key: cord-1055877-uo8otkg3 authors: Sato, Ken; Yamazaki, Yuichi; Uraoka, Toshio title: Strategy for the control of drug-induced liver injury due to investigational treatments/drugs for COVID-19 date: 2021-12-28 journal: World J Gastroenterol DOI: 10.3748/wjg.v27.i48.8370 sha: 73a625b154fd995af4c2fecd61e58f25efbb5455 doc_id: 1055877 cord_uid: uo8otkg3 Investigational treatments/drugs for coronavirus disease 2019 (COVID-19) have been applied, with repurposed or newly developed drugs, and their effectiveness has been evaluated. Some of these drugs may be hepatotoxic, and each monotherapy or combination therapy may increase the risk of drug-induced liver injury (DILI). We should aim to control dysregulation of liver function, as well as the progression of COVID-19, as much as possible. We discussed the potential risks of investigational treatments/drugs and promising drugs for both COVID-19 and DILI due to investigational treatments/drugs. fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: htt ps://creativecommons.org/Licens es/by-nc/4.0/ Received: July 29, 2021 Peer-review started: July 29, 2021 First decision: November 7, 2021 Revised: November 18, 2021 Accepted: November 10, 2021 Article in press: December 10, 2021 Published online: December We read with great interest the review by Huang et al [1] , which summarized the current understanding and perspectives on dysregulation of liver function in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.We generally agree with the authors' comprehensive review. Additional information regarding the potential hepatotoxicity of investigational treatments/drugs for coronavirus disease 2019 (COVID-19) and the strategy for dealing with drug-induced liver injury (DILI) associated with investigational treatments/drugs is useful in clinical practice. The investigators [1] cited that the synthetic corticosteroid dexamethasone worsens outcomes in patients with COVID-19 who show milder respiratory symptoms, which was reported in the RECOVERY trial [2] . However, to be technically accurate, dexamethasone therapy had several strengths in reducing the 28-d mortality rate, increasing the rate of patients who were discharged alive from hospital within 28 d, and reducing progression to invasive mechanical ventilation or death in comparison to those with usual care, while these merits were not observed in patients who did not receive oxygen [2] . The World Health Organization (WHO) announced guidelines regarding dexamethasone therapy for COVID-19 [3] . Corticosteroids (i.e., dexamethasone, hydrocortisone or prednisone) were recommended for the treatment of patients with severe and critical but not nonsevere COVID-19 on September 2, 2020 [3] . The current situation has changed with the emergence of new genetic variants of SARS-CoV-2 [4] . SARS-CoV-2 mutation may facilitate transmissibility or virulence, reduce neutralization by antibodies produced in response to natural infection or vaccination, promote the ability to evade detection, or decrease the effectiveness of therapeutics or vaccination [4] . They may affect the disease progression of COVID-19, and thus, we believe that the treatment strategy has a more important role in the control of COVID-19. The role of dexamethasone is to ameliorate inflammatory organ injury in viral pneumonia [2] . However, dexamethasone is a cytochrome P450 (CYP3A4) inducer and has a high chance of drug-drug interactions with investigational treatments/drugs or agents used to treat comorbidities, especially CYP3A4 substrates. Importantly, CYP enzymes can be inhibited by an increase in infection-related cytokine levels and inflammation [5] . Both investigational treatments/drugs and agents used to treat comorbidities can be affected by compromised CYP-mediated hepatic metabolism, irrespective of the onset/Length of COVID-19 and the extent of liver dysfunction [5] . Subsequently, these drug-drug and drug-disease interactions and dysfunctional CYPmediated hepatic metabolism might cause dysregulation of liver function, including drug-induced liver injury (DILI) [5] . In addition, dexamethasone therapy caused elevated liver enzymes, increased hepatic lipid peroxidation, and decreased antioxidant activities in rats [6] . On the other hand, dexamethasone is a type of corticosteroid that can be used to treat drug-induced cholestatic hepatitis [7] ; in particular, corticosteroids are used for the treatment of DILI associated with hypersensitivity features[8]. The mechanism of dexamethasone against DILI might be involved in alleviation of tissue damage caused by inflammatory responses of the immune system within the liver [7] . Thus, dexamethasone has pros and cons in relation to liver injury. Dexamethasone could be used in combination with antiviral drugs, such as remdesivir (RDV), for COVID-19 patients, although the WHO announced a conditional recommendation against the use of RDV in hospitalized patients on November 20, 2020 [9] . As a direct role of RDV in hepatocellular toxicity was suggested [10] , combination therapy with dexamethasone and RDV is more likely to cause liver dysfunction, especially for patients with comorbidities, and we should perform careful observation during combination therapy or each monotherapy. Regarding the treatment of DILI due to investigational treatments/drugs, glycyrrhizic acid was advocated as a treatment candidate for COVID-19 patients, especially those with complex liver injury [11] . In Japan, glycyrrhizic acid has been used for more than 40 years as a treatment for liver diseases [11] . It works as a hepatoprotective drug for a variety of liver diseases, including DILI [11] , and has safe and economical features [11] . The possible mechanism of monoammonium glycyrrhizin, the main component of glycyrrhizin, against drug-induced hepatotoxicity involves Table 1 Anti-coronavirus disease 2019 drugs and drugs for drug-induced liver injury Name Type Mechanisms as anti-COVID-19 drugs and/or drugs for drug-induced liver injury Mechanisms of hepatotoxicity Ref. Dexamethasone Antiinflammatory drug Amelioration of inflammatory organ injury in viral pneumonia. Alleviation of tissue damage caused by inflammatory responses of the immune system within the liver. Drug-drug interactions due to cytochrome P450 induction. Elevation of liver enzyme levels, increase in hepatic lipid peroxidation, and decrease in antioxidant activities. [2, 6, 7] Remdesivir Antiviral drug Inhibition of RNA polymerase, as a nucleotide analog. Hepatocellular toxicity. [10] Glycyrrhizic acid Hepatoprotector Regulation of the expression of hepatobiliary membrane transporters. [12] Ursodeoxycholic acid Hepatoprotector Anti-inflammatory, antioxidant, immunomodulatory and antiapoptotic profiles. Inhibition of proinflammatory cytokine production. [14] COVID-19: Coronavirus disease 2019. regulating the expression of hepatobiliary membrane transporters [12] . Another therapeutic candidate for DILI due to investigational treatments/drugs is ursodeoxycholic acid (UDCA), which has been used in cholestatic DILI to reduce the time to resolution [13] . UDCA is a hydrophilic bile acid that has anti-inflammatory, antioxidant, immunomodulatory and antiapoptotic profiles [14] and inhibits proinflammatory cytokine production [14] . Thus, UDCA is also beneficial for cytokine storm syndrome, which is caused by a sudden, abnormal release of inflammatory cytokines due to overreaction of innate immunity [14] , which is one of the critical pathogeneses of COVID-19. UDCA has been promoted as a candidate therapeutic agent for COVID-19 [14, 15] . Anti-COVID-19 drugs and drugs for DILI are summarized in Table 1 . We should manage dysregulation of liver function regardless of the association with treatment for COVID-19. We introduced the potential risks of investigational treatments/drugs and promising drugs for both COVID-19 and DILI due to investigational treatments/drugs. Further studies should confirm this hypothesis and may help to establish an effective strategy for the management of COVID-19 and DILI due to investigational treatments/drugs. Dysregulated liver function in SARS-CoV-2 infection: Current understanding and perspectives Dexamethasone in Hospitalized Patients with Covid-19 WHO. Coronavirus disease (COVID-19): Dexamethasone. Available from Evaluation, and Treatment of Coronavirus (COVID-19) Potential Effects of COVID-19 on Cytochrome P450-Mediated Drug Metabolism and Disposition in Infected Patients Grape Seed Extract Alleviates Dexamethasone-Induced Hyperlipidemia, Lipid Peroxidation, and Hematological Alteration in Rats Steroid and ursodeoxychoclic acid combination therapy in severe drug-induced liver injury Current and future directions in the treatment and prevention of drug-induced liver injury: a systematic review Liver injury in remdesivir-treated COVID-19 patients Clinical efficacy and security of glycyrrhizic acid preparation in the treatment of anti-SARS-CoV-2 drug-induced liver injury: a protocol of systematic review and meta-analysis Monoammonium glycyrrhizinate protects rifampicin-and isoniazid-induced hepatotoxicity via regulating the expression of transporter Mrp2, Ntcp, and Oatp1a4 in liver Drug induced liver injury: an update Ursodeoxycholic acid as a candidate therapeutic to alleviate and/or prevent COVID-19-associated cytokine storm Merit of an Ursodeoxycholic Acid Clinical Trial in COVID-19 Patients. Vaccines (Basel) 2020