Effect of butyrate-producing enterobacteria on advanced hepatocellular carcinoma treatment with atezolizumab and bevacizumab.

AIM: Multiple studies have revealed the correlation between gut microbiome and the response to checkpoint inhibitors (CPIs) in patients with cancer, and oral administration of butyrate-producing enterobacteria has been reported to enhance the efficacy of CPIs. However, the effects of enterobacteria on patients with hepatocellular carcinoma (HCC) are not well understood. METHODS: In this retrospective multicenter study, we enrolled 747 patients with advanced HCC, treated with atezolizumab and bevacizumab combination therapy. Tumor response, survival, and adverse effects were compared between 99 patients who ingested drugs containing butyric acid-producing enterobacteria (butyric acid group) and the remaining patients (control group). RESULTS: Objective response and disease control rates in butyric acid group (29.7% and 77.8%, respectively) were higher than those in the control group (26.4% and 72.7%, respectively). However, the differences were not statistically significant (p = 0.543 and p = 0.222, respectively). No difference in median survival time was observed between the two groups (20.0 months and 21.4 months, respectively; p = 0.789), even after matching the backgrounds of the patients with propensity scores (p = 0.714). No adverse effects occurred upon the administration of butyrate-producing bacteria. However, proteinuria (41.4% vs. 30.9%; p = 0.041), fever (17.2% vs. 10.2%, p = 0.036), and diarrhea (15.2% vs. 6.2%; p = 0.001) occurred more frequently in the butyric acid group. CONCLUSION: Butyrate-producing bacteria does not enhance the efficacy of atezolizumab-bevacizumab combination therapy in patients with HCC.

Corticosteroid-refractory autoimmune hepatitis after COVID-19 vaccination: a case report and literature review.

Several vaccines have been developed for coronavirus disease 2019 (COVID-19) and are used worldwide. Here we report a case of severe acute hepatitis induced by COVID-19 vaccination. A 54-year-old woman received two doses of the Pfizer-BioNTech COVID-19 mRNA vaccine and an additional dose of the Moderna COVID-19 mRNA vaccine. Seven days after the third dose, she noticed fatigue, appetite loss and dark urine. Laboratory tests were consistent with severe liver injury and jaundice. Anti-smooth muscle antibody and HLA-DR4 were positive; thus, we suspected that she had autoimmune hepatitis (AIH). Intravenous methylprednisolone followed by oral prednisolone were administered. Because remission was not achieved, we performed percutaneous liver biopsy. Histologically, pan-lobular inflammation with moderate infiltration of lymphocytes and macrophages, interface hepatitis, and rosette formation were present. We regarded these findings as confirmation of the diagnosis of AIH. As she had not responded to corticosteroids, we added azathioprine. Liver biochemistry tests gradually improved, and prednisolone could be tapered without relapse of AIH. Dozens of cases of AIH after COVID-19 vaccination have been reported. Corticosteroids were effective in most cases, but some patients have died from liver failure after vaccination. This case illustrates the efficacy of azathioprine for steroid-refractory AIH induced by COVID-19 vaccination.

Predictive Factors for Recovery from Alcoholic Liver Failure.

Alcoholic liver disease is a risk factor for non-virus-related hepatocellular carcinoma (HCC), which is increasing in prevalence. This study aimed to identify the factors for recovery from alcoholic liver failure. Sixty-two consecutive patients hospitalized for alcoholic liver failure at Okayama City Hospital were enrolled. The characteristics of patients who survived to the 1-month follow-up and whose liver function improved to Child-Pugh A at 3 months (CPA3) and 12 months (CPA12) were compared with the rest of the patients. The survivors at 1 month (50 patients) were significantly younger than the deceased patients and had better liver and renal function with higher levels of γ-glutamyl transferase (GGT). The same factors, except renal function, were correlated with achieving CPA3. High AST, ALT, and GGT levels as well as short spleen length, total abstinence, and good Child-Pugh scores at admission were identified as factors for achieving CPA12. The extent of alcohol intake before admission was not identified as a risk factor in any analysis. In conclusion, baseline liver function is crucial for survival and achieving CPA3, whereas high transaminase and γ-GTP levels, the absence of splenomegaly, and total abstinence are significant factors for achieving CPA12.

Sequential hydrolysis of FAD by ecto-5' nucleotidase CD73 and alkaline phosphatase is required for uptake of vitamin B2 into cells.

Extracellular hydrolysis of flavin-adenine dinucleotide (FAD) and flavin mononucleotide (FMN) to riboflavin is thought to be important for cellular uptake of vitamin B2 because FAD and FMN are hydrophilic and do not pass the plasma membrane. However, it is not clear whether FAD and FMN are hydrolyzed by cell surface enzymes for vitamin B2 uptake. Here, we show that in human cells, FAD, a major form of vitamin B2 in plasma, is hydrolyzed by CD73 (also called ecto-5' nucleotidase) to FMN. Then, FMN is hydrolyzed by alkaline phosphatase to riboflavin, which is efficiently imported into cells. We determined that this two-step hydrolysis process is impaired on the surface of glycosylphosphatidylinositol (GPI)-deficient cells due to the lack of these GPI-anchored enzymes. During culture of GPI-deficient cells with FAD or FMN, we found that hydrolysis of these forms of vitamin B2 was impaired, and intracellular levels of vitamin B2 were significantly decreased compared with those in GPI-restored cells, leading to decreased formation of vitamin B2-dependent pyridoxal 5'-phosphate and mitochondrial dysfunction. Collectively, these results suggest that inefficient uptake of vitamin B2 might account for mitochondrial dysfunction seen in some cases of inherited GPI deficiency.