A 17-year-old girl (weight: 53 kg; height: 160 cm; BMI: 20.70 kg/m2) was admitted to our hospital on 6 July 2020 complaining of dysphoria, fatigue, vomiting, and yellow eyes which began 9 days before admission. She had been treated with a Chinese patent medicine, QubaiBabuqi tablets (4 tablets t.i.d. for more than 3 months) for vitiligo before the onset of the symptoms. Physical examination showed severe jaundice of the skin and sclera, and localized whitish patches on her face. No cardiopulmonary abnormalities were noted. Laboratory studies on July 7 revealed: TBil, 439.60 mumol/L; DBil, 325.70 mumol/L; ALT, 1174 U/L; AST, 505 U/L; gamma-GT, 131 U/L; ALP, 166 U/L; PT, 44.5 s; prothrombin time activity (PTA), 16.00%; INR, 4.84; and blood ammonia, 258 mumol/L. A diagnosis of drug-induced acute liver failure was considered.
The patient developed hepatic encephalopathy and frequent vomiting on day 4, and she was placed on the liver transplant waiting list. She was treated with dexamethasone (10 mg q.d. i.v., gradually decreased after 3 days), liver protection, and NBAL (from July 7 to July 20, once every 3-4 days), and her liver function rapidly improved. After 10 days in a comatose state, she regained consciousness. She continued to have an intermittent low-grade fever on 24 July 2020, and no cough or other symptoms. Her TBil level had increased to 388 mumol/L, and the white blood cell (WBC) count was 12.13 x 109/L with 83.50% neutrophils. Her chest CT scan showed multiple nodules in both lungs on July 26 (Figures 3A,B), and IFI was diagnosed. A loading dose of caspofungin of 70 mg q.d. ivgtt was given on the first day, and then it was continued at a dose of 35 mg/d ivgtt for 23 days. However, a repeat chest CT showed an increase in the number of lung lesions and the presence of an air crescent sign (Figures 3C,D). Bronchoalveolar lavage fluid (BALF), G test, GM test, and next-generation sequencing (NGS) were all negative; however, based on her history and chest CT findings, a diagnosis of IPA was highly likely. Caspofungin was changed to voriconazole (loading dose on D1 of 6 mg/kg daily q12 h ivgtt, maintenance dose of 4 mg/kg q12 h orally was started on D2) on 19 August 2020, and her liver function gradually improved. A liver biopsy on 25 August 2020 was consistent with DILI (G 3-4 S 3-4) (Figures 4A,B). She was discharged on oral voriconazole (250 mg, q12 h), methylprednisolone (4 mg, q.d.), and other medications. A second liver biopsy after 10 weeks revealed an autoimmune-like phenomena hepatitis (G 1-2 S 2-3) (Figures 4C,D). A liver biopsy was performed, and ink staining, periodic acid-Schiff staining, hexamine silver staining, acid-fast staining, and NGS of liver tissue were negative. A diagnosis of DILI was made according to the RUCAM and 2008 IAIHG criteria: (1) DILI, hepatocellular damage-type, acute, RUCAM score calculated as 9 (highly likely); (2) IAIHG score 4, the diagnosis of DILI with autoimmune-like phenomena.
In order to confirm the diagnosis and efficacy, we performed a third liver biopsy a year later (12 August 2021). The liver histopathology indicated chronic hepatitis (G 1 S 2) (Figures 4E,F), which was significantly improved compared with the previous two. No autoimmune-like phenomena were observed. Therefore, we have discontinued glucocorticoids on 18 August 2021. After 406 days of voriconazole treatment, the pulmonary nodules were completely absorbed.
In both patients, serological studies for hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E virus (HEV), and human immunodeficiency virus (HIV) were negative. Laboratory studies for cytomegalovirus nucleic acid (CMV-DNA), Epstein-Barr virus nucleic acid (EBV-DNA), and herpes simplex virus (HSV) IgM antibody were negative. Serum copper, ceruloplasmin, iron, and ferritin levels were normal. Tests of thyroid function and for genetic metabolic liver diseases were normal. Ultrasound scans of the hepatobiliary system did not reveal any abnormalities. MRI plain scan, enhanced MRI scan, magnetic resonance cholangiopancreatography (MRCP), and diffusion-weighted imaging (DWI) of the liver indicated a diffuse liver injury, and no bile duct dilatation was observed on MRCP. Antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), anti-liver and kidney microsomal type 1 antibody (LKM1), anti-hepatocyte cytoplasmic type 1 antibody (LC1), anti-soluble liver antigen antibody (SLA) and immunoglobulin G (IgG), gamma-globulin, G test, GM test, blood cultures, and Cryptococcus capsular antigen tests were performed several times during the course of each patient's disease, and all tests were negative. In both patients, after voriconazole reached a steady state, that is, in the morning of the 4th day or after adjusting the dose for 5 days, in the morning of the 6th day, 30-60 min before fasting medication, the contralateral venous blood was collected to detect the concentration of voriconazole valley, and the therapeutic drug monitoring (TDM) of voriconazole was carried out. The regimen was adjusted according to the clinical situation and voriconazole TDM results (Table 1). The liver pathological examination results were read by two pathologists.