Hepatocellular carcinoma with gastric adenocarcinoma treated with atezolizumab and bevacizumab.

Atezolizumab and bevacizumab combination therapy might be one of the treatment options for hepatocellular carcinoma concurrent with gastric adenocarcinoma.

[Liver injury in patients with moderate II COVID-19 who received dexamethasone monotherapy].

We examined 171 patients with novel coronavirus disease 2019 (COVID-19) with liver injury in the respiratory failure groups and the nonrespiratory failure groups and investigated 41 patients with moderate II COVID-19 with respiratory failure who received dexamethasone (Dex) monotherapy in the liver injury group and the nonliver injury group at the time before treatment. The respiratory failure group had 64% more liver damage than the nonrespiratory failure group, was older, had more men, and had significantly more complications from lifestyle-related diseases such as hypertension and diabetes. Obesity was more common in the liver injury group prior to Dex monotherapy, and the liver CT value was significantly lower than in the nonliver injury group. Liver injury worsened in 41% of patients after Dex monotherapy, but there was no significant difference in the frequency before Dex monotherapy between the liver injury group and the nonliver injury group, and the degree of liver injury was mild in all cases, improving in 38% of the liver injury group. Dex monotherapy was a safe treatment for moderate II COVID-19, which frequently resulted in liver injury.

Adolescents with chronic hepatitis C might be good candidates for direct-acting antiviral therapy.

Three Japanese adolescents with chronic hepatitis C were treated by direct-acting antivirals (DAAs). No adverse events or laboratory abnormalities were observed during and after DAA therapy, and a sustained virological response was achieved in all cases. The emotional functioning of the patients and their mothers were improved after DAA therapy.

Successful treatment of Japanese hemophilia patient co-infected with HIV and HCV genotype 4a by glecaprevir/pibrentasvir therapy.

Although direct-acting antiviral (DAA)-based anti-hepatitis C virus (HCV) therapies are very effective for patients with genotypes 1 and 2, evidence of the efficacy of DAA-based therapy for the special population of patients with genotypes 3-6 is insufficient due to the relatively small number of these subjects in Japan. Human immunodeficiency virus (HIV)/HCV-co-infected patients are recommended to be treated as HCV-mono-infected patients by the latest version of the Japan Society of Hepatology guidelines. However, evidence of efficacy in patients with HIV/HCV genotype 3-6 co-infection is insufficient. Currently, HCV genotypes 3-6 can be treated with two DAA-based therapies, including glecaprevir (GLE)/pibrentasvir (PIB) therapy in Japan. We experienced a relatively rare case of a Japanese hemophilia patient co-infected with HIV/HCV genotype 4a. We evaluated resistance-associated substitutions (RASs) against GLE and PIB before GLE/PIB therapy and found that he had no RASs. He was treated with 12 weeks of GLE/PIB therapy and achieved a sustained virologic response at post-treatment weeks 24. Although the treatment was well tolerated, the patient developed hyper-low-density lipoproteinemia that was probably associated with HCV elimination during the therapy. Additional studies are needed to confirm the efficacy and safety of GLE/PIB therapy for this special population in Japan.

Disordered branched chain amino acid catabolism in pancreatic islets is associated with postprandial hypersecretion of glucagon in diabetic mice.

Dysregulation of glucagon is associated with the pathophysiology of type 2 diabetes. We previously reported that postprandial hyperglucagonemia is more obvious than fasting hyperglucagonemia in type 2 diabetes patients. However, which nutrient stimulates glucagon secretion in the diabetic state and the underlying mechanism after nutrient intake are unclear. To answer these questions, we measured plasma glucagon levels in diabetic mice after oral administration of various nutrients. The effects of nutrients on glucagon secretion were assessed using islets isolated from diabetic mice and palmitate-treated islets. In addition, we analyzed the expression levels of branched chain amino acid (BCAA) catabolism-related enzymes and their metabolites in diabetic islets. We found that protein, but not carbohydrate or lipid, increased plasma glucagon levels in diabetic mice. Among amino acids, BCAAs, but not the other essential or nonessential amino acids, increased plasma glucagon levels. BCAAs also directly increased the intracellular calcium concentration in α cells. When BCAAs transport was suppressed by an inhibitor of system L-amino acid transporters, glucagon secretion was reduced even in the presence of BCAAs. We also found that the expression levels of BCAA catabolism-related enzymes and their metabolite contents were altered in diabetic islets and palmitate-treated islets compared to control islets, indicating disordered BCAA catabolism in diabetic islets. Furthermore, BCKDK inhibitor BT2 suppressed BCAA-induced hypersecretion of glucagon in diabetic islets and palmitate-treated islets. Taken together, postprandial hypersecretion of glucagon in the diabetic state is attributable to disordered BCAA catabolism in pancreatic islet cells.

The first reported case of Noonan syndrome complicated with hepatocellular carcinoma.

Noonan syndrome is a genetic multisystem disorder and is associated with mutation of genes encoding the proteins in the RAS-MAPK pathway. We reported the first case of Noonan syndrome complicated with hepatocellular carcinoma.

Ipragliflozin-induced improvement of liver steatosis in obese mice may involve sirtuin signaling.

BACKGROUND: Sodium glucose cotransporter 2 (SGLT2) inhibitors are newly developed oral antidiabetic drugs. SGLT2 is primarily expressed in the kidneys and reabsorbs approximately 90% of the glucose filtered by the renal glomeruli. SGLT2 inhibitors lower glucose levels independently of insulin action by facilitating urinary glucose excretion. The SGLT2 inhibitor ipragliflozin has reportedly improved liver steatosis in animal models and clinical studies. However, the mechanisms by which SGLT2 inhibitors improve liver steatosis are not fully understood. AIM: To investigate the ameliorative effects of ipragliflozin on liver steatosis and the mechanisms of these effects in obese mice. METHODS: We analyzed 8-wk-old male obese (ob/ob) mice that were randomly divided into a group receiving a normal chow diet and a group receiving a normal chow diet supplemented with ipragliflozin (3 mg/kg or 10 mg/kg) for 4 wk. We also analyzed their lean sex-matched littermates receiving a normal chow diet as another control group. Body weight and liver weight were evaluated, and liver histology, immunoblotting, and reverse transcription-polymerase chain reaction analyses were performed. RESULTS: Hepatic lipid accumulation was significantly ameliorated in ob/ob mice treated with 10 mg/kg ipragliflozin compared to untreated ob/ob mice irrespective of body weight changes. Ipragliflozin had no appreciable effects on hepatic oxidative stress-related gene expression levels or macrophage infiltration, but significantly reduced hepatic interleukin-1ß (IL-1ß) mRNA expression levels. Ipragliflozin increased both the mRNA and protein expression levels of sirtuin 1 (SIRT1) in the liver. The hepatic mRNA levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), peroxisome proliferator-activated receptor α (PPARα), and fibroblast growth factor-21 (FGF21) were also significantly higher in ipragliflozin-treated ob/ob mice than in untreated ob/ob mice. CONCLUSION: Our study suggests that the liver steatosis-ameliorating effects of ipragliflozin in ob/ob mice may be mediated partly by hepatic SIRT1 signaling, possibly through the PGC-1α/PPARα-FGF21 pathway.

SGLT1 in pancreatic α cells regulates glucagon secretion in mice, possibly explaining the distinct effects of SGLT2 inhibitors on plasma glucagon levels.

OBJECTIVES: It is controversial whether sodium glucose transporter (SGLT) 2 inhibitors increase glucagon secretion via direct inhibition of SGLT2 in pancreatic α cells. The role of SGLT1 in α cells is also unclear. We aimed to elucidate these points that are important not only for basic research but also for clinical insight. METHODS: Plasma glucagon levels were assessed in the high-fat, high-sucrose diet (HFHSD) fed C57BL/6J mice treated with dapagliflozin or canagliflozin. RT-PCR, RNA sequence, and immunohistochemistry were conducted to test the expression of SGLT1 and SGLT2 in α cells. We also used αTC1 cells and mouse islets to investigate the molecular mechanism by which SGLT1 modulates glucagon secretion. RESULTS: Dapagliflozin, but not canagliflozin, increased plasma glucagon levels in HFHSD fed mice. SGLT1 and glucose transporter 1 (GLUT1), but not SGLT2, were expressed in αTC1 cells, mouse islets and human islets. A glucose clamp study revealed that the plasma glucagon increase associated with dapagliflozin could be explained as a response to acute declines in blood glucose. Canagliflozin suppressed glucagon secretion by inhibiting SGLT1 in α cells; consequently, plasma glucagon did not increase with canagliflozin, even though blood glucose declined. SGLT1 effect on glucagon secretion depended on glucose transport, but not glucose metabolism. Islets from HFHSD and db/db mice displayed higher SGLT1 mRNA levels and lower GLUT1 mRNA levels than the islets from control mice. These expression levels were associated with higher glucagon secretion. Furthermore, SGLT1 inhibitor and siRNA against SGLT1 suppressed glucagon secretion in isolated islets. CONCLUSIONS: These data suggested that a novel mechanism regulated glucagon secretion through SGLT1 in α cells. This finding possibly explained the distinct effects of dapagliflozin and canagliflozin on plasma glucagon levels in mice.

Neuronal SIRT1 regulates macronutrient-based diet selection through FGF21 and oxytocin signalling in mice.

Diet affects health through ingested calories and macronutrients, and macronutrient balance affects health span. The mechanisms regulating macronutrient-based diet choices are poorly understood. Previous studies had shown that NAD-dependent deacetylase sirtuin-1 (SIRT1) in part influences the health-promoting effects of caloric restriction by boosting fat use in peripheral tissues. Here, we show that neuronal SIRT1 shifts diet choice from sucrose to fat in mice, matching the peripheral metabolic shift. SIRT1-mediated suppression of simple sugar preference requires oxytocin signalling, and SIRT1 in oxytocin neurons drives this effect. The hepatokine FGF21 acts as an endocrine signal to oxytocin neurons, promoting neuronal activation and Oxt transcription and suppressing the simple sugar preference. SIRT1 promotes FGF21 signalling in oxytocin neurons and stimulates Oxt transcription through NRF2. Thus, neuronal SIRT1 contributes to the homeostatic regulation of macronutrient-based diet selection in mice.

Probable case of drug reaction with eosinophilia and systemic symptom syndrome due to combination therapy with daclatasvir and asunaprevir.

A 66-year-old, interferon-ineligible, treatment-naive man who was diagnosed with chronic hepatitis C due to hepatitis C virus genotype 1b began combination therapy with daclatasvir and asunaprevir. On day 14 of treatment, hepatic reserve and renal function deterioration was observed, while his transaminase levels were normal. Both daclatasvir and asunaprevir were discontinued on day 18 of treatment, because the patient complained of dark urine and a rash on his trunk and four limbs. After discontinuing antiviral therapy, the abnormal laboratory finding and clinical manifestations gradually improved, without recurrence. Our case fulfilled the diagnostic criteria of probable drug reaction with eosinophilia and systemic symptom (DRESS) syndrome. Despite the 18-d treatment, sustained virological response 12 was achieved. Based on the clinical course, we concluded that there was a clear cause-and-effect relationship between the treatment and adverse events. To our knowledge, this patient represents the first case of probable DRESS syndrome that includes concomitant deterioration of hepatic reserve and renal function due to combination therapy with daclatasvir and asunaprevir, regardless of normalization of transaminase levels. Our case suggests that we should pay attention not only to the transaminase levels but also to allergic symptoms associated with organ involvement during combination therapy with daclatasvir and asunaprevir.