Acute fibrinous and organizing pneumonia complicated with hemophagocytic lymphohistiocytosis caused by chronic active Epstein-Barr virus infection: a case report

Background Acute fibrinous and organizing pneumonia (AFOP) is a rare lung condition that is associated with acute lung injury. Its etiology may be idiopathic or secondary to a series of conditions, including immune-related diseases, unclassified connective tissue diseases, hematopoietic stem cell transplantation, infections, hematological diseases and drug induced lung toxicity. We report for the first time a case of AFOP complicated with hemophagocytic lymphohistiocytosis (HLH) caused by chronic active Epstein-Barr virus (CAEBV) infection. Case presentation A 64-year-old man was admitted with a complaint of fever and dyspnea for 2 weeks. The patient presented with elevated serum aminotransferase levels, splenomegaly, progressive decrease of red blood cells and platelets, hyperferritinemia, hypofibrinogenemia, and elevated of Soluble interleukin-2 receptor (sCD25). His chest computed tomography (CT) scan revealed multiple patchy consolidation in both lungs and multiple lymphadenopathy in the mediastinum and hilum. The serology for antibodies of VCA-IgG was positive, EBV-DNA in peripheral blood was elevated, and EBV nucleic acid was detected in the alveolar lavage fluid. Histopathology of the lung tissue showed a dominant of intra-alveolar fibrin and organizing pneumonia. Hemophagocytic cells was found in the bone marrow smear and biopsy. EBV-DNA was detected in lung tissue and bone marrow using in situ hybridization with an EBV-encoded RNA (EBER) probe. After 50 days of hospitalization, he was improved in lung and hemogram. Conclusion We report a case of AFOP with HLH caused by CAEBV in an immunocompetent adult, suggesting that AFOP may be a rare but serious complication caused by CAEBV, and glucocorticoid therapy may improve short-term prognosis.

487. Experience with Remdesivir for Treatment of SARS-CoV-2 in Patients with Liver Cirrhosis

Background Remdesivir is a nucleotide analogue antiviral that was FDA approved for the treatment of hospitalized patients with coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS CoV-2). Remdesivir has been associated with elevations in serum aminotransferase levels but most cases being mild to moderate and reversible upon discontinuation. Although national COVID-19 guidelines and the American Association for the Study of Liver Diseases (AASLD) currently recommend remdesivir for use in hospitalized patients requiring supplemental oxygen, data is limited using remdesivir in patients with chronic liver disease. Here, we describe our experience with remdesivir in patients with liver cirrhosis. Methods Patients with liver cirrhosis who received remdesivir were identified either prospectively or retrospectively by primary or secondary ICD-10 codes indicating liver disease. Data collected included patient demographics, underlying cause of cirrhosis, co-morbidities, Child-Pugh score, laboratory values (serum aminotransferase levels, serum creatinine) during and following remdesivir, adverse reactions attributed to remdesivir, and mortality (in-hospital, 30-day, and 90-day). Results A total of 4 patients with underlying liver cirrhosis completed a 5-day course of remdesivir treatment. On admission, Child-Pugh class was A for 1 patient, B for 2 patients, and C for 1 patient. Causes for cirrhosis were nonalcoholic steatohepatitis (NASH), hepatic amyloidosis, and chronic hepatitis B. There were no acute elevations in aminotransferase levels or adverse events attributed to remdesivir therapy. Mortality was high with 50% in-hospital mortality. Of the 2 other patients who survived to discharge, one was discharged to home hospice and the other was readmitted within 30 days and expired during that admission. Conclusion Since there is limited data available using remdesivir in patients with advanced liver disease, we did not identify any safety concerns related to remdesivir in our cirrhotic patients. Mortality was high illustrating the poor outcomes of patients with advanced liver disease and COVID-19. Patients with cirrhosis should be offered remdesivir if clinically appropriate. Disclosures All Authors: No reported disclosures

Chlorogenic Acid Alleviated Liver Dysfunction Through Activating PINK1/Parkin Dependent Mitophagy

Background: Chlorogenic acid (CGA) is a natural polyphenolic compound with anti-inflammatory, antioxidant effects. It could improve mitochondrial dysfunction that was a key feature of acetaminophen (APAP) -induced liver injury. This study aimed to identify whether promoting mitophagy was associated with the hepatocyte protection for CGA.Methods: Acute hepatic injury model was induced by APAP in mice after CGA administration for 14 days. Survival rate was recoded within 24h of modeling. Serum aminotransferase, hepatic histopathology and TUNEL assays were simultaneously performed. The expression of apoptosis-related proteins (Bax and Bcl-2) and mitophagy-related genes and proteins (LC3Ⅱ, P62, PINK1 and Parkin) were analyzed. The fluorescence co-localization of LC3Ⅱ and Tom20 was analyzed with immunofluorescence.Results: Compared with APAP group, CGA pretreatment significantly increased survival rate of APAP-induced mice, inhibited the activity of ALT, AST and LDH in serum, and alleviated pathological features of liver such as inflammatory cell infiltration, necrosis of liver cells and vacuolation (p<0.05). Moreover, our data from the TUNEL and western blotting analysis showed that CGA significantly decreased the number of apoptotic cells and reversed the elevated Bax level and decreased Bcl-2 level(p<0.05). Furthermore, we found that CGA promoted the fluorescence co-localization of LC3Ⅱ and Tom20 and enhanced the protein expression of LC3Ⅱ (p<0.05). Finally, CGA significantly promoted mitophagy by exhibiting the increased gene and protein expression of PINK1 and Parkin.Conclusions: Our results demonstrated that CGA promoted PINK1/Parkin dependent mitophagy and inhibited hepatic apoptosis to exert protection against liver damage in APAP-induced mice.

Early postoperative serum aspartate aminotransferase for prediction of post-hepatectomy liver failure

Background Post-hepatectomy liver failure (PHLF) is a serious complication of hepatectomy. The current criteria for PHLF diagnosis (ISGLS consensus) require laboratory data on or after postoperative day (POD) 5, which may delay treatment for patients at risk. The present study aimed to determine the associations between early postoperative (POD1) serum aminotransferase levels and PHLF. Methods The medical records of patients who underwent hepatectomy at Ramathibodi Hospital from January 2008 to December 2019 were retrospectively examined. Patients were classified into PHLF and non-PHLF groups. Preoperative characteristics, intraoperative findings, and early postoperative laboratory data (serum AST, ALT, bilirubin, and international normalized ratio (INR) on POD0 to POD5) were analyzed. Results A total of 890 patients were included, of whom 31 (3.4%) had PHLF. Cut-off points for AST of 260 U/L and ALT of 270 U/L on POD1 were predictive of PHLF. In multivariate analysis, AST >260 U/L on POD1, ICG-R15, major hepatectomy, blood loss, and INR were independently associated with PHLF. Conclusions Early warning from elevated serum AST on POD1, before a definitive diagnosis of PHLF is made on POD5, can help alert physicians that a patient is at risk, meaning that active management and vigilant monitoring can be initiated as soon as possible.

A RETROSPECTIVE OBSERVATINAL STUDY OF SERUM AMINOTRANSFERSASE LEVELS IN THE ASSESSMENT OF SEVERITY OF DENGUE FEVER

Liver involvement in dengue fever is manifested by the elevation of transaminases due to direct attack of virus itself or the use of hepatotoxic drugs.Objective of our study was to assess the serum aminotransferase level in patient with dengue fever and to correlate serum aminotransferase level and severity of dengue fever. This is a prospective observational study. Atotal of 50 fever patients admitted with positive dengue serology in Medicial ward, ZMCH ,Dahod,were included after satisfying the inclusion and exclusion criteria. All the patients were subjected to complete history taking and clinical examination. Investigations like complete blood count, liver function test, dengue serology and abdominal ultrasound were done in all patients.A total of 50 dengue serology positive patient were included in the study. Among them there were 27 (54%) males and 24(46%) females. In our study 41 patients (82%) had elevated serum transaminase level, Mean ASTlevel was 134.84 IU/Land the mean ALTlevel was 107.88 IU/L. The level of AST is higher when compared to ALT in most of the patients. Among those who had elevated aminotransferase level 12 patients (24%) had both elevated aminotransferase level and free uid in the abdomen. Out of 50 patients 32 (64%) had reduced platelet count (less than one lakh) and all the 32 patients had elevated serum aminotransferase level. There was signicant negative correlation between serum aminotransferase level and platelet count (P value < 0.001).Hepatic dysfunction is very common in all forms of Dengue infection. Serum Aminotransferase level correlate with severity of Dengue fever. Aspartate Aminotransferase was signicantly raised when compared to Alanine Aminotransferase in most of the patients

UPLC-MS/MS method for simultaneously determining nucleosides and methyl-nucleosides in liver mRNA of Epimedin C-induced liver injury mouse model

Background Epimedin C, one of the main active ingredients of Epimedium, has been reported to have potential hepatotoxicity. However, the mechanism of Epimedin C-induced liver injury has not been studied. mRNA methylation, mainly including N6-methyladenosine and N5-methylcytidine, is implicated in the regulation of many biological processes and diseases. The study of quantifying mRNA methylation alterations in Epimedin C-induced liver injury mice may contribute to clarify the mechanism of its hepatotoxicity. Therefore, an analysis method needs to be established to determine nucleoside and methyl-nucleoside levels in liver mRNA. Methods An ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to simultaneously determine six nucleosides (adenosine, uridine, cytidine, guanosine, N6-methyladenosine and N5-methylcytidine) in liver mRNA. Besides, the Epimedin C-induced liver injury mouse model was studied by intragastrical administration Epimedin C at a daily dose of 10 or 40 mg/kg for 4 weeks. The nucleoside samples of the mice liver mRNA were prepared and separated on an UPLC column using 0.1% formic acid water and methanol after enzymatic digestion. Then the sample was detected by a Qtrap 6500 mass spectrometer. Results In this method, calibration curves of the six nucleosides showed good linearity over their concentration ranges. The linear ranges were 40–20,000 pg/mL for adenosine, cytidine, N6-methyladenosine and N5-methylcytidine, 0.2–100 ng/mL for guanosine, and 2–1000 ng/mL for uridine. Epimedin C-induced liver injury mouse model was successfully established,which could be proved by the elevation of serum aminotransferase levels, and the increased inflammatory cell infiltration as well as vacuolar degeneration in liver. The N6-methyladenosine and N5-methylcytidine levels, and the ratios of N6-methyladenosine to adenosine and N5-methylcytidine to cytidine of the mice liver mRNA were all significantly increased after Epimedin C treatment. Conclusion The established method was successfully applied to the determination of six nucleosides levels in liver mRNA of the Epimedin C-induced liver injury mice model and the control group. The results indicated that mRNA methylation might be associated with Epimedin C-induced liver injury. This study will facilitate the mechanism research on the hepatotoxicity of Epimedin C.

Association of elevated serum aminotransferase levels with chronic kidney disease measures: hispanic community health study/study of latinos

Background Previous studies have shown an association between non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD), but it is unclear whether the association is independent of metabolic syndrome. Methods Data from 13,006 participants aged 18 to 74 years in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) without viral hepatitis, excessive alcohol consumption, or high transferrin saturation levels were analyzed. Suspected NAFLD was defined as presence of sex-specific elevations in serum aminotransferase levels (aspartate aminotransferase (AST) > 37 U/L or alanine aminotransferase (ALT) > 40 U/L for men and AST or ALT > 31 U/L for women). Logistic regression was used to examine cross-sectional associations of elevated serum aminotransferase levels with low estimated glomerular filtration rate (eGFR < 60 ml/min/1.73 m2 based on cystatin C), and with high urinary albumin-to-creatinine ratio (UACR) (> 17 mg/g in men and > 25 mg/ g in women) in separate models adjusting for demographic characteristics and metabolic syndrome. Results Mean (SD) age was 41 (0.27) years, and 45 % were male. Elevated serum aminotransferase levels were noted in 18.8 % of the population and were associated with greater odds of high UACR (OR = 1.31; 95 % CI = 1.10, 1.56) after adjusting for demographic characteristics; this association became non-significant after adjustment for metabolic syndrome (OR = 1.11, 95 % CI = 0.92, 1.33). In contrast, elevated serum aminotransferase levels were not associated with low eGFR (odds ratio (OR) = 0.73; 95 % confidence interval (CI) = 0.45, 1.18) after adjusting for covariates. Conclusions In this sample of diverse U.S. Hispanic Latino adults, elevated serum aminotransferase levels were not independently associated with measures of CKD.

Transient liver enzyme derangement following Remdesivir use: a case series

Remdesivir, a nucleotide analog RNA polymerase inhibitor, which was originally evaluated in clinical trials to thwart the Ebola outbreak in 2014, has shown in vitro efficacy against SARS-CoV-2. Experience on its efficacy and safety in COVID-19 is accumulating. In COVID-19, Remdesivir therapy is given intravenously for 5 to 10 days and is frequently accompanied by transient, reversible mild-to-moderate elevations in serum aminotransferase levels but has been only rarely linked to instances of clinically apparent liver injury as a drug-induced liver injury (DILI). It may be caused by direct toxicity possibly due to inhibition of mitochondrial RNA polymerase. Here, we have discussed two cases where liver enzyme levels increased dramatically on the day next after initiating Remdesivir. Case one and two showed grade 4 and grade 3 hepatotoxicity respectively. In both cases, a positive de-challenge was observed and concomitant drugs were not considered to be confounders. Hence, Remdesivir has a causal relationship with the occurrence of this adverse drug reaction.

Lysimachiae Herba Inhibits Inflammatory Reactions and Improves Lipopolysaccharide/D-Galactosamine-Induced Hepatic Injury

This study aimed to determine the anti-inflammatory and hepatoprotective effects of Lysimachiae Herba ethanolic extract (LHE) in lipopolysaccharide (LPS)-stimulated macrophages and in a LPS/D-galactosamine (GalN)-induced acute hepatitis mouse model. Then, the production of inflammatory mediators and the activation of related pathways in macrophages were explored. Finally, we assessed the serum aminotransferase levels and the expression of inflammatory/antioxidant molecules in liver tissues in mice. Results revealed that LHE treatment significantly inhibited the production of inflammatory mediators in LPS-stimulated RAW 264.7 macrophages. Molecular data showed that LHE remarkably increased the activities of the antioxidant pathway and inhibited the phosphorylation of mitogen-activated protein kinase as well as the transcriptional activity of nuclear factor-κB induced by LPS. Furthermore, it prevented acute liver damage caused by LPS/D-GalN-induced hepatitis by inhibiting aminotransferase levels and histopathological changes in mice. Moreover, treatment with LHE significantly inhibited the activation of inflammatory pathways and increased the expression of antioxidant molecules including heme oxygenase-1/Nuclear factor erythroid 2-related factor 2. In conclusion, LHE has potent anti-inflammatory and hepatoprotective effects in LPS-stimulated macrophages and the LPS/D-GalN-induced acute hepatitis mouse model. Thus, it can be a treatment option for inflammation, hepatitis, and liver injury.