Drug-induced liver injury and COVID-19: A review for clinical practice

Table 1 Reports of drug-induced liver injury in patients with coronavirus disease 2019 (PubMed/Virtual Health Library)

Ref.	Study/site	Patient profile	Medication	DILI	Outcome
Muhović et al[23]	Case report; Montenegro	Man, 52-yr-old	Chloroquine, lopinavir/ritonavir, methylprednisolone, ceftriaxone and azithromycin. After 6 d: methylprednisolone, ceftriaxone, azithromycin	CIOMS/RUCAM: scored 8 points for a ‘probable’ cause of DILI by TCZ. Hepatocellular form of DILI diagnosed using the EASL guidelines	TCZ had a positive effect on clinical and laboratory parameters, with transaminases values normalizing in 10 d
Zampino et al[24]	Case series; Naples, Italy	None of the 5 treated patients had history of liver disease, visceral obesity, viral hepatitis, or prior hepatotoxic medication or alcohol intake. Liver ultrasound did not show signs of advanced liver disease. Patient 1 and 2 had history of hypertension and asthma	Before and during RDV treatment, 4 of 5 patients alsoreceived hydroxychloroquine patient 2 and 4 received ceftazidime–avibactam plus daptomycin and patient 3 meropenem and linezolid	Significant increase in AST/ALT	Adverse effect neither progressed to severe liver damage nor induced liver failure. In no cases, RDV was discontinued because of liver injury
Durante-Mangoni et al[25]	Case series; Naples, Italy	Four patients	All patients had been previously treated with LPV/r or darunavir/cobicistat (DRV/c) and also received hydroxychloroquine	3 patients experienced ALT and AST increase (5 times to 8 times the upper normal limit)	RDV was prematurely discontinued in patient 1 because of a torsade de pointes requiring cardiac resuscitation and in patient 3 because of death due to multiple organ failure. The study suggests a significant burden of adverse events
Montastruc et al[26]	Cross-sectional study; United States, Europe	387 reports with RDV side effects in VigiBase; 130 hepatic adverse effects, 87 from the United States; 43 from Europe; mostly men (81, 62%), mean age of 54.9 yr	In the majority of cases (122, 94%), RDV was the sole suspected drug	Increased hepatic enzymes (114, 88%), involving AST and ALT in 79 cases (61%) and bilirubin in 4 cases (3%). Other cases were reported as hepatic failure or hepatitis	Most cases were serious (94, 72%), resulting in hospitalization or prolongation of hospital stay. The use of RDV was associated with an increased risk of reporting hepatic disorders
Yamazaki et al[27]	Case reported; Japan	73-yr-old man. History of hypertension, hyperlipidemia, gastric ulcer, benign prostatic hyperplasia, and alcoholic hepatitis	Favipiravir was the suspected drug. Dosage was 6000 mg on day 1 and 2400 mg/d from day 2 onward, for a total of 14 d. Patient was using previously lopinavir/ritonavir combined with interferon β-1b, vancomycin and antithrombin III. After started fapinavir two more drugs were added Trimethoprim-sulfamethoxazole and micafungin	Transaminases were elevated until day 4: Aspartate aminotransferase (AST) from 70 U/L (day 0) to 112 U/L (day 4) and alanine aminotransferase (ALT) from 37 U/L to 59 U/L, respectively. Total bilirubin (T-BiL) increased until day 3 from 5.2 mg/dL to 12.6 mg/dL. On day 11, however, transaminases peaked again (AST, 268 U/L; ALT, 115 U/L) and total bilirubin was also rising	A case of cholestatic liver injury in the early stages of favipiravir treatment for COVID-19. Based on the CIMOS/RUCAM scoring system, it was classified as a cholestatic liver injury, with a score of 6 (possible)
Leegwater et al[28]	Case report; The Netherlands	A 64-yr-old male patient. History of hypertension and hypercholesterolemia	Remdesivir	5 d after start of remdesivir ALT was 1305 IU/L, AST 1461 U/L, alkaline phosphatase 269 U/L, total bilirubin 8 µmol/L, gammaglutamyltransferase 227 U/L and creatine kinase 103 U/L	Remdesivir toxicity was suspected based on the time-relation, the positive dechallenge, the known in vitro toxicity of remdesivir and the absence of alternative causes of hepatotoxicity. After stop of remdesivir the ALT/AST ratio reached normal values

CIOMS/RUCAM: Council for International Organizations of Medical Sciences/Roussel Uclaf Causality Assessment Method; DILI: Drug induce liver injury; EASL: European Association for the Study of the Liver; TCZ: Tocilizumab; RDV: Remdesivir.

Table 2 Hepatotoxicity of the most common drugs used to treat coronavirus disease 2019

Drug	Evidence of hepatotoxicity	Probability
Azithromycin	Liver damage is usually self-limited cholestatic hepatitis, which appears 1 wk to 3 wk after starting treatment. It may also appear after some time following medicine discontinuance. Cholestasis and elevated transaminases can persist for up to 6 mo. Despite presenting the hepatocellular and cholestatic forms of injury, cholestatic is more often related to acute liver failure, death, or liver transplantation	A
Lopinavir/ritonavir	Clinically apparent liver disease occurs in 3% to 10% of patients. The onset of symptoms or jaundice is usually 1 wk to 8 wk, and the pattern of elevations in serum enzymes varies from hepatocellular to cholestatic or mixed. The injury is usually self-limiting; however, fatal cases have been reported	D
Hydroxy-chloroquine	It has not been associated with significant elevations in serum enzymes during therapy for rheumatic diseases. When used in relatively high doses, it can trigger an acute liver injury with a sudden onset of fever and marked elevation of serum enzymes. Post COVID-19 data have not been assessed	C
Tocilizumab	It has been associated with several cases of clinically apparent liver injury with jaundice. Although the liver injury was severe, it was usually self-limiting, with complete recovery within 2 mo to 3 mo. In at least one case, however, the affected patient died of liver failure. Current recommendations are patient monitoring by routine liver tests before medication. In registration trials, serum aminotransferase elevations occurred in a high proportion (10% to 50%) of patients	C
Remdesivir	Between 10% and 50% of patients treated developed transient, mild-to-moderate serum ALT and AST elevations within 1 d to 5 d of starting therapy without changes in serum bilirubin or alkaline phosphatase levels. Elevations above 5 times ULN were reported in up to 9% of patients in several clinical trials, but the abnormalities resolved with discontinuance and were not associated with a clinically apparent injury	D
Nevirapine	Associated with significant elevations in ALT (above 5 times the ULN) in 4% to 20% of patients and symptomatic elevations in 1% to 5%	A
Ivermectin	Associated with minor, self-limiting elevations in serum aminotransferase and sporadic cases of clinically apparent liver damage. Post COVID-19 data have not been assessed	D

Adapted from LiverTox^© database[27]. A: Well know hepatotoxicity; B: Highly likely hepatotoxicity; C: Probably hepatotoxicity; D: Possible hepatotoxicity; COVID-19: Coronavirus disease 2019; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ULN: Upper limit of normal.

Table 3 Hepatoxicity of adjuvant therapy medications for coronavirus disease 2019 treatment

Drug	Evidence of hepatotoxicity	Probability
Heparin	Associated with a transient elevation of 10% to 60%, but the values ​​are generally less than 5 times the upper limit of normal and are rarely associated with symptoms or jaundice. Values ​​above 5 times the upper limit of normal occur around 2% of those receiving high heparin doses	NR
Enoxaparin	Associated with elevations in serum aminotransferases in 4% to 13% of patients, but values ​​greater than 5 times the upper limit of normal are not common and occur in higher doses. The typical liver injury in patients receiving low molecular weight heparins occurred with rapid onset (within 3 d to 5 d of onset), rapid recovery (from 1 wk to 4 wk), and the absence of symptoms and jaundice. Some patients have mild increases in serum bilirubin and alkaline phosphatase but generally remain within the normal range	E
Cortico-steroids	The use of glucocorticoids can result in hepatomegaly and steatosis. They can trigger or worsen non-alcoholic steatohepatitis. Long-term use can also exacerbate chronic viral hepatitis. High doses of intravenous corticosteroids, mainly methylprednisolone, have been associated with acute liver damage resulting in acute liver failure and death. Symptoms and jaundice develop 2 wk to 6 wk after discontinuance. Some cases have progressed to acute liver failure, resulting in death or the need for emergency liver transplantation	A
Voriconazole	Transient elevations in serum aminotransferase levels occur in 11% to 19% of patients on voriconazole. These elevations are generally asymptomatic and self-limited, but approximately 1% of patients require voriconazole discontinuance due to ALT elevations. Cases of acute liver failure have been described. Testing for serum bilirubin and aminotransferase levels is recommended at the time of initiation and weekly during the first month of therapy and monthly thereafter	B
Anidulafungin	Transient elevation of transaminases from 2% to 15%. There are rarely serious cases. Monitoring of liver tests during therapy is recommended, especially in patients with previous liver disease	D
Colchicine	It is rarely associated with elevations in serum aminotransferase or alkaline phosphatase. The cases of acute liver injury attributed to the overdose of colchicine were self-limiting, and the other toxicities of this agent, such as rhabdomyolysis, generally overshadowed the liver injury. No convincing cases of liver failure have been reported	C

Adapted from LiverTox^© database[27]. A: Well know hepatotoxicity; B: Highly likely hepatotoxicity; C: Probably hepatotoxicity; D: Possible hepatotoxicity; E: Unlikely hepatotoxicity; NR: Not reported; ALT: Alanine aminotransferase.