Chi Ho Lee

Amiodarone-Induced Thyrotoxicosis Is a Predictor of Adverse Cardiovascular Outcome

BACKGROUND Amiodarone-induced thyrotoxicosis (AIT) is a clinical condition that is notoriously difficult to manage; the relative risk of adverse cardiovascular events in these patients compared with euthyroid patients is largely unknown. OBJECTIVE We compared the clinical characteristics and major adverse cardiovascular events (MACE) in AIT and euthyroid patients. METHOD Patients at a tertiary referral center who had been prescribed amiodarone for at least 3 months were retrospectively analyzed. Baseline clinical characteristics, laboratory parameters, and outcome events were evaluated. MACE was defined as cardiovascular mortality, myocardial infarction, stroke and heart failure, or ventricular arrhythmias that required hospitalization. RESULTS A total of 354 patients (61.8 +/- 14.1 yr; 64.7% male) with a mean follow-up of 48.6 +/- 26.7 months were studied. AIT, euthyroid status, and amiodarone-induced hypothyroidism were identified in 57 (16.1%), 224 (63.3%), and 73 (20.6%) patients, respectively. No differences in baseline clinical characteristics were observed between AIT and euthyroid patients. Nonetheless AIT patients demonstrated a higher MACE rate (31.6 vs. 10.7%, P < 0.01), mostly driven by a higher rate of ventricular arrhythmias that required admission (7.0 vs. 1.3%, P = 0.03). Cox-regression multivariate analysis revealed that AIT (hazard ratio 2.68; confidence interval 1.53-4.68; P < 0.01) and left ventricular ejection fraction less than 45% (hazard ratio 2.52; confidence interval 1.43-4.42; P < 0.01) were independent predictors of MACE. CONCLUSION In patients prescribed long-term amiodarone therapy, occurrence of AIT is associated with a 2.7-fold increased risk of MACE. Regular and close biochemical surveillance is thus advisable to identify and treat this high-risk group of patients.

Circulating Fibroblast Growth Factor 21 Levels Predict Progressive Kidney Disease in Subjects With Type 2 Diabetes and Normoalbuminuria

BACKGROUND Elevated fibroblast growth factor 21 (FGF21) levels have been suggested, from cross-sectional studies, as an indicator of subclinical diabetic nephropathy. We investigated whether serum FGF21 was predictive of the development of diabetic nephropathy. METHOD Baseline serum FGF21 levels were measured in 1136 Chinese type 2 diabetic subjects recruited from the Hong Kong West Diabetes Registry. The role of serum FGF21 in predicting decline in estimated glomerular filtration rate (eGFR) over a median follow-up of 4 years was analyzed using Cox regression analysis. RESULTS At baseline, serum FGF21 levels increased progressively with eGFR category (P for trend <.001). Among 1071 subjects with baseline eGFR ≥ 30 mL/min/1.73 m(2), serum FGF21 levels were significantly higher in those with eGFR decline during follow-up (n = 171) than those without decline (n = 900) (P < .001). In multivariable Cox regression analysis, baseline serum FGF21 was independently associated with eGFR decline (hazard ratio, 1.21; 95% confidence interval [CI], 1.01-1.43; P = .036), even after adjustment for baseline eGFR. In a subgroup of 559 subjects with baseline eGFR ≥ 60 mL/min/1.73 m(2) and normoalbuminuria, serum FGF21 level remained an independent predictor of eGFR decline (hazard ratio, 1.36; 95% CI, 1.06-1.76; P = .016). Integrated discrimination improvement (IDI) suggested that the inclusion of baseline serum FGF21 significantly improved the prediction of eGFR decline (IDI, 1%; 95% CI, 0.1-3.0; P = .013) in this subgroup, but not in the initial cohort involving all subjects. CONCLUSIONS Elevated serum FGF21 levels may be a useful biomarker for predicting kidney disease progression, especially in the early stages of diabetic nephropathy.

Serum fibroblast growth factor 21 is a superior biomarker to other adipokines in predicting incident diabetes

Fibroblast growth factor 21 (FGF21) improves glucose and lipid metabolism, but high circulating levels are found in type 2 diabetes, suggesting FGF21 resistance. Serum FGF21 predicts incident diabetes, but its performance compared to established and emerging predictors is not known. We aimed to study the performance of FGF21 in diabetes prediction, relative to other adipokines and established risk factors including 2‐h plasma glucose (2hG) during the oral glucose tolerance test (OGTT).

Impact of Genetic Loci Identified in Genome-Wide Association Studies on Diabetic Retinopathy in Chinese Patients With Type 2 Diabetes

Purpose Diabetic retinopathy (DR) is a common microvascular complication of type 2 diabetes (T2DM). Genome-wide association studies (GWAS) had identified novel DR-susceptibility genetic variants in various populations. We examined the associations of these DR-associated single nucleotide polymorphisms (SNPs) with severe DR in a Chinese T2DM cohort. Methods Cross-sectional case-control studies on sight-threatening DR (STDR) and proliferative DR (PDR) were performed. We genotyped 38 SNPs showing top association signals with DR in previous GWAS in 567 STDR cases, including 309 with PDR and 1490 non-DR controls. Multiple logistic regression models with adjustment for conventional risk factors, including age, sex, duration of diabetes, and presence of hypertension, were employed. Results The strongest association was found at INSR rs2115386, an intronic SNP of INSR: Padjusted = 9.13 × 10-4 (odds ratio [OR],1.28; 95% confidence interval [95%CI], 1.11-1.48) for STDR, and Padjusted= 1.12 × 10-4 (OR [95%CI],1.44 [1.20-1.74]) for PDR. rs599019 located downstream of COLEC12 (Padjusted = 0.019; OR [95%CI],1.19 [1.03-1.38]) and rs4462262 located at an intergenic region between ZWINT and MRPS35P3 (Padjusted = 0.041; OR [95%CI],1.38[1.01-1.89]) also were significantly associated with STDR, but not with PDR alone. On the other hand, MYT1L-LOC729897 rs10199521 (Padjusted = 0.022; OR [95%CI],1.25 [1.03-1.51]) and API5 rs899036 (Padjusted = 0.049; OR [95%CI],1.36 [1.00-1.85]) showed significant independent associations only with PDR. Similar results were obtained when hemoglobin A1c also was included in the adjustment models. Conclusions We demonstrated the significant and independent associations of several GWAS-identified SNPs with DR in Chinese T2DM patients with severe DR. The findings on INSR rs2115386 are supportive of the role of insulin resistance, or the compensatory hyperinsulinemia, in the pathogenesis of DR.

Exome-chip association analysis reveals an Asian-specific missense variant in PAX4 associated with type 2 diabetes in Chinese individuals

Aims/hypothesisGenome-wide association studies (GWASs) have identified many common type 2 diabetes-associated variants, mostly at the intronic or intergenic regions. Recent advancements of exome-array genotyping platforms have opened up a novel means for detecting the associations of low-frequency or rare coding variants with type 2 diabetes. We conducted an exomechip association analysis to identify additional type 2 diabetes susceptibility variants in the Chinese population.MethodsAn exome-chip association study was conducted by genotyping 5640 Chinese individuals from Hong Kong, using a custom designed exome array, the Asian Exomechip. Single variant association analysis was conducted on 77,468 single nucleotide polymorphisms (SNPs). Fifteen SNPs were subsequently genotyped for replication analysis in an independent Chinese cohort comprising 12,362 individuals from Guangzhou. A combined analysis involving 7189 cases and 10,813 controls was performed.ResultsIn the discovery stage, an Asian-specific coding variant rs2233580 (p.Arg192His) in PAX4, and two variants at the known loci, CDKN2B-AS1 and KCNQ1, were significantly associated with type 2 diabetes with exome-wide significance (pdiscovery < 6.45 × 10−7). The risk allele (T) of PAX4 rs2233580 was associated with a younger age at diabetes diagnosis. This variant was replicated in an independent cohort and demonstrated a stronger association that reached genome-wide significance (pmeta-analysis [pmeta] = 3.74 × 10−15) in the combined analysis.Conclusions/interpretationWe identified the association of a PAX4 Asian-specific missense variant rs2233580 with type 2 diabetes in an exome-chip association analysis, supporting the involvement of PAX4 in the pathogenesis of type 2 diabetes. Our findings suggest PAX4 is a possible effector gene of the 7q32 locus, previously identified from GWAS in Asians.

Optimal Cut-Offs of Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) to Identify Dysglycemia and Type 2 Diabetes Mellitus: A 15-Year Prospective Study in Chinese

Background The optimal reference range of homeostasis model assessment of insulin resistance (HOMA-IR) in normal Chinese population has not been clearly defined. Here we address this issue using the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS), a prospective population-based cohort study with long-term follow-up. Material & Methods In this study, normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) were defined according to the 1998 World Health Organization criteria. Dysglycemia referred to IFG, IGT or T2DM. This study comprised two parts. Part one was a cross-sectional study involving 2,649 Hong Kong Chinese subjects, aged 25–74 years, at baseline CRISPS-1 (1995–1996). The optimal HOMA-IR cut-offs for dysglycemia and T2DM were determined by the receiver-operating characteristic (ROC) curve. Part two was a prospective study involving 872 subjects who had persistent NGT at CRISPS-4 (2010–2012) after 15 years of follow-up. Results At baseline, the optimal HOMA-IR cut-offs to identify dysglyceia and T2DM were 1.37 (AUC = 0.735; 95% confidence interval [CI] = 0.713–0.758; Sensitivity [Se] = 65.6%, Specificity [Sp] = 71.3%] and 1.97 (AUC = 0.807; 95% CI = 0.777–0.886; Se = 65.5%, Sp = 82.9%) respectively. These cut-offs, derived from the cross-sectional study at baseline, corresponded closely to the 75th (1.44) and 90th (2.03) percentiles, respectively, of the HOMA-IR reference range derived from the prospective study of subjects with persistent NGT. Conclusions HOMA-IR cut-offs, of 1.4 and 2.0, which discriminated dysglycemia and T2DM respectively from NGT in Southern Chinese, can be usefully employed as references in clinical research involving the assessment of insulin resistance.

Role of Circulating Fibroblast Growth Factor 21 Measurement in Primary Prevention of Coronary Heart Disease Among Chinese Patients With Type 2 Diabetes Mellitus

Background Fibroblast growth factor 21 (FGF21) has demonstrated beneficial effects on lipid and carbohydrate metabolism. In cross‐sectional studies, an association of raised circulating FGF21 levels with coronary heart disease (CHD) was found in some but not all studies. Here we investigated prospectively whether baseline serum FGF21 levels could predict incident CHD in subjects with type 2 diabetes mellitus and no known cardiovascular diseases. Methods and Results Baseline serum FGF21 levels were measured in 3528 Chinese subjects with type 2 diabetes mellitus recruited from the Hong Kong West Diabetes Registry. The role of baseline serum FGF21 levels in predicting incident CHD over a median follow‐up of 3.8 years was analyzed using Cox regression analysis. Among 3528 recruited subjects without known cardiovascular diseases, 147 (4.2%) developed CHD over a mean follow‐up of 4 years. Baseline serum log‐transformed FGF21 levels were significantly higher in those who had incident CHD than those who did not (222.7 pg/mL [92.8–438.4] versus 151.1 pg/mL [75.6–274.6]; P<0.001). On multivariable Cox regression analysis, baseline serum FGF21 levels, using an optimal cutoff of 206.22 pg/mL derived from our study, independently predicted incident CHD (hazard ratio, 1.55; 95% CI, 1.10–2.19; P=0.013) and significantly improved net reclassification index and integrated discrimination improvement after adjustment for conventional cardiovascular risk factors. Conclusions We have demonstrated, for the first time, that serum FGF21 level is an independent predictor of incident CHD and might be usefully utilized as a biomarker for identifying type 2 diabetes mellitus subjects with raised CHD risk, for primary prevention.

Managing non-alcoholic fatty liver disease in diabetes: challenges and opportunities.

Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus are two common health problems worldwide. Globally, it has been estimated that one-quarter of the adult population in the world currently suffers from NAFLD. In Asia, probably attributed to the obesity epidemic, the prevalence of NAFLD was similar, or even slightly higher, when compared with that in the Western population (27% in Asia vs 24.1% in North America and 23.7% in Europe), and the incidence was approximately 52 per 1,000 person-years. Similarly, there are more than 380 million people with diabetes worldwide, and the International Diabetes Federation estimates that this will rise to almost 592 million within a generation. Importantly, individuals with NAFLD are often comorbid with type 2 diabetes, or vice versa. Type 2 diabetes is present in almost one-quarter of patients with NAFLD and in almost half of those with non-alcoholic steatohepatitis (NASH), a critical stage in the spectrum of NAFLD. In contrast, NAFLD is found in as many as 75% of patients with type 2 diabetes. Strikingly, these two conditions can interact with each other and cause a significant negative health impact. The presence of NAFLD increases the risk of allcause mortality among patients with type 2 diabetes, whereas type 2 diabetes increases the risk of advanced fibrosis by threefold, doubles the risk of hepatocellular carcinoma, and independently predicts the overall and liver mortality in NAFLD. However, given the large scale of the problem and the projected considerable healthcare burden, multiple limitations and unmet needs in the management of NAFLD in type 2 diabetes patients remain to be addressed. First, despite this strong and proven bidirectional relationship between NAFLD and type 2 diabetes, specific guidelines are still lacking on whom, when and how to screen for NAFLD among patients with type 2 diabetes. Universal screening for NAFLD in type 2 diabetes patients is not advocated in the current practice guidelines for NAFLD management in the USA, partly related to the issue of cost-effectiveness. NAFLD is defined as the presence of more than 5% of hepatic steatosis. Commonly used imaging techniques, such as hepatic ultrasound, are insensitive to mild hepatic steatosis (<30%). In contrast, more sensitive tools, such as magnetic resonance spectroscopy, are however, limited by cost and availability. In addition, as NAFLD spans a spectrum from simple hepatic steatosis to NASH, liver cirrhosis and hepatocellular carcinoma, universal screening for NAFLD in type 2 diabetes patients could result in the inclusion of a proportion of patients who might remain as simple hepatic steatosis with minimal risk of progression. Second, although type 2 diabetes is well known to be a risk factor for NAFLD progression, monitoring of disease progression is challenging. Measuring alanine aminotransferase (ALT) levels is an insensitive method of disease monitoring, as ALT fluctuates within the spectrum of NAFLD. Liver biopsy used to be the gold standard for evaluating the different stages of NAFLD. However, this is limited by its invasive nature, sampling errors and complication rates. Indeed, given the large number of type 2 diabetes patients suffering from NAFLD, it is both impractical and technically difficult to follow them up individually for their hepatic progression using serial liver biopsies. The advent of transient elastography has rendered a non-invasive monitoring of both hepatic steatosis and fibrosis feasible, while utilizing estimates from the controlled attenuation parameter and liver stiffness measurements, respectively. Currently, however, it is still not possible to differentiate NASH from simple hepatic steatosis using noninvasive and commercially available tools, including transient elastography. Over the years, there has been extensive research looking for sensitive and well-validated biomarkers for NASH. Some are quite promising, such as circulating cytokeratin-18 fragment, a hepatocyte apoptotic marker, as well as several adipokines or obesity-related protein markers that have also been investigated as emerging NASH biomarkers, partly because obesity serves as a common risk factor for NAFLD and type 2 diabetes. Our observation of a protective role of adiponectin in NASH, published in the Journal of Clinical Investigation in 2003 has been extensively replicated. We also found, in a study published in Journal of Hepatology in 2013, that the expression of adipocyte fatty acid-binding protein, an adipokine involved in the trafficking of lipids, was elevated in the Kupffer cells of mice with NASH, and treatment with a small molecule of adipocyte fatty acid-binding protein inhibitor could protect obese mice from NASH. In addition, along with our Australian collaborators, we found that circulating adipocyte fatty acid-binding protein levels positively correlated with the degree of inflammation and fibrosis in NAFLD. In humans, serum levels of fibroblast growth factor 21 (FGF21), an emerging metabolic regulator closely related to various obesity-related conditions, were elevated in patients with biopsy-proven NASH compared with that of healthy controls. Whether these circulating proteins could be usefully employed as NASH biomarkers, especially in type 2

An Exome-Chip Association Analysis in Chinese Subjects Reveals a Functional Missense Variant of GCKR That Regulates FGF21 Levels

Fibroblast growth factor 21 (FGF21) is increasingly recognized as an important metabolic regulator of glucose homeostasis. Here, we conducted an exome-chip association analysis by genotyping 5,169 Chinese individuals from a community-based cohort and two clinic-based cohorts. A custom Asian exome-chip was used to detect genetic determinants influencing circulating FGF21 levels. Single-variant association analysis interrogating 70,444 single nucleotide polymorphisms identified a novel locus, GCKR, significantly associated with circulating FGF21 levels at genome-wide significance. In the combined analysis, the common missense variant of GCKR, rs1260326 (p.Pro446Leu), showed an association with FGF21 levels after adjustment for age and sex (P = 1.61 × 10−12; β [SE] = 0.14 [0.02]), which remained significant on further adjustment for BMI (P = 3.01 × 10−14; β [SE] = 0.15 [0.02]). GCKR Leu446 may influence FGF21 expression via its ability to increase glucokinase (GCK) activity. This can lead to enhanced FGF21 expression via elevated fatty acid synthesis, consequent to the inhibition of carnitine/palmitoyl-transferase by malonyl-CoA, and via increased glucose-6-phosphate–mediated activation of the carbohydrate response element binding protein, known to regulate FGF21 gene expression. Our findings shed new light on the genetic regulation of FGF21 levels. Further investigations to dissect the relationship between GCKR and FGF21, with respect to the risk of metabolic diseases, are warranted.

Genetics of Apparently Sporadic Pheochromocytoma and Paraganglioma in a Chinese Population

Identification of germline mutation in patients with apparently sporadic pheochromocytomas and paragangliomas is crucial. Clinical indicators, which include young age, bilateral or multifocal, extra-adrenal, malignant, or recurrent tumors, predict the likelihood of harboring germline mutation in Caucasian subjects. However, data on the prevalence of germline mutation, as well as the applicability of these clinical indicators in Chinese, are lacking. We conducted a cross-sectional study at a single endocrine tertiary referral center in Hong Kong. Subjects with pheochromocytomas and paragangliomas were evaluated for the presence of germline mutations involving 10 susceptibility genes, which included NF1, RET, VHL, SDHA, SDHB, SDHC, SDHD, TMEM 127, MAX, and FH genes. Clinical indicators were assessed for their association with the presence of germline mutations. Germline mutations, 2 being novel, were found in 24.4% of the 41 Chinese subjects recruited and 11.4% among those with apparently sporadic presentation. The increasing number of the afore-mentioned clinical indicators significantly correlated with the likelihood of harboring germline mutation in one of the 10 susceptibility genes. (r=0.757, p=0.026). The presence of 2 or more clinical indicators should prompt genetic testing for germline mutations in Chinese subjects. In conclusion, our study confirmed that a significant proportion of Chinese subjects with apparently sporadic pheochromocytoma and paraganglioma harbored germline mutations and these clinical indicators identified from Caucasians series were also applicable in Chinese subjects. This information will be of clinical relevance in the design of appropriate genetic screening strategies in Chinese populations.