Yoon Jun Kim

Nonalcoholic Fatty Liver Disease is Associated with Coronary Artery Calcification

Nonalcoholic fatty liver disease (NAFLD) is related to risk factors of coronary artery disease, such as dyslipidemia, diabetes, and metabolic syndrome, which are closely linked with visceral adiposity. The aim of this study was to investigate whether NAFLD was associated with coronary artery calcification (CAC), which is used as a surrogate marker for coronary atherosclerosis independent of computed tomography (CT)‐measured visceral adiposity. Out of 5,648 subjects who visited one of our health screening centers between 2003 and 2008, we enrolled 4,023 subjects (mean age, 56.9 ± 9.4 years; 60.7% males) without known liver disease or a history of ischemic heart disease. CAC score was evaluated using the Agatston method. On univariate analysis, the presence of CAC (score >0) was significantly associated with age, sex, body mass index, aspartate aminotransferase, alanine aminotransferase, high‐density lipoprotein cholesterol, triglycerides, and increased risk of diabetes, hypertension, smoking, and NAFLD. Increasing CAC scores (0, <10, 10‐100, ≥100) were associated with higher prevalence of NAFLD (odds ratio [OR], 1.84; 95% confidence interval [CI], 1.61‐2.10; P<0.001). Multivariable ordinal regression analysis was adjusted for traditional risk factors, and CT‐measured visceral adipose tissue area in a subgroup of subjects showed that the increased CAC scores were significantly associated with the presence of NAFLD (OR, 1.28, 95% CI, 1.04‐1.59; P = 0.023) independent of visceral adiposity. Conclusion: Patients with NAFLD are at increased risk for coronary atherosclerosis independent of classical coronary risk factors, including visceral adiposity. These data suggest that NAFLD might be an independent risk factor for coronary artery disease. (HEPATOLOGY 2012)

Hepatic steatosis index: A simple screening tool reflecting nonalcoholic fatty liver disease

BACKGROUND/AIMS To optimize management of nonalcoholic fatty liver disease (NAFLD), a simple screening tool is necessary. In this study, we aimed to devise a simple index of NAFLD. STUDY A cross-sectional study with 10,724 health check-up subjects (5362 cases with NAFLD versus age- and sex-matched controls) was conducted. Study subjects were randomly assigned to a derivation cohort or a validation cohort. RESULTS Multivariate analysis indicated that high serum alanine aminotransferase (ALT) to serum aspartate aminotransferase (AST) ratio, high body mass index (BMI), and diabetes mellitus were independent risk factors of NAFLD (all P<0.001). Using these variables, a formula was derived by a logistic regression model: hepatic steatosis index (HSI)= 8 x(ALT/AST ratio)+BMI (+2, if female; +2, if diabetes mellitus). HSI had an area under receiver-operating curve of 0.812 (95% confidence interval, 0.801-0.824). At values of <30.0 or >36.0, HSI ruled out NAFLD with a sensitivity of 93.1%, or detected NAFLD with a specificity of 92.4%, respectively. Of 2692 subjects with HSI <30.0 or >36.0 in the derivation cohort, 2305 (85.6%) were correctly classified. HSI was validated in the subsequent validation cohort. CONCLUSION HSI is a simple, efficient screening tool for NAFLD that may be utilized for selecting individuals for liver ultrasonography and for determining the need for lifestyle modifications.

Transarterial Chemoembolization Can Be Safely Performed in Patients with Hepatocellular Carcinoma Invading the Main Portal Vein and May Improve the Overall Survival

PURPOSE To determine the efficacy and safety of transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC) and main portal vein (MPV) invasion. MATERIALS AND METHODS This study was approved by the institutional review board, and the requirement to obtain informed consent was waived. The authors retrospectively assessed the electronic medical records of patients in whom HCC with MPV invasion was newly diagnosed from January 2004 to December 2007 at a single tertiary medical center. Patients with decompensated hepatic function were excluded. Outcomes of patients treated with TACE were compared with those of patients given supportive care according to Child-Pugh class. RESULTS One hundred twenty-five patients (104 men and 21 women; mean age, 55.7 years; age range, 33.4-83.0 years) were included. The median overall survival was 3.7 months (range, 0.2-33.3 months). Eighty-three of the 125 patients (66.4%) were treated with TACE and 42 (33.6%) received supportive care. Repeated TACE showed significant survival benefits compared with supportive care in patients with Child-Pugh class A (median survival, 7.4 months vs 2.6 months, respectively; P < .001) and class B (median survival, 2.8 months vs 1.9 months, respectively; P = .002) disease. Results of multivariate analysis showed that treatment with TACE (hazard ratio, 0.263; 95% confidence interval [CI]: 0.164, 0.424; P < .001) and Child-Pugh class A status (hazard ratio, 0.550; 95% CI: 0.368, 0.822; P = .004) were independent predictive factors of a favorable outcome. There were no procedure-related deaths within 4 weeks after TACE, and patient morbidity was 28.9% (24 of 83 patients). CONCLUSION TACE can be performed safely and may improve the overall survival of patients with HCC and MPV invasion.

Transcriptomic profiling reveals hepatic stem‐like gene signatures and interplay of miR‐200c and epithelial‐mesenchymal transition in intrahepatic cholangiocarcinoma

Intrahepatic cholangiocellular carcinoma (ICC) is the second most common type of primary liver cancer. However, its tumor heterogeneity and molecular characteristics are largely unknown. In this study, we conducted transcriptomic profiling of 23 ICC and combined hepatocellular cholangiocarcinoma tumor specimens from Asian patients using Affymetrix messenger RNA (mRNA) and NanoString microRNA microarrays to search for unique gene signatures linked to tumor subtypes and patient prognosis. We validated the signatures in an additional 68 ICC cases derived from Caucasian patients. We found that both mRNA and microRNA expression profiles could independently classify Asian ICC cases into two main subgroups, one of which shared gene expression signatures with previously identified hepatocellular carcinoma (HCC) with stem cell gene expression traits. ICC‐specific gene signatures could predict survival in Asian HCC cases and independently in Caucasian ICC cases. Integrative analyses of the ICC‐specific mRNA and microRNA expression profiles revealed that a common signaling pathway linking miR‐200c signaling to epithelial‐mesenchymal transition (EMT) was preferentially activated in ICC with stem cell gene expression traits. Inactivation of miR‐200c resulted in an induction of EMT, whereas activation of miR‐200c led to a reduction of EMT including a reduced cell migration and invasion in ICC cells. We also found that miR‐200c and neural cell adhesion molecule 1 (NCAM1) expression were negatively correlated and their expression levels were predictive of survival in ICC samples. NCAM1, a known hepatic stem/progenitor cell marker, was experimentally demonstrated to be a direct target of miR‐200c. Conclusion: Our results indicate that ICC and HCC share common stem‐like molecular characteristics and poor prognosis. We suggest that the specific components of EMT may be exploited as critical biomarkers and clinically relevant therapeutic targets for an aggressive form of stem cell‐like ICC. (HEPATOLOGY 2012;56:1792–1803)

Identification of a Cholangiocarcinoma-Like Gene Expression Trait in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are the major adult liver cancers. The existence of combined hepatocellular-cholangiocarcinoma (CHC), a histopathologic intermediate form between HCC and CC, suggests phenotypic overlap between these tumors. Here, we applied an integrative oncogenomic approach to address the clinical and functional implications of the overlapping phenotype between these tumors. By performing gene expression profiling of human HCC, CHC, and CC, we identified a novel HCC subtype, i.e., cholangiocarcinoma-like HCC (CLHCC), which expressed cholangiocarcinoma-like traits (CC signature). Similar to CC and CHC, CLHCC showed an aggressive phenotype with shorter recurrence-free and overall survival. In addition, we found that CLHCC coexpressed embryonic stem cell-like expression traits (ES signature) suggesting its derivation from bipotent hepatic progenitor cells. By comparing the expression of CC signature with previous ES-like, hepatoblast-like, or proliferation-related traits, we observed that the prognostic value of the CC signatures was independent of the expression of those signatures. In conclusion, we suggest that the acquisition of cholangiocarcinoma-like expression traits plays a critical role in the heterogeneous progression of HCC.

Gene Expression–Based Recurrence Prediction of Hepatitis B Virus–Related Human Hepatocellular Carcinoma

Purpose: The poor prognosis of hepatocellular carcinoma (HCC) is, in part, due to the high rate of recurrence even after “curative resection” of tumors. Therefore, it is axiomatic that the development of an effective prognostic prediction model for HCC recurrence after surgery would, at minimum, help to identify in advance those who would most benefit from the treatment, and at best, provide new therapeutic strategies for patients with a high risk of early recurrence. Experimental Design: For the prediction of the recurrence time in patients with HCC, gene expression profiles were generated in 65 HCC patients with hepatitis B infections. Result: Recurrence-associated gene expression signatures successfully discriminated between patients at high-risk and low-risk of early recurrence (P = 1.9 × 10−6, log-rank test). To test the consistency and robustness of the recurrence signature, we validated its prognostic power in an independent HCC microarray data set. CD24 was identified as a putative biomarker for the prediction of early recurrence. Genetic network analysis suggested that SP1 and peroxisome proliferator–activated receptor-α might have regulatory roles for the early recurrence of HCC. Conclusion: We have identified a gene expression signature that effectively predicted early recurrence of HCC independent of microarray platforms and cohorts, and provided novel biological insights into the mechanisms of tumor recurrence.

Visceral adipose tissue area is an independent risk factor for hepatic steatosis

Background and Aim:  Recent data indicate that hepatic steatosis is associated with insulin resistance, dyslipidemia and obesity (especially central body fat distribution). There have been few studies on the correlation between biopsy‐proven hepatic steatosis and the above factors in a disease‐free population. The aim of the present study was to evaluate the relation between hepatic steatosis assessed by biopsy and clinical characteristics including regional fat distribution measured by computed tomography (CT) in living liver donors.

The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection

BACKGROUND & AIMS GS-9620 is an oral agonist of toll-like receptor 7, a pattern-recognition receptor whose activation results in innate and adaptive immune stimulation. We evaluated the safety, pharmacokinetics, and pharmacodynamics of GS-9620 in patients with chronic hepatitis B. METHODS In two double-blind, phase 1b trials of identical design, 49 treatment-naïve and 51 virologically suppressed patients were randomized 5:1 to receive GS-9620 (at doses of 0.3mg, 1mg, 2mg, 4mg) or placebo as a single dose or as two doses seven days apart. Pharmacodynamic assessment included evaluation of peripheral mRNA expression of interferon-stimulated gene 15 (ISG15), serum interferon gamma-induced protein 10 and serum interferon (IFN)-alpha. RESULTS Overall, 74% of patients were male and 75% were HBeAg negative at baseline. No subject discontinued treatment due to adverse events. Fifty-eight percent experienced ⩾1 adverse event, all of which were mild to moderate in severity. The most common adverse event was headache. No clinically significant changes in HBsAg or HBV DNA levels were observed. Overall, a transient dose-dependent induction of peripheral ISG15 gene expression was observed peaking within 48 hours of dosing followed by return to baseline levels within seven days. Higher GS-9620 dose, HBeAg positive status, and low HBsAg level at baseline were independently associated with greater probability of ISG15 response. Most patients (88%) did not show detectable levels of serum IFN-alpha at any time point. CONCLUSIONS Oral GS-9620 was safe, well tolerated, and associated with induction of peripheral ISG15 production in the absence of significant systemic IFN-alpha levels or related symptoms.

Non-alcoholic fatty liver disease across the spectrum of hypothyroidism

BACKGROUND & AIMS The aim of this study was to characterize the relationship between the broad spectrum of hypothyroidism and NAFLD. METHODS A cross-sectional study with 4648 health check-up subjects (2324 cases with hypothyroidism vs. age- and sex-matched controls) was conducted. The subjects were categorized as having either subclinical [thyroid-stimulating hormone (TSH) ≥4.1 mIU/L and normal free thyroixine (T(4)) level (0.7-1.8 ng/dl)] or overt hypothyroidism [free T(4)<0.7 ng/dl]. NAFLD was diagnosed on the basis of typical ultrasonographic findings, and alcohol consumption of less than 20 g/day in the absence of other causes of liver disease. RESULTS The mean age of the subjects was 48.6±11.8 years and 62.4% were female. NAFLD was significantly associated with hypothyroidism (30.2% patients vs. 19.5% control, p<0.001). The prevalence of NAFLD and abnormal liver enzyme levels (ALT>33/25 IU/L) increased steadily with increasing grades of hypothyroidism (for NAFLD, subclinical: 29.9% and overt: 36.3%; for abnormal ALT, 20.1% and 25.9%, p<0.001, respectively). Multivariate regression analysis showed that NAFLD was statistically significantly associated with hypothyroidism (odds ratio (OR) 1.38, 95% confidence interval (CI), 1.17-1.62) and the grade of hypothyroidism in a dose-dependent manner (OR 1.36, 95% CI, 1.16-1.61 in subclinical hypothyroidism and OR 1.71, 95% CI, 1.10-2.66 in overt hypothyroidism). CONCLUSIONS Subclinical hypothyroidism, even in the range of upper normal TSH levels, was found to be related to NAFLD in a dose-dependent manner. Hypothyroidism is closely associated with NAFLD independently of known metabolic risk factors, confirming a relevant clinical relationship between these two diseases.

Radiofrequency Ablation of Hepatocellular Carcinoma as First-Line Treatment: Long-term Results and Prognostic Factors in 162 Patients with Cirrhosis

PURPOSE To evaluate the long-term outcomes of radiofrequency ablation (RFA) as a first-line therapy for early-stage hepatocellular carcinoma (HCC) and determine the prognostic factors for survival. MATERIALS AND METHODS The institutional review board approved this retrospective study. From January 2006 to December 2007, 162 consecutive patients with cirrhosis (Child-Pugh class A and B, 137 and 25 patients, respectively) who underwent RFA as a first-line treatment for up to three HCCs with a maximum diameter of 5 cm (182 HCCs; mean diameter ± standard deviation, 2.59 cm ± 0.79; 17 multinodular forms) were included. After a mean follow-up of 50.3 months ± 19.9, results were analyzed for tumor recurrence, as well as overall and recurrence-free survival time. The Kaplan-Meier method and Cox proportional hazards regression model were used to evaluate the prognostic factors. RESULTS The cumulative incidence of local tumor progression (LTP) was 14.5% at 5 years, with tumor size as the only significant predictive factor (relative risk = 2.13, P = .007). Overall 5-year survival and recurrence-free survival rates were 67.9% and 25.9%, respectively. Significant predictive factors for poor overall survival were Child-Pugh class B (relative risk = 2.43, P = .011), serum α-fetoprotein level (relative risk per 100 units = 1.01; P < .001), and presence of portosystemic collaterals (relative risk = 2.15, P = .025). The development of LTP significantly shortened median recurrence-free survival (28.0 months without LTP vs 12.0 months with LTP) and necessitated a higher number of interventional procedures (2.2 sessions without LTP vs 5.1 sessions with LTP). CONCLUSION RFA is a safe and effective first-line treatment for early-stage HCC, with a 5-year survival rate of 67.9%. High serum α-fetoprotein level, advanced Child-Pugh class, and presence of portosystemic collateral vessels had a significant negative effect on overall survival.