Case Report: Hepatotoxicity Associated with the Use of Hydroxychloroquine in a Patient with Novel Coronavirus Disease (COVID-19).

Hydroxychloroquine (HCQ) has been used for the treatment of novel coronavirus disease (COVID-19) cases. However, evidence of efficacy remains limited, and adverse events can be associated with its use. Here, we report a case of a patient with severe COVID-19 who, after being administered HCQ, exhibited a 10-fold increase in serum levels of transaminases, followed by a rapid decrease after HCQ was withdrawn. Considering the significantly increased use of HCQ during the COVID-19 pandemic, this case alerts us to the potential for HCQ to be associated with hepatotoxicity and the need to monitor liver function during HCQ therapy.

In December 2019, a severe acute respiratory syndromecoronavirus-2 epidemic was reported in Wuhan, Hubei Province, China. In the months since, the novel coronavirus disease  pandemic has spread to more than 200 countries and caused numerous documented infections. [1][2][3] The high incidence and lethality of COVID-19 have caused tens of thousands of deaths. Approximately 20% of identified cases progress to pneumonia requiring hospitalization, and approximately 5% require treatment in intensive care units (ICUs). 4,5 In the current context of global threat, different therapies are being tested in patients with COVID-19, including antiviral drugs, in an effort to reduce the severity of cases. Among potential therapies, hydroxychloroquine (HCQ) has been used in several countries, despite the limited number of studies published and divergent opinions regarding its use. [6][7][8][9][10][11][12] Importantly, HCQ may be associated with adverse cardiac, ophthalmological, hematological, neurological, musculoskeletal, and gastrointestinal effects, among others. [13][14][15] Here, we describe the case of a patient with severe COVID-19 pneumonia who developed hepatotoxicity associated with the use of HCQ, marked by a 10-fold increase in transaminase levels; these levels rapidly regressed following drug withdrawal.
In view of the increased use of HCQ during the COVID-19 pandemic, this report seeks to warn clinical practitioners and policymakers about the potential for HCQ to be associated with hepatotoxicity and the importance of properly monitoring liver function in patients receiving HCQ therapy.

CASE REPORT
On March 20, 2020, a 29-year-old woman gave birth at term via cesarean delivery. Despite vaginal bleeding in the immediate postpartum period, she soon reached a stable condition with hemoglobin of 7.0 g/dL and was discharged after 2 days. The newborn, weighing 3.900 kg, showed no complications.
On returning home, the patient had contact with her parents, who had recently arrived from the city of Brasilia, Brazil, with symptoms of fever and dry cough. After 5 days of contact, she experienced the first symptoms of the disease, with weakness, dry cough, dyspnea, and an episode of hemoptysis on March 25, 2020.
On day 8 post-delivery (March 28), the patient was admitted to the hospital with severe dyspnea. Chest tomography (CT) showed bilateral pleural effusions, air space opacities, and confluent areas of ground-glass attenuation dispersed in the peripheral and central regions of the lungs ( Figure 1). Angiotomography did not reveal thromboembolism, and a duplex ultrasound venous and arterial scan of the lower limbs and abdominal tomography showed normal findings. However, the patient exhibited a marked increase in D-dimer (8,446 ng/mL), C-reactive protein (270 mg/L), and lactate dehydrogenase (1,000 IU/L), and the reverse transcriptionpolymerase chain reaction (RT-PCR) test result for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) via nasal swab was positive.
On day 2 of hospitalization (March 29), the patient's chest CT showed marked worsening, and after a sharp drop in oxygen saturation requiring mechanical ventilation and supportive measures, she was transferred to the ICU.
At the ICU, on the third day of hospitalization (March 30), the patient received azithromycin and piperacillin-tazobactam. After 3 days in the ICU (day 7 of hospitalization), HCQ at a dose of 400 mg twice per day was prescribed on April 3. One day later, after two doses of HCQ, she exhibited an approximately 10-fold increase in levels of transaminases ( Figure 2). Hydroxychloroquine was immediately discontinued, whereas all other medications in use were maintained. Within 5 days after the suspension of HCQ, her levels of transaminases regressed to near-normal values ( Figure 2). Serum levels of bilirubin, alkaline phosphatase, and gamma-glutamyl trasferase, and prothombin time and kidney function were normal.
At the time of this article's submission (April 12), the patient remained in intensive care but showed progressive improvement in clinical, laboratory, and imaging parameters.
The results of RT-PCR tests performed on the patient's parents, brother-in-law, and newborn were positive. All exhibited mild symptoms.

DISCUSSION
In the case reported, the patient with acute respiratory distress syndrome due to COVID-19 presented with a rapid increase in transaminases after the introduction of HCQ, followed by a rapid reduction after the drug was discontinued.
Hepatic dysfunction and the elevation of liver enzymes have been reported in 30-60% of cases of COVID-19, more frequently in patients admitted to the ICU, albeit with only slight elevations of liver enzymes. [16][17][18][19][20] In a study involving 138 hospitalized patients with COVID-19, elevations in transaminases were higher in ICU patients (P < 0.001), but with a mean value of 52 U/L and a maximum value of 70 U/L. 16 In an analysis of 82 deaths caused by COVID-19, levels of enzymes were normal at admission and increased approximately 24 hours before death, often more significantly for AST, with an average of 74.5 U/L and variations from 35.5 to 184 U/L. 21 In the case reported, the change in liver enzymes did not appear to be due directly to COVID-19. However, we cannot definitively exclude the possibility of other etiologies that may cause hepatic damage in a critically ill patient, such as hypovolemic shock, and the use of other drugs, however, was not observed in this case. The levels of the enzymes were normal in the days before HCQ was introduced and after the drug was withdrawn, and the levels showed a rapid recovery, despite the patient's persistent severe medical condition, without withdrawal or introduction of other drugs.
Although hepatotoxicity in users of HCQ is uncommon, in some clinical conditions, this risk is higher, including patients using this drug with porphyria cutanea tarda or viral hepatitis. [22][23][24][25] Severe liver dysfunction during the use of HCQ is rare, although it has been documented. [26][27][28][29] Makin et al. reported two cases of patients with rheumatological disease, who, after 2 weeks of using 400 mg of HCQ daily, were admitted with fulminant hepatitis; one required liver transplant, and both patients died. 27 A rapid normalization of liver enzymes has been described after the withdrawal of HCQ. 28,29 In another case report, a patient with systemic lupus erythematosus, using 400 mg HCQ daily, had abdominal pain, nausea, vomiting, and diarrhea. There was no evidence of autoimmune disease activity, viral infections were excluded, and the only abnormalities that explained the clinical picture were transaminase elevations alanine aminotransferase 987 U/L and aspartate aminotransferase (AST) 745 U/L. With the withdrawal of the drug, the symptoms regressed and there was a rapid normalization of liver enzymes suggesting drug-induced hepatitis. 28 In another case, Galvañ et al. reported a patient with mixed connective tissue disease who developed fever, abdominal pain, vomiting, and rapid elevation of liver enzymes, with AST 399 U/L within 10 hours after initiation of HCQ therapy. Symptoms resolved and AST returned to basal levels 5 days after the drug's withdrawal. 29 Another factor that may increase the adverse effects of HCQ is the high dose recommended in some protocols for COVID-19. In China, for instance, a described alternative regimen is 500 mg of HCQ twice daily for 7 days, a higher dose than typically used for rheumatological and autoimmune diseases, porphyria cutanea tarda, or malaria prophylaxis, all of which are typically treated with doses of 200-600 mg per day. 10,30 The mechanisms of hepatic injury related to HCQ are poorly established, and toxicity may be due to reactive metabolites and oxidative stress induced by this drug or an idiosyncratic toxic or synergistic effect associated with inflammatory processes. 26,31,32 Referring to an experimental rat model, Nikanahad et al. have suggested that concomitant inflammatory processes, including those induced by infections such as malaria, may increase liver damage caused by antimalarial drugs. 32 Therefore, the potential deleterious synergistic effect of COVID-19 infection and antimalarial drugs needs to be assessed. 33 Although beyond the scope of this discussion, the case also highlights the high degree of transmissibility of SARS-CoV-2, which reached all family members in a short period, all of whom tested positive according to RT-PCR.  In summary, this case report warns of the potential for hepatotoxicity during the COVID-19 pandemic due to the use of HCQ, which has been administered to patients with COVID-19 in many centers, at varied doses and for those with both mild and severe disease. The case draws attention to the need to reinforce the monitoring of liver function soon after HCQ therapy commences and to maintain monitoring during its use.