Effects of drugs on liver function
The liver is a principal site for the metabolization and elimination of chemical substances. Besides, it is involved in the metabolism of various drugs, including nucleoside analogs and protease inhibitors, which are currently repurposed for COVID-19 treatment. In addition to the manifestation of COVID-19, drugs implemented in its treatment may aggravate liver injury. Thus, DILI should be further evaluated especially for those patients with underlying liver disease.13 It has remained unclear where the elevated liver enzymes originate from (either the disease or DILI) in this population. It has also been difficult to confirm the direct relationship between a specific drug and liver injury, due to the common combined use of antimalarials, antivirals, antimicrobials, and anticoagulants during COVID-19.14 Finally, inflammatory cytokine storms in severe COVID-19 can result in liver damage.13
Some medications previously used to treat a variety of other diseases, i.e. antivirals (such as LPV/r, remdesivir, ribavirin, favipiravir, umifenovir), antimalarials (chloroquine and hydroxychloroquine), antimicrobials (azithromycin, interferons), and immunomodulators (corticosteroids, tocilizumab) have been the widely repurposed in the fight against COVID-19.15 These drugs have a comparable risk for liver injury (Table 1).10,11,16–37
Table 1Changes in liver functions and liver enzymes in COVID-19 trials
Drugs | Toxicity | Type of toxicity | Reference |
---|
LPV/r | 8.8% | ALT elevation (>3 ULN) | 10 |
| 4.8% | AST elevation (>3 ULN) | |
| 10.3% | GGT elevation (>3 ULN) | |
| 2.6% | Total bilirubin elevation (>3 ULN) | |
| 18.6% | Liver injury | 11 |
| 37.2% | Liver injury | 17 |
| 63.8% | Any adverse drug effect | 16 |
| 57.8% | Elevation is more than the ULN value (ALT, AST, ALP, GGT, and total bilirubin) | 19 |
Umifenovir | 18.1% | Any adverse drug effect | 16 |
Remdesivir | 15.2% | Liver injury | 17 |
| 3.4% | AST elevation | 21 |
| 2.3% | ALT elevation | |
| 7% | ALT elevation | 22 |
| 5.8% | AST elevation | |
| 32% | AST-ALT elevation | 23 |
| 23% | Increased LFTs | 24 |
| 10% | Hyperbilirubinemia | 25 |
| 5% | AST elevation | |
| 2% | ALT elevation leading to discontinuation of remdesivir | |
Ribavirin Favipiravir | No data | Elevation in serum aminotransferases | 18 |
| 2.1-fold | ALT and AST elevation | CPT A | 26–28 |
| 2.0-fold | | CPT B | |
| 3.7-fold | | CPT C | |
Hydroxychloroquine | 10-fold | Elevation in transaminases | 18,20 |
Azithromycin | 1–2% | Elevation in serum aminotransferases | 18 |
Interferons | 25% | ALT and AST elevation, and mildly elevated ALP | 18,19 |
Corticosteroids | N/A | No ADEs for short duration | 18,32,33 |
Convalescent plasma (antibody) | N/A | No detailed information | 28,34 |
Tocilizumab | Mild | Liver enzyme elevation | 18,29–31 |
Acetaminophen | 48%max | Dose-related hepatotoxicity | 35–37 |
Cai et al.10 demonstrated that patients under LPV/r had higher total bilirubin and GGT levels during hospitalization. In a study by Sun et al.,16 evaluating adverse drug events (ADEs) in 217 COVID-19 patients, ADEs were associated with LPV/r and umifenovir, at rates of 63.8% and 18.1%, respectively; in addition, liver system disorders were the most frequently observed ADEs, after gastrointestinal disorders. In a meta-analysis,17 the pooled incidence of DILI among COVID-19 patients was 25.4%; DILI occurred in 37.2% and 15.2% of COVID19 patients receiving LPV/r and remdesivir, respectively.
Interferon-β is produced by recombinant technology and is a cytokine with antiviral, immunomodulatory and antiproliferative properties. Interferon-β is available in three subtypes – 1a, 1b and pegylated β-1a – and all are approved for use in multiple sclerosis by either subcutaneous or intramuscular administration.38 All forms of interferon-β may also induce liver injury, though most of such cases are mild and even asymptomatic. Interferon-related DILI is transient, with mild elevations in serum aminotransferases (ALT and AST), and with normal or mildly elevated ALP levels.18 Whereas, LPV/r treatment had a higher rate of enzymes elevation (56% vs. 25%).19
LPV/r administration will induce moderate to severe elevations in serum aminotransferase levels (>5×ULN). Low-dose ritonavir has less impact on the frequency or severity of LFT elevations. Additionally, ritonavir has some properties similar to an enzymatic inhibitor and it can increase the serum level of co-administered drugs, resulting in a higher risk of hepatotoxicity.18
Hydroxychloroquine and chloroquine are antiviral/immune modulators that are used for the treatment and prophylaxis of malaria, rheumatoid arthritis, lupus erythematosus, photodermatosis, and liver amoebiasis. Hydroxychloroquine is metabolized by several CYP enzymes in the liver, with desethylhydroxychloroquine being an active metabolite. The USA’s Food and Drug Administration’s prescribing information cautions use in patients with existing liver disease and/or concomitant use with hepatotoxic drugs.39,40 Hydroxychloroquine is known to accumulate in the liver.41 and animal studies have shown that accumulation occurs rapidly, in the first 2 weeks of treatment.42 However, hydroxychloroquine was found to have a low hepatic extraction ratio, indicating that a reduction in liver blood flow in cirrhosis may not directly result in increased exposure to the drug.43 Hydroxychloroquine is also known to be hydrophilic,44 and this should be a consideration in patients with ascites and decompensated cirrhosis. Based on these lines of evidence, hydroxychloroquine is regarded as a possible but rare cause of DILI.18 Falcao et al.20 reported a severe COVID-19 patient who showed a 10-fold increase of transaminases after using hydroxychloroquine, which returned to normal levels after withdrawal of the drug.
Remdesivir is a nucleotide analog for treatment of hepatitis C virus, used formerly.45,46 Currently, data regarding hepatotoxicity of remdesivir is inadequate to draw firm conclusions. There was no liver injury in LiverTox,18 and liver toxicity data were not reported in Ebola trials; however, abnormal liver enzyme profiles are common during Ebola infection, making it difficult to rule-out accompanying drug-induced liver toxicity.47–49 The specificity of the cyano group in the remdesivir molecule allows for it to avoid inhibition by the host mitochondrial DNA polymerase and consequently limits the potential risk for lactic acidosis or mitochondrial toxicity. LFT elevations have varied widely among trials of remdesivir, accounting for 1% to 32% of participants.21–23 LFT elevation rate was 23% among 53 patients, which led to remdesivir discontinuation in two patients, while bilirubin elevation was not detected in that trial.24 Wang et al.25 showed that hypoalbuminemia, hyperbilirubinemia, and AST elevation were present in 13%, 10%, and 5% of patients treated with remdesivir, respectively; also, in the remdesivir group, three patients discontinued treatment due to ALT elevation. Sabers et al.50 reported that a patient presented with high liver enzymes (≥20×ULN) and had received remdesivir; eventually, the patient’s liver enzymes improved through the course of the disease and they were discharged on day 10 of hospitalization.
There is a theoretical risk of P-glycoprotein interaction with remdesivir. Inhibition of P-glycoprotein with comedications reduces efflux of remdesivir from hepatocytes, raising cellular remdesivir concentration to supratherapeutic levels. However, the occurrence of this interaction is very low, because of remdesivir being the minor substrate of P-glycoprotein, as well as its short half-life.51 In the recent case report by Carothers et al.,52 the benefit of acetylcysteine continuous infusion was investigated in acute liver injury related to remdesivir. Both of the two patients investigated showed significant increases in transaminase levels with coagulopathy and encephalopathy in response to remdesivir therapy; the continuous infusion of acetylcysteine rapidly resolved the high transaminase levels in these patients.
Favipiravir is a type of RNA-dependent RNA polymerase (RdRp) inhibitor. It presumably acts as a nucleotide analog that selectively inhibits the viral RdRp or causes lethal mutagenesis upon embedding into the virus RNA.53–57 Favipiravir, when used for the treatment of influenza, is administered at a dose of 1600 mg twice daily on day 1, followed by 600 mg twice daily on days 2–5. Besides being a treatment for influenza virus,58 favipiravir has shown potent antiviral activity against other segmented negative-strand RNA viruses in both in vitro and in vivo studies.59,60 Furthermore, some positive-strand RNA viruses can also be inactivated by favipiravir,61,62 and the virus replication process can be interfered with by the drug’s competition with purine nucleosides, as has been shown to consequently inhibit the viral RdRp of SARS-CoV-2.26 Studies have also shown that favipiravir administration provides better prognosis in COVID-19 patients in terms of disease progression and viral clearance.27 ALT and AST elevation is just a possible adverse effect of favipiravir, however no data are available in cirrhosis patients.28
Tocilizumab is a monoclonal antibody against the interleukin-6 (IL-6) receptor, which is usually used to treat the cytokine storm that occurs in the advanced stages of the disease.63 Though small series and case reports suggest its beneficial effects, it was not proven in randomized controlled trials.29,64,65 Tocilizumab administration can lead to liver enzyme elevation but rarely to severe liver injury.18 Recently, a patient with COVID-19 was reported on due to their transaminase levels increasing 40-fold after 24 h of initiation of tocilizumab administration.66 Tocilizumab may pose a risk of hepatitis B virus (HBV) reactivation, thereby causing risk of indirect liver damage.67 A study predicted that patients with severe COVID-19 and resolved HBV under immune modulator treatment had a low risk for HBV reactivation, and recommended that patients without antibodies to hepatitis B surface antigen (anti-HBs) be followed-up after discharge, if possible, and suggested that a short course of antiviral prophylaxis may be preferred. No hepatitis B surface antigen seroreversion was detected in their cohort and only two (3%) patients had detectable serum HBV-DNA.30 In another study, liver injury was observed in COVID-19 patients with or without chronic HBV. Also, three patients experienced hepatitis B reactivation. Thus, monitoring of LFTs and HBV-DNA levels was recommended in COVID-19 patients treated with tocilizumab.31
Furthermore, membrane transporters localized on the cell membrane, especially those on tissues in the central organ for drug metabolism, such as the liver, can effectively influence pharmacokinetic characteristics and ADEs. Canalicular ABC transporters in hepatocytes, such as ABCC2/MRP2, ABCG2/BCRP, ABCB1/MDR1/P-gp and ABCB11/BSEP, mediate the extrusion of endo- and xenobiotics into the bile. P-gp, MRP2 and ABCG2 are multispecific transporters mediating the efflux of hydrophobic or partially detoxified amphiphilic compounds. MRP2 is the key transporter for bilirubin conjugates. The SLC-type transporter MATE1 in the hepatocyte canalicular membrane mainly transports cationic drugs, but also some zwitterionic and anionic molecules,68,69 and mediates their biliary excretion. Inhibition of these drug exporters may cause elevated liver toxicity, such as cholestasis or DILI. All of the above repurposed drugs have various effects in inducing DILI through the special inhibition to transporters. A recent study showed that lopinavir and ritonavir, given in low micromolar concentrations, inhibited BSEP and MATE1 exporters as well as OATP1B1/1B3 uptake transporters. Ritonavir had a similar inhibitory pattern but also inhibiting OCT1. Specifically, remdesivir strongly inhibited MRP4, OATP1B1/1B3, MATE1 and OCT1. Favipiravir had no significant effect on any of these transporters.70
Corticosteroid is used in the treatment of a variety of inflammatory and autoimmune conditions. It is used at a wide range of doses, ranging from 0.5 to 80 mg daily.71 Other glucocorticoids, including prednisolone, are used regularly for patients with significant liver disease in the treatment of autoimmune and alcoholic hepatitis, including for patients with cirrhosis, acute liver failure, ALT/AST >10×ULN and post-liver transplant.72,73 Dexamethasone is metabolized in the liver via CYP3A4,74 and has very limited influence in hepatic impairment, though its half-life is prolonged in severe liver disease.71 Corticosteroid treatments are associated with hepatic steatosis, hepatic glycogenosis, and hepatic enlargement.18 Corticosteroids can also promote hepatic gluconeogenesis, reduce peripheral use of glucose, and increase insulin levels consequently. Glucocorticoids have a pro-adipogenic function of increasing deposition of abdominal fat, and leading to glucose intolerance and hypertriglyceridemia. In addition, these drugs play a role in controlling liver metabolism and can lead to the development of hepatic steatosis.32 But, in COVID-19 patients, this effect is unlikely to be significant given the very low dose (6 mg daily) and short duration.33 Although toxicities that may arise in long-term use are not a problem for COVID-19 patients, it should be considered that there are short-term risks, such as HBV reactivation.30
Convalescent plasma has shown a potential therapeutic effect, with low risk for the treatment of severe COVID-19 patients.34 At the same, there are still few experiences of convalescent plasma therapy in COVID-19 patients with chronic liver disease.28
Azithromycin is a macrolide antibiotic used in treatment of various infections, such as community-acquired pneumonia, bronchitis, soft tissue infections and uncomplicated genital infections due to Chlamydia trachomatis and Neisseria gonorrhoeae. The liver is the main site for metabolism of azithromycin and 50% is excreted unchanged in the bile, although some inactive metabolites are also found.35 A previous study demonstrated that azithromycin has an association with a low rate of acute, transient, and asymptomatic elevations in serum aminotransferases, occurring in 1% to 2% of patients treated for short periods.18 This drug can, thus, be exempted for further evaluation when used in COVID-19 patients, especially with low dose and short duration.
Ribavirin is a guanosine nucleoside analogue, approved for use in combination with direct acting antivirals or pegylated-interferon 2a or 2b for treatment of hepatitis C. In the treatment of hepatitis C, ribavirin is given orally and is dosed dependent on weight, ranging from 800 mg to 1200 mg daily. However, it has not been associated with serum aminotransferase elevations. Ribavirin treatment is usually used in COVID-19 patients with underlying liver disease; however, it is difficult to interpret increases in serum aminotransferase levels during therapy.18
Because of the fever and pain experienced by COVID-19 patients, several medicines agencies have warned physicians against the excessive use of non-steroidal anti-inflammatory drugs (NSAIDs), while the acetaminophen (paracetamol) was strongly recommended.35 However, this recommendation could possibly result in the misuse of acetaminophen and consequently increase liver injury. Acetaminophen use is associated with generally mild ADEs, such as hepatitis, cholestasis, or other nonspecific liver enzyme elevation, but acetaminophen-induced hepatotoxicity is mostly estimated to account for 48% of acute liver injury diagnoses, providing caution for acetaminophen-caused dose-related hepatotoxicity.36,37
Another important point is the potential drug-drug interactions (DDIs) between the drugs used in patients with transplantation (such as tacrolimus and steroids) and COVID-19. These DDIs may also indirectly increase the risk of hepatotoxicity if the effect of the immunosuppressive or the COVID-19 drug were to become altered pharmacodynamically or pharmacokinetically.75
Recommendation on drug use in liver injury
Liver injury can change metabolism, excretion, dosing, and expected concentrations of drugs, which may make it difficult to achieve an effective therapeutic dose or can increase the risk of ADEs.76
Acute liver injury has been commonly defined by the ULN of serum ALT, ALP, and serum concentration of total bilirubin based on the biological criteria, that is, elevation of ALT ≥5×ULN or ALP ≥2×ULN, or combination of ALT ≥3×ULN with a simultaneous total bilirubin concentration exceeding 2 ×ULN.77,78
Till now, the pharmacokinetics of remdesivir have not been evaluated in patients with hepatic injury. Hence, the hepatic function should be monitored in all patients before initiating and during daily treatment with remdesivir. Currently, remdesivir is not recommended in patients with ALT ≥5×ULN at baseline. It should be discontinued if ALT rises to higher than 5×ULN during treatment or if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, ALP, or INR, however, this therapy can be restarted if ALT is less than 5×ULN79,80
Since hydroxychloroquine commonly accumulates in the liver, it is recommended to monitor LFTs continuously and administrate it cautiously with concurrent hepatotoxic drugs.81 It is also recommended that LFTs should be closely monitored for each patient while initiating tocilizumab; if ALT or AST are higher than 1.5×ULN, the treatment needs to be discontinued immediately.82
Since LPV/r is primarily metabolized by the liver, it is recommended to evaluate patient response and use with caution in case of liver injury. Although there is no need to reduce the dose for mild to moderate hepatic injury, frequent monitoring of LFTs is strongly recommended.33 LPV/r administration has not been studied in patients with severe hepatic injury and its use is contraindicated.83
Azithromycin is eliminated predominantly in liver, and as such it should be used with caution due to its potential risk of hepatotoxicity and it should be avoided in patients with severe liver disease. A study has demonstrated that azithromycin pharmacokinetics do not differ consistently in patients with Child-Pugh A or B cirrhosis, in comparison with healthy volunteer; therefore, dosage modification is not required in these patient groups.84 No difference in single-dose pharmacokinetics of ribavirin was noted in patients with mild, moderate, or severe hepatic dysfunction (Child-Pugh score A, B, or C).85 Full-dose ribavirin can be used in severe hepatic dysfunction with caution; mild and moderate hepatic dysfunction associated renal impairment are suggested to make a proper dose reduction based on estimated glomerular filtration rate (eGFR).33 Alteration of favipiravir dose is not recommended in mild and moderate hepatic impairment (Child-Pugh A and B), while it should be considered in severe hepatic injury (Child-Pugh C).33
Altogether, the detailed information of these repurposed drugs for COVID-19 treatment, including the family of the drug, the mode of action, and the possible mechanism by which it induces liver injury, are presented in the Table 3.10,16–25,50–52,27–37,63–67
Table 3Four categories of repurposed drugs for COVID-19 treatment and their detailed information
Drug category | Drug | Dose recommendation | Metabolism | Reference |
---|
I. Anti-malarial/anti-parasitic drugs | Hydroxychloroquine | Maximum dosage based on minimal data and risk of hepatotoxicity | Major: CYP3A4/5, Minor: CYP2D6, CYP2C8 | 18,20 |
II. Drugs used for rheumatoid arthritis | Hydroxychloroquine | | | |
| Tocilizumab | In patients with baseline ALT or AST >5×ULN, treatment is not recommended | Catabolic pathway | 18,63,29,64,65,66,67,30,31 |
| corticosteroids | / | Hydroxylation via CYP3A4, followed by glucuronidation or sulfation | 30,32,33 |
| Interferon-β | Caution if ALT >2.5×ULN, Dose reduction advised if ALT >5×ULN | Metabolized and excreted by liver and kidneys | 18 |
| Azithromycin | Discontinue if signs of hepatic dysfunction | Liver: 35% to inactive metabolites | 18 |
III. Anti-retroviral/anti-viral drugs | LPV/r | Use with caution in mild to moderate hepatic impairment and monitor for toxicities | CYP3A4/5, auto-induction own metabolism; stabilization after 10–16 days | 10,16,17,18,19 |
| Remdesivir | Discontinuation: ALT >5×ULN or ALT elevation | In vitro: CYP2C8 CYP2D6, CYP3A4, OATP1B1, P-gp substrate | 17,18,21–25,50,51,52 |
| Favipiravir | Dose adjustment should be considered | Extensive metabolism by hydroxylation (aldehyde oxidase and xanthine oxidase) to M1 and M2 | 27,28 |
| Ribavirin | Discontinue if progressive and clinically significant ALT rises, despite dose reduction, or accompanied by increased bilirubin | Intracellular phosphorylation by adenosine kinase to ribavirin mono-, di-, and triphosphate metabolites | 18 |
IV. Others | Acetaminophen | / | / | 35–37 |
| Convalescent plasma (antibody) | / | / | 28,34 |