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Epidemiology of non-alcoholic fatty liver disease-related hepatocellular carcinoma and its implications

Wong SW, Ting YW, Chan WK

JGH Open, 2018 Oct;2(5):235-241.
PMID: 30483595 DOI: 10.1002/jgh3.12070

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related mortality worldwide. Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver pathology that is characterized by the excessive accumulation of fat in the liver attributable to overnutrition and is strongly associated with the metabolic syndrome. Non-alcoholic steatohepatitis is the more severe form of NAFLD that is defined histologically by the presence of lobular inflammation and hepatocyte ballooning. Non-alcoholic steatohepatitis patients have a greater tendency to develop advanced liver fibrosis, cirrhosis, and HCC. This review focuses on the epidemiology of NAFLD-related HCC and its implications. NAFLD has been estimated to contribute to 10-12% of HCC cases in Western populations and 1-6% of HCC cases in Asian populations. NAFLD-related HCC is expected to increase in Asian populations, in line with the increased prevalence of NALFD similar to that of Western populations in recent years. The increasing burden of NAFLD-related HCC over time has been demonstrated in studies from both Western and Asian populations. Certain factors such as ethnicity, obesity, and diabetes mellitus appear to have an incremental effect on the risk of developing HCC among NAFLD patients. The difficulty in identifying NAFLD patients with cirrhosis and the possibility of HCC developing in noncirrhotic NAFLD patients are challenges that need to be addressed. Further understanding of these gaps may contribute to better surveillance strategies for the early detection of HCC in NAFLD patients to reduce the mortality and improve the survival of these patients.
Fulltext Triglyceride to high-density lipoprotein cholesterol ratio is an independent predictor of liver fibrosis among pediatrics non-alcoholic fatty liver disease

Ting YW, Jalaludin MY, Zaini AA, Mohamed R

Front Endocrinol (Lausanne), 2022;13:1071350.
PMID: 36589844 DOI: 10.3389/fendo.2022.1071350

BACKGROUND: Insulin resistance (IR), one of the key components of the metabolic syndrome, is recognized as the pathophysiological hallmark of non-alcoholic fatty liver disease (NAFLD). This study aims to investigate the relationship between surrogate markers of IR and the severity of NAFLD among overweight or obese children.
METHODOLOGY: A total of 56 consecutive children aged 6 to 18 years old were recruited from the pediatric obesity and type 2 diabetes mellitus (T2DM) clinic in University Malaya Medical Centre (UMMC) from 2016 to 2019. Data on anthropometric measurements, clinical components of metabolic syndrome and fasting serum insulin were collected. Triglyceride to high-density lipoprotein cholesterol ratio (TG: HDL-C), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and Single Point Insulin Sensitivity Estimator (SPISE) were calculated. Transient elastography was performed with hepatic steatosis and liver fibrosis assessed by controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), respectively.
RESULTS: A total of 44 children (78.6%) had liver steatosis and 35.7% had presence of significant liver fibrosis (stage F≥2). Majority (89.3%) are obese and 24 children (42.9%) were diagnosed with metabolic syndrome. Higher number of children with T2DM and significant liver fibrosis were associated with higher tertiles of TG: HDL-C ratio (p<0.05). Top tertile of TG: HDL-C ratio was an independent predictor of liver fibrosis (OR=8.14, 95%CI: 1.24-53.36, p=0.029). ROC analysis showed that the area under the curve (AUC) of HOMA-IR (0.77) and TG: HDL-C ratio (0.71) were greater than that of metabolic syndrome (0.70), T2DM (0.62) and SPISE (0.22). The optimal cut-off values of HOMA-IR and TG: HDL-C ratio for detecting liver fibrosis among children with NAFLD are 5.20 and 1.58, respectively.
CONCLUSION: Children with NAFLD and higher TG: HDL-C ratio are more likely to have liver fibrosis. TG: HDL-C ratio is a promising tool to risk stratify those with NAFLD who are at risk of developing advanced liver disease.
Fulltext Metabolic Syndrome Is Associated With Advanced Liver Fibrosis Among Pediatric Patients With Non-alcoholic Fatty Liver Disease

Ting YW, Wong SW, Anuar Zaini A, Mohamed R, Jalaludin MY

Front Pediatr, 2019;7:491.
PMID: 31850288 DOI: 10.3389/fped.2019.00491

Background: Non-alcoholic fatty liver disease (NAFLD) among children is a growing concern with potential significant outcome. This study aims to investigate the relationship between hepatic steatosis, metabolic syndrome, and liver fibrosis among children with obesity and diabetes mellitus. Methodology: Children aged 6-18 years old were recruited from pediatric obesity and diabetes clinic in University Malaya Medical Center (UMMC) between year 2016 and 2019. Data on basic demographics, anthropometric measurements and clinical components of metabolic syndrome were collected. Transient elastography was performed with hepatic steatosis and liver fibrosis assessed by controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) respectively. Mild, moderate and severe steatosis were defined as >248, >268, and >280 dB/m respectively, and LSM above 7.0 kPa for fibrosis stage F ≥ 2, 8.7 kPa for F ≥ 3, and 10.3 kPa for F4 (cirrhosis). Results: A total of 57 children (60% male) with median age of 13 years old were recruited. Fifty (87.7%) of the children are obese and 27 (54%) out of 50 are morbidly obese. Among 44 (77.2%) patients with steatosis, 40 (70.2%) had severe steatosis and 18 (40.9%) had developed liver fibrosis of stage 2 and above. Advanced fibrosis or cirrhosis was detected in 8 (18.2%) children with presence of steatosis. Twenty-three out of 57 (40.4%) was diagnosed with metabolic syndrome. Fibrosis is three times more likely to occur in the presence of metabolic syndrome (OR = 3.545, 95% CI: 1.135-11.075, p = 0.026). Waist circumference is a significant predictor of fibrosis after multiple regression analysis. Conclusion: Obese children with metabolic syndrome are more likely to have advanced liver fibrosis compared to those without metabolic syndrome. Waist circumference predicts development of liver fibrosis.
Fulltext Loss-of-function HSD17B13 variants, non-alcoholic steatohepatitis and adverse liver outcomes: Results from a multi-ethnic Asian cohort

Ting YW, Kong AS, Zain SM, Chan WK, Tan HL, Mohamed Z, et al.

Clin Mol Hepatol, 2021 Jul;27(3):486-498.
PMID: 33618508 DOI: 10.3350/cmh.2020.0162

BACKGROUND/AIMS: 17β-hydroxysteroid dehydrogenase 13 (HSD17B13) variants were recently reported to have significantly lower odds of non-alcoholic fatty liver disease (NAFLD). This is a two-part study that aimed to evaluate the association of HSD17B13 variants with NAFLD and its histological severity, and to identify the association of the variants with clinical outcomes in a cohort of biopsy-proven NAFLD patients.
METHODS: Consecutive biopsy-proven NAFLD patients and controls without fatty liver were recruited for this study between 2009 and 2014. Genotyping for HSD17B13 variants was performed using rhAmp assays. A total of 165 patients with NAFLD were monitored up until August 2019. Clinical outcomes were recorded.
RESULTS: HSD17B13 rs72613567 TA allele and rs6834314 G allele were associated with lower odds of non-alcoholic steatohepatitis (NASH) in the overall cohort and among ethnic Chinese, but not among ethnic Malays or Indians (P<0.05). During a mean follow-up of 89 months, 32 patients (19.4%) experienced at least one clinical outcome (cardiovascular events, n=22; liver-related complications, n=6; extra-hepatic malignancy, n=5; and mortality, n=6). The rs72613567 homozygous TA allele and the rs6834314 homozygous G allele were independently associated with a lower incidence of liver-related complications (hazard ratio [HR], 0.004; 95% confidence interval [CI], 0.00-0.64; P=0.033 and HR, 0.01; 95% CI, 0.00-0.97; P=0.048, respectively) and were associated with lower grade of hepatocyte ballooning among the ethnic Chinese.
CONCLUSION: HSD17B13 rs72613567 and rs6834314 variants were inversely associated with NAFLD and NASH, and were associated with lower incidence of adverse liver outcomes in a cohort of multi-ethnic Asian patients with NAFLD.
Chronic inflammation involves CCL11 and IL-13 to facilitate the development of liver cirrhosis and fibrosis in chronic hepatitis B virus infection

Wong SW, Ting YW, Yong YK, Tan HY, Barathan M, Riazalhosseini B, et al.

Scand J Clin Lab Invest, 2021 Apr;81(2):147-159.
PMID: 33528280 DOI: 10.1080/00365513.2021.1876245

The pathogenesis involving non-alcoholic fatty liver disease (NAFLD) in the context of chronic HBV (CHB) virus infection requires to be understood for developing improved modalities of diagnosis and treatment. We retrospectively investigated the association between NAFLD and CHB virus infection in the context of liver fibrosis. Among the 522 consecutive CHB patients who underwent transient elastography between years 2013 and 2016, we studied 455 subjects in the current investigation. Controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) scores were generally higher in patients with steatosis and fibrosis or cirrhosis. Antiviral treatment had significantly reduced the hepatitis B virus (HBV) viral load. Other liver function markers showed a significant positive correlation with both CAP and LSM scores. Plasma IL-13 was independently associated with increased CAP score where every increase of 1 unit of IL-13 was associated with an increase in CAP score by 0.98 unit. CCL11 was independently associated with LSM with every increase of CCL11 by a unit that, in turn, was associated with an increase of LSM score. We found that there was a high concurrence of NAFLD among patients with CHB virus infection. The presence of metabolic syndrome and chronic inflammation in CHB virus-infected patients were two independent factors that led to the progression of liver cirrhosis, with IL-13 playing the key role in linking the metabolic with the inflammatory components.