A 44-year-old man patient was admitted to another hospital for hemoptysis and diagnosed with pulmonary aspergillosis based on the pathological result (Figure 1). The patient had a history of old tuberculosis and chronic gastritis, not currently treated with any medication. Subsequently, the patient was admitted to Tongji Hospital for fungal infection and started antifungal treatment with a standard dose (200 mg twice daily) of intravenous voriconazole for one week without liver enzyme abnormalities (Figure 2). After discharge, he was prescribed oral voriconazole at the same dose.  
After six weeks, severe hepatotoxicity with significant liver enzyme elevations was found at the first liver function test, including alanine transaminase (ALT) [899U/L (<=41 U/L)], aspartate transaminase (AST) [821 U/L (<=40 U/L)], alkaline phosphatase (ALP) [256 U/L (40~130U/L)], and gamma-glutamyl transpeptidase (gamma-GGT) [451 U/L (10~71U/L)]. It was worth noting that the patient has not received any other medications recently, including herbal products or dietary supplements, besides voriconazole. Therefore, he was advised to discontinue voriconazole due to consideration of voriconazole-induced hepatotoxicity and elevations of ALT and AST more than five times the upper limit of normal (ULN). After five days, liver enzymes slightly declined, including ALT (826 U/L), AST (598 U/L), ALP (227 U/L), and gamma-GGT (427 U/L). As a result, the patient was re-admitted to our hospital with hepatic insufficiency.
After admission, laboratory tests revealed increased levels of ALT (879 U/L), AST (529 U/L), ALP (219 U/L), gamma-GGT (410U/L), direct bilirubin [16.7 mumol/L (<=8.0 mumol/L)], lactate dehydrogenase [409 U/L (135~225 U/L)], 5'-nucleotidase [11.2 U/L (<=10 U/L)], alpha-L-fucosidase [52 IU/L (5~40 IU/L)], and blood ammonia [91 mumol/L (16~60 mumol/L)]. The patient was then given hepatoprotective medications for injection (Polyene Phosphatidylcholine, Glutathione, Compound Ammonium Glycyrrhetate S) and Micafungin Sodium for injection (150 mg once daily). Some examinations, including ultrasound and tests for viral hepatitis and autoimmune liver diseases, revealed no abnormalities except for small cysts. Serum ceruloplasmin was within the normal range [0.49 g/L (0.22~0.58 g/L)]. After eight days of discontinuation and three days of treatment, the patient was discharged with a significant decline of liver enzymes, including ALT (350 U/L), AST (100 U/L), ALP (145 U/L) and gamma-GGT (309 U/L). The blood ammonia also returned to normal (58 mumol/L).
Based on the above information and the Roussel-Ucalaf Causality Assessment Method (RUCAM), the patient scored six points, indicating a "probable" drug-induced liver injury (DILI). According to the judgment criteria of the Council for International Organizations of Medical Sciences (CIOMS), the type of liver injury in the patient was characterized as a mixed hepatocellular-cholestatic injury due to ALT >= 3 ULN, ALP >= 2 ULN, and 2 < R < 5 (the R-value was obtained by dividing the ratio of the measured ALT value to the ULN of ALT by the ratio of the measured ALP value to the ULN of ALP).
After discharge, the patient was advised to continue hepatoprotective therapy and to follow up regularly. One week later, liver enzymes declined further, including ALT (123 U/L), AST (69 U/L), APL (116 U/L), and gamma-GGT (225 U/L). Then the patient was prescribed posaconazole suspension at 100 mg once daily due to concerns about the same adverse event. Fortunately, liver enzymes remained progressively lower after two weeks. But posaconazole trough concentrations were below the therapeutic range (>=1.0 mug/mL) according to weekly therapeutic drug monitoring (TDM) (Figure 2). Hence, he was prescribed posaconazole suspension at 100 mg twice daily starting the third week. The trough concentration reached 1.17 mug/mL, within the therapeutic range. All liver enzymes returned to normal after three weeks and to the baselines after five weeks. During antifungal therapy, the patient's symptoms gradually resolved, and chest computed tomography (CT) showed gradual resorption of the lesion in the upper lobe of the right lung (Figure 3). 
However, the patient strongly requested antifungal therapy with the remaining previous voriconazole for his family economy. Considering its safety, the patient was advised to take oral voriconazole at 50 mg twice daily. One week later, liver enzyme elevations, including ALT (111 U/L) and AST (60 U/L), were found again, suggesting intolerance to voriconazole. Therefore, according to the RUCAM scoring scale, the patient scored an additional three points for nine points, indicating a "high probable" DILI. Meanwhile, the TDM of voriconazole revealed a trough concentration of 0.32 mug/mL (reference range: 1~5.5 mug/mL). The pharmacogenetic test showed that the patient was a normal metabolizer with a genotype of CYP2C19*1/*1 and could be treated with the standard dose of voriconazole. Finally, the patient discontinued voriconazole and was prescribed posaconazole suspension at 100 mg twice daily for continuous antifungal treatment. Liver enzymes returned to the baselines after two weeks.