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.

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 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.

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.

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.

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.

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.

Bariatric Surgery-induced High-density Lipoprotein Functionality Enhancement Is Associated With Reduced Inflammation.

BACKGROUND: Emerging evidence suggests an association between impaired high-density lipoprotein (HDL) functionality and cardiovascular disease (CVD). HDL is essential for reverse cholesterol transport (RCT) and reduces inflammation and oxidative stress principally via paraoxonase-1 (PON1). RCT depends on HDL's capacity to accept cholesterol (cholesterol efflux capacity [CEC]) and active transport through ATP-binding cassette (ABC) A1, G1, and scavenger receptor-B1 (SR-B1). We have studied the impact of Roux-en-Y gastric bypass (RYGB) in morbidly obese subjects on RCT and HDL functionality. METHODS: Biomarkers associated with increased CVD risk including tumour necrosis factor-α (TNF-α), high-sensitivity C-reactive protein (hsCRP), myeloperoxidase mass (MPO), PON1 activity, and CEC in vitro were measured in 44 patients before and 6 and 12 months after RYGB. Overweight but otherwise healthy (mean body mass index [BMI] 28 kg/m2) subjects acted as controls. Twelve participants also underwent gluteal subcutaneous adipose tissue biopsies before and 6 months after RYGB for targeted gene expression (ABCA1, ABCG1, SR-B1, TNF-α) and histological analysis (adipocyte size, macrophage density, TNF-α immunostaining). RESULTS: Significant (P < 0.05) improvements in BMI, HDL-cholesterol, hsCRP, TNF-α, MPO mass, PON1 activity, and CEC in vitro were observed after RYGB. ABCG1 (fold-change, 2.24; P = 0.005) and ABCA1 gene expression increased significantly (fold-change, 1.34; P = 0.05). Gluteal fat adipocyte size (P < 0.0001), macrophage density (P = 0.0067), and TNF-α immunostaining (P = 0.0425) were reduced after RYBG and ABCG1 expression correlated inversely with TNF-α immunostaining (r = -0.71; P = 0.03). CONCLUSION: RYGB enhances HDL functionality in association with a reduction in adipose tissue and systemic inflammation.

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.

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.

Bariatric Surgery Leads to a Reduction in Antibodies to Apolipoprotein A-1: a Prospective Cohort Study.

PURPOSE: Autoantibodies against apolipoprotein A-1 have been associated with cardiovascular disease, poorer CV outcomes and all-cause mortality in obese individuals. The impact of bariatric surgery (BS) on the presence of circulating anti-apoA-1 IgG antibodies is unknown. This study aimed to determine the effect of bariatric surgery on auto-antibodies titres against Apolipoprotein A-1 (anti-apoA-1 IgG), looking for changes associated with lipid parameters, insulin resistance, inflammatory profile and percentage of excess body mass index loss (%EBMIL). MATERIALS AND METHODS: We assessed 55 patients (40 women) before, 6 and 12 months post-operatively. Baseline and post-operative clinical history and measurements of body mass index (BMI), serum cholesterol, triglycerides, high- and low-density lipoprotein cholesterol (HDL-C and LDL-C), apoA-1, highly sensitive C-reactive protein (hsCRP), fasting glucose (FG), glycated haemoglobin (HbA1c) and HOMA-IR were taken at each point. Human anti-apoA-1 IgG were measured by ELISA. RESULTS: The mean age of participants was 50 years. BS significantly improved BMI, %EBMIL triglycerides, HDL-C, apoA-1, hsCRP, HBA1c, FG and HOMA-IR. Baseline anti-apoA-1 IgG seropositivity was 25% and was associated with lower apoA-1 and higher hsCRP levels. One year after BS, anti-apoA-1 IgG seropositivity decreased to 15% (p = 0.007) and median anti-apoA-1 IgG values decreased from 0.70 (0.56-0.84) to 0.47 (0.37-0.61) AU (p < 0.001). Post-operative anti-apoA-1 IgG levels were significantly associated with a decreased post-surgical %EBMIL at 1 year. CONCLUSION: Bariatric surgery results in significant reduction in anti-apoA-1 IgG levels, which may adversely influence weight loss. The exact mechanisms underpinning these results are elusive and require further study before defining any clinical recommendations.

The role of abnormalities of lipoproteins and HDL functionality in small fibre dysfunction in people with severe obesity.

Obesity and associated dyslipidemia may contribute to increased cardiovascular disease. Obesity has also been associated with neuropathy. We have investigated presence of peripheral nerve damage in patients with severe obesity without type 2 diabetes and the status of metabolic syndrome and lipoprotein abnormalities. 47participants with severe obesity and 30 age-matched healthy controls underwent detailed phenotyping of neuropathy and an assessment of lipoproteins and HDL-functionality. Participants with severe obesity had a higher neuropathy symptom profile, lower sural and peroneal nerve amplitudes, abnormal thermal thresholds, heart rate variability with deep breathing and corneal nerve parameters compared to healthy controls. Circulating apolipoprotein A1 (P = 0.009), HDL cholesterol (HDL-C) (P < 0.0001), cholesterol efflux (P = 0.002) and paroxonase-1 (PON-1) activity (P < 0.0001) were lower, and serum amyloid A (SAA) (P < 0.0001) was higher in participants with obesity compared to controls. Obese participants with small nerve fibre damage had higher serum triglycerides (P = 0.02), lower PON-1 activity (P = 0.002) and higher prevalence of metabolic syndrome (58% vs. 23%, P = 0.02) compared to those without. However, HDL-C (P = 0.8), cholesterol efflux (P = 0.08), apoA1 (P = 0.8) and SAA (P = 0.8) did not differ significantly between obese participants with and without small nerve fibre damage. Small nerve fibre damage occurs in people with severe obesity. Patients with obesity have deranged lipoproteins and compromised HDL functionality compared to controls. Obese patients with evidence of small nerve fibre damage, compared to those without, had significantly higher serum triglycerides, lower PON-1 activity and a higher prevalence of metabolic syndrome.

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.

Effect of bariatric surgery on plasma levels of oxidised phospholipids, biomarkers of oxidised LDL and lipoprotein(a).

BACKGROUND: Obesity is associated with adverse cardiovascular outcomes and this is improved following bariatric surgery. Oxidised phospholipids (OxPL) are thought to reflect the pro-inflammatory effects of lipoprotein(a) [Lp(a)], and both are independent predictors of cardiovascular disease. OBJECTIVE: Our study sought to determine the impact of bariatric surgery on OxPL, biomarkers of oxidised LDL (OxLDL) and Lp(a). METHODS: This is a prospective, observational study of 59 patients with severe obesity undergoing bariatric surgery. Blood samples were obtained prior to surgery and at 6 and 12 months after. Sixteen patients attending the tertiary medical weight management clinic at the same centre were also recruited for comparison. Lipid and metabolic blood parameters, OxLDL, OxPL on apolipoprotein B-100 (OxPL-apoB), IgG and IgM autoantibodies to MDA-LDL, IgG and IgM apoB-immune complexes and Lp(a) were measured. RESULTS: Reduction in body mass index (BMI) was significant following bariatric surgery, from median 48 kg/m2 at baseline to 37 kg/m2 at 6 months and 33 kg/m2 at 12 months. OxPL-apoB levels decreased significantly at 12 months following surgery [5.0 (3.2-7.4) to 3.8 (3.0-5.5) nM, p = 0.001], while contrastingly, Lp(a) increased significantly [10.2 (3.8-31.9) to 16.9 (4.9-38.6) mg/dl, p = 0.002]. There were significant post-surgical decreases in IgG and IgM biomarkers, particularly at 12 months, while OxLDL remained unchanged. CONCLUSIONS: Bariatric surgery results in a significant increase in Lp(a) but reductions in OxPL-apoB and other biomarkers of oxidised lipoproteins, suggesting increased synthetic capacity and reduced oxidative stress. These biomarkers might be clinically useful to monitor physiological effects of weight loss interventions.

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.

Corneal Keratocyte Density and Corneal Nerves Are Reduced in Patients With Severe Obesity and Improve After Bariatric Surgery.

Purpose: Obesity is associated with peripheral neuropathy, which bariatric surgery may ameliorate. The aim of this study was to assess whether corneal confocal microscopy can show a change in corneal nerve morphology and keratocyte density in subjects with severe obesity after bariatric surgery. Methods: Twenty obese patients with diabetes (n = 13) and without diabetes (n = 7) underwent assessment of hemoglobin A1c (HbA1c), lipids, IL-6, highly sensitive C-reactive protein (hsCRP), and corneal confocal microscopy before and 12 months after bariatric surgery. Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), and keratocyte density (KD) from the anterior, middle, and posterior stroma were quantified. Twenty-two controls underwent assessment at baseline only. Results: CNFL (P < 0.001), CNBD (P < 0.05), and anterior (P < 0.001), middle (P < 0.001), and posterior (P < 0.001) keratocyte densities were significantly lower in obese patients compared to controls, and anterior keratocyte density (AKD) correlated with CNFL. Twelve months after bariatric surgery, there were significant improvements in body mass index (BMI; P < 0.001), HDL cholesterol (P < 0.05), hsCRP (P < 0.001), and IL-6 (P < 0.01). There were significant increases in CNFD (P < 0.05), CNBD (P < 0.05), CNFL (P < 0.05), and anterior (P < 0.05) and middle (P < 0.001) keratocyte densities. The increase in AKD correlated with a decrease in BMI (r = -0.55, P < 0.05) and triglycerides (r = -0.85, P < 0.001). There were no significant correlations between the change in keratocyte densities and corneal nerve fiber or other neuropathy measures. Conclusions: Corneal confocal microscopy demonstrates early small fiber damage and reduced keratocyte density in obese patients. Bariatric surgery leads to weight reduction and improvement in lipids and inflammation and an improvement in keratocyte density and corneal nerve regeneration.

Corneal confocal microscopy identifies small fibre damage and progression of diabetic neuropathy.

Accurately quantifying the progression of diabetic peripheral neuropathy is key to identify individuals who will progress to foot ulceration and to power clinical intervention trials. We have undertaken detailed neuropathy phenotyping to assess the longitudinal utility of different measures of neuropathy in patients with diabetes. Nineteen patients with diabetes (age 52.5 ± 14.7 years, duration of diabetes 26.0 ± 13.8 years) and 19 healthy controls underwent assessment of symptoms and signs of neuropathy, quantitative sensory testing, autonomic nerve function, neurophysiology, intra-epidermal nerve fibre density (IENFD) and corneal confocal microscopy (CCM) to quantify corneal nerve fibre density (CNFD), branch density (CNBD) and fibre length (CNFL). Mean follow-up was 6.5 years. Glycated haemoglobin (p = 0.04), low-density lipoprotein-cholesterol (LDL-C) (p = 0.0009) and urinary albumin creatinine ratio (p < 0.0001) improved. Neuropathy symptom profile (p = 0.03), neuropathy disability score (p = 0.04), vibration perception threshold (p = 0.02), cold perception threshold (p = 0.006), CNFD (p = 0.03), CNBD (p < 0.0001), CNFL (p < 0.0001), IENFD (p = 0.04), sural (p = 0.02) and peroneal motor nerve conduction velocity (p = 0.03) deteriorated significantly. Change (∆) in CNFL correlated with ∆CPT (p = 0.006) and ∆Expiration/Inspiration ratio (p = 0.002) and ∆IENFD correlated with ∆CNFD (p = 0.005), ∆CNBD (p = 0.02) and ∆CNFL (p = 0.01). This study shows worsening of diabetic neuropathy across a range of neuropathy measures, especially CCM, despite an improvement in HbA1c and LDL-C. It further supports the utility of CCM as a rapid, non-invasive surrogate measure of diabetic neuropathy.