Elevated Liver Function Tests Research Articles

E-Cigarette Flavoring Chemicals Induce Cytotoxicity in HepG2 Cells.

E-cigarette-related hospitalizations and deaths across the U.S. continue to increase. A high percentage of patients have elevated liver function tests indicative of systemic toxicity. This study was designed to determine the effect of e-cigarette chemicals on liver cell toxicity. HepG2 cells were exposed to flavoring chemicals (isoamyl acetate, vanillin, ethyl vanillin, ethyl maltol, l-menthol, and trans-cinnamaldehyde), propylene glycol, and vegetable glycerin mixtures, and cell viability was measured. Data revealed that vanillin, ethyl vanillin, and ethyl maltol decreased HepG2 cell viability; repeated exposure caused increased cytotoxicity relative to single exposure, consistent with the hypothesis that frequent vaping can cause hepatotoxicity.

Abstract PS12-10: Phase II study of nivolumab in combination with abemaciclib plus endocrine therapy in patients with HR+, HER2- metastatic breast cancer: WJOG11418B NEWFLAME trial

Abstract Background: Currently, the standard immunotherapy treatment for anti-programmed death-ligand 1 (PD-L1)-positive triple-negative breast cancer is a combination of PD-L1 antibody and nab-paclitaxel. PD-1/PD-L1 antibody was investigated as a treatment for hormone receptor positive (HR+) breast cancer; however, the efficacy of single agents is poor. In pre-clinical studies, anti-PD-1/PD-L1 antibody, CDK4/6 inhibitors, and endocrine therapy (ET) have synergistic effects. We initiated this investigator-initiated trial to evaluate the efficacy and safety of the combination of nivolumab, abemaciclib, and ET (fulvestrant [FUL] or letrozole [LET]) as a first- or second-line treatment for patients (pts) with HR+, human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC). Methods: This multicenter, multi-cohort, nonrandomized, open-label phase II study evaluated the efficacy and safety of nivolumab, abemaciclib, and ET (FUL or LET) in pts with HR+, HER2- MBC. Key eligibility criteria for the FUL cohort were: HR+, HER2- MBC with ECOG PS ≤ 1; measurable disease; no more than one ET; no prior chemotherapy for MBC; and had exhibited disease progression while receiving ET, adjuvant ET, or ≤ 12 months after adjuvant ET. Key eligibility criteria for the LET cohort were: postmenopausal HR+, HER2- MBC with ECOG PS ≤ 1; measurable disease; and no prior systemic therapy. ET as an adjuvant was permitted if the patient had a disease-free interval > 12 months after the completion of ET. Patients received 240 mg nivolumab on days 1 and 15, 150 mg abemaciclib twice daily, and either 500 mg FUL on days 1, 15, 29, and every 4 weeks thereafter (FUL cohort) or 2.5 mg LET once daily (LET cohort) until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR). Key secondary endpoints included toxicity, disease control rate (DCR: CR+PR+SD), progression-free survival (PFS), and the overall survival (OS). The threshold and expected ORR of the FUL cohort were 45% and 60%, respectively; and 32 pts would ensure a statistical power of 80% (α = 0.20). The threshold and expected ORR of the LET cohort were 55% and 75%, respectively; and 16 pts would ensure a statistical power of 80% (α = 0.20). Results: Between June and December 2019, 17 pts were enrolled (FUL cohort: n = 12, LET cohort: n = 5). One patient in the FUL cohort was excluded due to prior treatment history. Enrollment was closed and combination treatment was discontinued mid-study due to safety concerns. All pts had ≥ 1 adverse event (AE). AEs ≥ Grade 3 were observed in 91.7% and 100% of pts in the FUL and LET cohorts, respectively. Immune-related AEs ≥ Grade 3 were observed in 66.7% and 60.0% of pts in the FUL and LET cohorts, respectively. The most frequent AEs ≥ Grade 3 were elevated liver function tests (LFT; FUL cohort: 50.0%, LET cohort: 60.0%). Immune-related (elevated LFT) AEs ≥ Grade 3 were observed in 50.0% and 40.0% of pts in the FUL and LET cohorts, respectively. Severe AEs (SAEs) were observed in 50.0% and 60.0% of pts in the FUL and LET cohorts, respectively. One treatment-related patient death occurred in the LET cohort due to interstitial lung disease (ILD). ORR was 54.5% (6/11) and 20% (1/5) in the FUL and LET cohorts, respectively. DCR was 90.9% (10/11) in the FUL cohort and 80.0% (4/5) in the LET cohort. Due to the discontinuation, PFS and OS were undetermined. Conclusions: Although nivolumab + abemaciclib + FUL appeared to have activity, our findings do not support further investigation of this combination therapy due to toxicity. Toxicity profiles vary with CDK4/6 inhibitors; therefore, a different inhibitor may improve tolerability. Results of the ongoing nivolumab, palbociclib, and ET trial are awaited (CheckMate 7A8, NCT04075604). Clinical trial information: JapicCTI-194782. Citation Format: Jun Masuda, Junji Tsurutani, Norikazu Masuda, Yuko Tanabe, Tsutomu Iwasa, Masato Takahashi, Manabu Futamura, Koji Matsumoto, Kenjiro Aogi, Hiroji Iwata, Mari Hosonaga, Toru Mukohara, Kenichi Yoshimura, Toshimi Takano. Phase II study of nivolumab in combination with abemaciclib plus endocrine therapy in patients with HR+, HER2- metastatic breast cancer: WJOG11418B NEWFLAME trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-10.

Endoscopic retrograde cholangiopancreatography and liver biopsy in the evaluation of elevated liver function tests after liver transplantation.

BACKGROUNDAbnormal liver function tests (LFTs) in post-liver transplant (LT) patients pose a challenge in the timing and selection of diagnostic modalities. There are little data regarding the accuracy of endoscopic retrograde cholangiopancreatography (ERCP) and liver biopsy (LB) in diagnosing post-transplant complications. AIMTo evaluate the diagnostic performance of ERCP and LB in patients with non-vascular post-LT complications.METHODSThis single-center retrospective study evaluated patients undergoing both ERCP and LB for evaluation of elevated LFTs within 6 mo of LT from 2000 to 2017. Diagnostic operating characteristics including accuracy, sensitivity and specificity for various diagnoses were calculated for ERCP and LB. The R factor (ratio of alkaline phosphatase to alanine aminotransferase) was also calculated for each patient. RESULTSOf the 1284 patients who underwent LT, 91 patients (74.7% males, mean age of 51) were analyzed. Anastomotic strictures (AS, 24.2%), acute cellular rejection (ACR, 11%) and concurrent AS/ACR (14.3%) were the most common diagnoses. ERCP carried an accuracy of 79.1% (95%CI: 69.3-86.9), LB had an accuracy of 93.4% (95%CI: 86.2-97.5), and the combination of the two had an accuracy of 100% (95%CI: 96-100). There was no difference between patients with AS and ACR in mean R factor (AS: 1.9 vs ACR: 1.1, P = 0.24). Adverse events did not differ between the two tests (ERCP: 3.1% vs LB: 1.1%, P = 0.31). CONCLUSIONIn patients with abnormal LFTs after LT without vascular complications, the combination of LB and ERCP carries low risk and improves diagnostic accuracy over either test alone.

Cisplatin-conjugated gold nanoparticles-based drug delivery system for targeting hepatic tumors.

Cisplatin is a highly cytotoxic anticarcinogenic drug used to treat several kinds of solid tumors such as liver tumors. With the increase in the incidences associated with hepatic tumors and a lack ofselectivity of cisplatin to cancer cells, it is important to explore new therapeutic strategies against them. The present study was designed to verify the ability of gold nanoparticles (GNPs) to improve the hepatotherapeutic effect of cisplatin against DENA-induced hepatic tumors and to declare its ability to reduce the renal toxicity induced by cisplatin. Forty male Wistar rats were divided into two groups (n = 20): Group (A)-negative control andgroup (B)-model of hepatocellular tumor induction. After 4 months, each group was subdivided into four subgroups as the following: Group (1) received normal saline, Group (2) was treated by cisplatin, Group (3) was treated by GNPs, Group (4) was treated by GNPs-cisplatin conjugates. Our results revealed a marked elevation in liver and kidney function tests and oxidant levels with a reduction in antioxidant levels in the DENA-administrated group. Remarkable histopathological alterations in the liver and kidney tissue sections were observed and confirmed by theoverexpression of the immunohistochemical staining of placental glutathione S-transferase, Hep Par 1, and proliferating cell nuclear antigen. Noticeable improvements in all the measurable toxicological parameters were recorded in the group treated with either GNPs or GNPs-cisplatin conjugate not observed in the group treated with cisplatin. We can conclude that GNPs not only improvethe distribution of cisplatin, targeting it to the site of tumors, but it also reduces the renal toxicity induced by cisplatin, which are the primary concerns in cancer therapy.

Pediatric discard risk index for predicting pediatric liver allograft discard.

Of the 600 pediatric candidates added to the liver waiting list annually, 100 will remain waiting while over 100 liver allografts are discarded, often for subjective reasons. We created a risk index to predict discard to better optimize donor supply. We used the UNOS database to retrospectively analyze 17367 deceased donors (≤18years old) through univariate and multivariate logistic regression models. Deceased donor clinical characteristics and laboratory values were independent variables with discard being the dependent variable in the analysis. Significant univariate factors (P-value<.05) comprised the multivariate analysis. Significant variables from the multivariate analysis were incorporated into the pDSRI, producing a risk score for discard. From 17 potential factors, 11 were identified as significant predictors (P<.05) of pediatric liver allograft discard. The most significant risk factors were as follows: DCD; total bilirubin >10mg/dL, and alanine transaminase (ALT) ≥500IU/L. The pDSRI has a C-statistic of 0.846 for the training set and 0.840 for the validation set. The pDSRI uses 11 significant risk factors, including elevated liver function tests, donor demographics, and donor risk/type to accurately predict risk of pediatric liver allograft discard and serve as a tool that may maximize donor yield.

A Multicenter Study of Real-world Practice for Management of Abnormal Liver Function Tests in Children with Acute Infectious Diseases.

BackgroundAbnormal liver function tests (LFTs) are commonly seen in pediatric patients with acute infectious diseases. Few studies and no definite clinical guidelines for these conditions are available. The present study aimed to elucidate the causes and factors associated with prolongation of liver enzyme elevation. We also investigated actual real-world practices in Korea.MethodsA retrospective study was performed on all patients younger than 18 years, who visited six tertiary teaching hospitals around Korea in 2018 for acute infectious diseases and showed alanine aminotransferase (ALT) levels above 60 IU/L without other specific conditions that could cause ALT elevation. We categorized the infections that cause LFT elevation into six groups: respiratory infection, gastrointestinal infection, urinary tract infection, other febrile disease, Epstein-Barr virus infection, and cytomegalovirus infection. We collected data on the medical specialty of the attending physician who followed up the subject, follow-up duration, percentage of follow-up loss, and their investigation.ResultsA total of 613 patients were enrolled in this study, half of whom (50.7%) were younger than 12 months. The mean initial aspartate aminotransferase and ALT values were 171.2 ± 274.1 and 194.9 ± 316.1 IU/L (range 23–2,881, 60–2,949 IU/L), respectively; however, other LFTs were within the normal range. Respiratory infection was the most common diagnosis (45.0%), and rhinovirus was the most commonly identified pathogen (9.8%). The follow-up rate was higher with pediatric gastroenterologists (90.5%) and non-gastroenterology pediatricians (76.4%) than with pediatric residents and emergency doctors. Older age was related to better ALT recovery (odds ratio [OR] of age for month = 1.003; 95% confidence interval [CI], 1.001–1.004; P = 0.004), while the number of infection episodes (OR = 0.626; 95% CI, 0.505–0.777; P < 0.001) was associated with poor ALT recovery. Abdominal sonography was the most commonly used diagnostic tool (36.9%), followed by the hepatotropic virus workup. The modalities of hepatitis workup were significantly differently applied by physicians based on their specialties and institutions.ConclusionAbnormal liver function test after a systemic infection was common in respiratory infection and under the age of 1 year. Age, number of infections, and initial results of LFTs were related to ALT recovery time. Inter-physician, inter-institution, and inter-specialty variances were observed in real-world practice.

1270. Early Real-world Evidence in the Use of Eravacycline for the Management of Draconian Infections

BackgroundEravacycline (ERV) is a next-generation tetracycline approved for complicated intra-abdominal infections (cIAI) with in-vitro activity to multidrug-resistant organisms such as carbapenem resistant Enterobacteriaceae, extended spectrum beta-lactamase, and carbapenem-resistant Acinetobacter baumannii (CRAB). The purpose of this study was to identify the utility of ERV in clinical practice.MethodsRetrospective case series was conducted on patients at AdventHealth that received at least two doses of ERV. Primary endpoint for the study was clinical success while on ERV, meeting none of the following criteria: changing therapy, mortality, or lack of improvement from sign/symptoms.ResultsOf 23 patients, 74% were males with a mean age of 55 ±18 years and mean body weight of 79 ±27 kg. Mean APACHE II and Charleson scores were 20 (±11) and 6 (±4), respectively. 91% received ERV for an off-label indication or organism. Infection types were respiratory (44%), cIAI (35%), skin (9%), and other (13%). All patients had positive cultures, while 61% were treated as a polymicrobial infection and 17% had bacteremia. Microorganisms included A. xylosoxidans, S. maltophilia, CRAB, and K pneumoniae. 48% had ERV susceptibilities from .06-4 mcg/mL, including two MIC ≥32mcg/mL for S. maltophilia. 70% were given another antibiotic prior to ERV with a median duration of 5 (1-35) days. Median duration of ERV was 8 (3-30) days. 83% percent received ERV in combination with another antibiotic. During treatment, 26% had a Child-Pugh Class C at baseline and 30% had elevated liver function tests. No adverse drug reactions were reported. Upon discharge, 35% continued ERV. Clinical success was observed in 57% (12/21) of patients. Clinical outcome by infection type is summarized in Figure 1. Of 9 cases of clinical failure, 14% were changed to alternative, 19% died while on ERV, and 10% failed to resolve signs/symptoms. Two cases of M. abscessus infections had insufficient follow-up to assess clinical outcome.Figure 1. Eravacycline Clinical Outcome by Infection Type ConclusionInitial real-world experience with ERV differs significantly from the trials regarding severity of illness, types of infection, and clinical outcomes. Further evaluation is necessary for using ERV as combination therapy and in off-label indications.Disclosures All Authors: No reported disclosures

1182. The Real-World Use of Isavuconazole as Primary or salvage Therapy of Invasive Fungal infections in High-Risk Patients with Hematologic Malignancy or Stem Cell Transplant

BackgroundInvasive fungal infections (IFIs) are a major cause of morbidity and mortality among immunocompromised patients with hematologic malignancies (HM) and stem cell transplants (SCT). Isavuconazole was approved by FDA as a primary therapy for Invasive Aspergillosis (IA) and Mucormycosis. The aim of this study is to look at the real-world use of Isavuconazole in patients with HM and evaluate their clinical outcomes and safety.MethodsWe conducted a retrospective study of 200 HM patients at MD Anderson Cancer Center who had definite, probable or possible mold infections between April 2016 and January 2020 and were treated with Isavuconazole for a period of at least 7 days. Clinical and radiological findings were assessed at baseline and at 6 and 12 weeks of follow up.ResultsHM patients with IFIs were classified as definite (11), probable (66) and possible (123). IA was the most commonly isolated pathogen followed by mucor and candida. The majority of patients (65%) received prophylaxis with anti-mold therapy, 73% consisted of azoles and 22% of echinocandins. Isavuconazole was used as a primary therapy in 57.5% of patients, and as salvage therapy in 42.5%. The switch to Isavuconazole was driven by failure of the primary therapy in 50% of the cases and by adverse effects in 28%. These included elevated liver function tests (LFTs), subtherapeutic voriconazole levels and prolonged QT. Isavuconazole was used as monotherapy in 30% of the cases and combination in 70% mostly with a polyene (54%) and/or an echinocandin (27%). A favorable response with Isavuconazole was observed in 57% at 6 weeks of therapy. Adverse events possibly related to Isavuconazole were reported in 6 patients (3%) leading to drug discontinuation. These included 5 elevated transaminases and 1 nausea. All-cause mortality was reported in 46% of patients and IFI-attributable mortality in 25%.ConclusionSelecting Isavuconazole therapy was mainly driven by failure of other antifungal agents or adverse events to other antifungals such as increased LFTs, subtherapeutic voriconazole levels or prolonged QT. Isavuconazole seems to have a promising clinical response and a good safety profile as an antifungal therapy in high risk cancer patients with HM.Disclosures Issam I. Raad, MD, Citius (Other Financial or Material Support, Ownership interest)Cook Medical (Grant/Research Support)Inventive Protocol (Other Financial or Material Support, Ownership interest)Novel Anti-Infective Technologies (Shareholder, Other Financial or Material Support, Ownership interest)

Ameliorating Effect of Green Tea Aqueous Extract against Histo pathophysiological Changes Induced by Ciprofibrate in the liver of Male Albino Rats

Background: The liver is a specific target for drug toxicity because of its role in removal and metabolism of chemicals by converting drugs into another forms that can be readily removed from the body. It is known that the main function of the liver is the elimination of toxins that may enter the body, thus becoming vulnerable damaged during this mechanism, which can be revealed as bleeding, congestion, necrosis or other conditions of liver injury. Ciprofibrate belongs to widely used class of lipid-regulating agents, which stimulate hepatic cells and the hepatic cell becomes uncontrollably divided, causing liver growth. It causes liver cell proliferation in addition to other pleiotropic effects such as peroxisome proliferation and induction of certain peroxisomal and cytosolic enzymes in liver. Objective: The present study aimed to evaluate the potential beneficial effects of green tea aqueous extract administration against the biochemical and histological alterations induced in the liver by ciprofibrate in male rats. Materials and Methods: In the current study 3 groups of 6 male rats were used (Control group, 100mg\Kg body weight, and Cipro 100mg\Kg body weight with green tea). The rats have been treated daily orally by gavages for 21 days. On the last day of the experiment the animals were killed then blood samples and parts from the liver were collected. Liver function was examined for the serum Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), alkaline phosphates (ALP), enzyme activities, and serum total &amp; direct bilirubin concentrations. The histopathological investigation was conducted for the liver tissues of all groups. Results: Treatment of male rats with 100 mg\Kg body weight of ciprofibrate caused a significant increase in serum ALT, AST, and ALP activities, total, and direct bilirubin concentration. Histologically, there were histological changes in central vein area and portal zones, revealed congestion in blood sinusoids, necrosis in hepatic cells, and damage in central vein lining epithelium. Co-administration of green tea aqueous extract with Ciprofibrate significantly improved the structural changes in the liver and the serum ALT, AST, and ALP activities, total, and direct bilirubin concentrations were significantly declined. Conclusion: It can be concluded that Ciprofibrate treatment induced elevation in liver function tests and severe histopathological changes and green tea aqueous extract was able to protect the liver against these effects in male rats. So, the patients should be advised to take green tea aqueous extract while they are treated by ciprofibrate.

Elevated liver function tests in COVID-19: Causes, clinical evidence, and potential treatments.

COVID-19 causes severe respiratory and multiorgan failure, including liver damage and elevated transaminase levels. This article addresses the potential causes of liver function abnormalities in patients diagnosed with COVID-19 and management approaches for NPs focusing on preventing and alleviating liver injury.

Remdesivir Use in the Setting of Severe Renal Impairment: A Theoretical Concern or Real Risk?

IntroductionRemdesivir (RDV) is FDA approved for COVID-19, but not recommended for patients with severe renal impairment (SRI, i.e. creatinine clearance < 30ml/min). Few studies have evaluated RDV in patients with SRI due to theoretical toxicity concerns.MethodsHospitalized patients receiving RDV for COVID-19 between 5/1/2020-10/31/2020 were analyzed in a retrospective chart review. We compared incident adverse events (AEs) following RDV in patients with and without SRI, including hepatotoxicity, nephrotoxicity, any reported AE, mortality and length of stay.ResultsA total of 135 patients received RDV, 20 patients had SRI. Patients with SRI were significantly older (70 vs. 54 years, p=0.0001). The incidence of possible AEs following RDV was 20% among those with SRI versus 11% without (p=0.26). LFT elevations occurred in 10% vs. 4% (p=0.28), and SCr elevations occurred in 20% vs. 6% (p=0.06) of patients with SRI versus those without, respectively. The LFT and SCr elevations were not attributed to RDV in either group. Mortality and length of stay were comparable and consistent with historical controls.ConclusionRDV AEs occurred infrequently with low severity and were not significantly different between those with and without SRI. While a higher percentage of patients with SRI experienced SCr elevations, 3 (75%) patients were in AKI prior to RDV. Overall, the use of RDV in this small series of patients with SRI appeared to be relatively safe, and the potential benefit outweighed the theoretical risk of liver or renal toxicity; however, additional studies are needed to confirm this finding.

Non-alcoholic fatty liver disease in lean individuals or another rare differential diagnosis - a clinical case

Non-alcoholic fatty liver disease in lean individuals or another rare differential diagnosis - a clinical case

Development of amoebic liver abscess in early pregnancy years after initial amoebic exposure: a case report

BackgroundInfection with Entamoeba histolytica and associated complications are relatively rare in developed countries. The overall low prevalence in the Western world as well as the possibly prolonged latency period between infection with the causing pathogen and onset of clinical symptoms may delay diagnosis of and adequate treatment for amoebiasis. Amoebic liver abscess (ALA) is the most common extraintestinal manifestation of invasive amoebiasis. Pregnancy has been described as a risk factor for development of invasive amoebiasis and management of these patients is especially complex.Case presentationA 30-year-old Caucasian woman in early pregnancy presented to our emergency department with abdominal pain alongside elevated inflammatory markers and liver function tests. Travel history revealed multiple journeys to tropic and subtropic regions during the past decade and a prolonged episode of intermittently bloody diarrhea during a five month stay in Indonesia seven years prior to admission. Sonographic and magnetic resonance imaging revealed a 5 × 4 cm hepatic abscess. After ultrasound-guided transcutaneous liver drainage, both abscess fluids and blood cultures showed neither bacterial growth nor microscopic signs of parasitic disease. Serological testing confirmed an infection with Entamoeba histolytica, which was treated with metronidazole, followed by eradication therapy with paromomycin. Subsequent clinical, laboratory and imaging follow-up exams showed regression of the ALA. In addition, the pregnancy completed without complications and a healthy baby boy was born 7 months after termination of treatment.ConclusionsThis case of invasive amoebiasis in early pregnancy outside of endemic regions and several years after exposure demonstrates the importance of broad differential diagnostics in the context of liver abscesses. The complex interdisciplinary decisions regarding the choice of imaging techniques as well as interventional and antibiotic therapy in the context of pregnancy are discussed. Furthermore, we present possible explanations for pregnancy as a risk factor for an invasive course of amoebiasis.

Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy

Spinal muscular atrophy (SMA) is an autosomal recessive, childhood-onset motor neuron disease. Onasemnogene abeparvovec (OA) is a gene therapy designed to address SMA's root cause. In pivotal mouse toxicology studies, the liver was identified as a major site of OA toxicity. Clinical data reflect elevations in serum aminotransferase concentrations, with some reports of serious acute liver injury. Prophylactic prednisolone mitigates these effects. Herein, we aim to provide pragmatic, supportive guidance for identification, management, and risk mitigation of potential drug-induced liver injury. Data from 325 patients with SMA who had received OA through 31 December 2019, in 5 clinical trials, a managed access program (MAP), and a long-term registry (RESTORE), and through commercial use, were analyzed. Liver-related adverse events, laboratory data, concomitant medications, and prednisolone use were analyzed. Based on adverse events and laboratory data, 90 of 100 patients had elevated liver function test results (alanine aminotransferase, and/or aspartate aminotransferase, and/or bilirubin concentrations). Of these, liver-associated adverse events were reported for 34 of 100 (34%) and 10 of 43 (23%) patients in clinical trials and MAP/RESTORE, respectively. Two patients in MAP had serious acute liver injury, which resolved completely. While all events in the overall population resolved, prednisolone treatment duration varied (range: 33-229 days), with a majority receiving prednisolone for 60-120 days. More than 60% had elevations in either alanine aminotransferase, aspartate aminotransferase, or bilirubin concentrations prior to dosing. Greater than 40% received potentially hepatotoxic concomitant medications. Hepatotoxicity is a known risk associated with OA use. Practitioners should identify contributing factors and mitigate risk through appropriate monitoring and intervention. Onasemnogene abeparvovec is a type of medicine called a "gene therapy," which is used to treat babies and young children who have a rare, serious inherited condition called "spinal muscular atrophy" (SMA). It works by supplying a fully functioning copy of the survival motor neuron or SMN gene, which then helps the body produce enough SMN protein. However, it can cause an immune response that could lead to an increase in enzymes produced by the liver. This article provides information about the liver injury and how to prevent and recognize if it happens, so that it may be treated properly.

A Real-World Assessment of Hepatic Dysfunction Among Chronic Phase Chronic Myeloid Leukemia (CP-CML) Patients Receiving First-Line (1L) Tyrosine Kinase Inhibitors (TKIs) in the United States

Introduction:Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the unregulated proliferation of myeloid cells in the bone marrow and their accumulation in the blood. The approval of imatinib (IM) and second-generation TKIs have substantially improved survival for patients with CML. Despite the effectiveness of these TKIs in controlling CML, continuous therapy is necessary for most patients, and may be associated with the development of unfavorable adverse events such as hepatotoxicity. Although patients with elevated liver function tests are excluded from key clinical trials, case reports and small single-center studies have described cases of TKI-associated hepatotoxicity among patients with CML. This study sought to describe the prevalence and incidence of hepatotoxicity in patients with newly diagnosed Philadelphia chromosome-positive chronic-phase (Ph+ CP) CML treated with 1L TKIs in community oncology practices. Methods:This retrospective, observational cohort study identified adult patients newly diagnosed with Ph+ CP CML and treated with 1L dasatinib (DAS), IM, or nilotinib (NIL) within the US Oncology Network (USON) between 1 January 2008 and 30 November 2018. Patients were required to have at least one comprehensive metabolic panel (CMP) within 90 days of treatment start, and ≥ 1 CMP during follow-up. Additionally, patients had to have at least two visits within the USON, no enrollment in any clinical trial during the study period, and no documentation of other primary cancer diagnoses. Descriptive statistics were generated for baseline patient characteristics and prevalence and incidence of hepatotoxicity, and were stratified by 1L TKI treatment initiation. Grades for hepatotoxicity were derived from laboratory data using the Common Terminology Criteria for Adverse Events version 5. Results:A total of 2743 patients with CP-CML were identified. Of those, 730 (26.6%), 1455 (53.0%), and 558 (20.3%) patients were treated with 1L DAS, IM, or NIL, respectively. With the exception of age and region, patient demographic characteristics were well balanced across cohorts. However, baseline hepatic functioning differed across TKIs (Table 1). Prevalence of any-grade liver enzyme elevation was observed in almost one-third (31.9%) of patients, including 246 (33.7%) patients treated with DAS, 416 (28.6%) patients treated with IM, and 213 (38.2%) patients treated with NIL. Among all patients with normal baseline hepatic function, 48.9% developed any-grade hepatotoxicity while on 1L therapy. Across TKI cohorts, significantly more patients treated with NIL developed any-grade hepatotoxicity (70.1%) compared to patients treated with DAS (45.5%) or IM (43.5%) (P&amp;lt; 0.0001). Among all patients receiving 1L treatment, 1.5% to 3.8% of patients experienced grade 3-4 hepatotoxicity. Significant differences in the proportion of patients that developed grade 3-4 hepatotoxicity were observed across treatments and were most common among patients treated with NIL (Table 2). Conclusions:Findings from this analysis suggest that hepatic dysfunction may be common at baseline among patients with CP-CML treated in real-world community oncology settings. Among patients with normal baseline hepatic function, more patients treated with NIL experienced any-grade hepatotoxicity. Patients treated with NIL were also more likely to develop grade 3-4 hepatotoxicity compared to patients treated with DAS or IM. These findings may provide insight into the effects of long-term TKI treatment on hepatic functioning and help to inform treatment choices for patients. Disclosures Kolibaba: AbbVie:Research Funding;Compass Oncology:Ended employment in the past 24 months;Janssen:Research Funding;TG Therapeutics:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;McKesson Life Sciences:Consultancy;Sumitomo Dainippon Pharma Oncology:Consultancy, Other: travel, accommodations, expenses, ;Gilead:Research Funding;Genentech:Research Funding;Cell Therapeutics:Research Funding;Celgene:Research Funding;Acerta:Research Funding;Atara Biotech:Membership on an entity's Board of Directors or advisory committees;Verastem:Honoraria;Seattle Genetics:Research Funding;Novartis:Research Funding;Pharmacyclics:Research Funding.Zhou:McKesson Corporation:Current Employment.Keating:Bristol Myers Squibb:Current Employment.Clark:McKesson Life Sciences:Current Employment, Current equity holder in publicly-traded company.Brokars:Bristol Myers Squibb:Current Employment.Kee:Bristol Myers Squibb:Current Employment.Copher:Bristol Myers Squibb:Current Employment.Stwalley:Bristol Myers Squibb:Current Employment, Current equity holder in publicly-traded company.Jabbour:Adaptive Biotechnologies:Other: Advisory role, Research Funding;Genentech:Other: Advisory role, Research Funding;BMS:Other: Advisory role, Research Funding;Amgen:Other: Advisory role, Research Funding;Pfizer:Other: Advisory role, Research Funding;Takeda:Other: Advisory role, Research Funding;AbbVie:Other: Advisory role, Research Funding.

Endocrine consequences of treatment with the new androgen receptor axis-targeted agents for advanced prostate cancer.

Prostate cancer (PCa) is the commonest non-cutaneous malignancy worldwide and the second cause of cancer death among males in the USA. Approval of the new androgen receptor axis-targeted (ARAT) agents (abiraterone acetate, enzalutamide, apalutamide, and darolutamide) has altered the course of advanced PCa. We aimed to assess the endocrine and metabolic adverse events associated with treatment using ARAT compounds. We searched the PubMed, Cochrane Library, and Scopus databases from database inception to August 2020. We included randomized controlled trials reporting the endocrine and metabolic side effects of ARAT agents compared to each other or to placebo. Although metastatic PCa remains incurable, ARAT medications combined with androgen deprivation therapy improve overall metastasis-free and progression-free survival in metastatic hormone-sensitive PCa, non-metastatic castration-resistant PCa, and metastatic castration-resistant PCa patients. This benefit comes at the cost of certain endocrine and metabolic consequences. Treatment with abiraterone acetate induces mineralocorticoid excess, hypokalemia, hypertension, elevated liver function tests, insulin resistance, and hyperglycemia. Enzalutamide may induce or worsen hypertension and increase the risk of falls and fractures in elderly patients, while common endocrine adverse events of apalutamide include hypothyroidism, hypertension, and skin rash. On the other hand, darolutamide seems to have a somewhat safer endocrine and metabolic profile. Treatment of advanced PCa should be personalized, with administration of a combination of androgen deprivation therapy, ARAT agents, and chemotherapy being based on the patient's safety profile and the risk of side effects.

Prognostic role of gamma-glutamyl transferase in metastatic melanoma patients treated with immune checkpoint inhibitors.

Hepatic immune-related adverse events (irAE) including elevated liver function tests (transaminases) occur in 1.4-22.3% of melanoma patients receiving immune checkpoint inhibitors (ICPI) and constitute a potentially serious toxicity that is challenging to treat. In contrast to the liver transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST), only little is known about the frequency and impact of gamma-glutamyl transferase (GGT) elevations. GGT determined prior to and during therapy of metastatic melanoma patients treated with ICPI were retrospectively assessed in two independent cohorts (PD-1: n = 218, Ipi + Nivo: n = 148). Overall survival (OS) and best objective response were analyzed according to baseline and immune-related GGT (irGGT) elevations during treatment. In multivariate analysis, OS was reduced in patients with elevated baseline GGT (PD-1 group: hazard ratio [HR] 1.76, p = .0073; Ipi + Nivo group: HR 1.77, p = .032). Immune-related GGT elevation was recorded in 17% (PD-1 group) and 38.5% (Ipi + Nivo group). Of these patients, the majority (81 and 68%, respectively) had normal ALT and AST and showed no clinical signs of hepatotoxicity. Patients who experienced irGGT elevation had superior response (PD-1 group: odds ratio [OR] 3.57, p = .00072; Ipi + Nivo group: OR 1.74, p = .12) and OS (PD-1 group: HR 0.37, p = .0016; Ipi + Nivo group: HR 0.33, p = .00050). The frequency of hepatic irAE is currently underestimated. The addition of the sensitive enzyme GGT to the laboratory panel before and during therapy with ICPI allows to detect two to three times more patients developing hepatic or hepatobiliary toxicity than known so far. Immune-related GGT elevations correlate with response and favorable survival. Precis for use in the Table of Contents The frequency of hepatotoxicity under immune checkpoint blockade is currently underestimated. We suggest the addition of gamma-glutamyl transferase to the laboratory panel in checkpoint inhibitor patients for the detection of hepatobiliary toxicity.

Acute Hepatitis Is a Prominent Presentation of the Multisystem Inflammatory Syndrome in Children: A Single-Center Report.

A newly recognized multisystem inflammatory syndrome in children (MIS-C) has had a paradigm-shifting effect on the perception of severe acute respiratory syndrome, coronavirus-2 (SARS-CoV-2) illness severity in children. We report the clinical and biochemical features of liver involvement, and the comorbidities that present with hepatitis, in a substantial cohort of patients. This is a retrospective cohort study of 44 patients with MIS-C admitted at Morgan Stanley Children's Hospital of New York-Presbyterian during April and May 2020. We evaluated the number of patients who developed hepatitis and examined both demographics and inflammatory laboratory values to ascertain those that were at higher risk for liver involvement and more severe disease. Hepatitis was present in 19 subjects (43%) and was associated with more severe disease. Persons with hepatitis had significantly higher rates of shock at presentation (21.1% vs. 0%; P=0.008), greater respiratory support requirement (42.1% vs. 12%; P=0.005), and longer hospitalization times (median, 7 [interquartile range {IQR}, 5, 10] vs. 4days [IQR, 3.5, 6.5]; P<0.05). Patients with hepatitis also had significantly higher levels of ferritin (706.9 vs. 334.2mg/mL; P<0.01), interleukin-6 (233.9 vs. 174.7pg/mL; P<0.05), troponin (83.0 vs. 28.5ng/L; P<0.05), and B-type natriuretic peptide (7,424.5 vs. 3,209.5pg/mL; P<0.05). The single patient with liver failure also developed multiorgan failure requiring vasopressors, hemodialysis, and mechanical ventilation. All patients were discharged, though >50% had persistent hepatitis up to 1month after discharge. Hepatitis is common in children with MIS-C and is associated with a more severe presentation and persistent elevation of liver function tests in many. Despite the positive outcomes reported here, close follow-up is warranted given the limited knowledge of the long-term impact of SARS-CoV-2 on the liver.

Abnormal Liver Function Tests in Patients With COVID-19: Relevance and Potential Pathogenesis.

Abnormal liver function tests (LFTs) are reported frequently in hospitalized coronavirus disease 2019 (COVID-19) patients. A review of the literature shows that 46% of admitted COVID-19 patients had elevated plasma aspartate aminotransferase (AST) and 35% had elevated alanine aminotransferase (ALT) levels on admission. Elevations of both AST and ALT are mostly below 5 times the upper reference limit and are associated with severe disease and increased inflammatory markers. AST and ALT elevations are more frequent in US patients compared to Chinese patients. Mild elevations in gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP) and total bilirubin are also reported, although less frequently. Significant impairment of liver function or overt liver failure as the cause of death in COVID-19 rarely occur. There is no direct evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hepatic infection, although a subset of hepatocytes and cholangiocytes express the host receptor utilized for cellular entry by SARS-CoV-2. The presence of pre-existing liver disease in patients with elevated LFTs on admission has not been comprehensively assessed in most studies but is unlikely to account for all abnormalities in LFTs. Although abnormal LFTs are already frequently present upon admission before the start of treatment, drug-induced liver injury should be taken into consideration, especially after the use of acetaminophen, lopinavir/ritonavir and remdesivir, which are potentially hepatotoxic. In conclusion, these initial observations suggest that the prevalence of abnormal LFTs is high in COVID-19 patients, but that the clinical relevance is limited and that treatment is not required. The mechanisms underlying abnormal LFTs in COVID-19 are likely multifactorial and related to a hyper-inflammatory status and thrombotic microangiopathy that are observed in severe COVID-19 disease.

Adverse effects of chronic nitrofurantoin therapy in women with recurrent urinary tract infections in an outpatient setting.

To review the frequency of adverse events reported with nitrofurantoin (NF) in perimenopausal and menopausal women on prolonged daily prophylaxis in an outpatient setting. Electronic medical records of women aged 50-95 prescribed NF by 2 primary urology providers for at least 3 consecutive months from 2006 to 2018 were retrospectively reviewed. Demographics, reason for the initiation, dose and duration of therapy, explanation of therapy interruptions, occurrence of adverse events, comorbid conditions, and relevant lab and imaging results were recorded. The number of months on prolonged therapy were summed. Of the 221 patients included, 167 (77%) were prescribed 100mg of NF dailywith a mean duration of therapy of1.5years. The most common indication for therapywas recurrent urinary tract infection prophylaxis. Breakthrough urinary tract infections developed in 88 (40%) patients on prolonged NF therapy but only 10 were not restarted on NF. Four patients (1.8%) were determined to have pulmonary adverse events and 1 (0.4%) developed elevated liver function tests. In peri-menopausal and menopausal women, the risks and benefits of chronic NF therapyshould be weighed by the clinician and patient prior to prescribing long term NF. Patients must be educated about the potential NF toxicities and clinically monitored for signs and symptoms of potential adverse events while on chronic NF therapy.