André P. van Beek

Extra-intestinal manifestations of familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disorder, which results from a germ line mutation in the APC (adenomatous polyposis coli) gene. FAP is characterized by the formation of hundreds to thousands of colorectal adenomatous polyps. Although the development of colorectal cancer stands out as the most prevalent complication, FAP is a multisystem disorder of growth. This means, it is comparable to other diseases such as the MEN syndromes, Von Hippel-Lindau disease and neurofibromatosis. However, the incidence of many of its clinical features is much lower. Therefore, a specialized multidisciplinary approach to optimize health care—common for other disorders—is not usually taken for FAP patients. Thus, clinicians that care for and counsel members of high-risk families should have familiarity with all the extra-intestinal manifestations of this syndrome. FAP-related complications, for which medical attention is essential, are not rare and their estimated lifetime risk presumably exceeds 30%. Affected individuals can develop thyroid and pancreatic cancer, hepatoblastomas, CNS tumors (especially medulloblastomas), and various benign tumors such as adrenal adenomas, osteomas, desmoid tumors and dental abnormalities. Due to improved longevity, as a result of better prevention of colorectal cancer, the risk of these clinical problems will further increase.We present a clinical overview of extra-intestinal manifestations, including management and treatment options for the FAP syndrome. Furthermore, we provide recommendations for surveillance of FAP complications based on available literature.

Vasopressin, Copeptin, and Renal Concentrating Capacity in Patients with Autosomal Dominant Polycystic Kidney Disease without Renal Impairment

BACKGROUND AND OBJECTIVES Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary renal disease, characterized by cyst formation in the kidneys leading to end stage kidney failure. It is clinically acknowledged that ADPKD patients have impaired urine concentrating capacity, but the mechanism behind this observation is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Fifteen ADPKD patients (estimated GFR ≥60 ml/min per 1.73 m(2)) and 15 age- and sex-matched healthy controls underwent a standard prolonged water deprivation test in which urine and plasma osmolality, vasopressin, and copeptin were measured. The effect of a synthetic vasopressin analog (desmopressin) injected at the moment of maximal urine concentrating capacity was also studied. RESULTS After 14 hours of water deprivation, ADPKD patients tended to have higher plasma osmolality (P=0.07) and significantly higher vasopressin and copeptin levels (both P<0.05), whereas urine osmolality was similar in ADPKD patients and controls (710 versus 742 mOsmol/kg; P=0.61). Maximal urine concentrating capacity was lower in ADPKD patients (758 versus 915 mOsmol/kg in controls; P<0.001). At maximal urine concentrating capacity, plasma osmolality, vasopressin, and copeptin levels were significantly higher in ADPKD patients. The median increase in urine osmolality after desmopressin administration in ADPKD patients was less than in healthy controls. CONCLUSIONS Already early in their disease, ADPKD patients have impaired maximal urine concentrating capacity brought out upon dehydration, with no evidence of impaired hypothalamic response. To maintain fluid balance, vasopressin concentration increases, which is hypothesized to play a role in ADPKD disease progression.

Associations between smoking, components of metabolic syndrome and lipoprotein particle size

BackgroundThe clustering of metabolic and cardiovascular risk factors is known as metabolic syndrome (MetS). The risk of having MetS is strongly associated with increased adiposity and can be further modified by smoking behavior. Apolipoproteins (apo) associated with low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) may be altered in MetS. This study aimed to examine the association between smoking and the following parameters: MetS and its components, levels of apolipoproteins and estimated lipoprotein particle size, separately for men and women, and in different body mass index (BMI) classes.MethodsWe included 24,389 men and 35,078 women aged between 18 and 80 years who participated in the LifeLines Cohort Study between December 2006 and January 2012; 5,685 men and 6,989 women were current smokers. Participants were categorized into three different body mass index (BMI) classes (BMI <25; BMI 25 to 30; BMI ≥30 kg/m2). MetS was defined according to the National Cholesterol Education Program’s Adult Treatment Panel III (NCEP:ATPIII) criteria. Blood pressure, anthropometric and lipid measurements were rigorously standardized, and the large sample size enabled a powerful estimate of quantitative changes. The association between smoking and the individual MetS components, and apoA1 and apoB, was tested with linear regression. Logistic regression was used to examine the effect of smoking and daily tobacco smoked on risk of having MetS. All models were age adjusted and stratified by sex and BMI class.ResultsPrevalence of MetS increased with higher BMI levels. A total of 64% of obese men and 42% of obese women had MetS. Current smoking was associated with a higher risk of MetS in both sexes and all BMI classes (odds ratio 1.7 to 2.4 for men, 1.8 to 2.3 for women, all P values <0.001). Current smokers had lower levels of HDL cholesterol and apoA1, higher levels of triglycerides and apoB, and higher waist circumference than non-smokers (all P <0.001). Smoking had no consistent association with blood pressure or fasting blood glucose. In all BMI classes, we found a dose-dependent association of daily tobacco consumption with MetS prevalence as well as with lower levels of HDL cholesterol, higher triglyceride levels and lower ratios of HDL cholesterol/apoA1 and, only in those with BMI <30, LDL cholesterol/apoB (all P <0.001).ConclusionsSmoking is associated with an increased prevalence of MetS, independent of sex and BMI class. This increased risk is mainly related to lower HDL cholesterol, and higher triglycerides and waist circumference. In addition, smoking was associated with unfavorable changes in apoA1 and apoB, and in lipoprotein particle size.Please see related commentary: http://www.biomedcentral.com/1741-7015/11/196.

Cognitive functioning in patients treated for nonfunctioning pituitary macroadenoma and the effects of pituitary radiotherapy

Context and objective  Cognitive deterioration is reported in patients with a nonfunctioning pituitary macroadenoma (NFA) and after pituitary radiotherapy. However, reported results are inconsistent and are potentially confounded by different underlying pituitary disorders. The aim of this study was to examine cognitive functions in patients previously treated for NFA with or without radiotherapy.

Combined effects of smoking and alcohol on metabolic syndrome: The LifeLines cohort study

Introduction The development of metabolic syndrome (MetS) is influenced by environmental factors such as smoking and alcohol consumption. We determined the combined effects of smoking and alcohol on MetS and its individual components. Methods 64,046 participants aged 18–80 years from the LifeLines Cohort study were categorized into three body mass index (BMI) classes (BMI<25, normal weight; BMI 25–30, overweight; BMI≥30 kg/m2, obese). MetS was defined according to the revised criteria of the National Cholesterol Education Program’s Adult Treatment Panel III (NCEP ATP III). Within each BMI class and smoking subgroup (non-smoker, former smoker, <20 and ≥20 g tobacco/day), the cross-sectional association between alcohol and individual MetS components was tested using regression analysis. Results Prevalence of MetS varied greatly between the different smoking-alcohol subgroups (1.7–71.1%). HDL cholesterol levels in all alcohol drinkers were higher than in non-drinkers (0.02 to 0.29 mmol/L, P values<0.001). HDL cholesterol levels were lower when they were also a former or current smoker (<20 and ≥20 g tobacco/day). Consumption of ≤1 drink/day indicated a trend towards lower triglyceride levels (non-significant). Concurrent use alcohol (>1 drink/day) and tobacco showed higher triglycerides levels. Up to 2 drinks/day was associated with a smaller waist circumference in overweight and obese individuals. Consumption of >2 drinks/day increased blood pressure, with the strongest associations found for heavy smokers. The overall metabolic profile of wine drinkers was better than that of non-drinkers or drinkers of beer or spirits/mixed drinks. Conclusion Light alcohol consumption may moderate the negative associations of smoking with MetS. Our results suggest that the lifestyle advice that emphasizes smoking cessation and the restriction of alcohol consumption to a maximum of 1 drink/day, is a good approach to reduce the prevalence of MetS.

The plasma leptin/adiponectin ratio predicts first cardiovascular event in men: A prospective nested case-control study

OBJECTIVE The plasma leptin/adiponectin (L/A) ratio has been proposed as a preferential marker of atherosclerosis susceptibility compared to leptin and adiponectin alone. We determined the extent to which the L/A ratio predicts incident cardiovascular disease (CVD) taking account of clinical risk factors, microalbuminuria, the total cholesterol/HDL cholesterol (TC/HDL-C ratio), triglycerides, high sensitive C-reactive protein (hs-CRP) and insulin sensitivity (homeostasis model assessment (HOMA(ir))). METHODS A community-based prospective nested case-control study was carried out in 103 non-diabetic men who developed a first cardiovascular event (cases) and 106 male control subjects (no clinically manifest CVD and no lipid lowering drug use at baseline; median follow-up of 3.0 and 10.5 years, respectively). Plasma leptin, adiponectin, the leptin/adipnectin (L/A) ratio, as well as hs-CRP, HOMA(ir) and the TC/HDL-C ratio were determined at baseline. RESULTS Plasma leptin levels and the L/A ratio were higher in cases vs. controls (p=0.002 for both), but the difference in adiponectin was not significant (p=0.10). Age-adjusted incident CVD was associated with plasma leptin, adiponectin and the L/A ratio (p=0.045 to p=0.001). The relationships of incident CVD with plasma leptin (p=0.19) and adiponectin (p=0.073) lost statistical significance after additional adjustment for smoking, waist circumference, hypertension, microalbuminuria, the TC/HDL-C ratio, hs-CRP and HOMA(ir). In this fully adjusted analysis, the L/A ratio remained predictive of incident CVD (hazard ratio: 1.40 (95% CI 1.05-1.87), p=0.024). CONCLUSION This study suggests that the L/A ratio may be a preferential marker of a first cardiovascular event in men compared to plasma leptin and adiponectin levels alone.

Cerebrospinal Fluid Corticosteroid Levels and Cortisol Metabolism in Patients with Idiopathic Intracranial Hypertension: A Link between 11β-HSD1 and Intracranial Pressure Regulation?

CONTEXT The etiology of idiopathic intracranial hypertension (IIH) is unknown. We hypothesized that obesity and elevated intracranial pressure may be linked through increased 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity. OBJECTIVE The aim was to characterize 11β-HSD1 in human cerebrospinal fluid (CSF) secretory [choroid plexus (CP)] and drainage [arachnoid granulation tissue (AGT)] structures, and to evaluate 11β-HSD1 activity after therapeutic weight loss in IIH. DESIGN AND SETTING We conducted in vitro analysis of CP and AGT and a prospective in vivo cohort study set in two tertiary care centers. PATIENTS OR OTHER PARTICIPANTS Twenty-five obese adult female patients with active IIH were studied, and 22 completed the study. INTERVENTION Fasted serum, CSF, and 24-h urine samples were collected at baseline, after 3-month observation, and after a 3-month diet. MAIN OUTCOME MEASURES Changes in urine, serum, and CSF glucocorticoids (measured by gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry) after weight loss were measured. RESULTS 11β-HSD1 and key elements of the glucocorticoid signaling pathway were expressed in CP and AGT. After weight loss (14.2±7.8 kg; P<0.001), global 11β-HSD1 activity decreased (P=0.001) and correlated with reduction in intracranial pressure (r=0.504; P=0.028). CSF and serum glucocorticoids remained stable, although the change in CSF cortisone levels correlated with weight loss (r=-0.512; P=0.018). CONCLUSIONS Therapeutic weight loss in IIH is associated with a reduction in global 11β-HSD1 activity. Elevated 11β-HSD1 may represent a pathogenic mechanism in IIH, potentially via manipulation of CSF dynamics at the CP and AGT. Although further clarification of the functional role of 11β-HSD1 in IIH is needed, our results suggest that 11β-HSD1 inhibition may have therapeutic potential in IIH.

The incidence of second tumours and mortality in pituitary adenoma patients treated with postoperative radiotherapy versus surgery alone

BACKGROUND AND PURPOSE To assess and compare the incidence of intra- and extracranial tumours and mortality in pituitary adenoma patients treated with postoperative radiotherapy and surgery alone. PATIENTS AND METHODS A total of 462 pituitary adenoma patients were treated between 1959 and 2008 at the University Medical Center Groningen in The Netherlands. Postoperative radiotherapy was administered on indication in 236 patients. RESULTS The median follow-up time was 14 (range 1-49) years in patients treated with radiotherapy and 6 (range 1-34) years in patients treated with surgery alone. Three radiotherapy patients developed an intracranial tumour compared to one patient treated with surgery alone. The numbers of extracranial tumours per follow-up year were 6.5 (95% CI 2.5-10.5) and 5.1 (95% CI 1.9-8.2) in patients treated with and without a technique with vertex field and central body axis irradiation and 7.1 (CI 95% 2.9-11.2) in surgery alone patients. Forty-five patients treated with radiotherapy died compared to twenty-four patients treated with surgery alone (log-rank test RR 1.26, 95% CI 0.77-2.08, p=0.36). CONCLUSION In this study postoperative radiotherapy and a radiotherapy treatment technique with vertex field and central body axis irradiation were not associated with an increased incidence of second tumours and mortality in pituitary adenoma patients.

Co-morbidities in heart failure

Heart failure is a clinical syndrome characterized by poor quality of life and high morbidity and mortality. Co-morbidities frequently accompany heart failure and further decrease in both quality of life and clinical outcome. We describe that the prevalence of co-morbidities in patients with heart failure is much higher compared to age-matched controls. We will specifically address the most studied organ-related co-morbidities, that is, renal dysfunction, cerebral dysfunction, anaemia, liver dysfunction, chronic obstructive pulmonary disease, diabetes mellitus and sleep apnoea. The pathophysiologic processes underlying the interaction between heart failure and co-morbid conditions are complex and remain largely unresolved. Although common risk factors are likely to contribute, it is reasonable to believe that factors associated with heart failure might cause other co-morbid conditions. Inflammation, neurohumoral pathway activation and hemodynamic changes are potential factors. We try to provide explanations for the observed association between co-morbidities and heart failure, as well as its impact on survival.

Incidence, causative mechanisms, and anatomic localization of stroke in pituitary adenoma patients treated with postoperative radiation therapy versus surgery alone

PURPOSE To assess and compare the incidence of stroke and stroke subtype in pituitary adenoma patients treated with postoperative radiation therapy (RT) and surgery alone. METHODS AND MATERIALS A cohort of 462 pituitary adenoma patients treated between 1959 and 2008 at the University Medical Center Groningen in The Netherlands was studied. Radiation therapy was administered in 236 patients. The TOAST (Trial of ORG 10172 in Acute Stroke Treatment) and the Oxfordshire Community Stroke Project classification methods were used to determine causative mechanism and anatomic localization of stroke. Stroke incidences in patients treated with RT were compared with that observed after surgery alone. Risk factors for stroke incidence were studied by log-rank test, without and with stratification for other significant risk factors. In addition, the stroke incidence was compared with the incidence rate in the general Dutch population. RESULTS Thirteen RT patients were diagnosed with stroke, compared with 12 surgery-alone patients. The relative risk (RR) for stroke in patients treated with postoperative RT was not significantly different compared with surgery-alone patients (univariate RR 0.62, 95% confidence interval [CI] 0.28-1.35, P=.23). Stroke risk factors were coronary or peripheral artery disease (univariate and multivariate RR 10.4, 95% CI 4.7-22.8, P<.001) and hypertension (univariate RR 3.9, 95% CI 1.6-9.8, P=.002). There was no difference in TOAST and Oxfordshire classification of stroke. In this pituitary adenoma cohort 25 strokes were observed, compared with 16.91 expected (standard incidence ratio 1.48, 95% CI 1.00-1.96, P=.049). CONCLUSIONS In pituitary adenoma patients, an increased incidence of stroke was observed compared with the general population. However, postoperative RT was not associated with an increased incidence of stroke or differences in causative mechanism or anatomic localization of stroke compared with surgery alone. The primary stroke risk factor was pre-existent coronary or peripheral artery disease.