Search

Non

Vertaisarvioitu. Ohutsuolen loppuosan neuroendokriinisiä kasvaimia luonnehtii pieni koko, matala erilaistumisaste (gradus), hidaskasvuisuus ja pitkä ennuste, joista huolimatta niiden toteamishetkellä jopa kahdella kolmasosalla potilaista todetaan etäpesäkkeitä. Nämä kasvaimet erittävät usein serotoniinia, jolloin metastaattisessa taudissa voi karsinoidioireyhtymän merkkinä ilmaantua ripulia ja flush- eli lehahdusoireita. Osalle potilaista kehittyy karsinoidisydänoireyhtymä oikean puolen sydänläppien vaurioitumisen seurauksena. Umpilisäkkeen kasvaimista valtaosa on sattumalöydöksiä, joihin liittyy metastasointia vain harvoin. Diagnostisten menetelmien, erityisesti somatostatiinireseptorien positroniemissiotomografia (PET) -kuvauksen ja histologisen luokittelun kehityksen myötä taudin diagnosoiminen ja hoitoratkaisut ovat helpottuneet. Ainoa parantava hoitomuoto on edelleen leikkaus. Ohutsuolen leikkauksessa koko ohutsuoli ja suolilieve tunnustellaan ja kaikki kasvainmassa poistetaan. Umpilisäkkeen kasvainten osalta keskeistä on, tarvitaanko hemikolektomiaa. Somatostatiinianalogien (SSA) ohella viime vuosina on kertynyt tutkimustietoa somatostatiinileimatun radionuklidihoidon tehosta sekä kasvaintaudin että karsinoidioireiden hoidon osalta.

Aim: \ud To elucidate the impact of liraglutide on the kinetics of apolipoprotein (apo)B48- and apoB100-containing triglyceride-rich lipoproteins in subjects with type 2 diabetes (T2D) after a single fat-rich meal.\ud \ud Materials and Methods: \ud Subjects with T2D were included in a study to investigate postprandial apoB48 and apoB100 metabolism before and after 16 weeks on l.8 mg/day liraglutide (n = 14) or placebo (n = 4). Stable isotope tracer and compartmental modelling techniques were used to determine the impact of liraglutide on chylomicron and very low-density lipoprotein (VLDL) production and clearance after a single fat-rich meal.\ud \ud Results: \ud Liraglutide reduced apoB48 synthesis in chylomicrons by 60% (p

Vertaisarvioitu. Eturauhassyöpä ja sen androgeenideprivaatiohoito (ADT) altistavat potilaan osteoporoosille ja luunmurtumille. Eturauhassyövän toteamisvaiheessa tulisi arvioida murtumariski ja aloittaa ainakin elintapahoitoon perustuva murtumien ehkäisy. Luustolääkkeiden käyttö ADT:hen liittyvän osteoporoosin hoidossa ei ole riittävästi vakiintunut. Luuhun levinnyt eturauhassyöpä voi aiheuttaa kipua, palliatiivisen sädehoidon tarvetta, murtumia tai selkäydinkompressiota. Näiden luustokomplikaatioiden estossa ja hoidossa käytetään bisfosfonaatteja ja denosumabia, mutta niiden hyöty on osoitettu vasta eturauhassyövän edettyä kastraatioresistenttiin vaiheeseen. Eturauhassyövän systeemihoitokin voi vähentää luuston haittatapahtumia. Luustoetäpesäkkeiden aiheuttamaa kipua lievitetään kipulääkkeiden lisäksi ulkoisella sädehoidolla.

Non

Background:\ud Monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9) significantly lower the levels of low-density lipoprotein and very-low-density lipoproteins (VLDL), but their effect on postprandial lipoprotein metabolism in dyslipidemic subjects is unclear.\ud \ud Objective:\ud This study aimed to investigate the effects of evolocumab on postprandial lipid responses, ectopic fat depots, whole-body cholesterol synthesis, hepatic lipogenesis, and fat oxidation in patients with type II diabetes.\ud \ud Methods:\ud The trial was a single-phase, nonrandomized study of 12-week treatment with evolocumab 140 mg subcutaneously every 2 weeks in 15 patients with type II diabetes on background statin therapy. Cardiometabolic responses to a high-fat mixed meal were assessed before and at the end of the intervention period.\ud \ud Results:\ud Evolocumab treatment reduced significantly postprandial rises in plasma total triglyceride (by 21%; P < .0001) and VLDL1 triglyceride (by 15%; P = .018), but the increase in chylomicron triglyceride after the meal was not significantly perturbed (P = .053). There were reduced postprandial responses in plasma total apolipoprotein C-III (by 14%; P < .0001) and apolipoprotein B-48 concentration (by 17%; P = .0046) and in “remnant-like particles” cholesterol (by 29%; P < .0001) on the PCSK9 inhibitor. Treatment reduced the steady-state (ie, fasting and postprandial) concentrations of VLDL2 cholesterol by 50% (P < .0001) and VLDL2 triglyceride by 29% (P < .0001), in addition to the 78% reduction of low-density lipoprotein cholesterol (P < .001). The changes in apolipoprotein C-III associated significantly with reduction in postprandial responses of remnant-like particles cholesterol and triglyceride-rich lipoprotein cholesterol. Evolocumab therapy did not influence liver fat accumulation, hepatic de novo lipogenesis, or fasting β-hydroxybutyrate but did increase total body cholesterol synthesis (P < .01).\ud \ud Conclusion:\ud Evolocumab treatment improved postprandial responses of triglyceride-rich lipoproteins and measures of cholesterol-enriched remnant particles in type II diabetic subjects. These results indicate that postprandial phenomena need to be taken into account in assessing the full range of actions of PCSK9 inhibitors in dyslipidemic individuals.

Teema : krooninen haava

Aims:\ud \ud To investigate how apolipoprotein C‐III (apoC‐III) metabolism is altered in subjects with type 2 diabetes, whether the perturbed plasma triglyceride concentrations in this condition are determined primarily by the secretion rate or the removal rate of apoC‐III, and whether improvement of glycaemic control using the glucagon‐like peptide‐1 analogue liraglutide for 16 weeks modifies apoC‐III dynamics.\ud Materials and Methods:\ud \ud Postprandial apoC‐III kinetics were assessed after a bolus injection of [5,5,5‐2H3]leucine using ultrasensitive mass spectrometry techniques. We compared apoC‐III kinetics in two situations: in subjects with type 2 diabetes before and after liraglutide therapy, and in type 2 diabetic subjects with matched body mass index (BMI) non‐diabetic subjects. Liver fat content, subcutaneous abdominal and intra‐abdominal fat were determined using proton magnetic resonance spectroscopy.\ud Results:\ud \ud Improved glycaemic control by liraglutide therapy for 16 weeks significantly reduced apoC‐III secretion rate (561 ± 198 vs. 652 ± 196 mg/d, P = 0.03) and apoC‐III levels (10.0 ± 3.8 vs. 11.7 ± 4.3 mg/dL, P = 0.035) in subjects with type 2 diabetes. Change in apoC‐III secretion rate was significantly associated with the improvement in indices of glucose control (r = 0.67; P = 0.009) and change in triglyceride area under the curve (r = 0.59; P = 0.025). In line with this, the apoC‐III secretion rate was higher in subjects with type 2 diabetes compared with BMI‐matched non‐diabetic subjects (676 ± 208 vs. 505 ± 174 mg/d, P = 0.042).\ud Conclusions:\ud \ud The results reveal that the secretion rate of apoC‐III is associated with elevation of triglyceride‐rich lipoproteins in subjects with type 2 diabetes, potentially through the influence of glucose homeostasis on the production of apoC‐III.

Background Triglyceride-rich lipoproteins and their remnants have emerged as major risk factors for cardiovascular disease. New experimental approaches are required that permit simultaneous investigation of the dynamics of chylomicrons (CM) and apoB48 metabolism and of apoB100 in very low-density lipoproteins (VLDL). Methods Mass spectrometric techniques were used to determine the masses and tracer enrichments of apoB48 in the CM, VLDL1 and VLDL2 density intervals. An integrated non-steady-state multicompartmental model was constructed to describe the metabolism of apoB48- and apoB100-containing lipoproteins following a fat-rich meal, as well as during prolonged fasting. Results The kinetic model described the metabolism of apoB48 in CM, VLDL1 and VLDL2. It predicted a low level of basal apoB48 secretion and, during fat absorption, an increment in apoB48 release into not only CM but also directly into VLDL1 and VLDL2. ApoB48 particles with a long residence time were present in VLDL, and in subjects with high plasma triglycerides, these lipoproteins contributed to apoB48 measured during fasting conditions. Basal apoB48 secretion was about 50 mg day?1, and the increment during absorption was about 230 mg day?1. The fractional catabolic rates for apoB48 in VLDL1 and VLDL2 were substantially lower than for apoB48 in CM. Discussion This novel non-steady-state model integrates the metabolic properties of both apoB100 and apoB48 and the kinetics of triglyceride. The model is physiologically relevant and provides insight not only into apoB48 release in the basal and postabsorptive states but also into the contribution of the intestine to VLDL pool size and kinetics.

English summary

Aims Patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) exhibit considerable residual risk for cardiovascular disease (CVD). There is, therefore, increasing interest in targeting postprandial lipid metabolism and remnant cholesterol. Treatment with the glucagon-like peptide 1 (GLP-1) analogue liraglutide reduces CVD risk by mechanisms that remain unexplained in part. Here we investigated the effects of liraglutide intervention on ectopic fat depots, hepatic lipogenesis and fat oxidation, postprandial lipid metabolism and glycaemia in humans with type 2 diabetes. Methods The effect of liraglutide was investigated in 22 patients with adequately controlled type 2 diabetes. Patients were randomly allocated, in a single-blind fashion, to either liraglutide 1.8 mg or placebo once daily for 16 weeks. Because liraglutide is known to promote weight loss, the study included dietary counselling to achieve similar weight loss in the liraglutide and placebo groups. Cardiometabolic responses to a high-fat mixed meal were measured before and at the end of the liraglutide intervention. Results Weight loss at Week 16 was similar between the groups: -2.4 kg (-2.5%) in the liraglutide group and -2.1 kg (-2.2%) in the placebo group. HBA1c improved by 6.4 mmol/mol (0.6%) in the liraglutide group (P = 0.005). Liver fat decreased in both groups, by 31% in the liraglutide group and by 18% in the placebo group, but there were no significant changes in the rate of hepatic de novo lipogenesis or beta-hydroxybutyrate levels, a marker of fat oxidation. We observed significant postprandial decreases in triglycerides only in plasma, chylomicrons and VLDL, and remnant particle cholesterol after treatment in the liraglutide group. Fasting and postprandial apoCIII concentrations decreased after liraglutide intervention and these changes were closely related to reduced glycaemia. In relative importance analysis, approximately half of the changes in postprandial lipids were explained by reductions in apoCIII concentrations, whereas less than 10% of the variation in postprandial lipids was explained by reductions in weight, glycaemic control, liver fat or postprandial insulin responses. Conclusions Intervention with liraglutide for 16 weeks produces multiple improvements in cardiometabolic risk factors that were not seen in the placebo group, despite similar weight loss. Of particular importance was a marked reduction in postprandial atherogenic remnant particles. The underlying mechanism may be improved glycaemic control, which leads to reduced expression of apoCIII, a key regulator of hypertriglyceridaemia in hyperglycaemic patients.

Supplementary Table 1. Soinio et al.

•Litiumin terapeuttinen leveys on pieni. Oikea annos tulee määrittää seerumin lääkeainepitoisuuksien perusteella. •Potilailla esiintyy usein struumaa, kilpirauhasen toimintahäiriöitä ja lisäkilpirauhasen liikatoiminnan aiheuttamaa hyperkalsemiaa myös litiumpitoisuuden ollessa hoitotasolla. •Litiumin aiheuttama nefrogeeninen diabetes insipidus ilmenee polyuria-polydipsiaoireena. Se voi johtaa vakavaan kuivumaan ja hypernatremiaan. •Viime aikoina on tunnistettu uusi litiumhoitoon liittyvä haitta, lihavuusleikkauksen jälkeinen litiumintoksikaation vaara.

Käypä hoito -suositus. Päivitystiivistelmä

Teema : Diabetes avoterveydenhuollossa. English summary

English summary

HIV-potilaiden endokriinisten ongelmien kirjo on vaihtunut taudin muututtua kuolemaan johtavasta ¬immuunivajeesta krooniseksi sairaudeksi. Nykyään suurin osa HIV-potilaiden endokriinisista ongelmista diagnosoidaan ja hoidetaan samalla lailla kuin muidenkin potilaiden. Krooninen infektio ja HIV-lääkitys lisäävät osteoporoosin ja murtumien riskiä. Myös metaboliset haitat ja miesten hypogonadismi ovat yleisiä. HIV-lääkkeiden merkittävät yhteisvaikutukset on muistettava myös endokriinisia sairauksia hoidettaessa. Yhteisvaikutuksia voi ilmaantua esimerkiksi glukokortikoidien, tyroksiinin, kalsiumvalmisteiden ja statiinien kanssa.

English summary

Over time, reductions in the ethinylestradiol (EE) dose of combined oral contraceptives (COCs) from 100 μg to 20–30 μg have resulted in a lowered risk of COC-associated venous thromboembolism (VTE). Additionally, the development and incorporation of less androgenic progestins, administered in lower doses, have improved the tolerability and metabolic impact of COCs. EE in COCs has recently been replaced with estrogens based on natural estradiol (E2). E2-based COCs are expected to cause more moderate metabolic, endocrine and hemostatic effects than EE-based COCs. However, evidence remains limited, and previous studies investigating EE versus EV are difficult to interpret since they have compared COCs that also differ based on the progestin type. A meaningful comparison of the estrogens in COCs should focus on COCs differing only by the estrogen component since the progestin component exerts its own effects in addition to modulating the effects of the estrogen. Therefore, this thesis aimed to compare the metabolic, endocrine and hemostatic effects of COCs containing E2 (esterified with valeric acid; estradiol valerate [EV]) and EE. To this end, we conducted an open-label, randomized study. Participants were allocated to nine weeks of continuous treatment with 1) EV 2 mg and dienogest (DNG) 2–3 mg, 2) EE 0.03 mg and DNG 2 mg and 3) DNG 2 mg, which was included to specify the progestin effects. Participants were assessed at baseline, five and nine weeks of treatment for changes in insulin sensitivity (the Matsuda index; study I); the lipid profile and markers of low-grade inflammation (high sensitivity C-reactive protein [hs-CRP] and pentraxin-3 [PTX-3]; study II); levels of reproductive hormones (gonadotropins and ovarian hormones) and the induction of hepatic metabolism (sex hormone-binding globulin [SHBG]; study III); and blood coagulation biomarkers (in vitro thrombin generation and markers of in vivo coagulation activation; study IV). We recruited 77 women, of whom 59 were enrolled. The main inclusion criteria were being 18–35 years of age, a two-month wash-out from previous hormonal contraceptive use and normal body weight (body mass index 19–24.9 kg/m2). Three women discontinued participation due to mild side effects. The primary endpoint measure of this study was a change in the Matsuda Index, a whole-body insulin sensitivity index derived from the oral glucose tolerance test (OGTT). The Matsuda index, as well as glucose levels during the OGTT, remained unchanged after treatment with both EV+DNG and EE+DNG. By contrast, fasting insulin levels increased within the normal ranges in the EE+DNG group by +39% (p = 0.03) and in the DNG-alone group by +45% (p = 0.01), whereas they remained unchanged in the EV+DNG group (study I). In the EV+DNG group, the lipid profile changed negligibly. The mean triglyceride levels were minimally elevated at nine weeks, increasing by 0.18 mmol/L (p = 0.02). In the EE+DNG group, triglycerides increased by 0.45 mmol/L (p < 0.001) and high-density lipoproteins by 0.20 mmol/L (p < 0.01). These changes remained within the normal ranges and demonstrated changes in the lipid profile typical for estrogen treatment. Moreover, the mean levels of hs-CRP increased by 1.1 mg/L (p < 0.01) and PTX-3 by 0.22 ng/L (p = 0.02) in the EE+DNG-group, indicative of increased low-grade inflammation. In contrast, treatment with EV+DNG and DNG alone did not trigger increases in either inflammatory marker (study II). Compared with EE+DNG, treatment with EV+DNG resulted in less marked suppression of follicle-stimulating hormone (FSH), whereas luteinizing hormone levels were equally suppressed. As expected, all participants had low progesterone levels compatible with anovulation at five and nine weeks. As an indicator of follicular arrest, anti-Müllerian hormone (AMH) levels decreased in both COC groups by -9% (EV+DNG; p = 0.04) and -13% (EE+DNG; p = 0.01), while AMH remained unchanged in the DNG-alone group. The free androgen index (FAI), a surrogate for free testosterone levels, decreased less in the EV+DNG group than in the EE+DNG group (-39% vs. -72%, p < 0.001). In the EV+DNG group, reduced hepatic impact was demonstrated through a moderate increase in SHBG levels at nine weeks compared with the EE+DNG group, in which SHBG levels increased significantly more (+56% vs. +368%, p < 0.001) (study III). The effect on blood coagulation parameters differed between the EV+DNG and EE+DNG groups. In both groups, in vitro coagulation potential (assessed by thrombin generation) increased; however, the magnitude diverged in favor of EV+DNG, which induced a smaller increase in endogenous thrombin potential (+26% vs. +64%, p < 0.01). Levels of prothrombin fragment 1+2 (F1+2) were elevated in the EE+DNG group, compatible with coagulation activation in vivo, while F1+2 levels remained unaltered in the EV+DNG group (p = 0.04). In contrast, D-dimer levels remained unchanged in all groups. Treatment with DNG alone did not affect either the in vitro or in vivo coagulation parameters. These results indicate increased coagulation potential in the EE+DNG group compared with the EV+DNG group (study IV). In conclusion, these results show that in young, healthy women, short-term treatment with EV+DNG affected markers of low-grade inflammation, lipids, the FAI, SHBG synthesis and blood coagulation parameters less than treatment with EE+DNG. In addition, EV+DNG also appeared neutral on parameters of glucose metabolism, whereas EE+DNG elevated fasting insulin levels. The clinical significance of the differing effects of EV and EE on insulin levels, lipids, and inflammatory markers remains to be explored. However, the more minor impact of EV+DNG on the coagulation parameters may be clinically significant, possibly predicting a lower risk of venous thrombosis. These results encourage further development and research of E2-based COCs. Nykyaikaiset hormonaaliset yhdistelmäehkäisyvalmisteet sisältävät pääsääntöisesti synteettistä etinyyliestradiolia yhdistettynä synteettiseen keltarauhashormoniin, progestiiniin. Etinyyliestradiolin haittavaikutukset, erityisesti sen laskimotukoksen riskiä lisäävä vaikutus, tunnetaan hyvin. Siksi etinyyliestradioliannosta on vuosien mittaan pienenetty. Tiedetään myös, että yhdistelmäehkäisyvalmisteet heikentävät sokeriaineenvaihduntaa ja lisäävät matala-asteista tulehdusta. Markkinoille on viimeisten vuosien aikana tullut luonnollista estradiolia sisältäviä yhdistelmäehkäisyvalmisteita, joilla on mahdollisesti vähemmän aineenvaihdunnallisia haittavaikutuksia ja pienempi laskimotukosriski. Väitöskirjatutkimuksessa verrattiin yhdistelmäehkäisyvalmisteita, jotka sisältävät luonnollista estradiolivaleraattia tai synteettistä etinyyliestradiolia, ja selvitettiin niiden vaikutuksia sokeri- ja rasva-aineenvaihduntaan ja matala-asteiseen tulehdukseen, lisääntymishormoneihin, ja veren hyytymisjärjestelmään. Ainoastaan keltarauhashormonia sisältävä valmiste toimi vertailuvalmisteena. Tutkimus toteutettiin satunnaistettuna kliinisenä lääkeainetutkimuksena. Tutkimukseen osallistui 59 vapaaehtoista, 18–35-vuotiasta naista. Osallistujat satunnaistettiin käyttämään joko 1) estradiolivaleraatin ja dienogestin yhdistelmää (EV 2 mg + DNG 2-3 mg), 2) etinyyliestradiolin ja dienogestin yhdistelmää (EE 0.03 mg + DNG 2 mg), tai 3) pelkkää dienogestiä (DNG 2 mg) yhtäjaksoisesti yhdeksän viikon ajan. Verikokeita otettiin ennen tutkimusjakson alkua sekä viidennen ja yhdeksännen tutkimusviikon aikana. Tutkimuksen päämuuttuja oli insuliiniherkkyys. Kummassakaan yhdistelmävalmisteryhmässä (EV+DNG ja EE+DNG) ei havaittu muutosta insuliiniherkkyydessä. Veren rasvaprofiili pysyi lähes muuttumattomana EV+DNG ryhmässä, kun taas EE+DNG ryhmässä triglyseridien ja HDL-kolesterolin pitoisuudet nousivat jonkin verran. EV+DNG ryhmässä matala-asteista tulehdusta kuvaavat merkkiaineet pysyivät muuttumattomina, mutta nousivat merkittävästi EE+DNG ryhmässä. EV+DNG ryhmässä havaittiin lievempi vaikutus follikkelia stimuloivan hormonin pitoisuuksiin. Kaikilla naisilla oli kuitenkin matalat progesteronitasot, sopien ovulaation estoon. Veren vapaa testosteroni laski vähemmän EV+DNG ryhmässä (-38 %) kuin EE+DNG ryhmässä (-72 %). Myös sukuhormoneja sitova globuliinin pitoisuus lisääntyi vähemmän EV+DNG (+56 %) ryhmässä verrattuna EE+DNG ryhmään (+368 %), osoittaen EV+DNG:n lievempää vaikutusta maksan estrogeeniherkkien proteiinien tuotantoon. EE+DNG-yhdistelmä vaikutti enemmän veren hyytymisjärjestelmään kuin EV+DNG. Plasmanäytteistä tutkittiin veren hyytymisen keskeisen entsyymin, trombiinin, tuotantoa. Kokeellisessa asetelmassa, EE+DNG-ryhmässä trombiinin tuotanto nousi lähtötilanteesta +64 % kun vastaava nousu EV+DNG-ryhmässä oli 26 %. Tulosten perusteella estradiolivaleraattia sisältävä yhdistelmäehkäisyvalmiste vaikutti vähemmän rasva-aineenvaihduntaan, matala-asteiseen tulehdukseen ja veren hyytymisjärjestelmään kuin etinyyliestradiolia sisältävä valmiste. Koska molemmilla valmisteilla on hyvä ehkäisyteho, estradiolivaleraatin lievemmät vaikutukset, varsinkin hyytymisjärjestelmään, viittaavat edullisempaan hyöty-haittasuhteseen.