Established and potential cardiovascular risk factors in metabolic syndrome: Effect of bariatric surgery.

PURPOSE OF REVIEW: The aim of this review was to provide an overview of the role of novel biomarkers in metabolic syndrome, their association with cardiovascular risk and the impact of bariatric surgery on these biomarkers. RECENT FINDINGS: Metabolic syndrome encompasses an intricate network of health problems, and its constituents extend beyond the components of its operational definition. Obesity-related dyslipidaemia not only leads to quantitative changes in lipoprotein concentration but also alteration in qualitative composition of various lipoprotein subfractions, including HDL particles, rendering them proatherogenic. This is compounded by the concurrent existence of obstructive sleep apnoea (OSA) and nonalcoholic fatty liver disease (NAFLD), which pave the common pathway to inflammation and oxidative stress culminating in heightened atherosclerotic cardiovascular disease (ASCVD) risk. Bariatric surgery is an exceptional modality to reverse both conventional and less recognised aspects of metabolic syndrome. It reduces the burden of atherosclerosis by ameliorating the impact of obesity and its related complications (OSA, NAFLD) on quantitative and qualitative composition of lipoproteins, ultimately improving endothelial function and cardiovascular morbidity and mortality. SUMMARY: Several novel biomarkers, which are not traditionally considered as components of metabolic syndrome play a crucial role in determining ASCVD risk in metabolic syndrome. Due to their independent association with ASCVD, it is imperative that these are addressed. Bariatric surgery is a widely recognized intervention to improve the conventional risk factors associated with metabolic syndrome; however, it also serves as an effective treatment to optimize novel biomarkers.

Impact of Bariatric Surgery on Subtilisin/Kexin Type 9 (PCSK9) Gene Expression and Inflammation in the Adipose Tissue of Obese Diabetic Rats.

Bariatric surgery improves dyslipidaemia and reduces body weight, but it remains unclear how bariatric surgery modulates gene expression in fat cells to influence the proprotein convertase subtilisin/kexin type 9 (PCSK-9) and low-density lipoprotein receptor (LDLR) gene expression. The expression of the PCSK9/LDLR/tumor necrosis factor-alpha (TNFα) gene in adipose tissue was measured in two groups of Zucker Diabetic Sprague Dawley (ZDSD) rats after Roux-en-Y gastric bypass (RYGB) surgery or 'SHAM' operation. There was lower PCSK9 (p = 0.02) and higher LDLR gene expression (p = 0.02) in adipose tissue in rats after RYGB. Weight change did not correlate with PCSK9 gene expression (r = -0.5, p = 0.08) or TNFα gene expression (r = -0.4, p = 0.1). TNFα gene expression was positively correlated with PCSK9 gene expression (r = 0.7, p = 0.001) but not correlated with LDLR expression (r = -0.3, p = 0.3). Circulating triglyceride levels were lower in RYGB compared to the SHAM group (1.1 (0.8-1.4) vs. 1.5 (1.0-4.2), p = 0.038) mmol/L with no difference in cholesterol levels. LDLR gene expression was increased post-bariatric surgery with the potential to reduce the number of circulating LDL particles. PCSK9 gene expression and TNFα gene expression were positively correlated after RYGB in ZDSD rats, suggesting that the modulation of pro-inflammatory pathways in adipose tissue after RYGB may partly relate to PCSK9 and LDLR gene expression.

The impact of atherosclerotic cardiovascular disease, dyslipidaemia and lipid lowering therapy on Coronavirus disease 2019 outcomes: an examination of the available evidence.

PURPOSE OF REVIEW: Coronavirus Disease 2019 (COVID19) has caused significant global morbidity and mortality, especially in persons with underlying cardiovascular disease. There have been concerns that lipid-lowering therapy (LLT) increases angiotensin-converting enzyme 2 levels. Conversely, pleiotropic effects of statins can theoretically protect against severe COVID19 infection, supporting evidence from other respiratory illnesses in which statin use probably confers benefit. RECENT FINDINGS: There is an abundance of studies that show that statins are safe and potentially protect against severe COVID19 infection (critical illness and death), even when adjustment for potential confounders is undertaken. However, the evidence is limited to retrospective cohorts. The benefit for patients with diabetes is less clear. There is a paucity of evidence for other LLT agents. Available clinical guidelines recommend the ongoing use of LLT in patients with COVID19 (unless specifically contra-indicated) and the data from available studies support these. SUMMARY: In patients with COVID19 infection, LLT should be continued. However, the current findings need substantiating in larger prospective clinical studies with specific examination of the possible mechanisms by which LLT confers benefit from COVID19.

High density lipoprotein-associated miRNA is increased following Roux-en-Y gastric bypass surgery for severe obesity.

Roux-en-Y gastric bypass (RYGB) is one of the most commonly performed weight-loss procedures, but how severe obesity and RYGB affect circulating HDL-associated microRNAs (miRNAs) remains unclear. Here, we aim to investigate how HDL-associated miRNAs are regulated in severe obesity and how weight loss after RYGB surgery affects HDL-miRNAs. Plasma HDLs were isolated from patients with severe obesity (n = 53) before and 6 and 12 months after RYGB by immunoprecipitation using goat anti-human apoA-I microbeads. HDLs were also isolated from 18 healthy participants. miRNAs were extracted from isolated HDL and levels of miR-24, miR-126, miR-222, and miR-223 were determined by TaqMan miRNA assays. We found that HDL-associated miR-126, miR-222, and miR-223 levels, but not miR-24 levels, were significantly higher in patients with severe obesity when compared with healthy controls. There were significant increases in HDL-associated miR-24, miR-222, and miR-223 at 12 months after RYGB. Additionally, cholesterol efflux capacity and paraoxonase activity were increased and intercellular adhesion molecule-1 (ICAM-1) levels decreased. The increases in HDL-associated miR-24 and miR-223 were positively correlated with an increase in cholesterol efflux capacity (r = 0.326, P = 0.027 and r = 0.349, P = 0.017, respectively). An inverse correlation was observed between HDL-associated miR-223 and ICAM-1 at baseline. Together, these findings show that HDL-associated miRNAs are differentially regulated in healthy participants versus patients with severe obesity and are altered after RYGB. These findings provide insights into how miRNAs are regulated in obesity before and after weight reduction and may lead to the development of novel treatment strategies for obesity and related metabolic disorders.

Bariatric surgery leads to an improvement in small nerve fibre damage in subjects with obesity.

INTRODUCTION: Subjects with obesity have metabolic risk factors for nerve fibre damage. Because bariatric surgery improves these risk factors we have assessed whether this can ameliorate nerve fibre damage. METHODS: Twenty-six obese subjects without diabetes (age: 46.23 ± 8.6, BMI: 48.7 ± 1.5, HbA1c: 38.0 ± 4.5) and 20 controls (age: 48.3 ± 6.2, BMI: 26.8 ± 4.2, HbA1c: 39.1 ± 2.6) underwent detailed assessment of neuropathy at baseline and 12 months after bariatric surgery. RESULTS: Obese subjects had normal peroneal (45.9 ± 5.5 vs. 48.1 ± 4.5, P = 0.1) and sural (46.9 ± 7.6 vs. 47.9 ± 10.6, P = 0.1) nerve conduction velocity, but a significantly higher neuropathy symptom profile (NSP) (4.3 ± 5.7 vs. 0.3 ± 0.6, P = 0.001), vibration perception threshold (VPT) (V) (10.2 ± 6.8 vs. 4.8 ± 2.7, P < 0.0001), warm threshold (C°) (40.4 ± 3.5 vs. 37.2 ± 1.8, P = 0.003) and lower peroneal (3.8 ± 2.2 vs. 4.9 ± 2.2, P = 0.02) and sural (8.9 ± 5.8 vs. 15.2 ± 8.5, P < 0.0001) nerve amplitude, deep breathing-heart rate variability (DB-HRV) (beats/min) (21.7 ± 4.1 vs. 30.1 ± 14, P = 0.001), corneal nerve fibre density (CNFD) (n/mm2) (25.6 ± 5.3 vs. 32.0 ± 3.1, P < 0.0001), corneal nerve branch density (CNBD) (n/mm2) (56.9 ± 27.5 vs. 111.4 ± 30.7, P < 0.0001) and corneal nerve fibre length (CNFL) (mm/mm2) (17.9 ± 4.1 vs. 29.8 ± 4.9, P < 0.0001) compared to controls at baseline. In control subjects there was no change in neuropathy measures over 12 months. However, 12 months after bariatric surgery there was a significant reduction in BMI (33.7 ± 1.7 vs. 48.7 ± 1.5, P = 0.001), HbA1c (34.3 ± 0.6 vs. 38.0 ± 4.5, P = 0.0002), triglycerides (mmol/l) (1.3 ± 0.6 vs. 1.6 ± 0.8, P = 0.005) and low-density lipoprotein cholesterol (mmol/l) (2.7 ± 0.7 vs. 3.1 ± 0.9, P = 0.02) and an increase in high-density lipoprotein cholesterol (mmol/l) (1.2 ± 0.3 vs. 1.04 ± 0.2, P = 0.002). There was a significant improvement in NSP (1.6 ± 2.7 vs. 4.3 ± 5.7, P = 0.004), neuropathy disability score (0.3 ± 0.9 vs. 1.3 ± 2.0, P = 0.03), CNFD (28.2 ± 4.4 vs. 25.6 ± 5.3, P = 0.03), CNBD (64.7 ± 26.1 vs. 56.9 ± 27.5, P = 0.04) and CNFL (20.4 ± 1.2 vs. 17.9 ± 4.1, P = 0.02), but no change in cold and warm threshold, VPT, DB-HRV or nerve conduction velocity and amplitude. Increase in CNFD correlated with a decrease in triglycerides (r = -0.45, P = 0.04). CONCLUSION: Obese subjects have evidence of neuropathy, and bariatric surgery leads to an improvement in weight, HbA1c, lipids, neuropathic symptoms and deficits and small nerve fibre regeneration without a change in quantitative sensory testing, autonomic function or neurophysiology.

Metabolic and cardiovascular outcomes of bariatric surgery.

PURPOSE OF REVIEW: Bariatric surgery is an effective therapy for morbid obesity that also improves weight-related metabolic parameters and reduces morbidity and mortality. The purpose of this review is to consolidate our current understanding of metabolic, macrovascular and microvascular benefits of bariatric surgery and to provide an update. RECENT FINDINGS: Early resolution of insulin resistance and type 2 diabetes mellitus (T2DM) varies by type of bariatric surgery and appears to be mediated by changes in secretion of gut hormones, metabolism of bile acids, expression of glucose transporters and the gut microbiome. Dyslipidaemia, atherosclerosis, microvascular complications of obesity and diabetes, systemic and tissue-level inflammation show evidence of regression and hypertension improves significantly after bariatric surgery. SUMMARY: Bariatric surgery leads to improvements in obesity-related metabolic comorbidities such as dyslipidaemia, HDL functionality, hypertension, T2DM, insulin resistance and inflammation. It slows the atherosclerotic process and reduces cardiovascular and all-cause mortality. Recent data have demonstrated regression of the microvascular complications of obesity and diabetes including the regeneration of small nerve fibres. The magnitude of change in short-term metabolic effects depends on the surgical procedure whilst longer term effects are related to the amount of sustained excess weight loss.

Small fibre pathology is associated with erectile dysfunction in men with type 2 diabetes.

AIMS: The aim of this study was to evaluate the contribution of small and large fibre neuropathy to erectile dysfunction (ED) in men with type 2 diabetes (T2D). METHODS: Measures of small and large fibre neuropathy were evaluated in 49 participants with T2D and 20 age-matched controls. RESULTS: ED was present in 59% of participants with T2D. There was no difference in age, duration of diabetes, blood pressure, lipid profile, vibration perception threshold (V) (14.3 ± 7.8 vs 11.2 ± 6.6, P = .429), peroneal (41.4 ± 8.2 vs 44.8 ± 4.4, P = .10) and sural (45.4 ± 5.6 vs 47.1 ± 5.8) nerve conduction velocities (m/s), cold (25.1 ± 3.8 vs 26.2 ± 2.9, P = .815) and warm (43.2 ± 4.0 vs 41.0 ± 3.8) perception thresholds (°C), and deep breathing heart rate variability (18 ± 8 vs 18 ± 8) between participants with and without ED. However, intraepidermal nerve fibre density (no./mm2 ) (4.6 ± 2.8 vs 13.7 ± 2.7, P < .001), corneal nerve fibre density (no./mm2 ) (23.5 ± 6.8 vs 31.3 ± 8.2, P < .001), corneal nerve fibre branch density (no./mm2 ) (55.4 ± 35.3 vs 97.7 ± 46.4, P = .004), corneal nerve fibre length (mm/mm2 ) (17.6 ± 6.8 vs 27.3 ± 6.8, P < .001), and sural (7.7 ± 6.1 vs 14.6 ± 6.7, P = .003) and peroneal (2.5 ± 2.0 vs 4.7 ± 2.0, P = .003) nerve amplitudes were significantly lower in participants with ED compared with those without ED. CONCLUSION: ED affects almost 2/3 of men with T2D and is associated with small nerve fibre damage but preserved nerve conduction and cardiac autonomic function. Corneal confocal microscopy may serve as a useful non-invasive imaging method to identify small fibre damage in patients with T2D and ED.

Emergency ambulatory outpatient management of immune-mediated hypophysitis.

PURPOSE: Immune-mediated hypophysitis is an important toxicity related to immune checkpoint inhibitors (ICI). Optimal management is associated with improved outcomes. It represents a wide spectrum of clinical presentations, and a proportion may be suitable for emergency ambulatory management. METHODS: Emergency ambulatory management of patients presenting with clinical features and findings consistent with ICI-induced hypophysitis was considered at a tertiary cancer/endocrinology hospital. Suitable patients were initially investigated and treated in accordance with the UK emergency management guidelines for ICI induced hypophysitis. After an initial observation period of 4 h, patients were discharged with oral hydrocortisone (20, 10, 10 mg). RESULTS: An initial cohort of 4 patients with emergency presentations of ICI-induced hypophysitis has been managed in an ambulatory fashion in the first 3 months. There were no 30-day readmissions. CONCLUSION: Carefully selected emergency presentations with immune-mediated hypophysitis may be suitable for ambulatory management.

Non-HDL cholesterol should not generally replace LDL cholesterol in the management of hyperlipidaemia.

PURPOSE OF REVIEW: Non-HDL cholesterol was originally conceived as a therapeutic target for statin treatment in hypertriglyceridaemia when apolipoprotein B100 assays were not widely available. Recently non-HDL cholesterol has been recommended to replace LDL cholesterol in the clinical management of dyslipidaemia routinely in general medical practice. This is misguided. RECENT FINDINGS: Non-HDL cholesterol is heterogeneous, constituting a mixture of triglyceride-rich VLDL, intermediate density lipoprotein and LDL in which small dense LDL is poorly represented and to which VLDL cholesterol contributes increasingly as triglyceride levels rise. This makes it unsuitable as a goal of lipid-lowering treatment or as an arbiter of who should receive such treatment. Results of trials designed to lower LDL cholesterol are not easily translated to non-HDL cholesterol. Fasting is no longer thought essential for screening the general population for raised LDL cholesterol. ApoB100 measurement also does not require fasting even in rarer more extreme lipoprotein disorders encountered in the Lipid Clinic, provides greater precision and specificity and overcomes the problems posed by LDL and non-HDL cholesterol. It is more easily interpreted both in diagnosis and as a therapeutic goal and it includes SD-LDL. SUMMARY: If we are to discourage use of LDL cholesterol, it should be in favour of apoB100 not non-HDL cholesterol.

Evidence for more intensive cholesterol lowering.

PURPOSE OF REVIEW: In randomized clinical trials, reduction in cardiovascular disease (CVD) risk with cholesterol-lowering drugs correlates with the LDL cholesterol decrease. However, because the majority have investigated a fixed statin dose, current guidelines disagree about the use of statin dose titration or non-statin adjunctive cholesterol-lowering drugs. RECENT FINDINGS: We conducted a meta-analysis of all randomized controlled trials with CVD end-points, comparing two intensities of lipid-lowering regimens within the same population, using varying statins doses and/or potency, ezetimibe or PCSK9 inhibitors and compared the observed number of patients needed to be treated for 10 years to prevent one CVD event (NNT) with NNT predicted from trials of predominantly single-dose statin.Some 75439 participants in 10 randomized studies were included. The mean 10-year CVD risk in controls was around 50% and the incremental mean LDL cholesterol decrease 0.95 mmol/l (36.7 mg/dl). Observed NNT closely correlated with those predicted from predominantly single-dose statin trials [18.2 and 17.1; Pearson R=0.844 (P=0.001)]. When pre-treatment LDL cholesterol exceeded 4 mmol/l (155 mg/dl), achieving a target LDL cholesterol of 1.8 mmol/l (70 mg/dl) was the most effective strategy. At lower pre-treatment levels, fixed-dose statin equivalent to atorvastatin 80 mg daily was superior. The target of 40% reduction in non-high density lipoprotein cholesterol was least effective regardless of pre-treatment LDL cholesterol. SUMMARY: We conclude that when initial LDL cholesterol exceeds 4 mmol/l and absolute CVD risk demands it, a target value of 1.8 mmol/l should be achieved, if necessary by adding ezetimibe and/or PCSK9 inhibitors to statin treatment.

Diabetic dyslipidaemia.

PURPOSE OF REVIEW: The purpose is to discuss recent developments in the understanding of lipoprotein metabolism in diabetes, the cardiovascular risk associated with both type 1 and type 2 diabetes, recently published guidelines on the management of this risk, concerns over the use of statin treatment in diabetes, and other therapeutic options. RECENT FINDINGS: Diabetic dyslipidaemia can be gross with massive hypertriglyceridemia, or subtle with a lipid profile which would be regarded as normal in a nondiabetic patient, but which hides underlying increases in atherogenic subfractions of LDL (e.g., small dense LDL, glycated LDL) and remnant lipoproteins. Statins can decrease these without the clinician being aware from routine biochemistry. In type 2 diabetes, HDL cholesterol levels are often reduced, whereas in type 1, insulin can raise HDL, but its antiatherogenic properties are compromised. Dyslipidaemia and hypertension predate the onset of glycaemia of diabetic proportions (metabolic syndrome). Obese people can thus die of diabetes before they develop it. Obesity should be prevented and treated. Statins decrease the risk of cardiovascular disease in diabetes or metabolic syndrome regardless of whether glycaemia worsens. SUMMARY: One unassailable truth is that statin therapy is beneficial and should rarely, if ever, be withheld.

Liver Fat Measured by MR Spectroscopy: Estimate of Imprecision and Relationship with Serum Glycerol, Caeruloplasmin and Non-Esterified Fatty Acids.

Magnetic resonance spectroscopy (MRS) is a non-invasive method for quantitative estimation of liver fat. Knowledge of its imprecision, which comprises biological variability and measurement error, is required to design therapeutic trials with measurement of change. The role of adipocyte lipolysis in ectopic fat accumulation remains unclear. We examined the relationship between liver fat content and indices of lipolysis, and determine whether lipolysis reflects insulin resistance or metabolic liver disease. Imprecision of measurement of liver fat was estimated from duplicate measurements by MRS at one month intervals. Patients provided fasting blood samples and we examined the correlation of liver fat with indices of insulin resistance, lipolysis and metabolic liver disease using Kendall Tau statistics. The coefficient of variation of liver fat content was 14.8%. Liver fat was positively related to serum insulin (T = 0.48, p = 0.042), homeostasis model assessment (HOMA)-B% (T = -0.48, p = 0.042), and body mass index (BMI) (T = 0.59, p = 0.012); and inversely related to HOMA-S% (T = -0.48, p = 0.042), serum glycerol (T = -0.59, p = 0.014), and serum caeruloplasmin (T = 0.055, p = 0.047). Our estimate of total variability in liver fat content (14.8%) is nearly twice that of the reported procedural variability (8.5%). We found that liver fat content was significantly inversely related to serum glycerol but not to non-esterified fatty acids (NEFA), suggesting progressive suppression of lipolysis. Reduction of caeruloplasmin with increasing liver fat may be a consequence or a cause of hepatic steatosis.

Thyroid dysfunction after immune checkpoint inhibitors in a single-centre UK pan-cancer cohort: A retrospective study.

PURPOSE: This study investigated thyroid dysfunction with immune checkpoint inhibitors (ICIs) in terms of proportions affected, risk factors, thyroid sequelae, and overall survival (OS). METHODS: Among patients with normal baseline free T4 (fT4) and thyroid stimulating hormone (TSH) receiving ICIs at a large cancer centre, proportions of hyperthyroidism/hypothyroidism were determined (any, subclinical [normal fT4, abnormal TSH], overt [abnormal fT4, abnormal TSH], isolated hyperthyroxinaemia/hypothyroxinaemia and secondary) with onset times and subsequent thyroid statuses. Associations of overt dysfunction with OS were estimated using Cox regression and methods robust to immortal time bias (time-dependent Cox regression and 3- and 6-month landmark analyses). Associations of baseline variables with overt hyperthyroidism and hypothyroidism were estimated using Fine and Gray regression. RESULTS: Of 1349 patients, 34.2% developed hyperthyroidism (10.3% overt), including 54.9% receiving combination ICIs, while 28.2% developed hypothyroidism (overt 9.3%, secondary 0.5%). A third of overt hypothyroidism cases occurred without preceding hyperthyroidism. Subclinical thyroid dysfunction returned directly to normal in up to half. Overt hyperthyroidism progressed to overt hypothyroidism in 55.4% (median 1.6 months). Melanoma treatment in the adjuvant vs. advanced setting caused more overt hyperthyroidism (12.1% vs. 7.5%) and overt hypothyroidism (14.5% vs. 9.7%). Baseline eGFR < 60 mL/min/1.73 m2 (HR=1.68, 1.07-2.63) was associated with overt hyperthyroidism and sex (HR=0.60, 0.42-0.87) and TSH (4th vs. 1st quartile HR=1.87, 1.10-3.19) with overt hypothyroidism. Overt dysfunction was associated with OS in the Cox analysis (HR=0.65, 0.50-0.85, median follow-up 22.2 months) but not in the time-dependent Cox (HR=0.79, 0.60-1.03) or landmark analyses (3-month HR=0.74, 0.51-1.07; 6-month HR=0.91, 0.66-1.24). CONCLUSION: Thyroid dysfunction affects up to half of patients receiving ICIs. The association with OS is unclear after considering immortal time bias. The clinical courses include recovery, thyrotoxicosis and de novo overt hypothyroidism. Adjuvant treatment for melanoma, where longer-term harms are of concern, causes more frequent/aggressive dysfunction.

Impact of Lipid-lowering Therapy on Cancer Risk: A Narrative Review.

PURPOSE: There are inconsistent reports of an association between low cholesterol, use of lipid-lowering agents, and carcinogenesis. The purpose of this paper was to examine the relationship between cancer, lipids, statin use, and use of other lipid-lowering therapies. METHODS: This comprehensive literature review incorporated article searches in electronic databases (Embase, PubMed, OVID) and reference lists of relevant articles, with the authors' expertise in lipidology. This review considered seminal and novel research looking at the relationship between cholesterol, lipid-lowering therapies, and cancer. FINDINGS: Statin use has been reported to reduce the risk for incident cancer or progression of cancer; however, it is unknown whether this reduced risk of carcinogenesis is due to the pleotropic properties of statins or the effects of low cholesterol. The effect of ezetimibe on carcinogenesis has been regarded as neutral, despite earlier concerns of increased cancer risk with its use. Proprotein convertase subtilisin/kexin (PCSK)-9 monoclonal antibodies have been shown to have a neutral effect on carcinogenesis. Despite anti-cancer effects of fibrates in vitro, studies in humans have yielded inconsistent outcomes leaning toward protection against the development and progression of cancer. IMPLICATIONS: Statins, fibrates, PCSK9 monoclonal antibodies, and ezetimibe have a neutral effect on cancer risk, and the first three may provide some protection. PSCK9 monoclonal antibodies have the potential to enhance the response to checkpoint inhibitor therapy for cancer. Further research is needed to determine which drugs can be issued in adjuvant therapy to improve outcomes in patients undergoing cancer treatment.

Diagnostic criteria and proposed management of immune-related endocrinopathies following immune checkpoint inhibitor therapy for cancer.

Checkpoint inhibitors are now widely used in the management of many cancers. Endocrine toxicity is amongst the most common side effects. These endocrinopathies differ from most other immune-related toxicities in frequently being irreversible and rarely requiring cessation of checkpoint inhibitor therapy. This review considers an approach to the presentation and diagnosis of endocrinopathies, compared to classical endocrine diagnosis, suggesting improvements to classification and treatment based on fundamental endocrine principles. These will help to align management with other similar endocrine conditions and standardise the diagnosis and reporting of endocrine toxicity of checkpoint inhibitors to improve both endocrine and oncological care. In particular, the importance of considering any inflammatory phase (such as painful thyroiditis or hypophysitis resulting in the pituitary enlargement), from the endocrine consequences (transient hyperthyroidism followed by hypothyroidism, pan-hypopituitarism or isolated adrenocorticotrophic hormone deficiency), is highlighted. It is also important to consider the potential confounder of exogenous corticosteroids in adrenal suppression.

Immune checkpoint inhibitor-mediated hypophysitis: no place like home.

Ambulatory emergency care forms a fundamental part of the strategy of trying to ensure safe and sustainable acute care services. Immune checkpoint inhibitor(ICI)-mediated hypophysitis is an important life-threatening complication of therapy. Patients presenting with clinical features and findings consistent with ICI-mediated hypophysitis were considered in the current study. In the absence of severe features (sodium <125 mmol/L, hypotension, reduced consciousness, hypoglycaemia and/or visual field defect), patients were administered a single intravenous dose of hydrocortisone (100 mg), observed for at least 4 h and then discharged on oral hydrocortisone (20 mg, 10 mg and 10 mg). Patients were then seen urgently in the endocrinology outpatient setting for further management. Fourteen patients (median age 64, 10 male) were managed using the pathway. All patients had biochemically confirmed adrenocorticotropic hormone (ACTH) deficiency. Seven of the 14 were treated with combination ICI therapy, with four having pan-anterior hypopituitarism. There were no 30-day readmissions or any associated hypophysitis-related mortality. All patients continued ICI therapy without interruption.

Microvascular complications of obesity and diabetes-Role of bariatric surgery.

Bariatric surgery in people with obesity can lead to long-term remission of type 2 diabetes mellitus (T2DM) and a reduction in the incidence of macrovascular complications. The impact of bariatric surgery on microvascular complications is less clear. In this narrative review, we sought to evaluate the effect of bariatric surgery on microvascular complications in patients with and without diabetes. The risk of developing microvascular complications is increased in people with obesity, and this is amplified in those with T2DM. The impact of metabolic surgery on microvascular complications is limited to a subgroup analysis of studies or statistical modeling to predict the glycemia-independent effect of bariatric surgery. While bariatric surgery halts the progression of retinopathy in those with minimal retinopathy, it may worsen in those with advanced retinopathy. Bariatric surgery improves proteinuria and major renal outcomes, regardless of the severity of renal impairment. Bariatric surgery in patients with obesity with or without diabetes is associated with an improvement in neuropathic symptoms and regeneration of small nerve fibers. In conclusion, bariatric surgery is associated with an improvement in microvascular complications. Further studies are needed to elucidate the underlying mechanisms for the favorable effect of bariatric surgery on microvascular outcomes.

Mathematical modelling of the most effective goal of cholesterol-lowering treatment in primary prevention.

OBJECTIVE: To compare quantitatively different recommended goals for cholesterol-lowering treatment in the primary prevention of atherosclerotic cardiovascular disease (ASCVD). DESIGN: Outcomes at pretreatment low-density lipoprotein (LDL) cholesterol concentrations from 2 to 5 mmol/L and 10-year ASCVD risk from 5% to 30% were modelled, using the decrease in risk ratio per mmol/L reduction in LDL cholesterol derived from randomised controlled trials (RCTs) of cholesterol-lowering medication. DATA SOURCE: Summary statistics from 26 RCTs comparing treatment versus placebo or less versus more effective treatment and 12 RCTs in which statin was compared with a higher dose of the same statin or with a similar statin dose to which an adjunctive cholesterol-lowering drug was added. SETTING: The different recommended goals are: (1) LDL cholesterol≤2.6 mmol/L (100 mg/dL); (2) LDL cholesterol≤1.8 mmol/L (70 mg/dL); (3) non-high density lipoprotein (HDL) cholesterol decrease of ≥40%; or (4) LDL cholesterol≤1.8 mmol/L (70 mg/dL) or decreased by ≥50% whichever is lower. PARTICIPANTS: RCT participants. INTERVENTIONS: Statins alone or in combination with ezetimibe or proprotein convertase subtilisin/kexin type 9 inhibitors. MAIN OUTCOME MEASURES: For each of the recommended therapeutic goals, our primary outcome was the number of events prevented per 100 people treated for 10 years (N100) and the number of needed to treat (NNT) to prevent one event over 10 years. RESULTS: At pretreatment LDL cholesterol 4-5 mmol/L, all four goals provided similar benefit with N100 1.47-16.45 (NNT 6-68), depending on ASCVD risk and pretreatment LDL cholesterol. With initial LDL cholesterol in the range 2-3 mmol/L, the target of 2.6 mmol/L was the least effective with N100 between 0 and 2.84 (NNT 35-infinity). The goal of 1.8 mmol/L was little better. However, reductions in non-HDL cholesterol by ≥40% or of LDL cholesterol to 1.8 mmol/L and/or by 50%, whichever is lower, were more effective, delivering N100 of between 0.9 and 9.33 (NNT 11-111). Percentage decreases in LDL cholesterol or non-HDL cholesterol concentration are more effective targets than absolute change in concentration in people with initial values of <4 mmol/L. CONCLUSIONS: The LDL cholesterol target of 1.8 mmol/L is most effective when initial LDL cholesterol is >4 mmol/L. The time has probably come for the LDL cholesterol goal of <2.6 mmol/L to be abandoned.

Potential pitfalls in diagnosis of immunotherapy-induced hypothalamic-pituitary-adrenal axis abnormalities: a clinical case.

Summary: Short synacthen tests (SST) are frequently used for assessing adrenocorticotropin hormone (ACTH) deficiency. In this study, we present the case of a 53-year-old man receiving immunotherapy for metastatic melanoma, who subsequently developed immune checkpoint inhibitor (ICI)-induced hypothyroidism and was investigated for the presence of ICI-induced hypocortisolaemia on different occasions. Despite two reassuring SSTs, he subsequently developed clinical and biochemical evidence of ACTH deficiency. The ACTH on local measurement was not conclusive in keeping with ICI-related ACTH deficiency but when repeated using an alternative assay confirmed the diagnosis. The case illustrates the evolution of ACTH deficiency and exposes the potential pitfalls of screening strategies. Two important lessons may be gleaned from this case: (i) SSTs can be normal in early cases of secondary adrenal insufficiency, for example, hypophysitis due to adrenal reserve and (ii) when there is mismatch between the clinical and biochemical presentation, the ACTH should be repeated using a different assay. Learning points: Short synacthen tests, useful for ruling out adrenalitis and primary adrenal failure, may be normal in early adrenocorticotrophic hormone deficiency and secondary adrenal failure due to residual adrenal reserve.If clinical suspicion of adrenal insufficiency persists despite an initial satisfactory SST, it is important to recognise the need for re-assessment of cortisol levels.Insulin tolerance test remains a useful tool in the investigation of secondary adrenal insufficiency.Levothyroxine replacement may accelerate the metabolism of cortisol in cases of concurrent hypothyroidism and hypoadrenalism, and therefore, glucocorticoid replacement must precede levothyroxine treatment, to avoid adrenal crisis.The prevalence of immunotherapy-related endocrinopathies is likely to increase with increasing use of ICI and it is crucial that clinicians are alert to their subtle symptoms.

Glycated apolipoprotein B decreases after bariatric surgery in people with and without diabetes: A potential contribution to reduction in cardiovascular risk.

BACKGROUND AND AIMS: The causal relationship between LDL cholesterol (LDL-C) and the pathogenesis of atherosclerosis is well established. Previous studies have shown that modifications, glycation and oxidation of LDL enhance its atherogenic potential. Glycation of LDL occurs in it is main protein component, apolipoprotein B100 (ApoB). Our aim was to assess the effect of bariatric surgery on circulating glycApoB levels and understand the factors influencing changes in its circulating levels. METHODS: We measured glycApoB in 49 individuals before, 6 and 12 months after bariatric surgery. We also assessed clinical parameters, lipoproteins, markers of inflammation and glycaemia. Correlation analysis was done to understand associations between changes in variables from baseline to 12 months after surgery. RESULTS: Reductions in glycApoB post-bariatric surgery were significant regardless of whether the patients suffered from type 2 diabetes (T2DM) or took lipid-lowering therapy. There were no significant differences in glycApoB levels at baseline and follow-up between participants with T2DM and those without. GlycApoB declined from baseline in non-diabetics at 6 months and significantly at 12 months (1.09 mg/l vs 0.63 mg/l vs 0.49 mg/l, p < 0.05), and in those with T2DM at 6 months and significantly at 12 months (1.77 mg/l vs 1.03 mg/l vs 0.68 mg/l, p < 0.05). The percentage change in glycApoB correlated (p < 0.05) with changes in glucose (ρ = 0.40), insulin (ρ = 0.41) and HOMA-IR (%) (ρ = 0.43). There were no significant associations between changes in glycApoB and changes in total serum ApoB, LDL-C, high sensitivity C-reactive protein, weight, or BMI. CONCLUSIONS: Bariatric surgery reduces levels of glycApoB; this reduction is associated with decreased insulin resistance postoperatively. This potentially reflects the potent influence of obesity-related insulin resistance on lipoprotein glycation. Our observations are of potential importance in explaining the effectiveness of bariatric surgery in decreasing cardiovascular disease (CVD) risk in both T2DM and obese individuals without T2DM, as glycation of ApoB is known to be associated with increased atherogenesis.