Lars Østergaard Kristensen

Receptor binding of lactoferrin by human monocytes

Summary. The binding of iron‐saturated 125I‐lactoferrin to human monocytes was studied at pH 7·4 and 37°C. Monocytes in suspension bound 125I‐lactoferrin by a reversible, saturable and specific binding indicating the presence of a receptor. The dissociation constant (KD) of the binding was estimated at about 4·5 × 10−9 M and the number of receptors was about 1·6 × 106 per monocyte. The affinity of native lactoferrin (20% iron saturated) was only slightly below that of iron‐saturated lactoferrin (KD about 7·9 × 10−9 M). Human transferrin, horse cytochrome c and human immunoglobulin G were without inhibitory effect on the binding of 125I‐lactoferrin. The majority of cell‐bound 125I‐lactoferrin was dissociable. The dissociation rate was not affected by addition of unlabelled lactoferrin to the dissociation medium. The binding of 125I‐lactoferrin to adherent mononuclear blood cells showed an about 100‐fold lower affinity (KD about 2·5 × 10−7 M) than to cells in suspension, but the specificity of the binding was the same. These results are compatible with the idea that lactoferrin exerts a biological effect mediated by an interaction with cells of the monocyte/macrophage lineage.

Morbidity and GH deficiency: a nationwide study.

OBJECTIVE To estimate morbidity in Denmark in all patients with GH deficiency (GHD). DESIGN Morbidity was analyzed in 1794 GHD patients and 8014 controls matched on age and gender. All records in the GHD patients were studied and additional morbidity noted. Diagnoses and dates of admissions were identified in the National Patient Registry. Lag time until first admission was used as a measure of morbidity. Patients were divided into childhood onset (CO) and adult onset (AO), discriminated by an age cut-off of 18 years at onset of GHD. METHOD Sex- and cause-specific hazard ratios (HRs) in CO and AO GHD compared with controls. RESULTS Total morbidity was significantly increased in the GHD patients. HR for CO males: 3.1 (95% confidence interval (CI): 2.7-3.7), CO females: 3.2 (95% CI: 2.6-3.9), AO males: 2.9 (95% CI: 2.6-3.2), and AO females: 3.2 (95% CI: 2.8-3.6). In 18 out of 20 chapters from the International Classification of Diseases-10, a significantly increased morbidity was identified for at least one of the four subgroups of patients. Morbidity was significantly increased in all the four subgroups due to infectious, endocrine, pulmonary, urogenital, and neurological diseases; cancer; diseases of the eye, ear, and circulatory diseases; and traumas. Fractures were significantly increased in AO females, not in males. CONCLUSIONS Morbidity was significantly increased in the GHD patients. The increased morbidity was due to a variety of disorders, some of which can readily be explained by GHD and other pituitary deficiencies, while others cannot be easily explained.

IGF1 as predictor of all cause mortality and cardiovascular disease in an elderly population.

BACKGROUND IGF1 is believed to influence ageing and development of cardiovascular disease (CVD) through complex mechanisms. Reduced IGF1 levels might be causally associated with conditions accompanying ageing including development of CVD. However, in animal models reduced GH-IGF1 signalling increases lifespan. Reduced IGF1 activity might also be associated with longevity in humans. OBJECTIVE The objective was to investigate if plasma IGF1 levels were associated with all cause mortality, and the development of chronic heart failure (CHF) and a major CV event. PATIENTS AND DESIGN A population based study of 642 individuals, aged 50-89 years. Development of CHF was evaluated in 576 individuals with normal systolic function assessed by echocardiography and without the history of CHF or myocardial infarction. Development of the first major CV event was evaluated in 504 individuals with normal systolic function and without prevalent CVD. Outcomes were ascertained after 5 years using hospital discharge diagnoses. RESULTS Adjustment for risk factors IGF1 values in the fourth quartile versus values below the fourth quartile was associated with increased mortality (n=103), hazard ratio (HR) 1.52 (95% confidence interval (CI) 1.01-2.28; P=0.044). IGF1 in the fourth quartile was also independently associated with risk of development of CHF (n=19), HR 5.02 (95% CI 2.00-12.64; P=0.001) but showed no association with the overall incidence of major CV events (n=58), HR 1.05 (95% CI 0.59-1.90; P=0.861). CONCLUSIONS High IGF1 levels were independently associated with increased all cause mortality and risk of development of CHF, whereas no relation with the overall incidence of CVD was observed.

Acromegaly incidence, prevalence, complications, and long-term prognosis: A nationwide cohort study

DESIGN Valid data on acromegaly incidence, complications and mortality are scarce. The Danish Health Care System enables nationwide studies with complete follow-up and linkage among health-related databases to assess acromegaly incidence, prevalence, complications and mortality in a population-based cohort study. METHOD All incident cases of acromegaly in Denmark (1991-2010) were identified from health registries and validated by chart review. We estimated the annual incidence rate of acromegaly per 10(6) person-years (py) with 95% confidence intervals (95% CIs). For every patient, 10 persons were sampled from the general population as a comparison cohort. Cox regression and hazard ratios (HRs) with 95% confidence intervals (95% CIs) were used. RESULTS Mean age at diagnosis (48.7 years (CI: 95%: 47.2-50.1)) and annual incidence rate (3.8 cases/10(6) persons (95% CI: 3.6-4.1)) among the 405 cases remained stable. The prevalence in 2010 was 85 cases/10(6) persons. The patients were at increased risk of diabetes mellitus (HR: 4.0 (95% CI: 2.7-5.8)), heart failure (HR: 2.5 (95% CI: 1.4-4.5)), venous thromboembolism (HR: 2.3 (95% CI: 1.1-5.0)), sleep apnoea (HR: 11.7 (95% CI: 7.0-19.4)) and arthropathy (HR: 2.1 (95% CI: 1.6-2.6)). The complication risk was also increased before the diagnosis of acromegaly. Overall mortality risk was elevated (HR: 1.3 (95% CI: 1.0-1.7)) but uninfluenced by treatment modality. CONCLUSION (i) The incidence rate and age at diagnosis of acromegaly have been stable over decades, and the prevalence is higher than previously reported. (ii) The risk of complications is very high even before the diagnosis. (iii) Mortality risk remains elevated but uninfluenced by mode of treatment.

Normocalcemia and Persistent Elevated Serum Concentrations of 1-84 Parathyroid Hormone after Operation for Sporadic Parathyroid Adenoma: Evidence of Increased Morbidity from Cardiovascular Disease

Elevated serum concentrations of 1–84 parathyroid hormone (PTH) after operation for sporadic parathyroid adenoma have been re-ported in previous studies, years after operation for primary hyperparathyroidism (pHPT). The cause and significance of this finding have not been elucidated. Primary hyperparathyroidism was diagnosed in 195 patients from January 1987 to December 1998. Operation for pHPT was performed in 124 patients. To evaluate long-term effects of elevated serum 1–84 PTH, biochemical variables and pre- and postoperative diseases were investigated from hospital case records. Of the 124 patients operated on, 103 had a solitary adenoma. Among these patients, 60 had normal serum concentrations of 1–84 PTH and calcium postoperatively, 38 patients had follow-up for more than 12 months (range 12–207 months—group A). Persistent elevated serum concentrations of 1–84 PTH and normocalcemia were found in 23 patients. Fourteen patients had follow-up for more than 12 months (range 15–76 months—group B). Two patients had persistent pHPT, and 18 were normocalcemic, but in this retrospective study data on serum 1–84 PTH were not available. No significant differences were found between groups A and B at the time of diagnosis concerning clinical characteristics. More that 12 months after operation for pHPT, the patients in group B, with persistent elevated serum concentrations of 1–84 PTH, had a significantly (χ 2=11, p=0.005, and power of test 0.66) higher frequency of cardiovascular diseases from ischémie heart disease and hypertension. Persistent elevated serum concentrations of 1–84 PTH after operation for sporadic parathyroid adenoma may be associated with development of cardiovascular disease. This group of patients therefore needs lifelong control and, possibly, medical intervention. Plusieurs publications ont déjà fait état de la persistance de concentrations sériques élevées en 1–84 parathormone (PTH) après intervention pour adénome parathyroïdienne sporadique, parfois des années après l’opération initiale pour hyperparathyroïdie primitive (pHPT). La cause et la signification de ce phénomène n’ont pas encore été élucidées. Parmi 195 patients chez lesquels on a fait le diagnostic d’hyperparathyroïdie primitive entre jan 1987 et déc 1998, 124 ont été opérés. Grâce aux dossiers hospitaliers, les variables biochimiques et la morbidité pré et postopératoire ont été analysés pour évaluer les effets à long terme de l’élévation persistant de la PTH. Parmi les 124 patients opérés, 103 avaient un adénome solitaire dont 60 avaient des concentrations sériques postopératoires normales, en PTH comme en calcium. 38 patients ont été suivis plus de 12 mois (extrêmes 12–207 mois (group A). Chez 23 patients, on a trouvé des concentrations de PTH sériques élevées persistances alors que ces patients étaient normocalcémiques. Quatorze patients ont été suivis pendant plus de 12 mois, extrêmes 15–76 mois (groupe B). Deux patients avaient une pHPT persistante et 18 étaient normocalcémiques mais dans cette étude rétrospective, toutes les données en ce qui concerne la PTH sérique n’étaient pas disponsibles. On n’a trouvé aucune différence significative entre les groupes A et B au moment du diagnostic en ce qui concerne les caractéristiques cliniques. A plus de 12 mois après opération pour pHPT, les patients dans le groupe B avec une concentration de PTH sérique élevée persistante avaient significativement χ 2=11, p=0.005, et puissance du test 0.66) plus de pathologie cardiovasculaire en rapport avec une cardiopathie ischémique et l’hypertension. La persistance de concentrations sériquese élevées de PTH 1–84 après opération pour adénome sporadique de la parathyroïde pourrait être associée au développement de maladie cardiovasculaire. Ce groupe de patients demande donc une surveillance à vie et parfois une intervention chirurgicale. En estudios previos se constató que años después de una intervención quirúrgica por hipeparatiroidismo primario (pHPT) provocado por adenomas esporádicos de paratiroides, persistían concentraciones séricas elevadas de la 1–84 hormona paratiroidea (PTH). Su etiología y significación todavía no se ha dilucidado. Entre enero de 1987 ydiciembre de 1998, 195 pacientes fueron diagnosticados de hiperparatiroidismo primario, operándose 124. Merced a las historias clínicas, parámetros bioquímicos pre y postoperatorios se investigaron los efectos tardíos de la elevación sérica de la PTH. De los 124 pacientes intervenidos, 103 presentaban un adenoma solitario. De ellos, 60 mostraron valores séricos postoperatorios normales tanto de PTH como del calcio; 38 pacientes con un seguimiento superior a 12 meses (rango 12–207 meses) constituyeron el denominado grupo A. En 23 pacientes se registraron concentraciones séricas elevadas de PTH con normoclacemia; 14 pacientes con seguimientos superiores a los 12 meses (rango 15–76 meses) constituyeron el grupo B. Dos pacientes presentaron un pHPT recidivante; 18 eran normocalcémicos pero las cifras retrospectivas de PTH no se pudieron encontrarse en la búsqueda retrospectiva. No se observaron diferencias significativas por lo que al diagnóstico y características clínicas se refiere entre los pacientes del grupo A y B. Transcurridos más de 12 meses desde la operación por pHPT, en los pacientes del grupo B, con persistencia de concentraciones séricas elevadas de PTH, se desarrollaron con más frecuencia (χ 2=11, p=0.005, poder del test 0.66) enfermedades cardiovasculares debidas a isquemia cardiaca e hipertensión. El mantenimiento de concentraciones séricas elevadas de la 1–84 hormona paratiroidea tras la operación por adenoma esporádico de paratiroides provoca el desarrollo de enfermedades cardiovasculares. Este grupo de pacientes requiere un seguimiento de control a lo largo de toda su vida y posiblemente, un tratamiento médico.

Plasma insulin-like growth factor I as predictor of progression and all cause mortality in chronic heart failure.

OBJECTIVES Insulin-like growth factor I (IGF-I) is an anabolic growth factor that seems to increase cardiac contractility. Reduced levels of IGF-I may be implicated in progression of CHF. The objective was to compare plasma IGF-I in CHF patients with healthy controls, and to examine the associations between baseline IGF-I levels, cardiac contractility and the prognosis as judged by all cause mortality and progression of CHF requiring admission to hospital. METHODS A prospective study comprising 194 CHF outpatients, and 169 matched controls. All patients and controls underwent echocardiographic examination at baseline. Patients were followed for a median of 30 months. RESULTS There was no difference in IGF-I levels between patients and controls (median and interquartile range), 78 (58-91) vs. 77 (57-94)ng/mL (P=0.92). Age-adjusted IGF-I levels were not related to left ventricular ejection fraction (LVEF) (P=0.58) or levels of N-terminal B-Type natriuretic peptide (NT-proBNP) (P=0.42). During follow-up 44 patients died and 94 were admitted to hospital due to worsening of CHF. Adjusted for cardiovascular risk factors (age, gender, NT-proBNP, lipids, diabetes mellitus, blood pressure, renal function and LVEF) IGF-I levels did not influence the overall mortality risk or the admission rate to hospital, hazard ratio (HR) (95% confidence intervals) 1.05 (0.75-1.47) (P=0.77) and 1.00 (0.80-1.26) (P=0.96), respectively per each SD increase in log IGF-I levels. CONCLUSIONS IGF-I levels were not reduced in patients with CHF and did not influence cardiac status at baseline or the prognosis.

Sweat secretion rates in growth hormone disorders

While increased sweating is a prominent symptom in patients with active acromegaly, reduced sweating is gaining status as part of the growth hormone deficiency (GHD) syndrome.

GH activity and markers of inflammation: a crossover study in healthy volunteers treated with GH and a GH receptor antagonist.

INTRODUCTION The GH/IGF1 axis may modulate inflammatory processes. However, the relationship seems complicated as both pro- and anti-inflammatory effects have been demonstrated. METHODS/DESIGN Twelve healthy volunteers (mean age 36, range 27-49 years) were treated in random order with increasing doses of GH for 3 weeks (first week 0.01  mg/kg per day, second week 0.02  mg/kg per day, and third week 0.03  mg/kg per day) or a GH receptor antagonist (pegvisomant; first week 10  mg/day and last two weeks 15  mg/day), separated by 8 weeks of washout. Circulating levels of the pro-inflammatory cytokines tumor necrosis factor α (TNFα (TNFA)), interleukin 6 (IL6), and IL1β (IL1B) and the acute phase proteins (APPs) C-reactive protein (CRP), haptoglobin, orosomucoid, YKL40 (CHI3L1), and fibrinogen were measured. RESULTS During GH treatment, IGF1 (median 131 (Inter-quartile range (IQR) 112-166) vs 390 (322-524) μg/l, P=0.002) increased together with TNFα (0.87 (0.74-1.48) vs 1.27 (0.80-1.69) ng/l, P=0.003), IL6 (1.00 (0.83-1.55) vs 1.35 (0.80-4.28) ng/l, P=0.045), and fibrinogen (9.2 (8.8-9.6) vs 11.1 (9.4-12.4) μM, P=0.002). By contrast, orosomucoid decreased (18.0 (15.5-24.3) vs 15.0 (15.0-17.0) μM, P=0.018). CRP, YKL40, and haptoglobin were unchanged. During pegvisomant treatment, IGF1 decreased (139 (117-171) vs 91 (78-114) ng/ml, P=0.005). Orosomucoid (21.0 (16.3-23.8) vs 22.0 (17.0-29.3) μM, P=0.036) and CRP (1.00 (0.62-1.77) vs 1.43 (0.71-3.29) mg/l, P=0.074) increased without an increase in pro-inflammatory cytokines. CONCLUSIONS GH/IGF1 action appears to modulate the initial stage of the inflammatory response as well as downstream processes elucidated by levels of APPs. The data suggest a complicated relationship not allowing any simple conclusions as to whether GH/IGF1 actions have mainly pro- or anti-inflammatory effects in vivo.

Concentrations of the acute phase reactants high‐sensitive C‐reactive protein and YKL‐40 and of interleukin‐6 before and after treatment in patients with acromegaly and growth hormone deficiency

Background  Acromegaly is accompanied by increased cardiovascular mortality and a cluster of proatherogenic risk factors. In the general population, ischaemic heart disease (IHD) is associated with elevated levels of inflammatory markers. The acute phase reactant (APR) C‐reactive protein (CRP) has been reported to be reduced in acromegaly and increase after treatment, suggesting that excess of GH/IGF‐I could have anti‐inflammatory effects. This is in accordance with results obtained in patients with growth hormone deficiency (GHD), where increased levels of CRP have been reported.

Effects of perturbation of the Na+ electrochemical gradient on influx and efflux of alanine in isolated rat hepatocytes

Transmembrane alanine transport was studied in hepatocytes isolated from 48-h fasted rats. Aminooxyacetate was used to render alanine nonmetabolizable. Gramicidin D eliminated the transmembrane Na+ electrochemical gradient. At 135 mM Na+ and 0.1 mM alanine gramicidin D decreased the steady-state intracellular-to-extracellular alanine distribution ratio from 20.2 to 0.9. The underlying kinetic changes appeared to be a decrease in alanine influx to one-third of the control value and an increase in the rate constant of alanine efflux by a factor of 9. Analogous changes were observed when the Na+ gradient was decreased by ouabain. The inhibitory effect of gramicidin D on alanine influx was confined to the Na+-dependent, saturable component which showed a prominent increase in the apparent Km for alanine and a small decrease in the apparent Vmax. The effect of gramicidin D on alanine efflux was related to the increased cytosolic Na+ concentration: the rate constant of alanine efflux was increased by cytosolic Na+ with half-maximal stimulation at 30 mM; voltage-sensitive alanine efflux could not be demonstrated.