Model Output.

<p>(A) Simulation of No treatment vs. treatment with entecavir for a Korean CHB population: Model simulation of patient outcomes at year 30 in two hypothetical Korean cohorts of patients with chronic hepatitis B, 60% of whom were HBeAg-positive. A total of 1000 patients were untreated and 1000 patients received entecavir treatment for 5 years (B) Weighted value differentiations between entecavir versus lamivudine or telbivudine: Daily cost savings per patient with chronic hepatitis B (60% with HBeAg-positive CHB) in Korea over a 30-year period by use of entecavir instead of lamivudine or telbivudine assuming an average patient lifespan of 65 years and an average initiation age of 35 years and 5 years of treatment with 74% compliance (histological reversal stops when treatment stops). Sensitivity analysis was conducted within 95% Confidence Interval. (C) Weighted value differentiations between switching to entecavir versus maintaining on lamivudine of suboptimal responders for lamivudine: Daily cost savings per patient with chronic hepatitis B (60% with HBeAg-positive CHB) in Korea over a 30-year period by use of entecavir instead of maintain on lamivudine assuming an average patient lifespan of 65 years and an average initiation age of 35 years and 5 years of treatment with 74% compliance (histological reversal stops when treatment stops). Sensitivity analysis was conducted within 95% Confidence Interval.</p

Model Cost Input.

a<p>Antiviral drug cost not included</p>b<p>Calculated from fibrosis total cost, assuming F0F1/∶F2F3F4 = 1∶1.1 based on guidance of Korean advisory board, In addition, patient ratio is assumed to 1∶1</p>c<p>Calculated from cirrhosis total cost, assuming compensated∶ decompensated  = 1∶2.1 and patient ratio is assumed to be 1∶1.61 based on Yang et al. 2004</p>d<p>Calculated & updated liver transplant surgery cost & post liver transplant cost with Korea organ sharing networks database & Seoul national university organ transfer center data base</p>e<p>Assume about 50% of F0/F1 based on EASL guideline</p>f<p>Only consider direct medical cost of caring disease state</p

Model Assumption.

a<p>No patients entered the model in Ishak fibrosis stages F0/F1 or decompensated cirrhosis/HCC/liver transplant/post-liver transplant.</p>b<p>Sensitivity analysis input range for compliance rate 70%∼90%, for annual discount rate 3%∼7%, and for all other variables ±10% standard deviation.</p>c<p>Patients with uncontrolled viral load (HBV DNA level>300 copies/ml).</p>d<p>Patients with controlled viral load (HBV DNA level <300 copies/ml).</p>e<p>Assumptions for the population as a whole. The probability of death was linked to liver histology and not to viral load.</p><p>HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen, HBV = hepatitis B virus, HCC = hepatocellular carcinoma; CHB = chronic hepatitis B; HIRA = Health Insurance Review & Assessment Service in Korea</p

Low Vitamin D Status Is Associated with Nonalcoholic Fatty Liver Disease Independent of Visceral Obesity in Korean Adults

<div><p>Objective</p><p>To investigate the association between serum 25-hydroxyvitamin D [25(OH)D] levels and nonalcoholic fatty liver disease (NAFLD) independent of visceral obesity in Koreans and to examine whether the associations differ according to the presence of diabetes or insulin resistance.</p><p>Research Design and Methods</p><p>A total of 1081 adults were enrolled from a population-based cohort in Ansan city. Serum 25(OH)D concentrations were measured in all subjects. Insulin resistance was measured by homeostasis model assessment of insulin resistance (HOMA-IR). Using computed tomography, NAFLD was diagnosed if the liver attenuation index (LAI, the difference between the mean hepatic and splenic attenuation) was <5 Hounsfield Units.</p><p>Results</p><p>In subjects with diabetes (n = 282), 25(OH)D levels were negatively associated with waist circumference, fasting insulin, HOMA-IR, triglyceride levels, and visceral abdominal fat, and were positively associated with LAI after adjusting for age, sex, season, exercise, and vitamin supplementation. In subjects without diabetes, only triglyceride level was negatively associated with 25(OH)D. The adjusted odds ratio (OR) for NAFLD increased sequentially across decreasing quartiles of 25(OH)D in subjects with diabetes even after adjusting for visceral fat [Q1 vs. Q4; OR for NAFLD 2.5 (95% CI:1.0–6.2)]. In contrast, no significant difference in OR was observed in subjects without diabetes. When we classified non-diabetic subjects by HOMA-IR, an increase in the OR for NAFLD across decreasing quartiles of 25(OH)D was observed in the high HOMA-IR (≥2.5) group [n = 207, Q1 vs. Q4; OR 3.8(1.4–10.3)], but not in the low HOMA-IR (<2.5) group [n = 592, OR 0.8 (0.3–1.9)].</p><p>Conclusions</p><p>Low vitamin D status is closely associated with NAFLD, independent of visceral obesity in subjects with diabetes or insulin resistance.</p></div

Correlation plots between log-transformed 25(OH)D and liver attenuation index (LAI) in diabetic (A), non-diabetic (B), non-diabetic, IR+ (C) and non-diabetic, IR- (D) subjects, respectively.

<p>(correlation coefficient (<i>r</i>) and <i>p</i> value (<i>p</i>) of A, B, C, and D: A, <i>r = </i>0.1137, <i>p</i> = 0.057; B, <i>r</i> = −0.0005, <i>p</i> = 0.990; C, <i>r</i> = 0.1535, <i>p</i> = 0.027; D, <i>r</i> = −0.0570, <i>p</i> = 0.167).</p

Odds ratios for NAFLD in subjects with or without diabetes according to the month-matched 25(OH)D quartiles.

<p>Model 1: adjusted for age, sex, exercise, vitamin supplementation, active cancer, recent hospitalization, chronic pulmonary diseases, and cardiovascular diseases.</p><p>Model 2: model 1+ body mass index.</p><p>Model 3: model 1+ visceral abdominal fat.</p><p>Model 4: model 3+HbA1c, hypertension, total cholesterol, triglycerides, HDL-cholesterol.</p><p>Abbreviations: non-DM, IR-, non-diabetic subjects with HOMA-IR <2.5; non-DM, IR+, non-diabetic subjects with HOMA-IR ≥2.5; Q1∼Q4, month-matched 25(OH)D quartiles 1∼4.</p

Characteristics of study subjects according to the presence or absence of diabetes.

<p>Data are expressed as means ± S.D.</p>*<p>Data are expressed as median (1^st quartile, 3^rd quartile). <i>P</i> values are from the t-test using logarithmic transformed values due to skewed distribution.</p>†<p>Regular: ≥3 times/week, ≥30 minutes per session; light: <3 times/week.</p><p>Abbreviations: HOMA-IR, homeostasis model assessment of insulin resistance; NAFLD, non-alcoholic fatty liver disease; LAI, liver attenuation index; 25(OH)D, serum 25-hydroxyvitamin D.</p

Gene-set enrichment study of the significantly associated SNPs.

<p>The functional enrichment among the flanking genes of identified susceptibility-associated SNPs (<i>P</i> < 5.0×10⁻⁴⁾ was estimated by gene ontology and pathway analyses implemented using DAVID and i-GSEA4GWAS softwares, respectively. The significance of the susceptibility-associated SNPs was estimated with a cutoff of <i>P</i> < 5.0×10⁻⁴. * <i>P</i>-values obtained from the pathway analysis are indicated.</p

Genotype-tissue expression analysis of rs7944135.

<p><b>A.</b> A <i>cis</i>-expression quantitative trait locus analysis and multi-tissue posterior probability for rs7944135 and <i>DTX4</i> are shown using the GTEx portal database. The five tissues with the highest statistical significance in the <i>cis</i>-expression quantitative trait locus analysis (<i>P</i>-value < 10⁻⁵) are indicated. This means that the expression level of <i>DTX4</i> significantly differs according to the allele of rs7944135 in those five tissues. <b>B.</b> The graphs for expression level of <i>DTX4</i> according to the genotypes of rs7944135 in five tissues. With the alteration to A, minor allele, of rs7944135, that was associated with acquisition of HBsAg seroclearance, the expression of <i>DTX4</i> is decreased.</p

ROI3 enriched with significant SNPs for HBsAg seroclearance in CHB patients.

<p>ROI3 enriched with significant SNPs for HBsAg seroclearance in CHB patients.</p