The association of the serum levels of myostatin, follistatin, and interleukin-6 with sarcopenia, and their impacts on survival in patients with hepatocellular carcinoma

Kanghyug Choi,Hee Yoon Jang,Joong Mo Ahn,Sung Ho Hwang,Jung Wha Chung,Yun Suk Choi,Jin-Wook Kim,Eun Sun Jang,Gwang Hyeon Choi,Sook-Hyang Jeong 대한간학회 2020 Clinical and Molecular Hepatology(대한간학회지) Vol.26 No.4

Background/Aims: The role of serum myokine levels in sarcopenia and the outcome of hepatocellular carcinoma (HCC) patients are not clear. This study investigated the serum levels of myostatin, follistatin, and interleukin-6 (IL-6) in HCC patients and their association with sarcopenia and survival. Methods: Using prospectively collected pretreatment samples from 238 HCC patients in a hospital from 2012 to 2015, the serum levels of 3 myokines were determined and compared to 50 samples from age and sex-matched healthy controls. Sarcopenia was evaluated using the psoas muscle index (PMI) measured at the third lumbar level in the computed tomography, and clinical data were collected until 2017. Results: The median levels of the 3 myokines for the male and female HCC patients were as follow: myostatin (3,979.3 and 2,976.3 pg/mL), follistatin (2,118.5 and 2,174.6 pg/mL), and IL-6 (2.5 and 2.7 pg/mL), respectively. Those in the HCC patients were all significantly higher than in the healthy controls. In the HCC patient, the median PMI was 4.43 (males) and 2.17 cm2/m2 (females) with a sarcopenic prevalence of 56.4%. The serum levels of myostatin, IL-6 and follistatin in the HCC patients showed a positive, negative, and no correlation with PMI, respectively. The serum follistatin level was an independent factor for poor survival in HCC patients. Conclusions: The serum levels of myostatin, follistatin, and IL-6 and their correlation with sarcopenia and survival were presented in HCC patients for the first time. The role of the serum follistatin level as a poor prognostic biomarker warrants further study.

Serum Levels of Myostatin, Follistatin and IL-6 in the Patients with Hepatocellular Carcinoma with Their Association with Sarcopenia and Survival

( Kanghyug Choi ),( Hee Yoon Jang ),( Sung Ho Hwang ),( Jung Wha Chung ),( Jin-wook Kim ),( Eun Sun Jang ),( Sook-hyang Jeong ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: This study investigated the serum levels of myostatin, follistatin and IL-6 in the patients with hepatocellular carcinoma (HCC), and their association with sarcopenia and survival. Methods: Using prospectively collected pretreatment serum samples obtained from 238 HCC patients from 2012 to 2015, serum levels of myostatin, follistatin and IL-6 were determined using commercialized ELISA. The cross-sectional area of the psoas muscles at the third lumbar level of CT normalized for the patient’s height was presented a psoas muscle index (PMI). Sex-specific cut-offs of PMI to define the sarcopenica were ascertained by the maximal chi-square method. Results: The subjects showed a median age of 59 years, 81% of male, and hepatitis B virus infection in 70%. The median myostatin levels for males and females were 3,979.3 pg/mL (819.33-21,652.1 pg/mL) and 2,976.3 pg/mL (901.5-15,652.9 pg/mL), respectively, with the levels of follistatin [2,118.5 pg/ mL (573.7-16,923.6 pg/mL, male); 2,174.6 pg/mL (675.1- 8,337.3 pg/mL, female)] and IL-6 [2.5 pg/mL (0.11-106.79 pg/ mL, male); 2.7 pg/mL (0.01-122.97 pg/mL, female)]. PMI was 4.48 ± 1.25 (males) and 2.25 ± 0.82 ㎠/㎡ (females), showing sarcopenic prevalence of 56.7%. The sarcopenic group showed a significantly higher follistatin level, larger tumor size, more advanced BCLC stage and higher overall mortality than non-sarcopenic group. On multivariate analysis, follistatin level (≥2100 pg/mL) was an independent factor for poor survival [hazard ratio, 2.197; 95% confidence interval (CI), 1.123-4.296; P=0.021] along with a low PMI, high alpha-fetoprotein level, MELD score and TNM stage. However, serum follistatin level was not correlated with PMI, while myostatin level showed a positive correlation with PMI (R_s = 0.271, P<0.001). Conclusions: Serum follistatin level, rather than myostatin or IL- 6, was an independent factor for poor survival in HCC patients. Further study on the role of follistatin in prognosis of HCC is warranted.

New Prediction Model of Convolutional Neural Network for Hepatocellular Carcinoma in Patients of Hepatitis B Virus-Related Cirrhosis on Potent Antiviral Therapy with Comparison of Preexisting Models

( Joon Yeul Nam ),( Jong Ho Lee ),( Hee Yoon Jang ),( Kanghyug Choi ),( In-gyoon Ha ),( Eun Sun Jang ),( Jin-wook Kim ),( Sook-hyang Jeong ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Although there are several prediction models for hepatocellular carcinoma (HCC) development in chronic hepatitis B virus (HBV) infection including various proportion of liver cirrhosis, they are not based on the entirely cirrhotic patients on antiviral therapy. This study aimed to develop a new model of convolutional neural network (CNN) using deep learning technique for the prediction of HCC among HBV-related cirrhosis on the potent antivirals. Methods: The subjects were 424 patients with HBV-related cirrhosis on entecavir therapy and followed for median 62.0 months at a single tertiary hospital in Korea. Four existing models (PAGE-B, CU-HCC, HCC-RESCUE and ADRESS-HCC) were applied to our subjects and, compared for the accuracy of each model at 5 years using Harrell’s c-index. A New model using CNN was developed, and accuracy of the new model was calculated. Results: During the follow-up period, HCC developed in 86 out of 424 patients (20.3%) with 5 year cumulative incidence of 22%. In discrimination assessment, PAGE-B (c-index= 0.612), HCC-RESCUE (c-index=0.613), and ADRESS-HCC (c-index=0.606) showed a better discriminatory power compared to CU-HCC (c-index=0.563). The predicted 5 year cumulative HCC incidence among PAGE-B, CU-HCC, and HCC-RESCUE using the reported cutoff of each model were 16.0%, 21.1%, and 41.2%, respectively. However, application of the PAGE-B, CU-HCC, and HCC-RESCUE for our cohort showed a predicted 5 year HCC incidence of 23.6%, 17.2%, and 21.7%, respectively, suggesting an underestimation in PAGE-B, but overestimation in CU-HCC, and HCC-RESCUE. Accuracy of new model using CNN was 79.7 %, which seems to be a better performance. Conclusions: Our new model of CNN may present better prediction than the preexisting 4 models for HBV-related cirrhosis on potent antivirals. Further validation study is warranted.

Body Mass Index and FIB-4 Score Are Risk Factors for Development of Hepatocellular Carcinoma in Liver Cirrhosis on Entecavir Therapy

( Joon Yeul Nam ),( Jong Ho Lee ),( Hee Yoon Jang ),( Kanghyug Choi ),( In-gyoon Ha ),( Eun Sun Jang ),( Jin-wook Kim ),( Sook-hyang Jeong ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Prediction of development of hepatocellular carcinoma (HCC) among hepatitis B virus (HBV)-related cirrhosis patients on potent antiviral therapy is not well defined. This study aimed to investigate the incidence and predictors of HCC development in cirrhosis patients on entecavir therapy. Methods: This single center, retrospective cohort study included 424 consecutive patients with HBV-related cirrhosis who underwent entecavir therapy from 2007 to 2013. Surveillance for HCC was based on semiannual ultrasonography and serum alpha fetoprotein (AFP) measurement. HCC incidence and the related factors were analyzed. Results: The subjects showed a median age of 52.7±10.1 years with 63.5% of male, mean body mass index (BMI) of 24.2±3.1 kg/㎡, HBeAg positivity in 41.5%, baseline HBV DNA level of 1.39x10⁸ IU/mL, and mostly Child-Pugh class A (80.9%). During median follow-up of 62.0 months (interquartile range, 29.0-83.0), 90.8% (385/424) reached complete virologic response of entecavir therapy. The overall incidence of HCC was 86 out of 424 patients (20.3%); incidence rate of 2.54/100 person-yr at 1 yr, 8.07/100 at 3 yr, and 8.37/100 at 5 years of follow-up. The multivariate analysis showed that the independent factors related to HCC development were BMI ≥23 (hazard ratio (HR), 1.89; 95% confidence interval (CI), 1.23-3.39; P=0.006), and high FIB-4 (≥3.25; HR, 5.65; 95% CI, 1.35-23.72; P=0.018) or intermediate FIB-4 (≥1.45 and <3.25; HR, 4.58; 95% CI, 1.08-19.41; P=0.039). Conclusions: HCC incidence rate among HBV-related liver cirrhosis on entecavir therapy was 2.54/100, 8.07/100, and 8.37/100 person-yr at 1, 3 and 5 yr, respectively. High BMI and high to intermediate FIB-4 score were independent factors for HCC development.

아데포비어 구조요법을 받은 라미부딘 내성 만성 B형 간염 환자에서 간세포암종 발생 빈도

김지현 ( Jihyun Kim ),이세환 ( Sae Hwan Lee ),최강혁 ( Kanghyug Choi ),이윤나 ( Yun Nah Lee ),정승원 ( Soung Won Jeong ),김상균 ( Sang Gyune Kim ),장재영 ( Jae Young Jang ),김영석 ( Young Seok Kim ),김홍수 ( Hong Soo Kim ),김부성 대한간암학회 2013 대한간암학회지 Vol.13 No.2

Background/Aims: Suboptimal virological response to adefovir (ADV) rescue therapy was commonly experienced in patient with lamivudine-resistant chronic hepatitis B. The aim of this study is to compare occurrence of hepatocellular carcinoma (HCC) of patients with adefovir rescue therapy to naive patients with entecavir. Methods: Electronic medical records of 156 patients with lamivudine-resistant chronic hepatitis B who treated with ADV and of 186 naive-patients who received entecavir 0.5 mg, as control group, were reviewed retrospectively. Study subjects were matched using estimated propensity score and 107 matched subjects in each group were analyzed. Cumulative occurrence of HCC was evaluated during antiviral therapy and the association between clinical variables and development of HCC were analyzed using Kaplan-Meyer curve and risk factor for HCC was evaluated with Cox-proportional hazard model. Results: Age, gender, Child-Pugh score, underlying cirrhosis, HBeAg, and HBV DNA level were not different in both groups, except treatment duration with ADV or entecavir (mean 52.6±17.5 vs 46.7±11.4 months, P=0.004). Cumulative virological response rates were 16% and 42% in patient with ADV rescue therapy and 68% and 85% in naive-patients received entecavir at 1 and 3 years (P<0.001), respectively. HCC were diagnosed in 6 of 107 patients with lamivudineresistance and 9 of 107 naive-patients during follow-period and cumulative occurrence rates of HCC was not different between both group (P=0.308). Cumulative occurrence rates of HCC in total 214 subjects were 2.3%, 4.8%, and 9.6% at 1, 3, and 5 years, respectively. Age, underlying cirrhosis, and baseline HBV DNA level were associated with the occurrence of HCC, however gender, HBeAg status, ADV rescue therapy, and cumulative virological response were not correlated in univariate analysis. In multivariate analysis, age (P=0.008) and underlying cirrhosis (P=0.002) were independent risk factors for occurrence of HCC. Conclusions: Long-term ADV rescue therapy in patients with lamivudine-resistant chronic hepatitis B did not increase the occurrence rates of HCC.