Best practice & research. Clinical endocrinology & metabolism最新文献

The increasing affordability of and access to next-generation DNA sequencing has increased the feasibility of incorporating genetic analysis into the diagnostic pathway for dyslipidaemia. But should genetic diagnosis be used routinely? DNA testing for any medical condition has potential benefits and pitfalls. For dyslipidaemias, the overall balance of advantages versus drawbacks differs according to the main lipid disturbance. For instance, some patients with severely elevated low-density lipoprotein cholesterol levels have a monogenic disorder, namely heterozygous familial hypercholesterolaemia. In these patients, DNA diagnosis can be definitive, in turn yielding several benefits for patient care that tend to outweigh any potential disadvantages. In contrast, hypertriglyceridaemia is almost always a polygenic condition without a discrete monogenic basis, except for ultrarare monogenic familial chylomicronaemia syndrome. Genetic testing in patients with hypertriglyceridaemia is therefore predominantly non-definitive and evidence for benefit is presently lacking. Here we consider advantages and limitations of genetic testing in dyslipidaemias.

Randomized trials suggest moderate-intensity statins increase type 2 diabetes risk by around 11% with a potential further 12% moving to high-intensity statins, such that high intensity may increase risk by 20% or more relative to placebo. These data translate into one extra diabetes case per 100–200 statin recipients over 5 years, with ∼10-fold greater benefits on major vascular outcomes. The underlying mechanisms for diabetes harm are not clear but could include modest weight gain (noted in randomized trials), or, speculatively, beta cell harm. Concordant genetic studies link HMG CoA Reductase inhibition to diabetes risk and weight gain. Patients should be warned about a slight diabetes risk when prescribed statin and told that modest lifestyle improvements can i) nullify diabetes risk, and ii) improve cardiovascular risks beyond statins. Doctors should also measure glycemia status post statin commencement, most commonly with HbA1c, and tailor lifestyle advice and care dependent on the results.

We have used DNA sequencing in our lipid clinic for >20 years. Dyslipidaemia is typically ascertained biochemically. For moderate deviations in the lipid profile, the etiology is often a combination of a polygenic susceptibility component plus secondary non-genetic factors. For severe dyslipidaemia, a monogenic etiology is more likely, although a discrete single-gene cause is frequently not found. A severe phenotype can also result from strong polygenic predisposition that is aggravated by secondary factors. A young age of onset plus a family history of dyslipidaemia or atherosclerotic cardiovascular disease can suggest a monogenic etiology. With severe dyslipidaemia, clinical examination focuses on detecting manifestations of monogenic syndromic conditions. For all patients with dyslipidaemia, secondary causes must be ruled out. Here we describe an experience-based practical approach to genetic testing of patients with severe deviations of low-density lipoprotein, triglycerides, high-density lipoprotein and also combined hyperlipidaemia and dysbetalipoproteinemia.

Despite cardiovascular disease (CVD) reductions with high-intensity statins, there remains residual risk among patients with metabolic disorders. Alongside low-density lipoproteins (LDL-C), elevated triglycerides (TG) are associated with incident CVD events. Omega-3 fatty acids (n3-FAs), specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), lower TG levels, but their ability to reduce CV risk has been highly inconsistent. Trials using icosapent ethyl (IPE), a purified EPA ethyl ester, produced reductions in CVD events and atherosclerotic plaque regression compared with mixed EPA/DHA formulations despite similar TG-reductions. The separate effects of EPA and DHA on tissue distribution, oxidative stress, inflammation, membrane structure and endothelial function may contribute to these discordant outcomes. Additional mechanistic trials will provide further insights into the role of n3-FAs in reducing CVD risk beyond TG lowering.

Intravascular catabolism of chylomicrons and very low-density lipoproteins (VLDLs) gives rise to a spectrum of partially lipolyzed remnant particles. Their plasma levels and properties are influenced by lipases, lipid transfer proteins, and content of exchangeable lipoproteins. Particularly important among the latter are apoE, which mediates hepatic binding and uptake of remnants, and apoCIII, which can retard this process. In the course of their plasma transit, remnants can acquire pathologic properties that promote the development of atherosclerotic cardiovascular disease (ASCVD) including increased cholesterol content and transport of thrombogenic and inflammatory mediators. Levels of cholesterol-enriched remnant particles determined by various analytic techniques have been significantly linked to the incidence of ASCVD, most dramatically in dyslipidemic patients homozygous for the apoE2 genetic isoform. Further research is warranted for development of clinical assays that can better capture the pathologic impact of remnant lipoprotein subspecies, and for testing the impact on ASCVD of therapies that reduce their levels.

Recent discoveries from the past 15 years of human genetic association studies have provided new insights into the common genetic basis of coronary artery disease and its risk factors including molecular traits like circulating lipid/lipoprotein levels. Polygenic risk scores, which aggregate findings from these large genetic studies, have been developed to predict clinical disease and stratify treatment response in clinical trials. In this review, we describe common methods for calculating polygenic risk scores, highlight examples related to coronary artery disease and lipid traits, and discuss opportunities and challenges for clinical implementation.

Women with thyroid autoimmunity (TAI), predominately characterized by increased levels of thyroid peroxidase antibody (TPOAb), are at risk for developing pregnancy related complications. In this review, we discuss the importance of TAI during natal and perinatal stages. Before pregnancy, TAI is associated with higher mean serum TSH levels and certain causes of subfertility. During pregnancy, TAI increases the risk of an insufficient response of the thyroid to an increasing strain induced by pregnancy, and consequently (subclinical) hypothyroidism might develop. Euthyroid women with TAI have a higher rate of maternal and foetal complications, but it seems that causality cannot be pinned down to thyroid dysfunction alone. Almost half of the women known with TAI prior to pregnancy will also develop post-partum thyroiditis (PPT). However, any relation between PPT and post-partum depression remains uncertain. More research is required to explain possible associations between TAI and pregnancy morbidities, and studies should focus on a better understanding of TAI as such. Given the many unanswered questions, at present, it is not recommended to screen all (potentially) pregnant women for the presence of TAI.

Hashimoto's thyroiditis (HT) and Graves' disease (GD) are prevalent autoimmune disorders, representing opposite ends of the clinical spectrum of autoimmune thyroid diseases (AITD). The pathogenesis involves a complex interplay between environment and genes. Specific susceptibility genes have been discovered that predispose to AITD, including thyroid-specific and immune-regulatory genes. Growing evidence has revealed that genetic and epigenetic variants can alter autoantigen presentation during the development of immune tolerance, can enhance self-peptide binding to MHC (major histocompatibility complex), and can amplify stimulation of T- and B-cells. These gene-driven mechanistic discoveries lay the groundwork for novel treatment targets. This review summarizes recent advances in our understanding of key AITD susceptibility genes (Tg¹, TSHR, HLA-DR3, and CD40) and their translational therapeutic potential.

Background and objective

The recurrence risk ratio (λ) expresses the risk ratio of index patients’ first-degree relatives developing a disease as compared to the general population and is a quantitative measure of the genetic contribution to the disease. This paper offers the results of a specialized center as well as a review of the pertinent literature.

Methods

Data from 3315 consecutive subjects followed at an ORPHAN academic tertiary referral expert center for endocrine autoimmunity as well as 419 unrelated German families were collected. λ was assessed based on 806 well-documented subjects, 299 index patients with autoimmune glandular (AIGD) and non-endocrine diseases and 507 of their first-degree relatives (328 children, 179 siblings).

Results

As many as 36% of relatives of patients with autoimmune diseases (AID) were affected by various autoimmune conditions. Twenty-five percent and 23% of all relatives had an AIGD or an autoimmune thyroid disease (AITD), respectively. Furthermore, 29% and 25% of relatives of index cases with polyglandular (PGA) and monoglandular (MGA) autoimmunity were affected. The recurrence risk for AITD was increased 16-fold in both children and siblings compared to the general population (λ, 95% CI 16, 11–21 and 16, 12–19, respectively). Furthermore, λ for AITD/AIGD was 21.62 (95% CI 14.17–30.69)/17.57 (11.80–24.36) and 13.48 (8.42–20.52)/10.68 (6.76–16.02) for siblings of patients with PGA and MGA, respectively. Overall, a strong genetic component for AITD and AIGD with a significant genetic impact on the development of PGA was demonstrated.

Conclusion

These novel results strongly recommend the screening for AITD and AIGD in children and siblings of index patients with AITD.

Bioassays using animal models were essential tools in the discovery of thyrotropin and in enhancing our understanding of the physiology of the pituitary-thyroid axis. These same bioassays were also instrumental in the discovery of autoantibodies to the thyrotropin receptor (TSH-R-Ab) and in identifying their role in the pathophysiology of Graves’ disease. The development of cell-based bioassays led to further advances in our knowledge of the functional activity of TSH-R-Ab and to the discovery that TSH-R-Ab can be either thyroid-stimulating or thyroid blocking, and that they occur in other types of autoimmune thyroid diseases (AITD) besides Graves’ disease. More recently, TSH-R-Ab bioassays have been advanced from research tools to clinical laboratory tests. Whereas TSH-R-Ab can be measured with competitive-binding immunoassays, these assays do not provide information on the functional activity of TSH-R-Ab. Bioassays, in contrast, can differentiate between the stimulatory or blocking activity of TSH-R-Ab which provides clinically useful information that can inform the management of patients with AITD. The clinical use of TSH-R-Ab bioassays, however, has been limited to-date by their inherent complexity and long turn-around-time. Recent advances in biosensors have been applied to the development of TSH-R-Ab bioassays that are rapid and simple to perform. We now are entering an era in which bioassays for TSH-R-Ab can be measured routinely by virtually any clinical laboratory.