Patient with Pleural Mesothelioma and Direct Bilirubin-predominant Constitutional Jaundice Treated with a Combination of Nivolumab and Ipilimumab

Background. Patients with pleural mesothelioma and constitutional jaundice characterized by predominantly elevated direct bilirubin (DBL) are treated with a combination of nivolumab (Nivo) and ipilimumab (Ipi). Case. A 73-year-old man visited our hospital with a chief complaint of right pleural effusion. Constitutional jaundice with DBL predominance (total bilirubin [TBL] 3.3 mg/dl, DBL 2.2 mg/dl) had been observed for an extended time. A pleural biopsy confirmed the diagnosis of pleural mesothelioma. The tumor was judged to be unresectable, and combination therapy with Nivo and Ipi was initiated. Immediately prior to administration of therapy, TBL was 1.8 mg/dl, DBL was 1.6 mg/dl, aspartate aminotransferase (AST) was 13 U/l, and alanine aminotransferase (ALT) was 15 U/l. Two weeks after the administration, the patient complained of a fever and general fatigue. Hepatic impairment appeared on day 21 after administration. TBL was 16.4 mg/dl, DBL was 13.0 mg/dl, AST was 2,289 U/l, ALT was 1,594 U/l, prothrombin (PT) activity was 16%, and ammonia (NH3) was 151 μg/dl. The patient was diagnosed with immune checkpoint inhibitor (ICI)-induced liver injury. Oral prednisolone (PSL) 60 mg (1 mg/kg) was administered. On day 9 after ICI-induced liver injury, TBL rose to 26.1 mg/dl and DBL to 19.7 mg/dl. However, AST decreased to 236 U/l, ALT to 434 U/l, NH3 to 91 μg/dl, and PT activity rose to 31%. By day 38 of ICI-induced liver injury, AST, ALT, and PT levels were normal. A liver biopsy performed on day 125 of ICI-induced liver injury showed no dark melanin-like pigments in the hepatocytes. On day 211 following the onset of ICI-induced liver injury, the TBL and DBL levels returned to pre-treatment levels. Conclusions. A patient with DBL-predominant constitutional jaundice developed ICI-induced liver injury. After the administration of PSL, the AST and ALT levels improved immediately, but jaundice persisted.