Glycemic burden and the risk of adverse hepatic outcomes in patients with chronic hepatitis B with type 2 diabetes.

BACKGROUND AND AIMS: Type 2 diabetes (T2D) is common among patients with chronic hepatitis B infection (CHB) and has been associated with increased risk of carcinogenesis, including HCC. We investigated factors associated with HCC and fibrosis progression among patients with CHB with T2D (CHB+T2D). APPROACH AND RESULTS: Chinese patients with CHB were prospectively recruited for the incidence of HCC and fibrosis progression defined by transient elastography. Among patients with CHB+T2D, glycemic control was assessed by mean glycated hemoglobin (HbA1c) and HbA1c variability determined using HbA1c measurements in the 5 years preceding recruitment. A total of 2330 patients with CHB were recruited (mean age 54.6 ±11.8 years old, 55.5% male, 57.9% antiviral-treated), with 671 (28.8%) having CHB+T2D (mean T2D duration 7.2 ± 4.6 years, mean HbA1c 7.2 ± 0.9%). T2D was independently associated with HCC (HR 2.080, 95% CI 1.343-3.222) and fibrosis progression (OR 4.305, 95% CI 3.416-5.424) in the overall cohort. In patients with CHB+T2D, factors reflecting glycemic burden (T2D duration [HR 1.107, 95% CI 1.023-1.198]), mean HbA1c (HR 1.851, 95% CI 1.026-3.339), time reaching target HbA1c (HbA1c-TRT; HR 0.978, 95% CI 0.957-0.999), liver stiffness (HR 1.041-1.043), and smoking (HR 2.726-3.344) were independently associated with HCC (all p < 0.05), but not HbA1c variability or controlled attenuation parameter. The same glycemic burden-related factors (T2D duration, mean HbA1c, and HbA1c-TRT), in addition to baseline fasting glucose, baseline HbA1c, AST and antiviral therapy, were independently associated with fibrosis progression at 3 years. CONCLUSIONS: High glycemic burden was associated with HCC development and fibrosis progression among patients with CHB+T2D, highlighting the importance of glycemic control in reducing liver-related complications.

SGLT2i reduces risk of developing HCC in patients with co-existing type 2 diabetes and hepatitis B infection: A territory-wide cohort study in Hong Kong.

BACKGROUND AND AIMS: Type 2 diabetes (T2D) and chronic hepatitis B infection (CHB) are risk factors of HCC. Sodium glucose co-transporter 2 inhibitors (SGLT2i) inhibit HCC oncogenesis in preclinical studies. However, clinical studies are lacking. This study aimed to evaluate the impact of SGLT2i use on incident HCC using a territory-wide cohort of exclusively patients with co-existing T2D and CHB. APPROACH AND RESULTS: Patients with co-existing T2D and CHB between 2015 and 2020 were identified from the representative electronic database of the Hong Kong Hospital Authority. Patients with and without SGLT2i use were 1:1 matched by propensity score for their demographics, biochemistry results, liver-related characteristics, and background medications. Cox proportional hazards regression model was used to assess the association between SGLT2i use and incident HCC. A total of 2,000 patients with co-existing T2D and CHB (1,000 in each SGLT2i and non-SGLT2i group; 79.7% on anti-HBV therapy at baseline) were included after propensity-score matching. Over a follow-up of 3,704 person-years, the incidence rates of HCC were 1.39 and 2.52 cases per 100 person-year in SGLT2i and non-SGLT2i groups, respectively. SGLT2i use was associated with a significantly lower risk of incident HCC (HR 0.54, 95%CI: 0.33-0.88, p =0.013). The association remained similar regardless of sex, age, glycemic control, diabetes duration, presence of cirrhosis and hepatic steatosis, timing of anti-HBV therapy, and background antidiabetic agents including dipeptidyl peptidase-4 inhibitors, insulin, or glitazones (all p interaction>0.05). CONCLUSIONS: Among patients with co-existing T2D and CHB, SGLT2i use was associated with a lower risk of incident HCC.

Serum thrombospondin-2 level changes with liver stiffness improvement in patients with type 2 diabetes.

OBJECTIVE: Baseline circulating thrombospondin-2 (TSP2) level was identified as a potential novel hepatic fibrosis biomarker that associates with development and progression of hepatic fibrosis in patients with nonalcoholic fatty liver disease and type 2 diabetes. Here, we investigated whether circulating TSP2 levels changed with improvement in liver stiffness (LS), which reflects liver fibrosis on transient elastography. DESIGN: Serum TSP2 levels were measured in participants from a randomized, open-label intervention study, at baseline and after 24-weeks treatment of either dapagliflozin 10 mg (N = 30) or sitagliptin 100 mg daily (N = 30). Vibration-controlled transient elastography was performed to evaluate the severity of hepatic fibrosis and steatosis using LS and controlled attenuation parameter (CAP), respectively. PATIENTS AND MEASUREMENTS: Among all 60 participants with similar clinical characteristics at baseline (mean HbA1c 8.9%, CAP 289 dB/m and LS 5.8 kPa), despite similar HbA1c lowering, treatment with dapagliflozin, but not sitagliptin, led to significant improvements in body weight (BW) (p = .012), CAP (p = .015) and LS (p = .011) after 24 weeks. RESULTS: Serum TSP2 level decreased significantly from baseline in dapagliflozin-treated participants (p = .035), whereas no significant change was observed with sitagliptin. In correlation analysis, change in serum TSP2 levels only positively correlated with change in LS (r = .487, p = .006), but not with changes in BW, CAP or HbA1c after dapagliflozin treatment. CONCLUSIONS: Serum TSP2 level decreased with LS after dapagliflozin treatment, and was independent of improvements in BW, glycemic control and hepatic steatosis, further supporting the potential of serum TSP2 level as a novel hepatic fibrosis biomarker in type 2 diabetes.

Risk of Incident Thyroid Dysfunction in the Post-Acute Phase of COVID-19: A Population-Based Cohort Study in Hong Kong.

OBJECTIVE: The evidence of thyroid dysfunction in the post-acute phase of SARS-CoV-2 infection is limited. This study aimed to evaluate the risk of incident thyroid dysfunction in the post-acute phase of COVID-19. METHODS: This retrospective, propensity-score matched, population-based study included COVID-19 patients and non-COVID-19 individuals between January 2020 and March 2022, identified from the electronic medical records of the Hong Kong Hospital Authority. The cohort was followed up until the occurrence of outcomes, death, or 31 January 2023, whichever came first. Patients with COVID-19 were 1:1 matched to controls based on various variables. The primary outcome was a composite of thyroid dysfunction (hyperthyroidism, hypothyroidism, initiation of antithyroid drug or levothyroxine, and thyroiditis). Cox regression was employed to evaluate the risk of incident thyroid dysfunction during the post-acute phase. RESULTS: A total of 84 034 COVID-19 survivors and 84 034 matched controls were identified. Upon a median follow-up of 303 days, there was no significant increase in the risk of diagnosed thyroid dysfunction in the post-acute phase of COVID-19 (hazard ratio [HR] 1.058, 95% confidence interval 0.979-1.144, P = .154). Regarding the secondary outcomes, patients with COVID-19 did not have increased risk of hyperthyroidism (HR 1.061, P = .345), hypothyroidism (HR 1.062, P = .255), initiation of antithyroid drug (HR 1.302, P = .070), initiation of levothyroxine (HR 1.086, P = .426), or thyroiditis (P = .252). Subgroup and sensitivity analyses were largely consistent with the main analyses. CONCLUSION: Our population-based cohort study provided important reassuring data that COVID-19 was unlikely to be associated with persistent effects on thyroid function.

Effect of type 2 diabetes on the inducible degrader of LDL receptor.

The inducible degrader of LDL receptor (IDOL) acts as a post-transcriptional degrader of the LDL receptor (LDLR). IDOL is functionally active in the liver and in peripheral tissues. We have evaluated IDOL expression in circulating monocytes in subjects with and without type 2 diabetes and determined whether changes in IDOL expression could affect macrophage function like cytokine production in vitro. One hundred forty individuals with type 2 diabetes and 110 healthy control subjects were recruited. Cellular expression of IDOL and LDLR in peripheral blood CD14+ monocytes was measured by flow cytometry. The expression of intracellular IDOL was lower in individuals with diabetes than control (21.3 ± 4.6 mean fluorescence intensity × 1,000 vs. 23.8 ± 6.2, P < 0.01), and this was accompanied by an increase in cell surface LDLR (5.2 ± 3.0 mean fluorescence intensity × 1,000 vs. 4.3 ± 1.5, P < 0.01), LDL binding, and intracellular lipid (P < 0.01). IDOL expression correlated with HbA1c (r = -0.38, P < 0.01) and serum fibroblast growth factor-21 (FGF21) (r = -0.34, P < 0.01). Multivariable regression analysis, including age, sex, BMI, smoking, HbA1c, and log(FGF21), showed that HbA1c and FGF21 were significant independent determinants of IDOL expression. IDOL knockdown human monocyte-derived macrophages produced higher concentrations of interleukin 1 beta, interleukin 6, and TNFα than control macrophages upon stimulation with lipopolysaccharide (all P < 0.01). In conclusion, the expression of IDOL in CD14+ monocytes was decreased in type 2 diabetes and was associated with glycemia and serum FGF21 concentration.

Incidence of diabetes following COVID-19 vaccination and SARS-CoV-2 infection in Hong Kong: A population-based cohort study.

BACKGROUND: The risk of incident diabetes following Coronavirus Disease 2019 (COVID-19) vaccination remains to be elucidated. Also, it is unclear whether the risk of incident diabetes after Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is modified by vaccination status or differs by SARS-CoV-2 variants. We evaluated the incidence of diabetes following mRNA (BNT162b2), inactivated (CoronaVac) COVID-19 vaccines, and after SARS-CoV-2 infection. METHODS AND FINDINGS: In this population-based cohort study, individuals without known diabetes were identified from an electronic health database in Hong Kong. The first cohort included people who received ≥1 dose of COVID-19 vaccine and those who did not receive any COVID-19 vaccines up to September 2021. The second cohort consisted of confirmed COVID-19 patients and people who were never infected up to March 2022. Both cohorts were followed until August 15, 2022. A total of 325,715 COVID-19 vaccine recipients (CoronaVac: 167,337; BNT162b2: 158,378) and 145,199 COVID-19 patients were 1:1 matched to their respective controls using propensity score for various baseline characteristics. We also adjusted for previous SARS-CoV-2 infection when estimating the conditional probability of receiving vaccinations, and vaccination status when estimating the conditional probability of contracting SARS-CoV-2 infection. Hazard ratios (HRs) and 95% confidence intervals (CIs) for incident diabetes were estimated using Cox regression models. In the first cohort, we identified 5,760 and 4,411 diabetes cases after receiving CoronaVac and BNT162b2 vaccines, respectively. Upon a median follow-up of 384 to 386 days, there was no evidence of increased risks of incident diabetes following CoronaVac or BNT162b2 vaccination (CoronaVac: 9.08 versus 9.10 per 100,000 person-days, HR = 0.998 [95% CI 0.962 to 1.035]; BNT162b2: 7.41 versus 8.58, HR = 0.862 [0.828 to 0.897]), regardless of diabetes type. In the second cohort, we observed 2,109 cases of diabetes following SARS-CoV-2 infection. Upon a median follow-up of 164 days, SARS-CoV-2 infection was associated with significantly higher risk of incident diabetes (9.04 versus 7.38, HR = 1.225 [1.150 to 1.305])-mainly type 2 diabetes-regardless of predominant circulating variants, albeit lower with Omicron variants (p for interaction = 0.009). The number needed to harm at 6 months was 406 for 1 additional diabetes case. Subgroup analysis revealed no evidence of increased risk of incident diabetes among fully vaccinated COVID-19 survivors. Main limitations of our study included possible misclassification bias as type 1 diabetes was identified through diagnostic coding and possible residual confounders due to its observational nature. CONCLUSIONS: There was no evidence of increased risks of incident diabetes following COVID-19 vaccination. The risk of incident diabetes increased following SARS-CoV-2 infection, mainly type 2 diabetes. The excess risk was lower, but still statistically significant, for Omicron variants. Fully vaccinated individuals might be protected from risks of incident diabetes following SARS-CoV-2 infection.

Risks of stroke, its subtypes and atrial fibrillation associated with glucagon-like peptide 1 receptor agonists versus sodium-glucose cotransporter 2 inhibitors: a real-world population-based cohort study in Hong Kong.

BACKGROUND: There are limited data on head-to-head comparative risk of stroke between sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA). We compared risk of stroke with its subtypes and incident atrial fibrillation (AF) between them. METHODS: A population-based, retrospective cohort of patients with type 2 diabetes between 2008 and 2020 were identified from the electronic health records of Hong Kong Hospital Authority. Patients who received SGLT2i or GLP-1RA were matched pairwise by propensity score. Risks of stroke and AF were evaluated by hazard ratios (HRs) from the Cox proportional hazard regression models. RESULTS: A total of 5840 patients (2920 SGLT2i users; 2920 GLP-1RA users) were included (mean age 55.5 years, 56.1% men, mean HbA1c 8.9% and duration of diabetes 13.7 years). Upon median follow-up of 17 months, there were 111 (1.9%) events of stroke (SGLT2i: 62, 2.1%; GLP-1RA: 49 1.7%). SGLT2i users had comparable risk of all stroke as GLP-1RA users (HR 1.46, 95% CI 0.99-2.17, p = 0.058). SGLT2i users had higher risk of ischemic stroke (HR 1.53, 95% CI 1.01-2.33, p = 0.044) but similar risk of hemorrhagic stroke compared to GLP-1RA users. Although SGLT2i was associated with lower risk of incident AF (HR 0.43, 95% CI 0.23-0.79, p = 0.006), risk of cardioembolic stroke was similar. CONCLUSIONS: Our real-world study demonstrated that GLP-1RA use was associated with lower risk of ischemic stroke, despite the association between SGLT2i use and lower risk of incident AF. There was no significant difference in hemorrhagic stroke risk. GLP-1RA may be the preferred agent for patients with type 2 diabetes at risk of ischemic stroke.

Circulating thrombospondin-2 level for identifying individuals with rapidly declining kidney function trajectory in type 2 diabetes: a prospective study of the Hong Kong West Diabetes Registry.

BACKGROUND: Thrombospondin-2 (TSP2) is a matricellular protein with tissue expression induced by hyperglycaemia. TSP2 has been implicated in non-diabetic renal injury in preclinical studies and high circulating levels were associated with worse kidney function in cross-sectional clinical studies. Therefore, we investigated the prospective associations of circulating TSP2 level with kidney function decline and the trajectories of estimated glomerular filtration rate (eGFR) in type 2 diabetes. METHODS: Baseline serum TSP2 level was measured in 5471 patients with type 2 diabetes to evaluate its association with incident eGFR decline, defined as ≥ 40% sustained eGFR decline, using multivariable Cox regression analysis. Among participants with relatively preserved kidney function (Baseline eGFR ≥ 60 ml/min/1.73m2), joint latent class modelling was employed to identify three different eGFR trajectories. Their associations with baseline serum TSP2 was evaluated using multinomial logistic regression analysis. The predictive performance of serum TSP2 level was examined using time-dependent c-statistics and calibration statistics. RESULTS: Over a median follow-up of 8.8 years, 1083 patients (19.8%) developed eGFR decline. Baseline serum TSP2 level was independently associated with incident eGFR decline (HR 1.21, 95%CI 1.07-1.37, P = 0.002). With internal validation, incorporating serum TSP2 to a model of clinical risk factors including albuminuria led to significant improvement in c-statistics from 83.9 to 84.4 (P < 0.001). Among patients with eGFR ≥ 60 ml/min/1.73m2, baseline serum TSP2 level was independently associated with a rapidly declining eGFR trajectory (HR 1.63, 95%CI 1.26-2.10, P < 0.001). CONCLUSION: Serum TSP2 level was independently associated with incident eGFR decline, particularly a rapidly declining trajectory, in type 2 diabetes.

Pre-operative Cinacalcet Administration Reduces Immediate Post-operative Hypocalcemia Following Total Parathyroidectomy in Severe Renal Hyperparathyroidism.

BACKGROUND: In severe renal hyperparathyroidism (RHPT), whether administrating Cinacalcet before total parathyroidectomy can reduce post-operative hypocalcemia remains unclear. We compared post-operative calcium kinetics between those who took Cinacalcet before surgery (Group I) and those who did not (Group II). METHODS: Patients with severe RHPT (defined by PTH ≥ 100 pmol/L) who underwent total parathyroidectomy between 2012 and 2022 were analyzed. Standardized peri-operative protocol of calcium and vitamin D supplementation was followed. Blood tests were performed twice daily in the immediate post-operative period. Severe hypocalcemia was defined as serum albumin-adjusted calcium < 2.00 mmol/L. RESULTS: Among 159 patients who underwent parathyroidectomy, 82 patients were eligible for analysis (Group I, n = 27; Group II, n = 55). Demographics and PTH levels before Cinacalcet administration were comparable (Group I: 169 ± 49 pmol/L vs Group II: 154 ± 45, p = 0.209). Group I had significantly lower pre-operative PTH (77 ± 60 pmol/L vs 154 ± 45, p < 0.001), higher post-operative calcium (p < 0.05), and lower rate of severe hypocalcemia (33.3% vs 60.0%, p = 0.023). Longer duration of Cinacalcet use correlated with higher post-operative calcium levels (p < 0.05). Cinacalcet use for > 1 year resulted in fewer severe post-operative hypocalcemia than non-users (p = 0.022, OR 0.242, 95% CI 0.068-0.859). Higher pre-operative ALP independently correlated with severe post-operative hypocalcemia (OR 3.01, 95% CI 1.17-7.77, p = 0.022). CONCLUSION: In severe RHPT, Cinacalcet led to significant drop in pre-operative PTH, higher post-operative calcium levels, and less frequent severe hypocalcemia. Longer duration of Cinacalcet use correlated with higher post-operative calcium levels, and the use of Cinacalcet for > 1 year reduced severe post-operative hypocalcemia.

Risk of thyroid dysfunction associated with mRNA and inactivated COVID-19 vaccines: a population-based study of 2.3 million vaccine recipients.

BACKGROUND: In view of accumulating case reports of thyroid dysfunction following COVID-19 vaccination, we evaluated the risks of incident thyroid dysfunction following inactivated (CoronaVac) and mRNA (BNT162b2) COVID-19 vaccines using a population-based dataset. METHODS: We identified people who received COVID-19 vaccination between 23 February and 30 September 2021 from a population-based electronic health database in Hong Kong, linked to vaccination records. Thyroid dysfunction encompassed anti-thyroid drug (ATD)/levothyroxine (LT4) initiation, biochemical picture of hyperthyroidism/hypothyroidism, incident Graves' disease (GD), and thyroiditis. A self-controlled case series design was used to estimate the incidence rate ratio (IRR) of thyroid dysfunction in a 56-day post-vaccination period compared to the baseline period (non-exposure period) using conditional Poisson regression. RESULTS: A total of 2,288,239 people received at least one dose of COVID-19 vaccination (57.8% BNT162b2 recipients and 42.2% CoronaVac recipients). 94.3% of BNT162b2 recipients and 92.2% of CoronaVac recipients received the second dose. Following the first dose of COVID-19 vaccination, there was no increase in the risks of ATD initiation (BNT162b2: IRR 0.864, 95% CI 0.670-1.114; CoronaVac: IRR 0.707, 95% CI 0.549-0.912), LT4 initiation (BNT162b2: IRR 0.911, 95% CI 0.716-1.159; CoronaVac: IRR 0.778, 95% CI 0.618-0.981), biochemical picture of hyperthyroidism (BNT162b2: IRR 0.872, 95% CI 0.744-1.023; CoronaVac: IRR 0.830, 95% CI 0.713-0.967) or hypothyroidism (BNT162b2: IRR 1.002, 95% CI 0.838-1.199; CoronaVac: IRR 0.963, 95% CI 0.807-1.149), GD, and thyroiditis. Similarly, following the second dose of COVID-19 vaccination, there was no increase in the risks of ATD initiation (BNT162b2: IRR 0.972, 95% CI 0.770-1.227; CoronaVac: IRR 0.879, 95%CI 0.693-1.116), LT4 initiation (BNT162b2: IRR 1.019, 95% CI 0.833-1.246; CoronaVac: IRR 0.768, 95% CI 0.613-0.962), hyperthyroidism (BNT162b2: IRR 1.039, 95% CI 0.899-1.201; CoronaVac: IRR 0.911, 95% CI 0.786-1.055), hypothyroidism (BNT162b2: IRR 0.935, 95% CI 0.794-1.102; CoronaVac: IRR 0.945, 95% CI 0.799-1.119), GD, and thyroiditis. Age- and sex-specific subgroup and sensitivity analyses showed consistent neutral associations between thyroid dysfunction and both types of COVID-19 vaccines. CONCLUSIONS: Our population-based study showed no evidence of vaccine-related increase in incident hyperthyroidism or hypothyroidism with both BNT162b2 and CoronaVac.

Cardiovascular benefits of SGLT2 inhibitors in type 2 diabetes, interaction with metformin and role of erythrocytosis: a self-controlled case series study.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have proven cardiovascular benefits in patients with type 2 diabetes (T2D). This self-controlled case series study aims to evaluate whether metformin use and SGLT2i-associated erythrocytosis influence its cardiovascular benefits. METHODS: T2D patients with metformin and/or SGLT2i prescriptions between 2015 and 2020 were identified from the Hong Kong population. Study outcomes were composite cardiovascular diseases (CVD), coronary heart disease (CHD), hospitalisation for heart failure (HHF), stroke, and erythrocytosis. Risk periods were patient-time divided into four mutually exclusive windows: (i) 'baseline period' of metformin use without SGLT2i; (ii) pre-SGLT2i period; (iii) exposure to SGLT2i without metformin; and (iv) exposure to the drug combination. Another SCCS model was applied to evaluate the association between erythrocytosis and cardiovascular outcomes regarding SGLT2i exposure. Four mutually exclusive risk periods included (i) SGLT2i exposure with erythrocytosis; (ii) SGLT2i exposure without erythrocytosis; (iii) absence of SGLT2i exposure with erythrocytosis; and (iv) absence of SGLT2i exposure without erythrocytosis. Incidence rate ratios (IRR) of events at different risk periods were estimated using conditional Poisson regression model. RESULTS: Among 20,861 patients with metformin and/or SGLT2i prescriptions, 2575 and 1700 patients with events of composite CVD and erythrocytosis were identified, respectively. Compared to metformin use without SGLT2i, SGLT2i initiation was associated with lower risks of composite CVD, CHD, and HHF-regardless of the presence (CVD: IRR = 0.43, 95% CI 0.37-0.51; CHD: IRR = 0.44, 95% CI 0.37-0.53; HHF: IRR = 0.29, 95% CI 0.22-0.40; all p < 0.001) and absence of concomitant metformin (CVD: IRR = 0.31, 95% CI 0.20-0.48; CHD: IRR = 0.38, 95% CI 0.25-0.59; HHF: IRR = 0.17, 95% CI 0.09-0.31; all p < 0.001); while SGLT2i was neutral on stroke risk. Compared to metformin-SGLT2i combination, exposure to SGLT2i alone was associated with comparable risks of all cardiovascular outcomes (all p > 0.05). Incidence rates of erythrocytosis at baseline, SGLT2i without and with metformin use periods were 0.75, 3.06 and 3.27 per 100 person-years, respectively. SGLT2i users who developed erythrocytosis had lower risk of HHF (IRR = 0.38, 95% CI 0.14-0.99, p = 0.049) than those who did not. CONCLUSIONS: Our real-world data suggested that SGLT2i-associated cardiovascular benefits were not attenuated by metformin use. Further studies will delineate the role of erythrocytosis as a surrogate marker of SGLT2i-associated cardiovascular benefit in reducing HHF.

Role of non-thyroidal illness syndrome in predicting adverse outcomes in COVID-19 patients predominantly of mild-to-moderate severity.

OBJECTIVE: Existing studies reported the potential prognostic role of non-thyroidal illness syndrome (NTIS), characterized by low triiodothyronine (T3) with normal/low thyroid-stimulating hormone (TSH), mainly in severe COVID-19. None considered the significant impact of SARS-CoV-2 viral load on adverse outcomes. We aimed to clarify the prognostic role of NTIS among predominantly mild-to-moderate COVID-19 patients. DESIGN: A prospective study of COVID-19 patients. PATIENTS AND MEASUREMENTS: Consecutive adults admitted to Queen Mary Hospital for confirmed COVID-19 from July to December 2020 were prospectively recruited. SARS-CoV-2 viral load was represented by cycle threshold (Ct) values from real-time reverse transcription-polymerase chain reaction of the respiratory specimen on admission. Serum TSH, free thyroxine and free T3 were measured on admission. The outcome was deterioration in clinical severity, defined as worsening in ≥1 category of clinical severity according to the Chinese National Health Commission guideline. RESULTS: We recruited 367 patients. At baseline, 75.2% had mild disease, and 27 patients (7.4%) had NTIS. Fifty-three patients (14.4%) had clinical deterioration. Patients with NTIS were older, had more comorbidities, worse symptomatology, higher SARS-CoV-2 viral loads and worse profiles of inflammatory and tissue injury markers. They were more likely to have clinical deterioration (p < .001). In multivariable stepwise logistic regression analysis, NTIS independently predicted clinical deterioration (adjusted odds ratio 3.19, p = .017), in addition to Ct value <25 (p < .001), elevated C-reactive protein (p = .004), age >50 years (p = .011) and elevated creatine kinase (p = .017). CONCLUSIONS: Non-thyroidal illness syndrome was not uncommon even in mild-to-moderate COVID-19 patients. NTIS on admission could predict clinical deterioration in COVID-19, independent of SARS-CoV-2 viral load, age and markers of inflammation and tissue injury.

The Potential Role of Preoperative Trabecular Bone Score in Predicting Changes in Bone Mineral Density After Parathyroidectomy.

BACKGROUND: The skeletal indication for parathyroidectomy for primary hyperparathyroidism (PHPT) is based on bone mineral density (BMD) T-score < - 2.5. Whether trabecular bone score (TBS) additionally identifies patients who benefit from parathyroidectomy in terms of bone health is unknown. We aimed to study changes in BMD and TBS among Chinese who underwent curative parathyroidectomy for PHPT, in relation to their preoperative parameters, especially in those with worst site BMD T-score ≥ - 2.5 (non-osteoporotic range). METHODS: We included consecutive Chinese individuals who underwent curative parathyroidectomy during 2002-2015 for PHPT and completed preoperative and postoperative BMD and TBS measurements in Queen Mary Hospital. Correlations between preoperative parameters and changes in densitometric parameters were studied. RESULTS: 45 Chinese individuals (13 men, 32 women) were included (mean age 62.0 ± 10.0 years and BMI 24.6 ± 4.7 kg/m2). After parathyroidectomy, BMD at lumbar spine (LS) improved by 6.7% (p < 0.001) while TBS did not change. Among women, peak preoperative parathyroid hormone and calcium levels independently predicted LS BMD gain. Among women with BMD in non-osteoporotic range, LS BMD also improved after parathyroidectomy, where preoperative TBS was the only significant variable inversely correlating with percentage change in LS BMD (ρ - 0.775, p = 0.005). Particularly, those with preoperative TBS ≤ 1.25 gained 7.1% LS BMD post-parathyroidectomy (p = 0.003). CONCLUSIONS: LS BMD, but not TBS, improved after parathyroidectomy. Among non-osteoporotic PHPT women, preoperative TBS inversely correlated with postoperative BMD improvement. Hence, low preoperative TBS may be an additional indication for surgical benefit with parathyroidectomy in non-osteoporotic PHPT women, as those with worse preoperative TBS tend to benefit more from surgery.

Thyroid Immune-Related Adverse Events in Patients with Cancer Treated with anti-PD1/anti-CTLA4 Immune Checkpoint Inhibitor Combination: Clinical Course and Outcomes.

OBJECTIVE: Thyroid immune-related adverse events (irAEs) have been reported to have prognostic significance among patients with cancer treated with anti-programmed cell death-1 (PD1) and anti-programmed death-ligand 1 monotherapies. We evaluated the clinical course and predictors of thyroid irAEs in relation to outcomes of patients with advanced cancer treated with combination anti-PD1/anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4). METHODS: We conducted a regional study and identified patients with advanced cancer who received ≥1 cycle of combination anti-PD1/anti-CTLA4 between 2015 and 2019 in Hong Kong. Thyroid function tests (TFTs) were monitored every 3 weeks. Thyroid irAE was defined by ≥2 abnormal TFTs after initiation of combination anti-PD1/anti-CTLA4 in the absence of other causes. RESULTS: One hundred and three patients were included (median age: 59 years; 71.8% men). About 45% had prior anti-PD1 exposure. Upon median follow-up of 6.8 months, 17 patients (16.5%) developed thyroid irAEs, where 6 initially presented with thyrotoxicosis (overt, n = 4; subclinical, n = 2) and 11 with hypothyroidism (overt, n = 2; subclinical, n = 9). Eventually, 10 patients (58.8%) required continuous thyroxine replacement. Systemic steroid was not required in all cases. Prior anti-PD1 exposure (odds ratio, 3.67; 95% CI, 1.19-11.4; P = .024) independently predicted thyroid irAEs. Multivariable Cox regression analysis revealed that occurrence of thyroid irAEs was independently associated with better overall survival (adjusted hazard ratio, 0.34; 95% CI, 0.17-0.71; P = .004). CONCLUSION: Thyroid irAEs are common in routine clinical practice among patients with advanced cancer treated with anti-PD1/anti-CTLA4 combination and might have potential prognostic significance. Regular TFT monitoring is advised for timely treatment of thyroid irAEs to prevent potential morbidities.

Long COVID in Patients With Mild to Moderate Disease: Do Thyroid Function and Autoimmunity Play a Role?

OBJECTIVE: Post-acute sequelae of coronavirus disease 2019 (COVID-19) or long COVID (LC) is an emerging global health issue. Fatigue is a common feature. Whether thyroid function and autoimmunity play a role is uncertain. We aimed to evaluate the prevalence and predictors of LC and the potential role of thyroid function and autoimmunity in LC. METHODS: We included consecutive adults without a known thyroid disorder who were admitted to a major COVID-19 center for confirmed COVID-19 from July to December 2020. Thyroid function tests and antithyroid antibodies were measured for all patients on admission and at follow-up. LC was defined by the presence or persistence of symptoms upon follow-up. RESULTS: In total, 204 patients (median age, 55.0 years; 95 men [46.6%]) were reassessed at a median of 89 days (interquartile range, 69-99) after acute COVID-19. Of the 204 patients, 41 (20.1%) had LC. Female sex (adjusted odds ratio, 2.48; P = .018) and severe acute respiratory syndrome coronavirus 2 polymerase chain reaction cycle threshold value of <25 on admission (adjusted odds ratio, 2.84; P = .012) independently predicted the occurrence of LC. Upon follow-up, most abnormal thyroid function tests in acute COVID-19 resolved, and incident thyroid dysfunction was rare. Nonetheless, we observed incident antithyroid peroxidase (anti-TPO) positivity. Although baseline or follow-up thyroid function tests were not associated with the occurrence of LC, among 172 patients with symptomatic acute COVID-19, symptom resolution was more likely in those with positive anti-TPO upon follow-up (P = .043). CONCLUSION: LC is common among COVID-19 survivors, with females and those with higher viral load in acute COVID-19 particularly being vulnerable. The observation of incident anti-TPO positivity warrants further follow-up for thyroid dysfunction. Whether anti-TPO plays a protective role in LC remains to be elucidated.

High-density lipoprotein in diabetes: Structural and functional relevance.

Low levels of high-density lipoprotein-cholesterol (HDL-C) is considered a major cardiovascular risk factor. However, recent studies have suggested a more U-shaped association between HDL-C and cardiovascular disease. It has been shown that the cardioprotective effect of HDL is related to the functions of HDL particles rather than their cholesterol content. HDL particles are highly heterogeneous and have multiple functions relevant to cardiometabolic conditions including cholesterol efflux capacity, anti-oxidative, anti-inflammatory, and vasoactive properties. There are quantitative and qualitative changes in HDL as well as functional abnormalities in both type 1 and type 2 diabetes. Non-enzymatic glycation, carbamylation, oxidative stress, and systemic inflammation can modify the HDL composition and therefore the functions, especially in situations of poor glycemic control. Studies of HDL proteomics and lipidomics have provided further insights into the structure-function relationship of HDL in diabetes. Interestingly, HDL also has a pleiotropic anti-diabetic effect, improving glycemic control through improvement in insulin sensitivity and ß-cell function. Given the important role of HDL in cardiometabolic health, HDL-based therapeutics are being developed to enhance HDL functions rather than to increase HDL-C levels. Among these, recombinant HDL and small synthetic apolipoprotein A-I mimetic peptides may hold promise for preventing and treating diabetes and cardiovascular disease.

Long-term kidney outcomes in patients with permanent hypoparathyroidism after total thyroidectomy for benign disease: A population-based study.

BACKGROUND: Permanent hypoparathyroidism is a significant complication after total thyroidectomy. This study aimed to evaluate the long-term impact of postoperative permanent hypoparathyroidism on kidney outcomes. METHODS: Data of patients undergoing total thyroidectomy from 1999 to 2014 were retrieved. The estimated glomerular filtration rate was determined from serum creatinine results. Permanent hypoparathyroidism was defined as requiring oral calcium and vitamin D supplements postoperatively for at least 6 months. The primary outcome was a sustained decline in the estimated glomerular filtration rate from baseline by ≥50%. Secondary outcomes were end-stage kidney disease (a composite of sustained estimated glomerular filtration rate <15 mL/min/1.73 m2, need for dialysis, and kidney transplantation) and rate of estimated glomerular filtration rate decline. Patients with and without permanent hypoparathyroidism were compared. Multivariable Cox regression analysis was performed to identify independent risk factors for sustained estimated glomerular filtration rate decline by ≥50%. RESULTS: In total, 3,245 patients were eligible for analysis; 418 patients (12.9%) had permanent hypoparathyroidism. Upon median follow-up of 11.6 years, more patients with permanent hypoparathyroidism had a sustained decline in estimated glomerular filtration rate from baseline by ≥50% compared to those without (15.6% vs 6.9%, P < .001). Similar findings were obtained on Kaplan-Meier analysis (P < .001). Permanent hypoparathyroidism was an independent risk factor for sustained estimated glomerular filtration rate decline by ≥50% (adjusted hazard ratio 2.77, P < .001). Other risk factors included age, preoperative estimated glomerular filtration rate <60 mL/min/1.73m2, and diabetes mellitus. Patients with permanent hypoparathyroidism had a more rapid estimated glomerular filtration rate decline (-1.60 vs -0.70 mL/min/1.73 m2/year, difference -0.91 mL/min/1.73m2/year, P < .001). CONCLUSION: Patients with postsurgical permanent hypoparathyroidism were at greater risk of renal impairment. Further research is warranted to improve the identification and preservation of parathyroid glands during thyroidectomy to minimize patient morbidity.

Thyroid dysfunction in COVID-19.

The COVID-19 pandemic has affected over 772 million people globally. While lung damage is the major contributor to the morbidity and mortality of this disease, the involvement of multiple organs, including the endocrine glands, has been reported. This Review aims to provide an updated summary of evidence regarding COVID-19 and thyroid dysfunction, incorporating highlights of recent advances in the field, particularly in relation to long COVID and COVID-19 vaccination. Since subacute thyroiditis following COVID-19 was first reported in May 2020, thyroid dysfunction associated with COVID-19 has been increasingly recognized, secondary to direct and indirect effects on the hypothalamic-pituitary-thyroid axis. Here, we summarize the epidemiological evidence, pattern and clinical course of thyroid dysfunction following COVID-19 and examine radiological, molecular and histological evidence of thyroid involvement in SARS-CoV-2 infection. Beyond acute SARS-CoV-2 infection, it is also timely to examine the course and implication of thyroid dysfunction in the context of long COVID owing to the large population of survivors of COVID-19 worldwide. This Review also analyses the latest evidence on the relationship between the therapeutics and vaccination for COVID-19 and thyroid dysfunction. To conclude, evidence-based practice recommendations for thyroid function testing during and following COVID-19 and concerning COVID-19 vaccination are proposed.

A Prospective 1-Year Follow-Up of Glycemic Status and C-Peptide Levels of COVID-19 Survivors with Dysglycemia in Acute COVID-19 Infection.

Background: We evaluated changes in glycemic status, over 1 year, of coronavirus disease 2019 (COVID-19) survivors with dysglycemia in acute COVID-19. Methods: COVID-19 survivors who had dysglycemia (defined by glycosylated hemoglobin [HbA1c] 5.7% to 6.4% or random glucose ≥10.0 mmol/L) in acute COVID-19 were recruited from a major COVID-19 treatment center from September to October 2020. Matched non-COVID controls were recruited from community. The 75-g oral glucose tolerance test (OGTT) were performed at baseline (6 weeks after acute COVID-19) and 1 year after acute COVID-19, with HbA1c, insulin and C-peptide measurements. Progression in glycemic status was defined by progression from normoglycemia to prediabetes/diabetes, or prediabetes to diabetes. Results: Fifty-two COVID-19 survivors were recruited. Compared with non-COVID controls, they had higher C-peptide (P< 0.001) and trend towards higher homeostasis model assessment of insulin resistance (P=0.065). Forty-three COVID-19 survivors attended 1-year reassessment. HbA1c increased from 5.5%±0.3% to 5.7%±0.2% (P<0.001), with increases in glucose on OGTT at fasting (P=0.089), 30-minute (P=0.126), 1-hour (P=0.014), and 2-hour (P=0.165). At baseline, 19 subjects had normoglycemia, 23 had prediabetes, and one had diabetes. Over 1 year, 10 subjects (23.8%; of 42 non-diabetes subjects at baseline) had progression in glycemic status. C-peptide levels remained unchanged (P=0.835). Matsuda index decreased (P=0.007) and there was a trend of body mass index increase from 24.4±2.7 kg/m2 to 25.6±5.2 (P=0.083). Subjects with progression in glycemic status had more severe COVID-19 illness than non-progressors (P=0.030). Reassessment was not performed in the control group. Conclusion: Subjects who had dysglycemia in acute COVID-19 were characterized by insulin resistance. Over 1 year, a quarter had progression in glycemic status, especially those with more severe COVID-19. Importantly, there was no significant deterioration in insulin secretory capacity.