[Thyroid hormone therapy in old age]. / Therapie mit Schilddrüsenhormonen im Alter.

BACKGROUND: There is evidence that the treatment of overt hyperthyroidism with thyroid hormones is able to reduce mortality as well as cardiovascular and musculoskeletal morbidity. It remains unclear whether these data can be extrapolated to the mildest form of hypothyroidism, subclinical hypothyroidism. Furthermore, it is uncertain whether and to what extent the threshold for therapeutic intervention needs to be modified in the elderly, in whom hypothalamo-pituitary regulation is increasingly insensitive to the negative feedback by thyroid hormones and the patients' response to thyroid hormones changes. OBJECTIVE: The aim of this review is to evaluate the current evidence on the treatment of hypothyroidism in old age with regard to the initiation of therapy and the therapeutic goals. RESULTS AND CONCLUSIONS: According to new original data and meta-analyses, therapy with thyroid hormones does not alter morbidity and mortality in patients with subclinical hypothyroidism with thyroid stimulating hormone (TSH) below the range of 7-10 mU/l. These data support the TSH threshold of 10 mU/l recommended in guidelines, particularly in elderly patients over the age of 65 years, in whom TSH serum levels increase with age. In contrast to the recommendations, the prescription of thyroxine more than doubled in a large study from Denmark and TSH levels decreased from 10 mU/l to under 7 mU/l between 2001 and 2015. As (the primarily unspecific) symptoms and quality of life are not altered by thyroxine replacement in studies on subclinical hypothyroidism and elderly patients are more susceptible to side effects, thyroid hormone substitution should generally not be started at TSH levels <10 mU/l.

[Physiology and clinical importance of white, beige and brown adipose tissue]. / Physiologie und klinische Bedeutung von weißem, beigem und braunem Fettgewebe.

The metabolic functions of different kinds of adipose tissue are of growing scientific and clinical interest. White adipose tissue is not only an energy store but as a highly active endocrine organ it also plays an essential role in the development of diabetes mellitus, dyslipidemia, arterial hypertension and cardiovascular diseases. Brown adipose tissue, on the other hand, can convert chemical energy into heat and could therefore have an opposing, protective effect. The activation of brown adipose tissue and the induction of the development of adipocytes with the characteristics of brown fat cells could make a significant contribution to the treatment of these civilization diseases. This article provides an overview of the current understanding of the physiology and pathophysiology of different adipose tissue types and the resulting therapeutic potential.

[Thyroid and pregnancy]. / Schilddrüse und Schwangerschaft.

During pregnancy thyroid hormones have profound effects on embryonal/fetal development and maternal health. Therefore, thyroid gland disorders should be immediately diagnosed and adequately treated. Pregnancy-specific physiological alterations during pregnancy cause changes in the reference interval for thyroid-stimulating hormone levels and trimester-specific thresholds must be taken into account. This article summarizes the most important diagnostic and therapeutic aspects before, during and after pregnancy. With reference to the period prior to pregnancy, the article discusses iodide supplementation, preconceptional examination of thyroid gland metabolism and the importance of thyroid gland functional disorders for fertility and fulfilling the desire to have children. With a view to the period during pregnancy, the effect of hypothyroxinemia, hypothyroidism, and hyperthyroidism as well as the effects of their treatment on the development of the child are explained. Finally, a description is given of what must be paid attention to in the breast-feeding period and in postpartum thyroiditis.

[Overweight. A valid predictor of cardiometabolic risk?]. / Adipositas. Valider Prädiktor für das kardiometabolische Risiko?

A commonly held notion directly correlates overweight and obesity with cardiometabolic risk. A number of studies have recently questioned this belief. The classic measure of obesity, the body mass index, appears less valid to properly indicate increased fat mass and, in particular, potentially harmful changes in fat depots. Moreover, depot- and age-specific alterations including increases in fat mass are physiologic throughout life and may not be associated with an increased risk for diabetes or cardiovascular complications. In contrast, they may rather entail multi-system adaptations that are protective, e. g. to cardiovascular and bone health, and represent an explanation for what has recently been called "benign obesity". Endocrine as well as thermogenic functions of fat cells appear to be critical for the underlying biology. In this article, we highlight recent epidemiologic and biologic insights arguing against the assumption of overweight as a simple measure of disease. Finally, using selected clinical cases we demonstrate the ill-informed nature of an "overweight-focused" approach and delineate a practical algorithm to identify overweight patients at cardiometabolic risk.

Hepatic gene expression patterns in thyroid hormone-treated hypothyroid rats.

Thyroid hormone (T3) is essential for normal development, differentiation and metabolic balance. We have performed DNA microarray experiments using hepatic RNA from hypothyroid and T3-treated hypothyroid rats in order to characterize T3-induced gene expression patterns after various time points (6, 24 and 48 h after the administration of the hormone). Sixty-two of 4608 different genes displayed a reproducible T3-response, and cluster analysis divided these differentially regulated genes into six expression patterns. Thirty-six genes were not significantly regulated within the first 24 h. Transient transfection experiments of eight late-induced gene promoters failed to detect a thyroid hormone response element within their regulatory elements, suggesting an indirect activation mechanism(s). In search for an intermediate factor of T3 action, we examined whether various rather ubiquitous transcription factors, peroxisome proliferator-activated receptors (PPARs) and coactivators of the PPARgamma coactivator 1 family (PGC-1) are regulated by T3. Only PPARgamma and PERC/PGC-1beta exhibit a significant T3-response within the first 6 h after treatment, identifying these factors as candidate components for mediating the late-induced expression pattern. Regulation of early-induced genes within the first 6 h after administration of T3 on transcript levels correlates with altered protein levels after 24 and 48 h in vivo.

Maturity-onset diabetes of the young and hepatic adenomatosis - characterisation of a new mutation.

Hepatocyte nuclear factor 1 alpha (HNF1A) mutations cause maturity-onset diabetes of the young (MODY) type 3. Further extending the phenotypic spectrum, HNF1A mutations are associated with hepatic adenomatosis. A 20-year old lean, female patient with newly diagnosed diabetes mellitus was negative for diabetes-associated autoantibodies and had no relevant family history. Hepatic adenomatosis was diagnosed. Her HNF1A gene was examined and identified alterations further analysed.Sequencing of her HNF1A gene revealed a previously uncharacterised Q495X nonsense mutation, along with the known A98V polymorphism, both in the heterozygous state. The patient's father was also a carrier of both the mutation and the polymorphism. An oral glucose tolerance test (OGTT) revealed impaired glucose tolerance, whereas imaging of his liver was unremarkable. Wild type HNF1A and HNF1A carrying the Q495X mutation were co-transfected in reporter gene assays. The mutation causes a dominant-negative HNF1A protein variant which blocks HNF1A wild-type-mediated gene expression.The novel Q495X mutation is the likely cause of our patient's diabetes and hepatic adenomatosis. It may also cause her father's impaired glucose tolerance. More generally speaking, if non-autoimmune diabetes is suspected, examination of the liver may provide important diagnostic clues. Furthermore, patients with hepatic adenomatosis without known diabetes should be screened by OGTT. Relatives of patients with HNF1A mutations should also be screened by OGTT to detect potential early-stage diabetes.

[Diabetes and hypertension]. / Diabetes und Hypertonie.

Diabetes mellitus and arterial hypertension are major cardiovascular risk factors with high co-morbidity. Microalbuminuria is an independent risk marker, and routine monitoring of urinary albumin is mandatory in patients with diabetes and hypertension. The therapeutic goal of antihypertensive treatment is < 130/80 mm Hg, however in the presence of nephropathy < 125/75 mm Hg should be achieved. Therapy is based on lifestyle-interventions including 1) weight reduction, 2) regular moderate physical activity, 3) modification of diet with restriction of salt- and alcohol consumption as well as 4) cessation of smoking. Renin- and ACE-inhibitors as well as AT1-receptor antagonists are drugs of first choice, delaying the progression of diabetic nephropathy most effectively.

Expression of ATRAP in adipocytes and negative regulation by beta-adrenergic stimulation of JAK/STAT.

Sympatho-adrenergic activity and the renin-angiotensin system are considered critical regulators of obesity and hypertension. The novel angiotensin II type 1 receptor-associated protein (ATRAP) has been demonstrated to modulate angiotensin II signalling in smooth muscle cells and cardiomyocytes. Adipose tissue expresses important renin angiotensin system components and contributes to cardiometabolic disease. However, ATRAP expression and regulation in adipocytes are unknown. We investigated expression of this novel modulator of angiotensin signalling and its regulation by beta-adrenergic receptors. We found ATRAP to be expressed in differentiated brown and white adipocytes. Stimulation of beta-adrenoceptors strongly suppressed ATRAP expression. We hypothesised a role for JAK/STAT signalling elements. Indeed, beta3-adrenergic stimulation robustly stimulated both STAT1 and STAT3 phosphorylation in a time- and dose-dependent manner. This effect was abrogated by inhibition of PKA and JAK2 signalling. Moreover, inhibition of JAK/STAT and PKA signalling reversed the beta3-adrenergic suppression of ATRAP expression. This study provides the first evidence for expression and adrenergic regulation of the angiotensin II signalling modulator ATRAP in adipocytes. Further, it indicates a novel regulatory link between beta-adrenergic and JAK/STAT signalling.