a high risk of recurrence in subsequent pregnancies of womenwho have had a child with neonatal hemochromatosis.Case presentation: A 40-year-old para 13 with one living child and three previous cesarian scarspresented at ten weeks with a history of recurrent neonatal deaths. Her last infant death was at fourmonths after she delivered a baby via cesarian birth at 36 weeks. The infant developed severe jaundicewith reduced urine output. Laboratory investigations revealed deranged liver function tests with elevatedserum ferritin levels. The infant received repeated exchange transfusions, immunoglobulin, anddexoferamine. However, she succumbed at four months. Her management for the current pregnancyrequired close follow-up and she delivered at 37 weeks gestation to a live male infant who is faring well.Discussion: The cause of NH is not fully understood. Significant evidence indicates that most cases ofneonatal hemochromatosis result from fetal liver disease due to maternal-fetal alloimmunity, a conditiontermed gestational alloimmune liver disease (GALD). In GALD, these antibodies bind to fetal liverantigen and activate the terminal complement cascade, resulting in hepatocyte injury and death.Conclusion: NH is the most common cause of neonatal acute liver injury and should be considered in allcases of severe fetal liver injury as well as in cases of stillbirth, fetal demise, and early postnatal death.

A91 PYOGENIC LIVER ABSCESSES DUE TO FUSOBACTERIUM NUCLEATUM ARE ASSOCIATED WITH SEVERE INFLAMMATORY RESPONSE AND ACUTE LIVER FAILURE: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Background Pyogenic liver abscesses (PLAs) are uncommon entities with potentially devastating consequences requiring early diagnosis and treatment. Fusobacterium nucleatum is an anaerobic, gram-negative bacterium that is a rare cause of liver abscesses. F. nucleatum initiates a severe pro-inflammatory cascade that promotes abscess formation through the gut-liver axis especially when the gastrointestinal (GI) barrier is compromised. Aims In this study, we explore the characteristics of PLAs due to F.nucleatum, including the duration and mode of therapy. This may inform clinical decisions when treating persons with suspected F.nucleatum PLAs and improve mortality. Methods A systematic literature search was conducted in MEDLINE, PubMed, and the Cochrane Library, from 1977 to September 2023. We included full-text abstracts and articles written in English that reported patients with F.nucleatum PLA aged ampersand:003E18. Demographics, history of GI diseases, pertinent laboratory markers, abscess characteristics, and the approaches taken to treat the abscess were collected. Pooled data were assessed qualitatively and reported as mean±SEM when appropriate. Results We included 32 studies. The mean patient age was 52±20 years with 71% being male. In total, 47% of patients had a recent history of GI disease: sigmoid diverticulosis (n=6), colonic adenomas (n=5), duodenitis (n=2), appendicitis (n=1) and ulcerative colitis (n=1). On presentation, only 53% (n=17) reported abdominal pain. Labs were significant for leukocytosis at 22±2 K/µL, C-reactive protein 199±37 mg/L, aspartate transferase (AST) 128±24 U/L, alanine aminotransferase (ALT) 116±16 U/L, Alkaline phosphatase (ALP) 275±35 IU/L, and bilirubin 11±3 mg/dL suggestive of severe inflammatory response and cholestatic liver injury. The average abscess size was approximately 10.2±0.7 cm, 28% of which had loculations (n=9) requiring multiple drainages (n=7) or laparoscopy (n=2). The initial antibiotic of choice was piperacillin/tazobactam (Zosyn) (n=12), ceftriaxone + metronidazole (n=7), Ampicillin/Sulbactam (Unasyn) (n=5), followed by Meropenem, Metronidazole, and Ciprofloxacin. The estimated length of stay was 23±4 days with a need for long-term antibiotic therapy (54±10 days) upon discharge. The majority of patients were discharged on Metronidazole (n=11), or Amoxicillin/Clavulanic acid (Augmentin) (n=6). With appropriate source control, the estimated survival was 91% (n=29). Conclusions Our findings suggest that PLAs due to F.nucleatum are associated with large abscesses, a severe inflammatory response, cholestatic liver injury, and prolonged hospitalization. Multiple drainages with targeted gram-negative coverage may be required for adequate source control and favorable outcomes. Funding Agencies None

Effectiveness of a thrombin-gelatin flowable for treating severe liver bleeding: an experimental study

BackgroundCurrent scientific evidence has pointed out the relevance of hemostatic products for improving clinical outcomes in liver trauma, including increased survival rates and reductions in bleeding-related complications. The purpose of this study was to compare the use of the gelatin-thrombin flowable (Flowable) versus the standard technique of Packing in a new experimental liver injury model.MethodsTwenty-four swine were prospectively randomized to receive either Flowable or standard packing technique. We used a novel severe liver injury model, in which the middle and left suprahepatic veins were selectively injured, causing an exsanguinating hemorrhage. The main outcome measure was the percentage of lost blood volume.ResultsThe median total percentage of total blood volume per animal lost, from injury to minute 120, was significantly lower in the Flowable group (15.2%; interquartile range: 10.7–46.7%) than in the Packing group (64.9%; Interquartile range: 53.4–73.0%) (Hodges-Lehmann median difference: 41.1%; 95% CI: 18.9–58.0%, p = 0.0034). The 24-hour survival rate was significantly higher in the Flowable group (87.0%) than in the Packing group (0.0%) (Hazard ratio (HR) 0.08; 95% confidence interval 0.102 to 0.27; p < 0.0001). Mean-arterial pressure was significantly lower at minute 60 and 120 in the Flowable group than in the packing group (p = 0.0258 and p = 0.0272, respectively). At minute 120, hematocrit was higher in the Flowable than in the packing group (Hodges-Lehmann median difference: 5.5%; 95%CI: 1.0 to11.0, p = 0.0267). Finally, the overall-surgical-procedure was significantly shorter with Flowable than with Packing (Hodges-Lehmann median difference: 39.5 s, 95% CI: 25.0 to 54.0 s, p = 0.0004).ConclusionsThe use of the Flowable was more effective in achieving hemostasis, reducing blood loss, and improving survival rates than standard packing in a severe porcine-liver bleeding model.

The presence of abdominal pain associated with acetaminophen overdose does not predict severity of liver injury

AimWhilst it is known that abdominal pain is a common symptom in patients with acetaminophen overdose, its association with severity of liver injury has not been clearly defined. This study investigates the association between the symptom of abdominal pain on presentation to hospital and the degree of liver injury post-acetaminophen overdose. MethodsAdmissions with acetaminophen poisoning, requiring treatment with acetylcysteine were identified and reviewed from a search of a large Australian tertiary hospital network from February 20th, 2014, to August 30th, 2018. Parameters such as presence of abdominal pain, time post-ingestion and peak ALT were collected. Single acute ingestions, staggered and repeated supratherapeutic ingestions were analysed. Results539 cases were identified in the study period, 79% female, with mean age 25 (17–43) years. Patients presenting to the emergency department with abdominal pain post-acetaminophen overdose had a similar risk of developing hepatotoxicity or acute liver injury compared to patients without abdominal pain regardless of time to presentation.Patients presenting <8-h post-overdose with abdominal pain were as likely to develop hepatotoxicity (1/46, 2.2%) compared to those without abdominal pain (1/54 [1.9%]; OR = 1.18 [0.07 to 19.4]). Those presenting >8-h post-overdose with abdominal pain were as likely to develop hepatotoxicity (13/92, 14.1%) compared to those without abdominal pain (4/35 [11.4%]; OR = 1.28 [0.39 to 4.21]). ConclusionsThe presence of abdominal pain after acetaminophen overdose was not predictive of the development of liver injury in patients receiving acetylcysteine treatment. Further prospective studies are required to confirm this finding.The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Treatment strategy for erythropoietic protoporphyria accompanied by severe abdominal pain and liver injury

Treatment strategy for erythropoietic protoporphyria accompanied by severe abdominal pain and liver injury

An algorithm based on immunotherapy discontinuation and liver biopsy spares corticosteroids in two thirds of cases of severe checkpoint inhibitor-induced liver injury.

There are few data on corticosteroids (CS)-sparing strategies for checkpoint inhibitor (ICI)-induced liver injury (ChILI). We aimed to assess the performance of a 2-step algorithm for severe ChILI, based on ICI temporary discontinuation (step-1) and, if lack of biochemical improvement, CS based on the degree of necroinflammation at biopsy (step-2). Prospective study that included all subjects with grade 3/4 ChILI. Peripheral extended immunophenotyping was performed. Indication for CS: severe necroinflammation; mild or moderate necroinflammation with later biochemical worsening. From 111 subjects with increased transaminases (January 2020 to August 2023), 44 were diagnosed with grade 3 (N = 35) or grade 4 (N = 9) ChILI. Main reason for exclusion was alternative diagnosis. Lung cancer (13) and melanoma (12) were the most common malignancies. ICI: 23(52.3%) anti-PD1, 8(18.2%) anti-PD-L1, 3(6.8%) anti-CTLA-4, 10(22.7%) combined ICI. Liver injury pattern: hepatocellular (23,52.3%) mixed (12,27.3%) and cholestatic (9,20.5%). 14(32%) presented bilirubin >1.2 mg/dL. Overall, 30(68.2%) patients did not require CS: 22(50.0%) due to ICI discontinuation (step-1) and 8/22 (36.4%) based on the degree of necroinflammation (step-2). Biopsy mainly impacted on grade 3 ChILI, sparing CS in 8 out of 15 (53.3%) non-improvement patients after ICI discontinuation. CD8+ HLA-DR expression (p = 0.028), central memory (p = 0.046) were lower in CS-free managed subjects, but effector-memory cells (p = 0.002) were higher. Time to transaminases normalisation was shorter in those CS-free managed (overall: p < 0.001, grade 3: p < 0.001). Considering our results, a strategy based on ICI discontinuation and biopsy for grade 3 ChILI is proposed. An algorithm based on temporary immunotherapy discontinuation and biopsy allows CS avoidance in two thirds of cases of severe ChILI.

Aldo-keto reductase family 1 member A1 (AKR1A1) exerts a protective function in alcohol-associated liver disease by reducing 4-HNE accumulation and p53 activation

BackgroundThe development of alcohol-associated liver disease (ALD) is influenced by the amount and duration of alcohol consumption. The resulting liver damage can range from reversible stages, such as steatosis, steatohepatitis and alcoholic fibrosis, to the advanced and irreversible stage of cirrhosis. Aldo-keto reductase family 1 member A1 (AKR1A1) is a member of the aldo-keto reductase family that catalyzes the reduction of aldehyde groups to their corresponding alcohols in an NADPH-dependent manner. AKR1A1 was found to be downregulated in patients diagnosed with ALD. This study aims to interpret the protective effects of AKR1A1 on the development of ALD.MethodsA 5% alcohol-fed (AF) Akr1a1 knockout (Akr1a1−/−) mouse model and an AML12 hepatocyte model were used. The effects of AKR1A1 on liver function, inflammation, oxidative stress, lipid accumulation, and fibrosis were assessed by ELISA, western blotting, RT‒PCR, and a variety of histological staining methods in AF-induced wild-type (WT) and Akr1a1−/− mice compared to control liquid diet-fed (PF) WT and Akr1a1−/− mice.ResultsThe results demonstrated that AF-WT mice expressed higher levels of AKR1A1 than WT mice fed a control diet, and they did not show any noticeable liver steatosis. However, AF-Akr1a1−/− mice displayed a lower survival rate and more severe liver injury than AF-WT mice, as demonstrated by increased proinflammatory cytokines, oxidative stress, lipid accumulation, fibrosis, and reduced antioxidant enzymes in their livers. Additionally, elevated levels of 4-HNE and p53 phosphorylation were observed in AF-Akr1a1−/− mice, suggesting that the loss of AKR1A1 led to increased 4-HNE accumulation and subsequent activation of p53, which contributed to the progression of ALD. Furthermore, in AML12 hepatocytes, Akr1a1 knockdown aggravated oxidative stress and steatosis induced by palmitic acid/oleic acid (P/O) inflammation induced by lipopolysaccharide (LPS), and fibrosis induced by TGF-β1.ConclusionsThis loss-of-function study suggests that AKR1A1 plays a liver-protective role during chronic alcohol consumption by reducing the accumulation of 4-HNE and inhibiting 4-HNE-mediated p53 activation.

Abstract TP196: Ischemic Stroke With Large Vessel Occlusion and Systemic Acidosis: Associations With Functional Outcomes and Mortality

Introduction: Systemic acidosis is common in critical conditions, including severe myocardial infarction, renal and liver injuries, and traumatic brain injury. However, the potential connection between ischemic stroke involving large vessel occlusion (LVO) and acidosis has not been extensively explored. With this study we aimed to assess the prevalence of respiratory and metabolic acidosis in ischemic stroke with LVO and their potential links to functional outcomes and mortality. Methods: Retrospective single center cohort of patients with ischemic stroke and LVO status post endovascular thrombectomy. Univariate logistic regression was used to examine the relationship between acidosis on admission and (1) hospital mortality and (2) 90-day modified Rankin Scale (mRS) dichotomized as unfavorable (&gt;3) vs favorable (≤3). In addition, we investigated association with acidosis and symptomatic ICH. Metabolic acidosis was defined by the presence of one of the following: Serum bicarbonate &lt;22 mEq/L, lactic acid &gt;2 mmol/L or pH &lt;7.35. Respiratory acidosis was defined by pCO2 &gt;45 mmHg. Results: There was a total of 346 patients, average age was 68.5 (±15) years, 169 (49%) were females. 168 (49%) patients were acidotic on admission, 4 (1%) had respiratory acidosis, 7 (2%) had mixed acidosis and the remaining 157 (45%) had metabolic acidosis. There was no statistically significant association between systemic acidosis with either hospital mortality (p=0.31]) or 90-day favorable functional outcome (p=0.23]). There was no association between acidosis with symptomatic ICH (p=0.47). Conclusion: In our retrospective cohort study, we observed that approximately half of the patients with stroke and LVO had systemic acidosis. Unlike other critical neurological conditions like traumatic brain injury, we did not identify a substantial correlation between systemic acidosis and either mortality or the functional outcome at the 90-day mark. Given the high prevalence of acidosis in patients with LVO, larger multi-center studies are needed to further investigate its association with the outcomes and mortality.

Therapeutic potential of berberine in attenuating cholestatic liver injury: insights from a PSC mouse model

Background and aimsPrimary sclerosing cholangitis (PSC) is a chronic liver disease characterized by progressive biliary inflammation and bile duct injury. Berberine (BBR) is a bioactive isoquinoline alkaloid found in various herbs and has multiple beneficial effects on metabolic and inflammatory diseases, including liver diseases. This study aimed to examine the therapeutic effect of BBR on cholestatic liver injury in a PSC mouse model (Mdr2−/− mice) and elucidate the underlying mechanisms.MethodsMdr2−/−mice (12–14 weeks old, both sexes) received either BBR (50 mg/kg) or control solution daily for eight weeks via oral gavage. Histological and serum biochemical analyses were used to assess fibrotic liver injury severity. Total RNAseq and pathway analyses were used to identify the potential signaling pathways modulated by BBR in the liver. The expression levels of key genes involved in regulating hepatic fibrosis, bile duct proliferation, inflammation, and bile acid metabolism were validated by qRT-PCR or Western blot analysis. The bile acid composition and levels in the serum, liver, small intestine, and feces and tissue distribution of BBR were measured by LC–MS/MS. Intestinal inflammation and injury were assessed by gene expression profiling and histological analysis. The impact on the gut microbiome was assessed using 16S rRNA gene sequencing.ResultsBBR treatment significantly ameliorated cholestatic liver injury, evidenced by decreased serum levels of AST, ALT, and ALP, and reduced bile duct proliferation and hepatic fibrosis, as shown by H&E, Picro-Sirius Red, and CK19 IHC staining. RNAseq and qRT-PCR analyses indicated a substantial inhibition of fibrotic and inflammatory gene expression. BBR also mitigated ER stress by downregulating Chop, Atf4 and Xbp-1 expression. In addition, BBR modulated bile acid metabolism by altering key gene expressions in the liver and small intestine, resulting in restored bile acid homeostasis characterized by reduced total bile acids in serum, liver, and small intestine and increased fecal excretion. Furthermore, BBR significantly improved intestinal barrier function and reduced bacterial translocation by modulating the gut microbiota.ConclusionBBR effectively attenuates cholestatic liver injury, suggesting its potential as a therapeutic agent for PSC and other cholestatic liver diseases.

ASSOCIATION COVID-19 AND LIVER INJURY : A SYSTEMATIC REVIEW

Background: Most COVID-19 patients present with typical respiratory symptoms (i.e., cough, dyspnea) and fever. However, abnormal liver function is often developed in patients with COVID-19, and liver injury has been related with severe disease. Liver damage ranges from mild asymptomatic elevation of liver enzymes to severe liver injury, while a few cases of acute liver failure have also been reported. The aim: This study aims to show association COVID-19 and liver injury. Methods: By comparing itself to the standards set by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020, this study was able to show that it met all of the requirements. So, the experts were able to make sure that the study was as up-to-date as it was possible to be. For this search approach, publications that came out between 2013 and 2023 were taken into account. Several different online reference sources, like Pubmed and SagePub, were used to do this. It was decided not to take into account review pieces, works that had already been published, or works that were only half done. Result: In the PubMed database, the results of our search brought up 44 articles, whereas the results of our search on SagePub brought up 334 articles. The results of the search conducted for the last year of 2013 yielded a total 7 articles for PubMed and 111 articles for SagePub. The result from title screening, a total 4 articles for PubMed and 46 articles for SagePub. In the end, we compiled a total of 10 papers. We included five research that met the criteria. Conclusion: COVID-19-associated liver injury is caused by the cumulative effects of multiple factors, including hepatotropic SARS-CoV-2, drug-induced liver injury, hypoxic reperfusion, immune stress and inflammatory factor storms.

Clinical Features of Hepatic Manifestations among Adult Patients with Hemophagocytic Lymphohistiocytosis: A Retrospective Study

Introduction: Liver dysfunction is common in patients with hemophagocytic lymphohistiocytosis (HLH). However, whether the severity of liver injury is associated with the prognosis of patients with HLH remains to be determined. This study aims to assess the association of the severity of liver involvement with short-term prognosis among adult patients with HLH. Methods: A retrospective study was performed from January 2012 to December 2020, including 150 patients with newly diagnosed HLH and liver injury. Results: The majority of our cohort suffered from mild to moderate hepatic damage, presenting with Child-Turcotte-Pugh (CTP) class A (55, 36.7%) or B (74, 49.3%). The prevalence of acute liver failure (ALF) was 9.3% in our cohort. The overall 30-day mortality rate was 49.3% among the study population. HLH patients with ALF showed an extremely adverse prognosis, with a mortality rate as high as 92.9%. In a multivariate analysis, age ≥60 years (p = 0.016), blood urea nitrogen (BUN) ≥7 μmol/L (p < 0.001), and malignancy-associated HLH (p < 0.001) at the diagnosis of HLH were identified as being strongly correlated with 30-day prognosis. An excellent predictive power was found. Among the predictive scores used to assess early death of HLH patients with liver injury, the prognostic efficiency of chronic liver failure-sequential organ failure assessment (CLIF-SOFA) (AUROC: 0.936 ± 0.0211) and SOFA score (0.901 ± 0.026) were significantly better than those of the APACHE II (p < 0.001), model for end-stage liver disease score (p < 0.001) and CTP scores (p < 0.001). Conclusion: Patients with old age, elevated BUN, and malignancy had inferior survival. CLIF-SOFA and SOFA enable more accurate prediction of early death in HLH patients with liver injury than other liver-specific and general prognostic models.

Epcam regulates intrahepatic bile duct reconstruction in zebrafish, providing a potential model for primary cholangitis model

Epithelial cell adhesion molecules (EpCAMs) have been identified as surface markers of proliferating ductal cells, which are referred to as liver progenitor cells (LPCs), during liver regeneration and correspond to malignancies. These cells can differentiate into hepatocytes and biliary epithelial cells (BECs) in vitro. EpCAM-positive LPCs are involved in liver regeneration following severe liver injury; however, the in vivo function of EpCAMs in the regenerating liver remains unclear. In the present study, we used a zebrafish model of LPC-driven liver regeneration to elucidate the function of EpCAMs in the regenerating liver in vivo. Proliferating ductal cells were observed after severe hepatocyte loss in the zebrafish model. Analyses of the liver size as well as hepatocyte and BEC markers revealed successful conversion of LPCs to hepatocytes and BECs in epcam mutants. Notably, epcam mutants exhibited severe defects in intrahepatic duct maturation and bile acid secretion in regenerating hepatocytes, suggesting that epcam plays a critical role in intrahepatic duct reconstruction during LPC-driven liver regeneration. Our findings provide insights into human diseases involving non-parenchymal cells, such as primary biliary cholangitis, by highlighting the regulatory effect of epcam on intrahepatic duct reconstruction.

Model-Based Assessment of the Liver Safety Profile of Acetaminophen to Support its Combination Use with Topical Diclofenac in Mild-to-Moderate Osteoarthritis Pain.

The use of combination therapy of oral acetaminophen and topical diclofenac, having complementary mechanisms of action, is an attractive strategy to enhance the analgesic response in osteoarthritis (OA) pain. While topical diclofenac is considered as well tolerated due to its low systemic exposure, concerns of liver toxicity with acetaminophen at standard analgesic doses remain. Thus, this study aimed to assess the liver safety profile of acetaminophen, particularly in OA management, using a model-based meta-analysis (MBMA). A literature review was conducted using the MEDLINE database to identify randomized clinical trials (RCTs) reporting liver toxicity on acetaminophen use. An MBMA was implemented to assess the deviation from the upper limit of normal (ULN) of alanine aminotransferase or aspartate aminotransferase, namely > 0-1 × ULN, > 1.5-2 × ULN, and > 3 × ULN representing mild, moderate, and severe risk of liver abnormality, respectively. A total of 15 RCTs were included in the MBMA, encompassing over 4800 subjects and exposure to acetaminophen ranging from 2 to 26weeks. Of the 15 included studies, eight involved patients with OA pain, four involved healthy subjects and three were in patients with conditions such as asthma, glaucoma, chronic pain, and cardiovascular disease. Acetaminophen 1500-4000mg/day was found to exhibit 23% (95% confidence interval (CI): 17.74-29.20), 1.35% (95% CI: 0.17-2.51) and 0.01% (95% CI: 0.00-0.32) increased risk for mild, moderate, and severe liver injury, respectively, versus placebo. Moreover, at therapeutic doses, no correlation was identified between acetaminophen intake and liver abnormality risk. Overall, our analysis shows that short-term (~ 8-16weeks) acetaminophen use at therapeutically recommended doses is associated with a low risk of clinically relevant changes in liver enzymes. Given the good tolerability of topical diclofenac, the findings support the safety of the combination of acetaminophen and topical diclofenac, at least over the short term, as treatment for mild-to-moderate OA pain.

Divinyl sulfone, an oxidative metabolite of sulfur mustard, induces caspase-independent pyroptosis in hepatocytes.

Sulfur mustard (SM) is a highly toxic blister agent which has been used many times in several wars and conflicts and caused heavy casualties. Ease of production and lack of effective therapies make SM a potential threat to public health. SM intoxication causes severe damage on various target organs, such as the skin, eyes, and lungs. In addition, SM exposure can also lead to hepatotoxicity and severe liver injuries. However, despite decades of research, the molecular mechanism underlying SM-induced liver damage remains obscure. SM can be converted into various products via complex hepatic metabolism in vivo. There are some pieces of evidence that one of the oxidation products of SM, divinyl sulfone (DVS), exhibits even more significant toxicity than SM. Nevertheless, the molecular toxicology of DVS is still hardly known. In the present study, we confirmed that DVS is even more toxic than SM in the human hepatocellular carcinoma cell line HepG2. Further mechanistic study revealed that DVS exposure (200μM) promotes pyroptosis in HepG2 cells, while SM (400μM) mainly induces apoptosis. DVS induces gasdermin D (GSDMD) mediated pyroptosis, which is independent of caspases activation but depends on the large amounts of reactive oxygen species (ROS) and severe oxidative stress produced during DVS exposure. Our findings may provide novel insights for understanding the mechanism of SM poisoning and may be helpful to discover promising therapeutic strategies for SM intoxication.

Risk Factors Analysis of Severe Liver Injury Induced by Statins.

The aim of this study is to report the risk factors of severe statin induced liver injury (SILI). From the database of Shandong ADR Monitoring Center and Outpatients and inpatients in our hospital, SILI cases reported from 2013 to 2021 were extracted and screened. The diagnostic criteria of SILI, the inclusion and exclusion criteria of severe and general SILI were established separately. After the SILI cases were selected and confirmed, the socio-demographic and clinical characteristics were collected. Single factor chi-square test and multi-factor unconditional logistic regression analysis were used to analyze the influencing factors of severe SILI. From 1391 reported cases, 1211 met SILI diagnostic criteria, of which 157 were severe SILI and 964 were general SILI. Univariate analysis showed that age, drug combination, statin category were the influencing factors of severe SILI (p<0.1). Multivariate logistic analysis showed that drug combination and statin category were the influencing factors of severe SILI (p<0.05). Atorvastatin caused the most serious SILI, and its risk is 1.77 times higher than rosuvastatin. The serious SILI risk of drug combination was 2.08 times higher than statin alone. The patient with these factors should be monitored intensively during clinical treatment, to ensure their medication safety.