Background: Non-alcoholic fatty liver disease (NAFLD) is usually asymptomatic and lacks a specific biomarker; therefore, many individuals might remain undiagnosed even with advanced liver fibrosis. The aim of this study was to clarify the prevalence and clinical features of subjects with a high risk of advanced liver fibrosis in the general population, using the Fibrosis-4 (FIB-4) index.Methods: We retrospectively investigated 6,183 subjects without known liver disease who had participated in an annual health checkup examination. We analyzed the factors associated with high FIB-4 index (≥2.67) using a logistic regression analysis. Results: Among the 6,183 subjects, 76 (1.2%) had high FIB-4 index. Multivariate analysis identified hypertension (odds ratio [OR]=8.926; 95% confidence interval [CI] 4.031-19.768; P<0.001) and diabetes mellitus (OR=4.045; 95% CI 1.694-9.660; P=0.002) as important risk factors for high FIB-4 index. The rates of hypertension and diabetes mellitus in subjects with high FIB-4 index were 78.9% and 23.7%, respectively. No significant association was observed between obesity or large waist circumference and a high FIB-4 index. A history of cardiovascular disease was significantly more common in subjects with high FIB-4 index. These results were also observed in subjects with normal aminotransferase (ALT) levels. Conclusions: The present study revealed that approximately 1% of the general Japanese population has a high risk of advanced liver fibrosis. Many of these patients had hypertension and/or diabetes mellitus. Our findings suggest that there are many undiagnosed NAFLD patients with risk of advanced liver fibrosis in the general population.

Atezolizumab and bevacizumab are currently available as first-line treatments for unresectable hepatocellular carcinoma, but immune-related adverse events are a major concern. We herein report two cases of isolated adrenocorticotropic hormone (ACTH) deficiency. Both patients presented with general fatigue, appetite loss, eosinophilia, and hyponatremia after nine cycles in case 1 and three months after stopping treatment for inflammatory arthritis in case 2. Endocrinological investigations revealed unsatisfactory ACTH and cortisol responses despite the preservation of other anterior pituitary hormones, suggesting isolated ACTH deficiency. As it is rapidly improved by steroid replacement therapy, an early diagnosis and treatment make it possible to resume immunotherapy.