Mycophenolate mofetil for immune checkpoint inhibitor‐related hepatotoxicity relapsing during dose reduction of corticosteroid: A report of two cases and literature review

[Background] Immune checkpoint inhibitors (ICIs) sometimes cause immune-related liver injury, which can lead to cessation of treatment, hospitalization, and even mortality. Although high-dose corticosteroids are usually effective in treatment of ICI-related liver injury, one fifth of affected patients require additional immunosuppressive therapy. It remains uncertain how best to treat ICI-related liver injury that relapses under corticosteroid therapy after temporary remission. [Case] Here we report two cases of ICI-related liver injury successfully treated with mycophenolate mofetil (MMF). In the first case, a 74-year-old man with stage IIIA lung cancer underwent curative chemoradiotherapy. After the second infusion of durvalumab, grade 3 ICI-related liver injury (mixed pattern) developed. In the second case, a 46-year-old man with stage IVB lung cancer received pembrolizumab-containing chemotherapy. After the first cycle, grade 2 ICI-related hepatitis developed. In the both cases, liver injury improved with high-dose prednisolone but relapsed during tapering of the drug. After liver biopsy was performed to confirm the diagnosis of ICI-related liver injury, MMF (2000 mg/day) was added. MMF was effective for both patients and permitted discontinuation or reduction of prednisolone. [Conclusion] MMF appears to be an appropriate treatment option for ICI-related liver injury that respond to high-dose corticosteroids but relapse during steroid tapering

Evaluation of Serum Uric Acid to Creatinine Ratio in Fulminant Hepatitis

Of the eight patients with fulminant hepatitis placed under total parenteral nutrition with an amino acid solution rich in branched chain amino acids and treated by plasma exchange, four survived and four died from hepatic failure. Serum uric acid levels in the non-survived group were significantly lower on days 1-6 compared with the survived group. The concentration ratios of uric acid to creatinine and prothrombin time were significantly lower on days 5-8 and days 3-8, respectively, in a similar comparison. Thus, the uric acid to creatinine ratio, which corrects for the possible renal dysfunction associated with acute hepatic failure, may serve as a clinically useful prognostic indicator for patients with fulminant hepatitis

A ¹⁵N GC/MS Study of in Vivo Glutamine Synthesis in Liver Failure Rats

To clarify the nature of nitrogen metabolism between branched chain amino acid (BCAA) and glutamine (GIn) in liver failure, we measured arterial plasma concentrations of GIn and 15N uptake to amino-N and amide-N of GIn in normal and D-galactosamine-induced fulminant hepatic failure (FHF) rats after 15N-leucine (Leu) injection. Fifteen, 30 and 60 min after Leu injection, the arterial plasma concentrations of GIn were significantly higher in FHF rats than in controls. The concentrations of amino-15N GIn were also significantly higher in FHF rats than in controls at 5, 15, 30 and 60 min after injection. The concentrations of amide-15N GIn did not significantly differ between FHF and controls at 5, 15 and 30 min. However, at 60 min, the concentration was significantly higher in the FHF rats. The higher uptake of 15N to amino-N of GIn in FHF rats suggests the presence of an enhanced ability to synthesize GIn from Leu in FHF rats. The higher uptake of 15N to amide-N of GIn in FHF rats at 60 min after injection suggests that excessive administration of BCAA to patients with severely impaired urea-cycle capacity suffering with hepatic failure may lead to greater levels of hyperammonemia.</p

Administration of a Branched-Chain Amino Acid Preparation during Hepatic Failure: A Study Emphasizing Ammonia Metabolism

We administered a branched-chain amino acid (BCAA) infusion to 16 patients with hepatic failure and two healthy subjects, and then evaluated its effects on ammonia metabolism and amino acid metabolic pool. Immediately after the BCAA infusion, the venous blood ammonia concentration increased in 12 of 15 patients with hepatic failure and in both two healthy subjects. Glutamine (Gln) also rose in all cases following the BCAA infusion, and this rise was particularly marked in the hepatic failure group. The increase in Gln due to the BCAA infusion and the arteriovenous difference in the pre-administration ammonia concentration showed a good correlation. These results suggest an increase in glutamine cycle capacity in patients with hepatic failure. </p

Mortality rate of patients with asymptomatic primary biliary cirrhosis diagnosed at age 55 years or older is similar to that of the general population

Recent routine testing for liver function and anti-mitochondrial antibodies has increased the number of newly diagnosed patients with primary biliary cirrhosis (PBC). This study investigated the prognosis of asymptomatic PBC patients, focusing on age difference, to clarify its effect on the prognosis of PBC patients. The study was a systematic cohort analysis of 308 consecutive patients diagnosed with asymptomatic PBC. We compared prognosis between the elderly (55 years or older at the time of diagnosis) and the young patients (< 55 years). The mortality rate of the patients was also compared with that of an age- and gender-matched general population. The elderly patients showed a higher aspartate aminotransferase-to-platelet ratio, and lower alanine aminotransferase level than the young patients (P < 0.01 and P = 0.03, respectively). The two groups showed similar values for alkaline phosphatase and immunoglobulin M. Death in the young patients was more likely to be due to liver failure (71%), while the elderly were likely to die from other causes before the occurrence of liver failure (88%; P < 0.01), especially from malignancies (35%). The mortality rate of the elderly patients was not different from that of the age- and gender-matched general population (standardized mortality ratio, 1.1; 95% confidence interval, 0.6-1.7), although this rate was significantly higher than that of the young patients (P = 0.044). PBC often presents as more advanced disease in elderly patients than in the young. However, the mortality rate of the elderly patients is not different from that of an age- and gender-matched general population