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1.
Expert Rev Gastroenterol Hepatol ; : 1-19, 2022 Jul 22.
Article in English | MEDLINE | ID: covidwho-1948016

ABSTRACT

INTRODUCTION: In 2021, over 3,000 articles on Drug-Induced Liver Injury (DILI) were published, nearly doubling the annual number compared to 2011. This review selected DILI articles from 2021 we felt held the greatest interest and clinical relevance. AREAS COVERED: A literature search was conducted using PubMed between 1 March 2021 and 28 February 2022. 86 articles were included. This review discusses new and established cases of hepatotoxins, including new FDA approvals and COVID-19 therapeutics. Developments in biomarkers and causality assessment methods are discussed. Updates from registries are also explored. EXPERT OPINION: DILI diagnosis and prognostication remain challenging. Roussel Uclaf Causality Assessment Method (RUCAM) is the best option for determining causality and has been increasingly accepted by clinicians. Revised Electronic Causality Assessment Method (RECAM) may be more user-friendly and accurate but requires further validation. Quantitative systems pharmacology methods, such as DILIsym, are increasingly used to predict hepatotoxicity. Oncotherapeutic agents represent many newly approved and described causes of DILI. Such hepatotoxicity is deemed acceptable relative to the benefit these drugs offer. Drugs developed for non-life-threatening disorders may not show a favorable benefit-to-risk ratio and will be more difficult to approve. As the COVID-19 landscape evolves, its effect on DILI deserves further investigation.

2.
Journal of Clinical and Translational Hepatology ; 000(000):9, 2022.
Article in English | English Web of Science | ID: covidwho-1884770

ABSTRACT

Liver injury is an important complication that may arise in patients suffering from coronavirus disease 2019 (COVID-19) and is accompanied by a transient increase of transaminases and/or other liver enzymes. Liver function test (LFT) abnormalities generally disappear when the COVID-19 resolves or hepatotoxic drugs are discontinued. The LFT abnormalities are associated with drug-induced liver injury (DILI), due to the overuse of antimalarials, antivirals, and antimicrobials. Studies have reported varying levels of these liver injuries in COVID-19 patients;however, most involve elevated serum aminotransferases. Hepatic dysfunction is significantly high in patients with severe illness and has poor outcome. Normally, the liver is involved in the metabolism of many drugs, including nucleoside analogs and protease inhibitors, which are currently repurposed to treat COVID-19. In addition to the manifestation of COVID-19, drugs implemented in its treatment may aggravate liver injuries. Thus, DILI should be considered especially in those COVID-19 patients with underlying liver disease. It was unclear whether the elevated liver enzymes have originated from the underlying disease or DILI in this population. Furthermore, it is difficult to establish a direct relationship between a specific drug and liver injury. Another possible effect of liver damage may due to inflammatory cytokine storm in severe COVID-19. Liver injury can change metabolism, excretion, dosing, and expected concentrations of the drugs, which may make it difficult to achieve a therapeutic dose of the drug or increase the risk of adverse effects. These repurposed drugs have shown limited efficacy against the virus and the disease itself;however, they still pose risk of adverse effects. Careful and close monitoring of LFTs in COVID-19 patients can provide early diagnosis of liver injury, and the risk of DILI could be reduced. Also, drug interactions in liver-transplanted patients should always be kept in mind for certain immunosuppressive therapies and their known signs of DILI. Altogether, abnormal LFTs should not be regarded as a contraindication to use COVID-19 experimental therapies if needed under emergent status. Citation of this article: Zhang R, Wang Q, Yang J. Impact of Liver Functions by Repurposed Drugs for COVID-19 Treatment. J Clin Transl Hepatol 2022. doi: 10.14218/ JCTH.2021.00368.

3.
Int J Mol Sci ; 23(9)2022 Apr 27.
Article in English | MEDLINE | ID: covidwho-1809943

ABSTRACT

Patients with coronavirus disease 19 (COVID-19) commonly show abnormalities of liver tests (LTs) of undetermined cause. Considering drugs as tentative culprits, the current systematic review searched for published COVID-19 cases with suspected drug-induced liver injury (DILI) and established diagnosis using the diagnostic algorithm of RUCAM (Roussel Uclaf Causality Assessment Method). Data worldwide on DILI cases assessed by RUCAM in COVID-19 patients were sparse. A total of 6/200 reports with initially suspected 996 DILI cases in COVID-19 patients and using all RUCAM-based DILI cases allowed for a clear description of clinical features of RUCAM-based DILI cases among COVID-19 patients: (1) The updated RUCAM published in 2016 was equally often used as the original RUCAM of 1993, with both identifying DILI and other liver diseases as confounders; (2) RUCAM also worked well in patients treated with up to 18 drugs and provided for most DILI cases a probable or highly probable causality level for drugs; (3) DILI was preferentially caused by antiviral drugs given empirically due to their known therapeutic efficacy in other virus infections; (4) hepatocellular injury was more often reported than cholestatic or mixed injury; (5) maximum LT values were found for alanine aminotransferase (ALT) 1.541 U/L and aspartate aminotransferase (AST) 1.076 U/L; (6) the ALT/AST ratio was variable and ranged from 0.4 to 1.4; (7) the mean or median age of the COVID-19 patients with DILI ranged from 54.3 to 56 years; (8) the ratio of males to females was 1.8-3.4:1; (9) outcome was favorable for most patients, likely due to careful selection of the drugs and quick cessation of drug treatment with emerging DILI, but it was fatal in 19 patients; (10) countries reporting RUCAM-based DILI cases in COVID-19 patients included China, India, Japan, Montenegro, and Spain; (11) robust estimation of the percentage contribution of RUCAM-based DILI for the increased LTs in COVID-19 patients is outside of the current scope. In conclusion, RUCAM-based DILI with its clinical characteristics in COVID-19 patients and its classification as a confounding variable is now well defined, requiring a new correct description of COVID-19 features by removing DILI characteristics as confounders.


Subject(s)
Antiviral Agents , COVID-19 , Chemical and Drug Induced Liver Injury , Alanine Transaminase , Antiviral Agents/adverse effects , Aspartate Aminotransferases , COVID-19/drug therapy , Chemical and Drug Induced Liver Injury/diagnosis , Chemical and Drug Induced Liver Injury/epidemiology , Chemical and Drug Induced Liver Injury/etiology , Female , Humans , Male , Middle Aged , Publications
4.
Front Pharmacol ; 13: 799338, 2022.
Article in English | MEDLINE | ID: covidwho-1779956

ABSTRACT

The outbreak of coronavirus disease 2019 (COVID-19) has led to the emergence of global health care. In this study, we aimed to explore the association between drug treatments and the incidence of drug-induced liver injury (DILI) in hospitalized patients with COVID-19. A retrospective study was conducted on 5113 COVID-19 patients in Hubei province, among which 395 incurred liver injury. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards models. The results showed that COVID-19 patients who received antibiotics (HR 1.97, 95% CI: 1.55-2.51, p < 0.001), antifungal agents (HR 3.10, 95% CI: 1.93-4.99, p < 0.001) and corticosteroids (HR 2.31, 95% CI: 1.80-2.96, p < 0.001) had a higher risk of DILI compared to non-users. Special attention was given to the use of parenteral nutrition (HR 1.82, 95% CI: 1.31-2.52, p < 0.001) and enteral nutrition (HR 2.71, 95% CI: 1.98-3.71, p < 0.001), which were the risk factors for liver injury. In conclusion, this study suggests that the development of DILI in hospitalized patients with COVID-19 needs to be closely monitored, and the above-mentioned drug treatments may contribute to the risk of DILI.

6.
J Clin Exp Hepatol ; 12(1): 252-253, 2022.
Article in English | MEDLINE | ID: covidwho-1620788
7.
J Clin Exp Hepatol ; 11(6): 732-738, 2021.
Article in English | MEDLINE | ID: covidwho-1525841

ABSTRACT

The COVID-19 pandemic has resulted in widespread use of complementary and alternative medicines. Tinospora cordifolia is a widely grown shrub which has been commonly used in India's traditional system of Ayurveda for its immune booster properties and has been extensively used as prophylaxis against COVID-19. Six patients (4 women, 2 men) with a median (IQR) age of 55 years (45-56) and with an history of Tinospora cordifolia consumption presented with symptoms of acute hepatitis during the study period of 4 months in the COVID-19 pandemic. The median (IQR) duration of Tinospora cordifolia consumption was 90 days (21-210). The median (IQR) peak bilirubin and AST were 17.5 mg/dl (12.2-24.9) and 1350 IU/ml (1099-1773), respectively. The patients had either a definite (n = 4) or probable (n = 2) revised autoimmune hepatitis score with an autoimmune pattern of drug-induced liver injury on biopsy. Four of these patients (all women) had underlying silent chronic liver disease of possible autoimmune etiology associated with other autoimmune diseases - hypothyroidism and type 2 diabetes mellitus. One of the three patients treated with steroids decompensated on steroid tapering. The other five patients had resolution of symptoms, liver profile, and autoimmune serological markers on drug withdrawal/continuing steroid treatment. The median (IQR) time to resolution from discontinuing the herb was 86.5 days (53-111). Tinospora cordifolia consumption seems to induce an autoimmune-like hepatitis or unmask an underlying autoimmune chronic liver disease, which may support its immune stimulant mechanism. However, the same mechanism can cause significant liver toxicity, and we recommend that caution be exercised in the use of this herb, especially in those predisposed to autoimmune disorders. Besides, in patients presenting with acute hepatitis, even in the presence of autoimmune markers, a detailed complementary and alternative medicine history needs to be elicited.

8.
Diagnostics (Basel) ; 11(3)2021 Mar 06.
Article in English | MEDLINE | ID: covidwho-1458401

ABSTRACT

Causality assessment in liver injury induced by drugs and herbs remains a debated issue, requiring innovation and thorough understanding based on detailed information. Artificial intelligence (AI) principles recommend the use of algorithms for solving complex processes and are included in the diagnostic algorithm of Roussel Uclaf Causality Assessment Method (RUCAM) to help assess causality in suspected cases of idiosyncratic drug-induced liver injury (DILI) and herb-induced liver injury (HILI). From 1993 until the middle of 2020, a total of 95,865 DILI and HILI cases were assessed by RUCAM, outperforming by case numbers any other causality assessment method. The success of RUCAM can be traced back to its quantitative features with specific data elements that are individually scored leading to a final causality grading. RUCAM is objective, user friendly, transparent, and liver injury specific, with an updated version that should be used in future DILI and HILI cases. Support of RUCAM was also provided by scientists from China, not affiliated to any network, in the results of a scientometric evaluation of the global knowledge base of DILI. They highlighted the original RUCAM of 1993 and their authors as a publication quoted the greatest number of times and ranked first in the category of the top 10 references related to DILI. In conclusion, for stakeholders involved in DILI and HILI, RUCAM seems to be an effective diagnostic algorithm in line with AI principles.

9.
Front Med (Lausanne) ; 8: 731436, 2021.
Article in English | MEDLINE | ID: covidwho-1456294

ABSTRACT

Introduction: The severity of COVID-19 may be correlated with the risk of liver injury development. An increasing number of studies indicate that degrees of hepatotoxicity has been associated with using some medications in the management of COVID-19 patients. However, limited studies had systematically investigated the evidence of drug-induced liver injury (DILI) in COVID-19 patients. Thus, this study aimed to examine DILI in COVID-19 patients. Methods: A systematic search was carried out in PubMed/Medline, EMBASE, and Web of Science up to December 30, 2020. Search items included "SARS-CoV-2", "Coronavirus," COVID-19, and liver injury. Results: We included 22 related articles. Among included studies, there was five case report, five case series, four randomizes control trial (RCT), seven cohort studies, and one cross-sectional study. The drugs included in this systematic review were remdesivir, favipiravir, tocilizumab, hydroxychloroquine, and lopinavir/ritonavir. Among included studies, some studies revealed a direct role of drugs, while others couldn't certainly confirm that the liver injury was due to SARS-CoV-2 itself or administration of medications. However, a significant number of studies reported that liver injury could be attributable to drug administration. Discussion: Liver injury in COVID-19 patients could be caused by the virus itself or the administration of some types of drug. Intensive liver function monitoring should be considered for patients, especially patients who are treated with drugs such as remdesivir, lopinavir/ritonavir, and tocilizumab.

10.
J Clin Med ; 10(19)2021 Sep 27.
Article in English | MEDLINE | ID: covidwho-1438648

ABSTRACT

Coronavirus disease 2019 (COVID-19) has a wide spectrum of clinical manifestations. An elevation of liver damage markers has been observed in numerous cases, which could be related to the empirical use of potentially hepatotoxic drugs. The aim of this study was to describe the clinical and analytical characteristics and perform a causality analysis from laboratory signals available of drug-induced liver injury (DILI) detected by a proactive pharmacovigilance program in patients hospitalised for COVID-19 at La Paz University Hospital in Madrid (Spain) from 1 March 2020 to 31 December 2020. The updated Roussel Uclaf Causality Assessment Method (RUCAM) was employed to assess DILI causality. A lymphocyte transformation test (LTT) was performed on 10 patients. Ultimately, 160 patients were included. The incidence of DILI (alanine aminotransferase >5, upper limit of normal) was 4.9%; of these, 60% had previous COVID-19 hepatitis, the stay was 8.1 days longer and 98.1% were being treated with more than 5 drugs. The most frequent mechanism was hepatocellular (57.5%), with mild severity (87.5%) and subsequent recovery (88.1%). The most commonly associated drugs were hydroxychloroquine, azithromycin, tocilizumab and ceftriaxone. The highest incidence rate of DILI per 10,000 defined daily doses (DDD) was with remdesivir (992.7/10,000 DDD). Some 80% of the LTTs performed were positive, with a RUCAM score of ≥4. The presence of DILI after COVID-19 was associated with longer hospital stays. An immune mechanism has been demonstrated in a small subset of DILI cases.

11.
J Clin Exp Hepatol ; 12(1): 247-248, 2022.
Article in English | MEDLINE | ID: covidwho-1401582
12.
J Clin Exp Hepatol ; 11(4): 484-493, 2021.
Article in English | MEDLINE | ID: covidwho-1002704

ABSTRACT

COVID-19 is characterized by predominant respiratory and gastrointestinal symptoms. Liver enzymes derangement is seen in 15-55% of the patients. Advanced age, hypertension, diabetes, obesity, malignancy, and cardiovascular disease predispose them to severe disease and the need for hospitalization. Data on pre-existing liver disease in patients with COVID-19 is limited, and most studies had only 3-8% of these patients. Patients with metabolic dysfunction-associated fatty liver (MAFLD) had shown a 4-6 fold increase in severity of COVID-19, and its severity and mortality increased in patients with higher fibrosis scores. Patients with chronic liver disease had shown that cirrhosis is an independent predictor of severity of COVID-19 with increased hospitalization and mortality. Increase in Child Turcotte Pugh (CTP) score and model for end-stage liver disease (MELD) score increases the mortality in these patients. Few case reports had shown SARS-CoV-2 as an acute event in the decompensation of underlying chronic liver disease. Immunosuppression should be reduced prophylactically in patients with autoimmune liver disease and post-transplantation with no COVID-19. Hydroxychloroquine and remdesivir is found to be safe in limited studies in a patient with cirrhosis and COVID-19. For hepatologists, cirrhosis with COVID-19 is a pertinent issue as the present pandemic will have severe disease in patients with chronic liver disease leading to more hospitalization and decompensation.

13.
J Mol Struct ; 1228: 129433, 2021 Mar 15.
Article in English | MEDLINE | ID: covidwho-846050

ABSTRACT

Traditional medicines contain natural products (NPs) as main ingredient which always give new direction and paths to develop new advanced medicines. In the COVID-19 pandemic, NPs can be used or can help to find new compound against it. The SARS coronavirus-2 main protease (SARS CoV-2 Mpro) enzyme, arbitrate viral replication and transcription, is target here. The study show that, from the electronic features and binding affinity of all the NPs with the enzyme, the compounds with higher hydrophobicity and lower flexibility can be more favorable inhibitor. More than fifty NPs were screened for the target and one terpenoid (T3) from marine sponge Cacospongia mycofijiensis shows excellent SARS CoV-2 Mpro inhibitory activity in comparison with known peptide based inhibitors. The molecular dynamics simulation studies of the terpenoids with the protein indicates that the complex is stable and hydrogen bonds are involved during the complexation. Considering binding affinity, bioavailability, pharmacokinetics and toxicity of the compounds, it is proposed that the NP T3 can act as a potential drug candidate against COVID-19 virus.

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