Development of a prediction score (ThyroCOVID) for identifying abnormal thyroid function in COVID-19 patients.

PURPOSE: Thyroid dysfunction in COVID-19 carries clinical and prognostic implications. In this study, we developed a prediction score (ThyroCOVID) for abnormal thyroid function (TFT) on admission amongst COVID-19 patients. METHODS: Consecutive COVID-19 patients admitted to Queen Mary Hospital were prospectively recruited during July 2020-May 2021. Thyroid-stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3) were measured on admission. Multivariable logistic regression analysis was performed to identify independent determinants of abnormal TFTs. ThyroCOVID was developed based on a clinical model with the lowest Akaike information criteria. RESULTS: Five hundred and forty six COVID-19 patients were recruited (median age 50 years, 45.4% men, 72.9% mild disease on admission). 84 patients (15.4%) had abnormal TFTs on admission. Patients with abnormal TFTs were more likely to be older, have more comorbidities, symptomatic, have worse COVID-19 severity, higher SARS-CoV-2 viral loads and more adverse profile of acute-phase reactants, haematological and biochemical parameters. ThyroCOVID consisted of five parameters: symptoms (malaise), comorbidities (ischaemic heart disease/congestive heart failure) and laboratory parameters (lymphocyte count, C-reactive protein, and SARS-CoV-2 cycle threshold values). It was able to identify abnormal TFT on admission with an AUROC of 0.73 (95% CI 0.67-0.79). The optimal cut-off of 0.15 had a sensitivity of 75.0%, specificity of 65.2%, negative predictive value of 93.5% and positive predictive value of 28.1% in identifying abnormal TFTs on admission amongst COVID-19 patients. CONCLUSION: ThyroCOVID, a prediction score to identify COVID-19 patients at risk of having abnormal TFT on admission, was developed based on a cohort of predominantly non-severe COVID-19 patients.

Potential role of fibroblast growth factor 21 in the deterioration of bone quality in impaired glucose tolerance.

PURPOSE: Findings on trabecular bone score (TBS), an index of bone quality, have been reported in prediabetes defined by impaired fasting glucose or HbA1c. Here, we assessed the bone mineral density (BMD) and TBS in prediabetes individuals with impaired glucose tolerance (IGT), and investigated the association of these bone parameters with serum levels of fibroblast growth factor 21 (FGF21), a hormone implicated in bone metabolism and with higher levels in IGT. METHODS: Chinese postmenopausal women aged 55-80 years, without diabetes, were recruited from the Hong Kong Cardiovascular Risk Factor Prevalence Study in 2016-2018. Normal glucose tolerance (NGT) was defined by fasting glucose < 5.6 mmol/L and 2-h plasma glucose (2hG) < 7.8 mmol/L, and IGT by 2hG 7.8-11 mmol/L. Serum levels of FGF21 and other bone metabolism regulators were measured. Insulin sensitivity was assessed by the Matsuda index. Independent determinants of TBS were evaluated using multivariable stepwise linear regression. RESULTS: 173 individuals with NGT and 73 with IGT were included. TBS was lower in those with IGT compared to those with NGT, while BMD was comparable. Individuals with IGT had significantly higher serum FGF21 levels, which in turn showed an independent inverse relationship with TBS, attenuated after inclusion of the Matsuda index. Serum FGF21 levels, however, did not correlate with BMD. CONCLUSION: Among Chinese postmenopausal women, bone quality was worse in IGT, despite comparable bone density. FGF21 levels showed a significant independent inverse relationship with TBS, partly attributed to insulin resistance. Whether FGF21 contributes to the impaired bone quality in IGT remains speculative.

HbA1c variability, in addition to mean HbA1c, predicts incident hip fractures in Chinese people with type 2 diabetes.

Type 2 diabetes is associated with an increased risk of hip fractures. We hypothesize that long-term glycemic variability predicts incident hip fractures. We demonstrated that HbA1c variability predicted incident hip fractures independent of mean HbA1c, suggesting the potential benefits of minimizing glycemic variability in addition to optimizing mean glycemia for bone health. INTRODUCTION: Type 2 diabetes is associated with an increased risk of hip fractures, and a linear relationship between HbA1c levels and hip fracture incidence has been observed. We hypothesize that HbA1c variability also predicts incident hip fractures in type 2 diabetes. METHODS: Chinese individuals with type 2 diabetes aged ≥ 60 years were identified from electronic health records in Hong Kong between 2008 and 2012 and observed for incident hip fractures. Hip fracture was defined by the International Classification of Diseases (Ninth Revision) code 820. HbA1c variability was determined using standard deviation, adjusted standard deviation, and coefficient of variation of HbA1c measurements in the 5 years preceding the entry date. Multivariable Cox regression analysis was used to evaluate associations between HbA1c variability and incident hip fractures. RESULTS: A total of 83,282 participants were included. Their mean age was 71.3 ± 7.5 years, duration of diabetes 11.7 ± 7.7 years, baseline HbA1c 56.6 ± 13.5 mmol/mol (7.33 ± 1.23%), and median follow-up 6.8 years. All indices of HbA1c variability were significant independent predictors of incident hip fractures, with an adjusted hazard ratio of up to 1.29 (all p < 0.001), and remained to be independent predictors across groups of different intensity of glycemic control. Mean HbA1c ≥ 64 mmol/mol (8.0%) was associated with a 25% increase in incident hip fractures compared with mean HbA1c < 53 mmol/mol (7.0%). CONCLUSION: HbA1c variability is an independent positive predictor of hip fracture in type 2 diabetes, across the spectrum of varying degree of glycemic control, while a high HbA1c is also not advisable from the perspective of bone health.

A clinical prediction score using age at diagnosis and saline infusion test parameters can predict aldosterone-producing adenoma from idiopathic adrenal hyperplasia.

PURPOSE: Accurate subtyping of the primary aldosteronism into aldosterone-producing adenoma (APA) and idiopathic adrenal hyperplasia (IAH) is important to direct for specific treatment modalities. The objective of the study was to compare the clinical and biochemical parameters of APA and IAH patients to derive a Clinical Prediction Score reliably predicting APA from IAH. METHODS: This was a retrospective multi-centre study recruiting 38 APA patients and 42 IAH patients from four major hospitals in Hong Kong using database from Surgical Outcomes Monitoring and Improvement Programme and Clinical Data Analysis and Reporting System. Their clinical and biochemical parameters were evaluated. RESULTS: Patients in APA group were younger than IAH group (mean age 48.6 ± 9.2 vs. 57.1 ± 7.3 years old, p < 0.001), had more suppressed renin before saline infusion in saline infusion test (SIT) (median 0.19 [IQR 0.15-0.37] vs. 0.39 [IQR 0.19-0.69] ng/mL/h, p = 0.01), and higher aldosterone level after saline infusion in SIT (median 674 [IQR 498-1000] vs. 327 [IQR 242-483] pmol/L, p < 0.001). A clinical prediction score using three parameters was devised, comprising age at diagnosis < 50 years, PRA before saline infusion in SIT ≤ 0.26 ng/mL/h, and aldosterone level after saline infusion in SIT ≥ 424 pmol/L. A score of 2 would predict APA with a sensitivity of 84.2% and specificity of 88.1%, and a score of 3 would predict APA with a sensitivity of 31.6% and specificity of 100%. CONCLUSIONS: Clinical Prediction Score based on the combination of age at diagnosis, PRA, and aldosterone level in the saline infusion tests could reliably predict APA from IAH.

Which creatinine-based estimated glomerular filtration rate equation best predicts all-cause mortality in Chinese subjects with type 2 diabetes?

AIM: In Chinese, ethnicity-based and/or diabetes specific modifications of the Modification of Diet in Renal Disease (MDRD) and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations have been developed for determining estimated glomerular filtrate rate (eGFR). This study aimed to compare the performance of five different creatinine-based eGFR equations in predicting all-cause mortality among Chinese subjects with type 2 diabetes (T2DM). METHODS: A total of 6739 Chinese subjects with T2DM were included. Their eGFR was calculated using the MDRD, CKD-EPI, their respective modified equations for Chinese, and the diabetes specific CKD-EPI Chinese T2DM equations. Multiple Cox regression analysis was used to evaluate the associations of eGFR with all-cause mortality. C-statistics, net reclassification index (NRI) and integrated discrimination index (IDI) were applied to assess the discrimination and reclassification of each eGFR equation in predicting mortality outcome. RESULTS: Over a follow-up of 5.7years, the incidence of all-cause mortality was 12.9% (N=867). The CKD-EPI equation discriminated all-cause mortality better than the MDRD equation (C-statistics: 0.714 vs. 0.689, p<0.0001), and Chinese modification of their respective equations did not improve discrimination. Among the five eGFR equations evaluated, the CKD-EPI Chinese T2DM equation provided the best discrimination in predicting all-cause mortality among Chinese subjects with T2DM, and was the only equation providing a significantly positive NRI and IDI relative to the CKD-EPI equation. CONCLUSIONS: Among Chinese subjects with T2DM, our findings suggested that the CKD-EPI Chinese T2DM equation best predicted all-cause mortality, and relative to the CKD-EPI equation, conferred improved discrimination and reclassification.

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.

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.

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.

Cardiometabolic risk profile of participants with prediabetes diagnosed by HbA1c criteria in an urban Hong Kong Chinese population over 40 years of age.

AIMS: To investigate the usefulness of the additional measurement of HbA1c , compared with performing only the oral glucose tolerance test (OGTT), in identifying participants at increased cardiometabolic risk, in an urban Chinese population. METHODS: All participants from the fourth visit of the population-based Hong Kong Cardiovascular Risk Factors Prevalence Study, without known diabetes, were included. All had their glycaemic status assessed by OGTT and HbA1c , according to American Diabetic Association 2010 criteria. RESULTS: Based on OGTT criteria alone, 3.5% of the study cohort (N = 1300) had diabetes and 19.2% had prediabetes. Based on HbA1c criteria only, 6.2% had diabetes and 61.2% had prediabetes. The measurement of HbA1c , in addition to the OGTT, increased the proportion of participants with diabetes to 7.8% and with prediabetes to 65.3%. Subjects with prediabetes having raised HbA1c but normal glycaemia (N = 600) had waist circumference, systolic blood pressure, fasting glucose, insulin resistance index (HOMA-IR), Gutt Index and Framingham 10-year cardiovascular risk scores intermediate between those with both normal HbA1c and glycaemia (N = 350), and those with impaired fasting glucose and/or impaired glucose tolerance (N = 249; all P < 0.01). CONCLUSION: The measurement of HbA1c in our population, in addition to the OGTT, results in the detection of a large number of participants with prediabetes having raised HbA1c but normal glycaemia who have a cardiometabolic risk profile intermediate between impaired fasting glucose and/or impaired glucose tolerance and normal participants, and would benefit from early lifestyle intervention.

Serum adipocyte fatty acid-binding protein levels were independently associated with carotid atherosclerosis.

OBJECTIVE: Adipocyte fatty acid-binding protein (A-FABP) has been shown to be an important player in atherosclerosis in animal models. However, the clinical relevance of these findings is still unknown. This study aims to examine the relationship between serum A-FABP level and carotid intima-media thickness (IMT), an indicator of atherosclerosis in humans. METHODS AND RESULTS: The study cohort included 479 Chinese subjects who underwent carotid IMT measurement. Serum A-FABP levels were determined by enzyme-linked immunosorbent assays. Serum A-FABP levels positively correlated with carotid IMT in both men (r=0.211, P=0.001) and women (r=0.435, P<0.001). In women, but not in men, the presence of plaques was associated with significantly higher serum A-FABP levels (P<0.001 versus women without plaques). Stepwise multiple regression analysis showed that serum A-FABP level was independently associated with carotid IMT in women (P=0.034), together with age and hypertension (both P<0.001). CONCLUSIONS: A-FABP is an independent determinant of carotid atherosclerosis in Chinese women, but not in men. This gender difference may be attributed to the lower serum A-FABP levels in men, and the effect of other risk factors, such as smoking, among our male participants. Our results have provided clinical evidence supporting the role of A-FABP in the development of atherosclerosis.

Polymorphisms of the gene encoding adiponectin and glycaemic outcome of Chinese subjects with impaired glucose tolerance: a 5-year follow-up study.

AIMS/HYPOTHESIS: Polymorphisms of the gene encoding adiponectin (ADIPOQ) have previously been associated with type 2 diabetes in Europid and Japanese subjects, but not in Pima Indians. The aim of this study was to determine the contribution made by ADIPOQ gene variants to glycaemic status in southern Chinese individuals. SUBJECTS AND METHODS: Sixty unrelated subjects were screened for single-nucleotide polymorphisms (SNPs) in the ADIPOQ gene by direct sequencing. The association of tagging SNPs with the outcome of glycaemic status in 262 subjects with impaired glucose tolerance (IGT) was examined in a 5-year prospective study. RESULTS: We identified 15 polymorphisms in the ADIPOQ gene, ten of them constituting the tagging SNPs. At 5 years, 39.7% of the subjects with IGT had regressed to NGT, 41.2% had persistent IGT or impaired fasting glucose and 19.1% had developed diabetes. Only the T45G polymorphism was associated with persistent hyperglycaemia at 5 years (p=0.001). Haplotypes formed by the addition of other SNPs, as haplotype blocks or pairs, did not confer greater association than T45G alone. On logistic regression analysis, T45G independently predicted persistent hyperglycaemia at 5 years (OR=2.25, 95% CI 1.29-3.95, G carriers vs TT; p=0.005). It also predicted persistent hyperglycaemia in a nested case-control study involving 158 sex- and age-matched controls with persistent NGT (p=0.012, adjusted for BMI), and that of diabetes or glycaemia progression (p<0.05) in a meta-analysis that also included two published studies in Europid subjects. CONCLUSIONS/INTERPRETATION: Our findings support a significant role of this common ADIPOQ gene polymorphism in predicting glycaemic status in southern Chinese people.