Berta Soldevila

Regulatory T cells in diabetes and gastritis

Patients with Type 1 diabetes mellitus (T1D) have an increased prevalence of associated organ-specific autoimmune diseases such as pernicious anemia whose histological substrate is a chronic atrophic gastritis (CAG). Latent pernicious anemia precedes clinically-manifest pernicious anemia and may be difficult to detect solely on simple analytical grounds. We recently described an increased prevalence of clinically-latent pernicious anemia in T1D using low concentrations of pepsinogen I, a zymogen of pepsin present in gastric mucosa, as a useful additional diagnostic marker, besides parietal cell antibodies, for screening latent pernicious anemia in T1D. The failure of peripheral tolerance mechanisms such as regulatory T cells (Treg) might be involved in CAG development in T1D patients. Indeed, functional defects in Tregs have been described in T1D patients. To this end, the percentage of Tregs in peripheral blood of T1D-CAG patients was analyzed and compared with those of a group of T1D without associated autoantibodies and a healthy control group. Tregs levels were also analyzed in gastric biopsies of T1D-CAG patients. The results obtained have led to new questions regarding the pathogenic mechanisms implicated in the development of associated autoimmune diseases in T1D.

A prospective study of T- and B-lymphocyte subpopulations, CD81 expression levels on B cells and regulatory CD4+CD25+CD127low/−FoxP3+ T cells in patients with chronic HCV infection during pegylated interferon-alpha2a plus ribavirin treatment

Summary.  Resolution of hepatitis C virus (HCV) infection requires a complex interplay between innate and adaptative immune responses. The role of lymphocyte subpopulations during combined antiviral treatment remains to be defined. This study was conducted to assess the effect of pegylated interferon‐alpha2a (pegIFN‐α2a) and ribavirin treatment on peripheral blood lymphocytes, mainly on CD81 expression on B cells and CD4+CD25+CD127low/−FoxP3+ regulatory T cells (Tregs) in patients with chronic HCV infection. Thirty‐five patients with chronic HCV infection who started pegIFN‐α2a and ribavirin treatment were enrolled. Peripheral blood mononuclear cells (PBMC) were obtained at baseline before treatment (BT), mid‐treatment (MT), the end of treatment (ET) and 24 weeks post‐treatment (PT). During combined antiviral treatment, a significant decrease in the percentage of CD3+, CD8+, CD3+gamma/delta (γδ)+, CD19+ lymphocyte subpopulations and Tregs was observed. There was also a significant increase in the percentage of the CD4+ lymphocyte subpopulation and in CD81 expression levels on CD19+ B cells when BT was compared with ET (all P < 0.05). Seventeen patients were nonresponders (NR) and 18 had a sustained virological response (SVR). At baseline, NR patients had higher CD81 expression levels on CD19+ B cells (P = 0.017) and a higher Tregs percentage (P = 0.025) than SVR patients. Our results suggest that immunomodulation fluctuates during antiviral treatment and that percentage CD81 expression levels on B cells and Tregs might be useful as an immunological prognostic factor for pegIFN‐α2a and ribavirin treatment response in chronic HCV infection.

Low Prevalence of Subclinical Atherosclerosis in Asymptomatic Patients With Type 1 Diabetes in a European Mediterranean Population

OBJECTIVE To evaluate the presence of early carotid and coronary atherosclerosis in asymptomatic patients with type 1 diabetes with no history of ischemic heart disease. RESEARCH DESIGN AND METHODS One hundred and fifty patients with type 1 diabetes (58% males; 38.6 ± 8.1 years, 20.4 ± 8.1 years of evolution; HbA1c 8.1 ± 2.3%; 52% nonsmokers; 26% retinopathy; 9% microalbuminuria) and 50 nondiabetic control subjects age and sex matched were studied. Carotid ultrasonography to determine common carotid artery intima-media thickness (c-IMT) and the presence of atheroma plaques and cardiac computed tomography for calcium analysis and quantification (coronary artery calcium score [CACS]) were performed. RESULTS Most patients with type 1 diabetes and control subjects displayed a CACS of 0 (82 vs. 92%). Patients with type 1 diabetes with CACS ≥1 were older and had higher HbA1c (44.5 ± 5.1 vs. 36.7 ± 8.1 years [P < 0.001] and 8.5 ± 1.1 vs. 7.8 ± 1.0% [P < 0.003], respectively) and longer evolution of diabetes (25.4 ± 9.2 vs. 19.3 ± 7.4 years, P < 0.005) and mean c-IMT (0.67 ± 0.18 vs. 0.53 ± 0.11 mm, P < 0.001) compared with patients with CACS of 0. Smoking (P < 0.02), nephropathy (P < 0.05), retinopathy (P < 0.05), and male sex (P < 0.03) were significantly and positively associated with CACS ≥1. Mean c-IMT was significantly higher in patients with type 1 diabetes (0.55 ± 0.14 vs. 0.48 ± 0.14 mm, P < 0.01), and 11% of them presented atheroma plaques (8% of control subjects). Multivariant logistic regression analysis showed that c-IMT was related to CACS (β = 6.87, P < 0.001). CONCLUSIONS A small percentage of patients with type 1 diabetes showed data suggestive of subclinical atherosclerosis. Universal screening of coronary disease in this population is not justified. Carotid ultrasonography may be useful for screening in the subset of patients with cardiovascular risk factors and long disease evolution.

Thyroid Hormone Upregulates Zinc-α2-glycoprotein Production in the Liver but Not in Adipose Tissue

Overproduction of zinc-α2-glycoprotein by adipose tissue is crucial in accounting for the lipolysis occurring in cancer cachexia of certain malignant tumors. The main aim of this study was to explore whether thyroid hormone could enhance zinc-α2-glycoprotein production in adipose tissue. In addition, the regulation of zinc-α2-glycoprotein by thyroid hormone in the liver was investigated. We performed in vitro (HepG2 cells and primary human adipocytes) and in vivo (C57BL6/mice) experiments addressed to examine the effect of thyroid hormone on zinc-α2-glycoprotein production (mRNA and protein levels) in liver and visceral adipose tissue. We also measured the zinc-α2-glycoprotein serum levels in a cohort of patients before and after controlling their hyperthyroidism. Our results showed that thyroid hormone up-regulates zinc-α2-glycoprotein production in HepG2 cells in a dose-dependent manner. In addition, the zinc-α2-glycoprotein proximal promoter contains functional thyroid hormone receptor binding sites that respond to thyroid hormone treatment in luciferase reporter gene assays in HepG2 cells. Furthermore, zinc-α2-glycoprotein induced lipolysis in HepG2 in a dose-dependent manner. Our in vivo experiments in mice confirmed the up-regulation of zinc-α2-glycoprotein induced by thyroid hormone in the liver, thus leading to a significant increase in zinc-α2-glycoprotein circulating levels. However, thyroid hormone did not regulate zinc-α2-glycoprotein production in either human or mouse adipocytes. Finally, in patients with hyperthyroidism a significant reduction of zinc-α2-glycoprotein serum levels was detected after treatment but was unrelated to body weight changes. We conclude that thyroid hormone up-regulates the production of zinc-α2-glycoprotein in the liver but not in the adipose tissue. The neutral effect of thyroid hormones on zinc-α2-glycoprotein expression in adipose tissue could be the reason why zinc-α2-glycoprotein is not related to weight loss in hyperthyroidism.

A prospective study of lymphocyte subpopulations and regulatory T cells in patients with chronic hepatitis C virus infection developing interferon‐induced thyroiditis

Objective  One of the side effects of interferon‐alpha (IFN‐α) therapy is interferon‐induced thyroiditis (IIT). The role of lymphocyte subpopulations in IIT remains to be defined. The aim of this study was to assess different peripheral blood lymphocyte subpopulations, mainly CD4+CD25+CD127low/‐FoxP3+ regulatory T cells (Tregs), in patients with chronic hepatitis C virus (HCV) infection who developed IIT.

Perioperative Management of the Diabetic Patient

Patients with diabetes mellitus are at increased risk of intra and post-operative morbidity and mortality. Poor glycaemic control in these patients is associated with worse surgical outcomes. Additionally, diabetes mellitus is often complicated by the presence of late chronic complications that may further increase the risk associated to hyperglycaemia. Therefore, diabetic patients require a careful preoperative assessment. However, there is not enough evidence concerning the optimal perioperative glycaemic target and treatment strategy in diabetic patients. Current guidelines provide clinical recommendations on the management of glycaemia based on the limited available evidence. The treatment schedule may vary according to the patient’s individual characteristics and the type and duration of the surgical procedure. The aim of this chapter is give an overview of the available, clinically relevant, evidence on the management of patients with diabetes mellitus undergoing any surgical procedure.

Regulatory T cells and other lymphocyte subpopulations in patients with melanoma developing interferon‐induced thyroiditis during high‐dose interferon‐α2b treatment

One of the side effects of interferon‐alpha therapy is interferon‐induced thyroiditis (IIT). The role of lymphocyte subpopulations in IIT melanoma patients remains to be defined.

Hypothyroidism during pregnancy and its association to perinatal and obstetric morbidity: a review

Abstract There is currently no consensus among the different scientific societies on screening for thyroid dysfunction in the first trimester of pregnancy. Indeed, diagnosis and treatment of subclinical hypothyroidism during pregnancy are controversial, as no cut-off value for thyrotropin (TSH) is universally accepted. TSH measurement may be influenced by different factors throughout pregnancy, but especially during the first trimester. The association between overt hypothyroidism during pregnancy and obstetric and perinatal complications is well established. It is also accepted that thyroid hormones are important for neurodevelopment of the offspring. However, there is no scientific evidence available about the impact of subclinical hypothyroidism and its treatment during the first trimester of pregnancy on childrens neurodevelopment. In recent years, studies conducted in the offspring of mothers with subclinical hypothyroidism have reported new biochemical parameters which may eventually serve as biomarkers of offspring neurodevelopment and which are more reproducible and are measured at an earlier time than the conventional clinical tests.

Impact of TSH during the first trimester of pregnancy on obstetric and foetal complications: Usefulness of 2.5 mIU/L cut-off value

An association of pregnancy outcomes with subclinical hypothyroidism has been reported; however, there still exists a strong controversy regarding whether subclinical hypothyroidism ought to be dealt with or not. The objective of the study was to evaluate the association of foetal‐maternal complications with first trimester maternal Thyrotropin (TSH) values.

Prevalence and progression of subclinical atherosclerosis in patients with chronic kidney disease and diabetes

BACKGROUND AND AIMS Cardiovascular disease is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD) and diabetes. Traditional cardiovascular risk factors fail to fully account for the increase in cardiovascular risk in these patients. This study aims to analyse the prevalence and progression of subclinical atherosclerosis in CKD patients with and without diabetes. METHODS We included data from CKD patients with and without diabetes free from previous cardiovascular events from the NEFRONA cohort. Patients underwent baseline and 24-month follow-up carotid and femoral ultrasound examinations. Multivariable models were used to assess the contribution of diabetes to the presence and plaque progression. RESULTS A total of 419 patients with diabetes and 1129 without diabetes were included. Diabetic patients were older, had higher BMIs, more hypertension and dyslipidaemia. At baseline, the proportion of patients with plaque was higher among diabetic patients (81.4% vs. 64.1%, p < 0.001). Diabetic patients more frequently had more than two vascular territories with plaque (64.4% vs. 48.4%, p < 0.001). Multivariable analysis indicated that plaque at baseline was significantly associated with age, gender, smoking and renal replacement therapy (RRT) in the non-diabetic patients, but only with age and male gender in diabetic patients. Plaque progression was significantly associated with age, number of territories with basal plaque, smoking and RRT in both groups. CONCLUSIONS Subclinical atherosclerosis is more prevalent, carries a higher plaque burden and is more rapidly progressive in renal patients with diabetes. In these patients, diabetes outweighs other described risk factors associated with the presence of subclinical atherosclerosis.