A novel noninvasive formula for predicting cirrhosis in patients with chronic hepatitis C

Evaluating liver fibrosis is crucial for disease severity assessment, treatment decisions, and hepatocarcinogenic risk prediction among patients with chronic hepatitis C. In this retrospective multicenter study, we aimed to construct a novel model formula to predict cirrhosis. A total of 749 patients were randomly allocated to training and validation sets at a ratio of 2:1. Liver stiffness measurement (LSM) was made via transient elastography using FibroScan. Patients with LSM ≥12.5 kPa were regarded as having cirrhosis. The best model formula for predicting cirrhosis was constructed based on factors significantly and independently associated with LSM (≥12.5 kPa) using multivariate regression analysis. Among the 749 patients, 198 (26.4%) had LSM ≥12.5 kPa. In the training set, multivariate analysis identified logarithm natural (ln) type IV collagen 7S, ln hyaluronic acid, and ln Wisteria floribunda agglutinin positive Mac-2-binding protein (WFA+-Mac-2 BP) as the factors that were significantly and independently associated with LSM ≥12.5 kPa. Thus, the formula was constructed as follows: score = −6.154 + 1.166 × ln type IV collagen 7S + 0.526 × ln hyaluronic acid + 1.069 × WFA+-Mac-2 BP. The novel formula yielded the highest area under the curve (0.882; optimal cutoff, −0.381), specificity (81.5%), positive predictive values (62.6%), and predictive accuracy (81.6%) for predicting LSM ≥12.5 kPa among fibrosis markers and indices. These results were almost similar to those in the validated set, indicating the reproducibility and validity of the novel formula. The novel formula scores were significantly, strongly, and positively correlated with LSM values in both the training and validation data sets (correlation coefficient, 0.721 and 0.762; p = 2.67 × 10−81 and 1.88 × 10−48, respectively). In conclusion, the novel formula was highly capable of diagnosing cirrhosis in patients with chronic hepatitis C and exhibited better diagnostic performance compared to conventional fibrosis markers and indices.

Efficacy and Safety of Luseogliflozin in Patient with Type 2 Diabetes Complicated by Hepatic Dysfunction

Background: Improvements in glycemic control and hepatic function are clinically important goals in the treatment of patients with type 2 diabetes mellitus complicated by hepatic dysfunction. The favorable effects of the sodium-glucose co-transporter inhibitor luseogliflozin on hepatic dysfunction were anticipated for humans. Nevertheless, few clinical studies have confirmed its real-world efficacy on hepatic dysfunction. This trial was conducted to assess the safety and efficacy of luseogliflozin in patients with type 2 diabetes mellitus complicated by hepatic dysfunction.Methods: This prospective, single-site, single-arm, open-label trial included 55 subjects. Subjects were administered with luseogliflozin and observed for 52 weeks. The primary endpoints were the change and percent change in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-GTP), and hemoglobin A1c (HbA1c) from baseline to week 52. The secondary endpoints included body weight, body mass index (BMI), waist circumference, blood pressure, fasting plasma glucose (FPG), homeostatic model assessment beta (HOMA-β), homeostatic model assessment of insulin resistance (HOMA-IR), ferritin, Mac-2 binding protein (M2-BP), fatty liver index (FLI), fibrosis-4 (FIB-4) index, type IV collagen 7S domain, nonalcoholic fatty liver disease (NAFLD) fibrosis score, high-sensitivity C-reactive protein (hs-CRP), and interleukin-6 (IL-6).Results: AST, ALT, γ-GTP, and HbA1c significantly decreased from baseline to week 52. Body weight, BMI, waist circumference, and FPG also significantly decreased. HOMA-IR significantly decreased but HOMA-β was unchanged. FLI, ferritin, M2-BP, and NAFLD fibrosis scores significantly decreased whereas the FIB-4 index and type IV collagen 7S domain did not significantly change. The hs-CRP and IL-6 levels did not significantly change.Conclusion: Luseogliflozin administration in T2DM patients with hepatic dysfunction was well tolerated, improved hepatic function, reduced liver fat, and attenuated liver injury and fibrosis. The present study might help establish a therapeutic approach for T2DM patients with hepatic dysfunction induced by SGLT2 inhibitors.Trial registration: This study was registered under the University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR) (No. UMIN000025808) and the Japan Registry of Clinical Trials (No. jRCTs021180017).

Epidemiology, Pathogenesis, and Diagnostic Strategy of Diabetic Liver Disease in Japan

Type 2 diabetes (T2D) is closely associated with nonalcoholic fatty liver disease (NAFLD). Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to cirrhosis, hepatocellular carcinoma (HCC), and hepatic decompensation. Patients with T2D have twice the risk of HCC incidence compared with those without T2D. Because the hepatic fibrosis grade is the main determinant of mortality in patients with NAFLD, identifying patients with advanced fibrosis using non-invasive tests (NITs) or imaging modalities is crucial. Globally, the fibrosis-4 index (FIB-4 index), NAFLD fibrosis score, and enhanced liver fibrosis test have been established to evaluate hepatic fibrosis. Two-step algorithms using FIB-4 index as first triaging tool are globally accepted. It remains unknown which kinds of NITs or elastography are best as the second step tool. In Japan, type IV collagen 7s or the CA-fibrosis index (comprising type IV collagen 7s and aspartate aminotransferase (AST)) is believed to precisely predict advanced fibrosis in NAFLD. Patients with NAFLD who have high non-invasive test results should be screened for HCC or esophageal varices. Risk factors of rapid fibrosis progression in NAFLD includes age, severe obesity, presence of T2D, menopause in women, and a patatin-like phospholipase domain containing the 3 GG genotype. Patients with NAFLD who have these risk factors should be intensively treated with lifestyle modification or pharmacotherapies for preventing liver-related mortality.

Advancement of hepatic fibrosis among general women with/without NAFLD

Background Nonalcoholic fatty liver disease (NAFLD) is increasing, being prevalent at 30% of the general population worldwide. A part of NAFLD develops nonalcoholic steatohepatitis (NASH), liver cirrhosis and hepatocellular carcinoma. Hepatic fibrosis plays an important role in their pathogenesis. However, it is unclear how hepatic fibrosis is observed and advanced in NAFLD among general population. To investigate the hepatic fibrosis among general population, we prospectively observed hepatic fibrosis using serum markers. Methods The subjects were 228 women who participated as a part of the Japan Multi-Institutional Collaborative Cohort (J-MICC) study in Kagoshima, Japan, and were followed from 2005 to 2014. NAFLD was defined as fatty liver by abdominal ultrasonography; consuming ethanol < 20 g/day; and being none hepatitis B and C carriers. NAFLD were confirmed after two-time consecutive examination, because its disappearance is ambiguous in some cases. Hepatic fibrosis was evaluated using serum M2BPGi and Type IV collagen 7s. The comparison of their changed values between groups was done using the ANOVA adjusted for age. The association between their change and related factors was done using general linear regression model. Results The prevalence of NAFLD was 31.6% at baseline. In the 5-year observation, the NAFLD + => NAFLD + ( ++) group was 23.7%; − +, 2.6%; + −, 7.9%; and - - (control), 65.8%. The values of M2BPGi and Type IV collagen 7s were higher in ++, -+, +- groups than controls at baseline. The change of M2BPGi values was observed in all groups, including controls, and the changed values were higher in ++ and -+ groups. Higher creatinine levels were positively associated with change of M2BPGi values. In contrast, the change of Type IV collagen 7s was not apparent. Conclusions This study suggested hepatic fibrosis was advanced with age among general women without NAFLD, and the presence of NAFLD enhanced hepatic fibrosis more. Key messages Hepatic fibrosis may be slightly developing with age among general population, and will be enhanced with fatty liver. It is important to prevent fatty liver development to control risk factors, such as obesity and metabolic syndrome, to reduce the risk of NASH, liver cirrhosis and hepatocellular carcinoma.

P2623Measurement of liver fibrosis marker: type IV collagen 7S among patients with acute heart failure and its relationship with the Enhanced Liver Fibrosis (ELF) score

Background Hemodynamic disturbance in acute heart failure (HF) can cause injury to extra-cardiac organs such as the liver. Organ injury in HF might evoke a profibrotic response, which could adversely affect the prognosis. Methods Among 189 patients with acute HF, we simultaneously determined the liver fibrosis marker, type IV collagen 7S (P4NP 7S) and the Enhanced Liver Fibrosis (ELF) Score consisting of tissue inhibitor of metalloproteinases 1 (TIMP-1), amino-terminal propeptide of type III procollagen (PIIINP) and hyaluronic acid (HA) on admission and at discharge. Results During hospitalization, P4NP 7S and ELF score significantly decreased from 7.1 ng/mL to 6.1 ng/mL (P<0.001) and 10.39 to 10.13 (P<0.001), respectively. P4NP 7S and ELF score were correlated with each other on admission (r=0.4, P<0.001) and at discharge (r=0.4, P<0.001). %Change of (Δ) P4NP 7S during hospitalization was correlated with ΔBNP and ΔELF score (r=0.3, P<0.001 and r=0.4, P<0.001, respectively). Among the components of ELF score, PIIINP and HA were correlated with P4NP 7S on admission (r=0.5, P<0.001 and r=0.3, P<0.001, respectively) and at discharge (r=0.4, P<0.001 and r=0.3, P<0.001, respectively). ΔP4NP 7S was also correlated with ΔTIMP-1, ΔPIIINP and ΔHA (r=0.3, P<0.001, r=0.4, P<0.001 and r=0.3, P<0.001, respectively). Each patient was followed up up to 365 days after discharge. 69 patients died or were hospitalized for HF. When the patients were divided into two groups according to the median value of each marker at discharge, the cumulative 1-year incidences of all cause death or HF hospitalization were 32.0% and 45.5% in P4NP 7S-low and P4NP 7S-high group, respectively (log-rank P=0.051) and 43.2% and 34.9% in ELF score-low and ELF score-high group, respectively (log-rank P=0.44). After adjustment by the clinically relevant factors including age, sex, hemoglobin, sodium and left ventricular ejection fraction, P4NP 7S showed independent prognostic value (adjusted hazard ratio: 1.12, P=0.02), while ELF score did not (adjusted hazard ratio: 1.04, P=0.79). Conclusion Parallel elevation of P4NP 7S and ELF score were documented during acute phase of HF. P4NP 7S at discharge may identify patients at high risk for subsequent HF related events.