Acute Hepatocellular Injury Research Articles

Deubiquitinase JOSD1 tempers hepatic proteotoxicity

Derangements in protein homeostasis and associated proteotoxicity mark acute, chronic, and drug-induced hepatocellular injury. Metabolic dysfunction-associated proteasomal inhibition and the use of proteasome inhibitors often underlie such pathological hepatic proteotoxicity. In this study, we sought to identify a candidate deubiquitinating enzyme (DUB) responsible for reversing the proteotoxic damage. To this end, we performed a siRNA screening wherein 96 DUBs were individually knocked down in HepG2 cells under proteasomal inhibitor-induced stress for dual readouts, apoptosis, and cell viability. Among the putative hits, we chose JOSD1, a member of the Machado-Josephin family of DUBs that reciprocally increased cell viability and decreased cell death under proteotoxicity. JOSD1-mediated mitigation of proteotoxicity was further validated in primary mouse hepatocytes by gain and loss of function studies. Marked plasma membrane accumulation of monoubiquitinated JOSD1 in proteotoxic conditions is a prerequisite for its protective role, while the enzymatically inactive JOSD1 C36A mutant was conversely polyubiquitinated, does not have membrane localisation and fails to reverse proteotoxicity. Mechanistically, JOSD1 physically interacts with the suppressor of cytokine signalling 1 (SOCS1), deubiquitinates it and enhances its stability under proteotoxic stress. Indeed, SOCS1 expression is necessary and sufficient for the hepatoprotective function of JOSD1 under proteasomal inhibition. In vivo, adenovirus-mediated ectopic expression or depletion of JOSD1 in mice liver respectively protects or aggravates hepatic injury when challenged with proteasome blocker Bortezomib. Our study thus unveils JOSD1 as a potential candidate for ameliorating hepatocellular damage in liver diseases.

Diagnostic guide for immune checkpoint inhibitor-induced liver injury.

With the widespread use of immune checkpoint inhibitors (ICIs), liver injury (ICI-induced liver injury) as an immune-related adverse event has become a major concern in clinical practice. Because severe cases of liver injury require administration of corticosteroids, a comprehensive evaluation is crucial, including clinical course, blood and imaging tests, and if necessary, pathological examination through liver biopsy. As with liver injury induced by other drugs, classification of injury type by R-value is useful in deciding treatment strategies for ICI-induced liver injury. Histologically, themost representative feature is an acute hepatitis-like hepatocellular injury, characterized by diffuse lobular inflammation accompanied by CD8-positive Tlymphocytes. Another condition that can cause liver injury during ICI treatment is cholangitis accompanied by non-obstructive bile duct dilatation and bile duct wall thickening. Many cases of ICI-induced cholangitis are classified as non-hepatocellular injury type, and they have been reported to respond poorly to corticosteroids. It is essential that gastroenterologists/hepatologists and doctors in various departments work in cooperation to develop a system that achieves early diagnosis and appropriate treatment of ICI-induced liver injury.

The Epidemiology of Newly Recognized Causes of Drug-Induced Liver Injury: An Update.

The incidence and prevalence of drug-induced liver injury appear to be increasing globally, for example, with the introduction of checkpoint inhibitors. Several reviews have been published in the last decade on the epidemiology of DILI, both among hospitalized patients and in the general population, as well as from retrospective and prospective studies on DILI. Most of these reviews have not focused on newly recognized agents that have recently changed the landscape of DILI. Apart from liver injury associated with antibiotics, oncological agents, particularly checkpoint inhibitors, are increasingly being recognized as causing liver injury. The type of liver injury associated with these agents is not idiosyncratic but rather an indirect type of injury. Furthermore, recently, COVID-19 vaccines and green tea extract have been found to lead to liver injury. Checkpoint inhibitors have revolutionized the treatment of many malignancies, such as malignant melanoma, lung cancer, and renal cancer. Via the activation of T cells, they can increase immune activity against malignant cells, but at the same time, they can decrease immune tolerance and therefore lead to immune-related adverse effects in many organs. The most common adverse effect in clinical practice is liver injury. A recent prospective study demonstrated an 8% frequency of DILI due to the use of checkpoint inhibitors among patients with malignant melanoma and renal cancer. This rate is much higher than observed with drugs, leading to idiosyncratic liver injury. Shortly after the implementation of the worldwide vaccination program against COVID-19, several case reports were published on suspected vaccination-induced autoimmune-like hepatitis occurring shortly after the vaccination. At first, these reports were met with skepticism, but currently, around 100 reports have been published, and cases of positive recurrence have been reported. The clinical, biochemical, immunological, and histological features are indistinguishable from classic autoimmune hepatitis (AIH). These reactions are very similar to drug-induced autoimmune-like hepatitis (DI-ALH) due to drugs such as nitrofurantoin, minocycline, and infliximab, which do not relapse after a short course of corticosteroids, which is the general rule in classic autoimmune hepatitis (AIH). Green tea extract has been found to be a well-documented cause of acute hepatocellular liver injury with jaundice. A strong HLA association has been reported, showing a high prevalence of HLA-B*35:01 among patients suffering from green tea-induced liver injury. Overall, 3% of patients recruited in the DILIN study were supplemented with green tea extract as one of the ingredients. In a prospective population-based study from Iceland, green tea was implicated in approximately 8% of patients with DILI.

Herb induced liver injury by Xianling Gubao Tablets: A case assessed for causality using updated RUCAM and integrated evidence chain

ObjectiveA typical case of Xianling Gubao (XLGB) Tablets-induced liver injury was systematically studied in the clinic and the laboratory. MethodsA patient with herb-induced liver injury (HILI) and a history of taking XLGB Tablets before disease onset was engaged as the study subject, and the case was diagnosed according to the updated Roussel Uclaf Causality Assessment Method (RUCAM) and the integrated evidence chain (iEC) method recommended by the Guidelines for Diagnosis and Treatment of Herb-induced Liver Injury (HILI Guidelines). ResultsClinical history, biochemical indexes and imaging tests were used to exclude the influence of fundamental diseases and confusing liver diseases such as viral, alcoholic and autoimmune liver diseases on the diagnosis. Based on an investigation of the patient’s medication history, she was suspected to have HILI caused by XLGB Tablets, as the patient was only taking an oral preparation of XLGB Tablets, and the influence of other drugs on the diagnosis was excluded. This patient with alanine aminotransferase (ALT) ≥ 3 × upper limit of normal (ULN) and a calculated R of 6 was diagnosed with possible acute drug-induced hepatocellular injury. The relationship was considered “highly probable” (score of 9) using the updated RUCAM of 2016. Moreover, the fingerprint similarity between the preparation taken by the patient and a commercially available preparation was 0.99, suggesting that the patient was consuming XLGB Tablets rather than another drug. LC-MS technology and the Agilent Fake TCM-Drugs database were used to investigate the drug, and no chemical additions were found. Examination of the drug for pesticide residues, heavy metals, aflatoxins and other exogenous substances indicated compliance with the content limits of the Chinese Pharmacopoeia. ConclusionIn summary, the final diagnosis of XLGB-induced liver injury reached the clinical diagnosis of HILI and was acute severe hepatocellular injury type by the updated RUCAM and iEC. Therefore, this study provides scientific evidence regarding the causality evaluation of compound preparations of traditional Chinese medicines-induced liver injury.

Traditional medicine consumption in postpartum for HBV-infected women enrolled in the ANRS 12345 TA PROHM study in Cambodia.

In Cambodia, traditional medicine was commonly described as being used by pregnant women at two time points: one month before birth and during early postpartum. The present study aims to describe traditional medicine consumption during postpartum phase for women enrolled in the TA PROHM study and to investigate the possible association between traditional medicine consumption and acute liver toxicity. An ethnobotanical survey was conducted in 2 groups of HBV-infected pregnant women (with and without postpartum hepatocellular injury) enrolled in the study. Hepatocellular injury was defined by having Alanine Aminotransferase (ALT) > 2.5 times the Upper Limit of Normal (ULN = 40 U/L) at the 6th week postpartum visit. Interviews were done using a standardized questionnaire. Plant samples were collected and later identified by two traditional healers. Chi-square test was used to find the association between hepatocellular injury and traditional medicine consumption or a specific plant species. In total, 75 women were enrolled and 52 (69.3%) used at least one traditional remedy composed of 123 different plants and 12 alcoholic macerations of porcupine stomach. Orally consuming at least one remedy with alcohol was significantly associated with hepatocellular injury (33% vs 13%, p = 0.034). Among the 123 plants species identified, four were found to be associated with hepatocellular injury, namely Amphineurion marginatum (Roxb.) D.J.Middleton [Apocynaceae] (p = 0.022), Selaginella tamariscina (P.Beauv.) Spring [Selaginellaceae] (p = 0.048), Mitragyna speciosa Korth. [Rubiaceae] (p = 0.099) and Tetracera indica (Christm. & Panz.) Merr. [Dilleniaceae] (p = 0.079). Consumption of traditional medicine in postpartum is a common practice for women enrolled in the TA PROHM study. Alcohol-based remedies may exacerbate the risk of acute hepatocellular injury in HBV-infected women already exposed to immune restoration. The complex mixtures of herbs need to be further evaluated by in vitro and in vivo studies.

A Unique Case of Acute Renal Failure and Hepatocellular Injury Occurring in the Course of a Mild SARS-CoV-2 Infection

A Unique Case of Acute Renal Failure and Hepatocellular Injury Occurring in the Course of a Mild SARS-CoV-2 Infection

Fat Embolization Syndrome Secondary to Steroid Treatment for Intractable Migraine

Sickle vaso-occlusive crises secondary to steroid therapy are well reported in the medical literature. Fat embolization syndrome (FES) is an uncommon yet serious complication that occurs due to bone marrow necrosis and is usually associated with increased mortality or damaging neurologic sequelae to the surviving patient. We report a case of FES secondary to steroid therapy administered for an unrelated condition. Our patient was initially admitted for intractable migraine. The initial work up for other intracranial emergencies was negative and she was administered steroids for intractable migraine. Within 24 hours of initiating steroid therapy, she developed pain in her neck and shoulders progressing to her chest and lower extremities. The initial signs of FES following steroid therapy in this patient included altered mental status and hypoxic respiratory failure. Cerebral imaging showed diffuse bilateral cerebral/cerebellar and brainstem micro-hemorrhages. Lung imaging showed bilateral diffuse lung infiltrates confirming acute chest syndrome. The patient was transferred to the intensive care unit for further management of her hypoxic respiratory failure secondary to acute chest syndrome (ACS). In addition to ACS, she had acute kidney and hepatocellular injury in keeping with multi-organ failure. Steroid therapy was discontinued and she was treated with red cell exchange transfusion for multi-organ failure. The patient had an almost complete resolution of multiple organ damage except for hypoesthesia of her lower jaw and lower lip- the "numb chin syndrome". This case report highlights the importance of recognizing potentially fatal multi-organ failure secondary to steroid therapy and for hematologists to consider concurrent red cell transfusions to attenuate the risk of such complications from steroid therapy.

S2949 Case of Cholangiogram-Induced Acute Liver Injury Disease

Introduction: We present a female who had prolonged acute hepatocellular liver injury after undergoing a cholangiogram using Omnipaque contrast. About 10 cases of cholestatic liver injury have been reported after ERCP, however our case is unique being predominantly hepatocellular injury. Case Description/Methods: Initially presenting with abdominal pain then diagnosed with cholecystitis, she underwent cholecystectomy with cholangiogram. She subsequently underwent ERCP due to a retained stone and discharged home the next day without notable complications. She presented to the hospital two days later with pruritus. After ruling out infectious cause and further mechanical hepatobiliary pathology, she was discharged home due to improved symptoms with symptomatic management. Transaminases gradually resolved with close outpatient follow-up at two weeks and two months. Discussion: The exact mechanism remains unclear, liver injury due to idiosyncratic reaction from contrast was postulated. This is possibly due to local hepatic injury from the contrast agent in the biliary system. The contrast material being infused under high pressure, can have a toxic effect on the liver with disruption of canalicular plasma membranes. Systemic distribution of the contrast medium from the bile duct and the spreading of the agent extracellularly to the nearby tissues might be responsible for direct toxic liver injury. Awareness of this reaction is helpful in preventing unnecessary repeat ERCP to confirm bile duct clearance as well as liver biopsies. Prednisone may be considered if persistently elevated liver enzymes.Figure 1.: Title: Liver Function Tests during clinical course Caption: Patient's liver function test over the hospitalization, readmission, two-week outpatient follow-up, and two-month outpatient follow-up revealing fluctuating elevation in transaminases after cholangiogram performed on day of admission while total bilirubin remains within normal limits. Gradual resolution of elevated transaminases over two-week and two-month follow-up. ERCP occurred on hospital day 1. Legend: HD- Hospital day RD- Readmission day ALP- alkaline phosphatase AST- Aspartate transaminase ALT- Alanine Transaminase.

S3060 Labetalol, a Common Antihypertensive, an Uncommon Cause of Drug-Induced Liver Injury (DILI)

Introduction: Labetalol is an antihypertensive medication (AHM) commonly used as first line agent for non-severe hypertension in pregnancy. We present a case of DILI in a young woman transitioned to labetalol while attempting to conceive. Case Description/Methods: A 35-year-old woman with a h/o hypertension, hashimoto's thyroiditis, anxiety, obesity (BMI 34) was admitted to our hospital for abdominal pain, jaundice, pruritus and aminotransferase (LFT) elevations. She had been admitted previously at an outside facility with nausea, anorexia, and elevated LFTs (ALT 1264, AST 1419, ALP 294, TBili 5) 20 weeks after initiation of labetalol. There were no h/o alcohol abuse or risk factors for hepatitis B/C. Home medications including labetalol were stopped. Imaging studies including MRCP showed no evidence of biliary obstruction. Infectious workup (hepatitis A/B/C/E, CMV, HSV, EBV) and drug/tox screen were negative. A liver biopsy showed acute hepatocellular injury without eosinophils, steatosis, cholestasis or fibrosis; differentials included DILI and infectious hepatitis. LFTs improved, patient was discharged and labetalol restarted. Two weeks later, she presented to our hospital with worsening jaundice. Admission labs: ALT 905, AST 1553, ALP 257, TBili 19.8, INR 1.4 and creatinine 1. On exam, there was no stigmata of chronic liver disease or encephalopathy. Labetalol was discontinued. Infectious, hereditary, metabolic were negative. ANA was positive (1:320) homogenous pattern with mild elevation in IgG. Prednisolone 40 mg daily was started with rapid improvement in LFTs. At 8 week follow up, she was asymptomatic and LFTs were near normal (Tbili 2); prednisolone was tapered. Discussion: Mild to moderate, transient aminotransferase elevations are noted in up to 8% of patients on labetalol. But they are asymptomatic and resolve even with continuation of the medication. Severe liver injury however is rare and rapid resolution typically ensues after cessation of the drug. However acute liver failure, death and OLT have been reported. There are isolated case reports and small case series of labetalol induced DILI, mostly in pregnant women. In a case series, 3 out of 11 patients died and 1 of 5 patients who had liver biopsy had chronic active hepatitis. The mechanism of labetalol hepatic injury is believed to be idiosyncratic. Inadvertent rechallenge has been shown to cause recurrence of DILI. We present this case to increase awareness of labetalol induced DILI as it is the most commonly used AHM in pregnant women.

Pediatric Acute Liver Failure: A Clinicopathological Perspective

Pediatric acute liver failure (PALF) is a life-threatening disorder characterized by acute hepatocellular injury occurring in children without recognized underlying liver disease. The clinicopathologic evaluation of PALF requires a different approach from that in adults. The diagnostic considerations differ depending on the age, personal and family history, geographical region, and clinical presentation. Distinct entities such as gestational alloimmune liver disease, herpes simplex virus infection, and metabolic disorders should be considered in neonates with acute liver failure, while acetaminophen toxicity and autoimmune hepatitis are more frequently seen in older children and adolescents. An identified cause for PALF despite a negative complete evaluation (indeterminate) is lacking in 30 to 50% of cases. Although not routinely performed in the setting of PALF, liver biopsy may be helpful in assessing the etiology, potential mechanisms of injury, determining the appropriateness of liver transplantation, and prognostication of the patients. In this article, we review the clinicopathologic characteristics of PALF with an emphasis on general approach of pathologic evaluation and histopathologic characteristic of selected entities.

HiPSC-Derived Hepatocyte-like Cells Can Be Used as a Model for Transcriptomics-Based Study of Chemical Toxicity.

Traditional toxicity risk assessment approaches have until recently focussed mainly on histochemical readouts for cell death. Modern toxicology methods attempt to deduce a mechanistic understanding of pathways involved in the development of toxicity, by using transcriptomics and other big data-driven methods such as high-content screening. Here, we used a recently described optimised method to differentiate human induced pluripotent stem cells (hiPSCs) to hepatocyte-like cells (HLCs), to assess their potential to classify hepatotoxic and non-hepatotoxic chemicals and their use in mechanistic toxicity studies. The iPSC-HLCs could accurately classify chemicals causing acute hepatocellular injury, and the transcriptomics data on treated HLCs obtained by TempO-Seq technology linked the cytotoxicity to cellular stress pathways, including oxidative stress and unfolded protein response (UPR). Induction of these stress pathways in response to amiodarone, diclofenac, and ibuprofen, was demonstrated to be concentration and time dependent. The transcriptomics data on diclofenac-treated HLCs were found to be more sensitive in detecting differentially expressed genes in response to treatment, as compared to existing datasets of other diclofenac-treated in vitro hepatocyte models. Hence iPSC-HLCs generated by transcription factor overexpression and in metabolically optimised medium appear suitable for chemical toxicity detection as well as mechanistic toxicity studies.

Complement C5a and Clinical Markers as Predictors of COVID-19 Disease Severity and Mortality in a Multi-Ethnic Population.

Coronavirus disease-2019 (COVID-19) was declared as a pandemic by WHO in March 2020. SARS-CoV-2 causes a wide range of illness from asymptomatic to life-threatening. There is an essential need to identify biomarkers to predict disease severity and mortality during the earlier stages of the disease, aiding treatment and allocation of resources to improve survival. The aim of this study was to identify at the time of SARS-COV-2 infection patients at high risk of developing severe disease associated with low survival using blood parameters, including inflammation and coagulation mediators, vital signs, and pre-existing comorbidities. This cohort included 89 multi-ethnic COVID-19 patients recruited between July 14th and October 20th 2020 in Doha, Qatar. According to clinical severity, patients were grouped into severe (n=33), mild (n=33) and asymptomatic (n=23). Common routine tests such as complete blood count (CBC), glucose, electrolytes, liver and kidney function parameters and markers of inflammation, thrombosis and endothelial dysfunction including complement component split product C5a, Interleukin-6, ferritin and C-reactive protein were measured at the time COVID-19 infection was confirmed. Correlation tests suggest that C5a is a predictive marker of disease severity and mortality, in addition to 40 biological and physiological parameters that were found statistically significant between survivors and non-survivors. Survival analysis showed that high C5a levels, hypoalbuminemia, lymphopenia, elevated procalcitonin, neutrophilic leukocytosis, acute anemia along with increased acute kidney and hepatocellular injury markers were associated with a higher risk of death in COVID-19 patients. Altogether, we created a prognostic classification model, the CAL model (C5a, Albumin, and Lymphocyte count) to predict severity with significant accuracy. Stratification of patients using the CAL model could help in the identification of patients likely to develop severe symptoms in advance so that treatments can be targeted accordingly.

Picroside II Improves Severe Acute Pancreatitis-Induced Hepatocellular Injury in Rats by Affecting JAK2/STAT3 Phosphorylation Signaling.

Picroside II is an important ingredient agent in Traditional Chinese medicine and hoped to reduce hepatocellular injury caused by severe acute pancreatitis (SAP). An SAP-induced hepatocellular injury model was established in rats by using pentobarbital sodium. 27 rats were divided into 3 groups: the sham group (SG), model group (MG), and Picroside groups (PG). SAP-induced hepatocellular injury was assessed using hematoxylin and eosin staining. We measured hepatocellular enzymes (amylase (AMY), alanine aminotransferase (ALT), and aspartate aminotransferase (AST)), oxidative stress factors (superoxidase dismutase (SOD) and malondialdehyde (MDA)), and inflammatory factors (tumor necrosis factor α (TNF-α), interleukin- (IL-) 6, and IL-10), apoptotic factors (BAX and cleaved caspase 3), and inflammatory signaling (Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3), p-JAK2, and p-STAT3) in hepatocellular tissues. The SAP-induced hepatocellular injury model was successfully established. Picroside II treatment repaired hepatocellular injury by reducing the activities of AMY, ALT, and AST; reducing the levels of MDA, TNF-α, IL-1, IL-6, p-JAK2, p-STAT3, BAX, and cleaved caspase 3; and increasing the levels of SOD and IL-10. Picroside II exerted protective function for the SAP-induced hepatocellular injury model. Picroside II improved SAP-induced hepatocellular injury and antioxidant and anti-inflammatory properties by affecting JAK2/STAT3 phosphorylation signaling.

Case series and review of Ayurvedic medication induced liver injury

BackgroundComplementary and alternative medicine use among Americans is prevalent. Originating in India, Ayurvedic medicine use in the United States has grown 57% since 2002. CAM accounts for a significant proportion of drug induced liver injury in India and China, but there have been only three reports of drug induced liver injury from Ayurvedic medications in the U.S. We report three cases of suspected Ayurvedic medication associated liver injury seen at a Southern California community hospital and review literature of Ayurvedic medication induced liver injury.Case presentationsThree patients presented with acute hepatocellular injury and jaundice after taking Ayurvedic supplements for 90–120 days. First patient took Giloy Kwath consisting solely of Tinospora cordifolia. Second patient took Manjishthadi Kwatham and Aragwadhi Kwatham, which contained 52 and 10 individual plant extracts, respectively. Third patient took Kanchnar Guggulu, containing 10 individual plant extracts. Aminotransferase activities decreased 50% in < 30 days and all 3 patients made a full recovery. Roussel Uclaf Causality Assessment Method (RUCAM) scores were 7–8, indicating probable causality. These products all contained ingredients in other Ayurvedic and traditional Chinese medicines with previously reported associations with drug induced liver injury.ConclusionsThese patients highlight the risk of drug induced liver injury from Ayurvedic medications and the complexity of determining causality. There is a need for a platform like LiverTox.gov to catalog Ayurvedic ingredients causing liver damage.

Gastrointestinal Manifestations of COVID-19: A Review of What We Know.

Background: The coronavirus disease 2019 (COVID-19) is not just a disease of the respiratory system. The virus can affect the gastrointestinal (GI) tract as well. Recognizing the various manifestations in every organ system is important because these manifestations can contribute to community-based transmission.Methods: We outline the evidence of the pathophysiology of COVID-19 in the GI tract, the effects of the virus on the gut and liver, the presence of the virus in stool samples, and the potential for fecal-oral transmission of COVID-19. Most of the literature sources used in this paper are case studies from China following the surge of COVID-19 infection.Results: In patients with COVID-19, GI symptoms such as anorexia, nausea, vomiting, diarrhea, and abdominal pain have presented in conjunction with respiratory symptoms such as fever, shortness of breath, and cough. Evidence also shows acute hepatocellular injury, indicated by elevated liver enzymes such as alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase. Fecal-oral transmission of COVID-19 is suspected because of the presence of COVID-19 RNA in stool samples of COVID-19–positive patients.Conclusion: Even without the presence of respiratory symptoms, several GI symptoms are associated with COVID-19 infection, as well as possible fecal-oral transmission. Therefore, COVID-19 infection should be considered for patients presenting with primarily GI symptoms.

S1159 Hepatic Steatosis Is Associated With Elevated Alanine Aminotransferase (ALT) but Not Elevated Bilirubin or Hepatic Decompensation in Patients With Coronavirus Disease (COVID)-19

INTRODUCTION: COVID-19 is a global pandemic. However, the effects of underlying liver disease on COVID-19 in the United States is not well described. We investigated whether COVID-19 was associated with elevations in liver enzymes or hepatic decompensation in patients with underlying hepatic steatosis. METHODS: We retrospectively reviewed the charts of consecutive adults with RT-PCR positive for COVID-19 treated at Michigan Medicine between March 1 and April 30, 2020, who had ultrasound, computed tomography, or magnetic resonance imaging >30 days before COVID-19 diagnosis. Hepatic steatosis was defined based on imaging. Outcomes were: (1) peak ALT or bilirubin following COVID-19 diagnosis, (2) ALT >2 or 5 times upper limit of normal (ULN), defined as the higher of baseline ALT or 19 U/L in women and 30 U/L in men, (3) jaundice defined as bilirubin >2 or 4 mg/dl, and (4) new/worsening ascites or encephalopathy. We conducted regressions with the above outcomes as dependent variables and hepatic steatosis as the primary predictor, adjusting for age, sex, race, recent healthcare exposure, body mass index, hypertension, dyslipidemia, and diabetes. These regression models were logistic for outcomes of abnormal ALT or bilirubin, and linear for maximal ALT or bilirubin. RESULTS: Of patients with prior imaging, 80/159 (50.3%) had steatosis. Overall, 89% of patients were hospitalized, 51% were admitted to intensive care, and 16% died. 14% had chronic liver disease other than NAFLD, 5% had cirrhosis, and 2.7% had prior liver decompensation with ascites, variceal bleeding, or hepatic encephalopathy. Patients with steatosis were older, had higher body mass index, and were more often Black than those without steatosis (Table 1). Baseline ALT and total bilirubin were higher in the steatosis group (Table 1). Hepatic steatosis was associated with increased incidence of ALT >2x ULN (OR 2.93 [1.23–6.97]) or >5x ULN (OR 6.21 [1.45–26.62]), and with peak ALT (beta 39.7 [7.85–71.49]) (Table 2). Hepatic steatosis was not associated with increased bilirubin (Table 2). Rates of new/worsening ascites and encephalopathy were very low: 1.3% and 2.5%, respectively, with no difference based on NAFLD status (P > 0.4 for both). CONCLUSION: Hepatic steatosis is associated with acute hepatocellular injury with COVID-19 infection. Steatosis was not associated with jaundice. Rates of new/worsening ascites or hepatic encephalopathy were very low and unrelated to steatosis status.Table 1Table 2

S2557 A Case of Immune-Mediated Liver Injury Secondary to Olaparib

INTRODUCTION: Immune mediated drug-induced liver injury (IM-DILI) presents with a hepatocellular or mixed pattern of liver injury that, for some patients, persists after drug withdrawal. Olaparib is an oral inhibitor of poly-ADP-ribose polymerase and is approved for treatment of relapsed metastatic ovarian cancer with BRCA 1/2 mutations. Mild alterations in liver tests have been reported in < 5% of treated patients. CASE DESCRIPTION/METHODS: A 56-year-old female with BRCA1 mutation and relapsed metastatic ovarian cancer was admitted to the hospital in August 2019 due to a severe acute hepatocellular liver injury with jaundice, elevated INR, and concern for impending fulminant liver failure (Table 1). Her liver tests had previously been normal prior to and until three months after she had started olaparib in May 2019. She had no alcohol history or use of herbal supplements. Physical examination was notable for jaundice, mild right upper quadrant tenderness, and no hepatic encephalopathy. Computed tomography showed mild hepatomegaly with periportal edema. Laboratory work-up for infectious, metabolic, and autoimmune etiologies of liver injury was negative. Liver biopsy revealed areas of submassive necrosis with lobular collapse, moderate to severe portal and lobular inflammation with predominantly lymphocytes, cholestasis with focal hepatocyte rosette formation, acute cholangitis with bile duct injury and ductular proliferation, and ceroid-laden histiocytes, consistent with IM-DILI. No portal fibrosis was seen. Olaparib was promptly withdrawn and prednisone (60 mg/day) was initiated. Liver tests had significantly improved within 4 weeks (Table 1 and Figure 1) and prednisone was tapered while liver enzymes normalized. DISCUSSION: We report the first case of IM-DILI secondary to olaparib use in the United States. Olaparib is largely metabolized by the liver through cytochrome P450 and it is hypothesized that reactive metabolites can bind cellular proteins, leading to the creation of neo-antigens and subsequent liver injury. This case report highlights the need for close monitoring of liver tests while on olaparib and that the diagnosis of IM-DILI and prompt initiation of corticosteroids should be considered if an acute liver injury develops.Table 1.: Liver tests and INR values after olaparib withdrawalFigure 1.: A graphical illustration of livers tests and INR after olaparib was withdrawn and prednisone was started.Figure 2.: liver biopsy shows areas of submassive necrosis with lobular collapse. Note that no viable hepatocytes are identified in this microscopic area.

S2672 Influenza a Virus as a Trigger for Autoimmune Hepatitis

INTRODUCTION: Autoimmune hepatitis (AIH) is a chronic liver disease caused by an immune-mediated destruction of the hepatocytes. Studies have shed the light on the important role of infections in triggering AIH as many viral infections and vaccines have been associated with it. We present an atypical case of AIH possibly triggered by Influenza A virus. To our knowledge, this is the first case report showing autoimmune hepatitis induced by influenza A virus. CASE DESCRIPTION/METHODS: A 52-year-old previously healthy female presented with new-onset jaundice after Influenza A viral infection. Initial laboratory investigations revealed an aspartate aminotransferase level of 1211 U/liter, an alanine aminotransferase level of 1506 U/liter, an alkaline phosphatase level of 305 U/liter, a total bilirubin level of 5.1, a direct bilirubin level of 3.4 and an international normalized ratio of 1. Serologic testing for hepatitis A, B, and C, HSV, CMV, and EBV were negative. Influenza A PCR was detected on nasopharyngeal sampling. Covid-19 test was negative. ASMA was positive with a titer of 1:80. ANA was positive with a titer of 1:80. Anti-mitochondrial antibody was negative. IgG, Alpha 1 antitrypsin, ceruloplasmin levels were within normal limits. No acetaminophen was detected in the blood. A CT abdomen showed normal biliary tree with no biliary strictures and no cirrhotic changes of the liver. Her liver biopsy showed acute hepatitis with moderate acute hepatocellular injury and hepatocellular necrosis with mixed portal infiltrates which include both plasma cells and eosinophils. Based on the revised International Autoimmune Hepatitis Group Scoring System for the Diagnosis of Autoimmune Hepatitis, her pretreatment score was 13 points. She was started on prednisone and had significant biochemical improvement. Her steroids were tapered and steroid sparing therapy with azathioprine was initiated. DISCUSSION: Influenza virus and vaccine have been proposed to cause autoimmune disease in the literature such as type 1 diabetes, narcolepsy, recurrent ITP, and multiple sclerosis. There has been an association as well between influenza vaccine and AIH. In a study published by Saski et al, they describe two cases of middle-aged women who developed autoimmune hepatitis after receiving influenza vaccine. We suggest that in our patient, the influenza A virus infection triggered autoimmune hepatitis. Autoimmune hepatitis should be considered in patients with persistently elevated liver enzymes following infections such as influenza.Figure 1.: Liver biopsy cores show findings suggestive of acute hepatitis. Dense portal inflammatory infiltrates are present, comprised of macrophages, lymphocytes, neutrophils, eosinophils and plasma cells. Piecemeal acute hepatocellular necrosis is also noted at the limiting plate (H&E, original magnification 10x).Figure 2.: Prominent bile stasis with sinusoidal Kupffer cell hyperplasia (H&E, original magnification 10x).

Extrapulmonary manifestations of COVID-19.

Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.

Incidence and Sequelae of Liver Injury Among Children Treated for Solid Tumors: Analysis of a Large Single-Center Prospective Cohort.

Pediatric oncology patients are at risk of adverse drug events. The incidence and etiologies of liver injury in this population are not well characterized. We utilized a large, single-center pediatric oncology registry to investigate the incidence, causes, and outcomes of liver injury during treatment for solid tumor malignancies. We reviewed all young individuals (age <25 years) who received treatment for any solid tumor at the University of Michigan between January 2004 and July 2016. Subjects with liver injury meeting predetermined laboratory criteria were identified. Cases were independently reviewed by 2 expert hepatologists to assign a cause of liver injury. Clinical characteristics of drug-induced liver injury (DILI) and non-DILI cases were compared. Cases of liver injury occurring after bone marrow or liver transplant were excluded. Of 1136 solid tumor patients, 160 (14%) experienced liver injury, and the overall frequency of DILI was 4%. DILI was the leading identified cause of liver injury (31%), followed by infection (17%), metastatic/malignant biliary disease (13%), and perioperative liver injury (13%). Most DILI cases (>90%) were mild acute hepatocellular injury episodes that did not result in modification to the chemotherapy plan, and all DILI eventually resolved. Severe presentations involving jaundice and/or prolonged hospital course were significantly more common among non-DILI versus DILI cases (23% vs 2%, P < 0.001). DILI is the leading cause of liver injury events among pediatric solid tumor patients. In our registry, DILI was of mild severity and did not result in an alteration of the treatment plan in most patients. In contrast, non-DILI-related liver injury events, including infection, were more likely to have a more severe presentation and a complicated course with a greater mortality during follow-up.