Interaction between sarcopenia and nonalcoholic fatty liver disease

Sae Kyung Joo,Won Kim 대한간학회 2023 Clinical and Molecular Hepatology(대한간학회지) Vol.29 No.-

Sarcopenia and nonalcoholic fatty liver disease (NAFLD) are common health problems related to aging. Despite the differences in their diagnostic methods, several cross-sectional and longitudinal studies have revealed the close link between sarcopenia and NAFLD. Sarcopenia and NAFLD are linked by several shared pathogenetic mechanisms, including insulin resistance, hormonal imbalance, systemic inflammation, myostatin and adiponectin dysregulation, nutritional deficiencies, and physical inactivity, thus implicating a bidirectional relationship between sarcopenia and NAFLD. However, there is not sufficient data to support a direct causal relationship between sarcopenia and NAFLD. Moreover, it is currently difficult to conclude whether sarcopenia is a risk factor for nonalcoholic steatohepatitis (NASH) or is a consequence of NASH. Therefore, this review intends to touch on the shared common mechanisms and the bidirectional relationship between sarcopenia and NAFLD.

Genetic Variants Rather than Metabolic Phenotypes Determine the Histologic Severity of Nonalcoholic Fatty Liver Disease in Asian Populations

( Sae Kyung Joo ),( Bo Kyung Koo ),( Yong Jin Jung ),( Dong Hyeon Lee ),( Won Kim ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Recent genome-wide association studies have identified that variants in PNPLA3, TM6SF2, and MBOAT7 are significantly associated with nonalcoholic fatty liver disease (NAFLD) in multiple ethnic groups. Data on their genetic impact on NAFLD in Asian populations are limited. Methods: In a biopsy-proven NAFLD cohort, PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 were genotyped using a Taqman-based assay and we examined their association with histologic severity of NAFLD. We also investigated whether these genetic variants might have the additive effect on the risk of nonalcoholic steatohepatitis (NASH) or fibrosis. Insulin resistance was evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR). Results: Using the entire set of 461 subjects including 176 with NASH, 189 with non-alcoholic fatty liver (NAFL), and 96 controls, we replicated the significant association between histologic confirmed NAFLD and both PNPLA3 rs738409 (odds ratio [OR], 1.91; 95% confidence interval [CI], 1.33 - 2.73) and TM6SF2 rs58542926 (OR, 2.21; 95% CI, 1.00 - 4.90). Among NAFLD subjects, both genetic variants were also significantly associated with the risk of NASH (PNPLA3; OR, 1.95; 95% CI, 1.44 - 2.63 and TM6SF2; OR, 1.96; 95% CI, 1.10 - 3.52) and significant fibrosis (PNPLA3; OR, 1.53; 95% CI, 1.12 - 2.09 and TM6SF2; OR, 1.95; 95% CI, 1.08 - 3.53) even after adjustment for age, sex, and body mass index (BMI). Moreover, co-existence of both risk alleles in PNPLA3 and TM6SF2 additively increased the risk of NASH (age, sex, and BMI-adjusted OR, 3.93; 95% CI, 1.14 - 13.60) and significant fibrosis (age, sex, and BMI-adjusted OR, 4.68; 95% CI, 1.41 - 15.59). PNPLA3 rs738409 was significantly associated with HOMA-IR (P = 0.003) and aspartate aminotransferase (AST) level (P = 0.001); however, TM6SF2 rs58542926 was only associated with AST level (P = 0.049). In the case of MBOAT7 rs641738, there was no association between genotypes and histologic or metabolic parameters in the NAFLD cohort. Conclusions: In this large biopsy-proven NAFLD cohort, PNPLA3 rs738409 and TM6SF2 rs58542926, but not MBOAT7 rs641738, were significantly associated with NASH and significant fibrosis. We also found the difference in the metabolic profile according to both genotypes, and confirmed the additive effect of PNPLA3 and TM6SF2 on the risk of NASH and significant fibrosis.

The Severity of Portal Inflammation Is Associated with Hepatic Fibrosis Stage and Components of Metabolic Syndrome in NAFLD

( Sae Kyung Joo ),( Yong Jin Jung ),( Dong Hyeon Lee ),( Won Kim ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Portal inflammation is considered significant marker in pediatric NAFLD with severe liver disease and fibrosis. However, the prognostic significance of portal inflammation remains unclear in adult patients with NAFLD. Therefore, we assessed the relationship between portal inflammation, hepatic fibrosis and metabolic syndrome in adult NAFLD. Methods: Three hundred ninety nine patients with biopsy-proven NAFLD were prospectively included. Histology assessed using Kleiner classification for fibrosis and the Nonalcoholic Steatohepatitis Clinical Research Network system for portal inflammation. All enrolled patients were assessed for the presence of the metabolic syndrome. Patients were categorized according to severity of portal inflammation (no/mild/more than mild). Results: Approximately one-third of the patients had either diabetes mellitus (DM) or hypertension, and more than half had metabolic syndrome. Fibrosis was presented in 291 (72.9%) patients and significant fibrosis was seen in 67 (16.8%) patients. Almost half of the patients had mild portal inflammation. In terms of the NAFLD activity score (NAS), approximately one-third had definite NASH (NAS ≥5). Those with mild portal inflammation subgroup had more severe metabolic phenotype, with higher body mass index, waist circumference, and lower high-density lipoprotein than in no portal inflammation subgroup. Similarly, those with moderate to severe portal inflammation subgroup had more severe metabolic phenotype than in mild or no portal inflammation subgroup. Portal inflammation was associated with the severity of steatosis (P < 0.001), presence of ballooning (P < 0.001), lobular inflammation (P < 0.001) on logistic regression analysis. Moreover, stage of fibrosis is significantly increased with increasing portal inflammation severity (P < 0.001). Fibrosis was associated with portal inflammation (95% confidence interval 3.64-6.03, odds ratio = 4.69). Diabetes was also associated with portal inflammation (95% confidence interval 1.94-4.49, odds ratio = 2.95). Conclusions: Portal inflammation is associated with histological and clinical features in NAFLD patients. It suggests portal inflammation is a significant predictor of disease progression in patients with NAFLD.

LC : Spleen Stiffness Measurement Determines the Severity of Esophageal Varix in Patients with Liver Cirrhosis

( Sae Kyung Joo ),( Hwi Young Kim ),( Yong Jin Jung ),( Dong Hee Kim ),( Byung Kwan Kim ),( Kook Lae Lee ),( Won Kim ) 대한간학회 2013 춘·추계 학술대회 (KASL) Vol.2013 No.1

Backgrounds & aims: Portal hypertension is related to cirrhosis- related complications such as esophageal varix (EV), and splenic congestion might reflect the severity of portal hypertension. Hence, the aim of this study was to elucidate the potential role of spleen stiffness measurement in discriminating significant or ruptured EV from early or unruptured EV. Methods: The stiffness of liver and spleen was measured in 126 patients with cirrhosis by acoustic radiation force impulse ultrasonography. Simultaneously, all study participants underwent esophagoduodenoscopy for evaluating the presence and severity of EV. The diagnostic performance of noninvasive markers including stiffness of liver and spleen, APRI index, and spleen diameter was assessed by receiver operating characteristic curves. Results: Splenic or hepatic shear wave velocity (Vs; m/sec) was significantly higher in cirrhotic patients with EV than without EV (3.57±0.46 vs. 3.01±0.49 in spleen, 2.75±0.69 vs. 2.09±0.81 in liver; P<0.0001). A tendency toward increasing splenic Vs existed in a graded fashion across the grade of EV (3.01±0.49 without EV, 3.39±0.49 in grade I, 3.60±0.42 in II, 3.85±0.37 in III; P<0.0001). Among the patients with EV, splenic Vs was significantly higher in those with variceal rupture than without rupture of EV (3.80±0.36 vs. 3.20±0.51; P=0.002). An optimal cut-off value for significant EV≥grade II or rupture of EV was 3.40 of splenic Vs. Conclusion: Spleen stiffness, based on tissue strain analytics, might better reflect hemodynamics of portal flow in patients with cirrhosis than liver stiffness or spleen diameter. Therefore, spleen stiffness might be a reliable, promising, and noninvasive surrogate marker for predicting significant esophageal varix or variceal bleeding.

Free Paper Session : HCC ; Topographical impact on marginal recurrence of hepatitis B-related hepatocellular carcinoma following radiofrequency ablation: therapeutic impediments (초)

( Sae Kyung Joo ),( Won Kim ),( Joon Suk Kim ),( Young Ho So ),( Jeong Min Lee ),( Jae Young Lee ),( Se Hyung Kim ),( Dong Hee Kim ),( Yoon Jun Kim ),( Jung Hwan Yoon ),( Hyo Suk Lee ) 대한간학회 2011 Clinical and Molecular Hepatology(대한간학회지) Vol.17 No.3(S)

Comparison of Risk Factors for NASH and Advanced Fibrosis between Patients with Obese and Non-Obese Nonalcoholic Fatty Liver Disease

( Sae Kyung Joo ),( Donghee Kim ),( Won Kim ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Non-alcoholic fatty liver disease (NAFLD) has been frequently found in the non-obese as well as in the obese. Furthermore, Asians have a relatively higher prevalence of NAFLD despite lower body mass index (BMI). We investigated whether pathological features were comparable between obese and non-obese subgroups in a histologically confirmed NAFLD registry cohort. Methods: We analyzed the cross-sectional cohort derived from the ongoing prospective Boramae NAFLD registry. We graded steatosis, lobular inflammation, and hepatocellular ballooning according to the NAFLD activity score (NAS). Nonalcoholic steatohepatitis (NASH) was diagnosed based on an overall pattern of histological hepatic injury consisting of macrovesicular steatosis, inflammation, or hepatocellular ballooning according to Brunt et al.’s criteria. Additionally, fibrosis was assessed according to a 5-point scale proposed by Brunt and modified by Kleiner et al. Advanced fibrosis was defined as F3.F4. Results: Among the 365 biopsy-proven NAFLD patients, 87 had non-obese NAFLD and 278 had obese NAFLD in terms of BMI. Patients with obese NAFLD had significantly higher levels of serum alanine aminotransferase (ALT), insulin resistance (HOMA-IR), and adipose tissue insulin resistance than those with non-obese NAFLD. Histological features except steatosis grade were comparable between patients with obese and non-obese NAFLD. Under multivariate logistic regression analyses, serum aspartate aminotransferase (AST), triglycerides, and platelet counts in the non-obese NAFLD subgroup and gender, BMI, serum AST and ALT levels, and HOMA-IR in the obese NAFLD subgroup were independent risk factors for NASH, respectively. Diabetes, serum albumin levels, and HOMA-IR in the non-obese NAFLD subgroup and gender, diabetes, serum AST levels, platelet counts, and HOMA-IR in the obese NAFLD subgroup were significant risk factors for advanced fibrosis, respectively. Moreover, various noninvasive fibrosis tests such as FIB-4, APRI, and adipose tissue IR showed comparable diagnostic performances, irrespective of obesity status. Conclusions: In terms of the histological characteristics, non-obese NAFLD subtype is not significantly different from obese NAFLD subtype. However, different drivers might account for high-risk progression of non-obese and obese NAFLD.

It's Ready for Targeting Muscle in Nonalcoholic Fatty Liver in This Era of Aging

( Sae Kyung Joo ),( Won Kim ) 대한간학회 2019 Gut and Liver Vol.13 No.1

Additive Effects of PNPLA3 and TM6SF2 on the Histological Severity of Non-Alcoholic Fatty Liver Disease

( Sae Kyung Joo ),( Dong Hyeon Lee ),( Bo Kyung Koo ),( Won Kim ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: We investigated the effects of PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7-TMC4 rs641738 variants on metabolic phenotypes and their combined effects on the histological severity of non-alcoholic fatty liver disease (NAFLD). Methods: We genotyped rs738409, rs58542926, and rs641738 in biopsy-proven NAFLD patients (n = 416) and healthy controls (n = 109). Homeostasis model assessment of insulin resistance and adipose tissue insulin resistance were calculated. Results: The rs738409 and rs58542926 variants, but not rs641738, were associated not only with non-alcoholic steatohepatitis (NASH) (odds ratio [OR], 2.00; 95% confidence interval [CI], 1.46-2.73 and OR, 1.91; 95% CI, 1.04-3.51) but also with significant fibrosis (= F2) (OR, 1.53; 95% CI, 1.11-2.11 and OR, 1.88; 95% CI, 1.02-3.46) in NAFLD, even after adjustment for metabolic risk factors. Of both variants, only rs738409 was associated with homeostasis model assessment of insulin resistance and adipose tissue insulin resistance even in healthy controls (P=0.046 and 0.002, respectively) as well as in the entire study cohort (P=0.016 and 0.048, respectively). PNPLA3 and TM6SF2 risk variants additively increased the risk of NASH and significant fibrosis (OR per risk allele, 2.03; 95% CI, 1.50-2.73 and 1.61; 95% CI, 1.19-2.17). Even in subjects with low insulin resistance, the risk of NASH or significant fibrosis increased as the number of risk alleles increased (P=0.008 and 0.020, respectively). Conclusions: PNPLA3 and TM6SF2 determine the risk of NASH and significant fibrosis, even after adjustment for insulin resistance, and exert an additive effect on NASH and significant fibrosis.

Sex differences in metabolic dysfunction-associated steatotic liver disease: a narrative review

Sae Kyung Joo,Won Kim Ewha Womans University School of Medicine 2024 EMJ (Ewha medical journal) Vol.47 No.2

Understanding the effects of sex and sex differences on liver health and disease is crucial for individualized healthcare and informed decision-making for patients with liver disease. The impact of sex on liver disease varies according to its etiology. Women have a lower prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) than men. However, postmenopausal women face a higher risk of advanced liver fibrosis due to hormonal influences. Sex differences affect the pathogenesis of MASLD, which involves a complex process involving several factors such as hormones, obesity, and the gut microbiome. Furthermore, sex-related differences in the development of MASLD-related hepatocellular carcinoma have been observed. The sex-specific characteristics of MASLD necessitate an individualized management approach based on scientific evidence. However, research in this area has been lacking. This article reviews the current understanding of sex differences in MASLD.

Relationship between Appendicular Sarcopenia and Non-alcoholic Fatty Liver Disease in Korean Population

( Sae Kyung Joo ),( Koo Bo Kyung ),( Won Kim ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: Non-alcoholic fatty liver disease (NAFLD) is characterized byan accumulation of fat droplets in the hepatocyte, which is one ofthe major causes of liver disease worldwide. Previous studies haveshown that NAFLD and sarcopenia and visceral adiposity seem toshare similar pathophysiological mechanisms. However, the functionalroles of skeletal muscle and visceral adipose tissue in NAFLD havenot been elucidated. The aim of this study was to determine whetherthe skeletal muscle mass affects the progression of NAFLD.Methods: In the prospective cohort study, we recruited 223 patientswith biopsy-proven NAFLD and collected their anthropometric databetween January 2013 and August 2015. We performed abdominalfat-amount computed tomography to quantify the visceral and subcutaneousabdominal adipose tissue amount and underwent bioelectricalimpedance analysis to measure body fat and musclecomposition. Sarcopenia was defined as an appendicular skeletal musclemass % (ASM%) = [total appendicular skeletal muscle mass (kg)/ body weight (kg) × 100〕.Results: A total of 223 subjects were analyzed. The mean age was52.24 ± 14.87 years, and 53.4% of the subjects were men. Menwere significantly younger (46.61 ± 14.79 years in men and 58.68± 12.14 years in women, P <0.001) and had higher muscle massthan women (31.96 ± 5.16 kg in men and 21.76 ± 2.85 kg in women, P <0.001). In male group, subjects with advanced fibrosis (≥F3)showed significantly higher body mass index (BMI; P =0.006), totalbody fat mass (P <0.001), and total abdominal adipose tissue (TAT)amount (P =0.016), but lower ASMI (P<0.001) compare to withoutadvanced fibrosis. Meanwhile, there were no significant differencesin BMI, total body fat mass, TAT amount, and ASMI between womenNAFLD subjects with advanced fibrosis and without.Conclusions: Appendicular sarcopenia may play a role in fibrosis progressionin NAFLD. However, the gender-specific difference in theimpact of sarcopenia on NAFLD may be attributed to the interactionamong environmental, genetic, and hormonal factors. Therefore, furtherstudies are needed to reveal the causal relationship betweenappendicular sarcopenia and liver fibrosis in subjects with NAFLD,especially according to gender.