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OBJECTIVE Several noninvasive markers have been developed to predict nonalcoholic steatohepatitis (NASH). We investigated the predictive value of the cytokeratin-18 fragment (CK18-F) level and FIB-4 index for diagnosing NASH in patients with nonalcoholic fatty liver disease (NAFLD). METHODS A total of 246 patients histologically diagnosed with NASH (n = 185) or nonalcoholic fatty liver (n = 61) were enrolled. We analyzed weighted receiver operating characteristic (ROC) curves for the prediction of NASH and determined the relationship between the CK18-F level and the histological features of NASH. In addition, we investigated the predictive value of the combination of the CK18-F level and FIB-4 index for diagnosing NASH. RESULTS The area under the ROC curve (AUROC) value of the CK18-F level was 0.77. With a CK18-F cutoff level of 260 U/L, the sensitivity and specificity for diagnosing NASH were 82.7 and 57.4%, respectively. Multiple comparisons showed that the CK18-F level did not differ among fibrosis stages but did significantly differ among hepatocyte ballooning grades. Overall, 95.7% (66/69) of patients with a FIB-4 index of ≥2.67 had NASH. In patients with a FIB-4 index of

Background/aims There are substantial genetic components contributing to the susceptibility of nonalcoholic fatty liver disease (NAFLD). It has recently been reported that the rs641738 C>T variant in the membrane-bound O-acyltransferase domain-containing protein 7 (MBOAT7) gene increased severity of NAFLD in adults of European descent. We aimed to test the hypothesis that MBOAT7 rs641738 variant would increase hepatic steatosis and hepatocellular injury in obese children. Methods A total of 831 obese children aged 7-15 years were recruited. Hepatic steatosis was measured by ultrasonography. Because PNPLA3 rs738409, GCKR rs780094 and TM6SF2 rs58542926 variants are known to confer susceptibility to NAFLD, we assessed the influence of MBOAT7 rs641738 on hepatic steatosis, and serum levels of CK-18 fragment (a biomarker of hepatocellular injury and apoptosis for NAFLD) after adjusting the effects of PNPLA3, GCKR and TM6SF2 polymorphisms. Results Of the recruited obese children, 22.7% had hepatic steatosis. PNPLA3 rs738409, GCKR rs780094 and TM6SF2 rs58542926 variants were independent risk factors of hepatic steatosis and elevated ALT levels. In contrast, MBOAT7 rs641738 variants, neither heterozygous nor homozygous genotypes, were not associated with hepatic steatosis, insulin resistance, lipid levels and liver enzymes. The multiple linear regression model revealed that after adjusting for age, gender, body mass index z score, PNPLA3 rs738409 and GCKR rs780094 variants, but not MBOAT7 rs641738, were associated with serum levels of CK-18 fragment. Conclusions The variant MBOAT7 rs641738 genotype is not associated with hepatic steatosis and serum levels of CK-18 fragment in obese Taiwanese children.

Resumen La esteatohepatitis no alcoholica (EHNA) es la forma mas agresiva de higado graso no alcoholico (HGNA) e involucra el riesgo de progresion a etapas mas avanzadas de enfermedad hepatica. Se requieren metodos no invasivos para identificar a pacientes con EHNA. Objetivo Evaluar el rendimiento diagnostico de la determinacion de los niveles sericos de citoqueratina-18 como marcador no invasivo de EHNA en poblacion chilena. Metodos Se determinaron los niveles sericos de CK-18 en un grupo de 41 pacientes con HGNA-probado por biopsia. El diagnostico de EHNA se baso en los criterios histologicos recomendados (presencia de balonamiento) y se calculo el puntaje de actividad del HGNA (PAH) y grado de fibrosis. Mediante correlacion de Spearman se evaluo la asociacion entre CK-18 y PAH. Se confecciono una curva ROC para evaluar la capacidad de CK-18 como test diagnostico para EHNA. Ademas, se evaluo el rendimiento del puntaje de fibrosis en higado graso no alcoholico (NFS) para pesquisa de fibrosis y EHNA y se lo comparo con CK-18 por regresion lineal simple. Los datos son expresados en medianas [percentil 25-75] y evaluados con test de rangos de Wilcoxon. Resultados La edad promedio del grupo estudiado (23% hombres) fue de 50,4 ± 11,1 anos. Un 34,2% fue diagnosticado con EHNA (PAH≥5). Los niveles de CK-18 fueron mayores en los pacientes con EHNA versus los sin EHNA (183,6 UI/l [97,4-734,4] vs. 117,2 UI/l [83,8-954,8], p = 0,016). Los niveles de CK-18 fueron buenos predictores de la presencia de EHNA en la biopsia con un area bajo la curva (AUC) de 0,732 (IC95% 0,572-0,897). Un punto de corte de 130,5 UI/l de CK-18 exhibio una sensibilidad de 92,9% y una especificidad de 63%, con un VPP de 56,5% y un VPN 94,4%, y clasifico correctamente al 73,2% de los pacientes con EHNA. El NFS tuvo un buen rendimiento para diagnostico de fibrosis avanzada (AUC 0,739, IC95% 0,56–0,91), pero limitado para identificar EHNA (AUC 0,413, IC95% 0,21-0,61). Conclusion La determinacion de CK-18 es un buen marcador no invasivo de EHNA. Si bien, NFS tiene un buen rendimiento en la identificacion de pacientes con fibrosis avanzada, no fue de utilidad para diagnosticar EHNA. En pacientes con HGNA, la determinacion de CK-18 y NFS es util en la pesquisa de EHNA y fibrosis hepatica respectivamente.

Nonalcoholic steatohepatitis (NASH) is the most aggressive form of nonalcoholic fatty liver disease (NAFLD). Noninvasive methods to identify children with NASH are urgently needed. The aim of this study was to evaluate the use of plasma cytokeratin-18 (CK18) fragment levels, a marker of increased hepatocyte apoptosis, as a non-invasive biomarker for pediatric NASH.Consecutive children with biopsy-proven NAFLD were included and blood samples were collected at the time of the biopsy. The diagnosis of NASH was based on Brunt's criteria. Histological features were scored: steatosis (0-3), lobular inflammation (0-3), ballooning (0-2), and portal inflammation (0-2). NAFLD activity score was calculated (0-8) and fibrosis stage was scored (0-4). We measured plasma CK18 levels using the M30-Apoptosense enzyme-linked immunosorbent assay kit.A total of 201 subjects were included in the study. The mean age was 10.7±2.5 years and 37% were male. NASH was diagnosed in 140 patients with a mean NAFLD activity scoring of 4.4±1.3. CK18 levels were significantly higher in subjects with NASH compared with not NASH (322.1 U/l±104.8 vs. 164.2 U/l±62, respectively; P0.001). The risk of having NASH on liver biopsy increased with increased CK18 levels (P0.001). For every 10 U/l increase in CK18 levels, the likelihood of having NASH increased by 70% after adjusting for multiple confounders. The performance of CK18 level for the diagnosis of NASH was excellent with an area under the receiver operating characteristics curve of 0.933.CK18 is a promising non-invasive biomarker for NASH in children with fatty liver disease.

Background The serum cytokeratin-18 fragment (CK-18) concentration has been suggested to be a biomarker of nonalcoholic fatty liver disease (NAFLD), although its usefulness in patients with type 2 diabetes mellitus (T2DM) is unknown. Methods The study was divided into two parts. In the first cross-sectional study, a total of 200 patients with T2DM and 58 healthy control subjects were recruited. NAFLD was diagnosed using ultrasonography. In the subsequent longitudinal study, we evaluated the three-month change (Δ) in the CK-18 concentration and other parameters in 40 T2DM patients with NAFLD. Results The serum CK-18 values were significantly higher in the NAFLD group than in the nonNAFLD group among both diabetic and nondiabetic subjects. The CK-18 concentration was found to be an independent determinant of NAFLD and was positively correlated with the ultrasonography score and AST and ALT concentrations in the T2DM patients. Positive correlations were also identified between the CK-18 and transaminase concentrations in the T2DM and NAFLD cohorts. ΔCK-18 was found to be significantly associated with ΔBMI in the T2DM patients with NAFLD. Conclusions A dose effect between the CK-18 concentration and the severity of NAFLD was found in the T2DM patients; thus, the CK-18 concentration is a potentially useful biomarker for assessing the efficacy of treatment and the improvement in NAFLD in patients with T2DM.

Keywords: Ballooning; Fibrosis; Inflammation; Nonalcoholic Fatty Liver Disease (NAFLD); Nonalcoholic Steatohepatitis (NASH); Steatosis; Type 2 Diabetes mellitus